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1
UNIQUE IDENTIFIER          DRG-0310
NAME OF SUBSTANCE          L-756423 [FDA 300A]
CLASSIFICATION CODE        Protease inhibitor [FDA 300A]
MANUFACTURERS              Merck Laboratories; One Merck Drive / Natl
                           Svce Ctr; Whitehouse Station, NJ 08889
ENTRY MONTH                199902
LAST REVISION DATE         19990311

2
UNIQUE IDENTIFIER          DRG-0309
NAME OF SUBSTANCE          Bromodeoxyuridine [CHEMID]
REGISTRY NUMBER            59-14-3
STANDARD CHEMICAL NAME     5-Bromo-2'-deoxyuridine [USAN 1998]
SYNONYMS                   Broxuridine [USAN 1998]
SYNONYMS                   5-Bromo-2'-deoxyuridine [USAN 1998]
SYNONYMS                   5-Bromodeoxyuridine [CHEMID]
SYNONYMS                   5-Bromodesoxyuridine [CHEMID]
SYNONYMS                   Bromouridine [NLM] [CHEMID]
SYNONYMS                   Bromouracil deoxyriboside [MESH] [CHEMID]
SYNONYMS                   5-Bromouracil deoxyriboside [CHEMID]
SYNONYMS                   5-Bromouracil-2-deoxyriboside [CHEMID]
PROTOCOL ID NUMBERS        NIAID 97 I-0189
PHARMACOLOGICAL ACTION     To understand the mechanism behind
                           immunodeficiency in HIV patients it becomes
                           advantageous to quantitatively track
                           lymphocyte replication and destruction. This
                           can be done by infusing bromodeoxyuridine
                           (BrDU), a thymidine analog, into patients
                           where it is incorporated into the DNA of
                           target cells (i.e., lymphocytes). Measurement
                           of BrDU in subpopulations of cells can be
                           used to determine the replication rate of
                           these cells. In other studies, cell DNA
                           synthesis in peripheral blood lymphocytes was
                           measured ex vivo using BrDU incorporation.
                           BrDU detection was performed using the DNAse
                           method with an FITC-conjugated anti-BrDU
                           antibody. Cells were surface-stained with
                           paris of phycoerythrin or tricolor-conjugated
                           antibodies, and three-color fluorescence was
                           analyzed in a FACScan cytometer to determine
                           which peripheral blood lymphocyte
                           subpopulations were incorporating BrDU.
                           [NIAID 97-I-0189; Int Conf AIDS 1998;12]
DISEASES STUDIED/TREATED   Marker for incorporation into cellular DNA to
                           measure lymphocyte kinetics[NIAID 97-I-0189]
CLASSIFICATION CODE        Antimetabolite [CHEMID]
CLASSIFICATION CODE        Labelling agent [KISSMAN]
CLASSIFICATION CODE        Radiation-sensitizing agent [MeSH]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C9H11BrN205 [CHEMID]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 307.10 [USAN 1998]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Infusion into a vein.
                           [NIAID 97-I-0189]
MANUFACTURERS              NeoPharm Incorporated; 100 Corporate North /
                           Suite 215; Bannockburn, IL 60015
REFERENCES                 UI/99090823. Kogure K, Zhang YQ, Shibata H,
                           Kojima I. Immediate onset of DNA synthesis in
                           remnant rat liver after 90% hepatectomy by an
                     administration of follistatin. J Hepatol 1998
                     Dec;29(6):977-84.
REFERENCES           UI/99095542. Boutonnat J, Barbier M,
                     Rousselle C, Muirhead KA, Mousseau M,
                     Seigneurin D, Ronot X. Usefulness of PKHs for
                     studying cell proliferation. C R Acad Sci III
                     1998 Nov;321(11):901-7.
REFERENCES           UI/99057050. Rolink AG, Andersson J, Melchers
                     F. Characterization of immature B cells by a
                     novel monoclonal antibody, by turnover and by
                     mitogen reactivity, Eur J Immunol 1998
                     Nov;28(11):3738-48.
REFERENCES           UI/98294602. Tissot O, Viard JP, Rabian C,
                     Ngo N, Burgard M, Rouzioux C, Penit C. No
                     evidence for proliferation in the blod CD4+
                     T-cell pool during HIV- 1 infection and
                     triple comination therapy. AIDS 1998 May
                     28;12(8):879-84.
REFERENCES           UI/9839852. Viard JP, Tissot O, Rabian C, Ngo
                     N, Burgard M, Rouzioux C, Penit C. No
                     evidence for proliferation in blood CDA+ T
                     cells during HIV infection and treatment. Int
                     Conf AIDS. 1998;12:263 (abstract no. 21121).
REFERENCES           UI/98263366. Rosenzweig M, DeMaria MA, Harper
                     DM, Friedrich S, Jain RK, Johnson RP.
                     Increased rates of CD4(+) and CD8(+) T
                     lymphocyte turnover in simian
                     immunodeficiency virus-infected macaques.
                     Proc Natl Acad Sci U S A 1998 May
                     26;95(11):6388-93.
REFERENCES           UI/98136242. Mohri H, Bonhoeffer S, Monard S,
                     Perelson AS, Ho DD. Rapid turnover of T
                     lymphocytes in SIV-infected rhesus macaques.
                     Science 1998 Feb 20;279(5354):1223-7.
REFERENCES           UI/98119886. Tough DF, Sprent J. Lifespan of
                     gamma/delta T cells. J Exp Med 1998 Feb
                     2;187(3):357-65.
REFERENCES           MED/98005849. Schwyn U, Kaser-Hotz B, Hauser
                     B, Fodor G, Ruckstuhl H, Crompton NE.
                     Determination of the potential doubling time
                     of tumors using bromodeoxyuridine and flow
                     cytometry. Bromodeoxyuridin and
                     Durchflusszytometrie. Schweiz Arch Tierheilkd
                     1997;139(10):441-8.
REFERENCES           MED/98075897. Activated cell cycle
                     checkpoints in epirubicin-treated breast
                     cancer cells studied by BrDUrd-flow
                     cytometry. Hedenfalk IA, Baldetorp B, Borg A,
                     Oredsson SM. Cytometry 1997 Dec
                     1;29(4):321-7.
REFERENCES           MED/96018796. Ernst B, Surh CD, Sprent J.
                     Thymic selection and cell division. J Exp
                     Med. 1995 Oct 1;182(4):961-71.
ENTRY MONTH          199902
LAST REVISION DATE   19990209

3
UNIQUE IDENTIFIER    DRG-0308
NAME OF SUBSTANCE    (+)- Calanolide A [FDA 297A]
REGISTRY NUMBER      142632-32-4
SYNONYMS             (+)-Calanolide A [FDA 297A]
PROTOCOL ID NUMBERS        FDA 297A
PHARMACOLOGICAL ACTION     Calanolide A, is a novel inhibitor of HIV-1,
                           and is essentially inactive against the less
                           common HIV-2. In one study, the compound
                           inhibited a wide variety of laboratory
                           strains of HIV-1, with EC50 values ranging
                           from 0.10 to 0.17 microM. The compound
                           similarly inhibited promonocytotropic and
                           lymphocytotropic isolates from patients in
                           various stages of HIV disease, as well as
                           drug-resistant strains. Viral life-cycle
                           studies indicated that calanolide A acted
                           early in the infection process, similar to
                           the known HIV reverse transcriptase (RT)
                           inhibitor 2',3'-dideoxycytidine. In enzyme
                           inhibition assays, calanolide A potently and
                           selectively inhibited recombinant HIV-1 RT
                           but not cellular DNA polymerases or HIV-2 RT
                           within the concentration range tested. Serial
                           passage of the virus in host cells exposed to
                           increasing concentrations of calanolide A
                           yielded a calanolide A resistant virus
                           strain. RT from the resistant virus was not
                           inhibited by calanolide A, but retained
                           sensitivity to other nonnucleoside as well as
                           nucleoside RT inhibitors, including
                           3'-azido-2',3'-dideoxythymidine triphosphate
                           and nevirapine. Another study showed that
                           calanolide A inhibited HIV-1 RT by a complex
                           mechanism involving two calanolide A binding
                           sites. It bound near the active site of the
                           enzyme and interfered with deoxynucleotide
                           triphosphate binding. At certain
                           concentrations, calanolide A bound HIV-1 RT
                           in a mutually exclusive fashion with respect
                           to both the pyrophosphate analog,
                           phosphonoformic acid, and the acyclic
                           nucleoside analog
                           1-ethoxymethyl-5-ethyl-6-phenylthio-2-thioura-
                           cil. This indicates that calanolide A shares
                           some binding domains with both sutstances,
                           presumably reflecting that it interacts with
                           RT near both the pyrophosphate binding site
                           and the active site of the enzyme. [J
                           Pharmacol Exp Ther 1996 Nov;279(2); J
                           Pharmacol Exp Ther 1996 Nov;279(2)]
DISEASES STUDIED/TREATED   (+)-Calanolide A is a novel non-nucleoside
                           reverse transcriptase inhibitor with potent
                           in vitro activity against HIV-1 and unique
                           pharmacokinetic properties. [5th Conf
                           Retrovir Oppor Infect 1998 Feb 1-5]
CLASSIFICATION CODE        Non-nucleoside reverse transcriptase
                           inhibitor [Int Conf AIDS 1998;12]
SUBSTANCE INTERACTIONS     Calanolide A inhibited HIV-1 RT (reverse
                           transcriptase) in a synergistic fashion with
                           nevirapine, further distinguishing it from
                           the general class of nonnucleoside RT
                           inhibitors. In vitro studies have shown the
                           compound to be active against HIV-1 strains
                           resistant to AZT, nevirapine and other
                           nucleoside RT inhibitors, and to show
                          synergistic anti-HIV activity when used in
                          combination with AZT, nevirapine, ddI, ddC
                          and carbovir. [J Pharmacol Exp Ther 1996
                          Nov;279(2); PR Newswire;Thursday February 5,
                          1998]
ADVERSE EFFECTS           A phase IA single, escalating-dose study in
                          HIV-1-negative subjects showed that
                          (+)-calanolide A was generally well tolerated
                          in doses up to 600 mg. The most common
                          adverse event observed in the first 3 cohorts
                          was an oily aftertaste in 19 of 32 patients.
                          Fourteen subjects reported transient
                          dizziness which was mild (12 subjects), to
                          moderate (2 subjects). Headache occurred in 8
                          of 32 subjects, and 5 subjects reported
                          dyspepsia. The only significant abnormal
                          laboratory finding was a single report of
                          Grade 3 lipase which was completely
                          asymptomatic and which resolved
                          spontaneously. [5th Conf Retrovir Oppor
                          Infect 1998 Feb 1-5]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: (+)-Calanolide A, a novel
                          dipyranocoumarin from the Malaysian tree
                          Caulophyllum lanigerum var. austrocoriaceum
                          is a representative of a distinct class of
                          nonnucleoside HIV-1 specific
                          reverse-transcriptase inhibitor under
                          development as an AIDS drug. (+/-)-Calanolide
                          A has been synthesized in a five-step
                          approach starting with phloroglucinol
                          [-->5-->6-->11-->18-->(+/-)-1]. [J Nat Prod
                          1998 Oct;61(10); J Med Chem 1996 Mar
                          15;39(6)]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: Yellow-brown amorphous
                          solid. [Manufacture Source]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 374.95 [Manufacture Source]
CHEMICAL/PHYSICAL DATA    MELTING POINT: 47-50 C [Manufacture Source]
CHEMICAL/PHYSICAL DATA    SOLUBILITY: Slightly soluble in water.
                          Soluble in methanol, ethanol and a variety of
                          other organic solvents. It is also soluble in
                          vegetable oils and propylene glycol.
                          [Manufacture Source]
CHEMICAL/PHYSICAL DATA    DRUG PHYSICAL COMMENT: Synthetic
                          (+/-)-calanolide A has been
                          chromatographically resolved into its
                          optically active forms. Only the
                          (+)-calanolide A had anti-HIV activity. [J
                          Med Chem 1996 Mar 15;39(6)]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Soft Gelatin
                          capsules[Manufacture Source]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral[PR Newswire;Thursday
                          February 5, 1998]
MANUFACTURERS             Sarawak MediChem Pharmaceuticals, Inc.; 12305
                          South New Avenue / Suite O; Lemont, IL 60439
REFERENCES                ICA12/98387981. Buckheit R, Russell J, Boltz
                          VF, Pallansch LA, Xu ZQ, Flavin M.
                          Combination anti-HIV interactions and
                          resistance profile of the nonnucleoside RT
                          inhibitor (+)-calanolide A. Int Conf AIDS.
                          1998;12:86-7 (abstract no. 12366).
REFERENCES                UI/99003371. McKee TC, Covington CD, Fuller
                      RW, Bokesch HR, Young S, Cardellina II JH,
                      Kadushin MR, Soejarto DD, Stevens PF, Cragg
                      GM, et al. Pyranocoumarins from tropical
                      species of the genus Calophyllum: a
                      chemotaxonomic study of extracts in the
                      National Cancer Institute collection. J Nat
                      Prod 1998 Oct;61(10):1252-6.
REFERENCES            (PRn) Sarawak Medichem Pharmaceuticals Begins
                      Phase 1B Clinical Trial of Plant-Based
                      Anti-HIV Agent PRNewswire - Wednesday
                      September 30, 1998.
REFERENCES            AIDS/98929583. Creagh T, Xu ZQ, Ray L,
                      Giltner J, Nayer T, Ruckle J. Preliminary
                      clinical safety profile of (+)-calanolide A-a
                      new novel NNRTI. 5th Conf Retrovir Oppor
                      Infect. 1998 Feb 1-5;:202 (abstract no. 652).
REFERENCES            (PRn) Sarawak Medichem Pharmaceuticals'
                      (+)-Calanolide A Anti-HIV Compound Meets
                      Phase 1A Trial Endpoints. PR
                      Newswire;Thursday February 5, 1998.
REFERENCES            MED/97926569. Frank P, Flavin MT, Roca-Acin
                      J, Xu ZQ.; Safety assessment of
                      (+)-calanolide A, a naturally occurring
                      anti-HIV agent. 4th Conf Retro and Opportun
                      Infect. 1997 Jan 22-26;:106 (abstract no.
                      225).
REFERENCES            UI/97083823. Currens MJ, Gulakowski RJ,
                      Mariner JM, Moran RA, Buckheit RW Jr,
                      Gustafson KR, McMahon JB. Boyd MR. Antiviral
                      activity and mechanism of action of
                      calanolide A against the human
                      immunodeficiency virus type-1. J Pharmacol
                      Exp Ther 1996 Nov;279(2):645-51.
REFERENCES            UI/97083824. Currens MJ, Mariner JM, McMahon
                      JB, Boyd MR. Kinetic analysis of inhibition
                      of human immunodeficiency virus type-1
                      reverse transcriptase by calanolide A. J
                      Pharmacol Exp Ther 1996 Nov;279(2):652-61.
REFERENCES            UI/97049116. Galinis DL, Fuller RW, McKee TC,
                      Cardellina JH 2nd, Gulakowski RJ, McMahon JB,
                      Boyd MR. Structure-activity modifications of
                      the HIV-1 inhibitors (+)-calanolide A and
                      (-)- calanolide B. J Med Chem 1996 Oct
                      25;39(22).
REFERENCES            MED/96251034. Flavin MT, Rizzo JD, Khilevich
                      A, Kucherenko A, Sheinkman AK, Vilaychack V,
                      Lin L, Chen W, Greenwood EM, Pengsuparp T, et
                      al. Synthesis, chromatographic resolution,
                      and anti-human immunodeficiency virus
                      activity of (+/-)-calanolide A and its
                      enantiomers. J Med Chem. 1996 Mar
                      15;39(6):1303-13.
ENTRY MONTH           199902
LAST REVISION DATE    19990223

4
UNIQUE IDENTIFIER     DRG-0306
NAME OF SUBSTANCE     Pentafuside (T-20) [FDA295A]
PROTOCOL ID NUMBERS   FDA 295A
CLASSIFICATION CODE   Antiviral [FDA295A]
MANUFACTURERS         Trimeris Inc; 4727 University Drive; Durham,
                           NC 27707
ENTRY MONTH                199812
LAST REVISION DATE         19981204

5
UNIQUE IDENTIFIER          DRG-0302
NAME OF SUBSTANCE          MKC-442 [Triangle Pharmaceuticals 1998
                           Investigator's Brochure]
STANDARD CHEMICAL NAME     6-Benzyl-1-(ethoxymethyl)-5-isopropyluracil
                           [MKC-442 Investigator's Brochure]
SYNONYMS                   MKC-422 [AmFar Tx Dir December, 1997]
PROTOCOL ID NUMBERS        FDA 292A
PROTOCOL ID NUMBERS        FDA 292C
PROTOCOL ID NUMBERS        FDA 292D
PHARMACOLOGICAL ACTION     MKC-442 is a non-nucleoside reverse
                           transcriptase inhibitor (NNRTI). It is highly
                           selective for HIV-1 reverse transcriptase
                           (RT). It interacts directily with HIV-1 RT;
                           phosphorylation does not occur and is
                           unnecessary for antiviral activity. In cell
                           culture, the drug potently inhibits HIV-1
                           with IC50 and IC90 values of 1.5 nM and 10 nM
                           respectively. In animals, the drug is 68%
                           bioavailable and has good CSF penetration.
                           MKC-442 is metabolized by cytochrome P450.
                           Small scale phase IB studies with
                           HIV-infected volunteers at 100 mg bid, 250 mg
                           qd, 250 mg bid, 350 mg bid, 500 mg qd, and
                           500 mg bid showed that 500 mg twice daily
                           treatments brought about superior reduction
                           in viral load. There was no change in the
                           CD4+ count except in the 500 mg bid group. In
                           vitro data show that MKC-442 can act
                           synergistically and additively with other
                           anti-HIV compounds. MKC-442 was active
                           against HIV resistant to nevirapine at a
                           concentration slightly higher than required
                           to suppress wild-type virus. [MKC-442
                           Investigator's Brochure; AmFar Tx Dir
                           December, 1997; MKC-442 Investigator's
                           Brochure]
DISEASES STUDIED/TREATED   Being tested against HIV infection[AmFar Tx
                           Dir December, 1997]
CLASSIFICATION CODE        Non-nucleoside reverse transcriptase
                           inhibitor [Triangle Pharmaceuticals 1998
                           Investigator's Brochure]
CLASSIFICATION CODE        Antiviral [MKC-442 Investigator's Brochure]
SUBSTANCE INTERACTIONS     MKC-422 is metabolized in the liver by
                           cytochrome P450 and should be used with
                           caution in patients using other drugs that
                           are metabolized by or may affect liver
                           metabolism by cytochrome P450. [MKC-442
                           Investigator's Brochure]
ADVERSE EFFECTS            In phase I clinical trials, MKC-442 has
                           generally been well tolerated, with headache
                           (n=6) and loose stools (n=3) being the most
                           frequent adverse events. Only one patient
                           (out of 35) experienced a rash and
                           discontinued the drug. Minor elevations in
                           liver transaminase levels in 1/3 of the
                           patients was considered inconsequential.
                          [MKC-442 Investigator's Brochure]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C17H22N203 [MKC-442
                          Investigator's Brochure]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 302.37 [MKC-442
                          Investigator's Brochure]
CHEMICAL/PHYSICAL DATA    DRUG PHYSICAL COMMENT: Drug is available in
                          round white to off-white tablets [MKC-442
                          Investigator's Brochure]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: 100 and 250 mg tablets[MKC-442
                          Investigator's Brochure]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral[MKC-442 Investigator's
                          Brochure]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Stability data
                          demostrate that the dosage form is stable for
                          up to 9 months at 25 C at 60% RH and for up
                          to 3 months at 40 C at 75% RH. [MKC-442
                          Investigator's Brochure]
MANUFACTURERS             Triangle Pharmaceuticals Inc; 4 University
                          Place / 4611 University Dr; Durham, NC 27707
REFERENCES                AIDS/97926456. Furman P, Barry DW,
                          Borroto-Esoda K, Moxham C, Richman D,
                          Sommadossi JP, Endoh R, Niwa T, Yamamoto M,
                          Szczech G. Preclinical development of
                          MKC-442, a potent and selective
                          non-nucleoside inhibitor of HIV reverse
                          transcriptase. 4th Conf Retro and Opportun
                          Infect. 1997 Jan 22-26;:170 (abstract no.
                          571).
REFERENCES                AIDS/97926013. Moxham CP, Borroto-Esoda K,
                          Noel D, Furman PA, Szczech GM, Barry DW.
                          Preliminary efficacy and safety of repeated
                          multiple doses of MKC-442 in HIV-infected
                          volunteers. 4th Conf Retro and Opportun
                          Infect. 1997 Jan 22-26;:206 (abstract no.
                          LB1).
REFERENCES                AIDS/97926455. Moxham CP, Szczech GM, Blum
                          MR, Barry DW. Pharmacokinetics (PK) and
                          safety of single escalating doses of MKC-442
                          in HIV-infected volunteers. 4th Conf Retro
                          and Opportun Infect. 1997 Jan 22-26;:170
                          (abstract no. 573).
REFERENCES                MED/94304110. Baba M, Shigeta S, Yuasa S,
                          Takashima H, Sekiya K, Ubasawa M, Tanaka H,
                          Miyasaka T, Walker RT, De Clercq E.
                          Preclinical evaluation of MKC-442, a highly
                          potent and specific inhibitor of human
                          immunodeficiency virus type 1 in vitro.
                          Antimicrob Agents Chemother. 1994
                          Apr;38(4):688-92.
REFERENCES                ICA10/94371048. Yuasa S, Sadakata Y, Seki M,
                          Hashimoto K, Baba M. In vitro isolation and
                          characterization of HIV-1 mutants resistant
                          to both AZT and MKC-442. Int Conf AIDS. 1994
                          Aug 7-12;10(2):111 (abstract no. PA0325).
ENTRY MONTH               199803
LAST REVISION DATE        19980512

6
UNIQUE IDENTIFIER         DRG-0301
NAME OF SUBSTANCE         Voriconazole [AmFar Tx Dir December, 1997]
REGISTRY NUMBER           137234-62-9
STANDARD CHEMICAL NAME
                         1H-1,2,4-triazol-1-ylmethyl)-4-pyrimidineetha-
                         nol. [USAN 1997]
SYNONYMS                 UK-109,496 [USAN 1997]
PROTOCOL ID NUMBERS      NIAID 98 I-0028
PHARMACOLOGICAL ACTION   Voriconazole, a new antifungal triazole
                         derivative, was studied in vitro against 650
                         clinical isolates, representing yeasts, nolds
                         and dermatophytes, and was compared with
                         fluconazole, amphotericin B, and
                         griseofulvin. The mean minimum inhibitory
                         concentrations (MICs) of voriconazole were
                         0.06 microgram/ml against yeasts (n = 187),
                         0.74 microgram/ml against moulds (n = 260),
                         and 0.10 microgram/ml against dermatphytes (n
                         = 203). Data from these in vitro studies
                         showed that voriconazole was more potent than
                         fluconazole against most species studied, but
                         particularly against the isolates of moulds
                         and dermatophytes. The in vitro results
                         confirmed that voriconazole has indeed a
                         broad antifungal spectrum and could also be
                         effective against a wide range of fungal
                         infections. Voriconazole has potent activity
                         against various fungit hat are inherently
                         resistant to fluconazole, such as Candida
                         krusei. A study compared the effect of
                         subinhibitory concentrations of voriconazole
                         and fluconazole on sterol biosynthesis of
                         fluconazole-resistant and -susceptible
                         Candida albicans strains, as well as
                         C.krusei, in an effort to delineate the
                         precise mode of action of voriconazole.
                         C.krusei cells treated with voriconazole
                         accumulated the following biosynthetic
                         intermediates: squalene,
                         4,14-dimethylzymosterol, and
                         24-methylenedihydrolanosterol. Accumulation
                         of these methylated sterols is consistent
                         with the premise that this agent functions by
                         inhibiting fungal P-450-dependent
                         14alpha-demethylase. As expected, treating C.
                         Krusei with fluconazole minimally inhibited
                         ergosterol synthesis. These data indicate
                         that voriconazole is more effective than
                         fluconazole in blocking candidal sterol
                         biosynthesis, consistent with the different
                         antifungal potencies of these compounds.
                         Invasive aspergillosis is an increasing
                         problem in patients with acute leukemia, bone
                         marrow transplantation, immunosuppression
                         after solid organ transplantation, or AIDS.
                         Despite available antifungal treatment, the
                         mortality approaches 100% in patients with
                         dissemination of the infection into the
                         central nervous system (CNS). Voriconazole,
                         was used successfuly to treate an Aspergillus
                         brain abscess in a patient with acute
                         leukemia. Drug levels above the minimal
                         fungicidal concentration for Aspergillus
                         species were detected in cerebrospinal fluid
                           specimens, and the treatment achieved an
                           objective response. [Arzneimittelforschung
                           1997 Nov;47(11); Antimicrob Agents Chemother
                           1997 Nov;41(11); Br J Haematol 1997
                           Jun;97(3)]
DISEASES STUDIED/TREATED   Being tested for treatment of aspergillosis.
                           [AmFar Tx Dir December, 1997]
CLASSIFICATION CODE        Antifungal [AmFar Tx Dir December, 1997]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C16H14F3N50
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 349.32
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: oral[AmFar Tx Dir December,
                           1997]
MANUFACTURERS              Pfizer Central Research; Eastern Point Road;
                           Groton, CT 06340
REFERENCES                 98109332. Marco F, Pfaller MA, Messer S,
                           Jones RN. In vitro activities of voriconazole
                           (UK-109,496) and four other antifungal agents
                           against 394 clinical isolates of Candida spp.
                           Antimicrob Agents Chemother 1998 Jan;42(1) :
                           161-3.
REFERENCES                 98090677. Wildfeuer A, Seidl HP, Paule I,
                           Haberreiter A. In vitro activity of
                           voriconazole against yeasts, moulds and
                           dematophytes in comparison with fluconazole,
                           amphotericin B and griseofulvin.
                           Arzneimittelforschung 1997
                           Nov;47(11):1257-63.
REFERENCES                 98092243. Espinel-Ingroff A. In vitro
                           activity of the new triazole voriconazole
                           (UK-109,496) against opportunistic
                           filamentous and dimorphic fungi and common
                           and emerging yeast pathogens. J Clin
                           Microbiol 1998 Jan;36(1):198-202.
REFERENCES                 98037406. Sanati H, Belanger P, Fratti R,
                           Ghannoum M. A new triazole, voriconazole
                           (UK-109,496), blocks sterol biosynthesis in
                           Candida albicans and Candida krusei.
                           Antimicrob Agents Chemother 1997
                           Nov;41(11):2492-6.
REFERENCES                 97400279. McGinnis MR, Pasarell L, Sutton DA,
                           Fothergill AW, Cooper CR Jr, Rinaldi MG. In
                           vitro evaluation of voriconazole against some
                           clinically important fungi. Antimicrob Agents
                           Chemother 1997 Aug;41(8):1832-4.
REFERENCES                 97351042. Schwartz S, Milatovic D, Thiel E.
                           Successful treatment of cerebral
                           aspergillosis with a novel triazole
                           (voriconazole) in a patient with acute
                           leukaemia (see comments). Br J Haematol 1997
                           Jun;97(3):663-5.
REFERENCES                 97242502. Radford SA, Johnson EM, Warnock DW.
                           In vitro studies of activity of voriconazole
                           (UK-109,496), a new triazole antifungal
                           agent, against emrging and less-common mold
                           pathogens. Antimicrob Agents Chemother 1997
                           Apr;41(4):841-3.
REFERENCES                 97209074. Murphy M, Bernard EM, Ishimaru T,
                           Armstrong D. Activity of voriconazole
                           (UK-109,496) against clinical isolates of
                           Aspergillus species and its effectiveness in
                           an experimental model of invasive pulmonary
                         aspergillosis. Antimircrob Agents Chemother
                         1997 Mar;41(3):696-8.
REFERENCES               97135208. Martin MV, Yates J, Hitchcock CA.
                         Comparison of voriconazole (UK-109,496) and
                         itraconazole in prevention and treatment of
                         Aspergillus fumigatus endocarditis in guinea
                         pigs. Antimicrob Agents Chemother 1997
                         Jan;41(1):13-6.
REFERENCES               AIDS/98927679. Sutton DA, Fothergill AW,
                         Barchiesi FJ, Rinaldi MG. In vitro activity
                         of voriconazole against dimorphic fungi.
                         Program Abstr Intersci Conf Antimicrob Agents
                         Chemother. 1996 Sep 15-18;:114 (abstract no.
                         F85).
ENTRY MONTH              199803
LAST REVISION DATE       19980512

7
UNIQUE IDENTIFIER        DRG-0300
NAME OF SUBSTANCE        S-1153 [Fuji ImmunoPharmaceuticals Corp]
PROTOCOL ID NUMBERS      FDA 286A
CLASSIFICATION CODE      Non-nucleoside reverse transcriptase
                         inhibitor [Fuji ImmunoPharmaceuticals Corp]
MANUFACTURERS            Lexigen Pharmaceuticals; 125 Hartwell Avenue;
                         Lexington, MA 02421
ENTRY MONTH              199803
LAST REVISION DATE       19980304

8
UNIQUE IDENTIFIER        DRG-0299
NAME OF SUBSTANCE        Targretin [FDA 287A]
STANDARD CHEMICAL NAME   4-[1-(3,5,5,8,8-pentamethyl-5,
                         6,7,8-tetrahydro-2-naphthalenyl)-1-ethenyl]-b-
                         enzoic acid [FDA 287A]
SYNONYMS                 LGD1069 [FDA 287A]
SYNONYMS                 LGD100069 [FDA 287A]
PROTOCOL ID NUMBERS      FDA 287A
PHARMACOLOGICAL ACTION   Targretin (LGD1069) is a compound which
                         selectively activates a subclass of retinoid
                         receptors called RXRs which play an important
                         role in several cellular activities, most
                         importantly in an activity called apoptosis
                         (programmed cell death). In a clinical trial
                         of tagretin topical, 59 patients with biopsy
                         proven Kaposi'sarcoma (KS) were randomized at
                         5 study sites in an unblinded fashion to
                         either 0.5% vs. 1.0% gel, BID and increasing
                         to 1.0% QID, or the maximum dose tolerated.
                         Response was defined as complete flattening
                         of greater than or equal to 50% of raised
                         lesions or greater than or equal to 50%
                         decrease of the total area of lesions. Of 46
                         patients evaluable for response (on study
                         greater than or equal 12 weeks of therapy), 7
                         (15.2%) had a partial response: 1 at 0.1%
                         BID, 1 at 0.5% QD, 1 at 1.0% BID, 1 at 1.0%
                         TID and 3 at 1.0% QID. Three of 46 patients
                         (7%) met partial response criteria with a
                         complete flattening of at least 50% of the
                         raised treated index lesion. No patient had a
                         complete response in all treated lesions,
                           although some lesions had a complete
                           response. Targretin appears to have some
                           efficacy for KS lesions and is accompanied by
                           cutaneous irritation and the need for
                           multiple applications. It may be most
                           suitable for those patients who have limited
                           early disease. [Int Conf AIDS. 1996 Jul
                           7-12;11(2); PR Newswire 05 Jan 96]
DISEASES STUDIED/TREATED   Being tested as topical treatment against
                           Kaposi's sarcoma[PR Newswire 05 Jan 96]
CLASSIFICATION CODE        Antineoplastic (adjunct) [FDA 287A]
OTHER MAJOR USES           Being tested as a topical treatment of
                           mycosis fungoides (cutaneous T-cell
                           lymphoma)[PR Newswire 05 Jan 96]
ADVERSE EFFECTS            In a clinical study with targretin topical
                           gel, involving 59 patients with Kaposi's
                           sarcoma, no patient developed adverse drug
                           effects (ADEs) at 0.1% concentration. Eleven
                           of 33 patients (33%), while at 0.5% QD/BID
                           experienced possibly / probably / definitely
                           related ADEs of rash, exfoliative dermatitis,
                           maculopapular rash, eczema, or pain; none on
                           TID/QID dosing. Twelve or 45 patients (26% on
                           1.0% QD/BID experienced
                           possible/probable/definite related ADE. Two
                           patients randomized to 0.5% required dose
                           reduction to 0.1%; no non-dermatologic ADEs
                           were found at any strenght. ADEs were
                           classified as mild in 18 patients, moderate
                           in 11 patients and severe in 1 patient. [Int
                           Conf AIDS. 1996 Jul 7-12;11(2)]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Tetrahydronaphthalene
                           derivative[FDA 287A]
CHEMICAL/PHYSICAL DATA     DRUG PHYSICAL COMMENT: Topical gel [PR
                           Newswire 05 Jan 96]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Gel[PR Newswire 05 Jan 96]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Topically[PR Newswire 05
                           Jan 96]
MANUFACTURERS              Ligand Pharmaceuticals; 9393 Towne Center
                           Drive; San Diego, CA 92121
REFERENCES                 ICA11/96923593. Leoung GS, Aboulafla D,
                           Millikan L, Duvic M, MacGregor RR, Gill G,
                           Truglia J, Yocum R. Treatment of kaposi's
                           sarcoma using Targretin (LGD1069), a topical
                           retinoid gel. Int Cont AIDS. 1996 Jul
                           7-12;11(2):98 (abstract no. We.B.3241).
REFERENCES                 AIDS/95700426. Aboulafia DM. The
                           epidemiology, pathogenesis and treatment of
                           Kaposi's sarcoma. STEP Perspect. 1995
                           Spring;7(1):9-12.
REFERENCES                 Atkins S. Ligand updates market on targretin
                           (TM) (LGD1069) topical at Hambrecht & Quist
                           life sciences conference. PR Newswire - 05
                           Jan 96.
ENTRY MONTH                199802
LAST REVISION DATE         19980521

9
UNIQUE IDENTIFIER          DRG-0298
NAME OF SUBSTANCE          GEM 132 [Hybridon]
PROTOCOL ID NUMBERS        FDA UNAP 5
PHARMACOLOGICAL ACTION     GEM 132 is an antisense oligonucleotide. Such
                           compounds usually are short pieces of DNA
                           that work inside HIV-infected cells by homing
                           in on the virus's genes and stopping them
                           from working. GEM 132 is a 20-mer hybrid
                           phosphorothioate with 2 bases at the 5' end
                           and 4 bases at the 3' end being 2'0
                           methylated. This modification should improve
                           metabolic stability. GEM 132 is designed to
                           be complementary to the intron-exon boundary
                           of the UL36 and UL37 pre-mRNA transcripts of
                           human CMV. In vitro studies have shown GEM
                           132 to be about 1,000 times more potent than
                           ganciclovir. The tolerance and PK of single
                           ascending doses of GEM 132 by 2-hour IV
                           infusion were assessed in healthy male
                           volunteers in an open-label study. Eighteen
                           subjects were included, six at each of the
                           following doses: 0.125 mg/kg, 0.25mg/kg and
                           0.5mg/kg. Subjects were followed for safety
                           assessments as inpatients for 48 hours and in
                           an ambulatory setting for a total of two
                           weeks after administration of study drug.
                           Plasma concentrations of GEM 132 were
                           measured for 48 hours after dosing. The
                           pharmacokinetics of GEM 132 were nonlinear
                           with increasing dose. AUC and C(max)
                           increased disproportionately and Vd(ss) and
                           C1p decreased as the dose was escalated. GEM
                           132 is being evaluated for both systemic and
                           intravitreal administration in
                           immunocompromised patients. [PR NewsWire
                           April 7, 1997]
DISEASES STUDIED/TREATED   Under investigation for intravitreal use
                           against ocular CMV infection, and for
                           systemic use against CMV infections in AIDS
                           patients. [PR NewsWire April 7, 1997; PR
                           NewsWire April 7, 1997]
CLASSIFICATION CODE        Antisense [Hybridon]
ADVERSE EFFECTS            The most frequently reported adverse event in
                           one clinical trial was headache in 5 of 18
                           subjects which occurred at all dose levels
                           and resolved rapidly and without sequelae. A
                           minor and transient increase in aPTT was
                           observed immediately after the end of the
                           infusion in one subject dosed with 0.5 mg/kg
                           132. No other treatment-related events were
                           observed. [4th Conf Retro and Opportun
                           Infect. 1997 Jan 22-26]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Antisense
                           oligonucleotide[4th Conf Retro and Opportun
                           Infect. 1997 Jan 22-26]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Infusion[4th Conf Retro and
                           Opportun Infect. 1997 Jan 22-26]
MANUFACTURERS              Hybridon Inc; 155 Fortune Boulevard; Milford,
                           MA 01757
REFERENCES                 AIDS/97926754. Guinot P, Martin R, Bonvoisin
                           B, Toneatti C, Bourque A, Cohen A, Dvorchik
                           B, Schechter P. First phase I study of a new
                           systemic anti-CMV antisense compound (GEM
                           132) in healthy male volunteers. 4Th Conf
                           Retro and Oppotun Infect. 1997 Jan 22-26;:121
                           (abstract no. 309).
ENTRY MONTH                199802
LAST REVISION DATE         19981111

10
UNIQUE IDENTIFIER          DRG-0297
NAME OF SUBSTANCE          Zintevir [Aronex Pharmaceuticals Inc]
PROTOCOL ID NUMBERS        FDA 290A
PHARMACOLOGICAL ACTION     Zintevir belongs to a class of novel
                           oligonucleotides. Preclinical studies have
                           indicated that Zintevir inhibits the HIV
                           integrase enzyme, one of the key steps in the
                           life cycle of the HIV virus. Oligonucleotides
                           that can form a highly stable intramolecular
                           four-stranded DNA structure containing two
                           stacked guanosine-quartets (G-quartets) have
                           been reported to inhibit the replication of
                           the human immunodeficiency virus type 1
                           (HIV-1) in cell culture. Two possible
                           mechanisms for the observed antiviral
                           activity have been proposed: interference
                           with virus adsorption to the cell and/or
                           inhibition of HIV-1 integrase. The molecular
                           intercation of G-quartet-containing
                           oligonucleotides with HIV-1 integrase in
                           comparison with random oligonucleotides and
                           dextran sulphate was investigated. Zintevir,
                           the prototypical G-quartet-containing
                           oligonucleotide, inhibited the overall
                           integration reaction with an IC50 value of 80
                           nM. Preclinical studies have shown that
                           Zintevir is a very stable molecule widely
                           distributed throughout the body, and that
                           tissue concentration of the are maintained
                           for periods exceeding five days following
                           single doses. A single dose rising study and
                           a two-week, multiple-dose escalation study,
                           which involved a total of 27 HIV-positive
                           patients, have been completed. Results
                           indicate that Zintevir, administered at doses
                           up to 6mg/kg, is extremely well tolerated. No
                           clinically significant adverse events were
                           reported. Results also indicate that Zintevir
                           (TM) plasma concentrations exceeded in vitro
                           inhibitory concentration for the HIV virus
                           for periods of up to 10 hours following
                           administration of the higher doses. [Mol
                           Pharmacol 1998 Feb; 53(2); PR Newswire, 12
                           November 1996]
DISEASES STUDIED/TREATED   Anti-HIV activity. Currently in clinical
                           phase I trials[Mol Pharmacol 1998 Feb; 53(2)]
CLASSIFICATION CODE        Integrase Inhibitor [Aronex Pharmaceuticals
                           Inc]
ADVERSE EFFECTS            Results of Phase I clinical trials indicated
                           that Zintevir, administered at doses up to
                           6mg/kg, is extremely well tolerated. No
                           clinically significant adverse events were
                           reported. [PR Newswire, 12 November 1996]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Zintevir is a 17-base
                           oligonucleotide composed of deoxyguanosines
                          and thymidines on a phosphodiester backbone
                          supplemented by phosphorothioate
                          internucleoside linkages at the 5' and 3'
                          ends[Int Conf AIDS. 1996 Jul 7-12;11(1)]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: By infusion. [Int Conf
                          AIDS. 1996 Jul 7-12;11(1)]
MANUFACTURERS             Aronex Pharmaceuticals Inc; 3400 Research
                          Forest Drive; The Woodlands, TX 77381
REFERENCES                MED/98130706. Este JA, Cabrera C, Schols D,
                          Cherepanov P, Gutierrez A, Witvrouw M,
                          Pannecouque C, Debyser Z, Rando RF, Clotet B,
                          et al. Human Immunodeficiency virus
                          glycoprotein gp120 as the primary target for
                          the antiviral action of AR177 (Zintevir). Mol
                          Pharmacol. 1998 Feb;53(2):340-5.
REFERENCES                MED/98016250. Cherepanov P, Este JA, Rando
                          RF, Ojwang JO, Reekmans G, Steinfeld R, David
                          G, De Clercq E, Debyser Z, Mode of
                          interaction of G-quarters with the integrase
                          of human immunodeficiency virus type 1. Mol.
                          Pharmacol. 1997 Nov;52(5):771-80.
REFERENCES                ICA11/97926876. Kahn J, Graham E, Deeks S,
                          Gambertoglio J, Brewer T, Wallace T, Kennedy
                          B, Cossum P. Phase I study of AR-177
                          (Zintevir), an HIV-1 inhibitor with
                          significant activity against integrase
                          protein: safety, pharmokinetics, immunologic
                          and virologic activity. Int Conf AIDS. 1996
                          Jul 7-12;11(Program Supplement):21(abstract
                          no. Th.B.946).
ENTRY MONTH               199802
LAST REVISION DATE        19980508

11
UNIQUE IDENTIFIER         DRG-0296
NAME OF SUBSTANCE         AIDSVAX B/E Vaccine [UNAP 2]
PROTOCOL ID NUMBERS       NIAID AVEG 036
PROTOCOL ID NUMBERS       FDA 98 I-0028
PROTOCOL ID NUMBERS       NIAID VEU 202
CLASSIFICATION CODE       Vaccine [UNAP 2]
MANUFACTURERS             VaxGen Incorporated; 501 Forbes Blvd; South
                          San Francisco, CA 94080
ENTRY MONTH               199802
LAST REVISION DATE        19980203

12
UNIQUE IDENTIFIER         DRG-0295
NAME OF SUBSTANCE         AIDSVAX B/B Vaccine [UNAP 2]
PROTOCOL ID NUMBERS       FDA VAX 004
PROTOCOL ID NUMBERS       FDA 98 I-0028
PROTOCOL ID NUMBERS       NIAID VEU 027
PROTOCOL ID NUMBERS       NIAID VEU 202
PHARMACOLOGICAL ACTION    In general gp120-based vaccines have been
                          considered to be ineffective against HIV
                          infection. Thus, for the last three years,
                          NIAID has not funded gp120 vaccine clinical
                          trials. The AIDSVAX B/B vaccine, however, is
                          based on two types of gp120 proteins: one
                          from a laboratory strain already used in
                          previous tests, and a second that corresponds
                          to currently ciculating natural HIV strains
                           either in the US or Thailand, depending on
                           where the vaccine will be tested. This
                           approach is based on the observation that in
                           a trial with a recombinant gp120 vaccine
                           (MN-rgp120), six out of seven volunteers, who
                           became infected with HIV during the trial,
                           showed a virus strain different from that
                           used in the trial vaccine. These results
                           suggested that the breakthrough infections
                           might be related to incomplete immunization
                           or to infection with viruses that differed
                           from the vaccine immunogen at important
                           virus-neutralizing epitopes. AIDSVAX B/B has
                           been through phase I and II testing. As
                           stated, each AIDSVAX formulation is bivalent
                           - that is, created from recombinant copies of
                           the gp120 protein from the surface of two
                           tyes of HIV. The vaccine to be used in test
                           sites across North America is formulated to
                           protect against infection by the major types
                           of HIV-1 virus most typical of infections in
                           the Americas, Western Europe and Australia
                           (AIDSVAX B/B). The formulation of the vaccine
                           to be used in the Thai trial is designed to
                           protect against the major types of the virus
                           typical of infections in Southeast Asia and
                           the Pacific Rim (AIDSVAX B/E). [Science 1998
                           Jan 30:279(5351); J Infect Dis. 1997
                           Aug;176(2); BUSINESS WIRE; September 15,
                           1998]
DISEASES STUDIED/TREATED   Vaccine against HIV infection. The FDA has
                           granted permission for Phase III trials of
                           the vaccine. Such are being initiated in the
                           US with the AIDSVAX B/B vaccine, and in
                           Thailand with AIDSVAX B/E, a slightly
                           different version of the vaccine. [Science
                           1998 Jan 30:279(5351); AP, June 3, 1998]
CLASSIFICATION CODE        Vaccine [UNAP 2]
ADVERSE EFFECTS            The safety and immunogenicity of AIDSVAX has
                           been evaluated through administration of
                           monovalent subtype B formulations (MN and
                           IIIB) to over 1,000 humans. A second
                           geography-specific antigen was selected,
                           produced, combined with MN, and administered
                           to humans in the United States and in
                           Thailand using bivalent formulations - B/B
                           for the U.S. (120 volunteers) and B/E for
                           Thailand (90 volunteers). Minimal injection
                           site reactions are the only associated
                           adverse reactions observed. [Abstr paper XII
                           Intl Conf AIDS G/VA Switz/land 06/98]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Vaccine produced from a
                           genetically engineered HIV surface protein
                           gp120. [Science 1998 Jan 30:279(5351)]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: By injection[UNAP 2]
MANUFACTURERS              VaxGen Incorporated; 501 Forbes Blvd; South
                           San Francisco, CA 94080
REFERENCES                 MED/98125992. Graham BS, McElrath MJ, Connor
                           RI, Schwartz DH, Gorse GJ, Keefer MC,
                           Mulligan MJ, Matthews TJ, Wolinsky SM,
                           Montefiori DC, et al. Analysis of
             intercurrent human immunodeficiency virus
             type 1 infections in phase I and II trials of
             candidate AIDS vaccines. AIDS Vaccine
             Evaluation Group, and the Correlates of HIV
             Immune Protection Group. J Infect Dis. 1998
             Feb;177(2)310-9.
REFERENCES   MED/98125991. Corey L, McElrath MJ, Weinhold
             K, Matthews T, Stablein D, Graham B, Keefer
             M, Schwartz D, Gorse G. Cytotoxic T cell and
             neutralizing antibody responses to human
             immunodefficiency virus type 1 envelope with
             a combination vaccine regimen. AIDS Vaccine
             Evaluation Group. J Infect Dis. 1998
             Feb;177(2):301-9.
REFERENCES   MED/98140699. Bolognesi DP, Matthews TJ. HIV
             vaccines. Viral envelope fails to deliver?
             [news] Nature. 1998 Feb12;391(6668):638-9.
REFERENCES   MED/98129144. Balter M. Impending AIDS
             vaccine trial opens old wounds [news].
             Science. 1998 Jan 30;279(5351):650.
REFERENCES   MED/97379381. Berman PW, Gray AM, Wrin T,
             Vennari JC, Eastman DJ, Nakamura GR, Francis
             DP, Gorge G, Schwartz DH. Genetic and
             immunologic characterization of viruses
             infecting MN-rgp120-vaccinated volunteers. J
             Infect Dis. 1997 Aug;176(2):384-97.
REFERENCES   MED/98004261. Li D, Forrest BD, Li Z, Xue P,
             Hanson CV, Duan S, Cheng H, Li M, Wang CY,
             Koff WC. International clinincal trials of
             HIV vaccines: II. phase I trial of an HIV-1
             synthetic peptide vaccine evaluating an
             accelerated immunization schedule in Yunnan,
             China. Asian Pac J Allergy Immunol. 1997
             Jun;15(2):105-13.
REFERENCES   MED/97071928. Gorse GJ, Yang EY, Belshe RB,
             Berman PW. Salivary binding antibodies
             induced by human immunodeficiency virus type
             1 recombinant gp120 vaccine. The NIAID AIDS
             Vaccine Evaluation Group. Clin Diagn Lab
             Immunol. 1996 Nov;3(6):769-73.
REFERENCES   MED/97048118. Girard M, Yue L, Barre-Sinoussi
             F, van der Ryst E, Meignier B, Muchmore E,
             Fultz PN. Failure of a human immunodeficiency
             virus type 1 (HIV-1) subtype B-derived
             vaccine to prevent infection of chimpanzees
             by an HIV-1 subtype E strain. J Virol. 1996
             Nov;70(11):8229-33.
REFERENCES   MED/96132463. Berman PW, Murthy KK, Wrin T,
             Vennari JC, Cobb EK, Eastman DJ, Champe M,
             Nakamura GR, Davison D, Powell MF, et al.
             Protection of MN-rgp120-immunized chimpanzees
             from heterologous infection with a primary
             isolate of human immunodeficiency virus type
             1. J Infect Dis. 1996 Jan;173(1):52-9.
REFERENCES   MED/96188305. el-Amad Z, Murthy KK, Higgins
             K, Cobb EK, Haigwood NL, Levy JA, Steimer KS.
             Resistance of chimpanzees immunized with
             recombinant gp120sf2 to challenge by
             HIV-1SF2. AIDS. 1995 Dec;9(12):1313-22.
REFERENCES   Chicago Clinic Begins Inoculations in Phase
             III Trial of AIDSVAX. Business WIRE; Tuesday
                         September 15, 1998.
REFERENCES               Francis DP. AIDSVAX B/B and AIDSVAX B/E.
                         Likely to protect. But how well and for how
                         long must await results of planned efficacy
                         trials. Abstract of paper at XII
                         International Conference on AIDS Geneva,
                         Switzerland June, 1998.
REFERENCES               Empyrrhic Victory. Jubilation and Skepticism
                         Greet Announcement of First Phase III Trial
                         of an AIDS Vaccine. Watershed or Waterworld.
                         Treatment Action Group (TAG): Volume 5, Issue
                         6, July 1998.
ENTRY MONTH              199802
LAST REVISION DATE       19990301

13
UNIQUE IDENTIFIER        DRG-0294
NAME OF SUBSTANCE        Interleukin-6 [NIAID ACTG 928]
SYNONYMS                 Il-6 [In Vivo Veritas Jan 1996]
SYNONYMS                 B-Cell Stimulating Factor 2 (BSF-2) [In Vivo
                         Veritas Jan 1996]
SYNONYMS                 Interferon-beta2 (IFN-b2) [In Vivo Veritas
                         Jan 1996]
PHARMACOLOGICAL ACTION   MODE OF ACTION: Interleukin-6 (IL-6) is a
                         member of the family of cytokines
                         collectively termed the interleukin-6 type
                         cytokines. IL-6 expression is regulated by a
                         variety of factors, including steroidal
                         hormones, at both the transcriptional and
                         post-transcriptional levels. IL-6 achieves
                         its effets through the ligand-specific IL-6
                         receptor (IL-6R). Unlike most other cytokine
                         receptors, the IL-6R is active in both
                         membrane bound and soluble forms. Defining
                         mechanisms to control IL-6 or IL-6R
                         expression forms. Defining mechanisms to
                         control IL-6 or IL-6R expression may prove
                         useful for therapy of the many clinical
                         disorders in which IL-6 plays a role.
                         Overproduction of IL-6 is associated with a
                         number of diseases, which include: polyclonal
                         B-cell activation or autoimmune diseases
                         (cardiac myxoma, rheumatoid arthritis,
                         Castleman's disease, alcoholic liver
                         cirrhosis, type I diabetes); malignancies
                         (multiple myeloma, cholangiocarcinoma,
                         plasmacytoma, lymphoma, leukemia, and renal
                         cell carcinoma); chronic proliferative
                         diseases (mesangial proliferative
                         glomerulonephritis, psoriasis, and Kaposi's
                         sarcoma); and other diseases (AIDS, sepsis,
                         osteoporosis, Fanconi anemia, and hepatitis
                         type B). Indeed, these associations with
                         clinical disease suggest that IL-6 have
                         potential therapeutic and diagnostic roles.
                         Preclinical anti-tumor studies with IL-6 have
                         provided rationale for its utilization in the
                         therapy of certain malignancies. However,
                         phase I trials with IL-6 have yet to
                         demonstrate an antitumor effect in patients
                         with advanced cancer and hence suggests a
                           supportive rather than primary role for this
                           cytokine in immunotherapy. In particular, a
                           recent study demonstrated that the
                           combination of B7-1, IL-6, and IL-12 promoted
                           the generation of tumor-specific cytotoxic T
                           lymphocytes in vitro; this proposal may
                           potentially be applied to immunotherapeutic
                           approaches in patients with specific types of
                           cancer. [Frontiers Bioscience 1, Dec 1996; In
                           Vivo Veritas, January 1996]
DISEASES STUDIED/TREATED   Human IL-6 is characterized as a glycoprotein
                           consisting of 212 amino acids with numerous
                           post-translational modifications including
                           phosphorylations as well as N- and O-linked
                           glycosylations. [Frontiers Bioscience 1, Dec
                           1996; In Vivo Veritas Jan 1996]
CLASSIFICATION CODE        Immunomodulator [NIAID ACTG 928]
OTHER MAJOR USES           Possible utilization in the therapy of
                           certain malignancies. [In Vivo Veritas Jan
                           1996]
MANUFACTURERS              Natl Inst of Allergy & Infect Dis / Cln Ctr;
                           9000 Rockville Pike / RM 11C304; Bethesda, MD
                           20892
REFERENCES                 MED/98380419. Williams DM, Grubbs BG,
                           Darville T, Kelly K, Rank RG. A role for
                           interleukin-6 in host defense against murine
                           Chlamydia trachomatis infection. Infect
                           Immun. 1998 Sep;66(9):4564-7.
REFERENCES                 MED/98375851. Murakami-Mori K, Mori S,
                           Nakamura S. Endogenous basic fibroblast
                           growth factor is essential for cyclin E-CDK2
                           activity in multiple external
                           cytokine-induced proliferation of
                           AIDS-associated Kaposi's sarcoma cells: dual
                           control of AIDS-associated Kaposi's sarcoma
                           cell growth and cyclin E-CDK2 activity by
                           endogenous and external signals. J Immunol.
                           1998 Aug 15;161 (4):1694-704.
REFERENCES                 MED/98368644. Bewnveniste O, Vaslin B, Le
                           Grand R, Dormont D. Comparing IL-6,
                           TNF-alpha, and IL-1beta responses to acute
                           infection with attenuated nef-truncated or
                           pathogenic SIVmac251 in macaque peripheral
                           blood mononuclear cells [letter] J Acquir
                           Immune Defic Syndr Hum Retrovirol. 1998 Aug
                           1;18(4):389-90.
REFERENCES                 MED/98283303. de Martino M, Rossi ME, Azzari
                           C, Gelli MG, Galli L, Vierucci A. Different
                           meaning of CD38 molecule expression on CD4+
                           and CD8+ cells of children perinatally
                           infected with human immunodeficiency virus
                           type 1 infection surviving longer than five
                           years. Pediatr Res. 1998 Jun;43(6):752-8.
REFERENCES                 MED/98287066. Haslett PA. Anticytokine
                           approaches to the treatment of anorexia and
                           cachexia. Semin Oncol. 1998 Apr;25(2 Suppl
                           6):53-7.
REFERENCES                 MED/98268879. Haas DW, Lederman MM, Clough
                           LA, Wallis RS, Chernoff D, Crampton SL.
                           Proinflammatory cytokine and human
                           immunodeficiency virus RNA levels during
                         early Mycobacterium avium complex bacteremia
                         in advanced AIDS. J Infect Dis. 1998
                         Jun;177(6):1746-9.
REFERENCES               AIDS/98929742. Russell DG. Immunomodulation
                         in Mycobacterium infections. 5th Conf
                         Retrovir Oppor Infect. 1998 Feb 1-5;:236
                         (abstract no. S31).
REFERENCES               AIDS/98929649. Haas DW, Lederman M, Clough
                         LA, Wallis RS, Feiler JR. Effect of
                         clarithromycin prophylaxis on circulating
                         TNF-alpha and IL-6 levels in advanced HIV
                         infection. 5th Conf Retrovir Oppor Infect.
                         1998 Feb 1-5;:215 (abstract no. 725).
REFERENCES               MED/98085839. Papanicolaou DA, Wilder RL,
                         Manolagas SC, Chrousos GP. The
                         pathophysiologic roles of interleukin-6 in
                         human disease. Ann Intern Med 1998 Jan
                         15;128(2):127-37.
REFERENCES               MED/98226689. Wang XJ. Taga T. Yoshida K.
                         Saito M. Kishimoto T. Kikutani H. gp130, the
                         cytokine common signal-transducer of
                         interleukin-6 cytokine family, is
                         downregulated in T cells in vivo by
                         interleukin-6. Blood. 1998 May
                         1;91(9):3308-14.
ENTRY MONTH              199801
LAST REVISION DATE       19990322

14
UNIQUE IDENTIFIER        DRG-0293
NAME OF SUBSTANCE        CPI-1189 [FDA 289A]
SYNONYMS                 LU 02-584 [FDA 289A]
PROTOCOL ID NUMBERS      FDA 289A
PROTOCOL ID NUMBERS      FDA 289B
CLASSIFICATION CODE      Antidementia [FDA 289A]
MANUFACTURERS            Centaur Pharmaceuticals Inc; 484 Oakmead
                         Parkway; Sunnyvale, CA 94086
ENTRY MONTH              199801
LAST REVISION DATE       19980116

15
UNIQUE IDENTIFIER        DRG-0292
NAME OF SUBSTANCE        SCH 56592 [GMHC Treatment Issue 1996]
PROTOCOL ID NUMBERS      FDA 288A
PHARMACOLOGICAL ACTION   SCH 56592 has a low water solubility (less
                         than 2 micrograms/ml) which increases at
                         acidic pH, is stable at accelerated
                         conditions of temperature and light, and is
                         compatible with a wide variety of
                         pharmaceutical excipients. SCH 56592 is a
                         triazole antifungal agent. Triazole
                         antifungals are known to block sterol
                         biosynthesis by inhibiting the enzyme
                         lanosterol, a-C14 demthylase (CYP51). In a
                         study, examining the effect of SCH 56592 on
                         fungal sterol synthesis, it was found that
                         SCH 56592 inhibits sterol C14 demethylation
                         in candida albicans with an estimated IC50
                         comparable to that of itraconazole. In the
                         case of aspergillus flavus and aspergillus
                         fumigatus, SCH 56592 is at least ten-fold
                          more potent than itraconazole. The results
                          suggest that the superior in vitro and in
                          vivo activities of SCH 56592, against
                          aspergillus are related to its activity
                          against CYP51. Another study investigated the
                          in vitro activity of SCH 56592, itraconazole,
                          fluconazole, amphotericin B, and 5-
                          fluorocytosine against 268 clinical isolates
                          of candida species. SCH 56592 was equivalent
                          to itraconazole and greater than or equal to
                          8-fold more active than fluconazole. In
                          another study, it was found that SCH 56592
                          was effective against murine pulmonary
                          aspergillosis. Based on these studies, SCH
                          56592 has promising antigungal activity and
                          warrants further in vitro and in vivo
                          investigation. A multicenter, randomized,
                          double-blind, Phase II study to evaluate the
                          safety, tolerance and efficacy of multiple
                          doses of SCH 56592 versus fluconazole in the
                          treatment of oropharyngeal candidiasis in
                          HIV-positive patients is being started. [Prog
                          Abst Intersci Conf Antimicrob Agents
                          Chemother. '96 Sep; Prog Abst Intersci Conf
                          Antimicrob Agents Chemother. '96 Sep]
CLASSIFICATION CODE       Antifungal [GMHC Treatment Issue 1996]
OTHER MAJOR USES          SCH 56592 is the most powerful sterol
                          biosynthesis inhibitor ever tested against
                          trypanosoma cruzi and could be useful in the
                          treatment of chagas disease in humans. [Prog
                          Abst Intersci Conf Antimicrob Agents
                          Chemother. '96 Sep]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: SCH 56592 has been shown to
                          be very potent against Aspergillus, Candida,
                          Cryptococcus and other opportunistic fungi
                          both in vitro and in animal models. [Prog
                          Abst Intersci Conf Antimicrob Agents
                          Chemother. '96 Sep]
CHEMICAL/PHYSICAL DATA    DRUG PHYSICAL COMMENT: SCH 56592 has a low
                          water solubility (less than 2 micrograms/ml)
                          which increases at acidic pH, is stable at
                          accelerated conditions of temperature and
                          light and is compatible with a wide variety
                          of pharmaceutical excipients. [Prog Abst
                          Intersci Conf Antimicrob Agents Chemother.
                          '96 Sep]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral[Prog Abst Intersci
                          Conf Antimicrob Agents Chemother. '96 Sep]
MANUFACTURERS             Schering - Plough Research; 2000 Galloping
                          Hill Road; Kenilworth, NJ 07033
REFERENCES                AIDS/98927696. Nomeir AA, Kumari P,
                          Loebenberg D, Cacciapuoti A, Hare R, Miller
                          G, Sangekar S, Mahashabde S, Sequeira J,
                          Vadino Wa. Bioavailability of SCH 56592, a
                          new broad spectrum triazole antifungal agent,
                          from various formulations. Program Abstr
                          Intersci Conf Antimicrob Agents Chemother.
                          1996 Sep 15-18;:117 (abstract no. F103).
REFERENCES                AIDS/98927694. Wheat J, Bick C, Connolly P,
                          Smedema M, Durkin M, Kohler S, Loebenberg D.
                          Comparison of a new triazole, Schering 56592,
                     with itraconazole and amphotericin B for
                     treatment of murine histoplasmosis. Program
                     abstr Intersci Conf Antimicrob Agents
                     Chemother. 1996 Sep 15-18;:117 (abstract no.
                     F101).
REFERENCES           AIDS/98927693. Lutz JE, Clemons KV, Stevens
                     DA. Efficacy of SCH 56592 (SCH) in a murine
                     model of systemic Coccidioidomycosis. Program
                     Abstr Intersci Conf Antimicrob Agents
                     Chemother. 1996 Sep 15-18;:117 (abstract no.
                     F100).
REFERENCES           AIDS/98927692. Graybill J, Najvar L,
                     Bocanegra R, Fothergill A, Luther M.
                     Treatment of murine pulmonary Aspergillosis
                     with SCH 56592 (SCH). Program Abstr Intersci
                     Conf Antimicrob agents Chemother. 1996 Sep
                     15-18;:117 (abstract no.F99).
REFERENCES           AIDS/98927691. Patterson TF, Kirkpatrick WR.
                     Mcatee RK, Loebenberg D. Efficacy of SCH
                     56592 in a rabbit model of invasive
                     aspergillosis. Program Abstr Intersci Conf
                     Antimicrob Agents Chemother. 1996 Sep
                     15-18;:116 (abstract no.F98).
REFERENCES           AIDS/98927686. Dupont B, Improvisi L, Dromer
                     F. In vitro and in vivo activity of a new
                     antifungal agent SCH 56592 (SCH). Program
                     Abstr Intersci Conf Antimicrob agents
                     Chemother. 1996 Sep 15-18;:116 (abstract no.
                     F93).
REFERENCES           AIDS/98927684. Yarosh-Tomaine T, Munayyer H,
                     Shaw KJ, Hare RS, Heimark L, Pramanik B,
                     Greene JR. Studies on fungal resistance to
                     SCH 56592. Program Abstr Intersci Conf
                     Antimicrob Agents Chemother. 1996 Sep
                     15-18;:115 (abstract no. F91).
REFERENCES           AIDS/98927683. Oakley KL, Moore CB, Denning
                     DW. In vitro activity of SCH-56592 against
                     Aspergillus spp. And comparison with
                     itraconazole and amphotericin B. Program
                     Abstr Intersci Conf Antimirob Agents
                     Chemother. 1996 Sep 15-18;:115 (abstract no.
                     F90).
REFERENCES           AIDS/98927681. Law D, Denning DW. In vitro
                     activity of Schering 56592, compared with
                     fluconazole and itraconazole against Candida
                     spp. Program Abstr Intersci Conf Antimicrob
                     Agents Chemother. 1996 Sep 15-18;:115
                     (abstract no. F88).
REFERENCES           AIDS/98927680. Pfaller MA, Zerva L, Messer S,
                     Jones R. Antifungal activity of a new
                     triazole, SCH 56592, compared with four other
                     antifungal agents tested against clinical
                     isolates of Candida spp. Program Abstr
                     Intersci Conf Antimicrob Agents Chemother.
                     1996 Sep 15-18;:115 (abstract no. F87).
ENTRY MONTH          199801
LAST REVISION DATE   19980518

16
UNIQUE IDENTIFIER    DRG-0291
NAME OF SUBSTANCE    ABT-378 [FDA 285A]
PROTOCOL ID NUMBERS      FDA 285B
PROTOCOL ID NUMBERS      FDA 285A
CLASSIFICATION CODE      Protease inhibitor [FDA 285A]
CLASSIFICATION CODE      Antiretroviral [FDA 285A]
MANUFACTURERS            Abbott Laboratories; One Abbott Park Road;
                         Abbott Park, IL 60064
ENTRY MONTH              199801
LAST REVISION DATE       19980114

17
UNIQUE IDENTIFIER        DRG-0290
NAME OF SUBSTANCE        PMPA Prodrug [FDA 283A]
STANDARD CHEMICAL NAME   9-[2-(R)-[[bis[[(isopropoxycarbonyl)oxy]metho-
                         xy]- phosphinoyl]methoxy]propyl]adenine
                         fumarate [FDA 283A]
SYNONYMS                 Bis(POC)PMPA [4th Conf Retro and Opportun
                         Infect. 1997 Jan 22-26]
PROTOCOL ID NUMBERS      FDA 283A
PROTOCOL ID NUMBERS      FDA 283B
PHARMACOLOGICAL ACTION   MODE OF ACTION: PMPA
                         (9-(2-phosphonylmethoxypropyl)adenine) is an
                         acyclic nucleotide analogue which has shown
                         significant efficacy in the prevention of SIV
                         infection in macaques. In addition, treatment
                         of chronically SIV infected animals with PMPA
                         resulted in a 2-3 log drop in SIV RNA levels.
                         Resistance has not been observed. Results of
                         the first human trial with PMPA show viral
                         load reductions of 1.1 log after one week,
                         theoretically the most possible decline after
                         one week of treatment. In order to improve
                         the low oral bioavailability of PMPA,
                         researchers evaluated a large number of
                         potential prodrugs and selected bis
                         [(isopropyloxycarbonyl)oxymethyl] PMPA as a
                         clinical candidate. Bis(POC)PMPA was
                         chemically stable in solution over a broad pH
                         range and exhibited 30% oral bioavailability
                         in dogs, with minimal toxicity in a five day
                         repeat dose administration at 60 mg/kg/day of
                         PMPA equivalents. Bis(POC)PMPA showed
                         enhanced membrane permeability as evidenced
                         in tissue culture by 100 x increased
                         antiviral activity and increased
                         intracellular concentrations of the
                         triphophate analogue relative to PMPA. When
                         evaluated in murine sarcoma virus infected
                         SCID mice, oral administration of
                         Bis(POC)PMPA resulted in significantly
                         delayed tumor appearance. Bis(POC)PMPA is a
                         promising agent for the treatment and
                         prophylaxis of HIV infections. [AIDS
                         Treatment News; 4th Conf Retro and Opportun
                         Infect. 1997 Jan 22-26]
CLASSIFICATION CODE      Antiviral [FDA 283A]
CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Bis
                         [(isopropyloxycarbonyl)oxymethyl] is a
                         prodrug of the antiretroviral agent
                         (9-(2-phosphonylmethoxyprophyl)adenine)
                         (PMPA). It makes PMPA orally more readily
                         available. [AIDS Treatment News]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral. [AIDS Treatment News]
MANUFACTURERS             Gilead Sciences Incorporated; 353 Lakeside
                          Drive; Foster City, CA 94404
REFERENCES                MED/97311522. Tsai CC, Follis KE, Beck TW,
                          Sabo A, Bischofberger N, Dailey PJ. Effects
                          of (R)-9-(2-phophonylmethoxypropyl)adenine
                          monotherapy on chronic SIV infection in
                          macaques. AIDS Res Hum Retroviruses. 1997 May
                          20;13(8):707-12.
REFERENCES                AIDS/97702542. James JS. PMPA--first human
                          results. AIDS Treat News. 1997 Apr 18;(No
                          269):3, 6.
REFERENCES                AIDS/97926475. Bischofberger N, Naesens L, de
                          Clercq E, Fridland A, Srinivas RV, Robbins
                          BL, Arimilli M, Cundy K, Kim C, et al.
                          Bis(POC)PMPA, an orally bioavailable prodrug
                          of the antiretroviral agent PMPA. 4th Conf
                          Retro and Opportun Infect. 1997 Jan
                          22-26;:104 (abstract no. 214).
REFERENCES                AIDS/97926379. Merrill DP, Manion DJ, Walker
                          BD, Hirsch MS. Drug susceptiblities of HIV-1
                          clinical isolates to (R)PMPA in vitro. 4th
                          Conf Retro and Opportun Infect. 1997 Jan
                          22-26;:93 (abstract no. 155).
REFERENCES                MED/96193652. Balzarini J, Aquaro S, Perno
                          CF, Witvrouw M, Holy A, De Clercq E. Activity
                          of the (R)-enantiomers of
                          9-(2-phosphonylmethoxypropyl)-adenine and
                          9-(2-phosphonylmethoxypropyl)-2,6-diaminopuri-
                          ne against human immunodeficiency virus in
                          different human cell systems. Biochem Biophys
                          Res Commun. 1996 Feb 15;219(2):337-41.
REFERENCES                MED/96072971. Tsai CC, Follis KE, Sabo A,
                          Beck TW, Grant RF, BischofbergerN, Benveniste
                          RE, Black R. Prevention of SIV infection in
                          macaques by
                          (R)-9-(2-phophonymethoxypropyl)adenine [see
                          comments]. Science. 1995 Nov
                          17;270(5239):1197-9.
REFERENCES                MED/94079379. Srinivas RV, Robbins BL,
                          Connelly MC, Gong YF, Bischofberger N,
                          Fridland A. Metabolism and in vitro
                          antiretroviral activities of
                          bis(pivaloyloxymethyl) prodrugs of acyclic
                          nucleoside phosphonates. Antimicrob Agents
                          Chemother. 1993 Oct;37(100):2247-50.
ENTRY MONTH               199801
LAST REVISION DATE        19980415

18
UNIQUE IDENTIFIER         DRG-0289
NAME OF SUBSTANCE         Hepatitis A Vaccine (Inactivated) [Physicians
                          Gen RX 1997]
SYNONYMS                  Vaqta [Physicians Gen RX 1997]
SYNONYMS                  Havrix [Physicians Gen RX 1997]
PROTOCOL ID NUMBERS       NIAID ACTG 387
PHARMACOLOGICAL ACTION    Hepatitis A virus (HAV) is one of several
                          hepatitis viruses that cause systemic
                          infection with pathology in the liver. The
                          predominant mode of transmission is person-to
                          person via the fecal oral-route. In some
                         developing countries, 90% of children are
                         infected by age 5. In developed countries,
                         infections are rare and occur more in adults,
                         where the disease is more severe and more
                         likely to be fatal. In the US, infection
                         rates have increased from 9.2 per 100,000 in
                         1983 to 14.6 per 100,000 in 1989. The
                         presence of antibodies to HAV confers
                         protection against hepatitis A vaccine,
                         inactivated, in healty adults, specific
                         humoral antibodies against HAV were elicited
                         in 96% of the subjects 1-month after
                         vaccination. In other studies in which
                         booster shots of the vaccine were given 6
                         month following the initial dose, 100% of the
                         vaccines were seropositive 1 month after the
                         booster dose. A study of the influence of HIV
                         infection and vaccination schedule on the
                         immunogenicity of hepatitis A vaccine (HAC)
                         showed that seroconversion after two
                         vaccinations occurred more frequently in
                         HIV-negative men. Anti-HAV titler after two
                         vaccinations was also significantly greater
                         in HIV-negative men. HIV-positive men who
                         responded to vaccination had significantly
                         more CD4 cells at baseline than those who did
                         not. The vaccine schedule did not affect
                         response. Vaccination of susceptible patients
                         against hepatitis A should be recommended
                         early in HIV infection using the shorter
                         course to encourage compliance. At present,
                         duration of the protection afforded by the
                         vaccine has not been established. [J Infect
                         Dis 1997 Oct;176(4):1064-7; PDR 1997]
CLASSIFICATION CODE      Vaccine [Physicians Gen RX 1997]
OTHER MAJOR USES         Active immunization of persons, 2 years of
                         age or older, against disease caused by
                         hepatitis A. Primary immunization should be
                         completed at least 2 weeks before expected
                         exposure to hepatitis A. [PDR 1997]
SUBSTANCE INTERACTIONS   Preliminary results indicate that the
                         concomitant administration of a wide variety
                         of other vaccines is unlikely ti interfere
                         with hepatitis vaccine A, inactivated
                         (Havrix). As with other intramuscular
                         injections, the hepatitis vaccine should be
                         given with caution to individuals on
                         anticoagulant therapy. [PDR 1997]
ADVERSE EFFECTS          During clinical trials involving more than
                         31,000 individuals, hepatitis A, inactivated
                         (Havrix), has been well tolerated. The most
                         frequent adverse effect reported by trial
                         volunteers was injection-site soreness.
                         Heasdache was reported by 14% of adults and
                         9% of children. [PDR 1997]
CONTRAINDICATIONS        Contraindicated in people with known
                         hypersensitivity to any component of the
                         vaccine. [PDR 1997]
CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Hepatitis A virus vaccine
                         inactivated is a noninfectious, sterile
                         suspension of a cell-culture adapted,
                          attenuated strain of hepatitis A. After
                          inactivation with formaldehyde and
                          purification, it is absorbed onto an aluminum
                          hydroxide adjuvant. [AHFS Drug Information
                          1997]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: 360, 720, or 1440 EL.U./0.5 mL
                          in single dose vials. (Havrix).[EL.U or ELISA
                          Units. Viral antigen activity is referenced
                          to a standard using an enzyme-linked
                          immunosorbent assay (ELISA)]. [PDR 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Intramuscular injection.
                          [PDR 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store between 2-8 c
                          (36-47 F). Do not freeze. Discard product
                          that has been frozen. Do not dilute to
                          administer. [PDR 1997]
MANUFACTURERS             SmithKline Beecham Pharmaceuticals; 1
                          Franklin Plaza / P.O. Box 7929; Philadelphia,
                          PA 19101
REFERENCES                97472343. Neilsen GA, Bodsworth, Watts N.
                          Response to hepatitis A vaccination in human
                          immunodeficiency virus-infected and -infected
                          homosexual men. J Infect Dis 1997
                          Oct;176(4):1064-7
REFERENCES                97425672. Flehmig B, Staedele H, Xueref C,
                          Vidor E, Zuckerman J, Zuckerman A. Early
                          appearance of neutralizing antibodies after
                          vaccination with an inactivated hepatitis A
                          vaccine. J Infect 1997 Jul;35(1):37-40.
REFERENCES                98034018. CDC sets interim strategy for
                          hepatitis A control [news]. Am J Health Syst
                          Pharm 1997 Mar 15;54(6):625.
REFERENCES                97284068. Goilav C, Zuckerman J, Lafrenz M,
                          Vidor E, Briantais P, Lauwers S, Ratheau C,
                          Benichou G, Zuckerman A. Persistence of
                          antibodies after inactivated hepatitis A
                          vaccines in a comparative study [letter]. J
                          Infect 1997 Mar;34(2):158.
REFERENCES                97237442. Fujiyama S, Odoh K, Tanaka M,
                          Kuramoto I, Tomita K. Evaluation of the
                          timing of the booster injection after a
                          primary vaccination against hepatitis A. J
                          Gastroenterol Hepatol 1997 Feb;12(2):172-5
REFERENCES                97133527. Vidor E, Xueref C, BLondeau C,
                          Bajard A, Francon A, Goudeau A, Peyron F,
                          Brasseur P, Zuckerman A. Analysis of the
                          antibody response in humans with a new
                          inactivated hepatitis A vaccine. Biological
                          1996 Sep;24(3):235-42.
REFERENCES                96189976. Bader TF. Hepatitis A vaccine [See
                          comments in: Am Gastroentero; 1996 Aug;91(8):
                          1670-1].
REFERENCES                97111917. Carlsson U, Brudin L, Eliasson I,
                          Hansson BG. Hepatitis A vaccination by
                          intracutaneous low dose administration: a
                          less expensive alternative. Scand J Infect
                          Dis 1996;28(5):435-8.
REFERENCES                97005143. Iwarson S,. Immunization against
                          hepatitis A--active or passive? Infection
                          1996 Jan0Feb;24(1):2-4.
REFERENCES                MED/95348667. Hess G, Clemens R, Bienzle U,
                           Schonfeld C, Schunck B, Bock HL.
                           Immunogenicity and safety of an inactivated
                           hepatitis A vaccine in anti-HIV positive and
                           negative homosexual men. J Med Virol. 1995
                           May;46(1):40-2.
ENTRY MONTH                199712
LAST REVISION DATE         19980217

19
UNIQUE IDENTIFIER          DRG-0288
NAME OF SUBSTANCE          Topotecan [FDA 284A]
REGISTRY NUMBER            123948-87-8
STANDARD CHEMICAL NAME     (S)-10-[Dimethylamino)methyl]-4ethyl-4,9-dihy-
                           droxy-
                           -1H-pyranol[3',4':6,7]indazolinol[1,2-b]-quin-
                           oline- -3,14(4H,12H)-dione. [USAN 1997]
SYNONYMS                   Hycamptamine [Merck Index 1996]
SYNONYMS                   Hycamtin [PDR 1997]
SYNONYMS                   9
                           [(Dimethylamino)methyl]-10hydroxy-(20S)-campt-
                           othecin [Merck Index 1996]
PROTOCOL ID NUMBERS        FDA 284A
PHARMACOLOGICAL ACTION     MODE OF ACTION: Topoisomerase I relieves
                           torsional strain in DNA by inducing
                           reversible single strand breaks. Topotecan
                           binds to the topoisomerase I-DNA complex and
                           prevents realignment of these single strand
                           breaks. Cytotoxicity of the substance is
                           thought to be due to double strand DNA damage
                           produced during DNA synthesis when
                           replication enzymes interact with the ternary
                           complex formed by topotecan, topoisomerase I
                           and DNA. Mammalian cells cannot efficiently
                           repair these double strand breaks. Topotecan
                           exhibits multiexponential pharmacokinetics
                           with a terminal half-life of 2 to 3 hours.
                           Binding of the drug to plasma proteins is
                           about 35%. Topotecan undergoes reversible,
                           pH-dependent hydrolysis of its lactone
                           moiety. It is the lactone form that is
                           pharmacologically active. At around pH 4 the
                           lactone form is present, whereas the
                           ring-opened form predominates at physiologic
                           pH. About 30% of the dose is excreted in the
                           urine and renal clearance is an important
                           determinant of topotecan elimination. [PDR
                           1997]
DISEASES STUDIED/TREATED   Non-Hodgkin's Lymphoma. [AmFAR Tx Dir
                           1997;8(3)]
CLASSIFICATION CODE        Antineoplastic (adjunct) [Merck Index 1996]
OTHER MAJOR USES           Studied in clinical trials of patients with
                           metastatic ovarian carcinoma. [PDR 1997]
SUBSTANCE INTERACTIONS     Interaction of topotecan with other
                           concomitantly administered medications have
                           not been formally investigated. In vitro
                           studies using marker substrates known to be
                           metabolized by human P450 enzymes of
                           dihydropyrimidine dehydrogenase indicate that
                           the activity of these enzymes were not
                           inhibited by topotecan. Concomitant
                           administration of G-CSF can prolong the
                          duration of neutropenia. Myelosuppression was
                          more severe when topotecan hydrochloride was
                          given in combination with cisplatin. [PDR
                          1997]
ADVERSE EFFECTS           The dose-limiting toxicity of topotecan is
                          leukopenia. White blood cell count decreases
                          with increasing topotecan dose. Bone marrow
                          suppression (primarily neutropenia) is
                          another does-limiting toxicity of topotecan.
                          Neutropenia is not cumulative over time.
                          Grade 4 thrombocytopenia occurred in 26% of
                          patients, while severe anemia occurred in 40%
                          of patients. Incidence of nausea was 77% and
                          vomiting occurred in 58% of patients. Total
                          alopecia occurred in 42% of patients. Grade 1
                          transient elevation in SGOT/AST and SGPT/ALT
                          occurred in 5 % of patients. The drug may
                          cause fetal harm when administered to
                          pregnant women. [PDR 1997]
CONTRAINDICATIONS         Contraindicated in patients who have a
                          history of hypersensitivity to topotecan
                          preparations or any of their ingredients.
                          Should not be used in patients who are
                          pregnant or breast-feeding, or those with
                          severe bone marrow depression. [PDR 1997]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: Topotecan hydrochloride is
                          a semisynthetic derivative of camptothecin
                          and is an anti-tumor drug with topoisomerase
                          I-inhibitory activity. [PDR 1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C23H23N3O5 [Merck Index
                          1996]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 421.5 [PDR 1997]
CHEMICAL/PHYSICAL DATA    ELEMENTAL COMP: C65.55%, H5.50%, N9.97%,
                          O18.98% [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    SOLUBILITY: Hydrochloride is soluble in
                          water. [PDR 1997]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Hycamtin (topotecan
                          hydrochloride) for injections is supplied in
                          4 mg (free base) single-dose vials. [PDR
                          1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Intravenous infusion. [PDR
                          1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store vials protected
                          from light at controlled temperature between
                          20-25 C (68-77 F). [PDR 1997]
MANUFACTURERS             SmithKline Beecham Pharmaceuticals; 1
                          Franklin Plaza / P.O. Box 7929; Philadelphia,
                          PA 19101
REFERENCES                97466819. Gerrits CJ, de Jonge MJ, Schellens
                          JH, Stoter G, Verweij J. Topoisomerase I
                          inhibitors: the relevance of prolonged
                          exposure for present clinical development. Br
                          J Cancer 1997;76(7):952-62.
REFERENCES                97446301. Swisher EM, Mutch DG, Rader JS,
                          Elbendary A, Herzog TJ. Topotecan in
                          platinum- and paclitaxel-resistant ovarian
                          cancer. Gynecol Oncol 1997 Sep;66(3):480-6.
REFERENCES                97377926. Gwyther S, Bolis G, Gore M, ten
                          Bokkel Huinink W, Verweij J, Hudson IR,
                          Despax R, Jimenez-Lacave A. Experience with
                          independent radiological review during a
                      topotecan trial in ovarian cancer. Ann Oncol
                      1997 May;8(5):463-8.
REFERENCES            97388935. Kraut EH, Walker MJ, Staubus A,
                      Gochnour D, Balcerzak SP. Phase II trial of
                      topotecan in malignant melanoma. Cancer
                      Invest 1997;15(4):318-20.
REFERENCES            97291241. Zhang JL, Sharma PL, Li CJ, Dezube
                      BJ, Pardee AB, Crumpacker CS. Topotecan
                      inhibits human immunodeficiency virus type 1
                      infection through a topoisomerase-independent
                      mechansim in a cell line with altered
                      topoisomerase I. Antimicrob Agents Chemother
                      1997 May;41(5):977-81.
REFERENCES            97339531. ten Bokkel Huinink W, Gore M,
                      Carmichael J, Gordon A, Malfetano J, Hudson
                      I, Broom C, Scarabelli C, Davidson N,
                      Spancynski M, et al. Topotecan versus
                      paclitaxel for the treatment of recurrent
                      epithelial ovarian cancer [see comments in: J
                      Clin Oncol 1997 Jun;15(6):2177-80]. J Clin
                      Oncol 1997 Jun;15(6):2183-93.
REFERENCES            97339529. Ozols RF. Treatment of recurrent
                      ovarian cancer: increasing
                      options--recurrent results [editorial;
                      comment in J Clin Oncol 1997
                      Jun;15(6):2183-93]. J Clin Oncol 1997
                      Jun;15(6):2177-80.
REFERENCES            97268177. Masson E, Zamboni WC.
                      Pharmacokinetic optimisation of cancer
                      chemotherapy. Effect on outcomes. Clin
                      Pharmacokinet 1997 Apr;32(4):324-43.
REFERENCES            97310591. Robert F, Soong SJ, Wheeler RH. A
                      phase II study of topotecan in patients with
                      recurrent head and neck cancer.
                      Indentification of an active new agent. Am J
                      Clin Oncol 1997 Jun;20(3):298-302.
REFERENCES            97307007. Ardizzoni A, Hansen H, Dombernowsky
                      P, Gamucci T, Kaplan S, Postmus P, Giaccone
                      G, Schaefer B, Wanders J, Verweij J.
                      Topotecan, a new active drug in the
                      second-line treatment of small-cell lung
                      cancer: a phase II study in patients with
                      refractory and sensitive disease. The
                      European Organization for Research and
                      Treatment of Cancer Early Clinical Studies
                      Group and New Drug Development Office, and
                      the Lung Cancer Cooperative Group. J Clin
                      Oncol 1997 May;15(5):2090-6.
ENTRY MONTH           199710
LAST REVISION DATE    19980313

20
UNIQUE IDENTIFIER     DRG-0287
NAME OF SUBSTANCE     HIV p24/MF59 Vaccine [FDA 095]
PROTOCOL ID NUMBERS   FDA 095
CLASSIFICATION CODE   Vaccine [FDA 095]
MANUFACTURERS         Chiron Vaccines; 4560 Horton Street;
                      Emeryville, CA 94608
ENTRY MONTH           199709
LAST REVISION DATE    19970923
21
UNIQUE IDENTIFIER          DRG-0286
NAME OF SUBSTANCE          Terbinafine Hydrochloride [Merck Index 1996]
REGISTRY NUMBER            78628-80-5
REGISTRY NUMBER            91161-71-6
STANDARD CHEMICAL NAME     (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-
                           -1-naphthalene methanamine monohydrochloride
                           [CHEMID]
SYNONYMS                   Lamasil (free base) [USAN 1997]
SYNONYMS                   Lamosil [CHEMID]
SYNONYMS                   1-Naphthalenemethanamine,
                           N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-,
                           (E)-, monohydrochloride [CHEMID]
SYNONYMS                   lamisil (free base) [Merck Index 1996]
PROTOCOL ID NUMBERS        FDA 282A
SECONDARY SOURCE ID        SF-86-327 [AHFS Drug Information 1997]
PHARMACOLOGICAL ACTION     MODE OF ACTION: The exact mechanism of action
                           of terbinafine hydrochloride's antifungal
                           activity has not been determined. The drug
                           interferes with sterol biosynthesis,
                           inhibiting the enzyme squalene monoxygenase.
                           The resulting accumulation of squalene in the
                           cells, and the decreased amount of sterols,
                           especially ergosterol, are thought to
                           contribute to the antifungal action. The drug
                           may be fungicidal or fungistatic depending on
                           concentration and the species tested. The
                           drug is well absorbed following oral
                           administration. Bioavailability of the drug
                           in tablet form is about 40% as a result of
                           first-pass metabolism. Peak plasma
                           concentrations of 1 microgram/mL appear
                           within 2 hours after a single 250 mg dose. In
                           plasma, terbinafine is 90% bound to plasma
                           proteins. No effect of gender on blood levels
                           of the drug was detected. Prior to,
                           terbinafine is extensively metabolized, but
                           no metabolites have been identified that have
                           antifungal activities similar to terbinafine.
                           Approximately 70% of the administered dose is
                           eliminated in the urine. Systemic absorption
                           of terbinafine hydrochloride applied
                           topically in 1% ointment form to various skin
                           areas was highly variable. Maximum measured
                           plasma concentration of terbinafine was 11.4
                           nanogram/mL. Urinary excretion accounted for
                           up to 9% of the topically applied dose. [AHFS
                           Drug Information 1997; PDR 1997]
DISEASES STUDIED/TREATED   In clinical trial against
                           fluconazole-resistant candidiasis. [AmFAR Tx
                           Dir 1997;8(3)]
CLASSIFICATION CODE        Antifungal [USAN 1997]
OTHER MAJOR USES           Terbinafine hydrochloride is used orally in
                           the treatment of dermatophytic infections of
                           toenails and fingernails (onychomycosis). It
                           is used topically for the treatment of tinea
                           pedis, t. corporis, and t. cruris caused by
                           Epidermophyton floccosum, Trichophyton
                           mentagrophytes or T. rubrum. [AHFS Drug
                           Information 1997]
SUBSTANCE INTERACTIONS     In vitro, terbinafine does not inhibit the
                          metabolism of tolbutamide, ethinylestradiol,
                          ethoxycoumarin, and cyclosporin. In humans,
                          terbinafine does not affect the clearance of
                          antipyrine, digoxin and the antihistamine
                          terfenadine. Terbinafine clearance is
                          increased 100% by rifampin and decreased 33%
                          by cimetidine. Clearance is unaffected by
                          cyclosporine. [PDR 1997]
ADVERSE EFFECTS           Adverse effects reported after oral use of
                          terbinafine hydrochloride encompass GI
                          symptoms (diarrhea, dyspepsia, abdominal
                          pain), liver test abnormalities, rashes,
                          urticaria, pruritus and taste disturbances.
                          [PDR 1997]
CONTRAINDICATIONS         Clearance of orally administered terbinafine
                          may be decreased substantially in patients
                          with renal impairment or in those with
                          preexisting liver disease. The drug is not
                          recommended in patients with such
                          dysfunctions. [AHFS Drug Information 1997]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: Terbinafine hydrochloride
                          is a synthetic allylamine antifungal agent.
                          [AHFS Drug Information 1997]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: Terbinafine
                          hydrochloride is a white to off-white fine
                          crystalline powder. [PDR 1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C21H25N.HCl [Merck Index
                          1996]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 327.90 [PDR 1997]
CHEMICAL/PHYSICAL DATA    MELTING POINT: 195-198 C [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    SOLUBILITY: The hydrochloride is freely
                          soluble in methanol and methylene chloride,
                          soluble in ethanol, and slightly soluble in
                          ether. [PDR 1997]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Tablets containing 250 mg of
                          terbinafine hydrochloride or cream form
                          containing 1% of the drug. [PDR 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Orally in tablets or
                          topically in cream form. [PDR 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store tablets below or
                          at 25 C (77 F) in tight container. Protect
                          from light. Store cream between 5 and 30 C
                          (41 and 86 F). [PDR 1997]
MANUFACTURERS             Novartis; 59 Route 10; East Hanover, NJ
                          07936-1080
REFERENCES                MED/97046213. Sanglard D, Ischer F, Monod M,
                          Bille J. Susceptibilities of Candida albicans
                          multidrug transporter mutants to various
                          antifungal agents and other metabolic
                          inhibitors. Antimicrob Agents Chemother. 1996
                          Oct;40(10):2300-5.
REFERENCES                MED/97058012. Chiritescu MM, Chiritescu ME,
                          Scher RK. Newer systemic antifungal drugs for
                          the treatment of onychomycosis. Clin Podiatr
                          Med Surg. 1996 Oct;13(4):741-58.
REFERENCES                MED/96296376. Nandwani R, Parnell A, Youle M,
                          Lacey CJ, Evans EG, Midgley J, Cartledge J,
                          Hawkins DA. Use of terbinafine in
                          HIV-positive subjects: pilot studies in
                          onychomycosis and oral candidiasis. Br J
                          Dermatol. 1996 Jun;134 Suppl 46:22-4:
                         discussion 39.
REFERENCES               MED/96302588. Aly R, Berger T. Common
                         superficial fungal infections in patients
                         with AIDs. Clin Infect Dis. 1996 May; 22
                         Suppl 2: S128-32.
REFERENCES               MED/96159652. Cirioni O, Giacometti A,
                         Balducci M, Burzacchini F, Scalise G.
                         In-vitro activity of terbinafine, atovaquone
                         and co-trimoxazole against Pneumocystis
                         carinii [letter]. J Antimicrob Chemother.
                         1995 Oct;36(4):740-2.
REFERENCES               MED/94358244. Degreef HJ, DeDoncker PR.
                         Current therapy of dermatophytosis. J Am Acad
                         Dermatol. 1994 Sep; 31 (3 Pt 2):S25-30.
REFERENCES               MED/94085017. Schafer-Korting M.
                         Pharmacokinetic optimisation of oral
                         antifungal therapy. Clin Pharmacokinet. 1993
                         Oct;25(4):329-41.
REFERENCES               MED/90048735. Dupont B. [Treatment of mycoses
                         and new antifungal agents]. Rev Prat. 1989
                         Sep 1;39(19):1688-94.
ENTRY MONTH              199708
LAST REVISION DATE       19980507

22
UNIQUE IDENTIFIER        DRG-0285
NAME OF SUBSTANCE        lamivudine/zidovudine tablet [FDA 280A]
SYNONYMS                 Combivir [FDA 280A]
PROTOCOL ID NUMBERS      FDA 280B
PROTOCOL ID NUMBERS      NIAID ACTG 384
PROTOCOL ID NUMBERS      NIAID ACTG 387
PROTOCOL ID NUMBERS      NIAID ACTG 388
PROTOCOL ID NUMBERS      NIAID ACTG 400
PROTOCOL ID NUMBERS      NIAID ACTG A5025
PROTOCOL ID NUMBERS      FDA 238K
PROTOCOL ID NUMBERS      FDA 280A
PROTOCOL ID NUMBERS      FDA UNAP 11
PROTOCOL ID NUMBERS      FDA UNAP 12
PHARMACOLOGICAL ACTION   MODE OF ACTION: Intracellularly, both
                         lamivudine and zidovudine are phosphorylated
                         to their active 5'-triphosphate metabolites.
                         Combinations of the two drugs (as in
                         combivir) have synergistic antiretroviral
                         activity. In patients receiving monotherapy
                         with lamivudine or combination therapy with
                         lamivudine plus zidovudine, HIV-1 isolates
                         from most patients become resistant to
                         lamivudine in 12 weeks. The combination
                         therapy delayed the emergence of mutations
                         conferring resistance to zidovudine, however
                         HIV-1 strains resistant to both drugs have
                         been isolated from patients after prolonged
                         combination therapy. One combivor tablet is
                         bioequivalent to one EPIVIR (150 mg
                         lamivudine) plus on RETROVIR tablet (300 mg
                         zidovudine) following single dose
                         administration to fasting healthy subjects.
                         The extent of absorption of the two drugs
                         following administration of comivir with food
                         was similar when compared to fasting healthy
                         subjects. Systemic clearance of lamivudine is
                           0.33 L/tvkg and of zidovudine is 1.6 L/tvkg.
                           A meta-analysis of the events in clinical
                           trials was conducted to determine whether
                           treatment with lamivudine/zidovudine was also
                           associated with a clinical benefit. The
                           combination treatment delays the progression
                           of CDC B/C disease compared with control
                           treatments. In another study the safety and
                           efficacy of combination therapy was studied
                           in antiretroviral-naive patients. This showed
                           superior treatment effects compared with
                           monotherapy during the first 24 weeks as
                           documented by changes in CD4+ cell counts,
                           cellular viremia, and viral load measured.
                           Observed changes were sustained to 48 weeks
                           for patients continuing to receive
                           combination therapy at week 24 showed
                           improvements in CD4+ cell count and viral
                           load to week 48. Mutation results suggested
                           that mutations associated with zidovudine
                           resistance may have developed more slowly
                           over the first 24 weeks in patients receiving
                           combination therapy. In contrast, mutations
                           associated with lamivudine resistance
                           appeared to develop rapidly, despite
                           sustained antiviral treatment effect.
                           CONCLUSIONS--The combination of lamivudine
                           and zidovudine results in a potent and
                           sustained antiviral effect in
                           antiretroviral-naive patients that is
                           superior to that observed with zidovudine
                           monotherapy. [GlaxoWellcome Package Insert
                           9/97; AIDS. 1997 Mar 15;11(4):477-83; JAMA
                           1996 Jul 10;276(2)]
DISEASES STUDIED/TREATED   Lamivudine/zidovudine reduces HIV RNA and
                           raises CD4 counts relative to control
                           treatments. FDA approved the combination drug
                           on 9/29/97 for the treatment of HIV
                           infection. [AIDS. 1997 Mar 15;11(4):477-83]
CLASSIFICATION CODE        Antiretroviral [FDA 280A]
SUBSTANCE INTERACTIONS     Co-administration of ganciclovir,
                           interferon-alpha or other bone marrow
                           suppressive or cytotoxic agents may increase
                           the hematologic toxicity of zidovudine.
                           [GlaxoWellcome Package Insert 9/97]
ADVERSE EFFECTS            No statistically significant differences in
                           incidence or severity of clincally manifested
                           or laboratory-measured toxic effects were
                           noted between patients on
                           lamivudine/zidovudine treatment and those
                           being treated with either drug alone. [JAMA
                           1996 Jul 10;276(2)]
CONTRAINDICATIONS          Contraindicated in patients with previously
                           demonstrated clinically significant
                           hypersensitivity to any of the components of
                           the product. Combivir is a fixed dose
                           combination of lamivudine and zidovudine; it
                           should not be co-administered with either
                           drug. Combivir should be used with caution in
                           patients who show bone marrow compromise.
                           Reduction of the dosage of the combination is
                          recommended in patients with impaired renal
                          function. Zidovudine is excreted in breast
                          milk. There is no relevant data available on
                          combivir, but mothers should be instructed
                          not to nurse their infants if they are
                          receiving the combination drug.
                          [GlaxoWellcome Package Insert 9/97]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: Combivir tablets are
                          combination tablets of lamivudine (EPIVIR,
                          3TC) and zidovudine (RETROVIR, AZT) two
                          synthetic nucleoside analogs active against
                          HIV. [GlaxoWellcome Package Insert 9/97]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: Film-coated tablets
                          containing 150 mg of lamivudine and 300 mg of
                          zidovudine plus inactive ingredients. [Glaxo
                          Wellcome 4/96]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Combivir tablets containing 150
                          mg of lamivudine and 300 mg of zidovudine,
                          are white film-coated, modified-capsule
                          shaped tablets, available in 60
                          tablets/bottle. [GlaxoWellcome Package Insert
                          9/97]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: The recommended oral dose
                          of combivir for adults and adolescents (at
                          least 12 years of age) is one tablet
                          (containing 150 mg of lamivudine and 300 mg
                          of zidovudine) twice daily. [GlaxoWellcome
                          Package Insert 9/97]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store between 2 and 30
                          C (36 and 86 F). [GlaxoWellcome Package
                          Insert 9/97]
MANUFACTURERS             Glaxo Wellcome; 5 Moore Drive / PO Box 13398;
                          Research Triangle Park, NC 27709
REFERENCES                MED/97239104. Staszewski S, Hill AM, Bartlett
                          J, Eron JJ, Katlama C, Johnson J, Sawyer W,
                          McDage H. Reductions in HIV-1 disease
                          progression for zidovudine/lamivudine
                          relative to control treatments: a
                          meta-analysis of controlled trials. AIDS.
                          1997 Mar 15;11(4):477-83.
REFERENCES                ICA11/97926878. Stazewski S, Bartlett I, Erin
                          J, Katlama C, Johnson J, Hill AM. Reductions
                          in HIV-1 disease progression for AZT/3TC
                          relative to control treatments: a meta
                          analysis. Int Conf AIDS. 1996 Jul
                          7-12;11(Program Supplement):21 (abstract no.
                          Th.B.948).
REFERENCES                MED/96272951. Katlama C, Ingrand D, Loveday
                          C, Clumeck N, Mallolas J, Stazewski S,
                          Johnson M, Hill AM, Pearce G, McDade H.
                          Safety and efficacy of lamivudine-zidovudine
                          combination therapy in antiretroviral-naive
                          patients. A randomized controlled comparison
                          with zidovudine monotherapy. Lamivudine
                          European HIV Working Group [see comments].
                          JAMA. 1996 Jul 10;276(2):118-25.
REFERENCES                MED/96272950. Staszewski S, Loveday C, Picazo
                          JJ, Dellarnonica P, Skinhoj P, Johnson MA,
                          Danner SA, Harrigan PR, Hill AM, Verity L, et
                          al. Safety and efficacy of
                          lamivudine-zidovudine combination therapy in
                         zidovudine-experienced patients. A randomized
                         controlled comparison with zidovudine
                         monotherapy. Lamivudine European HIV Working
                         Group [see comments]. JAMA. 1996 Jul
                         10;276(2):111-7.
REFERENCES               MED/96314090. Staszewski S, Miller V, Rehmet
                         S, Stark T, De Cree J, De Brabander M,
                         Peeters M, Andries K, Moeremans M, De
                         Raeymakerk M, et al. Virological and
                         immunological analysis of a triple
                         combination pilot study with loviride,
                         lamivudine and zidovudine in HIV-1-infected
                         patients. AIDS. 1996 May;10(5):F1-7.
REFERENCES               MED/96173469. Staszewski S. Zidovudine and
                         lamivudine: results of phase III studies. J
                         Acquir Immune Defic Syndr Hum Retrovirol.
                         1995; 10 Suppl 1:S57.
ENTRY MONTH              199708
LAST REVISION DATE       19980218

23
UNIQUE IDENTIFIER        DRG-0284
NAME OF SUBSTANCE        Fozivudine tidoxil [USAN 1997]
REGISTRY NUMBER          141790-23-0
STANDARD CHEMICAL NAME   (2RS)-2-Decyloxy)-3-(dodecylthio)propyl
                         hydrogen 3'-azido-3'-deoxy-5'-thymidylate.
                         [USAN 1997]
SYNONYMS                 BM 21.1290 [4th Conf Retro and Opportun
                         Infect 1997 Jan 22-26]
PHARMACOLOGICAL ACTION   MODE OF ACTION: Determination of the anti-HIV
                         activity and cytotoxicity of the new
                         anti-AIDS compound BM 21.1290 (Foxivudine
                         tidoxil) in different in vitro cell systems
                         indicated that BM 21.1290, AZT and DDI
                         inhibit virus infection and propagation
                         concentration independantly, as measured by
                         RT activity, p24 core antigen concentration
                         and infectious virus production. The IC50
                         values for BM 21.1290 ranged between 0.02-0.2
                         micromolar (15-150 ng/ml), dependent on the
                         cell type studied, the HIV isolate used and
                         the parameters for anti-HIV activity
                         measured. Anti-HIV activity of BM 21.1290 was
                         most pronounced in infected human T cells and
                         PBLs. On the other side, BM 21.1290 was
                         generally much less toxic to HIV-infected
                         cells compared to AZT or DDI. This finding is
                         in accordance with the lack of bone marrow
                         toxicity of BM 21.1290 in vitro and in vivo.
                         The results indicate that BM 21.1290 has a
                         higher differential selectivity index in
                         vitro in comparison to standard therapeutics.
                         Evaluation of the antiviral activity of BM
                         21.1290 under prophylactic and therapeutic
                         i.p. and p.o. treatment conditions in the
                         retroviral murine Friend-leukemia-virus(FLV)
                         animal model revealed a dose- and
                         time-dependent reduction in virus-induced
                         splenomegaly, reverse transcriptase titers in
                         the plasma and a highly significant increase
                         in survival time. The conjugate was also very
                          well tolerated by different species,
                          including mouse, rat, monkey, and human.
                          Recently, in an one week oral clinical phase
                          Ib study in HIV-1+ humans, BM 21.1290 in a
                          dose dependent manner reduced the plasma
                          virus load. After having successfully passed
                          pharmacological/toxicological and clinical
                          phase I development, BM 21.1290 has entered
                          phase II efficacy studies in ARC/AIDS
                          patients in January 1996. [Int Conf AIDS 1996
                          Jul 7-12;11(1):18; 4th Conf Retro and
                          Opportun Infect 1997 Jan 22-26]
CLASSIFICATION CODE       Antiretroviral [FDA 277A]
ADVERSE EFFECTS           Very well tolerated by different species,
                          including mouse, rat, monkey, and human.
                          [USAN 1997; 4th Conf Retro and Opportun
                          Infect 1997 Jan 22-26]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: Thioetherlipid nucleotide
                          conjugate potent with anti-HIV activity in
                          different in vitro systems. [4th Conf Retro
                          and Opportun Infect 1997 Jan 22-26]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C35H64N5O8PS [USAN 1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 745.97 [USAN 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral. [USAN 1997; 4th Conf
                          Retro and Opportun Infect 1997 Jan 22-26]
MANUFACTURERS             Boehringer Mannheim Corporation; 101 Orchard
                          Ridge Drive; Gaithersburg, MD 20878
REFERENCES                AIDS/97926567. Herrmann DB, Opitz HG, Kucera
                          LS. Anti-AIDS drug in vivo. 4th Conf Retro
                          and Opportun Infect. 1997 Jan 22-26;:92
                          (abstract no.149).
REFERENCES                ICA11/96921127. Herrmann DB, Kucera LS, Zilch
                          H, Mertens A, Opitz HG. BM 21.1290: in vitro
                          evaluation of a potential new anti-AIDS
                          compound. Int Conf AIDS. 1996 Jul
                          7-12;11(1):64 (abstract no. Mo.A.1057).
ENTRY MONTH               199708
LAST REVISION DATE        19980507

24
UNIQUE IDENTIFIER         DRG-0283
NAME OF SUBSTANCE         Rifapentine [USAN 1997]
REGISTRY NUMBER           61379-65-5
SYNONYMS                  MDL-473 [Merck Index 1996]
SYNONYMS                  DL-473 [Merck Index 1996]
SYNONYMS                  R-773 [Merck Index 1996]
SYNONYMS                  3-[N-(4-Cyclopentyl-1-piperazinyl)
                          formimidoyl) rifamycin] [USAN 1997]
PROTOCOL ID NUMBERS       FDA 275A
PHARMACOLOGICAL ACTION    MODE OF ACTION: The dose-response activity of
                          rifabutin and the comparative activities of
                          rifabutin and rifapentine were evaluated in
                          the beige mouse model of disseminated
                          Mycobacterium avium complex (MAC) infection.
                          Despite favorable in vitro susceptibility
                          results, rifabutin and rifapentine had
                          activities in the spleens against only two of
                          the five MAC isolates. For these two MAC
                          isolates, rifabutin was more active than
                          rifapentine. Rifapentine may be a useful drug
                          for the treatment of toxoplasmosis in
                           immunocopromised individuals. Rifapentine has
                           a long half-life, and has the potential to
                           lengthen intermittent treatment for
                           tuberculosis. It is believed that this long
                           half-life may mean it can maintain a higher
                           blood level and thereby maintain better
                           effectiveness than rifabutin against
                           fast-growing MAC organisms. [USAN 1997; AIDS
                           Alert. 1995 Nov;10(11); Antimicrob Agents
                           Chemother 1996 Jun;40(6)]
DISEASES STUDIED/TREATED   Prophylactic against Mycobacterium Avium
                           Complex in AIDS patients with CD4 count less
                           than or equal to 75/cubic mm. [USP DI 1997]
CLASSIFICATION CODE        Antibacterial (tuberculostatic) [USAN 1997]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C47H64N4O12 [Merck Index
                           1996]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 877.04 [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     MELTING POINT: 179-180 C [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     ELEMENTAL COMP: C64.37%, H7.36%, N6.39%,
                           O21.89%. [Merck Index 1996]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [USAN 1997]
MANUFACTURERS              Hoechst - Marion - Roussel Incorporated; PO
                           Box 9627; Kansas City, MO 64134-0627
REFERENCES                 97070558. Moghazeh SL, Pan X, Arain T, Stover
                           CK, Musser JM, Kreiswirth BN. Comparative
                           antimycobacterial activities of rifampin,
                           rifapentine, and KRM-1648 against a
                           collection of rifampin-resistant
                           Mycobacterium tuberculosis isolates with
                           known rpoB mutations. Antimicrob Agents
                           Chemother. 1996 Nov;40(11):2655-7.
REFERENCES                 97127285. Mitchison DA. Modern methods for
                           assessing the drugs used in the chemotherapy
                           of mycobacterial disease. Soc Appl Bacteriol
                           Symp Ser. 1996;25:72S-80S.
REFERENCES                 96338344. Araujo FG, Khan AA, Remington JS.
                           Rifapentine is active in vitro and in vivo
                           against Toxoplasma gondii. Antimicrob Agents
                           Chemother. 1996 Jun;40(6):1335-7.
REFERENCES                 97299003. Kenny MT, Reynolds DL, Brackman MA,
                           Dulworth JK. Comparison of biological and
                           chemical assays for the quantitation of
                           rifapentine in human plasma. Diagn Microbiol
                           Infect Dis. 1997 Apr;27(4):107-11.
REFERENCES                 96163839. Grassi C, Peona V. New drugs for
                           tuberculosis. Eur Respir J Suppl. 1995
                           Sep;20:714s-718s.
REFERENCES                 AIDS/96700982. Researchers find new drugs to
                           fight MAC. AIDS Alert. 1995 Nov;10(11):138-9.
REFERENCES                 MED/95040297. Chapuis L, Ji B, Truffot-Pernot
                           C, O'Brien RJ, Raviglione MC, Grosset JH.
                           Preventive therapy of tuberculosis with
                           rifapentine in immunocompetent and nude mice.
                           Am J Respir Crit Care Med. 1994 Nov;150(5 Pt
                           1):1355-62.
REFERENCES                 94249992. Klemens SP, Grossi MA, Cynamon MH.
                           Comparative in vivo activities of rifabutin
                           and rifapentine against Mycobacterium avium
                           complex. Antimicrob Agents Chemother. 1994
                           Feb;38(2):234-7.
REFERENCES                 MED/92305504. Fattorini L, Hu CQ, Jin SH,
                         Santoro C, Tsang AY, Mascellino MT, Mandler
                         F, Orefici G. Activity of antimicr obial
                         agents against Mycobacterium
                         avium-intracellulare complex (MAC) strains
                         isolated in Italy from AIDS-patients. Int J
                         Med Microbiol Virol Parasitol Infect Dis.
                         1992 Apr;276(4):512-20.
REFERENCES               MED/92027610. Perronne C, Gikas A,
                         Truffot-Pernot C, Grosset J, Vilde JL,
                         Pocidalo JJ. Activities of sparfloxacin,
                         azithromycin, temafloxacin, and rifapentine
                         compared with that of clarithromycin against
                         multiplication of Mycobacterium avium complex
                         within human macorphages. Antimicrob Agents
                         Chemother. 1991 Jul;35(7):1356-9.
ENTRY MONTH              199708
LAST REVISION DATE       19980507

25
UNIQUE IDENTIFIER        DRG-0282
NAME OF SUBSTANCE        L-743,872 [FDA 267A]
SYNONYMS                 Pneumocandin [Antimicrob Agents Chemother.
                         1997 Feb;41(2)]
PHARMACOLOGICAL ACTION   MODE OF ACTION: Extensive in vitro
                         susceptibility testing with L-743,872 against
                         approximately 200 clinical isolates of
                         Candida, Cryptococcus neoformans and
                         Aspergillus was conducted to determine
                         minimum inhibitory and fungicidal
                         concentrations. Susceptibility testing using
                         panels of antifungal-resistant species of
                         Candida and C. neoformans isolates showed
                         L-743,872 had MFC values comparable to those
                         against susceptible isolates. Serum studies
                         using between 0% to 50% pooled human or mouse
                         sera established that fungal susceptibility
                         with L-743,873 was not significantly
                         influenced by the presence of human or mouse
                         sera. The intravenous pharmacokinetics of
                         L-743,872 were investigated in mice, rats,
                         rhesus monkeys and chimpanzees. In contrast
                         to previous pneumocandins, this compound
                         behaves consitently across species. Serum
                         protein binding of L-743,872 was determined
                         to be 97% in mouse and human serum. The
                         compound exhibits a high affinity for human
                         serum albumin and, additionally, at least two
                         lipid components. Some measure of
                         accumulation is predicted for all tissues.
                         Dosage scaling for man was simulated by using
                         a graphical comparison of circulatory levels
                         in the chimpanzee vs. both rodent model
                         species over a 24 hour treatment cycle. A
                         planned, multicenter clinical study will
                         evaluate the potency of different doses of
                         L-743,872 compared to amphotericin B in
                         people with oral and eosphageal candidiasis
                         who have failed on fluconazole therapy (200
                         mg daily for 7 days), and the relative safety
                         and efficacy of both. [Prog Abst Intersci
                         Conf Antimicrob Agents Chemother. '96 Sep;
                           Prog Abst Intersci Conf Antimicrob Agents
                           Chemother. '96 Sep; Bull. Experiment.
                           Treatment AIDS (BETA); June 1997]
DISEASES STUDIED/TREATED   In combination with other antifungal agents,
                           being test against Cryptococcus neoformans
                           infections. [Antimicrob Agents Chemother.
                           1997 Feb;41(2)]
CLASSIFICATION CODE        Antifungal [FDA 267A]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: L-743872 is a water soluble
                           cyclic lipopeptide 1,3 beta-D-glucan
                           synthesis inibitor with proven efficacy as a
                           parenteral agent in animal models of
                           Pneumocystis carinii pneumonia and of
                           disseminated candidiasis and aspergillosis.
                           [Prog Abst Intersci Conf Antimicrob Agents
                           Chemother. '96 Sep]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Parenteral[Prog Abst
                           Intersci Conf Antimicrob Agents Chemother.
                           '96 Sep]
MANUFACTURERS              Merck Research Laboratories; 126 East Lincoln
                           Avenue; Rahway, NJ 07065
REFERENCES                 AIDS/98927664. Hajdu R, Pelak B, Sundelof J,
                           Thompson R, Rosen H, Kropp H.
                           Pharmacokinetics of L-743,872 in the mouse,
                           rat, rhesus and chimpanzee. Program Abstr
                           Intersci Conf Antimicrob Agents Chemother.
                           1996 Sep 15-18;:107 (abstract no. F44).
REFERENCES                 AIDS/98927663. Najvar L, Graybill J, Montalbo
                           E, Barchiesi F, Luther M. Evaluation of
                           L-743,872 (872) in the treatment of murine
                           histoplasmosis. Program Abstr Intersci Conf
                           Antimicrob Agents Chemother. 1996 Sep
                           15-18;:107 (abstract no. F43).
REFERENCES                 AIDS/98927662. Powles MA, Anderson J,
                           Liberator P, Schmatz DM. Efficacy of
                           semisynthetic pneumocandin analog L-743,872
                           against Pneumocystis carinii in murine
                           models. Program Abstr Intersci Conf
                           Antimicrob Agents Chemother. 1996 Sep
                           15-18;:107 (abstract no. F42).
REFERENCES                 AIDS/98927660. Flattery AM, Abruzzo GK, Smith
                           JG, Gill CJ, Rosen H, Kropp H, Bartizal K.
                           Activity of pneumocandin L-743872 in a CD4+
                           T-cell deficient mouse model or oropharyngeal
                           and gastrointestinal Candidiasis. Program
                           Abstr Intersci Conf Antimicrob Agents
                           Chemother. 1996 Sept 15-18;:106 (abstract no.
                           F40).
REFERENCES                 AIDS/98927659. Najvar L, Fothergill A, Luther
                           M, Graybill J. Efficacy of L-743,872 (872) in
                           murine disseminated Candidiasis. Program
                           Abstr Intersci Conf Antimicrob Agents
                           Chemother. 1996 Sep 15-18;:106 (abstract no.
                           F38).
REFERENCES                 AIDS/98927657. Franzot SP, Casadevall A. In
                           vitro synergy of pneumocandin L-743,872 with
                           fluconazole and amphotericin B against
                           Cryptococcus neoformans. Program Abstr
                           Intersci Conf Antimicrob Agents Chemother.
                           1996 Sep 15-18;:106 (abstract no. F36).
REFERENCES                 AIDS/98927651. Fothergill AW, Sutton DA,
                         Rinaldi MG, Antifungal susceptibility testing
                         of Merck L-743,872 against a broad range of
                         fungi. Program Abstr Intersci Conf Antimicrob
                         Agents Chemother. 1996 Sep 15-18;:105.
                         (abstract no. F29).
REFERENCES               AIDS/98927649. Bouffard FA. Dropinski JF,
                         Balkovec JM, Black RM, Hammond ML, Nollstadt
                         KH, Dreikorn S. L-743,872, a novel antifungal
                         lipopeptide: synthesis and structure-activity
                         relationships of new aza-substituted
                         pneumocandins. Program Abstr Intersci Conf
                         Antimicrob Agents Chemother. 1996 Sep
                         15-18;:104 (abstract no. F27).
REFERENCES               AIDS/98927654. Bartizal K, Flattery A, Lynch
                         L, Pacholok C, Gill CJ, Rosen H, Scott P,
                         Kropp H. In vitro preclinical evaluation
                         studies with pneumocandin antifungal
                         L-743872. Program Abstr Intersci Conf
                         Antimicrob Agents Chemother. 1996 Sep
                         15-18;:105 (abstract no. F32).
REFERENCES               MED/97173282. Franzot SP, Casadevall A.
                         Pneumocandin L-743,872 enhances the
                         activities of amphotericin B and fluconazole
                         against Cryptococcus neoformans in vitro.
                         Antimicrob Agents Chemother. 1997
                         Feb;41(2):331-6.
ENTRY MONTH              199708
LAST REVISION DATE       19990311

26
UNIQUE IDENTIFIER        DRG-0281
NAME OF SUBSTANCE        ALRT 1057 [FDA 271A]
REGISTRY NUMBER          5300-03-8
STANDARD CHEMICAL NAME   9-cis-Retinoic acid [Int Conf AIDS 1996 Jul
                         7-12;11(1):18]
SYNONYMS                 9-cis-Retinoic acid [Int Conf AIDS 1996 Jul
                         7-12;11(1):18]
PROTOCOL ID NUMBERS      FDA 271A
PROTOCOL ID NUMBERS      FDA 272A
PHARMACOLOGICAL ACTION   MODE OF ACTION: 9-cis-Retinoic acid binds to
                         different retinoid receptors than the
                         all-trans retinoic acid. Sixty-three patients
                         with biopsy-proven, multiple KS (Kapsoi's
                         Sarcoma) lesions applied 0.05% or 0.1% ALRT
                         1057 gel to selected index lesions 1-4 times
                         daily. Selected untreated control lesions
                         could be converted to treatment after 8 to 16
                         weeks. Response was evaluated by measuring
                         area and elevation and supported by
                         standardized serial photography. Partial
                         response was defined using ACTG criteria
                         applied to topical therapy as a complete
                         flattening greater than or equal to 50% of
                         raised lesions or greater than or equal 50%
                         decrease in the sum of area. Topical ALRT
                         1057 was well-tolerated with minimal
                         perilesional irritation and no systemic
                         absorption. Responses were seen in patients
                         with a wide range of CD4 counts, including 4
                         with counts below 50/mm3. Responses were
                         sustained with a median patient follow-up of
                           16 weeks (maximum 42 weeks). Only 4 of 28
                           lesions relapsed after a median of 12 weeks.
                           ALRT 1057 gel appears to be a safe and
                           well-tolerated new therapy for KS which is
                           capable of producing partial to complete
                           resolution of lesions in patients with low
                           CD4 counts. This the first topical therapy
                           evaluated for KS, which lends itself to
                           patient-controlled, conservative management
                           in the early phases of disease. [AmFAR Tx Dir
                           1997;8(3); Int Conf AIDS 1996 Jul
                           7-12;11(1):18]
DISEASES STUDIED/TREATED   Therapy for Kaposi's Sarcoma. [Int Conf AIDS
                           1996 Jul 7-12;11(1):18]
CLASSIFICATION CODE        Retinoid [FDA 271A]
SUBSTANCE INTERACTIONS     9-cis-Retinoic acid and beta-human chorionic
                           gonadotropin can induce remission of KS
                           lesions. [J Int Assoc Physicians AIDS Care.
                           1995 Jun;1(5)]
ADVERSE EFFECTS            Topical ALRT 1057 was well-tolerated with
                           minimal perilesional irritation and no
                           systemic absorption. [Int Conf AIDS 1996 Jul
                           7-12;11(1):18]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 0.05% and 0.1% gel. [Int Conf
                           AIDS 1996 Jul 7-12;11(1):18]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Topical. [Int Conf AIDS
                           1996 Jul 7-12;11(1):18]
MANUFACTURERS              Ligand Pharmaceuticals; 9393 Towne Center
                           Drive; San Diego, CA 92121
REFERENCES                 ICA11/96920939. Duvic M, Friedman-Kien AE,
                           Galpin J, Miles SA, Looney DJ, Myskowski PL,
                           Gill G, Truglia J, Yocum R. Phase I-II
                           clinical trial supports safety and efficacy
                           of ALRT 1057 topical retinoid gel for
                           Kaposi's sarcoma. Int Conf AIDS. 1996 Jul
                           7-12;11(1):27 (abstract no Mo.B.432).
REFERENCES                 AIDS/96701082. Vitamin A type drug for
                           Kaposi's Sarcoma. Treat Rev. 1995 Nov;(no
                           20):5.
REFERENCES                 AIDS/96700645. Mascolini M. Oncologists scout
                           new directions for KS and lymphoma therapies.
                           J Int Assoc Physicians AIDS Care. 1995
                           Jun;1(5):10-4.
ENTRY MONTH                199708
LAST REVISION DATE         19980515

27
UNIQUE IDENTIFIER          DRG-0280
NAME OF SUBSTANCE          Salmonella Typhi CVD 908-HIV-1 LAI gp 120
                           (VVG 203) [NIAID VEU 028]
PROTOCOL ID NUMBERS        NIAID VEU 028
PHARMACOLOGICAL ACTION     HIV is known to enter the host at parenteral
                           and mucosal sites and consequently an
                           effective vaccine should stimulate immunity
                           at both routes of entry. One approach toward
                           stimulating HIV-specific mucosal and systemic
                           immunity is the use of candidate live oral
                           Salmonella typhi vector vaccine, strain CVD
                           908, which has been shown to stimulate
                           mucosal and systemic immunity in volunteers.
                           Using recombinant DNA techniques, an
                           expression cassette which comprises the 1pp
                           promoter (P1pp) and sequences encoding
                           recombinant gp120 (rgp120) was constructed.
                           When the P1pp-rgp120 expression cassette is
                           integrated into the chromosome of CVD 908 in
                           the delta aroC allele, high levels of
                           recombinant gp120 expression are observed. It
                           is likely that effective immunity against HIV
                           in humans will require immunization with
                           multiple HIV antigens. Hence, a second
                           expression cassette, encoding two additional
                           HIV antigens with vaccine potential, p24 (a
                           HIV-1 gap gene product) and Nef (a putative
                           regulator of HIV-1 gene expression) has been
                           constructed. It is planned to integrate the
                           p24-Nef-encoding expression cassette into the
                           aroD locus in the chromosome of CVD 908 delta
                           aroC::rgp120 in a stable manner to produce a
                           CVD 908-HIV vector vaccine that expresses
                           multiple HIV antigens. High level expression
                           of rgp120 in Salmonella vectors is necessary
                           to stimulate a gp120-specific immune response
                           in mice. Also, Salmonella ::rgp120 stimulates
                           a gp120-specific Th1 response in mice. This
                           is the first report to describe the
                           construction of a Salmonella::rgp120 vector
                           vaccine that is immunogenic in mice. [Dev
                           Biol Stand. 1994;82; Vaccine 1995, Dec;
                           13(17)]
DISEASES STUDIED/TREATED   Anti-HIV vaccine[Vaccine 1995, Dec; 13(17)]
CLASSIFICATION CODE        Vaccine [NIAID VEU 028]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Using recombinant DNA
                           techniques, an expression casstte, which
                           comprises the 1pp promoter (P1pp) and
                           sequences encoding recombinant gp120 (rgp120)
                           was constructed. The preparation uses live
                           oral Salmonella typhi vector vaccine, strain
                           CVD 908, which has been shown to stimulate
                           mucosal and systemic immunity in volunteers.
                           [Dev Biol Stand. 1994;82]
MANUFACTURERS              Chiron Vaccines; 5560 Horton Street;
                           Emeryville, CA 94608
REFERENCES                 MED/97130053 Sizemore DR Elsinghorst EA Eck
                           LC Branstrom AA Hoover DL Warren RL Rubin FA
                           Interaction of Salmonella typhi strains with
                           cultureed human monocyte-derived macrophages.
                           Infect Immun. 1997 Jan; 65 (1) : 309-12.
REFERENCES                 MED/96363710 Fouts TR Tuskan RG Chada S Hone
                           DM Lewis GK Construction and immunogenicity
                           of Salmonella typhimurium vaccine vectors
                           that express HIV-1 gp120. Vaccine. 1995 Dec;
                           13(17): 1697-705.
REFERENCES                 Med/96065464 Fouts TR Lewis GK Hone DM
                           Construction and characterization of a
                           Salmonella typhi-based human immunodeficiency
                           virus type 1 vector vaccine. Vaccine. 1995
                           Apr; 13(6): 561-9.
REFERENCES                 MED/95046928 Hone DM Lewis GK Beier M Harris
                           A McDaniels T Fouts TR Expression of human
                           immunodeficiency virus antigens in an
                           attenuated Salmonella typhi vector vaccine.
REFERENCES           Dev Biol Stand. 1994; 82: 159-62.
                     ASM93/93291832 Branstrom A Benson J Aggarwal
                     A Franchini G Sadoff J Warren R Expression of
                     HIV-1 genes placed under the control of the
                     lac promoter in pUC18 tested in various
                     potential bacterial carrier strains. Abstr
                     Gen Meet Am Soc Microbiol. 1993; 93: 437
                     (abstract no. T-30).
REFERENCES           MED/88073375 Tagliabue A Nencioni L Romano M
                     Villa L De Magistris MT Boraschi D
                     Antibacterial Activity of lymphocytes armed
                     with IgA. Adv exp Med Biol. 1987; 216A:511-6.
REFERENCES           MED/85263719 Kleinerman ES Ceccorulli LM
                     Zwelling La Twilley T Herberman RB Jacob J
                     Gelmann EP Activation of monocyte-mediated
                     tuumoricidal activity in patients with
                     acquired immunodeficiency syndrome. J Clin
                     Oncol. 1985 Jul; 3(7) : 1005-12.
REFERENCES           AIDS/97927146. Hone DM, Pascual DW, Wu S,
                     Lewis GK. Induction of mucosal and systemic
                     responses against HIV-1 gp120 in mice after
                     oral immunization with a single dose of a
                     Salmonella-HIV vector. Conf Adv AIDS Vaccine
                     Dev. 1997 May 4-7;:182 (Poster 77).
REFERENCES           ASM95/96171221. Powell RJ, Wu S, Pascual Dw,
                     Van Cott J, McGhee J, Lewis GK, Hone DM. Oral
                     immunization of mice with a live attenuated
                     Salmonella vector expressing recombinant
                     gp120 of HIV-1 on the surface of the vector,
                     induces mucosal and systemic immunity against
                     gp120. Abstr Gen Meet Am Soc Microbiol.
                     1995;95:294 (abstract no. E-79).
ENTRY MONTH          199708
LAST REVISION DATE   19980512

28
UNIQUE IDENTIFIER    DRG-0279
NAME OF SUBSTANCE    Erythromycin [USAN 1997]
REGISTRY NUMBER      114-07-8
SYNONYMS             Emgel [USAN 1997]
SYNONYMS             Erythromycin A [Merck Index 1996]
SYNONYMS             Abomacetin [Merck Index 1996]
SYNONYMS             Ak-Mycin [Merck Index 1996]
SYNONYMS             Aknin [Merck Index 1996]
SYNONYMS             Eritrocina [Merck Index 1996]
SYNONYMS             Erythromast [Merck Index 1996]
SYNONYMS             Erythromid [Merck Index 1996]
SYNONYMS             Erycen [Merck Index 1996]
SYNONYMS             Erycinum [Merck Index 1996]
SYNONYMS             E-Mycin [USAN 1997]
SYNONYMS             ERYC [USAN 1997]
SYNONYMS             Erycette [USAN 1997]
SYNONYMS             EryDerm [USAN 1997]
SYNONYMS             Ergel [USAN 1997]
SYNONYMS             Erymax [USAN 1997]
SYNONYMS             Erythro [USAN 1997]
SYNONYMS             Erthrogran [USAN 1997]
SYNONYMS             Erythroguent [USAN 1997]
SYNONYMS             Ilotycin [USAN 1997]
SYNONYMS             Inderm [Merck Index 1996]
SYNONYMS             Retcin [Merck Index 1996]
SYNONYMS                   Staticin [Merck Index 1996]
SYNONYMS                   Stiemycin [Merck Index 1996]
SYNONYMS                   Torlamicina [Merck Index 1996]
PROTOCOL ID NUMBERS        FDA 200G
SECONDARY SOURCE ID        NCI-C55674, NSC 55929 [CHEMID]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Erythromycin is usually
                           bacteriostatic; however, in high
                           concentrations or against highly susceptible
                           organisms it may be bacteriocidal. It
                           inhibits protein synthesis in susceptible
                           organisms by binding to 50S ribosomal
                           subunits, thereby inhibiting translocation of
                           aminoacyl transfer-RNA and inhibiting
                           polypeptide synthesis. The site of action of
                           erythromycin is the same as that of other
                           antibiotics such as oleandomycin, clindamycin
                           or lincomycin. Erythromycin exerts its
                           effects only against multiplying organisms.
                           It penetrates the cell wall of gram-positive
                           bacteria more readily than that of
                           gram-negative bacteria. It is most active
                           against gram-positive cocci and bacilli, but
                           it also has some actibity against
                           gram-negative organisms such as Haemophilus
                           influenza. It is also active against
                           Chlamydia and treponema. Orally administered
                           erythromycin is readily absorbed. It diffuses
                           readily into body fluids. Only low
                           concentration are normally observed in the
                           spinal fluid; passage of the drug across the
                           blood-brain barrier increases in meningitis.
                           The drug is concentrated in the liver and
                           excreted in bile. Less than 5% is excreted in
                           active form in the urine. [AHFS Drug
                           Information 1997; PDR 1997]
DISEASES STUDIED/TREATED   Erythromycin is used to treat patients with
                           severe anemia that is ascribed to HIV
                           infection or to AZT treatment. [Ann Internal
                           Medicine 1992]
CLASSIFICATION CODE        Antibiotic [FDA 200G]
OTHER MAJOR USES           Erythromycin is used against infections by
                           (among others): streptococcus pyogenes,
                           Alpha-hemolytic syreptococci, Staphylococcus
                           aureus, Streptococcus pneumoniae, Mycoplasma
                           pneumoniae, Hemophilus influenza, Chlamdia
                           trachomatis, Treponema pallidum,
                           Corynebacterium diphtheriae, Entamoeba
                           histolytica, Listeria monocytogenes,
                           Neisseria gonorrhoeae, Bordetella pertussis,
                           organism causing Legionnaire's Disease. [PDR
                           1997]
SUBSTANCE INTERACTIONS     Concomitant use with high doses of
                           theophylline may increase theophylline
                           toxicity. Use of erythromycin with digoxin
                           may cause high serum digoxin levels.
                           Erythromycin may decrease clearance of
                           triazolam and increase the pharmacological
                           effects of the latter. Use of erythromycin
                           with drugs metabolized by the cytochrome P450
                           system may be associated with elevations in
                           serum erythromycin with carbamazepine,
                          cyclosporine, hexobarbital and phenytoin.
                          Cases of rhabdomyolysis have been reported in
                          seriously ill patients receiving erythromycin
                          and lovastatin. [PDR 1997]
ADVERSE EFFECTS           The most frequent side effects of oral
                          erythromycin are gastrointestinal; they are
                          dose-related. Symptoms of hepatic dysfunction
                          and/or abnormal liver function tests may
                          occur. There have been isolated reports of:
                          transient CNS side effects, cardiac
                          arrhythmias and other cardiovasuclar
                          symptoms, reversible hearing loss, and
                          allergic reactions. [PDR 1997]
CONTRAINDICATIONS         Contraindicated in patients with know
                          hypersensitivities to it. Use of erythromycin
                          may result in overgrowth of nonsusceptible
                          organisms including fungi. [AHFS Drug
                          Information 1997]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: Erythromycin is a macrolide
                          antibiotic obtained from cultures of
                          streptomyces erythraeus. [AHFS Drug
                          Information 1997; Ann Internal Medicine 1992]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: White or slightly
                          yellow, odorless, bitter crystalline powder.
                          [AHFS Drug Information 1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C37H67NO13 [Merck Index
                          1996]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 733.94 [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    MELTING POINT: 135-140 C [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    ELEMENTAL COMP: C60.55%, H9.20%, N1.91%,
                          O28.34%. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    SOLUBILITY: Solubility of approx. 1 mg/mL in
                          water; soluble in alchohol. [AHFS Drug
                          Information 1997]
CHEMICAL/PHYSICAL DATA    DRUG PHYSICAL COMMENT: pKa: 8.8. [Merck Index
                          1997]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: 250 mg capsules, 250 mg, 333mg
                          and 500 mg delayed release tablets, 2%
                          ophthalmic ointment, 2% topical gel, 2%
                          ointment, 1.5% and 2% solution. [AHFS Drug
                          Information 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Orally, topically. [AHFS
                          Drug Information 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Should be stored at
                          15-30 C (59-86 F). [AHFS Drug Information
                          1997]
MANUFACTURERS             Abbott Laboratories; One Abbott Park Road;
                          Abbott Park, IL 60064
REFERENCES                MED/97318713. Young H, Moyes A, McMillian A.
                          Azithromycin and erythromycin resistant
                          Neisseria gonorrhoeae following treatment
                          with azithromycin. Int J STD AIDS. 1997.
                          May;8(50:299-302.
REFERENCES                MED/97054988. Yau TH, Butrus SI. Presumed
                          bilateral herpes zoster ophthalmicus in an
                          AIDS patient: a case report. Cornea. 1996
                          Nov;15(6):633-4.
REFERENCES                MED/97069023. Nakagawa M, Nakahara K,
                          Maruyama Y, Kawabata M, Higuchi I, Kubota H,
                          Izumo S, Arimura K, Osame M. Therapeutic
                          trials in 200 patients with HTLV-I-associated
                         myelopathy/tropical spastic paraparesis. J
                         Neurovirol. 1996 Oct;2(5):345-55.
REFERENCES               MED/97008636. Chang AD, Drachenberg CI, James
                         SP. Bacillary angiomatosis angiomatosis
                         associated with extensive esophageal
                         polyposis: a new mucocutaneous manifestation
                         of acquired immunodeficiency disease (AIDS).
                         Am J Gastroenterol. 1996 Oct;91(10):2220-3.
REFERENCES               MED/97081329. Schmidt HU, Kaliebe T,
                         Poppinger J, Buhler C, Sander A. Isolation of
                         Bartonella quintana from an HIV-positive
                         patient with bacillary angiomatosis. Eur J
                         Clin Microbiol Infect Dis. 1996
                         Sep;15(9):736-41.
REFERENCES               MED/97050104. Ross JD, Crean A, McMillian A.
                         Efficacy of anti-chlamydial therapy with
                         oxytetracycline and erythromycin. Int J STD
                         AIDS. 1996 Aug-Sep;7(5):373-4.
REFERENCES               MED/96260596. Barrio J, Lecona M, Hernanz JM,
                         Sanchez M, Gurbindo MD, Lazaro P, Barrio JL.
                         Rosacea-like demodicosis in an HIV-positive
                         child. Dermatology. 1996;192(2):143-5.
REFERENCES               MED/96245961. Eden CG, Marker A, Pryor JP.
                         Human immunodeficiency virus-related
                         bacillary angiomatosis of the penis. Br J
                         Urol. 1996 Feb;77(2):323-4.
REFERENCES               MED/97059723. Kimani J, Bwayo JJ, Anzala AO,
                         MacLean I, Mwatha A, Choudri SH, Plummer FA,
                         Ronald AR. Low dose erythromycin regimen for
                         the treatment of chancroid. East Afr Med J.
                         1995 Oct;72(10):645-8.
REFERENCES               MED/96292823. Ramirez Ramirez CR, Saavedra S,
                         Ramirez Ronda c. Bacillary angiomatiosis:
                         microbiology, histopathology, clinical
                         presentation, diagnosis and management. Bol
                         Asoc Med P R. 1995 Jul-Sep;87(7-9):140-6.
ENTRY MONTH              199707
LAST REVISION DATE       19971126

29
UNIQUE IDENTIFIER        DRG-0278
NAME OF SUBSTANCE        Bupivacaine [Merck Index 1996]
REGISTRY NUMBER          2180-92-9
STANDARD CHEMICAL NAME   2-Piperidinecarboxamide,
                         1-butyl-N-(2,6-dimethylphenyl)- [CHEMID]
SYNONYMS                 Anekain [Merck Index 1996]
SYNONYMS                 Marcaine (Hydrochloride Monohydrate) [Merck
                         Index 1996]
SYNONYMS                 Carbostesin (Hydrochloride Monohydrate)
                         [Merck Index 1996]
SYNONYMS                 LAC-43 (Hydrochloride Monohydrate) [Merck
                         Index 1996]
SYNONYMS                 Sensorcaine (Hydrochloride Monohydrate) [USAN
                         1997]
PROTOCOL ID NUMBERS      NIAID VEU 031
SECONDARY SOURCE ID      AH-2250 [Merck Index 1996]
PHARMACOLOGICAL ACTION   MODE OF ACTION: Local anesthetics like
                         bupivacaine hydrochloride block the
                         generation and the conduction of nerve
                         impulses. Clinically the order of the loss of
                         nerve function is as follows: (1) pain, (2)
                         temperature, (3) touch, (4) proprioception,
                         and (5) skeletal muscle tone. Systemic
                         absorption produces effects on the
                         cardiovascular system. Following systemic
                         absorption, local anesthetics can produce CNS
                         stimulation, depression or both. The rate of
                         systemic absorption depends on total dose,
                         concentration of the drug, route of
                         administration, vascularity of the injection
                         site, and presence or absence of epinephrine
                         in the anesthetic solution. Bupivacaine has a
                         long duration of action. Onset of anesthesia
                         following 0.25% or 0.5% solution in epidural,
                         including caudal block and peripheral or
                         sympathetic nerve block, occurs in about 4-17
                         minutes and lasts from 3-7 hours. After
                         epidural or caudal administration of 125 or
                         150 mg of bupivacaine hydrochloride, peak
                         plasma concentrations of 0.45-1.25
                         microgram/mL have been demonstrated. The
                         elimination half-life of bupivacaine
                         hydrochloride is 1.5-5.5 hours in adults. It
                         is principally metabolized to
                         pipecolylxylidene (PPX) by N-dealkylation
                         probably in the liver. It is excreted in the
                         urine as small amounts of PPX, unchanged drug
                         (5%), and other metabolites as yet
                         unidentified. [PDR 1997; AHFS Drug
                         Information 1997]
CLASSIFICATION CODE      Anesthetic [USAN 1997]
OTHER MAJOR USES         Used for infiltration anesthesia and for
                         peripheral, sympathetic, nerve, and epidural
                         (including caudal) block anesthesia. [AHFS
                         Drug Information 1997]
SUBSTANCE INTERACTIONS   Administration of local anesthetic solutions
                         containing epinephrine or norepinehrine to
                         patients receiving monoamine oxidase
                         inhibitors or tricyclic antidepressants may
                         produce severe, prolonged hypertension. Some
                         commercially available formulations of
                         bupivacaine hydrochloride contain
                         metabisulfite. The latter may cause severe
                         allergic reactions in susceptible
                         individuals. [PDR 1997; AHFS Drug Information
                         1997]
ADVERSE EFFECTS          The most commonly encountered acute adverse
                         reactions with bupivacaine hydrochloride are
                         related to the central nervous and
                         cardiovascular systems. These effects are
                         generally dose-related and are due to high
                         plasma levels or unintentional intravascular
                         or subarachnoid injection of the drug.
                         Neurological effects, following epidural or
                         caudal anethesia, may include such effects as
                         spinal block of varying magnitude, urinary
                         retention, fecal and urinary incontinence and
                         loss of perineal sensation and sexual
                         function. [PDR 1997]
CONTRAINDICATIONS        Contraindicated in patients with a known
                         hypersensitivity to the bupivacaine
                         hydrochloride, to any local anesthetic agent
                          of the amide type or to other components of
                          the bupivacaine solutions. [PDR 1997]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: Bupivacaine hydrochloride
                          is a local anesthetic of the amide type with
                          a long duration of action. It is available
                          commercially in sterile water solution. It is
                          also available with epinephrine or
                          epinephrine bitartrate. [AHFS Drug
                          Information 1997]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: The hydrochloride
                          monohydrate is a white crystalline powder.
                          [PDR 1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C18H28N2O [Merck Index
                          1996]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 288.43 [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    MELTING POINT: 107-108 C [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    ELEMENTAL COMP: C74.96%, H9.78%, N9.71%,
                          O5.55% [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    SOLUBILITY: The hydrochloride monohydrate is
                          soluble in water or alcohol, and slightly
                          soluble in acetone, chloroform or ether.
                          [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    DRUG PHYSICAL COMMENT: PKa: 8.09. [Merck
                          Index 1996]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: 0.25%, 0.5%, 0.75% aqueous
                          solutions; 0.75% in 8.25 dextrose solution;
                          0.25% or 0.75% solutions with epinephrine
                          bitartrate (1:200,00 of epinephrine). [AHFS
                          Drug Information 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Parenteral injection. [AHFS
                          Drug Information 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Solutions should be
                          stored at 15-30 C (59-86 F). [PDR 1997]
MANUFACTURERS             Apollon Incorporated; One Great Valley
                          Parkway; Malvern, PA 19355
REFERENCES                MED/97366403. Stevens RA, Frey K, Liu SS, Kao
                          TC, Mikat-Stevens M, Beardsley D, Holman S,
                          White JL. Sympathetic block during spinal
                          anesthesia in volunteers using lidocaine,
                          tetracaine, and bupivacaine. Reg Anesth. 1997
                          Jul-Aug;22(4):325-31.
REFERENCES                MED/97377402. Leonard M, Moore L, Algozzine
                          R, Gregorino J, Giles B. Recovery times from
                          subarachnoid blocks using bupivacaine
                          hydrochloride and tetracaine hydrochloride
                          with and without epinephrine. AANA J. 1997
                          Jun;65(3):260-4.
REFERENCES                MED/97346497. Rucci FS, Barbagli R, Pippa P,
                          Boccaccini A. The optimal dose of local
                          anaesthetic in the orthogonal two-needle
                          technique. Extent of sensory block after the
                          injection of 20, 30 and 40 mL of anaesthetic
                          solution. Eur J Anaesthesiol. 1997
                          May;14(3):281-6.
REFERENCES                MED/97273190. Meyer RJ. Antimicrobial
                          properties of bupivacaine [letter]. Anaesth
                          Intensive Care. 1997 Apr;25(2):200.
REFERENCES                MED/97295136. Mikawa K, Akamatsu H, Nishina
                          K, Shiga M, Maekawa N, Obara H, Niwa Y.
                          Inhibitory effect of local anaesthetics on
                          reactive oxygen species production by human
                         neutrophils. Acta Anaesthesiol Scand. 1997
                         Apr;41(4):524-8.
REFERENCES               MED/97272387. Abbott PJ Jr, Sullivan G.
                         Cardiovascular toxicity following
                         preincisional intra-articular injection of
                         bupivacaine [letter]. Arthroscopy. 1997
                         Apr;13(2):282.
REFERENCES               MED/97037973. Myers KG, George RJ. Painful
                         neuropathy of the lateral cutaneous nerve of
                         the thigh in patients with AIDS: successful
                         treatment by injection with bupivacaine and
                         triamcinolone [letter]. AIDS. 1996
                         Sep;10(11):1302-3.
REFERENCES               MED/96432872. Collazos J, Mayo J, Martinez E,
                         Callejo A, Blanco I. Celiac plexus block as
                         treatment for refractory pain related to
                         sclerosing cholangitis in AIDS patients. J
                         Clin Gastroenterol. 1996 Jul;23(1):47-9.
ENTRY MONTH              199708
LAST REVISION DATE       19980430

30
UNIQUE IDENTIFIER        DRG-0277
NAME OF SUBSTANCE        Albendazole [FDA 274A]
REGISTRY NUMBER          54965-21-8
STANDARD CHEMICAL NAME   Carbamic acid,
                         [5-(propylthio)-1H-benzimidazol-2-yl]-,
                         methyl ester [USAN 1997]
SYNONYMS                 Valbazan [USAN 1997]
SYNONYMS                 Zentel [USAN 1997]
SYNONYMS                 Bilutac [Merck Index 1996]
SYNONYMS                 Eskazole [Merck Index 1996]
SYNONYMS                 Proftril [Merck Index 1996]
PROTOCOL ID NUMBERS      FDA 274A
SECONDARY SOURCE ID      SK&F 62979 [USAN 1997]
PHARMACOLOGICAL ACTION   MODE OF ACTION: Causes degenerative
                         alterations in the tegument and intestinal
                         cells of the worm by binding to the
                         colchicine-sensitive site of tubulin, thus
                         inhibiting its polymerization or assembly
                         into microtubules. This leads to impairment
                         in the uptake of glucose by the larval and
                         adult stages of the susceptible parasites and
                         depletes their glycogen stores. Due to
                         diminished energy production the parasite is
                         immobilized and eventually dies. Albendazole
                         itself is poorly absorbed from the GI tract
                         and concentrations in plasma are negligible
                         or undetectable. However, prior to reaching
                         systemic circulation it is rapidly converted
                         to the sulfoxide - its primary active
                         metabolite--in the liver. Oral
                         bioavailability is enhanced when the drug is
                         administered with a fatty meal. Maximal
                         plasma concentration of the sulfoxide
                         averages 1.31mcg/mL 2 to 5 hours after
                         administration of a 400 mg dose. Terminal
                         elimination of the sulfoxide ranges from 8 to
                         12 hours. The sulfoxide is further
                         metabolized in the liver to albendazole
                         sulfone and other oxidation products. Urinary
                           excretion of the sulfoxide is less than 1 %.
                           Billiary elmination presumably accounts for a
                           portion of the elimination. [USP DI 1997; PDR
                           1997]
DISEASES STUDIED/TREATED   Under investigation for treatment of
                           microsporidiosis. [AmFAR Tx Dir 1997;8(3)]
CLASSIFICATION CODE        Anthelmintic [Physicians GenRx 97]
OTHER MAJOR USES           Active antihelmintic against: ascariasis,
                           capillariasis, enterobiasis, hookwork
                           infection, hydatid disease,
                           neurocysticercosis (caused by pork tapeworm),
                           strongyloidiasis, taeniasis,
                           trichostrongyliasis, and trichuriasis. [USP
                           DI 1997]
SUBSTANCE INTERACTIONS     Steady state through concentrations of
                           albendazole sulfoxide were about 56% higher
                           when coadministered with dexamethasone.
                           Coadministration of praziquantel or
                           cimetidine also increased plasma
                           concentrations of the sulfoxide. [PDR 1997]
ADVERSE EFFECTS            Adverse events differ between hydatid disease
                           and neurocysticercosis. Abnormal liver
                           function tests and abdominal pain were rare
                           but somewhat more frequent under the former
                           condition. [PDR 1997]
CONTRAINDICATIONS          Risk-benefit should be considered in case of
                           hepatic impairment or hypersensitivity to
                           albendazole. [USP DI 1997]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Orally administered
                           broad-spectrum antihelmintic. [PDR 1997]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: White to off-white
                           powder. [PDR 1997]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C12H15N3O2S [Merck Index
                           1996]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 265.34 [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     MELTING POINT: 208-210 C [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     ELEMENTAL COMP: C54.32%, H5.70%, N15.84%,
                           O12.06%, S12.09% [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     SOLUBILITY: Soluble in dimethylsulfoxide and
                           strong acids and bases. Slightly soluble in
                           methanol, chloroform, ethyl acetate and
                           acetonitrile. Practically insoluble in water.
                           [PDR 1997]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Tablets (200 mg). [PDR 1997]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [USP DI 1997]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Store between 20-25 C
                           (68-77 F). [PDR 1997]
MANUFACTURERS              SmithKline Beecham Pharmaceuticals; 1
                           Franklin Plaza / P.O. Box 7929; Philadelphia,
                           PA 19101
REFERENCES                 MED/97160925. Weber R, Deplazes P, Flepp M,
                           Mathis A, Baumann R, Sauer B, Kuster H, Luthy
                           R. Cerebral microsporidiosis due to
                           Encephalitozoon cuniculi in a patient with
                           human immunodeficiency virus infection. N
                           Engl J Med. 1997 Feb 13;336(7):474-8.
REFERENCES                 MED/97052552. Field AS, Marriott DJ, Milliken
                           ST, Brew BJ, Canning EU, Kench JG, Darveniza
                           P, Harkness JL. Myositis associated with a
                           newly described microsporidian,
                           Trachipleistophora hominis, in a patient with
                      AIDS. J Clin Micorbiol. 1996
                      Nov;34(11):2803-11.
REFERENCES            MED/97037972. Dionishio D, Sterrantino G,
                      Meli M, Leoncini F, Orsi A, Nicoletti P.
                      Treatment of isosporiasis with combined
                      albendazole and ornidazole in patients with
                      AIDS [letter]. AIDS. 1996 Sep;10(11):1301-2.
REFERENCES            MED/96404994. Rigano R, Profumo E, Teggi A,
                      Siracusano A. Production of IL-5 and IL-6 by
                      peripheral blood mononuclear cells (PMBC)
                      from patients with Echinococcus granulosus
                      infection. Clin Exp Immunol. 1996
                      Sep;105(3):456-9.
REFERENCES            MED/96320334. Rossi RM, Wanke C, Federman M.
                      Microsporidian sinusitis in patients with the
                      acquired immunodeficiency syndrome.
                      Laryngoscope. 1996 Aug;106(8):966-71.
REFERENCES            MED/96356947. Kelly P, Lungu F, Keane E.
                      Albendazole may reduce diarrhea in HIV
                      patients. Nurs Times. 1996 May
                      22-28;92(21):12-3.
REFERENCES            MED/96249612. Didier ES, Rogers LB, Brush AD,
                      Wong S, Traina-Dorge V, Bertucci D. Diagnosis
                      of disseminated microsporidian
                      Encephalitozoon hellem infection by
                      PCR-Southern analysis and successful
                      treatment with albendazole and fumagillin. J
                      Clin Microbiol. 1996 Apr;34(4):947-52.
REFERENCES            MED/97224644. Brasil P, Sodre FC, Cuzzi-Maya
                      T, Gutierrez MC, Mattos H, Moura H.
                      Intestinal microsporidiosis in HIV-positive
                      patients with chronic unexplained diarrhea in
                      Rio de Janeiro, Brazil: diagnosis, clinical
                      presentation and follow-up. Rev Inst Med Trop
                      Sao Paulo. 1996 Mar-Apr;38(2):97-102.
REFERENCES            MED/97005700. Corcoran GD, Isaacson JR,
                      Daniels C, Chiodini PL. Urethritis associated
                      with disseminated microsporidiosis: clinical
                      response to albendazole. Clin Infect Dis.
                      1996 Mar;22(3):592-3.
REFERENCES            MED/96197785. Joste NE, Rich JD, Busam KJ,
                      Schwartz DA. Autop sy verification of
                      Encephalitozoon intestinalis
                      (microsporidiosis) eradication following
                      albendazole therapy. Arch Pathol Lab Med.
                      1996 Feb;120(2):199-203.
ENTRY MONTH           199707
LAST REVISION DATE    19980515

31
UNIQUE IDENTIFIER     DRG-0276
NAME OF SUBSTANCE     APL 400-047 [VEU 031]
PROTOCOL ID NUMBERS   NIAID VEU 031
CLASSIFICATION CODE   Vaccine [VEU 031]
MANUFACTURERS         Apollon Incorporated; One Great Valley
                      Parkway; Malvern, PA 19355
ENTRY MONTH           199708
LAST REVISION DATE    19970804

32
UNIQUE IDENTIFIER     DRG-0275
NAME OF SUBSTANCE          Cyclosporine [ACTG 334]
REGISTRY NUMBER            59865-13-3
STANDARD CHEMICAL NAME     Cyclo[[(E)-2S,3R,4R)-3-hydroxy-4-methyl-2-(me-
                           thylamino)
                           -6-octenoyl]-L-2-aminobutyryl-N-methylgly-N-m-
                           ethyl
                           -L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl--
                           D-alanyl-N-
                           methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L--
                           valyl] [USAN 1997]
SYNONYMS                   Sandimmune [USAN 1997]
SYNONYMS                   Cyclosporin A [Merck Index 1996]
SYNONYMS                   Ciclosporin [Merck Index 1996]
SYNONYMS                   Neoral [Merck Index 1996]
SYNONYMS                   Ramihyphin A [CHEMID]
PROTOCOL ID NUMBERS        NIAID ACTG 334
SECONDARY SOURCE ID        27-400 [USAN 1997]
PHARMACOLOGICAL ACTION     MODE OF ACTION: The exact mechanism of action
                           of cyclosporine is unknown. Experimental
                           evidence suggests that its effectiveness is
                           due to specific and reversible inhibition of
                           immunocompetent lymphocytes in the G0 or G1
                           phase of the cell cycle. Cyclosporine also
                           inhibits lymphokine production and release
                           including interleukin-2 or T-cell growth
                           factor. Cyclosporine does not cause bone
                           marrow suppression. Absorption from the GI
                           tract is incomplete and variable. Peak
                           concentrations (Cmax) in blood and plasma are
                           achieved in 3.5 hours. Cmax is approximately
                           1.0 ng/mL/mg of dose for plasma and 2.7-1.4
                           ng/mL/mg of dose for blood. In blood
                           distribution is concentration-dependent;
                           33%-97% in plasma, 4%-9% in lymphocytes,
                           5%-12% in granulocytes, and 41%-58% in
                           erythrocytes. Disposition from blood is
                           biphasic with a terminal half-life of ca. 19
                           hours. Elimination is primarily biliary with
                           only 6% of the dose excreted in the urine.
                           Cyclosporine is extensively metabolized but
                           there is no major metabolic pathway. [PDR
                           1997]
DISEASES STUDIED/TREATED   Study of immune activaton and HIV expression
                           in early HIV disease. [ACTG 334]
CLASSIFICATION CODE        Immunosuppressant [USAN 1997]
OTHER MAJOR USES           Indicated for the prophylaxis of organ
                           rejection in kidney, liver, and heart
                           allogenic transplants. [PDR 1997]
SUBSTANCE INTERACTIONS     Careful monitoring of renal function should
                           be practiced when cyclosporine is used with
                           nephrotoxic drugs. Drugs that exhibit such
                           nephrotoxic synergy are: gentamycin,
                           tobramycin, vancomycin, amphotericin B,
                           ketoconazole, melphalan, cimetidine,
                           ranitidine, diclofenac, trimethoprim with
                           sulfamethoxazole, azapropazone. Since
                           cyclosporine is extensively metabolized by
                           the liver, other drugs that affect hepatic
                           microsomal enzymes, and particularly the
                           cytochrome P-450 system, may influence the
                           circulating levels of cyclosporine.
                           Substances know to inhibit these enzymes will
                           increase cyclosporine levels, while
                           substances that are inducers of cytochrome
                           P-450 activity will increase hepatic
                           metabolism and thereby decrease cyclosporine
                           levels. Reduced clearance of prednisolone,
                           digoxin, and lovastatin has been observed
                           when these drugs are administered with
                           cyclosporine. Cyclosporine should not be used
                           with potassium-sparing diuretics because
                           hyperkalemia can occur. During treatment with
                           cyclosporine, vaccinations may be less
                           effective, and the use of live vaccines
                           should be avoided. [PDR 1997]
ADVERSE EFFECTS            The principal adverse reactions to
                           cyclosporine therapy are renal dysfunction,
                           tremors, hirsutism, hypertension, and gum
                           hyperplasia. Hypomagnesemia has been reported
                           in some, but not all, patients exhibiting
                           convulsions while on cyclosporine therapy.
                           [PDR 1997]
CONTRAINDICATIONS          Risk-benefit of cyclosporine administration
                           should be considered when the following
                           medical conditions exist: chickenpox
                           (existing or recent), herpes zoster, hepatic
                           function impairment, hyperkalemia,
                           infections, malabsorption, renal function
                           impairment, sensitivity to cyclosporine. [USP
                           DI 1997]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Member of a group of
                           nonpolar cyclic oligopeptides with
                           immunosuppressant activity. Produced by
                           Tolypocladium inflatum Gams and other Fungi
                           imperfecti. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: White prismatic needles
                           from acetone. [Merck Index 1996]
CHEMICAL/PHYSICAL   DATA   MOLECULAR FORMULA: C62H111N11O12 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR WEIGHT: 1202.64 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MELTING POINT: 148-151 C [Merck Index 1996]
CHEMICAL/PHYSICAL   DATA   SOLUBILITY: Relatively insoluble in water and
                           generally soluble in lipids and organic
                           solvents. [AHFS Drug Information 1997]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Soft gelatine capsules (25 mg,
                           50 mg, or 100 mg); 50 mL bottles containing
                           100 mg of cyclosporine per mL; and for
                           intravenous infusion, 5 mL sterile ampules
                           containing 50 mg of cyclosporine per mL. [PDR
                           1997]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral, or i.v. infusion.
                           [PDR 1997]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: In the original
                           unit-dose containers at temperatures below 86
                           F (30 C). [PDR 1997]
MANUFACTURERS              Novartis Pharmaceutical Corporation; 59 Route
                           10 / Building 419-2; East Hanover, NJ 07936
REFERENCES                 MED/97354217. St'astny M, Ulbrich K, Strohalm
                           J, Rossmann P, Rihova B. Abnormal
                           differentiation of thymocytes induced by free
                           cyclosporine is avoided when cyclosporine
                           bound to N-(2-hydroxypropyl)methacrylamide
                           copolymer carrier is used. Transplantation.
                           1997 Jun 27;63(12):1818-27.
REFERENCES                 MED/97331506. Lesnoni La Parola I, Masini C,
                           Nanni G, Diociaiuti A, Panocchia N, Cerimele
                           D. Kaposi's sarcoma in renal-transplant
                           recipients: experience at the Catholic
                           University in Rome, 1988-1996. Dermatology.
                           1997; 194(3):229-33.
REFERENCES                 MED/97295475. Waldmann V, Kempf W, Burg G,
                           Dummer R. Kaposi sarcoma in cyclosporin A
                           therapy of actinic reticuloid. Hautarzt. 1997
                           Apr;48(4):462-5.
REFERENCES                 MED/97184541. Braaten D, Ansari H, Luban J.
                           The hydrophobic pocket of cyclophilin is the
                           binding site for the human immunodeficiency
                           virus type 1 Gag polyprotein. J Virol. 1997
                           Mar;71(3):2107-13.
REFERENCES                 MED/97149469. Shapiro J, Lui H, Tron V, Ho V.
                           Systemic cyclosporine and low-dose prednisone
                           in the treatment of chronic severe alopecia
                           areata: a clinical and immunopathologic
                           evaluation. J Am Acad Dermatol. 1997
                           Jan;36(1):114-7.
REFERENCES                 MED/97131728. Sun Y, Pinchuk LM, Agy MB,
                           Clark EA. Nuclear import of HIV-1 DNA in
                           resting CD4+ T cells requires a cyclosporin
                           A-sensitive pathway. J Immunol. 1997 Jan
                           1;158(1):512-7.
REFERENCES                 MED/97152503. Briggs CJ, Tozser J, Oroszlan
                           S. Effect of cyclosporin A on the replication
                           cycle of human immunodeficiency virus type 1
                           derived from H9 and Molt-4 producer cells. J
                           Gen Virol. 1996 Dec;77(Pt 12):2963-7.
REFERENCES                 MED/96400134. Franke EK, Luban J. Inhibition
                           of HIV-1 replication by cyclosporine A or
                           related compounds correlates with the ability
                           to disrupt the Gag-cyclophilin A interaction.
                           Virology. 1996 Aug 1;222(1):279-82.
REFERENCES                 MED/96357041. Braaten D, Aberham C, Franke
                           EK, Yin L, Phares W, Luban J. Cyclosporine
                           A-resistant human immunodeficiency virus type
                           1 mutants demonstrate that Gag encodes the
                           functional target of cyclophilin A. J Virol.
                           1996 Aug;70(8):5170-6.
REFERENCES                 MED/96433987. Andrada-Serpa MJ, Schor D,
                           Araujo AQ, Rumjanek VM. Immunolgical features
                           of HTLV-I myelopathy in Rio de Janeiro,
                           Brazil, and in vitro effects of cyclosporin
                           A. J Neurol Sci. 1996 Jul;139(1):7-14.
ENTRY MONTH                199707
LAST REVISION DATE         19971010

33
UNIQUE IDENTIFIER          DRG-0274
NAME OF SUBSTANCE          Infant Formula [ACTG 247]
PROTOCOL ID NUMBERS        NIAID ACTG 247
DISEASES STUDIED/TREATED   Under investigation as a caloric
                           supplementation to improve growth in
                           HIV-infected infants. [NIAID ACTG 247]
CLASSIFICATION CODE        Nutritional support [ACTG 247]
CHEMICAL/PHYSICAL DATA     DRUG PHYSICAL COMMENT: Concentrated 25.7
                           KCal/fluid oz formula. [NIAID ACTG 247]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral administration. [NIAID
                          ACTG 247]
MANUFACTURERS             Abbott Laboratories, Ross Products Division;
                          625 Cleveland Ave; Columbus, OH 43215
ENTRY MONTH               199707
LAST REVISION DATE        19980420

34
UNIQUE IDENTIFIER         DRG-0273
NAME OF SUBSTANCE         Diphenhydramine [NIAID ACTG 350]
REGISTRY NUMBER           147-24-0
STANDARD CHEMICAL NAME    2-(Diphenylmethoxy)-N,N-Dimethylethylamine
                          hydrochloride [USAN 1997]
SYNONYMS                  Benadryl [PDR 1998]
SYNONYMS                  2-Diphenylmethoxy-N,N-dimethylethanamine
                          hydrochloride [Merck Index 1996]
SYNONYMS                  2-(Benzhydryloxy)-N,N-dimethylethylamine
                          hydrochloride [Merck Index 1996]
SYNONYMS                  Ethanamine,
                          2-(diphenylmethoxy)-N,N,dimethyl-,
                          hydrochloride [USAN 1997]
SYNONYMS                  Alledryl [Merck Index 1996]
SYNONYMS                  Allergina [Merck Index 1996]
SYNONYMS                  Amidryl [Merck Index 1996]
SYNONYMS                  Bagodryl [Merck Index 1996]
SYNONYMS                  Bax [Merck Index 1996]
SYNONYMS                  Benocten [Merck Index 1996]
SYNONYMS                  Benodine [Merck Index 1996]
SYNONYMS                  Benzantin [Merck Index 1996]
SYNONYMS                  Dibondrin [Merck Index 1996]
SYNONYMS                  Dihydral [Merck Index 1996]
SYNONYMS                  Diphantine [Merck Index 1996]
SYNONYMS                  Dolestan [Merck Index 1996]
SYNONYMS                  Fenylhist [Merck Index 1996]
SYNONYMS                  Halbmond [Merck Index 1996]
SYNONYMS                  Histacyl [Merck Index 1996]
SYNONYMS                  Noctomin [Merck Index 1996]
SYNONYMS                  Sedopretten [Merck Index 1996]
SYNONYMS                  Sekundal-D [Merck Index 1996]
SYNONYMS                  Syntedril [Merck Index 1996]
SYNONYMS                  Wehydryl [Merck Index 1996]
SYNONYMS                  S 8 [Merck Index 1996]
PROTOCOL ID NUMBERS       NIAID SPIRAT 3
PHARMACOLOGICAL ACTION    MODE OF ACTION: Antihistamines act by
                          competing with histamine for H1-receptor
                          sites on effector cells. They thereby
                          prevent, but do not reverse, responses
                          mediated by histamine alone. They antagonize
                          the effects of histamine such as urticaria
                          and pruritus. The anticholinergic effects of
                          antihistamines provide a drying effect on the
                          nasal mucosa. Diphenyhdramine is well
                          absorbed following oral administration. It
                          undergoes first-pass metabolism through the
                          liver and only 40-60% of the oral dose
                          reaches systemic circulation. The drug
                          appears in plasma within 15 minutes.
                          Following single oral doses of 50 and 100 mg
                          in healthy adults, peak plasma concentrations
                          of 37-83 and 81-159 ng/mL respectively have
                          been reported. In vitro, diphenhydramine is
                         approximately 80-85% bound to plasma protein.
                         Terminal elimination half-life appears to be
                         2.4-9.3 hours in healthly adults. Following a
                         single 100-mg dose in healthy adults, about
                         50-70% is excreted in the urine within 4
                         days, almost completely as metabolites. [USP
                         DI 1997; AHFS Drug Information 1997]
CLASSIFICATION CODE      Antihistamine [USAN 1997]
OTHER MAJOR USES         For amelioration of allergic reactions;
                         temporary relief of cough caused by minor
                         throat and bronchial irritation; treatment of
                         nausea, vomiting, and/or vertigo associated
                         with motion sickness; short-term management
                         of insomnia. [AHFS Drug Information 1997]
SUBSTANCE INTERACTIONS   Additive effects with alcohol and other CNS
                         depressants (hypnotics, sedatives,
                         tranquilizers, etc.). MAO inhibitors prolong
                         and intensify the anticholinergic effects of
                         antihistamines. [PDR 1998]
ADVERSE EFFECTS          Adverse effects include the following,
                         general: drug rash, anaphylactic shock,
                         photosensitivity, excessive perspiration,
                         chills, and dryness of mouth, nose, and
                         throat; cardiovascular system: hypotension,
                         headache, palpitations, tachycardia, and
                         extrasystoles; hematologic system: hemolytic
                         anemia, thrombocytopenia, and
                         agranulocytosis; nervous system: sedation,
                         sleepiness, dizziness, disturbed
                         coordination, fatigue, confusion,
                         restlessness, excitation, nervousness,
                         tremor, irritability, insomnia, fatigue,
                         confusion, restlessness, excitation,
                         nervousness, tremor, irritability, insomania,
                         euphoria, paresthesia, blurred vision,
                         diplopia, vertigo, tinnitus, acute
                         labyrinthitis, neuritis, and convulsions; GI
                         system: epigastric distress anorexia, nausea,
                         vomiting, diarrhea, and constipation; GU
                         system: urinary frequency, difficult
                         urination, urinary retention, and early
                         menses; respiratory system: thickening of
                         bronchial secretions, tightness of chest or
                         throat and wheezing, and nasal stuffiness.
                         The most frequent adverse effects include
                         sedation, sleepiness, dizziness, disurbed
                         coordination, epigastric distress, and
                         thickening of bronchinal secretions. [PDR
                         1998]
CONTRAINDICATIONS        Should not be used in neonates or premature
                         infants, nursing mothers, patients with
                         hypersensitivity to diphenhydramine
                         hydrochloride and other antihistamine of
                         similar chemical structure. Antihistamines
                         should be used with considerable caution in
                         patients with narrow-angle glaucoma,
                         stenosing peptic ulcers, pyloroduodenal
                         obstruction, sympotomatic prostatic
                         hypertrophy or bladder-neck obstruction. [PDR
                         1998]
CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Antihistamine with
                          anticholinergic and sedative side effects.
                          [PDR 1998]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: White, odorless,
                          cyrstalline powder, slowly darken on exposure
                          to air. Bitter taste. [AHFS Drug Information
                          1997; Merck Index 1996]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C17H21NO.HCL [Merck Index
                          1996]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 291.82 [PDR 1998]
CHEMICAL/PHYSICAL DATA    MELTING POINT: 166-170 C [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    BOILING POINT: 150-165 C (free base) [Merck
                          Index 1996]
CHEMICAL/PHYSICAL DATA    SOLUBILITY: Soluble in Water, alcohol,
                          chloroform, and acetone. Very slightly
                          soluble in benzene, ether. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    STABILITY: Slowly darkens when exposed to
                          light. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    DRUG PHYSICAL COMMENT: pH of 1% aqueous
                          solution is about 5.5. [Merck Index 1996]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: 25 mg and 50 mg capsules or
                          tablets; 10mg/mL and 50mg/mL parenteral
                          injections, 12.5mg/5ml elixir, 1% or 2%
                          topical cream. [AHFS Drug Information 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Usually oral; when that is
                          not feasible, by deep IM, or preferably IV,
                          injection. [AHFS Drug Information 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Should be stored at
                          15-30 C (59-86 F) in light-resistant
                          containers and protected from moisture.
                          Freezing of liquid preparations should be
                          avoided. [AHFS Drug Information 1997]
MANUFACTURERS             Drugs are provided by each participating unit
                          site
REFERENCES                AIDS/95921074. Saavedra A, Rodriguez N,
                          Rivera-Vazquez CR, Ramirez-Ronda CH, Bermudez
                          RH. Trimethoprim-sulfamethoxazole (TMP-SMZ)
                          desensitization in patients (PTS) with HIV
                          infection who have non-life threatening
                          allergy to TMP-SMZ. Initial report. Natl Conf
                          Hum Retroviruses Relat Infect (1st). 1993 Dec
                          12-16;:62.
REFERENCES                ICA9/93335041. Rich JD, Greineder D, Sullivan
                          TJ, Kazanjian PH. Successful oral
                          desensitization to TMP/SMX in persons with
                          HIV infection and prior hypersensitive
                          reactions. Int Conf AIDS. 1993 Jun
                          6-11;9(1):382 (abstract no.PO-B10-1482).
REFERENCES                MED/93076569. Gearhart MO, Bhutani MS.
                          Intravenous pentamidine-induced bronchospasm.
                          Chest. 1992 Dec;102(6):1891-2.
REFERENCES                MED/92016907. Toma E, Fournier S. Adverse
                          reactions to co-trimoxazole in HIV infection
                          [letter;comment]. Lancet. 1991 Oct
                          12;338(8772):954.
REFERENCES                MED/85108363. Gibbons RB, Lindauer JA.
                          Successful treatment of Pneumocystis carinii
                          pneumonia with trimethoprim-sulfamethoxazole
                          in hypersensitive AIDS patients. [letter].
                          JAMA. 1985 Mar 1;253(9):1259-60.
ENTRY MONTH               199705
LAST REVISION DATE        19980430
35
UNIQUE IDENTIFIER          DRG-0272
NAME OF SUBSTANCE          PMPA [FDA 269A]
STANDARD CHEMICAL NAME     9-[(R)-2-(phosphonomethoxy)propyl]adenine
                           [FDA 269A]
SYNONYMS                   9-(2-Phosphonylmethoxypropyl)adenine [MeSH]
SYNONYMS                   9-PmPA [MeSH]
SYNONYMS                   (R)-9-(2-phosphonylmethoxypropyl) adenine
                           [MeSH]
PROTOCOL ID NUMBERS        FDA 269A
DISEASES STUDIED/TREATED   Under investigation for the treatment of
                           primary HIV infections. [FDA 269A]
CLASSIFICATION CODE        Antiviral [FDA 269A]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: PMPA is an acyclic
                           nucleotide analogue. [PDR 1997; 4th Conf
                           Retro and Opportun Infect 1997 Jan 22-26]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral administration. [FDA
                           269A]
MANUFACTURERS              Gilead Sciences Incorporated; 353 Lakeside
                           Drive; Foster City, CA 94404
REFERENCES                 AIDS/97702542. James JS. PMPA-first human
                           results. AIDS Treat News,1997 Apr
                           18,No269,3,6.
REFERENCES                 AIDS/97926475. Bischofberger N, Naesens L, de
                           Clercq E, Fridland A, Srinivas RV, Robbins
                           BL, Arimilli M, Cundy K, Kim C, Lacy S, et
                           al. Bis (POC) PMPA, an orally bioavailable
                           prodrug of the antiretroviral agent PMPA. 4
                           Conf Retro and Opportun Infect. 1997 Jan
                           22-26;:104 (abstract no. 214).
REFERENCES                 AIDS/97926379. Merrill DP, Manion DJ, Walker
                           BD, Hirsch MS. Drug susceptibilities of HIV-1
                           clinical isolates to (R)PMPA in vitro. 4th
                           Conf Retro and Opportun Infect. 1997 Jan
                           22-26;:93 (abstract no.155).
REFERENCES                 MED/97070544. Van Rompay KK, Cherrington JM,
                           Marthas ML, Berardi CJ, Mulato AS, Spinner A,
                           Tarara RP, Canfield DR, Telm S, Bischofberger
                           N, et al. 9-[2-(Phosphonomethoxy)propyl]
                           adenine therapy of established simian
                           immunodeficiency virus infection in infant
                           rhesus macaques. Antimicrob Agents Chemother.
                           1996 Nov;40(11):2586-91.
REFERENCES                 MED/97189101. Perno CF, Santoro N, Balestra
                           E, Aquaro S, Cenci A, Lazzarino G, Di Pierro
                           D, Tavazzi B, Balzarini J, Garaci E, et al.
                           Red blood cells mediated delivery of
                           9-(2-phosphonylmethoxyethyl) adenine to
                           primary macrophages: efficiency metabolism
                           and activity against human immunodeficiency
                           virus or herpes simplex virus. Antiviral Res.
                           1997 Feb;33(3):153-64.
ENTRY MONTH                199705
LAST REVISION DATE         19980428

36
UNIQUE IDENTIFIER          DRG-0271
NAME OF SUBSTANCE          Valganciclovir [FDA 268A]
SYNONYMS                   RS-79070 [AIDS Clinical Trials Information
                           Service]
PROTOCOL ID NUMBERS        FDA 268A
PROTOCOL ID NUMBERS        FDA 268B
PHARMACOLOGICAL ACTION     Ongoing clinical trials are comparing
                           valganciclovir (RS-79070), the new
                           ganciclovir prodrug, to oral ganciclovir for
                           CMV retinitis. Based on the results of a
                           previous study which showed an absolute
                           bioavailability for ganciclovir of 61% from a
                           solution of RS-79070 in the fasted state, a
                           study was performed to determine whether
                           orally administered RS-79070 possessed the
                           potential to be used for the induction and
                           maintenance treatment of CMV retinitis.
                           Preliminary data from the study indicate that
                           plasma concentrations of ganciclovir are
                           approximately 20% higher when RS-79070 is
                           given following food, and that the
                           pharmacokinetics of ganciclovir are dose
                           proportional over the dose range studied.
                           Systemic exposure to RS-79070 was low (1-2%
                           relative to ganciclovir exposure assessed
                           using AUC(24). Since the mean AUC(24) value
                           associated with iv ganciclovir treatment is
                           52 micrograms.h/mL at a dose of 10mg/kg/day
                           this study demonstrates that systemic
                           exposures in excess of those achieved with iv
                           ganciclovir at the recommended dose can be
                           achieved with once-daily oral dosing of the
                           ganciclovir prodrug, RS-79070. The benefits
                           of valganciclovir over IV ganciclovir are
                           considerable: Induction with the prodrug
                           requires taking only two 450 mg pills twice a
                           day for three weeks, followed by just two 450
                           mg pills once a day for maintenance. [4th
                           Conf Retro and Opportun Infect 1997 Jan
                           22-26; GMHC Treatment Issue 1998]
DISEASES STUDIED/TREATED   Being tested as oral treatment of CMV
                           retinitis[AmFar Tx Dir December, 1997]
CLASSIFICATION CODE        Antiviral [FDA 268A]
ADVERSE EFFECTS            Possible side effects from valganciclovir
                           include neutropenia, anemia, diarrhea, and
                           nausea. [Treat Rev. 1997 Aug;(No 25)]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Oral prodrug for
                           ganciclovir[AmFar Tx Dir December, 1997]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Tablets (450 mg)[FDA 268A]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral administration. [AmFar
                           Tx Dir December, 1997]
MANUFACTURERS              Roche Global Development - Palo Alto; 3401
                           Hill View Avenue; Palo Alto, CA 94303
REFERENCES                 Cadman J, Improved Ganciclovir Regimens.
                           Valganciclovir: A new Name and a New Plan.
                           GMHC treatment Issues; Vol 12, NO. 1 December
                           1997/January 1998.
REFERENCES                 AIDS/98005624. Progan studies against CMV
                           disease on hold. Aids Patient Care STDS. 1997
                           Oct;11(5):375.
REFERENCES                 AIDS/97702908. Pill treatment for CMV. Treat
                           Rev. 1997 Aug;(No 25):7.
REFERENCES                 MED/97452124. Katlama C. Management of CMV
                           retinitis in HIV infected patients.
                           Genitourin Med. 1997 Jun;73(3):169-73.
REFERENCES               AIDS/97702611. CMV retinitis, newly
                         diagnosed: RS-79070 trial in Atlanta, Austin,
                         Boston, Durham, Houston, Irvine, Los Angeles,
                         Miami, Montreal, New York (3 sites), San
                         Diego, San Francisco (3 sites), Toronto, and
                         Washington. AIDS Treat News. 1997 May 1;(No
                         270):2-3.
REFERENCES               AIDS/97702610. James JS. CMV,
                         RS-79070:community concern as major drug's
                         development suspended. AIDS Treat News. 1997
                         May 1;(No 270):1-2.
REFERENCES               AIDS/97926031 Brown F, Arum I, Francis G,
                         Patel M, Malcolm S. Ganciclovir prodrug
                         (RS-79070)-multiple dose, dose-ranging study
                         with effect of food. 4th Conf Retro and
                         Opportun Infect. 1997 Jan 22-26;:209
                         (abstract no. LB19).
ENTRY MONTH              199705
LAST REVISION DATE       19980520

37
UNIQUE IDENTIFIER        DRG-0270
NAME OF SUBSTANCE        MN rgp 120/HIV-1 [VEU 014C]
PROTOCOL ID NUMBERS      NIAID VEU 014C
PHARMACOLOGICAL ACTION   MODE OF ACTION: The vaccine producing company
                         (Genentech Inc.) has halted development of
                         gp120 as a potential treatment for HIV
                         positive individuals. Their gp120 model,
                         designed to slow the development of
                         AIDS-related symptoms, has shown no clinical
                         benefit in trials involving 573 asymptotic
                         HIV+ individuals with CD4 counts greater than
                         600/mm3. The vaccine was also tested in HIV
                         seronegative individuals. It was safe and
                         immunogenic. Three injections induced
                         antibodies that neutralized MN rgp120, SF-2
                         or IIIB strains of HIV-1. [AmFAR Tx Dir
                         1997;8(3); J Infect Dis 1996 Feb; 173(2); Int
                         Conf AIDS 1993 Jun 6-11;9(1)]
CLASSIFICATION CODE      Vaccine [VEU 014C]
ADVERSE EFFECTS          No clinically adverse events attributable to
                         MN rgp120 HIV-1 occured in the phase 1 study.
                         [AmFAR Tx Dir 1997;8(3); JAMA 1994 Aug 10;
                         272(6)]
CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Genetically engineered form
                         of envelope glycoprotein gp120 derived from
                         HIV-1 strain MN. [AmFAR Tx Dir 1997;8(3)]
MANUFACTURERS            VaxGen Incorporated; 460 Point San Bruno
                         Boulevard; South San Francisco, CA 94080
REFERENCES               AIDS/95921086. Belshe RB. Cross-reactive
                         neutralizing antibody induced by (MN or
                         MN+IIIB) rgp120/HIV-1 vaccines in low risk
                         volunteers. Natl Conf Hum Retroviruses Relat
                         Infect (1st). 1993 Dec 12-16;: 64.
REFERENCES               MED/97213946. Binley JM, Klasse PJ, Cao Y,
                         Jones I, Markowitz M, Ho DD, Moore JP.
                         Differential regulation of the antibody
                         responses to Gag and Env proteins of human
                         immunodeficiency virus type 1. J Virol. 1997
                         Apr; 71(4):2799-809.
REFERENCES               MED/97240668. Zolla-Pazner S, Alving C,
             Belshe R, Berman P, Burda S, Chigurupati P,
             Clements ML, Duliege AM, Excler JL, Hioe C,
             et al. Neutralization of a clade B primary
             isolate by sera from human immunodeficiency
             virus-uninfected recipients of candidate AIDS
             vaccines. J Infect Dis. 1997 Apr;
             175(4):764-74
REFERENCES   AIDS/97920693. Belshe RB, Bolognesi D,
             Clements ML, Corey L, Fast P, Graham B,
             Keefer M, Mestecky J, Mulligan M. Candidate
             HIV-1 vaccines: what is available for
             expanded clinical trials? Conf Adv AIDS
             Vaccine Dev. 1996 Feb 11-15;: 107.
REFERENCES   MED/96301139. Graham BS, Keefer MC, McElrath
             MJ, Gorse GJ, Schwartz DH, Weinhold K,
             Mattews TJ, Esterlitz Jr, Sinangil F, Fast
             PE. Safety and immunogenicity of a candidate
             HIV-1 vaccine in healthy adults: recombinant
             glyycoprotein (rgp) 120. A randomized,
             double-blind trial. NIAID AIDS Vaccine
             Evaluation Group. Ann Intern Med, 1996 Aug
             15, 125:4,270-9.
REFERENCES   AIDS/97288124. Lambert JS, McNamara J, Katz
             S, Livingston R, Moye J. Safety and
             immunogenicity of HIV recombinant envelope
             vaccines in HIV-infected infants and
             children. Pediatric AIDS clinical Trials
             Group Study ACTG 218. American Pediatric
             Association and Society for Pediatric
             Research annual meeting; 1996 May 6-10;
             Washington, D.C. Pediatr AIDS HIV Infect,
             1996 Aug, 7:4, 279 (unnumbered abstract).
REFERENCES   ICA11/96920851. Berman PW, Gray A, Ashby M,
             Eastman D, Wrin T, Vennari Ja, Francis D,
             Gregory T, Fast P, Schwartz D; et. al.
             Genetic and immunologic characterization of
             viruses infecting MN-rgp120 vaccinated
             volunteers. Int Conf AIDS, 1996 Jul 7-12,
             11:1, 10 (abstract no. Mo. A.285).
REFERENCES   ICA11/96920850. McElrath MJ, Montefiori D,
             Wolff M, Clements M, Gorse G, Keefer M,
             Graham B, Duliege AM, Francis D, Matthews T;
             et.al. Safety, immunity, and risk behavior in
             HIV-1-uninfected volunteers representing
             diverse risk populations following
             recombinant envelope vaccinations: a
             three-year followup. Int Conf AIDS, 1996 Jul
             7-12, 11:1, 10 (abstract no. Mo.A.284).
REFERENCES   MED/97120481. Cleland JL, Barron L, Daugherty
             A, Eastman D, Kensil C, Lim A, Weissburg RP,
             Wrin T, Vennari J, Powell MF. Development of
             a single-shot subunit vaccine for HIV-1. 3.
             Effect of adjuvant and immunization schedule
             on the duration of the humoral immune
             response to recombinant MN gp120. J Pharm
             Sci. 1996 Dec; 85(12):1350-7.
REFERENCES   MED/97071928. Gorse GJ, Yang EY, Belshe RB,
             Berman PW. Salivary binding antibodies
             induced by human immunodeficiency virus type
             1 recombinant gp120 vaccine. The NIAID AIDS
             Vaccine Evaluation Group. Clin Diagn Lab
                          Immunol. 1996 Nov; 3(6):769-73.
REFERENCES                MED/96400824. Gorse GJ, Patel GB, Newman FK,
                          Belshe RB, Berman PW, Gregory TJ, Matthews
                          TJ. Antibody to native human immunodeficiency
                          virus type 1 envelope glycoproteins induced
                          by IIIB and MN recombinant gp120 vaccines.
                          The NIAID AIDS Vaccine Evaluation Group. Clin
                          Diagn Lab Immunol. 1996 Jul; 3(4):378-86.
REFERENCES                AIDS/97920667. Zolla-Pazner S, Berman P, Xu
                          S, Gregory T. Detection of primary
                          isolate-neutralizing antibodies in the sera
                          of humans immunized with a rgp120MN vaccine.
                          Conf Adv AIDS Vaccine Dev. 1996 Feb
                          11-15;:36.
REFERENCES                MED/96162091. Mascola JR, Snyder SW, Weislow
                          OS, Belay SM, Belshe RB, Schwartz DH,
                          Clements ML, Dolin R, Graham BS, Gorse GJ, et
                          al. Immunization with envelope subunit
                          vaccine products elicits neutralizing
                          antibodies against laboratory-adapted but not
                          primary isolates of human immunodeficiency
                          virus type 1. The National Institute of
                          Allergy and Infectious Diseases AIDS Vaccine
                          Evaluation Group. J Infect Dis. 1996
                          Feb;173(2):340-8.
REFERENCES                ICA9/93335754. Allan JD, Conant M, Lavelle J,
                          Mitsuyasu R, Twaddell T, Kahn J. Safety and
                          immunogenicity of MN and IIIB rgp 120/HIV-1
                          vaccines in HIV-1 infected subjects with CD4
                          counts > 500 cells/mm3. Int Conf AIDS. 1993
                          Jun 6-11;9(1):491. (abstract no.PO-B27-2137).
ENTRY MONTH               199704
LAST REVISION DATE        19990318

38
UNIQUE IDENTIFIER         DRG-0269
NAME OF SUBSTANCE         DMP-266 [NIAID ACTG 368]
SYNONYMS                  L-743,726 [Antimicrob Agents Chemother 1995
                          Dec;39(12)]
SYNONYMS                  Sustiva [AIDS Treatment News]
SYNONYMS                  Efavirenz [AmFar Tx Dir December, 1997]
PROTOCOL   ID   NUMBERS   FDA 232J
PROTOCOL   ID   NUMBERS   FDA 246K
PROTOCOL   ID   NUMBERS   FDA 246N
PROTOCOL   ID   NUMBERS   FDA 296A
PROTOCOL   ID   NUMBERS   FDA 299A
PROTOCOL   ID   NUMBERS   NIAID 98 I-0147
PROTOCOL   ID   NUMBERS   NIAID 99 I-0032
PROTOCOL   ID   NUMBERS   NIAID ACTG 382
PROTOCOL   ID   NUMBERS   NIAID ACTG 384
PROTOCOL   ID   NUMBERS   NIAID ACTG 388
PROTOCOL   ID   NUMBERS   NIAID ACTG 398
PROTOCOL   ID   NUMBERS   NIAID ACTG 400
PROTOCOL   ID   NUMBERS   NIAID CPCRA 057
PROTOCOL   ID   NUMBERS   NIAID CPCRA 058
PROTOCOL   ID   NUMBERS   FDA 264F
PROTOCOL   ID   NUMBERS   FDA 281A
PROTOCOL   ID   NUMBERS   FDA 281C
PROTOCOL   ID   NUMBERS   FDA 281D
PROTOCOL   ID   NUMBERS   NIAID ACTG 364
PROTOCOL   ID   NUMBERS   NIAID ACTG 368
PROTOCOL ID NUMBERS        NIAID ACTG 372
PHARMACOLOGICAL ACTION     MODE OF ACTION: DMP-266, a member of the
                           1,4-dihydro-2H-3, 1-benzoxazin-2-ones, a new
                           class of non-nucleoside reverse transcriptase
                           inhibitors (NNRTIs), was chosen for clinical
                           evaluation because the compound was a potent
                           inhibitor of the wild-type HIV-1 reverse
                           transcriptase (Ki = 2.93 nM) and exhibited a
                           95% inhibitory concentration of 1.5 mM for
                           the inhibition of HIV-1 replicative spread in
                           cell culture. In addition, DMP-266 was found
                           to be capable of inhibiting a panel of
                           NNRTI-resistant mutant viruses, each of which
                           expressed a single RT amino acid
                           substitution. A clinical trial of DMP-266
                           alone and in combination with indinavir has
                           been completed. Following 2 weeks of
                           monotherapy with DMP-266, a mean reduction in
                           HIV-RNA of 1.68 log and an increase in CD4+
                           count of 96 cells/mm3 were reported. However
                           12 weeks on DMP-266 plus indinavir caused an
                           HIV-RNA reduction of 2.2 log. These data were
                           not statistically significant when compared
                           to patients receiving indinavir monotherapy.
                           [AmFar Tx Dir December, 1997]
DISEASES STUDIED/TREATED   Inhibitor of HIV-1 reverse transcriptase.
                           [AmFAR Tx Dir 1997;8(3)]
CLASSIFICATION CODE        Non-nucleoside reverse transcriptase
                           inhibitor [AmFar Tx Dir December, 1997]
SUBSTANCE INTERACTIONS     Co-administration of (DMP-266) and indinavir
                           has been reported to reduce indinavir
                           concentration (AUC) by approximately 35%.
                           [AmFar Tx Dir December, 1997]
ADVERSE EFFECTS            The most common adverse effect is rash. Most
                           cases went away when treatment was stopped
                           and do not recur when the drug was resumed.
                           Other adverse effects include diarrhea,
                           headaches, dizziness, and vivid dreams.
                           Laboratory abnormalities possibly related to
                           this drug include elevated transaminase
                           levels (grade 4). [AmFar Tx Dir December,
                           1997]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Member of the
                           1,4-dihyro-2H-3, 1-benzoxazin-2-ones; a new
                           class of non-nucleoside reverse transcriptase
                           inhibitors (NNRTIs). [Antimicrob Agents
                           Chemother 1995 Dec;39(12); AmFar Tx Dir
                           December, 1997]
MANUFACTURERS              Dupont Merck Pharmaceutical Company; Dupont
                           Merck Plaza / Maple Run Building / PO Box
                           80721; Wilmington, DE 19880
REFERENCES                 Fiske WD et al. Pharmacokinetics of DMP 266
                           and indinavir multiple oral doses in HIV-1
                           infected individuals. 4th Conf Retro and
                           Opportun Infect., 1997.
REFERENCES                 AIDS/97702912. James JS. DMP 266 trials
                           recruiting, many cities--protease inhibitor
                           naive. AIDS Treat News, 1997 Sep 5,:No
                           278,5-6.
REFERENCES                 MED/97366702. Gupta P, Mellors J, Kingsley L,
                           Riddler S, Singh MK, Schreiber S, Cronin M,
                     Rinaldo CR. High viral load in semen of human
                     immunodeficiency virus type 1-infected men at
                     all stages of disease and its reduction by
                     therapy with protease and nonnucleoside
                     reverse transcriptase inhibitors. J Virol,
                     1997 Aug, 71:8,6271-5.
REFERENCES           AIDS/97926547. Fiske WD, Mayers D, Wagner K,
                     Riddler S, Drusano G, Stein D, Bach M, Havlir
                     D, Kahn J. Pharmacokinetics of DMP 266 and
                     indinavir multiple oral dosses in HIV-1
                     infected individuals. 4th Conf Retro and
                     Opportun Infect, 1997 Jan 22-26:169 (abstract
                     no.568).
REFERENCES           AIDS/97926546. Riddler S, Mayers D, Wagner K,
                     Bach M, Havlir D, Stein D, Kahn J. A
                     double-blind pilot study to evaluate the
                     antiviral activity, tolerability of DMP 266
                     alone and in combination with indinavir. 4th
                     Conf Retro and Opportun Infect, 1997 Jan
                     22-26:no pagination.
REFERENCES           AIDS/97926014. Ruiz N. A double-blind pilot
                     study to evaluate the antirectroviral
                     activit;y, tolerability of DMP 266 in
                     combination with indinavir (cohort III). 4th
                     Conf Retro and Opportun Infect, 1997 Jan
                     22-26:206(abstract no.LB2).
REFERENCES           MED/97037953. Winslow DL, Garber S, Reid C,
                     Scarnati H, Baker D, Rayner MM, Anton ED.
                     Selection conditions affect the evolution of
                     specific mutations in the reverse
                     transcriptase gene associated with resistance
                     to DMP 266. AIDS, 1996 Sep, 10:11, 1205-9.
REFERENCES           AIDS/96701666. Anonymous. DMP 266:keep the
                     drug but dump the trial? GMHC treat Issues,
                     1996 May, 10:5,8.
REFERENCES           ICA11/96921147. Young SD. L-743,726
                     (DMP-266): a novel, highly potent
                     nonnucleoside inhibitor of the human
                     immunodeficiency virus type 1 reverse
                     transcriptase. Int Conf AIDS. 1996 Jul
                     7-12;11(1):68 (abstract no.Mo.A.1077).
REFERENCES           Mayers D, et al. A double-blind pilot study
                     to evaluate the antiviral activity,
                     tolerability and pharmacokinetics of DMP-266
                     alone and in combination with indinavir.
                     Abstract LB8a, 36th ICAAC, New Orleans. 1996.
REFERENCES           MED/96161265. Young SD, Britcher SF, Tran LO,
                     Payne LS, Lumma WC, Lyle TA, Huff JR,
                     Anderson PS, Olsen DB, Carroll SS, et al.
                     L-743, 726 (DMP-266): a novel, highly potent
                     nonnucleoside inhibitor of the human
                     immunodeficiency virus type 1 reverse
                     transcriptase. Antimicrob Agents Chemother.
                     1995 Dec;39(12):2602-5.
ENTRY MONTH          199704
LAST REVISION DATE   19980424

39
UNIQUE IDENTIFIER    DRG-0268
NAME OF SUBSTANCE    Tin Ethyl Etiopurpurin [FDA 261A]
REGISTRY NUMBER      113471-15-1
STANDARD CHEMICAL NAME     Tin, (ethyl
                           ramethyl-20-phorbinecarboxylato(2-)-N23,N24,N-
                           25,N26)-, (SP-4-2)- [CHEMID]
SYNONYMS                   SNET2 [Int Conf AIDS. 1996 Jul 7-12;11(2)]
SYNONYMS                   Tin etiopurpurin [CHEMID]
SYNONYMS                   Etiopurpurin, tin [CHEMID]
SYNONYMS                   SnET [Ophthalmic Surg Lasers 1997 May;28(5)]
PROTOCOL ID NUMBERS        FDA 261A
PHARMACOLOGICAL ACTION     MODE OF ACTION: Photodynamic therapy (PDT)
                           involves drugs that are activated by light to
                           selectively destroy diseased cells, such as
                           cancer, with minimal effects on normal
                           tissue. Tin ethyl etiopurpurin (SnET2) is a
                           drug being evaluated clinically for such
                           activity. Phase I and II clinical studies
                           were carried out to define a PDT consisting
                           of drug (SnET2 by infusion) and light doses
                           to elicit response/remission of cutaneous
                           AIDS-associated Kaposi's sarcoma (KS) and to
                           determine the response/remission rate of KS
                           lesions in an expanded population of AIDS
                           patients. The Phase I threshold SnET2 dose
                           required for clinical tumor response was
                           greater than 0.8 mg/kg. At 1.2 mg/kg, the
                           respnse rate [CR (complete response rate) and
                           PR (partial response rate)] was 78%. The
                           overall response rate among the Phase II
                           trial patients was 34% for macular stage KS
                           lesions (22% CR and 12% PR) and 84% for
                           papular stage KS (32% CR and 53% PR). Over a
                           12-week evaluation interval, 3/24 macular
                           stage control lesions changed in morphology
                           to papular or nodular stage KS. Conclusions
                           from these trials were that SnET2-PDT
                           resulted in clinical responses of cutaneous
                           KS lesions in AIDS patients with advanced
                           disease. A therapeutic drug dose of SnET2 at
                           1.2 mg/kg with light irradiation at 300 J/cm2
                           elicited a response rate of 88% among papular
                           stage KS, and 37% among macular stage KS
                           demonstrating the potential clinical utility
                           of SnEt2-PDT in the management of local KS
                           disease. [Int Conf AIDS. 1996 Jul 7-12;11(2);
                           Business Wire July 11 / 1996]
DISEASES STUDIED/TREATED   Treatment of Kaposi's sarcoma[Int Conf AIDS.
                           1996 Jul 7-12;11(2)]
CLASSIFICATION CODE        Photochemotherapeutic [FDA 261A]
OTHER MAJOR USES           SnET2-based photodynamic therapy is being
                           tested in phase II/III studies for the
                           treatment of cutaneous metastatic breast
                           cancer. It is also being tested in phase I/II
                           PDT studies for the treatment of certain
                           serious eye diseases. [Business Wire July 11
                           / 1996; J Surg Oncol 1998 Feb;67(2)]
ADVERSE EFFECTS            In a limited clinical trial, treatment with
                           SnET2 and irradiation was generally found to
                           be well tolerated. The most common side
                           effect was mild, transient sensitivity of the
                           skin to sunlight. This did not require
                           treatment. No clinically significant abnormal
                           trends were noted in laboratory parameters.
                          [Business Wire July 11 / 1996]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: Substance used to augment
                          photodynamic therapy (with laser light) on
                          kaposi's sarcoma and other skin tumors. [Int
                          Conf AIDS. 1996 Jul 7-12;11(2)]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C37H42N402Sn [CHEMID]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Solution. [FDA 261A]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Infusion[Int Conf AIDS.
                          1996 Jul 7-12;11(2)]
MANUFACTURERS             Clinical Solutions; 103 Carnegie Center /
                          Suite 106; Princeton, NJ 08540
REFERENCES                UI/98146189. Kaplan MJ, Somers RG, Greenberg
                          RH, Ackler J. Photodynamic therapy in the
                          management of metastatic cutaneous
                          adenocarcinomas: case reports from phase 1/2
                          studies using tin ethyl etiopurpurin (SnET2).
                          J Surg Oncol 1998 Feb;67(2):121-5.
REFERENCES                UI/98048429. Hill RA, Crean DH, Doiron DR,
                          Ghosheh F, Ryan JA, Kelly H, Booth M, Liaw
                          LH, Newman L, Berns MW. Photodynamic therapy
                          of the ciliary body with tin ethyl
                          etiopurpurin and tin octaethyl benzochlorin
                          in pigmented rabbits. Ophthalmic Surg Lasers
                          1997 Nov;28(11):948-53.
REFERENCES                UI/97294851. Peyman GA, Moshfeghi DM,
                          Moshfeghi A, Khoobehi B, Doiron DR, Primbs
                          GB, Crean DH. Photodynamic therapy for
                          choriocapillaris using tin ethyl etiopurpurin
                          (SnET2). Ophthalmic Surg Lasers 1997
                          May;28(5):409-17.
REFERENCES                UI/97238341. Rocklin GB, Kelly HG, Anderson
                          SC, Edwards LE, Gimpelson RJ, Perez RE.
                          Photodynamic therapy of rat endometrium
                          sensitized with tin ethyl etiopurpurin. J Am
                          Assoc Gynecol Laparosc 1996 Aug;3(4):561-70.
REFERENCES                UI/97038244. Coats WD Jr, Currier JW, Mejias
                          Y, Narciso HL, Faxon DP. Tin ethyl
                          etiopurpurin significantly inhibits vascular
                          smooth muscle cell proliferation in vivo.
REFERENCES                ICA11/96923595. Grekin R, Razum N, Trommer R,
                          Doiron D, Snyder A, Tin ethyl etiopurpurin
                          (SNET2) photodynamic therapy (PDT): results
                          of a phase I/II clinical study conducted at
                          UCSF for the treatment of AIDS-associated
                          cutaneous Kaposi's sarcomas. Int Conf AIDS.
                          1996 Jul 7-12;11(2):98 (abstract no.
                          We.B.3243). PDT Inc. and UCSF present
                          photodynamic-therapy KS data at World AIDS
                          Conference. Business wire, July 11, 1996.
REFERENCES                UI/95368514. Kongshaug M, Moan J, Cheng LS,
                          Morgan AR. Binding of etiopurpurin to human
                          plasma proteins. Delivery in cremophor EL and
                          dimethyl sulphoxide. III. Int J Bichem Cell
                          Biol 1995 May;27(5):481-92.
REFERENCES                UI/95277603. Kongshaug M, Cheng LS, Moan J,
                          Morgan AR, Binding of etiopurpurin and
                          tin-coordinated etiopurpurin to human plasma
                          proteins. Delivery in cremophore EL and
                          dimethyl Sulfoxide (paper II). Int J Biochem
                          Cell Biol 1995 Jan;27(1):71-87.
REFERENCES                AIDS/97229493H. PDT Therapy for KS shows
                           promising results [news]. Aids Patient Care
                           STDs. 1996 Apr;10(2):135.
ENTRY MONTH                199703
LAST REVISION DATE         19990322

40
UNIQUE IDENTIFIER          DRG-0267
NAME OF SUBSTANCE          Memantine [USAN 1998]
REGISTRY NUMBER            19982-08-2
STANDARD CHEMICAL NAME     3,5-Dimethyl-1-adamantamine [USAN 1998]
SYNONYMS                   1-amino-3,5-dimethyladamantane [Merck Index
                           1996]
SYNONYMS                   3,5-Dimethyltricyclo(3.3.1.1(3,7))decan-1-ami-
                           ne [Merck Index 1996]
SYNONYMS                   Tricyclo(3.3.1.13,7)decan-1-amine,
                           3,5-dimethyl- [CHEMID]
SYNONYMS                   DMAA [Merck Index 1996]
SYNONYMS                   D-145 [Merck Index 1996]
PROTOCOL ID NUMBERS        NIAID ACTG 301
PHARMACOLOGICAL ACTION     MODE OF ACTION: Glutamate receptor
                           antagonists (such as memantine) with
                           selective action at the N-methyl-D-aspartate
                           (NMDA) receptor are promising agents for the
                           neuroprotective and symptomatic
                           pharmacotherapy of various neurophyschiatric
                           disorders. The Ki-value of memantine at eht
                           phencyclidine (PCP) binding site of the NMDA
                           receptor is 0.5 micorM in human frontal
                           cortex. The serum levels ranged from 0.025 to
                           0.529 microM with daily doses between 5 and
                           30 mg. CSF levels were highly correlated to
                           serum levels. Memantine, as well as the
                           antagonist MK-801, prevented the effects of
                           gp120 (a protein that protrudes from the HIV
                           surface and binds to CD4+ T cells) on
                           cortical cell cultures at micromolar
                           concentrations. [Nervanarzt 1996 Jan;67(1);
                           In Conf AIDS 1994 Aug 7-12;10(1)]
DISEASES STUDIED/TREATED   The cytoprotective effect of memantine in
                           cortical cell cultures may qualify the drug
                           for the treatment of AIDS-related dementia.
                           [Eur J Pharmacol 1993 Aug 10;240(1)]
CLASSIFICATION CODE        Antiparkinsonian [NIAID ACTG 301]
OTHER MAJOR USES           Memantine is currently used in the
                           neurodegenerative disease such as spasticity,
                           Parkinson's disease and dementia syndrome.
                           [Int Conf AIDS 1992 Jul 19-24;8(3); J Neural
                           Transm Suppl 1995;46]
SUBSTANCE INTERACTIONS     The clinical observation that
                           co-administration of L-dopa with either
                           memantine or amantadine results in
                           enhancement of their action is also reflected
                           in an animal model of Parkinson's disease.
                           Combination therapy should allow the use of
                           lower doses of both drugs which may reduce
                           the occurences of side effects and may also
                           be predicted to have additional benefits
                           related to the neuroprotective properties of
                           memantine, amantadine, and L-deprenyl. [J
                           Neural Transm Gen Sect 1994;98(1)]
ADVERSE EFFECTS            Amantadine and memantine have been
                         administered to human patients with
                         idiopathic Parkinson's disease and spasticity
                         for many years without serious adverse
                         effects. [Nervanarzt 1996 Jan;67(1)]
CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: Hydrochloride, crystals
                         from alcohol/ether. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C12h21n [Merck Index 1996]
CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 179.31 [Merck Index 1996]
CHEMICAL/PHYSICAL DATA   MELTING POINT: 258 C (hydrochloride salt)
                         [Merck Index 1996]
CHEMICAL/PHYSICAL DATA   ELEMENTAL COMP: C80.38%, H11.81%, N7.81%
                         [Merck Index 1996]
CHEMICAL/PHYSICAL DATA   SOLUBILITY: Oil. [Merck Index 1996]
MANUFACTURERS            Neurobiological Technologies Incorporated;
                         1387 Marina Way South; Richmond, CA 94804
REFERENCES               MED/98221370. Stroke, Alzheimer's patients
                         may benefit from AIDS dementia drug [news].
                         Dent Today. 1997 Feb;16(2):29.
REFERENCES               ASHM9/98095095. Brew BJ. HIV neurological
                         disease:--developments and new therapies.
                         Annu Conf Australas Soc HIV Med. 1997 Nov
                         13-16;9:57 (abstract no. IS 29).
REFERENCES               MED/97343848. Lipton SA. Treating AIDS
                         dementia [letter; comment]. Science, 1997 Jun
                         13,276:5319,1629-30.
REFERENCES               MED/97255662. Melton ST, Kirkwood CK, Ghaemi
                         SN. Pharmacotherapy of HIV dementia. Ann
                         Pharmacother, 1997 Apr,31:4,457-73.
REFERENCES               MED/97124661. Raber J, Toggas SM, Lee S,
                         Bloom FE, Epstein CJ, Mucke L. Central
                         nervous system expression of HIV-1 Gp120
                         activates the hypothalamic-pituitary-adrenal
                         axis: evidence for involvement of NMDA
                         receptors and nitric oxide sythase. Virology
                         996 Dec 15;226(2):362-73.
REFERENCES               MED/96314092. Pittaluga A, Pattarini R,
                         Severi P, Raiteri M. Human brain
                         N-methyl-D-aspartate receptors regulating
                         noradrenaline release are positively
                         modulated by HIV-1 coat protein gp120. AIDS,
                         1996 May,10:5,463-8.
REFERENCES               MED/96420092. Muller WE, Pergande G, Ushijima
                         H, Schleger C, Kelve M, Perovic S.
                         Neurotoxicity in rat cortical cells caused by
                         N-methyl-D-aspartate (NMDA) and gp120 of
                         HIV-1: induction and pharmological
                         intervention. Prog Mo1 Subcell Biol.
                         1996;16:44-57.
REFERENCES               MED/96419614. Toggas SM, Masliah E, Mucke L.
                         Preventive of HIV-1 gp120-induced neuronal
                         damage in the central nervous system of
                         transgenic mice by the NMDA receptor
                         antagonist memantine. Brian Res. 1996 Jan
                         15;706(2):303-7.
REFERENCES               MED/93261588. Kornhuber J, Bormann J,
                         Neuroprotective effects of memantine
                         (letter;comment). Neurology. 1993
                         May;43(5):1054-5.
REFERENCES               MED/93049850. Muller WE, Schroder HC,
                         Ushijima H, Dapper J, Bormann J. Gp120 of
                         HIV-1 induces apoptosis in rat cortical cell
                           cultures: prevention by memantine. Eur J
                           Pharmacol. 1992 Jul 1;226(3):209-14.
REFERENCES                 MED/92319302. Lipton SA. Memantine prevents
                           HIV coat protein-induced neuronal injury in
                           vitro (see comment in: Neurology 1993
                           May;43(5):1054-5]. Neurology. 1992
                           Jul;42(7):1403-5.
ENTRY MONTH                199809
LAST REVISION DATE         19990322

41
UNIQUE IDENTIFIER          DRG-0266
NAME OF SUBSTANCE          1263W94 [FDA 263A]
PROTOCOL ID NUMBERS        FDA 263A
DISEASES STUDIED/TREATED   In testing for treatment of cytomegalovirus
                           infection[4th Conf Retro and Opportun Infect.
                           1997 Jan 22-26]
CLASSIFICATION CODE        Antiviral [FDA 263A]
SUBSTANCE INTERACTIONS     The combination of 1263W94 and ganciclovir
                           was additive against CMV. 1263W94 did not
                           interfere with the anti-HIV activity of AZT,
                           ddI, ddC, 3TC, or nevirapine. [4th Conf Retro
                           and Opportun Infect. 1997 Jan 22-26]
ADVERSE EFFECTS            1263W94 was well tolerated by all 12
                           volunteers at all dose levels with no serious
                           adverse events reported. A frequently
                           reported adverse effect (by 9 subjects) was
                           bitter or stale taste in mouth occurring
                           with dose-dependent frequency and intensity.
                           No patient withdrew due to this effect. Other
                           infrequent drug-related events included:
                           headache (4), drowsiness/dizziness (3), and
                           feeling sleepy (1). There were no abnormal or
                           clinically significant findings in vital
                           signs, ECG and clinical laboratory values.
                           [4th Conf Retro and Opportun Infect. 1997 Jan
                           22-26]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: 1263W94 is a benzimidazole
                           riboside exhibiting potent and selective
                           inhibition of human cytomegalovirus. [Prog
                           Abst Intersci Conf Antimicrob Agents
                           Chemother. '96 Sep]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [4th Conf Retro and
                           Opportun Infect. 1997 Jan 22-26]
MANUFACTURERS              Glaxo Wellcome; 5 Moore Drive / PO Box 13398;
                           Research Triangle Park, NC 27709
REFERENCES                 AIDS/97926719. Wang LH, Peck R, Chan PQ,
                           Youle M, Eaves J, Bye A. A phase I
                           tolerability and pharmacokinetic (PK) trial
                           of 1263W94, a novel anti-HCMV agent, in
                           HIV-infected volunteers. 4th Conf Retro and
                           Opportun Infect, 1997 Jan22-26,189(abstract
                           no.674).
REFERENCES                 AIDS/98927771. Biron KK, Davis MG, Stanat SC,
                           Walton LM, Smith A, Koszalka GW, Drach JC,
                           Townsend LB, Harvey RJ. Antiviral activity
                           and mechanism of action of 1263w94, a
                           benzimidazole riboside inhibitor of human
                           cytomegalovirus. Program Abstr Intersci Conf
                           Antimicrob Agents Chemother. 1996 Sep
                           15-18;:178 (abstract no. H85).
REFERENCES               AIDS/98927755. Wang LH, Lyogendran S, Weller
                         S, Wiggs R, Bye A. A phase I trial evaluating
                         the tolerability and pharmacokinets (PK) of
                         1263W94 following single oral administration
                         of escalating doses in normal healthy
                         volunteers. Program Abstr Intersci Conf
                         Antimicrob Agents Chemother. 1996 Sep
                         15-18;:168 (abstrat no. H28).
REFERENCES               AIDS/98927754. Frick LW, Hsieh AY, Good SS.
                         Pharmacokinetics and metabolism in rats and
                         monkeys of 1263W94, a potent and selective
                         inhibitor of human cytomegalvirus. Program
                         Abstr Intersci Conf Antimicrob Agents
                         Chemother. 1996 Sep 15-18;:168 (abstract no.
                         H27).
REFERENCES               Cadman J. (GMHC) CMV trials struggle to
                         enroll. Slow but steady for Glaxo's 1263W94.
                         Treatment Issues, September 1997, Volume 11
                         Number 9.
REFERENCES               Bartnof H, Chang H, New drug 1263W94
                         effective against ganciclovir-resistant
                         cytomegalovirus in vitro. Bulletin of
                         Experimental Treatments for AIDS (BETA), No.
                         31, December 1996.
ENTRY MONTH              199703
LAST REVISION DATE       19980925

42
UNIQUE IDENTIFIER        DRG-0265
NAME OF SUBSTANCE        Influenza virus vaccine [AHFS Drug
                         Information 1997]
SYNONYMS                 Fluogen [AHFS Drug Information 1996]
SYNONYMS                 Fluvirin [AHFS Drug Information 1997]
SYNONYMS                 FluShield [AHFS Drug Information 1997]
SYNONYMS                 Fluzone [AHFS Drug Information 1997]
SYNONYMS                 Fluviral [USP DI 1996]
SYNONYMS                 Fluimmune [Physicians GenRx 97]
PROTOCOL ID NUMBERS      NCI 98 C-0011
PROTOCOL ID NUMBERS      NIAID ACTG 340
PHARMACOLOGICAL ACTION   MODE OF ACTION: Influenza virus vaccine
                         promotes active immunity to influenza virus
                         by inducing production of specific
                         antibodies. Protection is provided only
                         against those strains of virus from which the
                         vaccine is prepared and closely related
                         strains. Vaccine has been shown to induce
                         both a systemic (i.e., in serum) and, to a
                         lesser extent, local (i.e., in upper
                         respiratory tract) immune response. Local
                         mucosal immunity in the respiratory tract
                         (e.g., in tonsils) confers the initial line
                         of defense against influenza. Possibly,
                         migration of activated B cells, particularly
                         IgA-committed B cells, via lymphatic drainage
                         from the injection site to the mucosal
                         surface of the tonsils is responsible for the
                         local response after vaccination.
                         Influenza-specific antibodies are
                         predominantly IgG and IgM in serum and IgA in
                         oral fluids. The development of antibody
                         response to immunization occurs after
                           approximately 2 weeks. Duration of immunity
                           varies widely but lasts approximately 1 year.
                           The vaccine is available as either a
                           whole-virus or split-virus preparation. The
                           split-virus vaccine is produced by chemically
                           treating a whole-virus preparation to cause
                           inactivation and disruption of significant
                           portions of the virus into smaller subunit
                           particles called subvirions. [AHFS Drug
                           Information 1997]
DISEASES STUDIED/TREATED   Prophylactic to prevent influenza in
                           HIV-infected persons. [AHFS Drug Information
                           1997]
CLASSIFICATION CODE        Vaccine [AHFS Drug Information 1996]
OTHER MAJOR USES           To stimulate active immunity to the influenza
                           virus strains contained in the vaccine. [AHFS
                           Drug Information 1997]
SUBSTANCE INTERACTIONS     Antiviral agents such as amantadine and
                           rimantadine do not appear to interfere with
                           the antibody response to influenza virus.
                           Vaccination should be deferred until
                           immunosuppressive therapy (e.g.,
                           corticosteroids, alkylating agents,
                           corticotropin, antimetabolites, radiation
                           therapy) is discontinued. Patients on
                           warfarin should be monitored for possible
                           enhanced anticoagulant effects when influenza
                           vaccine is administered. Increased serum
                           concentrations of theophylline have been
                           reported after vaccination. Patients on this
                           medication should be observed for toxicity.
                           Concurrent administration of influenza
                           vaccine and polyvalent pneumococcal vaccine,
                           or routine pediatric vaccines including mmR,
                           poliovirus vaccine live oral (OPV), and
                           hemophilus b vaccines (at different sites),
                           can be considered. Interleukin-2 or aspirin
                           have been shown to increase the antibody
                           response to influenza vaccine in geriatric
                           patients. [AHFS Drug Information 1997]
ADVERSE EFFECTS            In adults adverse effects to influenza
                           vaccine are generally mild and occur rarely;
                           they are more frequent in children. Subvirion
                           and purified antigen preparations
                           (split-virus vaccines) have been associated
                           with fewer adverse effects than the
                           whole-virion preparations, especially in
                           children. The most frequent adverse effects
                           of influenza virus vaccine are local effects
                           including soreness, tenderness, erythema, and
                           induration at the injection site. These local
                           reactions generally are slight to moderate in
                           severity and persist up to 2 days. [AHFS Drug
                           Information 1997]
CONTRAINDICATIONS          Influenza virus should not be administered to
                           individuals with history of immediate
                           hypersensitivity - and especially
                           anaphylactic reactions - to chicken eggs or
                           egg products or to other ingredients in the
                           respective vaccine formulations. [AHFS Drug
                           Information 1997]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: Noninfectious suspensions
                          of suitably inactivated influenza virus types
                          A and B or virus subunits, formulated
                          annually; representative of the strains of
                          influenza virus that are likely to circulate
                          in the US in the upcoming winter. [AHFS Drug
                          Information 1997]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: Influenza Virus Vaccine
                          1966-1977, Trivalent Types A and B. Can be:
                          purified surface antigen, subvirion or whole
                          virion depending on type of product and
                          manufacturer. [AHFS Drug Information 1997]
CHEMICAL/PHYSICAL DATA    STABILITY: Potency is destroyed by freezing.
                          [AHFS Drug Information 1997]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Parenteral suspension. [AHFS
                          Drug Information 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Although it has been
                          administered subcutaneously in prior years,
                          IM injections are preferred. Should not be
                          given IV. [AHFS Drug Information 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store between 2 - 8 C.
                          Do not freeze. [AHFS Drug Information 1997]
MANUFACTURERS             Warner - Lambert Parke - Davis; 201 Tabor
                          Road; Morris Plains, NJ 07950
REFERENCES                MED/97366923. Fowke KR, D'Amico R, Chernoff
                          DN, Pottage JC Jr, Benson CA, Sha BE, Kessler
                          HA, Landay AL, Shearer GM. Immunologic and
                          virologic evaluation after influenza
                          vaccination of HIV-1-infected patients. AIDS,
                          1997 Jul, 11:8, 1013-21.
REFERENCES                AIDS/97927188. Moss RB, Wallace MR, Turner
                          JL, Giermakowska W, Lanza P, Ferre F, Trauger
                          RI, Daigle AE, Richieri SP, Theofan G; at.al.
                          A comparison of the effect of immunization
                          with a gp120 depleted inactivated HIV-1 in
                          incomplete Freund's adjuvant (HIV-1
                          immunogen) compared with immunization with an
                          influenza vaccine on virus specific immune
                          function. Conf Adv AIDS Vaccine Dev, 1997 May
                          4-7,:224 (Poster 119).
REFERENCES                ICA11/96923719. Salassa B, Zucco S, Macor A,
                          Sciullo D, Ruffatto R, Piro F, Soranzo ML.
                          Influenza vaccine response in HIV patients.
                          Int Conf AIDS, 1996 Jul 7-12, 11:2, 121
                          (abstract no. We.B.3371).
REFERENCES                ICA11/96923172. Ward C, Salvato P, Thompson
                          C. HIV RNA changes in HIV-positive patients
                          following influenza vaccination. Int Conf
                          AIDS, 1996 Jul 7-12, 11:2, 18 (abstract no.
                          We.B.114).
REFERENCES                AIDS/96920424. Jackson CR, Vavro CL,
                          Pennington KN, Lanier ER, Valentine ME,
                          McKinney RE, Dilibert JH, Wilfert CM, Katz
                          SL, St Claire MH. Effect of influenza
                          immunization on immunologic and virologic
                          parameters in HIV+ pediatric patients. 3rd
                          Conf Retro and Opportun Infect, 1996 Jan
                          28-Feb 1:132.
REFERENCES                MED/97094140. Glesby MJ, Hoover DR,
                          Farzadegan H, Margolick JB, Saah AJ. The
                          effect of influenza vaccination on human
                         immunodeficiency virus type 1 load: a
                         randomized, double-blind, placebo-controlled
                         study. J Infect Dis. 1996 Dec; 174(6):1332-6.
REFERENCES               MED/96417670. Pau AK, McNicholl IR, Pursell
                         KJ. Active immunization in HIV-infected
                         patients. Pharmacotherapy. 1996 Mar-Apr;
                         16(2):163-70.
REFERENCES               MED/97005607. Ramilo O, Hicks PJ, Borvak J,
                         Gross LM, Zhong D, Squires JE, Vitetta ES. T
                         cell activation and human immunodeficency
                         virus replication after influenza
                         immunization of infected children. Pediatr
                         Infect Dis J. 1996 Mar;15(3):197-203.
REFERENCES               AIDS/97920716. Crowley-Nowick PA, Bell MC,
                         Edward RP, Brockwell RC, Partridge EE,
                         Mestecky J. Rectal immunization with the flu
                         vaccine elicits genital tract reponses. Conf
                         Adv AIDS Vaccine Dev. 1996 Feb 11-15;:142
                         [Poster 22].
REFERENCES               MED/95289357. Simonsen L, Buffington J,
                         Shapiro CN, Homan RC, Strine TW, Grossman BJ,
                         Williams AE, Schonberger LB. Multiple false
                         reactions in viral antibody screening assays
                         after influenza vaccination. Am J Epidemiol.
                         1995 Jun 1; 141(11):1089-96.
ENTRY MONTH              199702
LAST REVISION DATE       19990312

43
UNIQUE IDENTIFIER        DRG-0264
NAME OF SUBSTANCE        Nandrolone Decanoate [USAN 1998]
REGISTRY NUMBER          360-70-3
STANDARD CHEMICAL NAME   17beta-hydroxyester-4-en-3-one decanoate
                         [USAN 1998]
SYNONYMS                 Deca-Durabolin [Merck Index 1996]
SYNONYMS                 Deca-Durabol [Merck Index 1996]
SYNONYMS                 Deca-Hybolin [Merck Index 1996]
SYNONYMS                 Hybolin Decanoate [Merck Index 1996]
SYNONYMS                 Retabolil [Merck Index 1996]
SYNONYMS                 Nandrobolic L.A. [USAN 1997]
SYNONYMS                 19-Nortestosterone decanoate [Merck Index
                         1996]
PROTOCOL ID NUMBERS      NIAID ACTG 329
PHARMACOLOGICAL ACTION   MODE OF ACTION: All anabolic steroids are
                         approximately equal in efficacy. They are
                         synthetic derivatives of testosterone.
                         Deletion of the C-19 methyl group results in
                         reduction -- but not total elimination -- of
                         androgenic properties, and retention of the
                         anabolic, tissue-building properties.
                         Anabolic steroids reverse catabolic processes
                         and negative nitrogen balance by promoting
                         protein anabolism and stimulating appetite.
                         Anabolic steroids are antianemic by
                         increasing production of erythropoietin,
                         hemoglobin and red blood cell volume. For
                         nandrolone decanoate, a 100mg intramuscular
                         dose reaches peak concentration in 3-6 days.
                         When nandrolone decanoate was given for 16
                         weeks to HIV+ men who had lost 5-15% of their
                         usual body weight, there were significant
                           increases in weight (mean, 0.14 kg per week)
                           and lean body mass (mean, 3 kg by
                           anthropometry). Quality of life parameters,
                           especially functionality, increased
                           significantly during the trial. No subject
                           experienced toxicity. [USP DI 1998; AIDS.
                           1996 Jun;10(7)]
DISEASES STUDIED/TREATED   Treatment of hypogonadism associated with
                           megestrol acetate administration in HIV+
                           women. Used in the management of HIV
                           associated anorexia and weight loss. [AmFar
                           Tx Dir December, 1997; Annu Conf Australas
                           Soc HIV Med 1997 Nov 13-16;9]
CLASSIFICATION CODE        Anabolic steroid (Androgen) [USAN 1998]
OTHER MAJOR USES           Nandrolone decanoate is used for the
                           treatment of anemia associated with renal
                           insufficiency. [USP DI 1998]
SUBSTANCE INTERACTIONS     Anabolic steroids can interact with
                           anticoagulants, adrenocorticoids (especially
                           those with significant mineralocorticoid
                           activity), sodium-containing medications or
                           foods, or hepatotoxic medications. [USP DI
                           1998]
ADVERSE EFFECTS            Virilism in females and prepubertal males;
                           bladder irritability, breast soreness
                           (gynecomastia), priapism in males;
                           hypercalcemia in females; iron deficiency,
                           edema, gastric irritation, suppression of
                           clotting factors (in both males and females).
                           Many of the side effects of anabolic steroids
                           are dose-related; therefore, patients should
                           be placed on the lowest possible effective
                           dose. [USP DI 1998]
CONTRAINDICATIONS          Breast cancer in males and females, severe
                           hepatic function impairment, hypercalcemia,
                           nephrosis, prostatic cancer. [USP DI 1998]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Injectable anabolic
                           steroid. [AmFar Tx Dir December, 1997]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: White to yellow
                           crystals[Merck Index 1996]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C28H44O3 [Merck Index
                           1996]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 428.66 [USAN 1998]
CHEMICAL/PHYSICAL DATA     MELTING POINT: 32-35 C [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     ELEMENTAL COMP: C78.45%, H1035%, O11.20%
                           [Merck Index 1989]
CHEMICAL/PHYSICAL DATA     SOLUBILITY: Insol. in water, freely soluble
                           in ethanol, ether, acetone, chloroform, oils.
                           [Merck Index 1996]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 50mg/ml, 100mg/ml or 200mg/ml
                           dosage forms are available. [USP DI 1998]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intramuscular injection,
                           50-100mg (females) or 50-200mg (males) at 1
                           to 4 week intervals. [USP DI 1998]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Store below 40 C
                           preferably between 15 and 30 C. [USP DI 1998]
MANUFACTURERS              Organon Incorporated; 375 Mount Pleasant
                           Avenue; West Orange, NJ 07052
REFERENCES                 MED/98287074. Muurahainen N, Mulligan K.
                           Clinical trials update in human
                           immunodeficiency virus wasting. Semin Oncol.
                          1998 Apr;25(2 Suppl 6):104-11.
REFERENCES                ASHM9/98095152. Batterham M, Garsia R.
                          Randomised prospective medium-term comparison
                          of megestrol acetate, nandrolone decanoate
                          and dietary therapy alone for HIV associted
                          weight loss. Annu Conf Australas Soc HIV Med.
                          1997 Nov 13-16;9:91 (abstrat no. IS 87).
REFERENCES                AIDS/98703400. Corcoran CP, Grinspoon S.
                          Diagnosis and treatment of endocrine
                          disorders in the HIV-infected patient. J Int
                          Assoc Physicians AIDS Care. 1998
                          Feb;4(2):10-4, 34.
REFERENCES                ASHM8/97153642. Gold J, High H, Li Y,
                          Michelmore H, Bodsworth N, Finlayson R,
                          Furner V, Allen B, Oliver C. Use of DECA
                          durabolin (nandrolone decanoate) in the
                          treatment of wasting in HIV patients. Annu
                          Conf Australas Soc HIV Med. 1996 Nov
                          14-17;8:70 (abstract no. 62).
REFERENCES                AIDS/96701937. Anonymous. Anabolic steroid
                          boosts weight. GMHC Treat Issues,1996
                          Sep,10:9,8-9.
REFERENCES                ICA11/96920934. Bucher G, Berger DS,
                          Fields-Gardner C, Jones R, Reiter WM. A
                          prospective study on the safety and effect of
                          nanadrolone decanoate in HIV-positive
                          patients. Int Conf AIDS. 1996 Jul 7-12;
                          11(1): 26 (abstract no.Mo.B.423).
REFERENCES                MED/96399354. Gold J, High HA, Li Y,
                          Michelmore h, Bodsworth NJ, Finlayson R,
                          Furner VL, Allen BJ, Oliver CJ. Safety and
                          efficacy of nandrolone decanoate for
                          treatment of wasting in patients with HIV
                          infection. AIDS. 1996 Jun; 10(7):745-52.
REFERENCES                ASHM6/95291840. Gold J, High H, Michelmore H,
                          Oliver C. The effect of the anabolic steroid,
                          nandrolone decanoate, on lean body mass and
                          quality of life in HIV+ men--a preliminary
                          analysis. Annu Conf Austalas Soc HIV Med.
                          1994 Nov 3-6; 6:264 (unnumbered poster).
ENTRY MONTH               199701
LAST REVISION DATE        19990322

44
UNIQUE IDENTIFIER         DRG-0263
NAME OF SUBSTANCE         Nelfinavir [Incomplete]
REGISTRY NUMBER           159989-65-8
STANDARD CHEMICAL NAME    (3s,4aS,8aS)-N-tert-Butyl-2-((2R,3R)-3-(3,2-c-
                          resotamido)
                          -2-hydroxy-4-(phenylthio)butyl)decahydro-3-is-
                          oquinoline- carboxamide monomethanesulfonate
                          (salt) (For the Nelfinar mesylate)
                          [Incomplete]
SYNONYMS                  Viracept [USAN 1997]
PROTOCOL   ID   NUMBERS   FDA 039E
PROTOCOL   ID   NUMBERS   FDA 228E
PROTOCOL   ID   NUMBERS   FDA 232H
PROTOCOL   ID   NUMBERS   FDA 244C
PROTOCOL   ID   NUMBERS   FDA 244D
PROTOCOL   ID   NUMBERS   FDA 246H
PROTOCOL   ID   NUMBERS   FDA 259A
PROTOCOL ID NUMBERS      FDA 259C
PROTOCOL ID NUMBERS      FDA 259D
PROTOCOL ID NUMBERS      FDA 259E
PROTOCOL ID NUMBERS      FDA 259F
PROTOCOL ID NUMBERS      FDA 292A
PROTOCOL ID NUMBERS      NCI 95 C-0192
PROTOCOL ID NUMBERS      NIAID 98 I-0147
PROTOCOL ID NUMBERS      NIAID 99 I-0032
PROTOCOL ID NUMBERS      NIAID ACTG 341
PROTOCOL ID NUMBERS      NIAID ACTG 366
PROTOCOL ID NUMBERS      NIAID ACTG 380
PROTOCOL ID NUMBERS      NIAID ACTG 382
PROTOCOL ID NUMBERS      NIAID ACTG 384
PROTOCOL ID NUMBERS      NIAID ACTG 388
PROTOCOL ID NUMBERS      NIAID ACTG 397
PROTOCOL ID NUMBERS      NIAID ACTG 398
PROTOCOL ID NUMBERS      NIAID CPCRA 057
PROTOCOL ID NUMBERS      NIAID CPCRA 058
PROTOCOL ID NUMBERS      FDA 200F
PROTOCOL ID NUMBERS      FDA 229G
PROTOCOL ID NUMBERS      FDA 229H
PROTOCOL ID NUMBERS      FDA 229J
PROTOCOL ID NUMBERS      FDA 229K
PROTOCOL ID NUMBERS      FDA 229P
PROTOCOL ID NUMBERS      FDA 232E
PROTOCOL ID NUMBERS      FDA 238J
PROTOCOL ID NUMBERS      FDA 245D
PROTOCOL ID NUMBERS      FDA 259B
PROTOCOL ID NUMBERS      FDA 264A
PROTOCOL ID NUMBERS      FDA UNAP 11
PROTOCOL ID NUMBERS      NIAID ACTG 353
PROTOCOL ID NUMBERS      NIAID ACTG 356
PROTOCOL ID NUMBERS      NIAID ACTG 359
PROTOCOL ID NUMBERS      NIAID ACTG 364
PROTOCOL ID NUMBERS      NIAID ACTG 372
PROTOCOL ID NUMBERS      NIAID ACTG 377
PROTOCOL ID NUMBERS      NIAID ACTG 378
PROTOCOL ID NUMBERS      NIAID CPCRA 042
SECONDARY SOURCE ID      AG1343 [USAN 1997]
PHARMACOLOGICAL ACTION   MODE OF ACTION: Nelfinavir is a selective,
                         competitive, reversible inhibitor of HIV
                         protease, an aspartic endopeptidase that
                         functions as a homodimer, and plays an
                         essential role in the HIV replication cycle
                         and the formation of infectious virus. By
                         interfering with the formation of essential
                         proteins and enzymes, nelfinavir blocks
                         maturation of the virus and causes the
                         formation of immature, noninfectious virions.
                         Nelfinavir is active in both acutely and
                         chronically infected cells since it targets
                         the HIV replication cycle afte translation
                         and before assembly. The antiviral activity
                         of nelfinavir does not depend on conversion
                         to an active metabolite. Nelfinavir is a
                         highly specific inhibitor of HIV protease and
                         does not appear to interfere with similar
                         human enzymes at clinically relevant
                         concentrations. Nelfinavir is well absorbed
                         following oral administration. Peak plasma
                         concentrations are attained within 2-4 hours
                           when 500-800 mg does are administered with
                           food. Nelfinavir is more than 98% bound to
                           plasma protein. It is not known whether
                           nelfinavir crosses the human placenta. While
                           it is not known whether nelfinavir is
                           distributed into human milk, the durg is
                           distributed into milk in rats. Nelfinavir is
                           metabolized to many oxidative metabolites in
                           the liver, and is excreted principally in the
                           feces, both as unchanged drug and as
                           metabolites. HIV variants resistant to
                           nelfinavir emerge rapidly when the drug is
                           used as monotherapy, but such emergence
                           appears to be delayed when nelfinavir is used
                           in combination with nucleoside analogs. There
                           is evidence that some degree to
                           cross-resistance can occur among various HIV
                           protease inhibitors. Cross-resistance between
                           nelfinavir and NRTIs and NNRTIs is highly
                           unlikely since the drugs target different
                           enzymes. [AHFS Drug Information 1999; AmFAR
                           Tx Dir 1998;9(2)]
DISEASES STUDIED/TREATED   FDA approved 03/14/97 for the treatment of
                           HIV infection when antiretroviral therapy is
                           warranted in adults and pediatrics >=2 years
                           old. [AmFAR Tx Dir 1996;8(2)]
CLASSIFICATION CODE        Protease inhibitor [Incomplete]
SUBSTANCE INTERACTIONS     Nelfinavir may be safely administered for
                           prolonged periods and with nucleoside
                           analogues. [Int Conf AIDS 1996 Jul
                           7-12;11(1):18]
ADVERSE EFFECTS            Adverse events include loose stools, poor
                           concentration, intermittent headaches,
                           moderate hypertension, and elevated liver
                           enzymes. No unexpected adverse events have
                           been reported in patients receiving
                           concomitant nucleoside analogues. [Int Conf
                           AIDS 1996 Jul 7-12;11(1):18; AmFAR Tx Dir
                           1996;8(2)]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Nelfinavir is a
                           non-peptidic protease inhibitor, which is
                           highly bioavailable after oral
                           administration. [AmFAR Tx Dir 1996;8(2)]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C32H45N304S.CH403S [USAN
                           1997]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 663.9 [USAN 1997]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: In clinical trials, 500 mg,
                           750 mg, or 1000 mg tid[Int Conf AIDS 1996 Jul
                           7-12;11(1):18]
MANUFACTURERS              Agouron Pharmaceuticals Incorporated; 10350
                           North Torrey Pines Road; La Jolla, CA 92037
REFERENCES                 MED/99125808. Aweeka F, Jayewardene A,
                           Staprans S, Bellibas SE, Kearney B, Lizak P,
                           Novakovic-Agopian T, Price RW. Failure to
                           detect nelfinavir in the crebrospinal fluid
                           of HIV-1--infected patients with and without
                           AIDS dementia complex. J Acquir Immune Defic
                           Syndr Hum Retrovirol. 1999 Jan 1;20(1):39-43.
REFERENCES                 MED/99079498. Markus R, Brew BJ. HIV-1
                           peripheral neuropathy and combination
                           antiretroviral therapy [letter] AUTHORS:
                         SOURCE: Lancet. 1998 Dec
                         12;352(352)(9144):1906-7.
REFERENCES               MED/98379946. Sharland M, Watkins AM,
                         Dalgleish AG, Cammack N, Westby M. Immune
                         reconstitution in HAART-treated children with
                         AIDS. Highly Active Anti-Retroviral Therapy
                         [letter] Lancet. 1998 Aug 15;352(9127):577-8.
REFERENCES               MED/98327095. Lillibridge JH, Liang BH, Kerr
                         BM, webber S, Quart B, Shetty BV, Lee CA.
                         Characterization of the selectivity and
                         mechanism of human cytochrome P450 inhibition
                         by the human immunodeficiency virus-protease
                         inhibitor nelfinavir mesylate. Drug Metab
                         Dispos. 1998 Jul;26(7):609-16.
REFERENCES               MED/98268846. Markowitz M, Conant M, Hurley
                         A, Schluger R, Duran M, Peterkin J, Chapman
                         S, Patick A, Hendricks A, Yuen GJ, et al. A
                         preliminary evaluation of nelfinavir
                         mesylate, an inhibitor of human
                         immunodeficiency virus (HIV)-protease, to
                         treat HIV infection. J Infect Dis. 1998
                         Jun;177(6):1533-40.
REFERENCES               MED/98281097. Carr A, Samaras K, Burton S,
                         Law M, Freund J, Chisholm DJ, Cooper DA. A
                         syndrome of peripheral lipodystrophy,
                         hyperlipidaemia and insulin resistance in
                         patients receiving HIV protease inhibitors.
                         AIDS. 1998 May 7;12(7):F51-8.
REFERENCES               MED/98269329. Paterson DL, Singh N.
                         Exacerbated hyperglycemia associated with
                         nelfinavir [letter] Ann Pharmacother. 1998
                         May;32(5):609-10.
REFERENCES               AIDS/98930327. Sousa AE, Chaes AF, Doroana M,
                         Antunes F, Victorino RM. Assessment of
                         immunological recovery after triple
                         antiretroviral therapy in HIV1 infection -
                         effects on lymphocyte activation markers and
                         T cell function. HIV Pathog Treat Conf. 1998
                         Mar 13-19;:56 (abstract no. 2038).
REFERENCES               AIDS/98930323. Ramirez CM, Gottlieb MS,
                         Becker M, Dubin J A. Viral suppression with
                         nelfinavir in a protease experienced
                         population. HIV Pathog Treat Conf. 1998 Mar
                         13-19;:55 (abstact no. 2034).
REFERENCES               AIDS/98930295. Chavan S, Kaplan M, Pahwa S.
                         Reduction in virus load leads to decrease in
                         lymphocyte apoptosis in HIV infected patients
                         treated with reverse transcriptase inhibitors
                         and a HIV specific protease inhibitor,
                         nelfinavir (Viracept). HIV Pathog Treat Conf.
                         1998 Mar 13-19;:48 (abstract no. 2006).
ENTRY MONTH              199701
LAST REVISION DATE       19990325

45
UNIQUE IDENTIFIER        DRG-0262
NAME OF SUBSTANCE        CI-1012 [NIAID 97 I-032]
REGISTRY NUMBER          2527-57-3
STANDARD CHEMICAL NAME   Benzamide, 2,2'-dithiobis- [CHEMID]
SYNONYMS                 2,2'-Dithiobisbenzamide [CHEMID]
SYNONYMS                 2,2'-Dithiobis(benzamide) [CHEMID]
PROTOCOL ID NUMBERS        NIAID 97 I-032
PROTOCOL ID NUMBERS        FDA 278A
PROTOCOL ID NUMBERS        FDA 278B
SECONDARY SOURCE ID        PD 159206 [3rd Conf Retro and Opportun Infect
                           1996]
PHARMACOLOGICAL ACTION     Zinc fingers are part of the viral
                           nucleocapsid protein that envelops HIV RNA
                           inside the virus. The zinc fingers are
                           believed to play a vital role in two stages
                           of the viral life cycle: (1) they bind to HIV
                           RNA and package into anew virus budding out
                           from the cell; and (2) they appear to
                           stabilize the RNA during reverse
                           transcription of HIV RNA into DNA. Compounds
                           that eject the zinc from one of the zinc
                           fingers may disrupt its bond with viral RNA
                           and thus with either the maturation of new
                           infectious virus or infection of the cell.
                           C1-1012 targets NCp7, a highly conserved,
                           multifunctional structural protein, and
                           inhibits production of virions in
                           HIV-infected cells in vitro. CI-1012 does not
                           have direct virucidal effect since pretreated
                           virions had similar level of infectivity as
                           untreated virions. In vitro experiments
                           indicate that CI-1012 inhibits an early stage
                           of HIV infection. Comparison with other drugs
                           such as AZT indicates that CI-1012 inhibits a
                           step after the virus binds to cells. DNA PCR
                           analysis of infected cells showed that the
                           rate of full length DNA synthesis was slowed.
                           Biochemical assay shows that CI-1012 can
                           extrude zinc ions from HIV nucleocapsid
                           protein. CI-1012 does not have any observable
                           effect on genomic RNA packaging. In a rising,
                           single-dose, placebo controlled clinical
                           trial, oral doses of 25-, 50-, 100-, 150- and
                           250-mg CI-1012 were administered to 24
                           healthy subjects. Clinical labortory
                           measurements, ECGs, and physical assessments
                           were performed throughout the trial. Serial
                           blood and urine samples were collected for
                           CI-1012 assay. Plasma Cmax and AUC increased
                           with increasing dose, tmax was observed 2 - 3
                           hours postdose, and the terminal elimination
                           half-life averaged 33 hours. In summary,
                           single oral doses of up to 250 mg CI-1012
                           demonstrated linera pharmacokinetic behavior
                           and were well tolerated by healthy
                           volunteers. [4th Conf Retro and Opportun
                           Infect 1997 Jan 22-26; 3rd Conf Retro and
                           Opportun Infect 1996; AmFar Tx Dir December,
                           1997]
DISEASES STUDIED/TREATED   Under investigation for the treatment of
                           primary HIV infections in asymptomatic HIV-1
                           infected patients. [NIAID 97 I-032]
CLASSIFICATION CODE        Antiretroviral [NIAID 97 I-032]
CLASSIFICATION CODE        Zinc Finger Inhibitor [NIAID 97 I-032]
ADVERSE EFFECTS            CI-1012 wal well tolerated at all dose
                           levels. The most frequently reported adverse
                           event was headache, noted by approximately
                          33% of subjects who received CI-1012 and
                          placebo. Abnormalities in clinical laboratory
                          parameters were transient and appeared to be
                          unrelated to CI-1012 dose. [4th Conf Retro
                          and Opportun Infect 1997 Jan 22-26]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: CI-1012 is a novel
                          benzamide-disulfide with antiviral activity
                          against HIV-1, HIV-2, clinical isolates and
                          AZT-resistant isolates. [3rd Conf Retro and
                          Opportun Infect 1996]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C14H12N202S2 [CHEMID]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral administration. [NIAID
                          97 I-032]
MANUFACTURERS             Warner - Lambert Parke - Davis; 201 Tabor
                          Road; Morris Plains, NJ 07950
REFERENCES                MED/98049536. de Rocquiqny H, Petitjean P,
                          Tanchou V, Decimo D, Drouot L, Delaunay T,
                          Darlix JL, Roques BP. The zinc fingers of HIV
                          nucleocapsid protein NCp7 direct interactions
                          with the viral regulatory protein Vpr. J Biol
                          Chem. 1997 Dec 5;272(49):30753-9.
REFERENCES                MED/97173291. Tummino PJ, Harvey PJ, McQuade
                          T, Domagala J, Gogliotti R, Sanchez J, Song
                          Y, Hupe D. The human immunodeficiency virus
                          type 1 (HIV-1) nucleocapsid protein Zinc
                          ejection activity of disulfide benzamides and
                          benzisothiazolones: correlation with anti-HIV
                          and virucidal activities. Antimicrob Agents
                          Chemother. 1997 Feb;41(2):394-400.
REFERENCES                AIDS/97926419. Shailer P, Brodfuehrer J,
                          Sedman A, Vassos A. Single-dose safety,
                          tolerance, and pharmacokinetics of CI-1012, a
                          new HIV antiretroviral agent, in healthy
                          volunteers. 4th Conf Retro and Opportun
                          Infect. 1997 Jan 22-26;:106(abstract no.
                          229).
REFERENCES                AIDS/97702501. Anonymous. Protease inhibitors
                          and beyond. PI Perspect, 1997 Mar, No
                          21,15-6.
REFERENCES                MED/96323138. Turpin JA, Terpening SJ,
                          Schaeffer CA, Yu G, Glover CJ, Felsted RL,
                          Sausville EA, Rice WG. Inhibitors of human
                          immunodeficiency virus type 1 zinc fingers
                          prevent normal processing of gag precursors
                          and result in the release of noninfectious
                          virus particles. J Virol. 1996
                          Sep;70(9):6180-9.
REFERENCES                AIDS/97926098. Sharmeen L, Heldsinger A,
                          Neorr B, McQuade T, Gracheck S, Gracheck S.
                          Role of zinc coordinating amino acids of
                          nucleocapsids in the HIV life cycle. 4th Conf
                          Retro and Opportun Infect. 1997 Jan
                          22-26;:141 (abstract no. 415).
REFERENCES                MED/96165501. Tummino PJ, Scholten JD, Harvey
                          PJ, Holler TP, Maloney L, Gogliotti R,
                          Domagala J, Hupe D. The in vitro ejection of
                          zinc from human immunodeficiency virus (HIV)
                          type 1 nucleocapsid protein by disulfide
                          benzamides with cellular anti-HIV activity.
                          Proc Natl Acad Sci U S A. 1996 Feb
                          6;93(3):969-73.
REFERENCES                 AIDS/96920338. Domagala J, Gogliotti R,
                           Sanchez J, Stier M, Tummino P, Gracheck S,
                           Hupe D, Bader J, Schultz R, Rice W. Two novel
                           classes of HIV-1 inhibitors which interact
                           with 338 nucleocapsid protein P7NC:
                           structure-activity relationships vs.
                           antiviral activity and correlation with Zn
                           ejection. 3rd Conf Retro and Opportun Infect.
                           1996 Jan 28-Feb 1;:116.
REFERENCES                 AIDS/96920341. McQuade T, Heldsinger A,
                           Domagala J, Gracheck S, Sharmeen L.
                           Anti-viral activity of CI-1012 (PD 159206)
                           and CI-1013 (PD 161374) : novel anti-HIV
                           agents which function at early steps of virus
                           replication. 3rd Conf Retro and Opportun
                           Infect. 1996 Jan 28-Feb 1;:116.
REFERENCES                 MED/96072970. Rice WG, Supko JG, Malspeis L,
                           Buckheit RW Jr, Clanton D, Bu M, Graham L,
                           Schaeffer CA, Turpin JA, et al. Inhibitors of
                           HIV nucleocapsid protein zinc fingers as
                           candidates for the treatment of AIDS.
                           Science. 1995 Nov 17;270(5239):1194-7.
REFERENCES                 MED/96015469. Yu X, Hathout Y, Fenselau C,
                           Sowder RC 2nd, Henderson LE, Rice WG,
                           Mendeleyev J, Kun E. Specific disulfide
                           formation in the oxidation of HIV-1 zinc
                           finger protein nucleocapsid p7. Chem Res
                           Toxicol. 1995 Jun;8(4):586-90.
ENTRY MONTH                199701
LAST REVISION DATE         19990322

46
UNIQUE IDENTIFIER          DRG-0261
NAME OF SUBSTANCE          LXR015-1 [FDA 258A]
PROTOCOL ID NUMBERS        FDA 258A
DISEASES STUDIED/TREATED   Under investigation for the treatment of
                           primary HIV infections. [FDA 258A]
CLASSIFICATION CODE        Antiretroviral [FDA 258A]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Capsules. [FDA 258A]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral administration. [FDA
                           258A]
MANUFACTURERS              LXR Biotechnology Incorporated; 1401 Marina
                           Way South; Richmond, CA 94804
ENTRY MONTH                199701
LAST REVISION DATE         19980422

47
UNIQUE IDENTIFIER          DRG-0260
NAME OF SUBSTANCE          Testosterone Enanthate [USAN 1997]
REGISTRY NUMBER            315-37-7
STANDARD CHEMICAL NAME     Androst-4-en-3-one, 17-[(1-oxoheptyl)oxy]-,
                           (17-beta)-; [USAN 1997]
SYNONYMS                   DePatestrye [USAN 1997]
SYNONYMS                   17-((1-Oxoheptyl) oxy)-androst-4-en-3-one
                           [Merck Index 1989]
SYNONYMS                   Androgyn L.A. [USAN 1997]
SYNONYMS                   Andropository [AHFS Drug Information 1996]
SYNONYMS                   Androtardyl [Merck Index 1989]
SYNONYMS                   Ditate [USAN 1997]
SYNONYMS                   Durathate [AHFS Drug Information 1996]
SYNONYMS                   Everone [AHFS Drug Information 1996]
SYNONYMS                   Malogen L.A. [Merck Index 1989]
SYNONYMS                   Orquisterone-E [Merck Index 1989]
SYNONYMS                   Primotestone [Merck Index 1989]
SYNONYMS                   Testosterone oenanthate [Merck Index 1989]
SYNONYMS                   Testoterone heptoate [Merck Index 1989]
SYNONYMS                   Testate [Merck Index 1989]
SYNONYMS                   Testinon [Merck Index 1989]
SYNONYMS                   Testoenant [Merck Index 1989]
SYNONYMS                   Testroval [Merck Index 1989]
PROTOCOL ID NUMBERS        NIAID ACTG 313
SECONDARY SOURCE ID        NSC-17591 [USAN 1997]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Testosterone is the principal
                           endogenous androgen, i.e., an essential
                           hormone responsible for the normal growth and
                           development of the male sex organs and for
                           maintenance of secondary sex characteristics
                           such as growth and maturation of the
                           prostate, seminal vesicles, penis, and
                           scrotum. Like other androgenic anabolic
                           hormones, it produces retention of nitrogen,
                           potassium, sodium and phosphorous; increases
                           protein anabolism and decreases amino acid
                           catabolism and urinary calcium
                           concentrations. Exogenous androgen
                           administration inhibits release of endogenous
                           testosterone via feedback inhibition of
                           pituitary luteinizing hormones. Androgens
                           reportedly stimulate production of
                           erythrocytes, apparently by enhancing
                           production of erythropoietic stimulating
                           factor. Low availability of orally
                           administered testosterone results from
                           metabolism of the drug in the GI mucosa
                           during absorption and on first pass through
                           the liver. The enanthate ester of
                           testosterone is absorbed slowly from the
                           lipid tissue phase at the IM injection site,
                           and has prolonged duration of action (2-4
                           weeks). Plasma half-life of testosterone
                           reportedly ranges from 10-100 minutes.
                           Testosterone is metabolized mainly in the
                           liver to 17-keto-testosterone via two
                           different pathways. Elimination is through
                           sulfuric and glucuronic acid conjugates in
                           the urine (90%). [AHFS Drug Information 1996]
DISEASES STUDIED/TREATED   Treatment of wasting syndrome. [AmFAR Tx Dir
                           1996;8(2)]
CLASSIFICATION CODE        Appetite stimulant [Incomplete]
OTHER MAJOR USES           In males, treatment of congenital or acquired
                           primary hypogonadism. In females, for
                           palliative treatment of androgen-responsive
                           metastatic breast carcinoma, and, in
                           combination with estrogens, in the management
                           of vasomotor symptoms associated with
                           menopause. [AHFS Drug Information 1996]
SUBSTANCE INTERACTIONS     Testosterone may potentiate the action of
                           oral anticoagulants, causing bleeding in some
                           patients. Increased serum oxyphenbutazone
                           concentrations have reportedly occurred in
                           patients concurrently on oxyphenbutazone.
                           Testosterone may decrease blood glucose
                           concentrations and insulin requirements in
                           diabetics. [AHFS Drug Information 1996]
ADVERSE EFFECTS            Acne, flushing of the skin, gynecomastia,
                           increased or decreased libido, habituation
                           and edema. Oligospermia and decreased
                           ejaculatory volume may occur in males,
                           amenorrhea and other menstrual irregularities
                           in women. Other adverse effects include
                           nausea, epididymitis, bladder irritability,
                           chills, excitation and sleeplessness, mental
                           depression, generalized paresthesia,
                           leukopenia and polycythemia. [AHFS Drug
                           Information 1996]
CONTRAINDICATIONS          The usual precautions of androgen therapy
                           should be observed. When testosterone esters
                           (e.g. enanthate) are used in combination with
                           estrogens, the usual precautions associated
                           with estrogen should also be observed.
                           Testosterone should be used with caution in
                           patients with cardiac, renal or hepatic
                           dysfunctions since edema may occur. Females
                           should be carefully monitored for signs of
                           virilization. Contraindicated in males with
                           carcinoma of the breast or the prostate. May
                           cause fetal harm when administered to
                           pregnant women. [AHFS Drug Information 1996]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Enanthate derivative
                           (ester) of testosterone. [PDR 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR FORMULA: C26H4003 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR WEIGHT: 400.60 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MELTING POINT: 36-37.5 C [Merck Index 1989]
CHEMICAL/PHYSICAL   DATA   ELEMENTAL COMP: C 77.95%, H 10.07%, O 11.98%
                           [Merck Index 1989]
CHEMICAL/PHYSICAL DATA     SOLUBILITY: Soluble in sesame oil [PDR 1997]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Available in 1 ml (200 mg/ml)
                           single dose syringes and in 5 ml (200 mg/ml)
                           multiple dose vials (Delatestryl) and in 100
                           mg/ml concentration (Everone). [PDR 1997;
                           AHFS Drug Information 1996]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: By intramuscular injection.
                           [PDR 1997]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Should be stored at
                           room temperature. Crystals may form at lower
                           temperatures but will dissolve when warmed to
                           room temperature. [PDR 1997]
MANUFACTURERS              BioTechnology General Corporation; 70 Wood
                           Avenue, South; Iselin, NJ 08830
REFERENCES                 ICA11/96923185. Strawford A, Neese R, Hoh R,
                           Pelfini A, Turner S, Papageorgopoulos C, Faix
                           D, Hellerstein M. Clinical heterogeneity for
                           metabolic and nutritional measures in
                           AIDS-wasting syndrome (AWS) compared to
                           HIV-negative controls. Int Conf AIDS. 1996
                           Jul 7-12; 11(2): 20 (abstract no. We.B.183).
REFERENCES                 ICA11/96925546. Hernandez-Lopez G,
                           Feregrino-Goyos M, Eid-Lidt G, Alvarado-Diez
                           R, Gomez-Caro WH, Gallegos-Perez H. Low
                           levels of testosterone in AIDS wasting
                           syndrome. The effect of anabolic steroids on
                           muscular body mass and better nutritional
                           support. Int Conf AIDS. 1996 Jul 7-12; 11(2):
                      454 (abstract no. Pub.B.1098).
REFERENCES            ICA11/96922582. Sattler FR, Antonipillai I,
                      Allen J, Briggs W, Horton R. Wasting and sex
                      hormones: evidence for the pathogenesis of
                      dihydrotestosterone in AIDS patients with
                      weight loss. Int Conf AIDS. 1996 Jul 7-12;
                      11(1): 331 (abstract no. Tu.B.2380)
REFERENCES            MED/96389567. Holzman D. Testosterone wasting
                      and AIDS [news]. Mol Med Today. 1996 Mar;
                      2(3): 93.
REFERENCES            AIDS/96701189. New studies on testosterone
                      and wasting. Posit Aware. 1996 Jan/Feb; 7(1):
                      7.
REFERENCES            MED/96246078. Hengge UR, Baumann M, Maleba R,
                      Brockmeyer NH, Goos M. Oxymetholone promotes
                      weight gain in patients with advanced human
                      immunodeficiency virus (HIV-1) infection. Br
                      J Nutr. 1996 Jan; 75(1): 129-38.
REFERENCES            AID/96700588. Getty J. Turning the corner on
                      wasting? A symposium on wasting disorders.
                      BETA. 1995 Jun;: 33-7.
REFERENCES            AIDS/95700087. Rosen GH. Pharmacologic agents
                      used for nutritional disorders of HIV/AIDS. J
                      Physicians Assoc AIDS Care. 1995 Jan;
                      2(1):30-2.
REFERENCES            MED/93362115. Jeantils V, Nguyen G, Bacle F,
                      Thomas M, Krivitzky A. Weight gain under oral
                      testosterone undecanoate in AIDS [letter].
                      Therapie. 1993 Jan-Feb; 48(1):71-2.
ENTRY MONTH           199701
LAST REVISION DATE    19980507

48
UNIQUE IDENTIFIER     DRG-0259
NAME OF SUBSTANCE     Interleukin-12 [Incomplete]
SYNONYMS              Interleukin-12 [MeSH]
PROTOCOL ID NUMBERS   NCI 96 C-0113
PROTOCOL ID NUMBERS   NCI 97 C-0040
PROTOCOL ID NUMBERS   NIAID 98 I-0091
PROTOCOL ID NUMBERS   NIAID ACTG 325
PROTOCOL ID NUMBERS   NIAID ACTG 387
CLASSIFICATION CODE   Immunomodulator [Incomplete]
MANUFACTURERS         Genetics Institute; 35 Cambridge Park Drive;
                      Cambridge, MA 02140
REFERENCES            ICA11/96925477. Daftarian PM, Kumar A,
                      Diaz-Mitoma F. Interleukin(IL)-12 induces
                      IL-10 expression in peripheral blood
                      mononuclear cells (PBMC) from HIV-infected
                      individuals. Int Conf AIDS. 1996 Jul
                      7-12;11(2):442 (abstract no.Pub.A.1027).
REFERENCES            AIDS/97920698. Gomez KC, Laraque F, Cervia
                      JS, Drago T, Sia C, Sypek J, He S, Noel GJ,
                      Ho JL. Altered cellular immunity to HIV
                      proteins and tetanus toxoid in HIV-infected
                      children: in vitro restoration by
                      interleukin-12. Conf Adv AIDS Vaccine Dev.
                      1996 Feb 11-15;124(poster no.4).
REFERENCES            AIDS/96920472. Chehimi J, Zyad A, Ruby B,
                      Trinchieri G, Starr S. Production and
                      immunomodulatory effects of IL-12 in
                      HIV-infected infants. 3rd Conf Retro and
                         Opportun Infect. 1996 Jan 28-Feb 1;:141.
REFERENCES               AIDS/96920309. Jacobson MA, Hardy D, Connick
                         E, Anderson R, Debruin M. Phase I trial of
                         recombinant human interleukin 12 (rhIL-12) in
                         309 HIV-infected subjects. 3rd Conf Retro and
                         Opportun Infect. 1996 Jan 28-Feb 1;:110.
REFERENCES               AIDS/96700677. Anonymous. Genetics Institute
                         suspends phase II study of rhiL-12. J Int
                         Assoc Physicians AIDS Care. 1995 Jun;1(5):34.
REFERENCES               AIDS/95920437. McFarland E, Harding PA,
                         Schooley RT, Kuritzkes DR. Interleukin-12
                         (IL-12) enhances natural killer cell activity
                         in peripheral blood mononuclear cells from
                         HIV-infected infants and children. Natl Conf
                         Hum Retroviruses Relat Infect (2nd). 1995 Jan
                         29-Feb 2;:129.
REFERENCES               AIDS/95920535. Perales MA, Lieberman J. IL-12
                         induces HIV-1 replication in CD8-depleted
                         PBMC from some seropositive donors. Natl Conf
                         Hum Retroviruses Relat Infect (2nd). 1995 Jan
                         29-Feb 2;:148.
ENTRY MONTH              199701
LAST REVISION DATE       19970709

49
UNIQUE IDENTIFIER        DRG-0258
NAME OF SUBSTANCE        Amprenavir [NIAID 94 I-202]
REGISTRY NUMBER          161814-49-9
STANDARD CHEMICAL NAME   4-Amino-N-[2(R)-Hydroxy-4-phenyl-3(S)
                         -{tetrahydrofuran-3
                         (S)-yloxycarbonamylamino}butyl}
                         -N-isobutylbenzenesulfonamide [Drugs of the
                         Future 1996; 21(4)]
SYNONYMS                 VX-478 [AIDS Therapies 1995]
SYNONYMS                 Vertex [AmFAR Tx Dir 1996;8(1)]
SYNONYMS                 Amprenavir [AmFar Tx Dir December, 1997]
PROTOCOL ID NUMBERS      FDA 264C
PROTOCOL ID NUMBERS      FDA 264G
PROTOCOL ID NUMBERS      FDA 264H
PROTOCOL ID NUMBERS      FDA 264J
PROTOCOL ID NUMBERS      FDA 264K
PROTOCOL ID NUMBERS      FDA 299A
PROTOCOL ID NUMBERS      NIAID 98 I-0147
PROTOCOL ID NUMBERS      NIAID ACTG 384
PROTOCOL ID NUMBERS      NIAID ACTG 398
PROTOCOL ID NUMBERS      NIAID ACTG 400
PROTOCOL ID NUMBERS      FDA 238J
PROTOCOL ID NUMBERS      FDA 264A
PROTOCOL ID NUMBERS      FDA 264B
PROTOCOL ID NUMBERS      FDA 264D
PROTOCOL ID NUMBERS      FDA 264E
PROTOCOL ID NUMBERS      FDA 264F
PROTOCOL ID NUMBERS      FDA UNAP 11
PROTOCOL ID NUMBERS      FDA UNAP 12
PROTOCOL ID NUMBERS      NIAID 94 I-202
PROTOCOL ID NUMBERS      NIAID ACTG 347
PROTOCOL ID NUMBERS      NIAID ACTG 373
PHARMACOLOGICAL ACTION   MODE OF ACTION: HIV encodes a homodimeric
                         aspartyl protease that plays a role in viral
                         replication. Inhibition of this enzyme blocks
                         the cleavage of gag and gag-pol polyprotein
                           precursors into key structural proteins and
                           replication enzymes, and results in the
                           production of morphologically altered,
                           non-infectious virus particles. It is assumed
                           that 141W94 inhibits the virally encoded
                           protease and causes the resulting inability
                           to process gag and gag-pol polyproteins.
                           Antiviral activity of 141W94 is specific for
                           HIV. In vitro no activity was observed
                           against HSV-1, HSV-2, VZV, HCMV or a variety
                           of other viruses. In a phase I study 150,
                           300, 600, 900 and 1,200 mg doses of 141W94.
                           The terminal half-life of the substance
                           remained relatively constant average plasma
                           concentrations at 8 and 12 h after dosing
                           were greater than 10 times the IC50. [Drugs
                           of the Future 1996; 21(4)]
DISEASES STUDIED/TREATED   HIV infection. [NIAID 94 I-202]
CLASSIFICATION CODE        Protease inhibitor [NIAID 94 I-202]
ADVERSE EFFECTS            The lack of cytotoxicity of 141W94 was
                           confirmed in several in vitro systems.
                           Preclinical toxicity studies were done in
                           mice and rats (p.o. and i.v. routes). The
                           acute toxicity of 141W94 was low. The oral
                           median lethal dose was greater than 3,000
                           mg/kg. The i.v. median lethal dose was
                           greater than 300 mg/kg in mice. A human phase
                           I trial showed 141W94 to be well tolerated
                           when administered to HIV+ individuals at
                           single doses up to 1,200 mg. No serious
                           adverse experience or laboratory test
                           abnormalities were found. [Drugs of the
                           Future 1996; 21(4)]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: 141W94 is a peptomimetic
                           with three asymmetric centers. It represents
                           one of the smaller, less stereochemically
                           complex of the protease inhibitors currently
                           under development. [Drugs of the Future 1996;
                           21(4)]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C251+35N306S [Drugs of the
                           Future 1996; 21(4)]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 505.63 [Drugs of the Future
                           1996; 21(4)]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Capsules. [Drugs of the Future
                           1996; 21(4)]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [Drugs of the Future
                           1996; 21(4)]
MANUFACTURERS              Glaxo Wellcome; 5 Moore Drive / PO Box 13398;
                           Research Triangle Park, NC 27709
MANUFACTURERS              Vertex Pharmaceuticals Incorporated; 40
                           Allston Street; Cambridge, MA 02139
REFERENCES                 MED/97275173. Lazdins JK, Mestan J, Goutte G,
                           Walker MR, Bold G, Capraro HG, Klimkait T. In
                           vitro effect of alphal-acid glycoprotein on
                           the anti-human immunodeficiency virus (HIV)
                           activity of the protease inhibitor CGP 61755:
                           a comparative study with other relevant HIV
                           protease inhibitors. J Infect Dis. 1997
                           May;175(5):1063-70.
REFERENCES                 AIDS/97926520. Tisdale M, Myers RE, Harrigan
                           PR, Larder BA. Analyses of HIV genotype and
              phentype during 4 weeks dose-escalating
              monotheraphy with the HIV protease inhibitor
              141W94 in Hiv-infected patients with CD4
              counts 150-400/mm3. 4th Conf Retro and
              Opportun Infect. 1997 Jan22-26;:174 (abstract
              no. 593).
REFERENCES    AIDS/97926513. Bilello JA, Bilello PA,
              Symonds W, McDowell J, Sadler B, Bye A,
              Drusano Gl. 1592U89, a novel carbocyclic
              nucleoside analog with potent anti-HIV
              activity, is synergistic in combination with
              141W94 an HIV protease inhibitor. 4th Conf
              Retro and Opportun Infect. 1997 Jan 22-26;:93
              (abstract no. 154).
REFERENCES    AIDS/97926015. Schooley R. Preliminary data
              from a phase I/II study on the safety and
              antiviral efficacy of the combination of
              141W94 plus 1592U89 in HIV-infected patients
              with 150 to 400 CD4+ cells/mm(3). 4th Conf
              Retro and Opportun Infect. 1997 Jan
              22-26;:206 (abstract no. LB3).
REFERENCES    MED/96298219. Singh R, Chang SY, Taylor LC.
              In vitro metabolism of a potent HIV-protease
              inhibitor (141W94) using rat, monkey and
              human liver S9. Rapid Commun Mass Spectrom.
              1996;10(9):1019-26.
REFERENCES    MED/97125958. Maschera B, Darby G, Palu G,
              Wright LL, Tisdale M, Blair ED, Furfine ES,
              Myers R. Human immunodeficiency virus.
              Mutations in the viral protease that confer
              resistance to saquinavir increase the
              dissociation rate constant of the
              protease-saquinavir complex. J Biol Chem.
              1996 Dec 27;271(52):33231-5.
REFERENCES    MED/97112989. Schock HB, Garsky VM, Kuo LC.
              Mutational anatomy of an HIV-1 protease
              variant conferring cross-resistance to
              protease inhibitors in clinical trials.
              Compensatory modulations of binding and
              activity. J Biol Chem. 1996 Dec
              13;271(50):31957-63.
REFERENCES    MED/96279343. Pazhanisamy S, Stuver CM,
              Cullinan AB, Margolin N, Rao BG, Livingston
              DJ. Kinetic characterization of human
              immunodeficiency virus type-1
              protease-resistant variants. J Biol Chem.
              1996 Jul 26;271(30):17979-85.
REFERENCES    MED/96283736. St. Clair MH, MIllard J, Rooney
              J, Tisdal M, Parry N, Sadler BM, Blum MR,
              Painter G. In vitro antiviral activity of
              141W94 (VX-478) in combination with other
              antiretroviral agents. Antiviral Res. 1996
              Jan;29(1):53-6.
REFERENCES    AIDS/95920638. Painter GR, St Clair MH,
              Demiranda P, Reynolds D, Ching S, Dornsife R,
              Livingston DJ, Pazhanisamy S, Tung R. An
              overview of the preclinical development of
              the HIV protease inhibitor VX-478 (141W94).
              Natl Conf Hum Retroviruses Relat Infect
              (2nd). 1995 Jan 29-Feb 2;:167.
ENTRY MONTH   199611
LAST REVISION DATE       19980423

50
UNIQUE IDENTIFIER        DRG-0257
NAME OF SUBSTANCE        1592U89 Succinate [AIDS Therapies 1996]
STANDARD CHEMICAL NAME   (1S,4R)-4- succinate [AIDS Therapies 1996]
SYNONYMS                 Abacavir [AIDS Therapies 1996]
PROTOCOL ID NUMBERS      FDA 264H
PROTOCOL ID NUMBERS      FDA 264K
PROTOCOL ID NUMBERS      FDA 280B
PROTOCOL ID NUMBERS      FDA 299A
PROTOCOL ID NUMBERS      NIAID 98 I-0147
PROTOCOL ID NUMBERS      NIAID ACTG 321
PROTOCOL ID NUMBERS      NIAID ACTG 398
PROTOCOL ID NUMBERS      FDA 238B
PROTOCOL ID NUMBERS      FDA 238C
PROTOCOL ID NUMBERS      FDA 238D
PROTOCOL ID NUMBERS      FDA 238E
PROTOCOL ID NUMBERS      FDA 238F
PROTOCOL ID NUMBERS      FDA 238G
PROTOCOL ID NUMBERS      FDA 238H
PROTOCOL ID NUMBERS      FDA 238J
PROTOCOL ID NUMBERS      FDA 238K
PROTOCOL ID NUMBERS      FDA 238L
PROTOCOL ID NUMBERS      FDA 238M
PROTOCOL ID NUMBERS      FDA 264B
PROTOCOL ID NUMBERS      FDA 264F
PROTOCOL ID NUMBERS      FDA UNAP 11
PROTOCOL ID NUMBERS      FDA UNAP 12
PROTOCOL ID NUMBERS      NIAID 94 I-202
PROTOCOL ID NUMBERS      NIAID ACTG 330
PROTOCOL ID NUMBERS      NIAID ACTG 356
PROTOCOL ID NUMBERS      NIAID ACTG 368
PROTOCOL ID NUMBERS      NIAID ACTG 372
PHARMACOLOGICAL ACTION   MODE OF ACTION: 1592U89 succinate is a
                         carbocyclic nucleoside analog that is
                         activated intracellularly to (-)- carbovir
                         triphosphate, the active form of the
                         guanosine analog carbovir. 1592U89 is
                         phosphorylated by adenosine
                         phosphotransferase to the monophosphate which
                         is converted by a novel cytosolic enzyme to
                         carbovir monophosphate; this is then further
                         phosphorylated to carbovir triphosphate by
                         cellular kinases. This unique activation
                         pathway enables 1592U89 to overcome the
                         pharmacokinetic and toxicological
                         deficiencies of carbovir while maintaining
                         potent and selective anti-HIV activity. In
                         vitro, 1592U89 showed minimal
                         cross-resistance (approximately two-fold)
                         with AZT and other approved HIV reverse
                         transcriptase (RT) inhibitors. 1592U89 was
                         synergistic in combination with AZT, the
                         nonnucleoside RT inhibitor nevirapine, and
                         the protease inhibitor 141W94 in MT4 cells
                         against HIV-1 (IIIB). The 5'- triphosphate of
                         carbovir was a potent, selective inhibitor of
                         HIV-1 RT. 1592U89 was relatively nontoxic to
                         human bone marrow progenitors erythroid
                         burst-forming unit and granulocyte-macrophage
                           CFU and human leukemic and liver tumor cell
                           lines. 1592U89 had excellent oral
                           bioavailability (105% in the rat) and
                           penetrated the CNS (rat brain and monkey
                           cerebrospinal fluid) as well as AZT. Toxicity
                           in monkeys given the drug for 28 days were
                           limited to reversible increases in serum
                           triglycerides and slight reversible increases
                           in liver weights (high doses). In phase I/II
                           clinical trials, patients on 1592U89 or
                           1592U89 plus AZT showed a decrease in viral
                           load and a mean increase in CD4 cell counts.
                           [AIDS Therapies 1996; Antimicrob Agents
                           Chemother. 1997 May;41(5)]
DISEASES STUDIED/TREATED   AIDS dementia complex. [FDA 238B]
CLASSIFICATION CODE        Antiretroviral [FDA 238B]
ADVERSE EFFECTS            Nausea (common at the highest dose, 600 mg
                           tid), headache, allergic reactions. [AIDS
                           Therapies 1996]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Prodrug of the carbocyclic
                           nucleoside analog (-)-carbovir triphosphate.
                           Differs from other nucleosides by
                           substitution of a methylene group for the
                           oxygen atom of the molecules carbohydrate
                           ring. [AIDS Therapies 1996]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [FDA 238B]
MANUFACTURERS              Glaxo Wellcome; 5 Moore Drive / PO Box 13398;
                           Research Triangle Park, NC 27709
REFERENCES                 AIDS/97702907. 1592U89 (abacavir)
                           compassionate use. Treat Rev. 1997 Aug;(No
                           25):6.
REFERENCES                 MED/97291262. Faletto MB, Miller WH, Garvey
                           EP, St. Clair MH, Daluge SM. Good SS.
                           Immunodeficiency virus agent 1592U89.
                           Antimicrob Agents Chemother. 1997
                           May;41(5)1099-107.
REFERENCES                 MED/97291261. Tisdale M, Alnadaf T, Cousens
                           D. Combination of mutations in human
                           immundeficiency virus type 1 reverse
                           transcriptase required for resistance to the
                           carbocyclic nucleoside 1592U89. Antimicrob
                           Agents Chemother. 1997 May;41(5):1094-8.
REFERENCES                 MED/97291260. Daluge SM, Good SS, Faletto MB,
                           Miller WH, St. Clair MH, Boone LR, Tisdale M,
                           Parry NR, Reardon JE, Dornsite RE, et al.
                           1592U89, a novel carbocyclic nucleoside
                           analog with potent, selective anti-human
                           immunodeficency virus activity. Antimicrob
                           Agents Chemother. 1997 May;41(5):1082-93
REFERENCES                 AIDS/97926558. Harrigan R, Stone C, Griffin
                           P, Bloor S, Tisdale M, Larder B.
                           Antiretroviral activity and resistance
                           profile of the carbocyclic nucleoside HIV
                           reverse transcriptase inhibitor 1592U89. 4th
                           Conf Retro and Opportun Infect. 1997
                           Jan22-26;:67 (abstract no. 15).
REFERENCES                 AIDS/97926513. Bilello PA, Symonds W,
                           McDowell J, Sadler B, Bye A, Drusano GL.
                           1592U89, a novel carbocyclic nucleoside
                           analog with potent anti-HIV activity, is
                           synergistic in combination with 141W94 an HIV
                         protease inhibitor. 4th Conf Retro and
                         Opportun Infect. 1997 Jan 22-26;:93 (abstract
                         no. 154).
REFERENCES               AIDS/97926015. Schooley R. Preliminary data
                         from a phase I/II study on the safety and
                         antiviral efficacy of the combination of
                         141W94 plus 1592U89 in HIV-infected patients
                         with 150 to 400 CD+ cells/mm(3). 4th Conf
                         Retro and Opportun Infect. 1997 Jan
                         22-26;:206 (abstract no. LB3).
REFERENCES               ICA11/96924280. Saag M, Lancaster D,
                         Sonnerborg A, Torres R, Thompson M, Mulder J,
                         Schooley R, Gazzard B, D'Aquila R, Santin M,
                         et al. Preliminary data on the safety and
                         antiviral effect of 1592U89, alone and in
                         combination with zidovudine (ZDV) in
                         HIV-infected patients with CD4+ counts
                         200-500/mm3. Int Conf AIDS. 1996 Jul
                         7-12;11(2):225 (abstract no.Th.B.294).
REFERENCES               ICA11/96921206. McDowell JA, Symonds WT,
                         LaFon SW. Single-dose and steady-state
                         pharmacokinetics of escalating regimens of
                         159U89 with and without zidovudine. Int Conf
                         AIDS. 1996 Jul 7-12;11(1):79 (abstract
                         no.Mo.B.1140).
REFERENCES               AIDS/96920195. Saag M, Lancaster D,
                         Sonnerberg A, Mulder J, Torres R, Schooley R,
                         Harrigan R, Kelleher D, Symonds W. A phase
                         I/II study of a novel nucleoside
                         reverse-transcriptase inhibitor; 1592U89
                         monotherapy vs. 1592U89+ zidovudine (ZDV) or
                         placebo in HIV infected patients with CD4
                         counts 200-500/mm3. 3rd Conf Retro and
                         Opportun Infect. 1996 Jan 28-Feb 1;:89.
ENTRY MONTH              199712
LAST REVISION DATE       19980507

51
UNIQUE IDENTIFIER        DRG-0256
NAME OF SUBSTANCE        Measles - Mumps - Rubella Virus Vaccine Live
                         [NIAID ACTG 225]
SYNONYMS                 M-M-R II [PDR 1997]
SYNONYMS                 Measles, mumps and rubella virus vaccine live
                         [Physicians GenRx 97]
SYNONYMS                 Measles, mumps, rubella vaccine [MeSH]
PROTOCOL ID NUMBERS      NIAID ACTG 225
PHARMACOLOGICAL ACTION   M-M-R II is highly immunogenic and generally
                         well tolerated. A single injection of the
                         vaccine induced measles
                         hemagglutination-inhibition (HI) antibodies
                         in 95%, mumps neutralizing antibodies in 96%,
                         and rubella HI antibodies in 99% of
                         susceptible persons. Vaccine induced antibody
                         levels following administration of M-M-R II
                         have been shown to persist up to 11 years
                         without substantial decline. [PDR 1997]
CLASSIFICATION CODE      Vaccine [NIAID ACTG 225]
OTHER MAJOR USES         Immunization against measles (rubeola), mumps
                         and rebella (German measles). [PDR 1997]
SUBSTANCE INTERACTIONS   Measles virus vaccine live may temporarily
                         suppress tuberculin skin sensitivity;
                  therefore, skin test should be done before,
                  simultaneously with, or 4-6 weeks after
                  administration of the vaccine. Manufacturer
                  states that administration of this vaccine
                  should be separated by at least 1 month from
                  administration of live virus vaccines other
                  than poliovirus, rubella, or mumps. Patients
                  receiving immunosuppressive agents may have a
                  diminished response to this vaccine and
                  replication of the virus may be potentiated.
                  The interval between discontinuance of above
                  therapy and regaining the ability to respond
                  to live virus vaccines is estimated to vary
                  from 3-12 months. Measles virus vaccine live
                  should be deferred for at least 3 months
                  following administration of hepatitis B
                  immune globulin, tetanus immune globulin,
                  IGIM used for preexposure or postexposure
                  prophylaxis of hepatitis A infection, or red
                  blood cells; for at least 4 months following
                  administration of rabies immune globulin; for
                  at least 5 months following administration of
                  varicella-zoster immune globulin or IGIM used
                  for measles prophylaxis in immunocompetent
                  patients; for at least 6 months following use
                  of IGIM for measles prophylaxis in
                  immunodeficient patients or administration of
                  packed red blood cells or whole blood; for at
                  least 7 months following administration of
                  plasma or platelet products; for at least 8
                  months following administration of IGIV for
                  replacement therapy of immunodeficiencies;
                  for at least 8-10 months following
                  administration of IGIV for the treatment of
                  idiopathic thrombocytopenic purpura (ITP); or
                  for at least 11 months following
                  administration of IGIV for Kawasaki syndrome.
                  [AHFS Drug Information 1997]
ADVERSE EFFECTS   Burning and/or stinging of short duration at
                  the injection site and anaphylaxis and
                  anaphylactoid reactions have been reported.
                  The adverse clinical reactions associated
                  with the use of M-M-R II are those expected
                  to follow administration of the monovalent
                  vaccines given separately. These may include
                  malaise, sore throat, cough rhinitis,
                  headache, dizziness, fever, rash, nausea,
                  vomiting or diarrhea; mild local reactions
                  such as erythema, induration, tenderness and
                  regional lymphadenopathy; parotitis,
                  orchitis, nerve deafness, thrombocytopenia
                  and purpura; allergic reactions such as wheal
                  and flare at the injection site or urticaria;
                  polyneuritis; and arthralgia and/or arthritis
                  (usually transient and rarely chronic).
                  Vasculitis, otitis media, and conjunctivitis
                  have also been reported. Moderate fever
                  [101-102.9F (38.3-39.4C)] may occur
                  occasionally, high fever [over 103F (39.4C)]
                  occurs less commonly. On rare occasions,
                  children developing fever may exhibit febrile
                          convulsions. Afebrile convulsions or
                          seizures; syncope; erythema multiforme; forms
                          of opti neuritis, including retrobulbar
                          neuritis, papillitis, and retinitis have been
                          reported. [PDR 1997]
CONTRAINDICATIONS         Contraindicated in patients with anaphylactic
                          or anaphylactoid reactions to neomycin or
                          eggs; patients with febrile respiratory
                          illness or other active febrile infections;
                          patients with active untreated tuberculosis;
                          patients who are receiving immunosuppressive
                          therapy; patients with blood dyscrasias,
                          leukemia, lymphomas of any type, or other
                          malignant neoplasms affecting the bone marrow
                          or lymphatic systems; patients with primary
                          and acquired immunodeficiency states,
                          including patients who are immunosuppressed
                          in association with AIDS or other clinical
                          manisfectations of infection with human
                          immunodeficiency viruses, cellular immune
                          deficiencies, and hypogammaglobulinemic and
                          dysgammaglobulinemic states; patients with a
                          history of congenital or hereditary
                          immunodeficiency. Do not give M-M-R II to
                          pregnant females; if vaccination of
                          postpubertal females is undertaken, pregnancy
                          should be avoided for 3 months following
                          vaccination. [PDR 1997]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: A sterile lyophilized
                          preparation of (1) ATTENUVAX (Measles Virus
                          Vaccine live), a more attenuated line of
                          measles virus, derived from Enders'
                          attenuated Edmonston strain and grown in cell
                          cultures of chick embryo; (2) MUMPSVAX (Mumps
                          Virus Vaccine live), the Jeryl Lynn (B level)
                          strain of mumps virus grown in cell culture
                          of chick embryo; and (3) MERUVAX II (Rubella
                          Virus Vaccine live), the Wistar RA 27/3
                          strain of live attenuated rubella virus grown
                          in human diploid cell (WI-38) culture. [PDR
                          1997]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Lyophilized vaccine in vial of
                          single dose, or 10 dose is supplied with a
                          vial of diluent. When reconstituted as
                          directed, the dose for injectin is 0.5ml and
                          contains not less than the equivalent of
                          1,000 TCID 50 of the U.S. Reference mumps
                          virus, and 1,000 TCID 50 of the U.S.
                          Reference Rubella Virus. [PDR 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Subcutaneous injection
                          preferably into the outer aspect of upper
                          arm. [PDR 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Before reconstitution,
                          store M-M-R II at 2-8 C (36-46 F) prot ected
                          from light. Store reconstituted vaccine in
                          the vaccine vial in a dark place at 2-8 C and
                          discard if not used within 8 hours. [PDR
                          1997]
MANUFACTURERS             Merck and Company Inc; P.O. Box 4; West
                          Point, PA 19486
REFERENCES                MED/96312573. Anonymous. Measles pneumonitis
                         following measles-mumps-rubella vaccination
                         of a patient with HIV infection, 1993. MMWR
                         Morb Mortal Wkly Rep. 1996 Jul;45(28):603-6.
ENTRY MONTH              199610
LAST REVISION DATE       19990318

52
UNIQUE IDENTIFIER        DRG-0255
NAME OF SUBSTANCE        Measles Virus Vaccine Live [PDR 1997]
SYNONYMS                 Attenuvax [PDR 1997]
SYNONYMS                 Measles virus vaccine live [AHFS Drug
                         Information 1997]
SYNONYMS                 Measles vaccine [MeSH]
PROTOCOL ID NUMBERS      NIAID ACTG 225
PHARMACOLOGICAL ACTION   MODE OF ACTION: Measles virus vaccine live
                         stimulates active immunity to measles by
                         inducing production of measles-specific
                         immunoglobulin G (IgG) and M (IgM) antibodies
                         (humoral immunity). The vaccine produces an
                         inapparent or mild, noncommunicable
                         infection. The antibody response to initial
                         vaccination (primary response) resembles that
                         caused by primary natural measles infection,
                         with an initial transient increase in serum
                         IgM titers and a subsequent increase in serum
                         IgG titers, although the titers achieved with
                         vaccination are lower. As with natural
                         infection, IgG antibody titers decline slowly
                         over time, but immunity is thought to persist
                         for many years and possibly lifelong in most
                         vaccines. Individuals who experience initial
                         antigenic stimulation from either natural
                         infection or vaccine generally exhibit and
                         anamnestic (secondary) response to subsequent
                         revaccination or exposure to natural measles.
                         This anamnestic response generally is
                         characterized by a rapid but often transient
                         increase in serum IgG titers, but little or
                         no detectable IgM production. [AHFS Drug
                         Information 1997]
CLASSIFICATION CODE      Vaccine [NIAID ACTG 225]
OTHER MAJOR USES         Immunization against measles (rubeola). [PDR
                         1997]
SUBSTANCE INTERACTIONS   Measles virus vaccine live may temporarily
                         suppress tuberculin skin sensitivity;
                         therefore, skin test should be done before,
                         simultaneously with, or 4-6 weeks after
                         administration of the vaccine. Manufacturer
                         states that administration of this vaccine
                         should be separated by at least 1 month from
                         administration of live virus vaccines other
                         than poliovirus, rubellla, or mumps. Patients
                         receiving immunosuppressive agents may have a
                         diminished response to this vaccine and
                         replication of the virus may be potentiated.
                         Vaccination should be deferred until
                         immunosuppressive agent is discontinued. The
                         interval between discontinuance of above
                         therapy and regaining the ability to respond
                         to live virus vaccines is estimated to vary
                         from 3-12 months. Measles virus vaccine live
                    should be deferred for at least 3 months
                    following administration of hepatitis B
                    immune globulin, tetanus immune globulin,
                    IGIM used for preexposure or postexposure
                    prophylaxis of hepatitis A infection, or red
                    blood cells; for at least 4 months following
                    administration of rabies immune globulin; for
                    at least 5 months following administration of
                    varicella-zoster immune globulin or IGIM used
                    for measles prophylaxis in immunocompetent
                    patients; for at least 6 months following use
                    of IGIM for measles prophylaxis in
                    immunodeficient patients or administration of
                    packed red blood cells or whole blood; for at
                    least 7 months following administration of
                    plasma or platelet products; for at least 8
                    months following administration of IGIV for
                    replacement therapy of immunodeficiencies;
                    for at least 8-10 months following
                    administration of IGIV for the treatment of
                    idiopathic thrombocytopenic purpura (ITP); or
                    for at least 11 months following
                    administration of IGIV for Kawasaki syndrome.
                    [PDR 1997; AHFS Drug Information 1997]
ADVERSE EFFECTS     Burning and/or stinging of short duration at
                    the injection site and anaphylaxis and
                    anaphylactoid reactions have been reported.
                    Occasionally, moderate fever
                    [101-102.9F(38.3-39.4)], rash, or both may
                    occur during the month after vaccination;
                    cough, rhinitis, and Erythema multiforme have
                    also been reported. High fever [over
                    103F(39.4C)] and lymphadenopathy have been
                    reported but are less common. Rarely,
                    allergic reactions such as wheal and flare at
                    the injectin site or urticaria; diarrhea;
                    febrile convulsions with children developing
                    fever; afebrile convulsions or seizures;
                    syncope; thrombocytopenia and purpura;
                    vasculitis; forms of optic neuritis,
                    including retrobulbar neuritis, papillistis,
                    and retinitis. [PDR 1997]
CONTRAINDICATIONS   Contraindicated in patients with anaphylactic
                    or anaphylactoid reactions to neomycin or
                    eggs; patients with febrile respiratory
                    illness or other active febrile infections;
                    patients with active untreated tuberculosis;
                    patients who are receiving immunosuppressive
                    therapy; patients with blood dyscrasias,
                    leukemia, lymphomas of any type, or other
                    malignant neoplasms affecting the bone marrow
                    or lymphatic systems; patients with primary
                    and acquired immunodeficiency states,
                    including patients who are immunosuppressed
                    in association with AIDS or other clinical
                    manisfestations of infection with human
                    immunodeficiency viruses, cellular immune
                    deficiencies, and hypogammaglobulinemic and
                    dysgammaglobulinemic states; patients with a
                    history of congenital or hereditary
                    immunodeficiency. Do not give Attenuvax to
                          pregnant females; if vaccination of
                          postpubertal females is undertaken, pregnancy
                          should be avoided for 3 months following
                          vaccination. [PDR 1997]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: A sterile lyophilized
                          preparation of a more attenuated line of
                          measles virus derived from Ender's attenuated
                          Edmonston strain. [PDR 1997]
CHEMICAL/PHYSICAL DATA    STABILITY: The expiration date of measles
                          virus vaccine live is 1-2 years, depending on
                          the manufacturer's data, after the date of
                          issue from the manufacturer's cold storage
                          (e.g., 1 year when the manufacturer's cold
                          storage was -20C). [AHFS Drug Information
                          1997]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Lyophilized vaccine in vial of
                          single dose, 10-dose, or 50-dose is supplied
                          with a vial of diluent. When reconstituted as
                          directed, the dose for injection is 0.5ml and
                          contains not less than 1,000 TCID (tissue
                          culture infectious doses) of the U.S.
                          Referance virus. [PDR 1997; AHFS Drug
                          Information 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Subcutaneous injection
                          preferably into the outer aspect of the upper
                          arm. [PDR 1997; AHFS Drug Information 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Before reconstitution,
                          store Attenuvax at 2-8 C (36-46 F) protected
                          from light. Store reconstituted vaccine in
                          the vaccine vial in a dark place at 2-8 C and
                          discard if not used within 8 hours. [PDR
                          1997]
MANUFACTURERS             Merck and Company Inc; P.O. Box 4; West
                          Point, PA 19486
REFERENCES                ASHM8/97153700. Crowe S. vaccination for the
                          person with HIV infection. Annu Conf
                          Australas Soc HIV Med.1996 Nov
                          14-17;8:104(abstract no.119).
REFERENCES                ICA11/96923168. Angel JB, Snydman DR, Udem
                          SA, Delellis RA, Walpita P, Lerch R, Sidhu
                          MS, Noble JT. A fatal case of pneumonitis due
                          to vaccine-strain measles virus in a man with
                          acquired immunodeficiency syndrome. Int Conf
                          AIDS.1996 Jul 7-12;11(2):17(abstract
                          no.WeB.110).
REFERENCES                MED/96333977. Anonymous. National Advisory
                          Committee on Immunization (NACI) Interim
                          advisory on measles revaccination of persons
                          with acquired immunodeficiency syndrome
                          (AIDS). Can Commun Dis Rep. 1996
                          Jul;22(14):116-7.
REFERENCES                ICA11/96921368 Embree J, Nagelkerke N, Datta
                          P, Njenga S, Ndinya-Achola Jo, Plummer FA.
                          Int Conf AIDS.1996 Jul 7-12;
                          11(1):107(abstract no.Mo.B.1304).
ENTRY MONTH               199610
LAST REVISION DATE        19980410

53
UNIQUE IDENTIFIER         DRG-0254
NAME OF SUBSTANCE         Bacteriophage phi X 174 [MeSH]
PROTOCOL ID NUMBERS        NIAID 96 I-58
CLASSIFICATION CODE        Immunizing [NIAID 96 I-58]
MANUFACTURERS              Drugs are provided by each participating unit
                           site
REFERENCES                 96351468. Szostak MP, Hensel A, Eko FO, Klein
                           R, Auer T, Mader H, Haslberger A, Bunka S,
                           Wanner G, Lubitz W. Bacterial ghosts:
                           non-living candidate vaccines. J Biotechnol
                           1996. Jan 26;44(1-3):161-70.
ENTRY MONTH                199610
LAST REVISION DATE         19970623

54
UNIQUE IDENTIFIER          DRG-0253
NAME OF SUBSTANCE          Hydroxyurea [USAN 1997]
REGISTRY NUMBER            127-07-1
STANDARD CHEMICAL NAME     Urea, hydroxy- [USAN 1997]
SYNONYMS                   Carbamohydroxamic acid [CHEMLINE]
SYNONYMS                   Carbamohydroximic acid [CHEMLINE]
SYNONYMS                   Carbamoyl oxime [CHEMLINE]
SYNONYMS                   Hidrix [CHEMLINE]
SYNONYMS                   Hidroxicarbamida [CHEMLINE]
SYNONYMS                   HU [CHEMLINE]
SYNONYMS                   Hydrea [USAN 1997]
SYNONYMS                   Hydroxycarbamide [USAN 1997]
SYNONYMS                   Litalir [Merck Index 1996]
PROTOCOL ID NUMBERS        FDA 244C
PROTOCOL ID NUMBERS        FDA 244D
PROTOCOL ID NUMBERS        FDA 292C
PROTOCOL ID NUMBERS        FDA 292D
PROTOCOL ID NUMBERS        FDA 296A
PROTOCOL ID NUMBERS        NIAID ACTG 384
PROTOCOL ID NUMBERS        NIAID ACTG A5025
PROTOCOL ID NUMBERS        NIAID ACTG 307
SECONDARY SOURCE ID        NSC 32065 [USAN 1997]
SECONDARY SOURCE ID        NSC-32065 [CHEMLINE]
SECONDARY SOURCE ID        NCI-C04831 [CHEMLINE]
SECONDARY SOURCE ID        AI3-51139 [CHEMLINE]
SECONDARY SOURCE ID        SQ 1089 [USAN 1997]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Inhibits HIV-1 replication
                           primarily by impeding HIV DNA synthesis due
                           to its effects on cellular
                           deoxyribonucleotide triphosphate
                           concentrations. It inhibits the enzyme
                           ribonucleoside diphosphate reductase, which
                           catalyzes the conversion of ribonucleotides
                           to deoxyribonucleotides, an essential step in
                           DNA synthesis. Hydroxyurea causes an
                           immediate inhibition of DNA synthesis without
                           interfering with the synthesis of ribonucleic
                           acid or of protein. After oral administration
                           in man, hydroxyurea is readily absorbed from
                           the gastrointestinal tract. The drug reaches
                           peak serum concentration within 2 hours; by
                           24 hours the concentration in the serum is
                           essentially zero. Approximately 80% of an
                           oral or intravenous dose of 7 to 30 mg/kg may
                           be recovered in the urine within 12 hours.
                           [NIAID ACTG 307; MeSH; PDR 1997]
DISEASES STUDIED/TREATED   HIV infection. [NIAID ACTG 307]
CLASSIFICATION CODE        Antiretroviral [NIAID ACTG 307]
CLASSIFICATION CODE        Antineoplastic (adjunct) [USAN 1997]
OTHER MAJOR USES           Solid tumors, myelogenous leukemia,
                           lymphoproliferative diseases, and sickle cell
                           disease. [NIAID ACTG 307; AHFS Drug
                           Information 1997]
ADVERSE EFFECTS            Adverse effects include myelosuppression
                           (neutropenia, decreased granulocytes);
                           cutaneous toxicities such as pruritis,
                           maculopapular rash, hyperpigmentation, and
                           erythema; mild gastrointestinal toxicity such
                           as nausea, vomiting, anorexia, diarrhea, and
                           constipation; transient renal effects such as
                           proteinuria and increased serum urea nitrogen
                           and creatinine; increased hepatic
                           transaminases and bilirubin; fever; headache;
                           drowsiness; confusion; and dizziness. Adverse
                           reactions have been primarily bone marrow
                           depression (leukopenia, anemia, and
                           occasionally thrombocytopenia) and less
                           frequently gastrointestinal symptoms
                           (stomatitis, anorexia, nausea, vomiting,
                           diarrhea, and constipation), and
                           dermatological reactions such as
                           maculopapular rash, skin ulceration and
                           facial erythema. Dysuria and alopecia occur
                           very rarely. Large doses may produce moderate
                           drowsiness. Neurological disturbances have
                           occurred extremely rarely and were limited to
                           headache, dizziness, disorientation,
                           hallucinations, and convulsions. It
                           occasionally may cause temporary impairment
                           of renal tubular function accompanied by
                           elevations in serum uric acid, BUN, and
                           creatinine levels. Abnormal BSP retention has
                           been reported. Fever, chills, malaise, and
                           elevation of hepatic enzymes have also been
                           reported. [NIAID ACTG 307; PDR 1997;
                           Physicians Gen RX 1997]
CONTRAINDICATIONS          Hydroxyurea is contraindicated in patients
                           with marked bone marrow depression, i.e.,
                           leukopenia (<2,500 WBC) or thrombocytopenia
                           (<100,000), or severe anemia. It should be
                           used with caution in patients with marked
                           renal dysfunction, and in male or female
                           patients who contemplate conception. Elderly
                           patients may require a lower dose regimen.
                           [PDR 1997; Physicians Gen RX 1997]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: Tasteless, white
                           crystalline powder. [PDR 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR FORMULA: C-H4-N2-O2 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR WEIGHT: 76.06 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MELTING POINT: 133-136 [Merck Index 1996]
CHEMICAL/PHYSICAL   DATA   ELEMENTAL COMP: C15.79%, H5.30%, N36.83%,
                           O42.07%. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     SOLUBILITY: Freely soluble in water, hot
                           alcohol. [Merck Index 1996]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 500 mg capsules. [NIAID ACTG
                           307; PDR 1997; Physicians Gen RX 1997]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [NIAID ACTG 307; PDR
                           1997; Physicians Gen RX 1997]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Store at 15-30 C (59-86
                F). Store at room temperature; avoid
                excessive heat. Keep tightly closed. [NIAID
                ACTG 307; PDR 1997; AHFS Drug Information
                1997]
MANUFACTURERS   Bristol - Myers Squibb Company; PO Box 4500;
                Princeton, NJ 08543-4500
REFERENCES      ICA11/96924277. Biron F, Peyramond D, Lucht
                F, Fresard A, Nugier F, Vallet T, Grange J,
                Hamedi-Sangsari, Vila J. Anti-HIV activity of
                the combination of didanosine and hydroxyurea
                in HIV-1-infected individuals. Int Conf AIDS.
                1996 Jul 7-12;11(2):224 (abstract
                no.Th.B.291).
REFERENCES      ICA11/96924278. Rae S, Montaner JS, Raboud
                JM, Conway B, Zala C, Patenaude P,
                Shillington A. Predictors of response in a
                pilot study of hydroxyurea (hourea) as
                adjuvant therapy among patients with advanced
                HIV disease receiving didanosine (ddI)
                therapy. Int Conf AIDS. 1996 Jul
                7-12;11(2):224 (abstract no.Th.B.292).
REFERENCES      ICA11/96923494. Simonelli C, Comar M, Zanussi
                S, Nasti G, Vaccher E, De Paoli P, Giacca M,
                Tirelli U. Feasibility and activity of
                combination therapy with didanosine (ddI) and
                hydroxyurea (HU) injuries patients (pts) with
                HIV infection. Int Conf AIDS. 1996 Jul
                7-12;11(2):80 (abstract no.We.B.3139).
REFERENCES      ICA11/96921209. Ruiz L, Clotet B, Cabrera C,
                Ibanez A, Puig T, Sirera G. Anti-HIV activity
                after 24 weeks of the didanosine and
                hydroxyurea combination in HIV-1 infected
                patients with CD4+ mean value below 200/mm3.
                Int Conf AIDS. 1996 Jul 7-12;11(1):79
                (abstract no.Mo.B.1143).
REFERENCES      MED/96262016. Giacca M, Zanussi S, Comar M,
                Simonelli C, Vaccher E, de Paoli P, Tirelli
                U. Treatment of human immunodeficiency virus
                infection with hydroxyurea: virologic and
                clinical evaluation. J Infect Dis. 1996
                Jul;174(1):204-9.
REFERENCES      AIDS/96920291. Biron F, Lucht F, Peyramond D,
                Fresard A, Contamin B, Vallet T, Nugier F,
                Grange J, Malley S, Hamedi-Sangsari F, et al.
                Follow up of HIV-1 infected patients treated
                with didanosine and hydroxyurea combination.
                3rd Conf Retro and Opportun Infect. 1996 Jan
                28-Feb 1;:107.
REFERENCES      AIDS/96920293. Steinhart CR, Jacobsen DA,
                George SA. Retrospective analysis of
                combination antiretroviral therapy (ART) with
                stavudine (d4T) and hydroxyurea (HU). 3rd
                Conf Retro and Opportun Infect. 1996 Jan
                28-Feb 1;:107.
REFERENCES      AIDS/96920244. Conway B, Raboud J, Montaner
                JS, O'Shaughnessy MV, Zala C. Evaluation of
                viral dynamics in patients on antiretroviral
                therapy. 3rd Conf Retro and Opportun Infect.
                1996 Jan 28-Feb 1;:98.
REFERENCES      AIDS/96920406. Montaner JS, Zala C, Raboud
                JM, Conway B, Patenaude P, Rae S, Schecter
                           MT, O'Shaughnessy MV. A pilot study of
                           hydroxyurea (HO-urea) as adjuvant therapy
                           among patients with advanced HIV disease
                           receiving didanosine (ddI) therapy. 3rd Conf
                           Retro and Opportun Infect 1996. Jan 28-Feb
                           1;:129.
REFERENCES                 AIDS/96700816. James JS. Hydroxyurea and ddI:
                           French study published. AIDS Treat News 1995.
                           Sep 1;:no 230(6).
ENTRY MONTH                199610
LAST REVISION DATE         19980423

55
UNIQUE IDENTIFIER          DRG-0252
NAME OF SUBSTANCE          Cyclodextrin-itraconazole [NCI 96 C-41]
SYNONYMS                   CD-itraconazole [NCI 96 C-41]
PROTOCOL ID NUMBERS        NCI 96 C-41
DISEASES STUDIED/TREATED   Oropharyngeal candidiasis. [NCI 96 C-41]
CLASSIFICATION CODE        Antifungal [NCI 96 C-41]
MANUFACTURERS              Drugs are provided by each participating unit
                           site
REFERENCES                 MED/97057727. Phillips P, Zemcov J, Mahmood
                           W, Montaner JS, Craib K, Clarke AM.
                           Itraconazole cyclodextrin solution for
                           fluconazole-refractory oropharyngeal
                           candidiasis in AIDS: correlation of clinical
                           response with in vitro susceptiblity. AIDS.
                           1996 Oct;10(12):1369-76.
REFERENCES                 ICA11/96920887. Moskovitz BL, Wilcox CM,
                           Darouiche R, Wu J, Mallegol I. Itraconazole
                           oral solution (IS) compared with fluconazole
                           (F) for treatment of esophageal candidiasis
                           (EC). Int Conf AIDS. 1996 Jul 7-12;11(1):17
                           (abstract no.Mo.B.116).
REFERENCES                 ICA9/93336139. Cartledge JD, Midgley J, Youle
                           M, Fisher M, Gazzard BG. The use of
                           cyclodextrin solution formulation of
                           itraconazole (ITR-SOL) to treat candidiasis
                           unresponsive to other azole preparations in
                           patients with AIDS. Int Conf AIDS. 1993 Jun
                           6-11;9(1):55 (abstract no. WS-B12-2).
REFERENCES                 ICA10/94371567. Mahmood W, Hamann-Trou D,
                           Phillips P, Zemcov SJ, Montaner JS, Clarke
                           AM, Itraconazole solution for
                           fluconazole-refratory oropharyngeal
                           candidiasis in AIDS: correlation of clinical
                           response with in vitro susceptibility. Int
                           Conf AIDS. 1994 Aug 7-12;10(2):23 (abstract
                           no. 386B).
ENTRY MONTH                199609
LAST REVISION DATE         19980511

56
UNIQUE IDENTIFIER          DRG-0251
NAME OF SUBSTANCE          Synthetic Peptide Construction 3 [FDA 257A]
SYNONYMS                   SPC3 [FDA 257A]
SYNONYMS                   SPC3 peptide [MeSH]
PROTOCOL ID NUMBERS        FDA 257A
PHARMACOLOGICAL ACTION     MODE OF ACTION: Data suggest that SPC3
                           prevents HIV-1 attachment to the surface of
                           CD4- cells that express galactosylceramide,
                           an alternative receptor for HIV-1 gp120. In
                           CD4+ lymphocytes, SPC3 interferes with a
                           post-binding step necessary for virus entry
                           into the cell. [Proc Natl Acad Sci USA 1995
                           May 23;92(11)]
DISEASES STUDIED/TREATED   HIV infection. [FDA 257A]
CLASSIFICATION CODE        Antiretroviral [FDA 257A]
CONTRAINDICATIONS          Contraindicated in women of reproductive
                           potential. [FDA 257A]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Synthetic multibranched
                           peptide containing eight HIV-1 gp120 V3 loop
                           GPGRAF motifs. [Biochemistry 1995 Jul
                           4;34(26)]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intravenous. [FDA 257A]
MANUFACTURERS              Columbia Research Laboratories Incorporated;
                           100 North Village Avenue / Suite 32;
                           Rockville Centre, NY 11570
REFERENCES                 MED/97121263. Delezay O, Hammache D, Fantini
                           J, Yahi N. SPC3, a V3 loop-derived synthetic
                           peptide inhibitor of HIV-1 infection, binds
                           to cell surface glycosphingolipids.
                           Biochemistry. 1996 Dec 10;35(49):15663-71.
REFERENCES                 MED/95322380. Mabrouk K, Van Rietschoten J,
                           Rochat H, Loret EP. Correlation of antiviral
                           activity with beta-turn types for V3
                           synthetic multibranched peptides from HIV-1
                           gp120. Biochemistry. 1995 Jul
                           4;34(26):8294-8.
REFERENCES                 MED/96172685. Sabatier JM, Baghdiguian S,
                           Yahi N, Rochat H, Van Rietschoten J, Fantini
                           J. SPC3, a nontoxic peptide inhibitor of HIV
                           infection [letter]. In Vitro Cell Dev Biol
                           Anim. 1995 Jun;31(6):415-8.
REFERENCES                 MED/95281557. Yahi N, Fantini J, Baghdiguian
                           S, Mabrouk K, Tamalet C, Rochat H, Van
                           Rietschoten J, Sabatier JM. SPC3, a synthetic
                           peptide derived from the V3 domain of human
                           immunodeficiency virus type 1 (HIV-1) gp120,
                           inhibits HIV-1 entry into CD4+ and CD4- cells
                           by two distinct mechanisms. Proc Natl Acad
                           Sci U S A. 1995 May 23;92(11):4867-71.
ENTRY MONTH                199608
LAST REVISION DATE         19980423

57
UNIQUE IDENTIFIER          DRG-0250
NAME OF SUBSTANCE          SNX-111 [FDA 256A]
REGISTRY NUMBER            107452-89-1
STANDARD CHEMICAL NAME     omega-Conotoxin M VIIA [CHEMID]
SYNONYMS                   Snx 111 [CHEMID]
SYNONYMS                   omega-Conopeptide mviia [CHEMID]
SYNONYMS                   omega-Conotoxin mviia conus majus [CHEMID]
PROTOCOL ID NUMBERS        FDA 256A
PHARMACOLOGICAL ACTION     MODE OF ACTION: In patients and animals with
                           painful peripheral neuropathies, spontaneous
                           ectopic discharge from injured primary
                           afferents is hypothesized to maintain a
                           central state of hyperexcitability that
                           underlies hyperalgesia and allodynia.
                           Temporary suppression of this discharge
                           allows the central state to normalize, such
                           that hyperalgesia and allodynia are absent or
                           reduced. Ca++ channels are involved in the
                           genesis of spontaneous discharge from injured
                           afferents. SNX-111 and SNX-124, synthetic
                           homologs of omega-conopeptides (MVIIA and
                           GVIA) and potent blockers of neuronal N-type
                           voltage-sensitive Ca++ channels, may be
                           useful in treatment of the abnormal pains
                           that occur after nerve injury.
                           Pharmacokinetic studies of SNX-111 were
                           conducted in rats and cynmolqus monkeys to
                           determine the disposition of this compound
                           when it is administered for 24 hr by
                           continuous, constant-rate intraveneous
                           infusion . In all cases apparent steady-state
                           plasma SNX-111 concentration were achieved
                           within 2-4 hrs. Steady-state volume of
                           distribution values were approximately 40% of
                           body weight, indicating extravascular
                           dissemination of SNX-111 to both
                           extracellular and intracellular fluids.
                           Elimination curves contained two exponential
                           components. The fast components (rat t1/2,
                           alpha= 0.375 hr; monkey t1/2, alpha = 0.730
                           hr) accounted for approximately 97% of the
                           unit impulse disposition function. The
                           apparent terminal half-life ranged from 4.61
                           hr (rat) to 6.48 hr (monkey). [J Pharmacol
                           Exp Ther 1995 Aug;274(2); Drug Metab Dispos
                           1997 Mar;25(3)]
DISEASES STUDIED/TREATED   Pain related to HIV. [FDA 256A]
CLASSIFICATION CODE        Calcium Channel Blocker [CHEMLINE]
OTHER MAJOR USES           Pain related to cancer. Areas of potential
                           therapeutic utility include treatment of
                           nociceptive and neuropathic pain and
                           neuroprotection after ischemic brain injury.
                           [FDA 256A; J Cardiovascular Pharmacology 1997
                           Sep; 30(3)]
SUBSTANCE INTERACTIONS      [USP DI 1995]
CONTRAINDICATIONS          Contraindicated in pregnant and nursing
                           women. [FDA 256A]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Synthetic homolog of
                           omega-conopeptide. First neuronal N-type,
                           voltage-sensitive calcium channel (VSCC)
                           blocker to enter clinical drug development.
                           [J Pharmacol Exp Ther 1995 Aug;274(2); J
                           Cardiovascular Pharmacology 1997 Sep; 30(3)]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C102H172N36O32S7 [CHEMID]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intrathecal. [FDA 256A]
MANUFACTURERS              Neurex Corporation; 3760 Haven Avenue; Menlo
                           Park, CA 94025
REFERENCES                 97445441. McGuire D, Bowersox S, Fellmann JD,
                           Luther RR. Sympatholysis after
                           neuron-specific, N-type, Voltage-sensitive
                           calcium channel blockade: first demonstration
                           of N-channel function in humans. J Cardivasc
                           Pharmacol 1997 Sep;30(3):400-3.
REFERENCES                 97459785. Sato K, Raymond C, Martin-Moutot N,
                           Sasaki T, Omori A, Ohtake A, Kim JI, Kohno T,
                           Takahashi M, Seager M. Binding of chimeric
                           analogs of omega-conotoxin MVIIA and MVIIC to
                         the N- and P/Q-type calcium channels. FEBS
                         Lett 1997 Sep 8;414(2):480-4.
REFERENCES               97422167. MacLachlan LK, Middleton DA,
                         Edwards AJ, Reid DG. A case history. NMR
                         studies of the structure of a small protein,
                         omega-conotoxin MVIIA. Methods Mol Biol
                         1997;60:337-62.
REFERENCES               97335722. Verweij BH, Muizelaar JP, Vinas FC,
                         Peterson PL, Xiong Y, Lee CP. Mitochondrial
                         dysfunction after experimental and human
                         brain injury and its possible reversal with a
                         selective N-type calcium channel antagonist
                         (SNX-111). Neurol Res 1997 Jun;19(3):334-9.
REFERENCES               97227275. Bowersox SS, Mandeme J,
                         Tarczy-Hornoch K, Miljanlch G, Luther RR.
                         Pharmacokinetics of SNX-111, a selective
                         N-type calcium channel blocker, in rats and
                         cynomolgus monkeys. Drug Metab Dispos 1997
                         Mar;25(3):379-83.
REFERENCES               97123098. Bowersox SS, Gadbois T, Singh T,
                         Pettus M, Wang YX, Luther RR. Selective
                         N-type neuronal voltage-sensitive calcium
                         channel blocker, SNX111, produces spinal
                         antinociception in rats models of acute,
                         persistent and neuropathic pain. J Pharmacol
                         Exp Ther 1996 Dec;279(3):1243-9.
REFERENCES               97070382. Nielsen KJ, Thomas L, Lewis RJ,
                         Alewood PF, Craik DJ. A consensus structure
                         for omega-conotoxins with different
                         selectivities for voltage-sensitive calcium
                         channel subtypes: comparison of MVIIA, SVIB
                         and SNX-202. J Mol Biol 1996 Oct
                         25;263(2):297-310.
REFERENCES               AIDS/97229579. Neurex launches phase III
                         program for the treatment of chronic pain
                         [news]. Aids Patients Care STDS. 1996
                         Oct;10(5):311-2.
REFERENCES               95367555. Kohno T, Kim JI, Kobayashi K,
                         Kodera T, Maeda T, Sato K. Three-dimensional
                         structure in solution of the calcium channel
                         blocker omega-conotoxin MVIIA. Biochemistry
                         1995 Aug 15;34(32):10256-65.
REFERENCES               95363679. Xiao WH, Bennett GJ. Synthetic
                         omega-conopeptides applied to the site of
                         nerve injury suppress neuropathic pains in
                         rats. J Pharmacol Exp Ther 1995
                         Aug;274(2):666-72.
ENTRY MONTH              199608
LAST REVISION DATE       19980128

58
UNIQUE IDENTIFIER        DRG-0249
NAME OF SUBSTANCE        Recombinant human nerve growth factor [NIAID
                         ACTG 291]
SYNONYMS                 rhNGF [NIAID ACTG 291]
PROTOCOL ID NUMBERS      NIAID ACTG 291
PHARMACOLOGICAL ACTION   MODE OF ACTION: The gene for human nerve
                         growth factor (NGF) has been cloned into a
                         mammalian cell line and large quantities of
                         recombinant human NGF (rhNGF) can now be
                         produce for clinical use, but little is known
                           about the fate of rhNGF following delivery to
                           the brain. In a study, polymer matrices
                           containing 125I-labled rhNGF were implanted
                           into the brains of adult rats and the spatial
                           distribution of the released protein was
                           measured for 8 weeks after implatation. For
                           the first several days, the rate of NGF
                           release from the polymer matrix was high
                           (approximately 100 ng/day). At later times,
                           the the release rate decreased (2-10 ng/day).
                           NGF levels were always highest in the tissue
                           closest to the polymer. The first 10-fold
                           decrease occurred during the first ten days
                           of study; a further 6 weeks was required to
                           achieve the second 10-fold decrease.
                           Comparsion of local rhNGF concentration
                           profiles with a simple mathematical model
                           indicated that rhNGF diffuses through the
                           brain interstitial space and is elimanted
                           with a half-life of approximately 45 min,
                           although elimination appears to be
                           substantially slower in white matter regions.
                           This limited ability of NGF to penetrate and
                           be retained within the brain tissue indicates
                           that NGF will need to be delivered almost
                           directly to the target tissue for efficacy. A
                           study evaluating the safety of a single
                           intravenous or subcutaneous doses of rhNGF in
                           healthy human volunteers at doses ranging
                           from 0.03 to 1 micrograms/kg showed no
                           life-threatening adverse events at any dose.
                           Antibodies to rhNGF were not detected in any
                           subject. These results indicate to
                           systemically administered rhNGF experts a
                           characteristic and reproducible biological
                           effect in healthy subjects at very low doses
                           and in a dose-dependent manner. In another
                           study, following mulitiple dosing, some
                           peripheral neuropathic patients reported an
                           improvement in clinical symptoms, which in
                           some case correlated with improvements in
                           neurological examinations. [Neurotoxicology
                           1996 Fall-Winter; 17(3-4); Brain Res 1996 Jul
                           15; 727(1-2); Ann Neurol 1994 Aug;36(2)]
DISEASES STUDIED/TREATED   HIV-related peripheral neuropathy. [NIAID
                           ACTG 291]
CLASSIFICATION CODE        Human nerve growth factor [NIAID ACTG 291]
OTHER MAJOR USES           Diabetic peripheral neuropathy. [NIAID ACTG
                           291]
ADVERSE EFFECTS            Adverse effects with intravenous
                           administration have included mild to moderate
                           pain with swallowing, pain in the masseter
                           muscles, pain in the throat, and painful
                           muscles in other areas. Adverse effects with
                           subcutaneous administration have included
                           moderate diffuse muscle pain and injection
                           site hyperalgesia, described as increased
                           sensitivity to touch or heat around the
                           injection site. Adverse effects with
                           intravenous administration have included mild
                           to moderate pain with swallowing, pain in the
                          masseter muscles, pain in the throat, and
                          painful muscle in other areas. Averse effects
                          with subcutaneous admininistration have
                          included moderate diffuse muscle pain and
                          injection site hyperalgesia, described as
                          increased sensitivity to touch or heat around
                          the injection site. Results from recent
                          preclinical studies indicated no safety
                          findings which would preclude the chronic
                          administration of rhNGF in clinical trials in
                          humans. [NIAID ACTG 291; Ann Neurol 1994
                          Aug;36(2); Neurotoxicology 1996 Fall-Winter;
                          17(3-4)]
CONTRAINDICATIONS         Contraindicated in pregnant and nursing
                          women. [NIAID ACTG 291]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: Homodimer consisting of
                          predominately a 118-amino acid residue
                          monomer. [NIAID ACTG 291]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: Clear, colorless
                          liquid. [NIAID ACTG 291]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: 2 mg/ml in 0.5 ml vials. [NIAID
                          ACTG 291]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Subcutaneous, intravenous.
                          [NIAID ACTG 291]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store at 2-8 C (35-46
                          F). Do not freeze. [NIAID ACTG 291]
MANUFACTURERS             Genentech Incorporated; 460 Point San Bruno
                          Boulevard; South San Francisco, CA 94080
REFERENCES                97435009. Mrak RE, Griffin WS. The role of
                          chronic self-propagating glial responses in
                          neurodegeneration: implications for
                          long-lived survivors of human
                          immunodeficiency virus. J Neurovirol 1997
                          Aug;3(4):241-6.
REFERENCES                97327439. Day-Lollini PA, Stewart GR, Taylor
                          MJ, Johnson RM, Chellman GJ. Hyperplastic
                          changes within the leptomeninges of the rat
                          and monkey in responses to chronic
                          intracerbroventricular infusion of nerve
                          growth factor. Exp Neurol 1997
                          May;145(1):24-37.
REFERENCES                97241110. Roger BC. Development of
                          recombinant human nerve growth factor (rhNGF)
                          as a treatment for periperal neuopathic
                          disease. Neurotoxicology 1996
                          Fall-Winter;17(3-4):865-70.
REFERENCES                97116619. Krewson CE, Dause R, Mak M,
                          Saltzman WM. Stabilization of nerve growth
                          factor in controlled release polymers and in
                          tissue. J Biomater Sci Polym Ed
                          1996;8(2):103-17.
REFERENCES                97001854. De Young LR, Burton LE, Liu J,
                          Powell MF, Schmelzer CH, Skelton NJ. RhNGF
                          slow unfolding is not due to proline is
                          merization: possibility of a cystine knot
                          loop-threading mechanism. Protein Sci 1996
                          Aug;5(8):1554-66.
REFERENCES                96309670. Emmet CJ, Stewart GR, Johnson RM,
                          Aswani SP, Chan RL, Jakeman LB. Distribution
                          of radioiodinated recombinant human nerve
                          growth factor in primate brain following
                         intracerebroventricular infusion. Exp Neurol
                         1996 Aug;140(2):151-60.
REFERENCES               96440084. Krewson CE, Saltzman WM. Transport
                         and elimination of recombinant human NGF
                         during long-termed deliverly to the brain.
                         Brain Res 1996 Jul;15727(1-2):169-81.
REFERENCES               96295126. Knepp VM, Whatley JL, Muchnik A,
                         Calderwood TS. Identification of antioxidants
                         of peroxide-mediated oxidation of recombinant
                         human ciliary neurotrophic factor and
                         recombinant human growth factor. PDA J Pharm
                         Sci Technol 1996 May-Jun;50(3):163-71.
REFERENCES               95330310. Emmett CJ, Aswani SP, Stewart GR,
                         Fairchild D, Johnson RM. Dose-response
                         comparison of recombinant human nerve growth
                         factor and recombinant human basic fibroblast
                         growth factor in the fimbria fornix model of
                         acute cholinergic degeneration. Brain Res
                         1996 Mar;673(2):199-207.
REFERENCES               95010541. Forander P, Bjorklund L , Stromberg
                         I. Dose-dependent effects of recombinant
                         human NGF on grated adult adrenal medullary
                         tissue. Exp Neurol 1994 Apr;126(2):168-77.
REFERENCES               94330699. Petty BG, Cornblath DR, Adornato
                         BT, Chaudhry V, Flexner C, Wachsman M,
                         Sinicropi D, Burton LE, Peroutka SJ. The
                         effect of systemically administered
                         recombinant human nerve growth factor in
                         healthy human subjects. Ann Neurol 1994
                         Aug;36(2):244-6.
ENTRY MONTH              199607
LAST REVISION DATE       19980128

59
UNIQUE IDENTIFIER        DRG-0248
NAME OF SUBSTANCE        Varicella Virus Vaccine Live [Merck & Co June
                         1996]
SYNONYMS                 Varivax [Physicians GenRx 1996]
SYNONYMS                 Chickenpox Vaccine Live [AHFS Drug
                         Information 1997]
PROTOCOL ID NUMBERS      NIAID ACTG 265
PHARMACOLOGICAL ACTION   MODE OF ACTION: Induces both humoral and
                         cell-mediated responses, although the role
                         and relative contribution of each type of
                         response to long-term immunity against
                         varicella has not been fully determined.
                         Responses elicited by Varivax appear to be
                         less than those elicited by natural infection
                         with wild-type varicella-zoster virus. In
                         some individuals, especially healthy adults
                         and immunocompromised children, the vaccine
                         provides partial immunity and modification of
                         varicella infection rather than complete
                         protection. Continued long-term studies are
                         necessary to determine the extent and
                         duration of protection against varicella
                         provided by primary immunization with the
                         vaccine. Seroconversion following
                         administration of varicella virus vaccine
                         live does not result in complete protection
                         for individuals and breakthrough varicella
                           infections may occur despite seroconversion.
                           [AHFS Drug Information 1997]
DISEASES STUDIED/TREATED   Prevention of varicella ( chickenpox ) in
                           HIV-infected patients. [NIAID ACTG 265]
CLASSIFICATION CODE        Vaccine [Physicians GenRx 1996]
OTHER MAJOR USES           Indicated for vaccination against varicella
                           virus infection (chickenpox, herpes, zoster,
                           shingles) in individuals 12 months of age and
                           older. FDA approved March 1995. [Physicians
                           GenRx 1996]
SUBSTANCE INTERACTIONS     Vaccination should be deferred for at least 5
                           months following blood or plasma transfusion,
                           or administration of immune globulin or
                           varicella zoster immune globulin. Following
                           administration of varicella virus vaccine
                           live, any immune globulin should not be given
                           for 2 months. Vaccine recipients should avoid
                           use of salicylates for 6 weeks after
                           vaccination, as Reye's Syndrome has been
                           reported following the use of salicylates
                           during natural varicella infection. The
                           varicella vaccine can be administered
                           concomitantly with M-M-R II (Measles, Mumps,
                           and Rubella Vaccine Live), and witrh DTap
                           (diphtheria, tetanus, acelluar pertussis) and
                           PedvaxHIB, using separate sites and syringes.
                           [PDR 1997]
ADVERSE EFFECTS            Generally well tolerated. Primary adverse
                           effects include pain, soreness, swelling,
                           redness, or itching at the injection site or
                           generalized rash. Other adverse effects may
                           include respiratory illness, cough,
                           irritability/ nervousness, fatigue, headache,
                           teething (in children), Malaise, Adominal
                           pain, nausea, eye complaints, chills,
                           lymphadenopathy, myalgia,allergic reactions,
                           stiff neck, heat rash or prickly heat,
                           arthralgia, eczema, dry skin, dermatitis,
                           constipation, and, rarely, febrile seizures
                           in children aged 1-12. Several case of herpes
                           zoster (shingles) have been reported in
                           children and adults in clinical trials. The
                           long term effect of varicella vaccine on the
                           incidence of herpes zoster; particularly in
                           those vaccinees exposed to natural varicella,
                           is unknown. [Physicians GenRx 1996; PDR 1997]
CONTRAINDICATIONS          Contraindicated in patients with blood
                           dyscrasias, leukemia, lymphoma, or other
                           malignant neoplasms affecting the bone marrow
                           or lymphatic system. Also contraindicated in
                           patients with hypersensitivity to vaccine
                           components, prior anaphylactoid reaction to
                           neomycin, active untreated tuberculosis,
                           immunosuppression, family history of
                           congenital or hereditary immunodeficiency
                           unless the disorder has been ruled out in the
                           patient, or febrile respiratory disease or
                           other active febrile infection.
                           Contraindicated in pregnant women and in
                           patients who are receiving immunosuppressive
                           therapy, including recent immunoglobulin
                          therapy or chronic aspirin therapy. Use with
                          caution in patients who have direct contact
                          with immunocompromised individuals, newborns,
                          or pregnant women. Safety and efficacy of the
                          varicella virus vaccine live in children and
                          adults with HIV infections have not been
                          established. In general HIV+ individuals
                          should not receive live viral vaccines. [AHFS
                          Drug Information 1997]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: Preparation of Oka/Merck
                          strain of live, attenuated varicella virus,
                          initially obtained from a child with natural
                          varicella and propagated in embryonic guinea
                          pig cell culture and finally propagated in
                          human diploid cell culture. [Physicians GenRx
                          1996; PDR 1997]
CHEMICAL/PHYSICAL DATA    STABILITY: To maintain potency, the
                          lyophilized vaccine must be kept frozen at an
                          average temperature of -15 C (+5F) or colder
                          and must be used before expiration date. [PDR
                          1997]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Vaccine is administered in 0.5
                          mL doses. When the vaccine is administered
                          within 30 minutes following reconstitution as
                          specific, each 0.5 mL dose contains at least
                          1350 plaque-forming units (PFU) of Oka/Merck
                          virus. Children 12 months to 12 years should
                          receive a single 0.5 mL dose subcutaneously.
                          Adolescents and adults 13 years and older
                          should receive a 0.5 mL dose subcutaneously
                          at elected date and a second 0.5 mL dose 4 to
                          8 weeks later. [AHFS Drug Information 1997;
                          PDR 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Subcutaneous. (WARNING:
                          Should NOT be administered IV). [Physicians
                          GenRx 1996]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store frozen at -15 C
                          (5 F)or colder. Protect from light. Use
                          within 30 minutes following reconstitution.
                          Discard it reconstituted vaccine is not used
                          within 30 minutes[Physicians GenRx 1996; PDR
                          1997]
MANUFACTURERS             Merck Research Laboratories; 126 East Lincoln
                          Avenue; Rahway, NJ 07065
REFERENCES                97383801. Reuman PD, Sawyer MH, Kuter BJ,
                          Matthews H. Safety and immunogenicity of
                          concurrent administration of measles-
                          mumps-rubella-varicella vaccine and PedvaxHIB
                          vaccines in healthy children twelve to
                          eighteen months old. The MMRV Study Group.
                          Pediatr Infect Dis J 1997 Jul;16(7):662-7.
REFERENCES                97333504. Arvin AM. The varicella vaccine.
                          Curr Clin Top Infect Dis 1997;17:110-46.
REFERENCES                97331799. Arvin AM. Live attenuated varicella
                          vaccine. Pediatr Ann 1997 Jun;26(6):384-8.
REFERENCES                97282937. Gerecitano J, Friedman-Kien A,
                          Chazen GD. Allergic reaction to varicella
                          vaccine [letter]. Ann Intern Med 1997 May
                          15;126(10):833-4.
REFERENCES                97329657. Pepose JS. The potential impact of
                          the varicella vaccine and new antivirals on
                           ocular disease related to varicello-zoster
                           virus. Am J Ophthamol 1997 Feb;123(2):243-51.
REFERENCES                 97194089. Krah DL, Cho I, Schofield RW, Ellis
                           RW. Comparison of gpELISA and neutralizing
                           antibody responses to Oka/Merck live
                           varicella vaccine (Varivax) in chldren and
                           adults. Vaccine 1997 Jan;15(1):61-4.
REFERENCES                 97061030. Arvin AM, Gershon AA. Live
                           attenauted varicella vaccine. Annu Rev
                           Microbiol 1996;50:59-100.
REFERENCES                 97051904. LaRussa P, Steinberg S, Gershon AA.
                           Varicella vaccine for immunocompromised
                           children: results of collaborative studies in
                           the United States and Canada. J Infect Dis
                           1996. Nov;174 Suppl 3:S320-3.
REFERENCES                 97056005. Schouten JW. Effects of the
                           varicella vaccine on long-term immunity
                           [etter] Am Fanm Physician 1996 Nov
                           1;54(6):1894-6.
REFERENCES                 97009248. Gershon AA, LaRusssa P, Steinberg
                           S. The varicella vaccine. Clinical trials
                           immunocompromised individuals. Infect Dis
                           Clin North Am 1996 Sep;10(3):583-94.
ENTRY MONTH                199607
LAST REVISION DATE         19980217

60
UNIQUE IDENTIFIER          DRG-0247
NAME OF SUBSTANCE          HIV-1 Immunogen [FDA 092]
SYNONYMS                   Remune [Immune Response Corporation June
                           1996]
SYNONYMS                   Salk Immunogen [Immune Response Corporation
                           June 1996]
SYNONYMS                   Salk HIV vaccine [Immune Response Corporation
                           June 1996]
PROTOCOL ID NUMBERS        NCI 95 C-172
PROTOCOL ID NUMBERS        FDA 092
PROTOCOL ID NUMBERS        FDA 093
PROTOCOL ID NUMBERS        FDA 094
PHARMACOLOGICAL ACTION     MODE OF ACTION: May slow replication of HIV-1
                           by stimulating the immune system to recognize
                           HIV proteins and destroy cells infected with
                           the virus. Theoretically, the use of
                           inactivated virus could stimulate broader
                           immune responses that are capable of
                           suppressing more diverse strains of HIV than
                           vaccines based on subunits of the virus.
                           [Immune Response Corporation June 1996]
DISEASES STUDIED/TREATED   HIV infection. [FDA 092]
CLASSIFICATION CODE        Vaccine [FDA 092]
SUBSTANCE INTERACTIONS     May complement action of antiretroviral drugs
                           against infection. [Immune Response
                           Corporation June 1996]
CONTRAINDICATIONS          Contraindicated in pregnant or nursing women.
                           [FDA 092]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: gp120-depleted HIV-1
                           derived from Zairian strain HZ-321 that is
                           propagated in HUT-78 cells, inactivated in
                           beta-propriolactone and irradiation, and
                           emulsified in mineral oil (Incomplete
                           Freund's Adjuvant). [Immune Response
                          Corporation June 1996]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Intramuscular. [FDA 092]
MANUFACTURERS             Immune Response Corporation; 5935 Darwin
                          Court; Carlsbad, CA 92008
REFERENCES                AIDS/97701999. Anonymous. Remune trials
                          recruiting. PI Perspect. 1996 Sep;: No 19,
                          17.
REFERENCES                MED/96302269. Wallace MR, Moss RB, Beecham HJ
                          3rd, Grace CJ, Hersh EM, Peterson E, Murphy
                          R, Shepp DH, Siegal FP, Turner JL, et al.
                          Early clinical markers and CD4 percentage in
                          subjects with human immunodeficiency virus
                          infection. J Acquir Immune Defic Syndr Hum
                          Retrovirol. 1996 Aug 1;12(4):358-62.
REFERENCES                AIDS/96701842. Anonymous. Immune Response and
                          NIH begin pediatric clinical trial of Remune
                          HIV therapy. National Institutes of Health. J
                          Int Assoc Physicians AIDS Care. 1996
                          Jul;2(7):44.
REFERENCES                AIDS/96701492. Anonymous. Salk therapy
                          begins. Posit Aware. 1996 May/Jun;7(3):7.
REFERENCES                MED/96183598. Levine AM, Groshen S, Allen J,
                          Munson KM, Carlo DJ, Daigle AE, Ferre F,
                          Jensen FC, Richieri SP, Trauger RF, Parker
                          JW, Salk PL, Salk J. Initial studies on
                          active immunization of HIV-infected subjects
                          using a gp 120-depleted HIV-1
                          Immunogen:long-term follow-up. J Acquir
                          Immune Defic Syndr Hum Retrovirol 1996 Apr
                          1;11(4):351-64.
REFERENCES                AIDS/97920707. Moss, RB, Jensen FC, Ferre F,
                          Trauger RJ, Daigle AE, Richieri SP, Carlo DJ.
                          Large-scale efficacy testing of the HIV-1
                          immunogen in seropositive subjects. Conf Adv
                          AIDS Vaccine Dev. 1996 Feb 11-15;:133 [Poster
                          13].
REFERENCES                AIDS/95700466. Lein B. HIV-1 immunogen. PI
                          Perspect. 1995 May;: no 16, 17.
REFERENCES                MED/95212064. Trauger RJ, Giermakowska W,
                          Wormsley S, Turner J, Jensen FC, Carlo DJ.
                          Autoproliferation in HIV-1-infected patients
                          undergoing active HIV-1-specific
                          immunotherapy. Clin Exp Immunol. 1995
                          Apr;100(1):7-12.
REFERENCES                AIDS/95920549. Moss RB, Ferre F, Trauger R,
                          Daigle A, Richieri S, Jensen F, Carlo DJ.
                          Clinical follow-up of subjects treated with
                          an inactivated gp120-depleted HIV-1
                          immunogen. Natl Conf Hum Retroviruses Relat
                          Infect (2nd). 1995 Jan 29-Feb 2;:150.
REFERENCES                MED/96033816. Trauger RJ, Daigle AE,
                          Giermakowska W, Moss RB, Jensen F, Carlo DJ.
                          Safety and immunogenicity of a gp
                          120-depleted, inactivated HIV-1 immunogen:
                          results of a double-blind, adjuvant
                          controlled trial. J Acquir Immune Defic Syndr
                          Hum Retrovirol 1995;10 Suppl 2:S74-82.
ENTRY MONTH               199606
LAST REVISION DATE        19980423

61
UNIQUE IDENTIFIER          DRG-0246
NAME OF SUBSTANCE          Lodenosine [AmFar Tx Dir December, 1997]
REGISTRY NUMBER            114849-59-1
SYNONYMS                   F-ddA [Fundam Appl Toxicol 1995 Sep;27(2)]
SYNONYMS                   beta-Fluoro-ddA [NCI 95 C-192]
SYNONYMS                   beta-F-ddA [Biochem Pharmacol 1994 Oct
                           7;48(7)]
SYNONYMS                   2-Fluoro-2',3'-dideoxyadenosine [Fundam Appl
                           Toxicol 1995 Sep;27(2)]
PROTOCOL ID NUMBERS        NCI 95 C-0192
PROTOCOL ID NUMBERS        NCI 97 C-0119
SECONDARY SOURCE ID        NSC-613792 [NCI 95 C-192]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Similar to dideoxyadenosine
                           (ddA), except that a fluorine atom is
                           introduced into the 2'-position of the
                           glycon. Like ddA and its metabolite ddI,
                           beta-F-ddA is metabolized intracellularly to
                           a triphosphate moiety that acts as a reverse
                           transcriptase inhibitor. Because of the
                           fluorine substitution, beta-F-ddA is expected
                           to be absorbed better than didanosine because
                           the fluorinated molecules become more stable
                           to acid conditions. beta-F-ddA has
                           demonstrated anti-HIV activity in vitro.
                           beta-F-ddA does not appear to have cross
                           resistance with ddI or other nucleoside
                           analogues, and is even active against strains
                           of HIV that have multi-dideoxynucleoside
                           resistance associated with a mutation at
                           codon 151 of reverse transcriptase. In
                           comparison with zalcitabine, beta-F-ddA is
                           22000 times less potent in suppressing
                           cellular mitochondrial DNA synthesis, while
                           anti-HIV potency is only modestly less
                           compared to the unfluorinated compound.
                           Inhibition of mitochondrial DNA could be
                           responsible for the delayed clinical toxicity
                           sometimes observed with dideoxynucleosides.
                           [NCI 95 C-192; Biochem Pharmacol 1994 Oct
                           7;48(7)]
DISEASES STUDIED/TREATED   HIV infection. [NCI 95 C-192]
CLASSIFICATION CODE        Antiviral [Fundam Appl Toxicol 1995
                           Sep;27(2)]
ADVERSE EFFECTS            Has shown cardiotoxicity in rats. [Fundam
                           Appl Toxicol 1995 Sep;27(2)]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Fluorinated analogue of
                           didanosine; a purine dideoxynucleoside. [NCI
                           95 C-192; Fundam Appl Toxicol 1995 Sep;27(2)]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [NCI 95 C-192]
MANUFACTURERS              Drugs are provided by each participating unit
                           site
REFERENCES                 ICA11/96921146. Johns DG, Driscoll J.
                           2'-beta-fluoro-2',3'-dideoxyadenosine
                           (F-ddA): a new anti-HIV clinical drug
                           candidate. Int Conf AIDS. 1996 Jul
                           7-12;11(1):68 (abstract no.Mo.A.1076).
REFERENCES                 AIDS/96095608. Pommier Y. Inhibition of HIV-1
                           integrase by mono- and oligonucleotides.
                           Abstr Meet Groups Stud Struct AIDS Relat Syst
                           Their Appl Target Drug Des. 1995 Jun 5-7;:9
                           (unnumbered abstract).
REFERENCES                 MED/95032193. Tsai CH, Doong SL, Johns DG,
                           Driscoll JS, Cheng YC. Effect of anti-HIV
                           2'-beta-fluoro-2',3'-dideoxynucleoside
                           analogues on the cellular content of
                           mitochondrial DNA and on lactate production.
                           Biochem Pharmacol. 1994 Oct 7;48(7):1477-81.
ENTRY MONTH                199606
LAST REVISION DATE         19980512

62
UNIQUE IDENTIFIER          DRG-0245
NAME OF SUBSTANCE          Levamisole hydrochloride [USAN 1997]
REGISTRY NUMBER            16595-80-5
RELATED REGISTRY NUMBER    14769-73-4
RELATED REGISTRY NUMBER    32093-35-9 (phosphate)
RELATED REGISTRY NUMBER    32161-51-6 (tartrate)
RELATED REGISTRY NUMBER    32339-82-5 (citrate)
RELATED REGISTRY NUMBER    98299-95-7 (acetate)
STANDARD CHEMICAL NAME     Imidazo[2,1-b]thiazole,
                           2,3,5,6-tetrahydro-6-phenyl-,
                           monohydrochloride, (S)- [USAN 1997]
SYNONYMS                   Ripercol [Merck Index 1996]
SYNONYMS                   Ascaridil [Merck Index 1996]
SYNONYMS                   Decaris [Merck Index 1996]
SYNONYMS                   Ergamisol [Merck Index 1996]
SYNONYMS                   Levacide [Merck Index 1996]
SYNONYMS                   Levadin [Merck Index 1996]
SYNONYMS                   Levasole [Merck Index 1996]
SYNONYMS                   Meglum [Merck Index 1996]
SYNONYMS                   Nemicide [Merck Index 1996]
SYNONYMS                   Nilverm [Merck Index 1996]
SYNONYMS                   Solaskil [Merck Index 1996]
SYNONYMS                   Spartakon [Merck Index 1996]
SYNONYMS                   Tramisol [Merck Index 1996]
PROTOCOL ID NUMBERS        NCI 95 C-184
SECONDARY SOURCE ID        R 12,564 [USAN 1997]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Appears to act as an
                           immunorestorative agent in the presence of
                           immunosuppression resulting from recent
                           surgery and chemotherapy, but does not
                           stimulate the immune response to above normal
                           levels. May be related to T-cell activation
                           and proliferation, augmentation of monocyte
                           and macrophage activity, and increases in
                           neutrophil mobility, adherence, and
                           chemotaxis. Does not have cytotoxic effects.
                           Rapidly absorbed from the gastrointestinal
                           tract. The plasma half-life is between 3-4
                           hours for levamisole and 16 hours for its
                           metabolites. It is extensively metabolized by
                           the liver and the metabolites excreted mainly
                           by the kidneys. [USP DI 1997; Physicians
                           GenRx 1996]
DISEASES STUDIED/TREATED   Enhancement of immune function in HIV
                           infection. [Physicians GenRx 1996]
CLASSIFICATION CODE        Immunomodulator [Physicians GenRx 1996]
OTHER MAJOR USES           Indicated, in combination with fluorouracil,
                           for treatment of Dukes C adenocarinoma of the
                           colon following complete resection of primary
                           tumor. [USP DI 1997]
SUBSTANCE INTERACTIONS     Has been reported to produce Antabuse-like
                           side effects when given with alcohol.
                           Concomitant administration of phenytoin and
                           levamisole plus fluorouracil has led to
                           increased plasma levels of phenytoin.
                           Concurrent use of levamisole and warfarin
                           sodium ( or other coumarin-like drugs) may
                           cause prolongation of prothrombin time beyond
                           the therapeutic range. [PDR 1997]
ADVERSE EFFECTS            Adverse effects (in combination with
                           fluorouracil) may include nausea, vomiting,
                           diarrhea, stomatitis, anorexia, rash,
                           pruritus, flu-like symptoms, fever, chills,
                           dizziness, ataxia, depression, confusion,
                           memory loss, weakness, inability to
                           concentrate, headache, reversible
                           neutropenia, sepsis, thrombocytopenia, and
                           hyperbilirubinemia. Adverse effects when
                           administered alone may include rash,
                           arthralgia/myalgia, fever, neutropenia,
                           urinary infection, and cough. Other adverse
                           effects reported in worldwide experience with
                           levamisole hydrochloride include exfoliative
                           dermatitis, periorbital edema, vaginal
                           bleeding, anaphylaxis, convulsions,
                           hallucinations, renal failure,
                           hyperlipidemia, elevated serum creatinine,
                           and increased alkaline phosphatase.
                           [Physicians GenRx 1996; PDR 1997]
CONTRAINDICATIONS          Contraindicated in patients with known
                           hypersensitivity to the drug or its
                           components. [Physicians GenRx 1996; PDR 1997]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: White to pale cream
                           colored crystalline powder that is almost
                           odorless. [PDR 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR FORMULA: C11H12N2S.HCl [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR WEIGHT: 240.76 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MELTING POINT: 227-229 C [Merck Index 1996]
CHEMICAL/PHYSICAL   DATA   STABILITY: Soluble in water. Stable in acid
                           aqueous media. [Merck Index 1996]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 50 mg tablets. [PDR 1997]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [Physicians GenRx
                           1996]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Store at 15-30 C (59-86
                           F). Protect from moisture. [Physicians GenRx
                           1996]
MANUFACTURERS              Janssen Research Foundation; 1125
                           Trenton-Harbourton Road; Titusville, NJ
                           08560-0200
REFERENCES                 AIDS/97220424. Salhany JM, Stevenson M.
                           Hypothesis: potential utility of pyridoxal
                           5'-phosphate (vitamin B6) and levamisole in
                           immune modulation and HIV-1 infection. AIDS
                           Patient Care STDS. 1996 Dec;10(6):353-6.
REFERENCES                 MED/96152477. De Brabander M, Vandebroek J,
                           Wassenaar H, De Cree J, Baisier A, Demoen B,
                           De Ridder R, Jagers E, Roels V, Vogels O, et
                           al. Immunological alterations induced by
                           adjuvant treatment of postoperative colon
                           carinoma Duke's B or C with levamisole in
                           combination with 5-FU. Anticancer Res. 1995
                           Sep-Oct;15(5B):2271-7.
REFERENCES                MED/95319356. Wigginton JM. Reversal of
                          ferritin-mediated immunosuppression by
                          levamisole: a rationale for its application
                          to management of the acquired immune
                          deficiency syndrome (AIDS). Med Hypotheses.
                          1995 Feb;44(2):85-8.
REFERENCES                MED/95161644. Bourinbaiar AS, Lee-Huang S,
                          Krasinski K, Borkowasky W. Anti-HIV effect of
                          immunomodulating agent, levamisole, in vitro.
                          Biomed Pharmacother. 1994;48(7):327-30.
REFERENCES                MED/94323613. Fleming TR, Prentice RL, Pepe
                          MS, Glidden D. Surrogate and auxiliary
                          endpoints in clinical trials, with potential
                          application in cancer and AIDS research. Stat
                          Med. 1994 May 15;13(9):955-68
REFERENCES                MED/94322276. Sun A, Chiang CP, Chiou PS,
                          Wang JT, Liu By, Wu YC. Immunomodulation by
                          levamisole in patients with recurrent
                          aphthous ulcers or oral lichen planus. J Oral
                          Pathol Med. 1994 Apr;23(4):172-7.
REFERENCES                MED/93140467. Matondo P, Kalima P. Levamisole
                          for HIV- infected children in Zambia (letter;
                          comment). Lancet. 1993 Jan
                          16;341(8838):178-9.
REFERENCES                MED/92317522. Glick M, Muzyka BC. Alternative
                          therapies for major aphthous ulcers in AIDs
                          patients. J Am Dent Assoc. 1992
                          Jul;123(7);61-5.
REFERENCES                ICA8/92401191. Laane H, Eussen R, Graafmans
                          J. The effects of levamisole on HIV-infected
                          patients. Int Conf AIDS. 1992 Jul
                          19-24;8(2):B163 (abstract no. PoB 3456)
ENTRY MONTH               199605
LAST REVISION DATE        19980217

63
UNIQUE IDENTIFIER         DRG-0244
NAME OF SUBSTANCE         Ritonavir [USAN 1997]
REGISTRY NUMBER           155213-67-5
STANDARD CHEMICAL NAME    10-Hydroxy-2-methyl-5-(1-methylethyl)-1-
                          [2-(1-methylethyl) -4-
                          thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)
                          -2,4,7,12- tetraazatridecan-13-oic acid,
                          5-thiazolylmethyl ester,
                          [5S-(5R*,8R*,10R*,11R*)] [Abbott Laboratories
                          Package Insert March 1996]
SYNONYMS                  Norvir [PDR 1997]
PROTOCOL   ID   NUMBERS   FDA 245E
PROTOCOL   ID   NUMBERS   FDA 285B
PROTOCOL   ID   NUMBERS   NCI 98 C-0041
PROTOCOL   ID   NUMBERS   NIAID 98 I-0147
PROTOCOL   ID   NUMBERS   NIAID ACTG 345
PROTOCOL   ID   NUMBERS   NIAID ACTG 366
PROTOCOL   ID   NUMBERS   NIAID ACTG 401
PROTOCOL   ID   NUMBERS   NIAID CPCRA 057
PROTOCOL   ID   NUMBERS   FDA 229G
PROTOCOL   ID   NUMBERS   FDA 229H
PROTOCOL   ID   NUMBERS   FDA 229J
PROTOCOL   ID   NUMBERS   FDA 238J
PROTOCOL   ID   NUMBERS   FDA 245C
PROTOCOL   ID   NUMBERS   FDA 245D
PROTOCOL ID NUMBERS        NCI 96 C-0003G
PROTOCOL ID NUMBERS        NCI 96 C-63
PROTOCOL ID NUMBERS        NIAID ACTG 223
PROTOCOL ID NUMBERS        NIAID ACTG 246/946
PROTOCOL ID NUMBERS        NIAID ACTG 315
PROTOCOL ID NUMBERS        NIAID ACTG 338
PROTOCOL ID NUMBERS        NIAID ACTG 354
PROTOCOL ID NUMBERS        NIAID ACTG 359
PROTOCOL ID NUMBERS        NIAID ACTG 364
PROTOCOL ID NUMBERS        NIAID ACTG 375
PROTOCOL ID NUMBERS        NIAID ACTG 377
PROTOCOL ID NUMBERS        NIAID ACTG 378
PROTOCOL ID NUMBERS        NIAID CPCRA 042
SECONDARY SOURCE ID        ABT 538 [AmFAR Tx Dir 1996;8(1)]
SECONDARY SOURCE ID        Abbott 845 38 [USAN 1997]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Peptidomimetic inhibitor of
                           both the HIV-1 and HIV-2 proteases.
                           Inhibition of HIV protease renders the enzyme
                           incapable of processing the gag-pol
                           polyprotein precursor which leads to
                           production of noninfectious immature HIV
                           particles. In vitro, the EC50 of ritonavir
                           was 3.8-153 nM depending on viral isolate and
                           type of cells used. Absolute bioavailability
                           of the drug has not been determined. After a
                           600 mg dose of oral solution, peak
                           concentrations of ritonavir occurred at
                           approximately 2 and 4 h after dosing under
                           fasting and non-fasting conditions,
                           respectively. Ritonavir is metabolized
                           primarily by the liver; cytochrome P450 3A is
                           the major isoform involved in ritonavir
                           metabolism. Ritonavir is a potent inhibitor
                           of the liver's cytochrome P450 metabolic
                           pathway. [Abbott Laboratories Package Insert
                           March 1996; AmFAR Tx Dir 1996;8(1); PDR 1997]
DISEASES STUDIED/TREATED   FDA Approved 03/14/97 for use alone or in
                           combination with nucleoside analogues for
                           treatment of HIV infection in pediatrics >=2
                           years old. Indicated in combination with
                           nucleoside analogs or as monotherapy for the
                           treatment of HIV-infection when therapy is
                           warranted. [Facts and Comparisons 1996; PDR
                           1997]
CLASSIFICATION CODE        Protease inhibitor [Abbott Laboratories
                           Package Insert March 1996]
CLASSIFICATION CODE        Antiretroviral [Abbott Laboratories Package
                           Insert March 1996]
SUBSTANCE INTERACTIONS     Clarithromycin, fluconazole, and fluoxetine
                           increase ritonavir blood levels.
                           Clarithromycin, desipramine, rifabutin,
                           saquinavir, and trimethoprim AUC's are
                           increased when given with ritonavir.
                           Didanosine, ethinyl estradiol,
                           sulfamethoxazole, theophylline and zidovudine
                           AUC's are decreased with concomitant
                           ritonavir. Ritonavir solutions contain
                           alcohol which can produce reactions when
                           given with disulfiram or other drugs that
                           produce disulfiram-like reactions, e.g.
                           metronidazole. Food also has an effect on
                         ritonavir absorption. When an oral solution
                         was given under nonfasting conditions, peak
                         ritonavir levels decreased 23% and the extent
                         of absorption decreased 7% relative to
                         fasting conditions. The extent of absorption
                         of ritonavir from capsules was 15% higher
                         when given with a meal relative to fasting
                         conditions. [Facts and Comparisons 1996; PDR
                         1997]
ADVERSE EFFECTS          Adverse effects most frequently reported
                         include asthenia, nausea, diarrhea, vomiting,
                         anorexia, abdominal pain, taste perversion,
                         and circumoral and peripheral paresthesias.
                         Less common adverse effects include fever,
                         headache, malaise, vasodilation,
                         constipation, dyspepsia, flatulence, local
                         throat irritation, increase in creatine
                         phosphokinase, hyperlipidemia, myalgia,
                         dizziness, insomnia, somnolence, abnormal
                         thinking, pharyngitis, rash, and sweating.
                         Other adverse events reported occurred in
                         less than 2% of the patients studied; these
                         included cardiovascular, GI, endocrine, CNS,
                         hematological and lymphatic system and
                         dermatological reactions. Ritonavir has also
                         been associated with alterations in
                         triglyceride, AST, ALT, GGT, CPK and uric
                         acid laboratory test values. [PDR 1997;
                         Abbott Laboratories Package Insert March
                         1996]
CONTRAINDICATIONS        CAUTION: Strongly contraindicated in patients
                         receiving nonsedating antihistamines,
                         sedative hypnotics, or antiarrhythmics.
                         Should not be coadministered with meperidine,
                         piroxicam, propoxyphene, amiodarone,
                         encainide, flecainide, propafenone,
                         quinidine, rifabutin, bepridil, astemizole,
                         terfenadine, cisapride, bupropion, clozapine,
                         alprazolam, clorazepate, diazepam, estazolam,
                         flurazepam, midazolam, triazolam, or
                         zolpidem. [Abbott Laboratories Package Insert
                         March 1996; PDR 1997]
CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Synthetic peptidomimetic
                         antiviral agent; HIV protease inhibitor.
                         Chemical structure was designed based on
                         structure of HIV protease. Symmetric nature
                         of ritonavir results in a highly selective,
                         potent inhibitor of HIV protease. [AmFAR Tx
                         Dir 1996;8(1); AHFS Drug Information 1997]
CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: White to light tan
                         powder with bitter metallic taste. [PDR 1997]
CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C37H48N6O5S2 [USAN 1997]
CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 720.96 [USAN 1997]
CHEMICAL/PHYSICAL DATA   ELEMENTAL COMP: C 61.64 %, H 6.71%, N 11.66%,
                         O 11.10%, S 8.90%. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA   SOLUBILITY: Freely soluble in methanol and
                         ethanol; soluble in isopropanol; practically
                         insoluble in water. [PDR 1997]
CHEMICAL/PHYSICAL DATA   STABILITY: The oral solution is stable for 30
                         days when kept at 25 C(77F). [Facts and
                         Comparisons 1996]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: 100 mg capsules and 80 mg/ml
                          oral solution. [Facts and Comparisons 1996;
                          PDR 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral. [Facts and
                          Comparisons 1996]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store capsules at 2-8 C
                          (36-46 F) and protect from light. Store oral
                          solution at 2-8 C (36-46 F) and avoid
                          exposure to excessive heat. [PDR 1997]
MANUFACTURERS             Abbott Laboratories; One Abbott Park Road;
                          Abbott Park, IL 60064
REFERENCES                AIDS/97702899. Combination therapies improve
                          outlook for children with HIV disease. NIAID
                          AIDS Agenda. 1997 Aug;:10.
REFERENCES                MED/97422441. Eagling VA, Back DJ, Barry MG.
                          Differential inhibition of cytochrome P450
                          isoforms by the protease inhibitors,
                          ritonavir, saquinavir and indinavir. Br J
                          Clin Pharmacol. 1997 Aug;44(2):190-4.
REFERENCES                MED/97442762. Hoetelmans RM, Meenhorst PL,
                          Mulder JW, Burger DM, Koks CH, Beijnen JH.
                          Clinical pharmacology of HIV protease
                          inhibitors: focus on saquinavir, indinavir,
                          and ritonavir. Pharm World Sci. 1997
                          Aug:19(4):159-75.
REFERENCES                MED/97406768. Ungvarski PJ, Rottner JE.
                          Errors in prescribing HIV-1 protease
                          inhibtors. J Assoc Nurses Aids Care. 1997
                          Jul-Aug;8(4):55-61.
REFERENCES                MED/97392324. Van Cleef GF, Fisher EJ, Polk
                          RE. Drug interaction potential with
                          inhibitors of HIV protease. Pharmacotheraphy.
                          1997 Jul-Aug;17(4):774-8.
REFERENCES                AIDS/97702727. Health advisory: high blood
                          sugar and diabetes seen in protease inhibitor
                          users. Crit Path Aids Proj. 1997 Summer;(No
                          32):28.
REFERENCES                AIDS/97927406. Currier JS, Yetzer E, Potthoff
                          A, Glassman H, Heath-Chiozzi M. Gender
                          differences in adverse events on ritonavir:
                          an analysis from the Abbott 247 study. Natl
                          Conf Women HIV. 1997 May 4-7;:154 (abstract
                          no. 304.7).
REFERENCES                MED/97291227. Hsu A, Granneman GR, Witt G,
                          Locke C, Denissen J, Molla A, Valdes J, Smith
                          J, Erdman K, Lyons N, et al. Multiple-dose
                          phamacokinetics of ritonavir in human
                          immunodeficiency virus-infected subjects.
                          Antimicrob Agents Chemother. 1997
                          May;41(5):898-905.
REFERENCES                AIDS/97702813. Baker R, Bowers M. Ritonavir
                          and ecstasy. BETA. 1997 Mar;:5.
REFERENCES                ICA11/97926906. Hirschel BJ, Rutschmann O,
                          Fathi M, Mendoula A, von Overbeck I, Iten A.
                          Treatment of advanced HIV infection with
                          ritonavir plus saquinavir. Int Conf AIDS.
                          1997 Jul 7-12;11(Program Supplement):28
                          (abstract no. LB.B.6030).
ENTRY MONTH               199604
LAST REVISION DATE        19980413
64
UNIQUE IDENTIFIER          DRG-0243
NAME OF SUBSTANCE          ALVAC-HIV MN120TMGNP ( vCP300 ) [NIAID VEU
                           026]
PROTOCOL ID NUMBERS        NIAID VEU 026
PHARMACOLOGICAL ACTION     MODE OF ACTION: Can induce cellular and
                           humoral responses in animals. In previous
                           experiments with mice, vCP300 induced a
                           cytotoxic reponse against target cells with
                           the V3 peptide and gag/pol epitopes and a
                           proliferative response to gp160. In vitro, it
                           has been shown to stimulate CD8+
                           env/gag/nef/pol specific CTL precursors
                           present in PBMCs derived from
                           HIV-seropositive patients. In a phase I
                           trial, healthy, non-HIV-infected volunteers
                           were given vCP300 either at 0, 1, 3, 6, and
                           12 months or at 0, 1, 6, and 12 months. Sera
                           and mucosal secretions were collected one
                           month after each injection. The results of
                           this trial suggest that vCP300 is well
                           tolerated and is able to induce both humoral
                           and cellular responses. A decrease in the
                           infectious titer of vCP300 (0.4 to 0.75 log),
                           observed between 3 and 6 months, however, may
                           have affected the results. In another trial,
                           cytotoxic T cell (CTL) responses were
                           evaluated in human volunteers who had been
                           immunized with the ALVAC (Canarypox-based
                           vectors containing multiple HIV-1 genes)
                           vectors vCP0205 and vCP300. HIV-1-specific
                           CTL have been detected in a small fraction of
                           trial participants. Both CD4 and CD8 + CTl
                           responses directed at multiple HIV-1 antigens
                           have been detected in certain individuals.
                           Strong env, gag and nef reactivity has been
                           observed, although responses have generally
                           been transient. However, a significant number
                           of vaccine recipients remained negative for
                           CTL activity despite repeated immunizations.
                           [Conf Adv AIDS Vaccine Dev. 1997 May 4-7;
                           Conf Adv AIDS Vaccine Dev. 1997 May 4-7;
                           NIAID VEU 026]
DISEASES STUDIED/TREATED   Prevention of HIV infection. [NIAID VEU 026]
CLASSIFICATION CODE        Vaccine [NIAID VEU 026]
ADVERSE EFFECTS            Adverse effects may include pain, soreness,
                           redness, and swelling at the site of
                           injection. Fever, chills, rash, aches and
                           pain, nausea, headache, fatigue, and allergic
                           reactions such as hives or difficulty
                           breathing may also occur. [NIAID VEU 026]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Immunogen constructed from
                           a live recombinant canarypox vector; it is a
                           complex antigen consisting of MN gp120, plus
                           the transmembrane portion of HIV-1 LAI gp41
                           as well as HIV-1 gag, protease, and multiple
                           CTL epitopes in nef and pol gene products.
                           [NIAID VEU 026]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: White to pink in
                           lyophilized form; slightly opalescent, pink
                           to purplish-blue after reconstitution. [NIAID
                          VEU 026]
CHEMICAL/PHYSICAL DATA    DRUG PHYSICAL COMMENT: pH 7.62. [NIAID VEU
                          026]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: 1.0 ml vials containing 1.3
                          million TCID50. [NIAID VEU 026]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Intramuscular. [NIAID VEU
                          026]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store lyophilized
                          vaccine at -20 C. [NIAID VEU 026]
MANUFACTURERS             Pasteur Merieux Serums et Vaccins; 3 Avenue
                          Pasteur / BP 10; Marnes la Coquette,
                          France92430
REFERENCES                MED/97454417. Ferrari G, Berend C, Ottinger
                          J, Dodge R, Bartlett J, Toso J, Moody D,
                          Tartaglia J, Cox WI, Paoletti E, et al.
                          Replication-defective canarypox (ALVAC)
                          vectors effectively activate anti-human
                          immunodeficiency virus-1 cytotoxic T
                          lymphocytes present in infected patients:
                          implication for antigen-specific
                          immunotherapy. Blood. 1997 Sep
                          15;90(6):2406-16.
REFERENCES                AIDS/97927175. Finkielsztejn L, Salmon-Ceron
                          D, Excler JL, Zak Dit Zbar O, Raux M, Gomard
                          E, Gluckman JC, Blondeau C, Sicard D. Safety
                          and immunogenicity of a live, recombinant
                          canarypox virus expressing
                          gp120TM-MN/gag/protease-LAI and CTL domains
                          of nef and pol- LAI (alvac-HIV vCP300) in
                          HIV-negative volunteers. Conf Adv AIDS
                          Vaccine Dev. 1997 May 4-7;:211 (poster 106).
REFERENCES                AIDS/97927172. Carruth LM, Castro MG, Crone
                          SN, Ferris RL, Siliciano RF. Induction of
                          HIV-1 specific CTL by canarypox vectors in
                          phase I vaccine trials. Conf Adv AIDS Vaccine
                          Dev. 1997 May 4-7;:208 (Poster 103).
REFERENCES                MED/97329080. Girard M, van der Ryst E,
                          Barre-Sinoussi F, Nara P, Tartaglia J,
                          Paoletti E, Blondeau C, Jennings M, Verrier
                          F, Meignier B, Fultz PN. Challenge of
                          chimpanzees immunized with a recombinant
                          canarypox-HIV-1 virus. Virology. 1997 May
                          26;232(1):98-104.
REFERENCES                MED/97188479. Ferrari G, Humphrey W, McElrath
                          MJ, Excler JL, Duliege AM, Clements ML, Corey
                          LC, Bolognesi DP, Weinhold KJ. Clade B-based
                          HIV-1 vaccines elicit cross-clade cytotoxic T
                          lymphocyte reactivities in uninfected
                          volunteers. Proc Natl Acad Sci U S A. 1997
                          Feb 18;94(4):1396-401.
REFERENCES                AIDS/97926165. Evans TG, Keefer TG, Wolff M,
                          Weinhold K, Excler JL, Duliege AM, McNamara
                          J, McElrath JM, Graham BJ, Clements ML, et
                          al. Immunization of HIV-1 non-infected
                          volunteers with a canarypox recombinant
                          containing HIV-1 env, gag, pol, and nef genes
                          (vCP300) given simultaneously or followed by
                          recombinant HIV-1 SF2 gp120. 4th Conf Retro
                          and Opportun Infect. 1997 Jan 22-26;:204
                          (abstract no. 754).
REFERENCES                AIDS/97926030. Corey L, Weinhold K,
                           Montefiori D, McElrath J, Excler JL, Duliege
                           AM, Stablein D. Combination candidate HIV
                           vaccines using a canarypox vector (vCP205)
                           followed by boosting with gp120(SF-2). 4th
                           Conf Retro and Opportun Infect. 1997 Jan
                           22-26;:209 (abstract no. LB18).
REFERENCES                 AIDS/97920726. Salmon D, Finkielsztejn L,
                           Excler JL, Blondeau C, Raux M, Renaudie C,
                           Belec L, Meillet D, Sicard D. Exploration of
                           mucosal immunity in HIV-1 infection and its
                           application to vaccine trials. Conf Adv AIDS
                           Vaccine Dev. 1996 Feb 11-15;:152 (Poster 32).
REFERENCES                 AIDS/96920441. Phillip R, Vertin B, Ashton J,
                           Tran K, Alters S, Cox W, Paoletti E,
                           Tartaglia J. Ex vivo generation of antigen
                           specific oligoclonal cytotoxic T-cells from
                           HIV sero-postive patients for adoptive
                           immunotherapy. 3rd Conf Retro and Opportun
                           Infect. 1996 Jan 28-Feb 1;:135.
ENTRY MONTH                199603
LAST REVISION DATE         19980507

65
UNIQUE IDENTIFIER          DRG-0242
NAME OF SUBSTANCE          Nitazoxanide [CHEMLINE]
REGISTRY NUMBER            55981-09-4
STANDARD CHEMICAL NAME     N-(5-Nitro-2-thiazolyl)-salicylamide
                           acetate(ester) [USAN 1997]
SYNONYMS                   NTZ [AmFAR Tx Dir 1996;8(1)]
PROTOCOL ID NUMBERS        FDA 253B
PROTOCOL ID NUMBERS        NIAID ACTG 336
DISEASES STUDIED/TREATED   AIDS-related cryptosporidiosis. [FDA 253B]
CLASSIFICATION CODE        Antiparasitic [FDA 253B]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C12-H9-N3-O5-S [USAN 1997]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 500 mg tablets. [FDA 253B]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [FDA 253B]
MANUFACTURERS              Unimed Pharmaceuticals Inc; 2150 East Lake
                           Cook Road; Buffalo Grove, IL 60089
REFERENCES                 AIDS/96701490. Anonymous. NTZ qualifies for
                           orphan drug status. Positiv Aware. 1996
                           May/June; 7(3):6.
REFERENCES                 AIDS/96700966. Smart T. NTZ trials for
                           cryptosporidiosis. GMHC Treat Issues. 1995
                           Sep; 9(9):14.
ENTRY MONTH                199602
LAST REVISION DATE         19980422

66
UNIQUE IDENTIFIER          DRG-0241
NAME OF SUBSTANCE          HBY 097 [FDA 252A]
STANDARD CHEMICAL NAME     (S)-3,4-dihydro-7-methoxy-2((methylthio)-meth-
                           yl)- 3-thioxo-1(2H)-quinoxalinecarboxylic
                           acid-1-methylethylester [FDA 252A]
SYNONYMS                   HBY-097 [MeSH]
PROTOCOL ID NUMBERS        FDA 252A
PHARMACOLOGICAL ACTION     MODE OF ACTION: Non-nucleoside reverse
                           transcriptase inhibitor specific for HIV-1.
                           HBY-097 was given orally at doses of 125,
                           250, 375, 500 and 750 mg tid for 7 days and
                           14 days (750 mg dose only) to asymptomatic
                           and mildly symptomatic HIV-positive subjects
                           with CD4 counts between 200 and 500
                           cells/mm3. HBY-097 was rapidly absorbed
                           following PO doses. The considerable overlap
                           in Cmax and AUC values between the dose
                           levels indicated high interindividual
                           variability. Following the 250, 500, and 750
                           mg doses, trough concentrations ranged from
                           206-720 micrograms/L, 364-1226 micrograms/L
                           and 461-2116 micrograms/L, respectively.
                           Based on the IC90 range of clinical isolates,
                           and the high protein binding (greater than
                           95%), it was predicted that these trough
                           concentrations would be clinically relevant.
                           Two of 3 subjects who completed 750 mg tid x
                           14 days treatment showed greater than one log
                           reduction in the viral load after 14 days of
                           treatment; the third subject had very low
                           viral load at baseline which reached 0 after
                           14 days of treatment. The data indicated that
                           HBY-097 is reasonably well tolerated and
                           exhibits promising antiviral properties.
                           Another study designed to characterize viral
                           load and viral characteristics during a
                           14-day treatment of HIV-1 positive
                           individuals with HBY-097, showed that all
                           viruses before and after therapy were of the
                           non-cytopathogenic phenotype with moderate or
                           low replication capacity. Genotypic analysis
                           of viral RNA from serum of cultured viruses
                           and of proviral DNA showed no induction of a
                           relevant non-nucleoside reverse transcriptase
                           inhibitor-resistance mutation. [Int Conf
                           AIDS. 1996 Jul 7-12;11(1); Int Conf AIDS.
                           1996 Jul 7-12;11(1)]
DISEASES STUDIED/TREATED   Primary HIV infection. [FDA 252A]
CLASSIFICATION CODE        Antiretroviral [Natl Conf Hum Retroviruses
                           Relat Infect (2nd) 1995]
CLASSIFICATION CODE        Non-nucleoside reverse transcriptase
                           inhibitor [Int Conf AIDS. 1996 Jul
                           7-12;11(1)]
ADVERSE EFFECTS            HBY-097 was safe and reasonably well
                           tolerated with no consistent dose-related
                           adverse event or laboratory abnormalities.
                           Two subjects in the 750 mg tid x 14 day
                           treatment group discontinued study medication
                           due to a generalized maculopapular rash which
                           emerged on Day 10. [Int Conf AIDS. 1996 Jul
                           7-12;11(1)]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Quinoxaline derivative.
                           [Natl Conf Hum Retroviruses Relat Infect
                           (2nd) 1995]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 250 mg tablets. [FDA 252A]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [FDA 252A]
MANUFACTURERS              Hoechst - Marion - Roussel Incorporated;
                           Route 202 - 206 / PO Box 2500; Somerville, NJ
                           08876-1258
REFERENCES                 ICA11/96921390. Shah A, Kumor K, Sullivan J,
                           Amand R, Cole S, Agarwal V, Krol G, Huguenel
                           E, Suarez JR, Heller AH. Safety, tolerability
                           and pharmacokinetics (PK) of HBY-097 in
                           asymptomatic and mildly symptomatic
                     HIV-positive patients. Int Conf AIDS. 1996
                     Jul 7-12;11(1):111 (abstract no.Mo.B.1326).
REFERENCES           ICA11/96921172. Rubsamen-Waigmann H, Wainberg
                     MA, Huguenel E, Shah A, Paessens A, Kleim JP,
                     Rosner M. Antiviral profile of HBY097, a
                     nonnucleoside inhibitor of HIV-1 RT in a
                     phase I study. Int Conf AIDS. 1996 Jul
                     7-12;11(1):72 (abstract no.Mo.A.1102).
REFERENCES           MED/96133872. Kleim JP, Rosner M, Winkler I,
                     Paessens A, Kirsch R, Hsiou Y, Arnold E,
                     Riess G. Selective pressure of a quinoxaline
                     nonnucleoside inhibitor of human
                     immunodeficiency virus type 1 (HIV-1) reverse
                     transcriptase (RT) on HIV-1 replication
                     results in the emergence of nucleoside
                     RT-inhibitor-specific (RT Leu-74-->Val or Ile
                     and Val-75-->Leu or Ile) HIV-1 mutants. Proc
                     Natl Acad Sci USA. 1996 Jan 9;93(1):34-8.
REFERENCES           MED/96109422. Kleim JP, Bender R, Kirsch R,
                     Meichsner C, Paessens A, Rosner M,
                     Rubsamen-Waigmann H, Kaiser R, Wichers M,
                     Schneweis KE, et al. Preclinical evaluation
                     of HBY 097, a new nonnucleoside reverse
                     transcriptase inhibitor of human
                     immunodeficiency virus type 1 replication.
                     Antimicrob Agents Chemother. 1995
                     Oct;39(10):2253-7.
REFERENCES           AIDS/95920498. Kleim JP, Paessens A, Bender
                     R, Kirsch R, Meichsner C, Rosner M, Winkler
                     I, Riess G. Evaluation of in vitro resistance
                     development against the quinoxaline HBY 097
                     reveals novel patterns of mutations within
                     the HIV-1 gene encoding the reverse
                     transcriptase. Natl Conf Hum Retroviruses
                     Relat Infect (2nd). 1995 Jan 29-Feb 2:141.
REFERENCES           AIDS/95920118. Paessens A, Blunck M, Kleim
                     JP, Meichsner C, Riess G, Rosner M, Rubsamen
                     HW, Winkler I. HBY 097, in vitro antiviral
                     profile against HIV-1 in acute and persistent
                     infection systems: combined drug interaction
                     with different inhibitors of HIV-1 or other
                     viruses. Natl Conf Hum Retroviruses Relat
                     Infect (2nd). 1995 Jan 29-Feb 2:70.
REFERENCES           AIDS/95920117. Rosner M, Bender R, Billhardt
                     UM, Dienst K, Kirsch R, Kleim JP, Meichsner
                     C, Paessens A, Riess G, Winkler I. HBY 097, a
                     new quinoxaline derivative with highly potent
                     and selective anti-HIV-1 activity. Natl Conf
                     Hum Retroviruses Relat Infect (2nd). 1995 Jan
                     29-Feb 2:70.
REFERENCES           AIDS/96701081. New type of HIV drug. Treat
                     Rev. 1995 Nov;(no 20):4.
REFERENCES           AIDS/96700963. Pieribone V. Overcoming
                     resistance to reverse transcriptase
                     inhibitors. GMHC Treat Issues. 1995
                     Sep;9(9):8-9.
REFERENCES           MED/95229100. [New substance against AIDS in
                     clinical trial (news)]. Fortschr Med. 1995
                     Feb 10;113(4):58.
ENTRY MONTH          199601
LAST REVISION DATE   19980422
67
UNIQUE IDENTIFIER          DRG-0240
NAME OF SUBSTANCE          Heptavalent pneumococcal conjugate vaccine (
                           7-valent ) [NIAID ACTG 292]
PROTOCOL ID NUMBERS        NIAID ACTG 292
PHARMACOLOGICAL ACTION     MODE OF ACTION: The chemical and immunologic
                           properties of a heptavalent vaccine composed
                           of high-molecular-weight polymers of the
                           lipopolysaccharide (LPS) O polysaccharides
                           representative of the most common clinical
                           isolates of Pseudomonas aeruginosa were
                           investigated; and the serum antibody response
                           to nonvaccine strains aeruginosa, including
                           strains expressing structural variants
                           (subtype strains) of the O side chain of the
                           vaccine strains were evaluated. Mouse and
                           rabbit immune sera showed different patterns
                           of opsonic activity against subtype strains,
                           indicating that different epitopes on these
                           antigens are immunodominant in the
                           representatives of these two animal species
                           tested. The polyvalent vaccine was effective
                           at eliciting antibodies to vaccine components
                           in mice and rabbits, but it remains to be
                           determined if the current heptavalent
                           formulation contains sufficient components to
                           provoke human antibodies reactive with a
                           majority of clinical strains of P.
                           aeruginosa. [Infect Immun 1994 Sep;62(9)]
DISEASES STUDIED/TREATED   HIV-associated pneumococcal disease. [NIAID
                           ACTG 292]
CLASSIFICATION CODE        Vaccine [NIAID ACTG 292]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Pneumococcal capsular
                           saccharides from serotypes 4, 6B, 9V, 14,
                           18C, 19F, and 23F bound to a diphtheria toxin
                           mutant (CRM197) carrier protein. [NIAID ACTG
                           292]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intramuscular. [NIAID ACTG
                           292]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Store at 2-8 C (35-46
                           F). Do not freeze. [NIAID ACTG 292]
MANUFACTURERS              Lederle - Praxis Biologicals; 211 Bailey
                           Road; West Henrietta, NY 14586-9728
REFERENCES                 MED/97005606. King JC Jr, Vink PE, Farley JJ,
                           Parks M, Smilie M, Madore D, Lichenstein R,
                           Malinoski F. Comparison of the safety and
                           immunogenicity of a pneumococcal conjugate
                           with a licensed polysaccharide vaccine in
                           human immunodeficiency virus and non-human
                           immunodeficiency virus-infected children.
                           Pediatr Infect Dis J. 1996 Mar;15(3):192-6.
REFERENCES                 MED/96217731. Rodriguez-Barradas MC, Groover
                           JE, Lacke CE, Gump DW, Lahart CJ, Pandey JP,
                           Musher DM. IgG antibody to pneumococcal
                           capsular polysaccharide in human
                           immunodeficiency virus-infected subjects:
                           persistence of antibody in responders,
                           revaccination in nonresponders, and
                           relationship of immunoglobulin allotype to
                           reponse. J Infect Dis. 1996
                           Jun;173(6):1347-53.
REFERENCES                 MED/96196149. Swiatlo E, Benton K, Briles DE.
                           Pneumococcal vaccine response in human
                           immunodeficiency virus-infected patients
                           [letter]. J Infect Dis. 1996
                           Mar;173(3):777-8.
REFERENCES                 MED/96132467. Ahmed F, Steinhoff MC,
                           Rodriguez-Barradas MC, Hamilton RG, Musher
                           DM, Nelson KE. Effect of human
                           immunodeficiency virus type 1 infection on
                           the antibody response to a glycoprotein
                           conjugate pneumococcal vaccine: results from
                           a randomized trial. J Infect Dis. 1996
                           Jan;173(1):83-90.
REFERENCES                 MED/95245225. Jain A, Jain S, Gant V. Should
                           patients positive for HIV infection receive
                           pneumococcal vaccine? [see comments]. BMJ.
                           1995 Apr 22;310(6986):1060-2.
REFERENCES                 MED/95367899. McDonald P, Lighton L, Anderson
                           R. Pneumococcal vaccine for HIV patients.
                           Patients with HIV infection should be
                           immunised...[letter; comment]. BMJ. 1995 Aug
                           5;311(7001):387-8.
REFERENCES                 MED/95263074. Willocks LJ, Vithayathil K,
                           Tang A, Noone A. Pneumococcal vaccine and HIV
                           infection:report of a vaccine failure and
                           reappraisal of its value in clinical
                           practice. Genitourin Med.1995 Apr;71(2):71-2.
REFERENCES                 MED/95158135. Peters VB, Diamant EP, Hodes
                           DS, Cimino CO. Impaired immunity to
                           pneumococcal polysaccharide antigens in
                           children with human immunodeficiency virus
                           infection immunized with pneumococcal
                           vaccine. Pediatr Infect Dis J. 1994
                           Oct;13(10):933-4.
REFERENCES                 94341860. Hatano K, Boisot S, DesJardins D,
                           Wright DC, Brisker J, Pier GB. Immunogenic
                           and antigenic properties of a heptavalent
                           high-molecular-weight O-polysaccharide
                           vaccine derived from Pseudomonas aeruginosa.
                           Infect Immun 1994 Sep;62(9):3608-16.
REFERENCES                 MED/94069234. Requejo HI. Polyvalent
                           pneumococcal polysaccharide vaccines; a
                           review of the literature. Rev Hosp Clin Fac
                           Med Sao Paulo. 1993 May-Jun;48(3):130-8.
ENTRY MONTH                199511
LAST REVISION DATE         19980422

68
UNIQUE IDENTIFIER          DRG-0239
NAME OF SUBSTANCE          Pneumococcal vaccine polyvalent ( 23-valent )
                           [NIAID ACTG 292]
SYNONYMS                   PNU-IMUNE 23 [PDR 1997]
PROTOCOL ID NUMBERS        NIAID ACTG 292
PROTOCOL ID NUMBERS        NIAID ACTG 340
DISEASES STUDIED/TREATED   HIV-associated pneumococcal disease. [NIAID
                           ACTG 292]
CLASSIFICATION CODE        Vaccine [NIAID ACTG 292]
OTHER MAJOR USES           Immunization against infections caused by the
                           23 most prevalent types of streptococcus
                           pneumoniae (pneumococci) included in the
                          vaccine. [PDR 1997]
SUBSTANCE INTERACTIONS    Patients with impaired immune responsiveness
                          whether due to the use of immunosuppresive
                          therapy, a genetic defect, HIV infection, or
                          other causes may have a reduced antibody
                          response to active immunization procedures.
                          Patients who have received extensive
                          chemotherapy and/or splenectomy for the
                          treatment of Hodgkin's disease have been
                          shown to have an impaired serum antibody
                          response to pneumococcal vaccine. In one
                          study, administration of the vaccine to
                          patients on immunosuppressive drugs and/or
                          irradiation for Hodgkin's disease resulted in
                          reduction of preexisting antibody levels in
                          several patients. It is unclear whether this
                          effect was due to the vaccine or to the
                          effects of irradiation and/or chemotherapy.
                          [PDR 1997]
ADVERSE EFFECTS           Incidence of adverse reactions is relatively
                          low, of short duration, and not serious.
                          Patients may experience local reaction
                          characterized by soreness at the injection
                          site within 3 days after immunization, low
                          grade fever and mild myalgia within 24 hours
                          after immunization. Rash, urticaria,
                          arthritis, arthralgia, and adenitis have been
                          reported rarely. [PDR 1997]
CONTRAINDICATIONS         Hypersensitivity to any component of the
                          vaccine, including thimerosal, a mercury
                          derivative, is a contraindication to the use
                          of this product. The occurrence of any type
                          of neurological symptoms or signs following
                          administration of this product is a
                          contraindication to future use. The vaccine
                          should not be administered to persons with
                          acute febrile illness until their temporary
                          symptoms and/or signs have abated. This
                          product should not be used in children under
                          2 years of age. This product is not
                          recommended for use in pregnant or nursing
                          women. [PDR 1997]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: Purified capsular
                          polysaccharide antigens of 23 types of
                          Streptococcus pneumoniae (Danish types 1, 2,
                          3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F,
                          14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F,
                          33F). [MMWR 1989 Feb 10;38(5); PDR 1997]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: Clear and colorless
                          liquid. [PDR 1997]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Sterile solution is formulated
                          to contain 25 ug of each of the 23 purified
                          polysaccharide types per 0.5 ml dose of
                          vaccine: 2.5 ml/vial (for use with syringe
                          only): 5 x 0.5 ml (one dose) LEDERJECT
                          (disposable syringes). [PDR 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Intramuscular or
                          subcutaneous. [NIAID ACTG 292; PDR 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store at 2-8 C (35-46
                          F). Do not freeze. [NIAID ACTG 292; PDR 1997]
MANUFACTURERS             Lederle - Praxis Biologicals; 211 Bailey
             Road; West Henrietta, NY 14586-9728
REFERENCES   MED/96217731. Rodriguez-Barradas MC, Groover
             JE, Lacke CE, Gump DW, Lahart CJ, Pandey JP,
             Musher DM. IgG antibody to pneumococcal
             capsular polysaccharide in human
             immunodeficiency virus-infected subjects:
             persistence of antibody in responders,
             revaccination in nonresponders, and
             relationship of immunoglobulin allotype to
             reponse. J Infect Dis. 1996
             Jun;173(6):1347-53.
REFERENCES   MED/97005606. King JC Jr, Vink PE, Farley JJ,
             Parks M, Smilie M, Madore D, Lichenstein R,
             Malinoksi F. Comparison of the safety and
             immunogenicity of a pneumococcal conjugate
             with a licensed polysaccharide vaccine in
             human immunodeficiency virus and non-human
             immunodeficiency virus-infected children.
             Pediatr Infect Dis J. 1996 Mar;15(3):192-6.
REFERENCES   MED/96132467. Ahmed F, Steinhoff MC,
             Rodriguez-Barradas MC, Hamilton RG, Musher
             DM, Nelson KE. Effect of human
             immunodeficiency virus type 1 infection on
             the antibody response to a glycoprotein
             conjugate pneumococcal vaccine: results from
             a randomized trial. J Infect Dis. 1996
             Jan;173(1):83-90.
REFERENCES   MED/96128450. Loeliger AE, Rijkers GT, Aerts
             P, Been-Tiktak A, Hoepelman AI, van Dijk H,
             Borleffs JC. Deficient antipneumococcal
             polysaccharide responses in HIV-seropositive
             patients. FEMS Immunol Med Microbiol. 1995
             Sep;12(1):33-41.
REFERENCES   MED/96002832. Keller DW, Breiman RF.
             Preventing bacterial respiratory tract
             infections among persons infected with human
             immunodeficiency virus. Clin Infect Dis. 1995
             Aug;21 Suppl 1:S77-83.
REFERENCES   MED/95271058. Weiss PJ, Wallace MR, Oldfield
             EC 3rd, O'Brien J, Janoff EN. Response of
             recent human immunodeficiency virus
             seroconverters to the pneumococcal
             polysaccharide vaccine and Haemophilus
             influenzae type b conjugate vaccine. J Infect
             Dis.1995 May;171(5):1217-22.
REFERENCES   MED/95263074. Willocks LJ, Vithayathil K,
             Tang A, Noone A. Pneumococcal vaccine and HIV
             infection: report of a vaccine failure and
             reappraisal of its value in clinical
             practice. Genitourin Med. 1995
             Apr;71(2):71-2.
REFERENCES   AIDS/95920708. Peters V, Hodes D, Cimino C.
             Antibody responses to pneumococcal
             polysaccharides (PnPS) in HIV-infected
             children immunized with pneumococcal vaccine
             (PV). Program Abstr Intersci Conf Antimicrob
             Agents Chemother. 1994 Oct 4-7;:34.
REFERENCES   MED/93139380. Sanders LA, Rijkers GT, Kuis W,
             Tenbergen-Meekes AJ, de Graeff-Meeder BR,
             Hiemstra I, Zegers BJ. Defective
             antipneumococcal polysaccharide antibody
                           response in children with recurrent
                           respiratory tract infections. J Allergy Clin
                           Immunol. 1993 Jan;91(1 Pt 1):110-9.
REFERENCES                 MED/92166439. Rodriguez-Barradas MC, Musher
                           DM, Lahart C, Lacke C, Groover J, Watson D,
                           Baughn R, Cate T, Crofoot G. Antibody to
                           capsular polysaccharides of Streptococcus
                           pneumoniae after vaccination of human
                           immunodeficiency virus-infected subjects with
                           23-valent pneumococcal vaccine. J Infect Dis.
                           1992 Mar;165(3):553-6.
ENTRY MONTH                199511
LAST REVISION DATE         19980506

69
UNIQUE IDENTIFIER          DRG-0238
NAME OF SUBSTANCE          A-007 [FDA 247A]
STANDARD CHEMICAL NAME     4,4'-Dihydroxybenzophenone-2,4-dinitrophenylh-
                           ydrazone [FDA 247A]
PROTOCOL ID NUMBERS        FDA 247A
DISEASES STUDIED/TREATED   Cutaneous lesions from Kaposi's sarcoma and
                           lymphoproliferative disorders. [FDA 247A]
CLASSIFICATION CODE        Antineoplastic (adjunct) [FDA 247A]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 0.25% gel. [FDA 247A]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Topical. [FDA 247A]
MANUFACTURERS              DEKK - TEC Incorporated; 3839 Ulloa Street;
                           New Orleans, LA 70119
ENTRY MONTH                199511
LAST REVISION DATE         19951120

70
UNIQUE IDENTIFIER          DRG-0237
NAME OF SUBSTANCE          Selegiline hydrochloride [USAN 1996]
REGISTRY NUMBER            14611-52-0
STANDARD CHEMICAL NAME     Benzeneethanamine,
                           N,alpha-dimethyl-N-2-propynyl-,
                           hydrochloride, (R)- [USAN 1997]
SYNONYMS                   Eldepryl [USAN 1997]
SYNONYMS                   Deprenyl [FDA 250A]
SYNONYMS                   1-deprenyl [PDR 1997]
SYNONYMS                   eldeprine [Merck Index 1996]
SYNONYMS                   Jumex [Merck Index 1996]
SYNONYMS                   Movergan [Merck Index 1996]
SYNONYMS                   Plurimen [Merck Index 1996]
SYNONYMS                   Alzene [Physicians GenRx 97]
PROTOCOL ID NUMBERS        FDA 250A
PHARMACOLOGICAL ACTION     MODE OF ACTION: Irreversibly inhibits
                           monoamine oxidase (MAO), an intracellular
                           enzyme associated with the outer membrane of
                           mitochondria, by acting as a suicide
                           substrate for the enzyme, i.e., it is
                           converted by MAO to an active moiety that
                           combines irreversibly with the active site
                           and/or the enzyme's essential FAD cofactor.
                           [PDR 1997]
DISEASES STUDIED/TREATED   HIV-associated dementia. [FDA 250A]
CLASSIFICATION CODE        Monoamine oxidase inhibitor [PDR 1995]
CLASSIFICATION CODE        Antidyskinetic [USAN 1997]
CLASSIFICATION CODE        Antiparkinsonian [USAN 1997]
OTHER MAJOR USES           Management of Parkinson's disease in patients
                           who experience deterioration on
                           levodopa/carbidopa therapy. [PDR 1997]
SUBSTANCE INTERACTIONS     Interacts with meperidine. [PDR 1997]
ADVERSE EFFECTS            Adverse effects may include nausea,
                           hallucinations, confusion, depression, loss
                           of balance, insomnia, orthostatic
                           hypotension, increased akinetic involuntary
                           movements, agitation, arrhythmia,
                           bradykinesia, chorea, delusion, hypertension,
                           new or increased angina pectoris and syncope,
                           headache, leg pain, back pain, tinnitus,
                           migraine, supraorbital pain, burning throat,
                           chills, numbness in fingers and toes, taste
                           disturbance, constipation, weight loss,
                           anorexia, dysphagia, diarrhea, rectal
                           bleeding, slow urination, urinary frequency,
                           increased sweating, diaphoresis, facial hair,
                           hair loss, hematoma, rash, and
                           photosensitivity. [PDR 1997]
CONTRAINDICATIONS          Contraindicated in patients with known
                           hypersensitivity to the drug and in those
                           receiving meperidine and other opioids. [PDR
                           1997; Physicians GenRx 97]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Levorotatory acetylenic
                           derivative of phenethylamine. [PDR 1997]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: White to near white
                           crystalline powder. [PDR 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR FORMULA: C13H17N.HCl [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR WEIGHT: 223.75 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MELTING POINT: 141-142 [Merck Index 1996]
CHEMICAL/PHYSICAL   DATA   SOLUBILITY: Freely soluble in water,
                           chloroform, and methanol. [PDR 1997]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 5 mg capsules or 5mg tablets
                           (uncoated). [PDR 1997; Physicians GenRx 97]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [PDR 1997]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Store at 15-30 C (59-86
                           F). [PDR 1997]
MANUFACTURERS              Somerset Pharmaceuticals Incorporated; 5215
                           West Laurel Street; Tampa, FL 33067-1729
REFERENCES                 90004129. Anonymous. FDA approves marketing
                           of two drugs previously available under
                           treatment IND regulations [news]. Clin Pharm.
                           1989 Sep;8(9):607.
REFERENCES                 90041079. Nightingale SL. From the Food and
                           Drug Administration. JAMA. 1989 Nov
                           10;262(18):2503.
REFERENCES                 MED/97082231. Lajtha A, Sershen H, Cooper T,
                           Hashim A, Gaal J. Metabolism of (-)-deprenyl
                           and PF-(-)-deprenyl in brain after central
                           and peripheral administration. Neurochem Res.
                           1996 Oct;21(10):1155-60.
REFERENCES                 MED/97166343. Wilfried K, Muller T, Kruger R,
                           Horst P. Selegiline stimulates biosynthesis
                           of cytokines interleukin-1 beta and
                           interleukin-6. Neuroreport. 1996 Nov
                           25;7(18):2847-8.
REFERENCES                 MED/97142238. Kuhn W, Muller T. The clinical
                           potential of Deprenyl in neurologic and
                           psychiatric disorders. J Neural Transm Suppl.
                           1996;48:85-93.
REFERENCES                 MED/97142236. Yasar S, Goldberg JP, Goldberg
                           SR. Are metabolites of 1-deprenyl
                          (selegiline) useful or harmful? Indications
                          from preclinical research. J Neural Transm
                          Suppl. 1996;48:61-73.
REFERENCES                MED/97142235. Tatton WG, Wadia JS, Ju WY,
                          Chalmers-Redman RM, Tatton NA. (-)-Deprenyl
                          reduces neuronal apoptosis and facilitates
                          neuronal outgrowth by altering protein
                          synthesis without inhibiting monoamine
                          oxidase. J Neural Trasm Suppl. 1996;48:45-59.
REFERENCES                MED/97142234. Magyar K, Szende B, Lengyel J,
                          Tekes K. The pharmacology of B-type selective
                          monoamine oxidase inhibitors; milestones in
                          (-)-deprenyl research. J Neural Transm Suppl.
                          1996;29-43.
REFERENCES                MED/97256338. Deprenyl--past and future.
                          Proceedings of a symposium. Lake Starnberg,
                          Bavaria, 1995, J Neural Transm Suppl.
                          1996;48:1-112.
REFERENCES                MED/97165376. Thomas CE, Huber EW, Ohlweiler
                          DF. Hydroxyl and peroxyl radical trapping by
                          the monoamine oxidase-B inhibitors deprenyl
                          and MDL 72, 974A:implications for protection
                          of biologic substrates. Free Radic Biol Med.
                          1997;22(4):733-7.
ENTRY MONTH               199511
LAST REVISION DATE        19980506

71
UNIQUE IDENTIFIER         DRG-0236
NAME OF SUBSTANCE         Thioctic acid [USAN 1997]
REGISTRY NUMBER           62-46-4
RELATED REGISTRY NUMBER   2319-84-8 (sodium)
RELATED REGISTRY NUMBER   94599-85-6 (olamine)
STANDARD CHEMICAL NAME    1,2-Dithiolane-3-valeric acid [USAN 1997]
SYNONYMS                  Biletan [Merck Index 1996]
SYNONYMS                  Thioctacid [Merck Index 1996]
SYNONYMS                  Thioctan [Merck Index 1996]
SYNONYMS                  Tioctan [Merck Index 1996]
SYNONYMS                  alpha-Lipoic acid [CHEMLINE]
SYNONYMS                  Lipoic acid [CHEMLINE]
SYNONYMS                  alpha-Liponic acid [CHEMLINE]
SYNONYMS                  Protogen A [Merck Index 1989]
SYNONYMS                  1,2-Dithiolane-3-pentanoic acid [Merck Index
                          1989]
SYNONYMS                  5-(1,2-Dithiolan-3-yl)valeric acid [CHEMID]
SYNONYMS                  6,8-Dithiooctanoic acid [CHEMID]
SYNONYMS                  Heparlipon [CHEMID]
SYNONYMS                  Lipothion [CHEMID]
SYNONYMS                  Thiooctanoic acid [CHEMID]
PROTOCOL ID NUMBERS       FDA 250A
PHARMACOLOGICAL ACTION    MODE OF ACTION: Enhances the free radical
                          scavenging mechanisms of vitamin E. Free
                          radicals can damage brain cells. It is
                          believed that HIV-infected patients have a
                          compromised antioxidant defense system. Blood
                          antioxidants are decreased and peroxidation
                          products of lipids and proteins are
                          increased. Such patients may benefit from
                          antioxidant supplementation therapy.
                          Short-term effects of the natural antioxidant
                          thioctic acid on blood antioxidants and
                           peroxidation products were investigated in
                           HIV positive patients. In the majority of
                           patients thioctic acid increased plasma
                           ascorbate (9 of 10 patients), total
                           glutathione (7 of 7 patients), total plasma
                           thiol groups (8 of 9 patients);T helper
                           lymphocytes and T helper/suppressor cell
                           ratio (6 of 10 patients), while the lipid
                           peroxidation products malondialdehyde (8 of 9
                           patients) and 4-hydroxynonenal (7 of 9
                           patients) were decreased. Gene expression of
                           human immunodeficiency virus (HIV) depends on
                           a host of cellular transcription factors
                           including nuclear factor-kappaB (NF-kappaB).
                           The involvement of reactive oxygen
                           intermediates has been implicated as
                           intracellular messengers in the inducible
                           activation of NF-kappaB. A study, compared
                           the efficacy of two antioxidants, thioctic
                           acid and N-acetylcysteine (NAC), which are
                           widely recognized NF-kappaB inhibitors.
                           Thioctic acid has a more potent activity in
                           inhibiting NF-kappaB-mediated gene
                           expression. It was also found that 0.2 mM
                           thioctic acid could cause 40% reduction in
                           the HIV-1 expression from the
                           TNF-alpha-stimulated OM 10.1, a cell line
                           latently infected with HIV-1. These findings
                           confirm the involvement of reactive oxygen
                           intermediates in NF-kappaB-mediated HIV gene
                           expression as well as the efficacy of
                           thioctic acid as a therapeutic regimen for
                           HIV infection and AIDS. [FDA 250A;
                           Arzneimittelforschung 1993 Dec;43(12); FEBS
                           Lett 1996 Sep 23;394(1)]
DISEASES STUDIED/TREATED   HIV-associated dementia. [FDA 250A]
CLASSIFICATION CODE        Antioxidant [Arzneimittelforschung 1993
                           Dec;43(12)]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Enzymatic cofactor. [FDA
                           250A]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C8H14O2S2 [USAN 1997]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 206.33 [USAN 1997]
CHEMICAL/PHYSICAL DATA     ELEMENTAL COMP: C46.57%, H6.84%, O15.51%,
                           S31.08%. [Merck Index 1996]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 200 mg tablets. [FDA 250A]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [FDA 250A]
MANUFACTURERS              ASTA Medica AG; Weismullerstrasse 45;
                           Frankfurt, GermanyD-6000
REFERENCES                 MED/97074193. Merin JP, Matsuyama M, Kira T,
                           Baba M, Okamoto T. Alpha-lipoic acid blocks
                           HIV-1 LTR-dependent expression of hygromycin
                           resistance in THP-1 stable transformants.
                           FEBS Lett. 1996 Sep 23;394(1):9-13.
REFERENCES                 95377664. Teichert J, Preiss R. Determination
                           of lipoic acid in human plasma by
                           high-performance liquid chromatography with
                           electrochemical detection. J Chromatogr B
                           Biomed Appl 1995 Oct 20;672(2):277-81.
REFERENCES                 95392479. Packer L, Witt EH, Tritschler HJ.
                           alpha-Lipoic acid as a biological
                           antioxidant. Free Radic Biol Med. 1995
                         Aug;19(2):227-50.
REFERENCES               95392479. Suzuki YJ, Mizuno M, Tritschler HJ,
                         Packer L. Redox regulation of NF-kappa B DNA
                         binding activity by dihydrolipoate. Biochem
                         Mol Biol Int. 1995 Jun;36(2):241-6.
REFERENCES               95160683. Han D, Tritschler HJ, Packer L.
                         Alpha-lipoic acid increases intracellular
                         glutathione in a human T-lymphocyte Jurkat
                         cell line. Biochem Biophys Res Commun. 1995
                         Feb 6;207(1):258-64.
REFERENCES               MED/95091847. Shoji S, Furuishi K, Misumi S,
                         Miyazaki T, Kino M, Yamataka K. Thiamine
                         disulfide as a potent inhibitor of human
                         immunodeficiency virus (type-1) production.
                         Biochem Biophys Res Commun. 1994 Nov
                         30;205(1):967-75.
REFERENCES               ICA10/94371739. Suzuki YJ, Packer L.
                         Inhibition of NF-kappa B DNA binding by
                         alpha-lipoic acid. Int Conf AIDS. 1994 Aug
                         7-12;10(2):27 (abstract no. 401A).
REFERENCES               ICA10/94371058. Shoji S, Furuishi K, Misumi
                         S, Miyazaki T, Kino M, Yamataka K, Matsuoka
                         H, Tachibana K. Anti-HIV effects of redox
                         reagents on HIV-1 infected cell lines. Int
                         Conf AIDS. 1994 Aug 7-12;10(2):114 (abstract
                         no.PA0336).
REFERENCES               MED/94190328. Fuchs J, Schofer H, Milbradt R,
                         Buhl R, Siems W, Grune T. Studies on lipoate
                         effects on blood redox state in human
                         immunodeficiency virus infected patients.
                         Arzneimittelforschung. 1993
                         Dec;43(12):1359-62.
REFERENCES               MED/92177673. Baur A, Harrer T, Peukert M,
                         Jahn G, Kalden JR, Fleckenstein B.
                         Alpha-lipoic acid is an effective inhibitor
                         of human immuno-deficiency virus (HIV-1)
                         replication. Klin Wochenschr. 1991 Oct
                         2;69(15):722-4.
ENTRY MONTH              199511
LAST REVISION DATE       19980416

72
UNIQUE IDENTIFIER        DRG-0235
NAME OF SUBSTANCE        Lobucavir [USAN 1997]
REGISTRY NUMBER          127759-89-1
STANDARD CHEMICAL NAME   6H-Purin-6-one,
                         2-amino-9-(2,3-bis(hydroxymethyl)-
                         cyclobutyl)-1,9-dihydro-,
                         (1R-(1alpha,2beta,3alpha))- [USAN 1997]
SYNONYMS                 Carbocyclic oxetanocin-G [FDA 248A]
SYNONYMS                 Cyclobut-G [FDA 248A]
PROTOCOL ID NUMBERS      FDA 248A
SECONDARY SOURCE ID      BMS-180194 [USAN 1997]
SECONDARY SOURCE ID      SQ 34,514 [USAN 1997]
PHARMACOLOGICAL ACTION   MODE OF ACTION: Two newly synthesized
                         carbocyclic oxetanocin analogs, (+/-)-9-[(1
                         beta, 2 alpha, 3 beta)-2,3-bis
                         (hydroxymethyl)-1-cyclobutyl]adenine
                         (cyclobut-A) and (+/-)-9-[(1 beta, 2 alpha, 3
                         beta)-2,3-bis
                         (hydroxymethyl)-1-cyclobutyl]guanine
                           (cyclobut-G) were tested for activity against
                           the infectivity of human immunodeficiency
                           virus (HIV) in vitro. Both compounds
                           protected CD4+ ATH8 cells against the
                           infectivity and cytopathic effects of HIV
                           type 1 (HIV-1) and suppressed proviral DNA
                           synthesis in ATH8 cells exposed to HIV-1
                           vitro at concentrations of 50 to 100 microM.
                           These compounds also inhibited the in vitro
                           infectivity of HIV-2. Both compounds
                           completely suppresed the replication of a
                           monocytotropic strain of HIV-1 in monocytes
                           and macrophages at concentrations as low as
                           0.5 microM as assessed by inhibition of HIV-1
                           p24 gag protein production. 2'-Deoxyguanosine
                           readily reversed the antiretroviral activity
                           of cyclobut-G in our system. Both cyclobut-A
                           and cyclobut-G appear to have a certain level
                           of in vitro toxicity. [Antimicrob Agents
                           Chemother. 1990 Feb;34(2)]
DISEASES STUDIED/TREATED   Cytomegalovirus (CMV) infections; HIV
                           infection; Herpes infection. [FDA 248A; AmFAR
                           Tx Dir 1997;8(3)]
CLASSIFICATION CODE        Antiviral [USAN 1997]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C11H15NO3 [USAN 1997]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 265.27 [USAN 1997]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [FDA 248A]
MANUFACTURERS              Bristol - Myers Squibb Company; 5 Research
                           Parkway / PO Box 5100; Wallingford, CT
                           06492-7660
REFERENCES                 90225763. Hayashi S, Norbeck DW, Rosenbrook
                           W, Fine RL, Matsukura M, Plattner JJ, Broder
                           S, Mitsuya H. Cyclobut-A and cyclobut-G,
                           carbocyclic oxetanocin analogs that inhibit
                           the replication of human immunodeficiency
                           virus in T cells and monocytes and
                           macrophages in vitro. Antimicrob Agents
                           Chemother. 1990 Feb;34(2):287-94.
REFERENCES                 MED/97125604. Katlama C. Consequences for the
                           management of cytomegalovirus. AIDS. 1996
                           Nov;10 Suppl 1:S43-6.
REFERENCES                 ASHM6/95291740. Mills J. Prophylaxis and
                           treatment of opportunistic viral infections
                           in patients with HIV infection. Annu Conf
                           Australas Soc HIV Med. 1994 Nov 3-6;6:134
                           (unnumbered abstract).
REFERENCES                 MED/94012339. De Clercq E. Antivirals for the
                           treatment of herpesvirus infections. J
                           Antimicrob Chemother. 1993 Jul;32 Suppl
                           A:121-32.
REFERENCES                 MED/93158382. De Clercq E. Antiviral agents:
                           characteristic activity spectrum depending on
                           the molecular target with which they
                           interact. Adv Virus Res. 1993;42:1-55.
REFERENCES                 MED/90230227. Norbeck DW, Kern E, Hayashi S,
                           Rosenbrook W, Sham H, Herrin T, Plattner JJ,
                           Erickson J, Clement J, Swanson R, et al.
                           Cyclobut-A and cyclobut-G: broad-spectrum
                           antiviral agents with potential utility for
                           the therapy of AIDS. J Med Chem. 1990
                           May;33(5):1281-5.
ENTRY MONTH                  199511
LAST REVISION DATE           19980506

73
UNIQUE IDENTIFIER            DRG-0234
NAME OF SUBSTANCE            ISIS 2922 [Int Conf AIDS 1994 Aug 7-12;10(2)]
REGISTRY NUMBER              160369-77-7
STANDARD CHEMICAL NAME       Deoxyribonucleic acid d(P-thio)
                             (G-C-G-T-T-T-G-C-T-C-T-T-C-T-T-C-T-T-G-C-G),
                             eicosasodium salt [USAN 1997]
SYNONYMS                     ISIS 2922 [Unspecified]
SYNONYMS                     Vitravene [ATN #302 4 Sept 1998]
PROTOCOL   ID NUMBERS        FDA 251A
PROTOCOL   ID NUMBERS        FDA 251B
PROTOCOL   ID NUMBERS        FDA 251C
PROTOCOL   ID NUMBERS        FDA 251D
DISEASES   STUDIED/TREATED   FDA approved on August 26, 1998 for the local
                             treatment of cytomegalovirus (CMV) retinitis
                             in patients with AIDS who are intolerant of
                             or have a contraindication to other
                             treatment(s) for CMV retinitis or who were
                             insufficiently responsive to previous
                             treatment(s) for CMV retinitis. [Int Conf
                             AIDS 1994 Aug 7-12;10(2)]
CLASSIFICATION CODE          Antiviral [MeSH]
OTHER MAJOR USES             CMV retinitis. [USAN 1997]
CHEMICAL/PHYSICAL DATA       DRUG DESCRIPTION: Phosphorothioate antisense
                             oligonucleotide. [Int Conf AIDS 1994 Aug
                             7-12;10(2)]
CHEMICAL/PHYSICAL DATA       MOLECULAR FORMULA: C204 H243 N63 Na20 O114
                             P20 S20 [USAN 1997]
CHEMICAL/PHYSICAL DATA       MOLECULAR WEIGHT: 71122.16 [USAN 1997]
SUBSTANCE DELIVERY DATA      MODE OF DELIVERY: Intravitreal. [Int Conf
                             AIDS 1994 Aug 7-12;10(2)]
MANUFACTURERS                Isis Pharmaceuticals Incorporated; 2292
                             Faraday Avenue; Carlsbad, CA 92008
REFERENCES                   AIDS/96701616. Anonymous. Isis presents data
                             on safety and effectiveness of antisense CMV
                             retinitis compound. J Int Assoc Physicians
                             AIDS Care. 1996 May;2(5):50.
REFERENCES                   AIDS/96701668. Anonymous. Anti-CMV drug
                             trials back on-line. GMHC Treat Issues. 1996
                             May;10(5):9.
REFERENCES                   AIDS/95700311. Anonymous. New drug for CMV in
                             trials. Treat Review. 1995 Jan;: no 16(3).
REFERENCES                   MED/96126403. Azad RF, Brown-Driver V,
                             Buckheit RW Jr, Anderson KP. Antiviral
                             activity of a phosphorothioate
                             oligonucleotide complementary to human
                             cytomegalovirus RNA when used in combination
                             with antiviral nucleoside analogs. Antiviral
                             Res. 1995 Oct;28(2):101-11.
REFERENCES                   94058190. Azad RF, Driver VB, Tanaka K,
                             Crooke RM, Anderson KP. Antiviral activity of
                             a phosphorothioate oligonucleotide
                             complementary to RNA of the human
                             cytomegalovirus major immediate-early region.
                             Antimicrob Agents Chemother 1993
                             Sep;37(9):1945-54.
REFERENCES                   ICA10/94370996. Palestine AG, Cantrill HL,
                             Luckie AP, Ai E. Intravitreal treatment of
                          CMV retinitis with an antisense
                          oligonucleotide, ISIS 2922. Int Conf AIDS
                          1994 Aug 7-12;10(2):10 (abstract no. 332B).
ENTRY MONTH               199510
LAST REVISION DATE        19981116

74
UNIQUE IDENTIFIER         DRG-0233
NAME OF SUBSTANCE         Indinavir sulfate [USAN 1997]
REGISTRY NUMBER           157810-81-6
STANDARD CHEMICAL NAME    [1(1S,2R),5(S)]-2,3,5-Trideoxy-N-
                          (2,3-dihydro-2-hydroxy-1H-inden-1-yl)-5-
                          [2-[[(1,1-dimethylethyl)-amino]carbonyl]-4-
                          (3-pyridinylmethyl)
                          -1-piperazinyl]-2-(phenylmethyl)-D-erythro
                          -pentonamide monohydrate (free base). [Merck
                          Index 1996]
SYNONYMS                  Crixivan [Facts and Comparisons 1996]
SYNONYMS                  MK-639 [USAN 1997]
SYNONYMS                  L-735,524 [USAN 1997]
PROTOCOL   ID   NUMBERS   FDA 245E
PROTOCOL   ID   NUMBERS   FDA 246F
PROTOCOL   ID   NUMBERS   FDA 246G
PROTOCOL   ID   NUMBERS   FDA 246H
PROTOCOL   ID   NUMBERS   FDA 246J
PROTOCOL   ID   NUMBERS   FDA 246K
PROTOCOL   ID   NUMBERS   FDA 246M
PROTOCOL   ID   NUMBERS   FDA 246N
PROTOCOL   ID   NUMBERS   FDA 246P
PROTOCOL   ID   NUMBERS   FDA 260A
PROTOCOL   ID   NUMBERS   FDA 260B
PROTOCOL   ID   NUMBERS   FDA 264K
PROTOCOL   ID   NUMBERS   NIAID 97 I-082
PROTOCOL   ID   NUMBERS   NIAID 99 I-0032
PROTOCOL   ID   NUMBERS   NIAID ACTG 365
PROTOCOL   ID   NUMBERS   NIAID ACTG 384
PROTOCOL   ID   NUMBERS   NIAID ACTG 387
PROTOCOL   ID   NUMBERS   NIAID ACTG 388
PROTOCOL   ID   NUMBERS   NIAID ACTG 398
PROTOCOL   ID   NUMBERS   NIAID ACTG 400
PROTOCOL   ID   NUMBERS   NIAID ACTG A5025
PROTOCOL   ID   NUMBERS   NIAID CPCRA 057
PROTOCOL   ID   NUMBERS   NIAID CPCRA 058
PROTOCOL   ID   NUMBERS   NIAID SPIRAT 3
PROTOCOL   ID   NUMBERS   FDA 228C
PROTOCOL   ID   NUMBERS   FDA 228F
PROTOCOL   ID   NUMBERS   FDA 232D
PROTOCOL   ID   NUMBERS   FDA 238J
PROTOCOL   ID   NUMBERS   FDA 238K
PROTOCOL   ID   NUMBERS   FDA 244B
PROTOCOL   ID   NUMBERS   FDA 246A
PROTOCOL   ID   NUMBERS   FDA 246D
PROTOCOL   ID   NUMBERS   FDA 246E
PROTOCOL   ID   NUMBERS   FDA 264A
PROTOCOL   ID   NUMBERS   FDA 264E
PROTOCOL   ID   NUMBERS   FDA 281A
PROTOCOL   ID   NUMBERS   FDA 281B
PROTOCOL   ID   NUMBERS   FDA ATLANTIC STUDY
PROTOCOL   ID   NUMBERS   NCI 95 C-163
PROTOCOL   ID   NUMBERS   NIAID 94 I-202
PROTOCOL   ID   NUMBERS   NIAID ACTG 223
PROTOCOL ID NUMBERS      NIAID ACTG 320
PROTOCOL ID NUMBERS      NIAID ACTG 328
PROTOCOL ID NUMBERS      NIAID ACTG 333
PROTOCOL ID NUMBERS      NIAID ACTG 338
PROTOCOL ID NUMBERS      NIAID ACTG 343
PROTOCOL ID NUMBERS      NIAID ACTG 358
PROTOCOL ID NUMBERS      NIAID ACTG 368
PROTOCOL ID NUMBERS      NIAID ACTG 370
PROTOCOL ID NUMBERS      NIAID ACTG 372
PROTOCOL ID NUMBERS      NIAID ACTG 373
PROTOCOL ID NUMBERS      NIAID ACTG 395
PROTOCOL ID NUMBERS      NIAID CPCRA 041
PROTOCOL ID NUMBERS      NIAID CPCRA 042
PHARMACOLOGICAL ACTION   MODE OF ACTION: Inhibits the HIV
                         protease-mediated cleavage of the viral
                         precursor polyproteins that results in
                         production of noninfectious progeny viral
                         particles. Specifically, the hydroxy group of
                         the hydroxyaminopentane amide moiety of
                         indinavir sulfate ligates to the carboxy
                         groups of the esential aspartyl 25 and 25'
                         enzymic residues. Also, the amide oxygens of
                         indinavir undergo hydrogen bonding to the
                         backbone amide nitrogen of Ile-50 and Ile-50'
                         via an intervening water molecule. In a
                         previous study, urinary excretion of
                         indinavir sulfate and its metabolites
                         represented a minor pathway of elimination.
                         Indinavir sulfate is effective against
                         viruses resistant to reverse transcriptase
                         inhibitors and is synergistically active when
                         used in combination with reverse
                         transcriptase inhibitors. Isolates of HIV
                         with reduced susceptibility to the drug have
                         been recovered from some patients. Viral
                         resistance was correlated with the
                         accumulation of mutations that resulted in
                         the expression of amino acid substitutions in
                         the viral protease. Cross-resistance between
                         indinavir and HIV reverse transcriptase
                         inhibitors is unlikely because the enzyme
                         targets involved are different.
                         Cross-resistance was noted between indinavir
                         and the protease inhibitor ritonavir. Varying
                         degrees of cross-resistance have been
                         observed between indinavir and other
                         HIV-proteases inhibitors. Oral doses of
                         indinivar were rapidly absorbed in the fasted
                         state with a time to peak plasma
                         concentration of 0.8 h. High calorie, fat and
                         protein meals decrease absorption. About 60%
                         of indinavir is bound to human plasma
                         proteins over a concentration range of 81 nM
                         to 16,300 nM. Following a labeled 400 mg
                         dose, 83% and 19% of the total radioactivity
                         was recovered in feces and urine,
                         respectively. Less than 20% of indinavir is
                         excreted unchanged in the urine. The drug has
                         a half-life of 1.8 h. Significant
                         accumulation was not observed after multiple
                         dosing at 800 mg every 8 h. Metabolism is
                           decreased in patients with cirrhosis. [Facts
                           and Comparisons 1996; J Biol Chem 1994 Oct
                           21;269(42); Drug Metab Dispos 1995 Feb;23(2)]
DISEASES STUDIED/TREATED   Primary HIV infection. FDA approved 3/14/96
                           for use alone or in combination with
                           nucleoside analogues for treatment of HIV
                           infection in adults. [Prog Abst Intersci Conf
                           Antimicrob Agents Chemother 1994 Oct; Merck &
                           Co Package Insert 3/96]
CLASSIFICATION CODE        Protease inhibitor [AIDS Therapies 1995 Sep]
CLASSIFICATION CODE        Antiretroviral [AIDS Therapies 1995 Sep]
SUBSTANCE INTERACTIONS     Metabolism of indinavir is mediated by the
                           P-450 isoenzyme CYP3A4 and the possibility
                           exists that drugs that induce this isoenzyme
                           may reduce plasma indinavir concentrations.
                           Conversely, concomitant administration of
                           indinavir with drugs that increase
                           concentration of that isoenzyme may increase
                           plasma indinavir concentration. Indinavir may
                           inhibit the metabolism of astemizole,
                           cisapride, midazolam, terfenadine and
                           triazolam, and has the potential for creating
                           serious or life threatening reactions with
                           these drugs. Concurrent use of
                           clarithromycin, ketoconazole, quinidine and
                           zidovudine can increase indinavir blood
                           levels. Didanosine, fluconazole, rifampin,
                           and rifabutin have produced decreases in
                           indinavir blood levels. Coadministration of
                           indinavir has resulted in increased blood
                           levels of oral contraceptives. Administration
                           of indinavir with grapefruit juice resulted
                           in a decrease in indinivar AUC. When
                           administered with
                           trimethoprim/sulfamethoxazole, trimethoprim
                           levels increased but the sulfa levels were
                           unaffected. Administration with isoniazid
                           resulted in increased levels of the
                           antitubercular. [Facts and Comparisons 1996;
                           AHFS Drug Information 1997]
ADVERSE EFFECTS            Adverse effects include changes in
                           hematologic and hepatic function tests,
                           nephrolithiasis ( kidney stones ), abdominal
                           pain, asthenia / fatigue, diarrhea, headache,
                           dizziness, insomnia, nausea, back and side
                           pain, rash, vomiting, acid regurgitation
                           (backflow of stomach acid to the esophagus),
                           and taste perversion. Indirect
                           hyperbilirubinemia has occurred frequently
                           with indinavir administration and has
                           sometimes been associated with increases in
                           serum transaminases. Both hyperbilirubinemia
                           and nephrolithiasis occurred more frequently
                           at doses exceeding 2.4 g/day compared to
                           doses = 2.4 g/day. [PDR 1997; Merck & Co
                           Package Insert 3/96]
CONTRAINDICATIONS          Contraindicated in pregnant and nursing
                           women. [NIAID ACTG 333]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Hydroxyaminopentane amide
                           class of peptidomimetics. [J Biol Chem 1995
                           Sep 15;270(37)]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: Indinavir sulfate is a
                          white to off-white, hygroscopic, crystalline
                          powder. [PDR 1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C36H47N5O4.H2S04 [USAN
                          1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 711.88 [USAN 1997]
CHEMICAL/PHYSICAL DATA    MELTING POINT: 150-153 (Sulfate) [Merck Index
                          1996]
CHEMICAL/PHYSICAL DATA    ELEMENTAL COMP: C70.45%, H7.72%, N11.41%,
                          O10.43 (free base) [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    SOLUBILITY: Soluble in water. [Merck Index
                          1996]
CHEMICAL/PHYSICAL DATA    STABILITY: Store in a tightly closed
                          container at room temperature, 15-30 C (59-86
                          F). Indinavir capsules are sensitive to
                          moisture and should be dispensed and stored
                          in the original container with a desiccant.
                          [PDR 1997]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: 200 mg and 400mg capsules. [PDR
                          1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral. [PDR 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store at 15-30 C (59-86
                          F). Protect from moisture. [PDR 1997]
MANUFACTURERS             Merck Research Laboratories; 126 East Lincoln
                          Avenue; Rahway, NJ 07065
REFERENCES                MED/97284992. McDonald CK, Kuritzkes DR.
                          Human immunodeficiency virus type 1 protease
                          inhibitors. Arch Intern Med. 1997 May
                          12;157(9):951-9.
REFERENCES                MED/97274204. Grube H, Ramratnam B, Ley C,
                          Flanigan TP. Resolution of AIDS associated
                          cryptosporidiosis after treatment with
                          indinavir [letter]. Am J Gastroenterol. 1997
                          Apr;(4):726.
REFERENCES                MED/97286976. Daudon M, Estepa L, Viard JP,
                          Joly D, Jungers P. Urinary stones in
                          HIV-1-positive patients treated with
                          indinavir [letter]. Lancet. 1997 May
                          3;349(9061):1294-5.
REFERENCES                MED/97286975. Hogg RS, O'Shaughnessy MV,
                          Gataric N, Yip B, Craib K, Schechter MT,
                          Montaner JS. Decline in deaths from AIDS due
                          to new antiretrovirals [letter]. Lancet. 1997
                          May 3;349(9061):1294.
REFERENCES                MED/97014709. Moyle G, Gazzard B. Current
                          knowledge and future prospects for the use of
                          HIV protease inhibitors. Drugs. 1996
                          May;51(5):701-12.
REFERENCES                MED/97239297. Barry M, Gibbons S, Back D,
                          Mulcahy F. Protease inhibitors in patients
                          with HIV disease. Clinically important
                          pharmacokinetic considerations. Clin
                          Pharmacokinet. 1997 Mar;32(3):194-209.
REFERENCES                MED/97253476. Rutschmann O. Hirschel B.
                          Antiretroviral therapy: a guide to the most
                          important trials. Schweiz Med Wochenschr.
                          1997 Mar 15;127(11):436-43.
REFERENCES                MED/97186971. Doran CM. New approaches to
                          using antiretroviral therapy for the
                          management of HIV infection. Ann
                          Pharmacother. 1997 Feb;31(2):228-36.
REFERENCES                 MED/97173300. Stein DS, Drusano GL. Modeling
                           of the change in CD4 lymphocyte counts in
                           patients before and after administration of
                           the human immunodeficiency virus protease
                           inhibitor indinavir. Antimicrob Agents
                           Chemother. 1997 Feb;41(2):449-53.
REFERENCES                 MED/97247126. Brau N, Leaf HL, Wieczorek RL,
                           Margolis DM. Severe hepatitis in three AIDS
                           patients treated with indinavir [letter].
                           Lancet. 1997 Mar 29;349(9056):924-5.
ENTRY MONTH                199510
LAST REVISION DATE         19980506

75
UNIQUE IDENTIFIER          DRG-0232
NAME OF SUBSTANCE          P3C541b Lipopeptide [FDA 090]
PROTOCOL ID NUMBERS        FDA 090
PROTOCOL ID NUMBERS        NIAID VEU 021
PHARMACOLOGICAL ACTION     MODE OF ACTION: Lipopeptide analogues of
                           bacterial lipoproteins activate macrophages
                           and B-lymphocytes. The products formed by
                           coupling these lipopeptides to low molecular
                           mass antigens can be used to induce
                           antigen-specific antibodies in mice.
                           Immunization with synthetic peptides is used
                           to induce cytotoxic T cell (CTL) responses in
                           vivo. However, CTL peptide vaccines require
                           the use of multiple peptides to overcome
                           genetic diversity associated with MHC
                           restriction, and prior epitope identification
                           from the chosen protein template. [Biol Chem
                           Hoppe Seyler. 1990 Oct;371(10); Vaccine. 1996
                           Dec;14(17-18)]
DISEASES STUDIED/TREATED   Primary HIV infection. [FDA 090]
CLASSIFICATION CODE        Vaccine [FDA 090]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Lipopeptide. [FDA 090]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Subcutaneous. [FDA 090]
MANUFACTURERS              United Biomedical Incorporated; 25 Davids
                           Drive; Hauppauge, NY 11788
REFERENCES                 MED/97185156. Kuebler PJ, Nixon DF. Cytotoxic
                           T cell induction with ratchet peptide
                           libraries. Vaccine. 1996
                           Dec;14(17-18):1664-70.
REFERENCES                 MED/97005302. Loleit M, Ihlenfeldt HG,
                           Brunjes J, Jung G, Muller B, Hoffmann P,
                           Bessler WG, Pierres M, Haas G. Synthetic
                           peptides coupled to the lipotripeptide P3CSS
                           induce in vivo B and T-helper cell responses
                           to HIV-1 reverse transcriptase.
                           Immunobiology. 1996 Jan;195(1):61-76.
REFERENCES                 MED/96155144. Sauzet JP, Deprez B, Martinon
                           F, Guillet JG, Gras-Masse H, Gomard E.
                           Long-lasting anti-viral cytotoxic T
                           lymphocytes induced in vivo with
                           chimeric-multirestricted lipopeptides.
                           Vaccine. 1995 Oct;13(14):1339-45.
REFERENCES                 MED/96329200. Deprez B, Sauzet JP, Boutillon
                           C, Martinon F, Tartar A, Sergheraert C,
                           Guillet JG, Gomard E, Gras-Masse H.
                           Comparative efficiency of simple lipopeptide
                           constructs for in vivo induction of
                           virus-specific CTL. Vaccine.1996
                           Apr;14(5)375-82.
REFERENCES                 AIDS/96700666. Boston: important trial of
                           treatment vaccine, CD4 over 500. AIDS Treat
                           News. 1995 Aug 4;(no 228):4-5.
REFERENCES                 MED/91166747. Loleit M, Troger W, Wiesmuller
                           KH, Jung G, Strecker M, Bessler WG.
                           Conjugates of synthetic lymphocyte-activating
                           lipopeptides with segments from HIV proteins
                           induce protein-specific antibody formation.
                           Biol Chem Hoppe Seyler. 1990
                           Oct;371(10):967-75.
ENTRY MONTH                199508
LAST REVISION DATE         19980416

76
UNIQUE IDENTIFIER          DRG-0231
NAME OF SUBSTANCE          PCLUS [AIDS Therapies 1995 Sep]
SYNONYMS                   Engineered peptide clusters [AIDS Therapies
                           1995 Sep]
PROTOCOL ID NUMBERS        NCI 94 C-0159
PHARMACOLOGICAL ACTION     MODE OF ACTION: Induction of cytotoxic T
                           lymphocytes and neutralizing antibodies.
                           Induction of virus-specific cytotoxic T
                           lymphocytes (CTL) is an important part of
                           vaccine strategy. CTL induction in vivo by
                           two hepatitis C virus (HCV) peptides
                           containing CTL epitopes, one from the NS5
                           region (P17) and one from the core (C7), was
                           compared. P17 required covalent attachment of
                           a helper peptide (PCLUS3 containing a cluster
                           of epitopes from the human immunodeficiency
                           virus envelope protein), whereas C7 did not.
                           The helper cells induced by PCLUS3-17 or by
                           C7 were shown to be CD4+ and to produce
                           interleukin-2 (IL-2). Thus, help can be
                           supplied by a natural helper epitope
                           intrinsic to the CTL peptide, as in C7, or by
                           attaching a helper epitope from another
                           protein, as in the case of P17. The cluster
                           peptides may be useful promiscuous helper
                           peptides for a variety of CTL epitopes from
                           diverse pathogens. [J Immunol 1994 Jan
                           15;152(2); J Infect Dis. 1996 Jan;173(1)]
DISEASES STUDIED/TREATED   Primary HIV infection. [NCI 94 C-159]
CLASSIFICATION CODE        Vaccine [AIDS Therapies 1995 Sep]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Multiple peptide sequences
                           from the HIV-1 MN envelope protein that are
                           recognized by multiple human and murine major
                           histocompatibility complex ( MHC ) types.
                           These sequences contain peptide 18. The
                           peptide clusters are held together in
                           Montanide Incomplete Seppic Adjuvant ( ISA ).
                           [AIDS Therapies 1995 Sep]
MANUFACTURERS              Peninsula Labs; 611 Taylor Way; Belmont, CA
                           94002
REFERENCES                 MED/96132459. Shirai M, Chen M, Arichi T,
                           Masaki T, Nishioka M, Newman M, Nakazawa T,
                           Feinstone SM, Berzofsky JA. Use of intrinsic
                           and extrinsic helper epitopes for in vivo
                           induction of anti-hepatitis C virus cytotoxic
                      T lymphocytes (CTL) with CTL epitope peptide
                      vaccines. J Infect Dis. 1996 Jan;173(1):
                      24-31.
REFERENCES            MED/95169519. Johnson RP, Hammond SA, Trocha
                      A, Siliciano RF, Walker BD. Epitope
                      specificity of MHC restricted cytotoxic T
                      lymphocytes induced by candidate HIV-1
                      vaccine. AIDS Res Hum Retroviruses. 1994;10
                      Suppl 2:S73-5.
REFERENCES            MED/94110609. Shirai M, Pendleton CD, Ahlers
                      J, Takeshita T, Newman M, Berzofsky JA.
                      Helper-cytotoxic T lymphocyte (CTL)
                      determinant linkage required for priming of
                      anti-HIV CD8+ CTL in vivo with peptide
                      vaccine constructs. J Immunol. 1994 Jan
                      15;152(2):549-56.
REFERENCES            MED/94039374. Bergmann C, Stohlmann SA,
                      McMillan M. An endogenously synthesized
                      decamer peptide efficiently primes cytotoxic
                      T cells specific for the HIV-1 envelope
                      glycoprotein. Eur J Immunol. 1993
                      Nov;23(11):2777-81.
REFERENCES            MED/93378321. Berzofsky JA. Epitope selection
                      and design of synthetic vaccines. Molecular
                      approaches to enhancing immunogenicity and
                      cross-reactivity of engineered vaccines. Ann
                      N Y Acad Sci. 1993 Aug 12;690:256-64.
REFERENCES            MED/93371734. Venet A, Walker BD. Cytotoxic
                      T-cell epitopes in HIV/SIV infection. AIDS.
                      1993;7 Suppl 1:S117-26.
REFERENCES            MED/93271830. Johnson RP, Walker BD.
                      Indentification of HIV-1 cytotoxic
                      T-lymphocyte epitopes and implications for
                      vaccine development. Biotechnol Ther.
                      1991;2(1-2):137-46.
REFERENCES            MED/93271829. Berzofsky JA. Progress toward
                      an artificial vaccine for HIV: identification
                      of helper and cytotoxic T-cell epitopes and
                      methods of immunization. Biotechnol Ther.
                      1991;2(1-2):123-35.
REFERENCES            91358746. Berzofsky JA, Pendleton CD, Clerici
                      M, Ahlers J, Lucey DR, Putney SD, Shearer GM.
                      Construction of peptides encompassing
                      multideterminant clusters of human
                      immunodeficiency virus envelope to induce in
                      vitro T cell responses in mice and humans of
                      multiple MHC types. J Clin Invest. 1991
                      Sep;88(3):876-84.
REFERENCES            MED/92113420. Cease KB. Peptide component
                      vaccine engineering: targeting the AIDS
                      virus. Int Rev Immunol. 1990;7(1):85-107.
ENTRY MONTH           199508
LAST REVISION DATE    19980416

77
UNIQUE IDENTIFIER     DRG-0230
NAME OF SUBSTANCE     ALVAC-HIV MN120TMG ( vCP205 ) [NIAID VEU 022]
SYNONYMS              ALVAC-HIV ( vCP205 ) [NIAID VEU 022]
PROTOCOL ID NUMBERS   FDA RV124
PROTOCOL ID NUMBERS   NIAID ACTG 326
PROTOCOL ID NUMBERS   NIAID VEU 022
PROTOCOL ID NUMBERS        NIAID VEU 022A
PROTOCOL ID NUMBERS        NIAID VEU 027
PROTOCOL ID NUMBERS        NIAID VEU 029
PROTOCOL ID NUMBERS        NIAID VEU 033
PROTOCOL ID NUMBERS        NIAID VEU 034
PROTOCOL ID NUMBERS        NIAID VEU 202
PHARMACOLOGICAL ACTION     MODE OF ACTION: In vitro, has been shown to
                           stimulate CD8+ env-specific and gag-specific
                           cytotoxic T-lymphocyte (CTL) precursors
                           present in PBMCs derived from
                           HIV-seropositive patients. In an in vitro
                           study, two canarypox (ALVAC)-based vectors
                           were evaluated for their capacity to induce
                           ex vivo activation/ expansion of HIV-specific
                           CD8+ cytotoxic lymphocyte precursors (CTLp)
                           obtained from HIV-1-infected donors. These
                           two vectors, vCp205, encoding HIV-1 gp120 +
                           TM (28 amino acid transmembrane anchor
                           sequence) in addition to Gag/protease, and
                           vCP300, encoding gp120 + Gag/protease as well
                           as Nef and Pol CTL determinants, are
                           pancytotropic but replication incompetent in
                           mammalian cells. These studies clearly showed
                           that HIV-recombinant ALVAC vectors represent
                           powerful polyvalent antigenic stimuli for
                           activation and expansion of the CD8
                           lymphocyte response that occurs as a result
                           of HIV infection. In a study, evaluating
                           cytotoxic lymphcyte (CTL) responses in human
                           volunteers who have been immunized with the
                           ALVAC vectors vCP205 and vCP300,
                           HIV-1-specific CTL have been detected in a
                           small fraction of trial participants. Both
                           CD4+ and CD8+ CTL responses directed at
                           multiple HIV-1 antgens have been detected in
                           a certain individual. Strong env, gag and nef
                           reactivity has been ob- served, although
                           responses have generally been transient.
                           Although the CTL assay detects responses in
                           almost all HIV-1-infected individuals, a
                           significant number of vaccine recipients
                           remained negative for CTL activity despite
                           repeated immunization. [Conf Adv AIDS Vaccine
                           Dev. 1997 May 4-7; Blood. 1997 Sep 15;90(6)]
DISEASES STUDIED/TREATED   Prevention of HIV infection. [NIAID VEU 022]
CLASSIFICATION CODE        Vaccine [NIAID VEU 022]
ADVERSE EFFECTS            Adverse effects include pain, soreness,
                           redness, and swelling at site of injection,
                           as well as fever, chills, rash, aches, pains,
                           nausea, headache, and fatigue. [NIAID VEU
                           022]
CONTRAINDICATIONS          Contraindicated in pregnant women. [NIAID VEU
                           022]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Canarypox recombinant
                           vaccine that involves a complex antigen
                           consisting of HIV-1 MN gp120, plus the
                           transmembrane portion of HIV-1 LAI gp41 as
                           well as HIV-1 gag and protease. [NIAID VEU
                           022]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: Pale yellow lyophilized
                           product. [NIAID VEU 022]
CHEMICAL/PHYSICAL DATA    DRUG PHYSICAL COMMENT: pH 7.66 [NIAID VEU
                          022]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Lyophilized product in vials
                          containing 580000 TCID50. [NIAID VEU 022]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Intramuscular. [NIAID VEU
                          022]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store at 3-5 C. Do not
                          freeze. [NIAID VEU 022]
MANUFACTURERS             Pasteur Merieux Serums et Vaccins; 3 Avenue
                          Pasteur / BP 10; Marnes la Coquette,
                          France92430
MANUFACTURERS             Pasteur Merieux Connaught / Connaught
                          Laboratories; Route 611 / Box 187;
                          Swiftwater, PA 18370
REFERENCES                AIDS/97702895. Doepel LK. New phase II HIV
                          vaccine study opens. NIAID AIDS Agenda. 1997
                          Aug;:3-4.
REFERENCES                MED/97454417. Ferrari G, Berend C, Ottinger
                          J, Dodge R, Bartlett J, Toso J, Moody D,
                          Tartaglia J, Cox WI, Paoletti E, et al.
                          Replication-defective canarypox (ALVAC)
                          vectors effectively activate anti-human
                          immunodeficiency virus-1 cytotoxic T
                          lymphocytes present in infected patients:
                          implications for antigen-specific
                          immunotherapy. Blood. 1997 Sep
                          15;90(6):2406-16.
REFERENCES                AIDS/97927180. Salmon-Ceron D, Pialoux G,
                          Excler JL, Finkielsztejn L, Autran B,
                          Gluckman JC, Moog C, Blondeau C, Sicard D.
                          Immunogenicity of booster injections of
                          recombinant canarypox vectors or peptide in
                          volunteers pre-immunized in HIV-1 phase I
                          trials. Conf Adv AIDS Vaccine Dev. 1997 May
                          4-7;:216 (Poster 111).
REFERENCES                AIDS/97927172. Carruth LM, Castro MG, Crone
                          SN, Ferris RL, Hall CS, Siliciano RF.
                          Induction of HIV-1-specific CTL by canarypox
                          vectors in phase I vaccine trials. Conf Adv
                          AIDS Vaccine Dev. 1997 May 4-7;:208 (Poster
                          103).
REFERENCES                AIDS/97927136. Schwartz D, Castillo R, Excler
                          JL, Arango Jaramillo S. Vaccine induced in
                          vitro protective immunity against TCLA and
                          macrophage tropic HIV. Conf Adv Vaccine Dev.
                          1997 May 4-7;:172 (poster 67)
REFERENCES                AIDS/97926030. Corey L, Weinhold K,
                          Montefiori D, McElrath J, Excler JL, Duliege
                          AM, Stablein D. Combination candidate HIV
                          vaccines using a canarypox vector (vCP205)
                          followed by boosting with gp120 (SF-2). 4th
                          Conf Retro and Opportun Infect. 1997 Jan
                          22-26;:209 (abstract no. LB18).
REFERENCES                ICA11/96923149. Finkielsztejn L, Salmon D,
                          Excler JL, Blondeau C, Raux M, Bouchez H,
                          Renaudie C, Belec L, Meillet D, Sicard D.
                          Exploration of mucosal immunity in HIV-1
                          infection and its application to vaccine
                          trials. Int Conf AIDS. 1996 Jul 7-12;11(2):14
                          (abstract no. We.A.394).
REFERENCES                ICA11/96920848. Corey L, Weinhold K, McElrath
                           K, Excler JL, Duliege AM, Clements ML, Belche
                           R, Dolin R, Graham B. AVEU 022: safety and
                           immunogenicity of live recombinant canarypox
                           vector containing the envelope, gag and
                           protease genes of HIV-1 in seronegative adult
                           volunteers. Int Conf AIDS. 1996 Jul
                           7-12;11(1):10 (abstract no. Mo A.282).
REFERENCES                 ICA11/96920833. Salmon D, Excler D,
                           Finkielsztejn L, Chapuis L, Heshmati F,
                           Gluckman JC, Autran B, Meignier B, Klein M,
                           Sicard D. Immunogenicity of a live
                           recombinant canarypox virus expressing
                           gp120tm-MN/gag/protease-LAI (vCP205) boosted
                           with a p24e/ve-MN peptide (CLTB-36) in HIV-
                           negative voluteers (anrs vac 03). Int Conf
                           AIDS. 1996 Jul 7-12;11(1):7 (abctract no.
                           Mo.A.155).
REFERENCES                 AIDS/97920726. Salmon D, Finkielsztejn L,
                           Excler JL, Blodeau C, Raux M, Renaudie C,
                           Belec L, Meillet D, Sicard D. Exploration of
                           mucosal immunity in HIV-1 infection and its
                           application to vaccine trials. Conf Adv
                           Vaccine Dev. 1996 Feb 11-15;:152 (poster 32).
ENTRY MONTH                199508
LAST REVISION DATE         19980506

78
UNIQUE IDENTIFIER          DRG-0229
NAME OF SUBSTANCE          Interleukin-10 [MeSH]
REGISTRY NUMBER            130068-27-8
STANDARD CHEMICAL NAME     Cytokine formation-inhibiting factor (mouse
                           clone F115 protein moiety reduced) [CHEMLINE]
SYNONYMS                   SCH 52000 [NIAID 95 I-125]
SYNONYMS                   IL-10 [MeSH]
SYNONYMS                   Cytokine synthesis inhibitory factor [MeSH]
SYNONYMS                   CSIF-10 [MeSH]
PROTOCOL ID NUMBERS        NIAID 98 I-0026
PROTOCOL ID NUMBERS        NIAID 95 I-125
PHARMACOLOGICAL ACTION     MODE OF ACTION: Suppresses cytokine
                           production from macrophages and T cells;
                           also, exerts complex regulatory effects on
                           CD8+ T cells, natural killer cells, vascular
                           endothelial cells, and B lymphocytes. Levels
                           of IL-10 are elevated in HIV-infected
                           individuals, suggesting that this cytokine
                           may play a role in the suppression of T cell
                           and monocyte/macrophage function typical of
                           HIV disease. IL-10 has blocked HIV-induced
                           tumor necrosis factor alpha and IL-6
                           secretion and inhibited HIV replication in
                           monocyte-derived macrophages. [AIDS Res Hum
                           Retroviruses 1994 Oct;10(10); J Clin Invest
                           1994 Feb;93(2); Blood 1994 Jun 15;83(12)]
DISEASES STUDIED/TREATED   Enhancement of immune response and inhibition
                           of tumor necrosis factor production in HIV
                           infection. [NIAID 95 I-125]
CLASSIFICATION CODE        Immunomodulator [CHEMLINE]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Factor that is coregulator
                           of mast cell growth. It is produced by
                           T-cells and B-cells and shows extensive
                           homology with the Epstein-Barr virus BCRFI
                          gene. [CHEMLINE]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Intravenous. [NIAID 95
                          I-125]
MANUFACTURERS             Schering - Plough Research; 2000 Galloping
                          Hill Road; Kenilworth, NJ 07033
REFERENCES                MED/96146742. Ludewig B, Gelderblom HR,
                          Becker Y, Schafer A, Pauli G. Transmission of
                          HIV-1 from productively infected mature
                          Langerhans cells to primary CD4+ T
                          lymphocytes results in altered T cell
                          responses with enhanced production of
                          IFN-gamma and IL-10. Virology. 1996 Jan
                          1;215(1):51-60.
REFERENCES                MED/96133016. Finnegan A, Roebuck KA, Nakai
                          BE, Gu DS, Rabbi MF, Song S, Landay AL. IL-10
                          cooperates with TNF-alpha to activate HIV-1
                          latently and acutely infected cells of
                          monocyte/macrophage lineage. J Immunol. 1996
                          Jan 15;156(2):841-51.
REFERENCES                96141091. Huhn RD, Radwanski E, O'Connell SM,
                          Sturgill MG, Clarke L, Cody RP, Affrime MB,
                          Culter DL. Pharmacokinetics and
                          immunomodulatory properties of intravenously
                          administered recombinant human interleukin-10
                          in healthy volunteers. Blood 1996 Jan
                          15;87(2):699-705.
REFERENCES                MED/96096449. Estaquier J, Idziorek T, Zou W,
                          Emilie D, Farber CM, Bourez JM, Ameisen JC. T
                          helper type 1/T helper type 2 cytokines and T
                          cell death: preventive effect of interleukin
                          12 on activation-induced and CD95
                          (FAS/APO-1)-mediated apoptosis of CD4+ T
                          cells from human immunodeficiency
                          virus-infected persons. J Exp Med. 1995 Dec
                          1;182(6):1759-67.
REFERENCES                MED/96022650. Katsikis PD, Cohen SB, Londei
                          M, Feldmann M. Are CD4+ Th1 cells
                          pro-inflammatory or anti-inflammatory? The
                          ratio of IL-10 to IFN-gamma or IL-2
                          determines their function. Int Immunol. 1995
                          Aug;7(8):1287-94.
REFERENCES                96005824. Cohen SB. IL-10 and IL-3 synergize
                          to cause proliferation of human T cells.
                          Immunology; VOL 85,ISS 3,1995,P351-6.
REFERENCES                MED/95151356. Weissman D, Poli G, Fauci AS.
                          Interleukin 10 blocks HIV replication in
                          macrophages by inhibiting the autocrine loop
                          of tumor necrosis factor alpha and
                          interleukin 6 induction of virus. AIDS Res
                          Hum Retroviruses. 1994 Oct;10(10):1199-206.
REFERENCES                MED/94157097. Clerici M, Wynn TA, Berzofsky
                          JA, Blatt SP, Hendrix CW, Sher A, Coffman RL,
                          Shearer GM. Role of interleukin-10 in T
                          helper cell dysfunction in asymptomatic
                          individuals infected with the human
                          immunodeficiency virus. J Clin Invest. 1994
                          Feb;93(2):768-75.
ENTRY MONTH               199508
LAST REVISION DATE        19971208

79
UNIQUE IDENTIFIER          DRG-0228
NAME OF SUBSTANCE          APL 400-003 [FDA 089]
PROTOCOL ID NUMBERS        FDA FDA 04
PROTOCOL ID NUMBERS        FDA FDA 05
PROTOCOL ID NUMBERS        NIAID 96 I-50
PROTOCOL ID NUMBERS        FDA 089
PHARMACOLOGICAL ACTION     MODE OF ACTION: Facilitated DNA inoculation
                           involves direct injection of noninfectious
                           HIV genes into a patient's muscle, along with
                           agents that promote uptake of the genes into
                           host cells. Host cells that have taken up
                           these genes then produce viral proteins in a
                           form that elicits immune responses in the
                           form of antibodies (which eradicate free
                           virus in the bloodstream), killer T-cells
                           (which destroy infected cells), and helper
                           T-cells (which expand the overall immune
                           response). The immune response is directed
                           against multiple sites and proteins of the
                           virus, giving the immune system many targets
                           for attacking the virus. The vaccine does not
                           use a viral vector. Genes are taken up by the
                           host cells but are not integrated into the
                           host chromosomes; thus, there are no
                           permanent changes in the host's genetic
                           material. 15 HIV-infected subjects given the
                           vaccine in a dose-ranging study. Subjects
                           with CD4 cell counts greater than or equal to
                           500 recieved 3 intramuscular vaccine doses at
                           10 week intervals with follow-up for 36 weeks
                           None of the subjects developed antinuclear or
                           anti-DNA antibodies. CD4 counts rose greater
                           than or equal to 20% in 2, and fell in 4; CD8
                           increased greater than or equal to 20% in 3,
                           and fell in 4. Viral load increased by
                           greater than or equal to 0.5 log in 1, and
                           fell by greater than or equal to 0.5 in 1.
                           Doses-related rises in anti-env antibody
                           occured, as did time-dependent CTL responses
                           to env-expressing target cells. The vaccine
                           appears safe and capable of inducing specific
                           immune responses to HIV antigens. [U of
                           Pennsylvania Press Release 06/16/95; 4th Conf
                           Retro and Opportun Infect. 1997 Jan 22-26]
DISEASES STUDIED/TREATED   Primary HIV infection. [FDA 089]
CLASSIFICATION CODE        Vaccine [U of Pennsylvania Press Release
                           06/16/95]
ADVERSE EFFECTS            In a clinical trial of the vaccine, all
                           subjects were without evidence of local or
                           systemic clinical toxicity. Neither have CBC,
                           urinalysis, serum creatinine, aldolase, or
                           liver chemistries changed. [4th Conf Retro
                           and Opportun Infect. 1997 Jan 22-26]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Segment of DNA -- called a
                           cassette -- that incorporates different
                           parts of the HIV genome, including genes for
                           the envelope protein and a regulatory gene of
                           the virus. [U of Pennsylvania Press Release
                           06/16/95]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intramuscular. [FDA 089]
MANUFACTURERS              Wyeth / Lederle Vaccines and Pediatrics; 1
                     Great Valley Parkway; Malvem, PA 19355
REFERENCES           ICALL/97926859. Boyer JD, Ugen KE, Wang B,
                     Bagarazzi M, Chattergoon M, Javadian A,
                     Ciccareli R, Weiner DB, Carrano RA. Induction
                     of protection from HIV-1 challenge in
                     chimpanzees by DNA vaccination. Int Conf
                     AIDS. 1996 Jul 7-12;11 (Program
                     Supplement):18 (abstract no. Th.A.923).
REFERENCES           MED/97362802. Kim JJ, Bagarazzi ML, Trivedi
                     N, Hu Y, Kazahaya K, Wilson DM, Ciccarelli R,
                     Chattergoon MA, Dang K, Mahalingam S. et al.
                     Engineering of in vivo immune responses to
                     DNA immunization via codelivery of
                     costimulatory molecule genes. Natl
                     Biotechnol. 1997 Jul;15(7):641-6.
REFERENCES           MED/97378953. Ugen KE, Boyer JD, Wang B,
                     Bagarazzi M, Javadian A, Frost P, Merva MM,
                     Agadjanyan MG, Nyland S, Williams WV. et al.
                     Nucleic acid immunization of chimpanzees as a
                     prophylactic immunotherapeutic vaccination
                     model for HIV-1: prelude to a clinicla trial.
                     Vaccine. 1997 Jun; 15(8):927-30.
REFERENCES           MED/97378927. Wang B, Dang K, Agadjanyan MG,
                     Srikantan V, Li F, Ugen KE, Boyer J, Merva M,
                     Williams WV, Weiner DB. Mucosal immunization
                     with a DNA induces immune responses against
                     HIV-1 at a mucosal site. Vaccine. 1997
                     Jun;15(8):821-5.
REFERENCES           MED/97378941. Kim JJ, Ayyavoo V, Bagarazzi
                     ML. Chattergoon M, Boyer JD, Wang B, Weiner
                     DB. Development of a multicomponet candidate
                     vaccine foe HIV-1. Vaccine. 1997
                     Jun;15(8):879-83.
REFERENCES           MED/97378942. Shiver JW, Davies ME, Yasutomi
                     Y, Perry HC, Freed DC, Letvin NL, Liu MA.
                     Anti-HIV env immunities elicited by nucleic
                     acid vaccines. Vaccine. 1997 Jun;15(8):884-7.
REFERENCES           MED/97378952. Fuller DH, Corb MM, Barnett S,
                     Steimer K, Haynes JR. Enhancement of
                     immunodeficiency virus-specific immune
                     responses in DNA-immunized rhesus macaques.
                     Vaccine. 1997 Jun;15(8):924-6.
REFERENCES           AIDS/97927032. Bagarazzi ML, Boyer JD, Dang
                     K, Chattergonn M, Javadian MA, Wang B, Weiner
                     DB. HIV-1 DNA vaccination of pregnant
                     chimpanzees induces cellular and humoral
                     immune responses including placental transfer
                     of antibodies and specific IgA antibodies in
                     breast milk. Conf Adv AIDS Vaccine Dev. 1997
                     May 4-7;:48.
REFERENCES           AIDS/97926164. MacGregor R, Gluckman S, Lacy
                     K, Wang B, Ugen K, Chattergoon M, Bagarazzi
                     J, Williams W, Ginsberg R, Higgins T, et al.
                     A DNA plasmid vaccine for HIV-1: experience
                     in the first human trial indicates humoral
                     and cell-immune responses. 4th Conf Retro and
                     Opportun Infect. 1997 Jan 22-26;:142
                     (abstract no. 421).
ENTRY MONTH          199508
LAST REVISION DATE   19981119
80
UNIQUE IDENTIFIER        DRG-0227
NAME OF SUBSTANCE        Prednisone [USAN 1997]
REGISTRY NUMBER          53-03-2
STANDARD CHEMICAL NAME   17,21-dihydroxy-pregna-1,4-diene-3,11,20-trio-
                         ne, [Merck Index 1996]
SYNONYMS                 Delta-Dome [USAN 1997]
SYNONYMS                 Deltasone [USAN 1997]
SYNONYMS                 Meticorten [USAN 1997]
SYNONYMS                 Orasone [USAN 1997]
SYNONYMS                 Paracort [USAN 1997]
SYNONYMS                 Ancortone [Merck Index 1996]
SYNONYMS                 Bicortone [CHEMLINE]
SYNONYMS                 Colisone [Merck Index 1996]
SYNONYMS                 Cortidelt [CHEMLINE]
SYNONYMS                 Dacortin [Merck Index 1996]
SYNONYMS                 Decortancyl [Merck Index 1996]
SYNONYMS                 Decortisyl [Physicians GenRx 97]
SYNONYMS                 Dehydrocortisone [MeSH]
SYNONYMS                 Dekortin [CHEMLINE]
SYNONYMS                 Delta E [Merck Index 1996]
SYNONYMS                 delta(1)-Cortisone [Merck Index 1996]
SYNONYMS                 delta(1)-Dehydrocortisone [Merck Index 1996]
SYNONYMS                 delta-Cortelan [CHEMLINE]
SYNONYMS                 delta-Cortisone [MeSH]
SYNONYMS                 Deltacortisone [Merck Index 1996]
SYNONYMS                 Deltacortone [Merck Index 1996]
SYNONYMS                 Deltason [Merck Index 1996]
SYNONYMS                 Deltra [CHEMLINE]
SYNONYMS                 Di-adreson [Merck Index 1996]
SYNONYMS                 Encorton [Physicians GenRx 97]
SYNONYMS                 Enkorton [CHEMLINE]
SYNONYMS                 Hostacortin [CHEMLINE]
SYNONYMS                 Metacortandracin [Merck Index 1996]
SYNONYMS                 Prednison [CHEMLINE]
SYNONYMS                 Prednisona [CHEMLINE]
SYNONYMS                 Prednisonum [CHEMLINE]
SYNONYMS                 Prednizon [CHEMLINE]
SYNONYMS                 Rectodelt [Merck Index 1996]
SYNONYMS                 Supercortil [CHEMLINE]
SYNONYMS                 Ultracorten [Merck Index 1996]
SYNONYMS                 Ultracortene [CHEMLINE]
SYNONYMS                 1-Dehydrocortisone [CHEMLINE]
SYNONYMS                 1,2-Dehydrocortisone [CHEMLINE]
SYNONYMS                 Retrocortine [Merck Index 1996]
SYNONYMS                 Cortancyl [Merck Index 1996]
SYNONYMS                 Fernisone [Physicians GenRx 97]
SYNONYMS                 Nurison [Merck Index 1996]
SYNONYMS                 Prednilonga [Merck Index 1996]
SYNONYMS                 Sone [Merck Index 1996]
SYNONYMS                 Pronison [Merck Index 1996]
SYNONYMS                 1,4-pregnadiene-17x,21-diol-3,11,20-trione
                         [Merck Index 1996]
SYNONYMS                 Delcortin [Merck Index 1996]
PROTOCOL ID NUMBERS      NCI 97 C-0040
PROTOCOL ID NUMBERS      NIAID ACTG 349
PROTOCOL ID NUMBERS      NIAID 95 I-133
PROTOCOL ID NUMBERS      NIAID ACTG 271
SECONDARY SOURCE ID      NSC-10023 [USAN 1997]
SECONDARY SOURCE ID      AI3-52939 [CHEMLINE]
SECONDARY SOURCE ID      CCRIS 2646 [CHEMLINE]
SECONDARY SOURCE ID        NCI-CO4897 [CHEMLINE]
SECONDARY SOURCE ID        HSDB 3168 [CHEMLINE]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Pharmacology of the
                           corticosteroids is complex and the drugs
                           affect almost all body systems. Maximum
                           pharmacologic activity lags behind peak blood
                           concentrations, suggesting that most effects
                           of the drugs result from modification of
                           enzyme activity rather than from direct
                           actions by the drugs. In pharmacologic doses,
                           systemically administered glucocorticoids
                           suppress release of corticotropins from the
                           pituitary; thus the adrenal cortex ceases
                           secretion of endogenous corticosteriods
                           (secondary adrenocortical insufficiency). The
                           duration of anti-inflammatory activity of
                           glucocorticoids approximately equals the
                           duration of hypothalamic-pituitary-adrenal
                           (HPA) axis suppression. The duration of
                           HPA-axis of prednisone is 1.25-1.5 days after
                           a single 50 mg oral dose. Most
                           glucocorticoids appear to be readily absorbed
                           when administered orally. Prednisone is
                           rapidly converted to prednisolone, but much
                           of cortisone is inactivated before it can be
                           converted to hydrocortisone.
                           Pharmacologically active glucocorticoids are
                           metabolized primarily in the liver, to
                           biologically inactive compounds. Inactive
                           metabolites are excreted by the kidneys.
                           Small amounts of unmetabolized drugs are also
                           excreted in urine. [AHFS Drug Information
                           1997]
DISEASES STUDIED/TREATED   HIV-associated nephropathy; HIV-associated
                           idiopathic esophageal ulcer. [Am J Med 1994
                           Aug;97(2); Am J Gastroenterol 1994
                           Dec;89(12)]
CLASSIFICATION CODE        Glucocorticoid [USAN 1997]
OTHER MAJOR USES           Considered the glucocorticoid of choice for
                           anti-inflammatory or immunosuppressant
                           effects, used in concomitant therapy with a
                           mineralocorticoid in the treatment of the
                           following diseases: adrenocortical
                           insufficiency; adrenogenital syndrome;
                           hypercalcemia due to sarcoidosis or vitamin D
                           intoxication; granulomatous thyroiditis;
                           symptomatic relief of inflammation and
                           symptoms of rheumatic disorders, collagen
                           diseases, selected ocular inflammations,
                           hematologic disorders, cancer
                           chemotherapy-induced nausea and vomiting,
                           cerebral edema, myasthenia gravis, nephrotic
                           syndrome, and dermatologic, respiratory,
                           gastrointestinal, neoplastic, or liver
                           diseases. [AHFS Drug Information 1997]
SUBSTANCE INTERACTIONS     Interact with drugs that induce hepatic
                           enzymes, such as barbiturates, phenytoin, and
                           rifampin; estrogens; nonsteroidal
                           anti-inflammatory agents, such as
                           indomethacin and aspirin; potassium-depleting
                           drugs, such as thiazides, furosemide,
                  ethacrynic acid, and amphotericin B;
                  anticholinesterase agents, such as
                  ambenonium, neostigmine, and pyridostigmine;
                  vaccines and toxoids; oral anticoagulants;
                  and cyclosporine. [AHFS Drug Information
                  1997]
ADVERSE EFFECTS   Short-term administration of glucocorticoids,
                  even in massive dosages, is unlikely to
                  produce harmful effects. When the drugs are
                  used for longer than brief periods, however,
                  they can produce a variety of adverse effects
                  including the following, adrenocortical
                  insufficiency; musculoskeletal effects:
                  protein catabolism manifested as muscle
                  wasting, muscle pain or weakness, delayed
                  wound healing, and atrophy of the protein
                  matrix of the bone resulting in osteoporosis,
                  vertebral compression fractures, aseptic
                  necrosis of femoral or humoral heads or
                  pathologic fractures of long bones; increased
                  susceptibility to infection; fluid and
                  electrolyte disturbances: sodium retention
                  with resultant edema, potassium loss,
                  hypokalemic alkalosis, and hypotension, and
                  congestive heart failure; ocular effects:
                  posterior subcapsular cataracts (particularly
                  in children), exophthalmos, or increased
                  intraocular pressure which may result in
                  glaucoma or may occasionally damage the optic
                  nerve; endocrine effects: hypercorticism
                  (cushingoid state), amenorrhea or other
                  menstrual difficulities, glucose intolerance
                  resulting in hyperglycemia, aggravation of
                  precipitation of diabetes mellitus, decrease
                  in sperm motility and sperm number in some
                  men; gastrointestinal effects: nausea,
                  vomiting, anorexia which may result in weight
                  loss, increased appetite which my result in
                  weight gain, diarrhea or constipation,
                  abdominal distension, pancreatitis, gastric
                  irritation, ulcerative esophagitis, and
                  development, reactivation, perforation,
                  hemorrhage and delayed healing of peptic
                  ulcers; nervous system effects: headache,
                  vertigo, insomnia, restlessness and increased
                  motor activity, ischemic neuropathy, EEG
                  abnormalities, seizures, precipitation of
                  mental disturbances ranging from euphoria,
                  mood swings, depression and anxiety,
                  personality changes to frank psychosis;
                  dermatologic effects: impaired wound healing,
                  skin atrophy and thinning, acne, increased
                  sweating, hirsutism, facial erythema, striae,
                  petechiae, ecchymoses, easy bruising, hives
                  and/or allergic dermatitis, urticaria, and
                  angioedema. Abrupt withdrawal of
                  glucocorticoids may result in anorexia,
                  nausea and vomiting, lethargy, headache,
                  fever, joint pain, desquamation, myalgia,
                  weight loss, and/or hypotension. [AHFS Drug
                  Information 1997]
CONTRAINDICATIONS         Contraindicated in patients with systemic
                          fungal infections and with known
                          hypersensitivity to drug components.
                          Contraindicated in patients with known
                          hypersensitivity to any of the other
                          corticosteroids. Contraindicated in women who
                          are either pregnant or nursing.
                          Administration of live or live, attenuated
                          vaccines is contraindicated in patients
                          receiving immunosuppressive doses of the
                          drug. Drug should not be used in patients
                          with peptic ulcer, and viral infections or
                          bacterial infections not controlled by
                          anti-infectives except in life-threatening
                          situations. Should be used with extreme
                          caution in patients with a known history of
                          drug allergy, those after recent myocardial
                          infarction, hypothyroidism, cirrhosis,
                          diverticulitis, nonspecific ulcerative
                          colitis, or those with recent intestinal
                          anastomosis, psychotic patients with
                          hypertension or congestic heart failure,
                          patients with myasthenia gravis receiving
                          anticholinesterase therapy, thromboembolic
                          disorders, seizure disorders, renal
                          insufficiency, osteoporosis, and herpes
                          simplex infections of the eye. Long-term
                          administration of pharmacologic dosages of
                          the drug to children should be avoided if
                          possible, since the drug may retard bone
                          growth. [Physicians GenRx 97; AHFS Drug
                          Information 1997]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: Synthetic anti-inflammatory
                          glucocorticoid (adrenocortical steroid)
                          derived from cortisone. [AHFS Drug
                          Information 1997; CHEMLINE]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: White to practically
                          white, odorless, crystalline powder. [AHFS
                          Drug Information 1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C21H26O5 [USAN 1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 358.44 [USAN 1997]
CHEMICAL/PHYSICAL DATA    ELEMENTAL COMP: C70.37%, H7.31%, O22.32%.
                          [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    SOLUBILITY: Very slightly soluble in water;
                          slightly soluble in alcohol. [AHFS Drug
                          Information 1997]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Oral solution (5mg/5ml), syrup
                          (5mg/5ml), solution concentrate (5mg/ml),
                          tablets (1, 2.5, 5, 10, 20, 25, 50 mg),
                          film-coated tablets (5mg). [AHFS Drug
                          Information 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral administration. [AHFS
                          Drug Information 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Prednisone tablets
                          should be stored in well-closed containers at
                          a temperature less than 40 C, preferrably
                          between 15-30 C. Syrup should be stored in
                          tight containers. Oral solution and oral
                          solution concentrate should be stored in a
                          tight container at 15-30 C. [AHFS Drug
                          Information 1997]
MANUFACTURERS        Upjohn Company; 7000 Portage Road /
                     9156-298-216; Kalamazoo, MI 49001
REFERENCES           MED/97254645. Watterson MK, Detwiler RK,
                     Bolin P Jr. Clinical response to prolonged
                     corticosteroids in a patient with human
                     immunodeficiency virus-associated
                     nephropathy. Am J Kidney Dis. 1997
                     Apr;29(4):624-6.
REFERENCES           AIDS/97926700. Craven DE, Duncan R, Jhamb K,
                     Hirschhorn L, Steger K, Stram JR. Medical
                     treatment of benign lymphoepithelial parotid
                     cysts (BLPC) in patients with human
                     immunodeficiency virus (HIV) infection. 4th
                     Conf Retro and Opportun Infect. 1997 Jan
                     22-26;:197 (abstract no. 717).
REFERENCES           MED/97118364. Zanussi S, Simonelli C,
                     D'Andrea M, Comar M, Bidoli E, Giacca M,
                     Tirelli U, Vaccher E, De Paoli P. The effects
                     of antineoplastic chemotherapy on HIV
                     disease. AIDS Res Hum Retroviruses. 1996 Dec
                     10;12(18):1703-7.
REFERENCES           MED/97120054. Bradley WG, Verma A. Painful
                     vasculitic neuropathy in HIV-1 infection:
                     relief of pain with prednisone therapy.
                     Neurology. 1996 Dec;47(6):1446-51.
REFERENCES           MED/96438596. Briggs WA, Tanawattanacharoen
                     S, Choi MJ, Scheel PJ Jr, Nadasdy T, Racusen
                     L. Clinicopathologic correlates of prednisone
                     treatment of human immunodeficiency
                     virus-associated nephropathy. Am J Kidney
                     Dis. 1996 Oct;28(4):618-21.
REFERENCES           ICA11/96921434. Graves M, Salvato P, Thompson
                     C. MAIC and the effect of prednisone on
                     disease progression in AIDS patients. Int
                     Conf AIDS. 1996 Jul 7-12;11(1):119 (abstract
                     no. Mo.B.1371).
REFERENCES           ICA11/96922077. Beardsell AD, Coker K,
                     Woodfall B, Conway B. Cotrimoxazole (TMP-SMX)
                     desensitization using adjunctive steroid
                     therapy in HIV/AIDS patients. Int Conf AIDS.
                     1996 Jul 7-12;11(1):237 (abstract no.
                     Tu.B.414).
REFERENCES           ICA11/96922580. Nemechek P, Whal D, Sackuvich
                     L. Evidence of subclinical adrenal
                     insufficiency in patients with AIDS, CDC
                     class III. Int Conf AIDS. 1996 Jul
                     7-12;11(1):331 (abstract no. Tu.B.2378).
REFERENCES           ICA11/96921327. Karmochkine M, Oksenhendler
                     E, Martinez F, Beaufils H, Valantin MA,
                     Coutellier A, Idatte JM, Herson S.
                     Effectiveness and side-effects of steroid
                     therapy in renal disease associated with HIV
                     infection. Int Conf AIDS, 1996 Jul
                     7-12;11(1):100 (abstract no. Mo.B.1263).
                     MED/96006293. de Asis ML, Bernstein LJ,
                     Schliozberg J. Treatment of resistant oral
                     aphthous ulcers in children with acquired
                     immunodeficiency syndrome. J Pediatr. 1995
                     Oct;127(4):663-5.
ENTRY MONTH          199507
LAST REVISION DATE   19971204
81
UNIQUE IDENTIFIER          DRG-0226
NAME OF SUBSTANCE          OPC 14117 [MeSH]
REGISTRY NUMBER            103233-65-4
STANDARD CHEMICAL NAME     1-Piperazineacetamide,
                           N-(2,3-dihydro-7-hydroxy-2,2,4,6-
                           tetramethyl-1H-inden-1-yl)-4-(3-methoxyphenyl-
                           )- [CHEMLINE]
SYNONYMS                   OPC-14117 [MeSH]
SYNONYMS                   7-hydroxy-1-(4-(3-methoxyphenyl)-1-piperaziny-
                           l) acetylamino-2,2,4,6-tetrame [MeSH]
PROTOCOL ID NUMBERS        FDA 242A
PHARMACOLOGICAL ACTION     MODE OF ACTION: Has both a brain
                           function-activating effect and protective
                           effect against cerebral ischemia. Acts by
                           inhibiting oxygen free radicals. Oxygen free
                           radicals generated by leukocytes may
                           contribute to tissue injury after central
                           nervous system (CNS) focal ischemia or
                           trauma. In vitro studies using stimulated
                           polymorphonuclear (PMN) leukocytes and
                           monocytes demonstrated that OPC 14117
                           significantly reduces PMN hydrogen peroxide
                           production, with the 100 microM concentration
                           of the drug significantly more effective than
                           the 10 microM concentration. [J Neurol Sci
                           1992 May;109(1); MeSH]
DISEASES STUDIED/TREATED   HIV-related cognitive dysfunction. [FDA 242A]
CLASSIFICATION CODE        Antioxidant [CHEMLINE]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C26H35N3O3 [CHEMLINE]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 60 mg tablets. [FDA 242A]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [FDA 242A]
MANUFACTURERS              Otsuka America Pharmaceutical Incorporated;
                           1290 Page Mill Road / Suite 200; Palo Alto,
                           CA 94304
REFERENCES                 AIDS/96700633. Anonymous. Vitamin E drug.
                           Treat Rev. 1995 May;:no 18(1).
REFERENCES                 MED/92388919. Fisher M and Arpano MM.
                           Inhibition of stimulated human leukocyte
                           hydrogen peroxide generation by a novel
                           antioxidant, OPC-14117. J Neurol Sci 1992
                           May;109(1):107-10.
REFERENCES                 MED/97365345. Safety and tolerability of the
                           antioxidant OPC-14117 in HIV-associated
                           cognitive impairment. The Dana Consortium on
                           the Therapy of HIV Dementia and Related
                           Cognitive Disorders. Neurology. 1997
                           Jul;49(1):142-6.
ENTRY MONTH                199507
LAST REVISION DATE         19980511

82
UNIQUE IDENTIFIER          DRG-0225
NAME OF SUBSTANCE          Clavulanate Potassium [USAN 1997]
REGISTRY NUMBER            61177-45-5
STANDARD CHEMICAL NAME     4-Oxa-1-azabicyclo[3.2.0]heptane-2-carboxylic
                           acid, 3-(2-hydroxyethylidene)-7-oxo-,
                           monopotassium salt, [2R-(2alpha,3Z,5alpha]-
                           [USAN 1997]
SYNONYMS                   Component of Augmentin (in combination with
                           amoxicillin trihydrate) [PDR 1997]
SYNONYMS                   Potassium clavulanate [MeSH]
SYNONYMS                   Component of Timentin (in combination with
                           ticarcillin disodium) [PDR 1997]
SYNONYMS                   Clavulanic acid [MeSH]
SYNONYMS                   Clavulanate [MeSH]
SYNONYMS                   MM-14151 [MeSH]
SYNONYMS                   BRL-14151 [MeSH]
PROTOCOL ID NUMBERS        FDA 243A
SECONDARY SOURCE ID        BRL 14151K [USAN 1997]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Clavulanic acid, which is
                           produced by fermentation of Streptomyces
                           clavulgerus, possesses the ability to
                           inactivate a wide variety of betalactamases
                           by blocking the active sites of these
                           enzymes. Clavulanic acid is particularly
                           active against the clinically important
                           blasmid mediated beta-lactamases frequently
                           responsible for transferred drug resistance
                           to penicillins and cephalosporins.
                           Clavulanate potassium is well absorbed from
                           the gastrointestinal tract after oral
                           administration. It is approximately 25% bound
                           to human serum. [PDR 1997]
DISEASES STUDIED/TREATED   AIDS-associated sinusitis. [FDA 243A]
CLASSIFICATION CODE        Antibacterial (tuberculostatic) [PDR 1997]
CLASSIFICATION CODE        Beta-lactamase Inhibitor [USAN 1997]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Potassium salt of
                           clavulanic acid, which is a beta-lactam
                           structurally related to the penicillins. [PDR
                           1997]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C8H8KNO5 [USAN 1997]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 237.25 [USAN 1997]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [PDR 1997]
MANUFACTURERS              Smith Kline Beecham; 1 Franklin Plaza / PO
                           Box 7929; Philadelphia, PA 19101-7929
REFERENCES                 96098371. Salvemini JN, Baldwin HE.
                           Botryomycosis in a patient with acquired
                           immunodeficiency syndrome. Cutis. 1995
                           Sep;56(3):158-60.
ENTRY MONTH                199506
LAST REVISION DATE         19980408

83
UNIQUE IDENTIFIER          DRG-0224
NAME OF SUBSTANCE          HIV-1 C4-V3 Polyvalent Peptide Vaccine [NIAID
                           DATRI 010]
PROTOCOL ID NUMBERS        NIAID DATRI 010
PROTOCOL ID NUMBERS        NIAID VEU 020
PHARMACOLOGICAL ACTION     MODE OF ACTION: Potential induction of
                           cross-reactive antibody responses. The
                           vaccine is composed of selected gp120
                           epitopes T1, SP10, and A. The peptide
                           sequences represent the minimally sufficient
                           epitopes necessary to generate neutralizing
                           antibody, MHC class I-restricted cytotoxic
                           T-lymphocyte (CTL), and helper cell
                           responses. The SP10(A) portions of gp120 are
                           amino acids 303-327, representing V3 loop
                           epitopes important for neutralizing
                           antibodies, and the T1 portion is amino acids
                           428-443, a helper T-cell epitope. The section
                           of SP10(A) composed of amino acids 304-313 is
                           an important epitope for MHC class
                           I-restricted CTL responses in individuals
                           with HLA-B7 phenotype. The HIV-1 C4-V3
                           polyvalent peptide vaccine not only utilizes
                           epitopes from gp120 but also is a prototype
                           multivalent immunogen containing the amino
                           acid sequences for selected epitopes from
                           four of the most common HIV isolates in the
                           United States and Europe -- EV91, MN, RF, and
                           CAN0 -- which are predicted to represent
                           50-90% of the HIV isolates in the United
                           States. The HIV env-encoded synthetic peptide
                           T1-SP1OMN(A) contains immunodominant epitopes
                           of the C4/V3 regions of gp120. The mucosal
                           immunogenicity of this peptide in various
                           vaccine preparations was first tested in
                           rabbits using chronically isolated
                           Thiry-Vella (T-V) ileal loops. Intestinal and
                           serum samples collected from rabbits
                           immunized via T-V loops demonstrated
                           secretory IgA (S-Iga) and IgG
                           anti-T1-SP1OMN(A), respectively, when assayed
                           by ELISA. Intranasal delivery of the peptide
                           supplemented with cholera toxin (CT) resulted
                           in serum IgG and S-Iga anti-T1-=SP1OMN(A) in
                           vaginal and nasal secretions. This study
                           further demonstrates the relationship between
                           nasal immunization and vaginal immunity.
                           [AIDS Res Hum Retroviruses. 1997
                           Jul;13(10):881-9; NIAID DATRI 010]
DISEASES STUDIED/TREATED   Primary HIV infection. [NIAID DATRI 010]
CLASSIFICATION CODE        Vaccine [NIAID DATRI 010]
ADVERSE EFFECTS            Anticipated adverse effects include local
                           reactions at the injection site, such as
                           discomfort, pain, tenderness, swelling,
                           itching, skin discoloration, and drainage of
                           clear fluid. Also, fever, fatigue, or body
                           aches (flu-like symptoms) may occur. [NIAID
                           DATRI 010]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Synthetic polyvalent
                           peptide vaccine. [NIAID DATRI 010]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Subcutaneous. [NIAID DATRI
                           010]
MANUFACTURERS              Lederle - Praxis Biologicals; Professional
                           Services Department; Pearl River, NY 10965
REFERENCES                 MED/97340908. Winchell JM, Van Kruiningen HJ,
                           Silbart LK. Mucosal immune response to an HIV
                           C4/V3 peptide following nasal or intestinal
                           immunization of rabbits. AIDS Res Hum
                           Retroviruses. 1997 Jul 1;13(10):881-9.
REFERENCES                 MED/95260530. Haynes BF, Moody MA, Heinley
                           CS, Kober B, Millard WA, Scearce RM. HIV type
                           1 V3 region primer-induced antibody
                           supression is overcome by administration of
                           C4-V3 peptide as a polyvalent immunogen. AIDS
                           Res Hum Retroviruses. 1995 Feb;11(2):211-21.
REFERENCES                 MED/95132652. Zaghouani H, Anderson SA,
                           Sperber KE, Daian C, Kennedy RC, Mayer L,
                           Bona CA. Induction of antibodies to the human
                         immunodeficiency virus type 1 by immunization
                         of baboons with immunoglobulin molecules
                         carrying the principal neutralizing
                         determinant of the envelope protein. Proc
                         Natl Acad Sci USA. 1995 Jan 17;92(2):631-5.
REFERENCES               ICA10/94371080. Sia C, Chong P, Matthews T,
                         Bolognesi D, Klein M. Improved construction
                         of synthetic HIV vaccine candidates. Int Conf
                         AIDS. 1994 Aug 7-12;10(2):119 (abstract no.
                         PA0357).
REFERENCES               MED/94202302. Johnson RP, Hammond SA, Trocha
                         A, Siliciano RF, Walker BD. Induction of a
                         major histocomatibility complex class
                         I-restricted cytotoxic T-lymphocyte response
                         to a highly conserved region of human
                         immunodeficiency virus type 1 (HIV-1) gp120
                         in seronegative humans immunized with a
                         candidate HIV-1 vaccine. J Virol. 1994
                         May;68(5):3145-53.
ENTRY MONTH              199506
LAST REVISION DATE       19980114

84
UNIQUE IDENTIFIER        DRG-0223
NAME OF SUBSTANCE        Mitoguazone dihydrochloride [Merck Index
                         1996]
REGISTRY NUMBER          7059-23-6
STANDARD CHEMICAL NAME   Hydrazinecarboximidamide,
                         2,2'-(1-methyl-1,2-ethanediylidene)bis-,
                         dihydrochloride [CHEMLINE]
SYNONYMS                 Methyl-GAG [Merck Index 1996]
SYNONYMS                 Methylglyoxal bis(guanylhydrazone)
                         dihydrochloride [CHEMID]
SYNONYMS                 Methyl glyoxal bis(amidinohydrazone)
                         dihydrochloride [CHEMID]
SYNONYMS                 Guanylhydrazone dihydrochloride [CHEMID]
SYNONYMS                 Mitoguazone [AmFAR Tx Dir 1997;8(3)]
SYNONYMS                 MGBG [AmFAR Tx Dir 1997;8(3)]
SYNONYMS                 Zyrkamine [AmFAR Tx Dir 1997;8(3)]
SYNONYMS                 Methylglyoxal-bis-guanylhydrazone [AmFAR Tx
                         Dir 1997;8(3)]
SYNONYMS                 Methylglyoxal Bis(guanylhydrazone) [MeSH]
PROTOCOL ID NUMBERS      FDA 241A
SECONDARY SOURCE ID      NSC-32946 [Merck Index 1996]
PHARMACOLOGICAL ACTION   MODE OF ACTION: Inhibits biosynthesis of
                         polyamines, which play an important role in
                         regulation of cell proliferation,
                         differentiation, and functional stimulation
                         of terminally differentiated cells. MGBG
                         crosses the blood brain barrier and appears
                         to work in patients with inanition (a
                         condition characterized by marked weakness,
                         extreme weight loss, and decreased
                         metabolism). In vitro studies with HeLa cells
                         treated with MGBG showed a marked depression
                         in levels of the cellular polyamines
                         putrescine, spermidine, and spermine. Other
                         studies indicate that MGBG diminishes the
                         respiratory burst activity of macrophages
                         induced by lipopolysaccharides and interferon
                         gamma; this inhibitory effect of MGBG was
                           concentration-dependent and could be reversed
                           by spermine, which is the final product of
                           polyamine biosynthesis. [Cancer Lett 1993 Aug
                           16;72(1-2); Ann Oncol 1994 Jul;5(6); J Leukoc
                           Biol 1992 Dec;52(6)]
DISEASES STUDIED/TREATED   Under investigation for the treatment of
                           AIDS-related non-Hodgkin's lymphoma. [AmFAR
                           Tx Dir 1997;8(3)]
CLASSIFICATION CODE        Antineoplastic (adjunct) [Merck Index 1996]
OTHER MAJOR USES           Non-small cell lung cancer, Hodgkin's
                           disease. [Invest New Drugs 1993 Feb;11(1);
                           Ann Oncol 1994 Jul;5(6)]
ADVERSE EFFECTS            Adverse effects have included flushing,
                           tingling, euphoria, or somnolence during
                           infusion. Other adverse effects have included
                           mild nausea, vomiting, fatigue, and
                           neutropenia. [Proc Annu Meet Am Soc Clin
                           Oncol 13 1994]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Structural analog of
                           spermidine. [Biochem Pharmacol 1993 Sep
                           14;46(6)]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C5H14Cl2N8 [Merck Index
                           1996]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intravenous. [FDA 241A]
MANUFACTURERS              ILEX Oncology Incorporated; 14785 Omicron
                           Drive / Suite 100; San Antonio, TX 78245-3217
REFERENCES                 97213861. Levine AM, Tulpule A, Tessman D,
                           Kaplan L, Giles F, Luskey BD, Scadden DT,
                           Northfelt DW, Silverberg I, Wernz J, et al.
                           Mitoguazone therapy in patients with
                           refactory or relapsed AIDS-related lymphoma:
                           results from a multicenter phase II trial. J
                           Clin Oncol. 1997 Mar;15(3):1094-103.
REFERENCES                 ICA11/96924266. Levine A, Tulpule A, Espina
                           BM, Von Hoff D, Tessman D. Mitoguazone (MGBG)
                           with radiation therapy in AIDS-related
                           primary CNS-lymphoma. Int Conf AIDS. 1996 Jul
                           7-12: 11(2):222 (abstract no. Th.B.184).
REFERENCES                 97070920. Rizzo J, Levine AM, Weiss GR,
                           Pearce T, Kraynak M, Mueck R, Smith S, Von
                           Hoff DD, Kuhn JG. Pharmacokinetic profile of
                           Mitoguazone (MGBG) in patients with AIDS
                           related non-Hodgkins lymphoma. Invest New
                           Drugs. 1996; 14(2):227-34.
REFERENCES                 AIDS/96701139. Mascolini M. Lymphoma: MGBG
                           new studies, compassionate use in earlier
                           disease. AIDS Treat News. 1995 Dec 22;:no
                           237,4.
REFERENCES                 AIDS/96700645. Mascolini M. Oncologists scout
                           new directions for KS and lymphoma therapies.
                           J Int Assoc Physicians AIDS Care. 1995
                           Jun;1(5):10-4.
REFERENCES                 96015008. Ferme C, Bastion Y, Lepage E,
                           Berger F, Brice P, Morel P, Gabarre J,
                           Nedellec G, Reman O, Cheron N, et al. The
                           MINE regimen as intensive salvage
                           chemotherapy for relapsed and refractory
                           Hodgkin's disease [see comments]. Ann Oncol.
                           1995 Jul;6(6):543-9.
REFERENCES                 ICDB/96614424. Lim SW, Look RM, Bick AB,
                           Hamburg SI, Lawrence GN, Fuerst MP, Kusuanco
                           DA, Kessler CE, Giles FJ. MGBG therapy of
                           relapsed extralymphatic HIV-associated
                           non-Hodgkin's lymphoma (HIV NHL) (Meeting
                           abstract). Proc Annu Meet Am Soc Clin Oncol;
                           14:A1274 1995.
REFERENCES                 95001580. Von Hoff, DD. MGBG: teaching an old
                           drug new tricks. Ann Oncol. 1994
                           Jul;5(6):487-93.
REFERENCES                 84288336. Knight WA 3d, Fabian C, Costanzi
                           JJ, Jones SE, Coltrman CA Jr. Methylglyoxal
                           bis guanylhydrazone (methyl-GAG, MGBG) in
                           lymphoma and Hodgkin's disease. A Phase II
                           trial of the Southwest Oncology Group. Invest
                           New Drugs. 1983;1(3):235-7.
REFERENCES                 82227522. Kelsen DP, Yagoda A, Warrell R,
                           Chapman R, Whittes R, Gralla RJ, Casper E,
                           Young CW. Phase II trials of
                           methylglyoxal-bis (guanylhydrazone). Am J
                           Clin Oncol. 1982 Apr;5(2):221-5.
ENTRY MONTH                199505
LAST REVISION DATE         19980408

85
UNIQUE IDENTIFIER          DRG-0222
NAME OF SUBSTANCE          HIV p17/p24:Ty-VLP [AIDS 1993 Oct;7(10)]
PROTOCOL ID NUMBERS        NIAID VEU 019
PHARMACOLOGICAL ACTION     MODE OF ACTION: Vaccine delivery system with
                           the potential for inducing broadly
                           cross-reactive CD8+ cytotoxic T-lymphocyte
                           (CTL) responses to p17 and p24. A previous
                           study indicated that hybrid p17/p24:Ty-VLP
                           was capable of inducing both cellular and
                           humoral immunity to HIV-1 gag p17 and p24
                           components. [AIDS 1993 Oct;7(10); NIAID VEU
                           019]
DISEASES STUDIED/TREATED   Prevention of HIV infection. [NIAID VEU 019]
CLASSIFICATION CODE        Vaccine [AIDS 1993 Oct;7(10)]
ADVERSE EFFECTS            Adverse effects of the intramuscular
                           injection may include pain, soreness,
                           redness, and swelling at the injection site.
                           Other adverse effects may include fever,
                           chills, rash, aches, pains, nausea, headache,
                           and fatigue. Side effects after rectal
                           administration of the vaccine may include
                           local discomfort, crampy abdominal pain, or
                           watery diarrhea immediately following
                           injection. [NIAID VEU 019]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Fusion product of the gag
                           gene of HIV-1 IIIB and a gene from the yeast
                           retrotransposon. Retrotransposons are
                           transposable elements (transposons) that
                           involve a retrovirus-like process of reverse
                           transcription. The TYA-gag fusion gene
                           produces a protein that retains the
                           self-assembly properties of the
                           retrotransposon and thereby expresses the
                           HIV-1 gag gene products p17 and p24 in a
                           virus-like particle (VLP). The fusion protein
                           contains amino acids 1-381 of yeast protein
                           p1, 33 C-terminal amino acids of p17, and 177
                           amino acids of p24 (not including the 48
                          C-terminal amino acids of p24). Together the
                          p17 and p24 components comprise 30% of the
                          mass. [NIAID VEU 019; MeSH]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 66,460 D [NIAID VEU 019]
CHEMICAL/PHYSICAL DATA    STABILITY: Virus-like particles (VLPs)
                          adjuvanted with aluminum hydroxide (alum) are
                          stable at 4 C for at least 30 months. [NIAID
                          VEU 019]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Adjuvanted with alum or
                          unadjuvanted. [NIAID VEU 019]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Intramuscular; oral;
                          rectal. [NIAID VEU 019]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store adjuvanted
                          formulation at 4 C. Store unadjuvanted
                          formulation at -70 C. [NIAID VEU 019]
MANUFACTURERS             British Biotech PLC; Watlington Road /
                          Cowley; Oxford, United KingdomOX4 5LY
REFERENCES                97229917. Klein MR, Veenstra J, Holwerda AM,
                          Roos MT, Gow I, Patou G, Coutinho RA, De Wolf
                          F, Miedema F. Gag-specific immune responses
                          after immunization with p17/p24:Ty virus-like
                          particles in HIV type 1-seropositive
                          individuals. AIDS Res Hum Retroviruses. 1997
                          Mar 20;13(5):393-9.
REFERENCES                97000088. Veenstra J, Williams IG,
                          Colebunders R, Dorrell L, Tchamouroff SE,
                          Patou G, Lange JM, Weller IV, Goeman J,
                          Uthayakumar S, et.al. Immunization with
                          recombinant p17/p24:Ty virus-like particles
                          in human immunodeficiency virus-infected
                          persons. J Infect Dis. 1996 Oct;174(4):862-6.
REFERENCES                MED/96066231. Weber J, Cheinsong-Popov R,
                          Callow D, Adams S, Patou G, Hodgkin K, Martin
                          S, Gotch F, Kingsman A. Immunogenicity of the
                          yeast recombinant p17/p24:Ty virus-like
                          particles (p24-VLP) in healthy volunteers.
                          Vaccine. 1995 Jun;13(9):831-4.
REFERENCES                95407117. Brookman JL, Stott AJ, Cheeseman
                          PJ, Adamson CS, Holmes D, Cole J, Burns NR.
                          Analysis of TYA protein regions necessary for
                          formation of the Ty1 virus-like particle
                          structure. Virology; VOL 212,ISS
                          1,1995,P69-76.
REFERENCES                MED/95065695. Luo L, Li Y, Dales S, Kang CY.
                          Mapping of functional domains for HIV-2 gag
                          assembly into virus-like particles. Virology;
                          VOL 205,ISS 2,1994,P496-502.
REFERENCES                MED/94092369. Martin SJ, Vyakarnam A,
                          Cheingsong-Popov R, Callow D, Jones KL,
                          Senior JM, Adams SE, Kingsman AJ, Matear P,
                          Gotch FM, et al. Immunization of human
                          HIV-seronegative volunteers with recombinant
                          p17/p24:Ty virus-like particles elicits HIV-1
                          p24-specific cellular and humoral immune
                          responses. AIDS 1993 Oct;7(10):1315-23.
ENTRY MONTH               199505
LAST REVISION DATE        19980408

86
UNIQUE IDENTIFIER         DRG-0221
NAME OF SUBSTANCE         CI-0694 [NIAID 95 I-126]
STANDARD CHEMICAL NAME     5-(Sulfamethoxazoyl)-glutaryl-dexamine [NIAID
                           95 I-126]
SYNONYMS                   Sulfasim [NIAID 95 I-126]
PROTOCOL ID NUMBERS        NIAID 95 I-126
PHARMACOLOGICAL ACTION     MODE OF ACTION: Therapeutic suppression of
                           IgG antibody response to SMX, probably by
                           acting at the level of B cells with receptor
                           specificity for SMX. [NIAID 95 I-126]
DISEASES STUDIED/TREATED   Possible prevention or reversal of
                           sensitivity to SMX in patients with HIV
                           infection and SMX intolerance. [NIAID 95
                           I-126]
CLASSIFICATION CODE        Immunomodulator [NIAID 95 I-126]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Dextran backbone to which
                           20-50 sulfamethoxazole (SMX) molecules are
                           covalently attached. [NIAID 95 I-126]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: Lyophilized powder.
                           [NIAID 95 I-126]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 28 +/- 8 kg/mole [NIAID 95
                           I-126]
CHEMICAL/PHYSICAL DATA     SOLUBILITY: Readily soluble in water or
                           saline. [NIAID 95 I-126]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 120 mg vials. [NIAID 95 I-126]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Subcutaneous. [NIAID 95
                           I-126]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Store at 2-8 C. [NIAID
                           95 I-126]
MANUFACTURERS              Cortech Incorporated; 7000 North Broadway;
                           Denver, CO 80221
ENTRY MONTH                199505
LAST REVISION DATE         19951102

87
UNIQUE IDENTIFIER          DRG-0220
NAME OF SUBSTANCE          Magnesium sulfate [USAN 1997]
REGISTRY NUMBER            10034-99-8
STANDARD CHEMICAL NAME     Sulfuric acid magnesium salt (1:1),
                           heptahydrate [USAN 1997]
SYNONYMS                   Magnesium sulfate heptahydrate [Merck Index
                           1996]
SYNONYMS                   Epsom salts [Merck Index 1996]
SYNONYMS                   Mg 5-Sulfat [Merck Index 1996]
SYNONYMS                   Bitter salts [Merck Index 1996]
SYNONYMS                   Epsomite [Merck Index 1996]
PROTOCOL ID NUMBERS        FDA 020J
PHARMACOLOGICAL ACTION     MODE OF ACTION: Parenterally in doses
                           sufficient to produce hypermagnesemia
                           (magnesium conc. > 2.5 mEq/L), magnesium
                           sulfate may depress the CNS and block
                           peripheral neuromuscular transmission
                           producing anticonvulsant effects. Excess
                           magnesium appears to decrease the amount of
                           acetylcholine liberated by the motor nerve
                           impulse. Magnesium also acts peripherally
                           producing vasodilation. Magnesium readily
                           crosses the placenta and is distributed into
                           milk. Magnesium sulfate is excreted by the
                           kidney. When magnesium sulfate is
                           administered intravenously, the onset of
                           action is immediate and the duration is about
                           30 minutes. Following intramuscular
                           administration of the drug, the onset of the
                           action occurs in about 1 hour and the
                           duration of action is 3-4 hours. As an
                           anticonvulsant, effective serum
                           concentrations of magnesium have been
                           reported to range from 2.5-7.5 m Eq/L. [AHFS
                           Drug Information 1997]
DISEASES STUDIED/TREATED   Alleviation or elimination of hypocalcemia
                           and hypomagnesemia associated with foscarnet
                           infusion. [FDA 020J]
CLASSIFICATION CODE        Electrolyte replenisher [USAN 1997]
CLASSIFICATION CODE        Anticonvulsant [USAN 1997]
CLASSIFICATION CODE        Laxative [USAN 1997]
OTHER MAJOR USES           Magnesium sulfate is mainly used as an
                           anticonvulsant for the prevention and control
                           of seizures in severe preclampsia or in
                           eclampsia. It is also used to inhibit uterine
                           contraction in preterm labor; to control
                           seizures associated with epilepsy,
                           glomerulonephritis, or hypothyroidism; to
                           treat acute magnesium deficiency which may be
                           associated with clinical conditions including
                           malabsorption syndromes, alcoholism,
                           cirrhosis of the liver, acute pancreatitis,
                           or prolonged intravenous therapy with
                           magnesium-free fluids; to counteract intense
                           muscle stimulating effects of barium
                           poisoning; to prevent magnesium deficiency in
                           patients receiving total parenteral
                           nutrition. [AHFS Drug Information 1997]
SUBSTANCE INTERACTIONS     Concomitant administration with CNS
                           depressants such as barbiturates, opiates, or
                           general anesthetics must be done with careful
                           adjustment of these agents to prevent
                           additive central depressant effects.
                           Concomitant administration of neuromuscular
                           blocking agents should be done with caution.
                           Magnesium sulfate should be administered with
                           extreme caution in digitalized patients
                           because serious changes in cardia conduction,
                           which can result in heart block, may occur if
                           calcium administration is required to treat
                           magnesium toxicity. [AHFS Drug Information
                           1997]
ADVERSE EFFECTS            Signs of magnesium intoxication which may
                           begin at serum concentration of 4 mEq/L,
                           include flushing, sweating, hypotension,
                           depression of reflexes, flaccid paralysis,
                           hypothermia, circulatory collapse, depression
                           of cardiac function, and CNS depression.
                           These symptoms can proceed to fatal
                           respiratory paralysis. Hypocalcemia with
                           signs of tetany secondary to magnesium
                           sulfate therapy for eclampsia has been
                           reported. [AHFS Drug Information 1997]
CONTRAINDICATIONS          Should be administered with caution to
                           patients with impaired renal functions.
                           Magnesium sulfate is contraindicated in
                           patients with heart blockage or myocardial
                           damage. [AHFS Drug Information 1997]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: Efflorescent crystals
                          or powder; bitter, saline, cooling taste.
                          [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: MgSO4.7H2O [USAN 1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 246.48 [USAN 1997]
CHEMICAL/PHYSICAL DATA    SOLUBILITY: Soluble in water; slightly
                          soluble in alcohol. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    DRUG PHYSICAL COMMENT: Aqueous solution is
                          neutral, pH 6-7. [Merck Index 1996]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Parenteral injection solutions
                          (10, 12.5, or 50%); parenteral injection
                          solutions (4 or 8%) for intravenous use only;
                          parenteral injection solutions (1 or 2%) in
                          5% dextrose for intravenous use only. [AHFS
                          Drug Information 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Intravenous or
                          intramuscular injections. [AHFS Drug
                          Information 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Magnesium sulfate
                          injection solutions should be stored at a
                          temperature less than 40 C, preferrably
                          between 15-30 C; freezing should be avoided.
                          [AHFS Drug Information 1997]
MANUFACTURERS             Astra USA Incorporated; 50 Otis Street / PO
                          Box 4500; Westborough, MA 01581-4500
REFERENCES                97417851. Bruner JP, Bruner TA, Sarno AP.
                          Long-term intravenous tocolytic therapy. Mil
                          Med. 1997 Aug;162(8):555-9.
REFERENCES                97412548. Lilley LL, Guanci R. Magnesium
                          Sulfate: is that the right dose? Am J Nurs.
                          1997 Aug;97(8):12-4.
REFERENCES                97374579. Verduyn SC, Vos MA, van der Zande
                          J, van der Hulst FF, Wellens HJ. Role of
                          interventricular dispersion of repolarization
                          in acquired torsade-de-pointes arrhythmias:
                          reversal by mangesium. Cardoivasc Res. 1997
                          Jun;34(3):453-63.
REFERENCES                97403929. Shechter M, Hod H, Chouraqui P,
                          Kaplinsky E, Rabinowitz B. Acute myocardial
                          infarction without thrombolytic therapy:
                          beneficial effects of magnesium sulfate.
                          Herz. 1997 Jun;22 Suppl 1:73-6.
REFERENCES                97331259. Hebert P, Mehta N, Wang J,
                          Hindmarsh T, Jones G, Cardinal P. Functional
                          magnesium deficiency in critically ill
                          patients using a magnesium-loading test. Crit
                          Care Med. 1997 May;25(5):749-55.
REFERENCES                97391038. Theophanides T. Biological
                          implications of magnesium salts at the
                          molecular level. Magnes Res. 1996 Dec;
                          9(4):259-62.
REFERENCES                ICA10/94369690. Stroud S, Salvato P, Thompson
                          C. Magnesium level and peripheral neuropathy.
                          Int Conf AIDS. 1994 Aug 7-12;10(1):202
                          (abstract no. PB0235).
ENTRY MONTH               199504
LAST REVISION DATE        19971203

88
UNIQUE IDENTIFIER         DRG-0219
NAME OF SUBSTANCE         Kynostatin 272 [MeSH]
REGISTRY NUMBER           147318-81-8
STANDARD CHEMICAL NAME     4-Thiazolidinecarboxamide,
                           N-(1,1-dimethylethyl)-3-(2-hydroxy-3-
                           ((2-(((5-isoquinolinyloxy)acetyl)amino)-3-
                           (methylthio)-1-oxopropyl)amino)-1-oxo-4-pheny-
                           lbutyl)-, (4R-(3(2S*,3S*(R*)),4R*))
                           [CHEMLINE]
SYNONYMS                   KNI-272 [MeSH]
SYNONYMS                   Kynostatin 272 [MeSH]
PROTOCOL ID NUMBERS        NCI 94 C-147
PROTOCOL ID NUMBERS        NCI 94 C-40
PHARMACOLOGICAL ACTION     MODE OF ACTION: Highly potent against HIV
                           protease with little inhibition of other
                           aspartic proteases in a wide spectrum of HIV
                           strains in vitro. In one study, IC50s of
                           KNI-272 against HIV type 1 LAI, RF, and MN,
                           and HIV type 2 ROD were 0.1, 0.02, 0.04 and
                           0.1 microM, respectively, when tested in
                           target CD4+ ATH8 cells. Ratio of 50%
                           cytotoxic concentration to IC50 was > 4000,
                           as assessed in peripheral blood mononuclear
                           cells. KNI-272 blocked the posttranslational
                           cleavage of the p55 precursor protein to
                           generate the mature p24 Gag protein in HIV-1
                           infected cells. Data from a later study
                           suggest that decreased virus sensitivity to
                           KNI-272 may develop. Detailed studies of
                           protein binding suggest that in human plasma
                           binding of KNI-272 occurs predominantly to
                           alpha 1-acid glycoprotein. These studies
                           further suggest that KNI-272 is extensively
                           (98-99%) protein bound at concentrations
                           likely to be achieved in the circulation.
                           [Antimicrob Agents Chemother 1993 Apr;37(4);
                           Int Conf AIDS 1994 Aug 7-12;10(2); Antimicrob
                           Agents Chemother 1994 May;38(5)]
DISEASES STUDIED/TREATED   Primary HIV infection. [Int Conf AIDS 1994
                           Aug 7-12;10(2)]
CLASSIFICATION CODE        Protease inhibitor [MeSH]
CLASSIFICATION CODE        Antiretroviral [NCI 94 C-40]
ADVERSE EFFECTS            Adverse effects experienced by patients thus
                           far include fatigue, parotitis (inflammation
                           of salivary gland), elevated liver function
                           tests, and elevated amylase without evidence
                           of pancreatitis. [NCI 94 C-40]
CONTRAINDICATIONS          Contraindicated in pregnant women. [NCI 94
                           C-40]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Transition-state mimetic
                           tripeptide HIV protease inhibitor containing
                           allophenylnorstatine with a
                           hydroxymethylcarbonyl isostere. [Int Conf
                           AIDS 1994 Aug 7-12;10(2)]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C33H41N5O6S2 [CHEMLINE]
CHEMICAL/PHYSICAL DATA     SOLUBILITY: Extremely low aqueous solubility
                           (4 mcg/ml). [J Pharm Sci 1994 Aug;83(8)]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Liquid, capsules, or tablets.
                           [NCI 94 C-40]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intravenous; oral. [NCI 94
                           C-40]
MANUFACTURERS              National Cancer Institute / Japan Energy
                           Corporation; 9000 Rockville Pike / Clinical
                           Center; Bethesda, MD 20892
REFERENCES           MED/97291248. Humphrey RW, Ohagen A, Davis
                     DA, Fukazawa T, Hayashi H, Hoglund S, Mitsuya
                     H, Yarchoan R. Removal of human
                     immunodeficiency virus type 1 (HIV-1)
                     protease inhibitors from preparations of
                     immature HIV-1 virions does not result in an
                     increase of infectivity or the appearance of
                     mature morphology. Antimocrob Agents
                     Chemother. 1997 May; 41(5):1017-23.
REFERENCES           AIDS/97926492. Yusa K, Kavlick MF, Mitsuya H.
                     HIV-1 acquires resistance to multiple classes
                     of antiviral drugs through recombination. 4th
                     Conf Retro and Opportun Infect. 1997 Jan
                     22-26;:173 (abstract no. 585).
REFERENCES           MED/97123278. Kiriyama A, Nishiura T, Ishino
                     M, Yamamoto Y, Ogita I, Kiso Y, Takada K.
                     Binding characteristics of KNI-272 to plasma
                     proteins, a new potent tripeptide HIV
                     protease inhibitor. Biopharm Drug Dispos.
                     1996 Dec;17(9):739-51.
REFERENCES           AIDS/97229611. Kynostatin 272. Pediatr AIDS
                     HIV Infect. 1996 Apr;7(2):132-4.
REFERENCES           MED/97063852. Kiriyama A, Sugahara M,
                     Yoshikawa Y, Kiso Y, Takada K. The
                     bioavailability of oral dosage forms of a new
                     HIV-1 protease inhibitor, KNI-272, in beagle
                     dogs. Biopharm Drugs Dispos. 1996
                     Mar;17(2):125-34.
REFERENCES           MED/96232640. Kiso Y. Design and synthesis of
                     substrate-based peptidomimetic human
                     immunodeficiency virus protease inhibitors
                     containing the hydroxymethylcarbonyl
                     isostere. Biopolymers. 1996;40(2):235-44.
REFERENCES           MED/96105495. Chokekijchai S, Shirasaka T,
                     Weinstein JN, Mitsuya H. In vitro anti-HIV-1
                     activity of HIV protease inhibitor KNI-272 in
                     resting and activated cells: implications for
                     its combined use with AZT or ddI. Antiviral
                     Res. 1995 Sep;28(1):25-38.
REFERENCES           MED/95352609. Gulnik SV, Suvorov LI, Liu B,
                     Yu B, Anderson B, Mitsuya H, Erickson JW.
                     Kinetic characterization and cross-resistance
                     patterns of HIV-1 protease mutants selected
                     under drug pressure. Biochemistry. 1995 Jul
                     25;34(29):9282-7.
REFERENCES           AIDS/95920125. Humphrey RW, Mitsuya H,
                     Yarchoan R. HIV protease inhibitors do not
                     prevent cell death during single-cycle HIV
                     infection of CEM-ss cells in vitro. Natl Conf
                     Hum Retroviruses Relat Infect (2nd). 1995 Jan
                     29-Feb 2;:71.
REFERENCES           AIDS/95920128. Anderson B, Kageyama S, Ueno
                     T, Shirasaka T, Liu B, Gulnick S, Erickson J,
                     Mitsuya H. In vitro induction HIV-1 with
                     reduced sensitivity to HIV protease
                     inhibitors, KNI-227 and KNI-272. Natl Conf
                     Hum Retroviruses Relat Infect (2nd). 1995 Jan
                     29-Feb 2;:72.
ENTRY MONTH          199502
LAST REVISION DATE   19980408
89
UNIQUE IDENTIFIER          DRG-0218
NAME OF SUBSTANCE          Acitretin [USAN 1997]
REGISTRY NUMBER            55079-83-9
STANDARD CHEMICAL NAME     2,4,6,8-Nonatetraenoic acid,
                           9-(4-methoxy-2,3,6-trimethyphenyl)-3,7-dimeth-
                           yl-, (all-E). [USAN 1997]
SYNONYMS                   Soriatane [USAN 1997]
SYNONYMS                   Neotigason [Merck Index 1996]
SYNONYMS                   Etretin [Merck Index 1996]
PROTOCOL ID NUMBERS        FDA 239A
SECONDARY SOURCE ID        Ro 10-1670/000 [USAN 1997]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Certain retinoids have been
                           shown in rats and mice to induce hepatic
                           cytochrome P-50 enzyme. Acitretin, the active
                           primary metabolite of etretinate (another
                           retinoid used in treatment of psoriasis) may
                           induce its own metabolism. Acitretin is
                           eliminated far more rapidly from the human
                           body than is etretinate. Re-esterification
                           (in the body) of acitretin to etretinate
                           results in a loss of the metabolic advantage
                           of the former. Retinoids (including
                           acitretin) contribute potentially to cancer
                           chemotherapy and chemoprevention. They induce
                           cell differentiation, inhibit cell
                           proliferation, suppress expression of viral
                           oncogenesis, and inhibit angiogenesis
                           necessary for tumor growth. [J Am Acad
                           Dermatol 1992 Dec;27(6 Pt 2); J Pharm Sci
                           1994 May;83(5); J Cell Biochem 1994
                           Dec;56(4)]
DISEASES STUDIED/TREATED   Treatment of psoriasis in HIV-positive
                           patients. [FDA 239A]
CLASSIFICATION CODE        Antipsoriatic [USAN 1997]
OTHER MAJOR USES           Various dermatoses. [Dermatologica
                           1988;176(4)]
ADVERSE EFFECTS            Adverse reactions are dose-related and
                           typical of hypervitaminosis A. They include
                           alopecia, cheilitis and drying of the mucous
                           membranes, hypertriglyceridemia, and
                           elevation of cholesterol levels. Acitretin
                           has teratogenic potential. It appears to be
                           connected to higher occurrence of
                           vulvo-vaginal candidiasis. Extensive
                           extraspinal hyperostosis after long-term oral
                           retinoid (acitretin) therapy was noted in one
                           patient. [Drugs 1992 Apr;43(4); J Clin
                           Epidemiol 1995 Aug;48(8); J Am Acad Dermatol
                           1995 Feb;32(2 Pt 2)]
CONTRAINDICATIONS          Contraindicated in women of childbearing
                           potential because of teratogenicity. [FDA
                           239A]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Synthetic retinoid; free
                           acid form and major metabolite of etretinate.
                           [Merck Index 1996]
CHEMICAL/PHYSICAL   DATA   MOLECULAR FORMULA: C21H26O3 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR WEIGHT: 326.44 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MELTING POINT: 228-230 C [Merck Index 1996]
CHEMICAL/PHYSICAL   DATA   ELEMENTAL COMP: C77.27%, H8.03%, O14.70%.
                           [Merck Index 1996]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Capsules 10 and 25 mg. [USP DI
                          1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral. [FDA 239A]
MANUFACTURERS             Hoffmann - La Roche Incorporated; 340
                          Kingsland Street; Nutley, NJ 07110-1199
REFERENCES                MED/97341497. Buccheri L, Katchen BR, Karter
                          AJ, Cohen SR. Acitretin therapy is effective
                          for psoriasis associated with human
                          immunodeficiency virus infection. Arch
                          Dermatol. 1997 Jun;133(6):711-5.
REFERENCES                97247353. Herrmann G, Jungblut RM, Goerz G.
                          Skeletal changes after long-term therapy with
                          synthetic retinoids [letter]. Br J Dermatol.
                          1997 Mar;136(3):275-8.
REFERENCES                97221704. van de Kerkhof PC, de Rooij MJ.
                          Multiple squamous cell carcinomas in a
                          psoriatic patient following high-dose
                          photochemotherapy and cyclosporin treatment:
                          response to long-term acitretin maintenance.
                          Br J Dermatol 1997 Feb;136(2):275-8.
REFERENCES                97129195. Koo J, Nguyen Q, Gambla C. Advances
                          in psoriasis therapy. Adv Dermatol
                          1997;12:47-72;discussion 73.
REFERENCES                9713845. Kuijpers AL, van Dooren-Greebe JV,
                          van de Kerkhof PC. Failure of combination
                          therapy with acitretin and cyclosporin A in 3
                          patients with erythrodermic psoriasis
                          [letter] REVIEW ARTICLE:11 REFS. Dermatology.
                          1997;194(1):88-90.
REFERENCES                97137029. Zachariae H, Heickendorff L,
                          Bjerring P. Plasma endothelin in psoriasis:
                          possible relations to therapy and toxicity.
                          Acta Derm Venereol. 1996 Nov;76(6):442-3.
REFERENCES                97028471. Maier H, Honigsmann H.
                          Concentration of etretinate in plasma and
                          subcutaneous fat after long-term acitretin
                          [letter] Lancet. 1996 Oct 19;348(9034):1107.
REFERENCES                96287795. Mork NJ, Kolbenstvedt A, Austad J.
                          Skeletal side effects of 5 years' acitretin
                          treatment [letter] Br J Dermatol. 1996
                          Jun;134(6):1156-7.
REFERENCES                96297444. Lister RK, Lecky BR, Lewis-Jones
                          MS, Young CA. Acitretin-induced myopathy
                          [letter] Br J Dermatol. 1996 May;
                          134(5):989-90.
REFERENCES                MED/97010279. Armstrong DK, Irvine A, Walsh
                          MY, Mayne EE, Burrows D. Multipble
                          dermatofibromas in a patient with HIV
                          infection. Clin Exp Dermatol. 1995
                          Nov;20(6):474-6.
ENTRY MONTH               199411
LAST REVISION DATE        19971208

90
UNIQUE IDENTIFIER         DRG-0217
NAME OF SUBSTANCE         Tecogalan sodium [USAN 1997]
REGISTRY NUMBER           134633-29-7
STANDARD CHEMICAL NAME    D-gluco-D-galactan sulfate [FDA 088A]
SYNONYMS                  DS-4152 [USAN 1997]
SYNONYMS                  SP-PG [AmFAR Tx Dir 1997;8(3)]
PROTOCOL ID NUMBERS       FDA 088A
PROTOCOL ID NUMBERS        FDA 088B
PROTOCOL ID NUMBERS        FDA 088C
PROTOCOL ID NUMBERS        FDA 088D
PHARMACOLOGICAL ACTION     MODE OF ACTION: Inhibitory effect of
                           tecogalan sodium on endothelial cell
                           migration and proliferation is thought to be
                           mediated by the inhibition of the binding of
                           fibroblast growth factor to endothelial
                           cells. Tecogalan sodium has shown potent and
                           selective inhibition of HIV-1 replication in
                           vitro. SP-PG (tecogalan sodium) controlled
                           the in vitro growth of AIDS-associated
                           Kaposi's sarcoma (KS)-derived spindle-shaped
                           cells at noncytotoxic concentrations. SP-PG
                           also inhibited the vascular hyperpermeability
                           response and the angiogenesis associated with
                           the induction of KS-like lesions. The
                           anti-tumor effect of tecogalan is thought to
                           be mediated by the inhibition of the binding
                           of fibroblast growth factors to cell
                           receptors. Pharmacokinetic studies (in phase
                           I trial) show that the peak plasma
                           concentration correlates with the peak
                           activated partial thromboplastin time and
                           that little of the drug is excreted in the
                           urine. [Proc Annu Meet Am Soc Clin Oncol 13
                           1994; Science 1992 Mar 13:255(5050); Proc
                           Annu Meet Am Assoc Cancer Res 1995;36]
DISEASES STUDIED/TREATED   Inhibitor of Kaposi's sarcoma. [AmFAR Tx Dir
                           1995;7(4)]
CLASSIFICATION CODE        Angiogenesis inhibitor [AmFAR Tx Dir
                           1995;7(4)]
CLASSIFICATION CODE        Antineoplastic (adjunct) [USAN 1997]
OTHER MAJOR USES           Treatment of solid tumors. [Proc Annu Meet Am
                           Soc Clin Oncol 13 1994]
ADVERSE EFFECTS            Adverse effects include prolongation of
                           activated partial thromboplastin time (with
                           peak times being 1.0-4.0 x the upper limit of
                           normal), fever, and chills. Toxicities in a
                           phase I study with 17 patients were transient
                           and include fevers in 16, chills in 12,
                           headaches in 10, rigors in 7, tachycardia in
                           5, and nausea in 5 patients. Neutropenia and
                           anemia were rare and there were no instances
                           of thrombocytopenia. [Proc Annu Meet Am Soc
                           Clin Oncol 13 1994; Blood; 84(10, Suppl 1),
                           1994]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Fermentation product of
                           Arthrobacter sp. AT-25, and composed of
                           sulfated polysaccharide and small amounts of
                           peptidoglycan and phosphorous. [USAN 1997]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: ca. 29,000 [USAN 1997]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intravenous. [FDA 088A]
MANUFACTURERS              Daiichi Pharmaceutical Corporation; 400 Kelby
                           Street / One Parker Plaza; Fort Lee, NJ 07024
REFERENCES                 96437090. Eckhardt SG, Burris HA, Eckardt JR,
                           Weiss G, Rodriguez G, Rothenberg M, Rinaldi
                           D, Barrington R, Kuhn JG, et al. A phase I
                           clinical and pharmacokinetic study of the
                           angiogenesis inhibitor, tecogalan sodium [see
                           comments in: Ann Oncol. 1996 Jul;
                         7(5):441-4]. Ann Oncol. 1996 Jul; 7(5):
                         491-6.
REFERENCES               96249989. Murata T, Ishibashi T, Yoshikawa H,
                         Khalil A, Inomata H. Tecogalan sodium
                         inhibits corneal neovascularization induced
                         by basic fibroblast growth factor. Ophthalmic
                         Res. 1995; 27(6): 330-4.
REFERENCES               ICDB/95608407. Eckardt SG, Eckardt JR, Weiss
                         G, Rinaldi D, Rodriguez G, Fields S, Kuhn J,
                         Smetzer L, Higashi L, Von Hoff DD, et al.
                         Results of a phase I trial of the novel
                         angiogenesis inhibitor, tecogalan sodium
                         (Meeting abstract). Proc Annu Meet Am Assoc
                         Cancer Res; 36:A628 1995.
REFERENCES               9524703. Sakamoto T, Ishibashi T, Kimura H,
                         Yoshikawa H, Spee C, Harris MS, Hinton DR,
                         Ryan SJ. Effect of tecogalan sodium on
                         angiogenesis in vitro by choroidal
                         endothelial cells. Invest Ophthalmol Vis Sci
                         1995 May;36(6):1076-83.
REFERENCES               94339000. Bicknell R. Vascular targeting and
                         the inhibition of angiogenesis. Ann Oncol.
                         1994;5 Suppl 4:45-50.
REFERENCES               94324941. Chleboun JO, Sellers P, Muir G,
                         Chew P, Martins RN. The effect of tecogalan
                         sodium on the development of the collateral
                         circulation after acute arterial occlusion.
                         Biochem Biophys Res Commun.1994 Jul
                         29;202(2):1149-55.
REFERENCES               ICDB/95606242. Krown SE. AIDS-related
                         Kaposi's sarcoma: clinical aspects (Meeting
                         abstract). Proc Annu Meet Am Assoc Cancer
                         Res;35:659-60 1994.
REFERENCES               ICDB/94600020. Eckhardt SG, Burris HA,
                         Eckardt JR, Weiss G, Rinaldi D, Barrington R,
                         Smith L, Fields S, Kuhn J, Smith S, et al.
                         Phase I assessment of the novel angiogenesis
                         inhibitor DS4152 (Tecogalan Sodium) (Meeting
                         abstract). Proc Annu Meet Am Soc Clin Oncol.
                         1994;13:A23.
REFERENCES               MED/94280703. Baba M, Shigeta S, Ikeuchi T,
                         Korenaga H, Osada Y. Anti-angiogenesis agent
                         DS-4152 is a potent and selective inhibitor
                         of HIV-1 replication in vitro. AIDS. 1994
                         Jan;8(1):43-8.
REFERENCES               ICDB/96615859. Tulpule A, Snyder JC, Espina
                         BM, Higashi L, Satomi M, Lombardy EE, Gill
                         PS. A phase I study of tecogalan, a novel
                         angiogenesis inhibitor in the treatment of
                         AIDS-related Kaposi's sarcoma and solid
                         tumors (Meeting abstract). Blood; 84(10,
                         Suppl 1): 248a 1994.
ENTRY MONTH              199409
LAST REVISION DATE       19980413

91
UNIQUE IDENTIFIER        DRG-0216
NAME OF SUBSTANCE        SC-52151 [NIAID ACTG 282]
REGISTRY NUMBER          143224-34-4
STANDARD CHEMICAL NAME   Butanediamide, N1-[[[(1,
                         1-dimethylethyl)amino]
                           carbonyl](2-methylpropyl)amino]-2-hydroxy-1-
                           (phenylmethyl)propyl-2-[(2-quinolinylcarbonyl-
                           )amino]-, [USAN 1997]
SYNONYMS                   Telinavir [USAN 1997]
PROTOCOL ID NUMBERS        NIAID ACTG 282
PHARMACOLOGICAL ACTION     MODE OF ACTION: HIV-infected cells produce
                           large polyproteins which are precursors to
                           the individual components of HIV. Protease,
                           which is also produced by HIV-infected cells,
                           cleaves the large precursor proteins, thereby
                           separating the final viral elements (e.g., p
                           24 and reverse transcriptase) in preparation
                           for viral assembly. If the precursor proteins
                           are not processed by the protease enzyme,
                           nonfunctioning non-infectious virons are
                           formed. The three dimensional structure of
                           the HIV protease has been fully determined;
                           researchers are therefore able to rationally
                           design compounds (i.e., protease inhibitors)
                           to inhibit it. Selectively inhibited HIV
                           protease in vitro and demonstrated antiviral
                           activity against HIV-1, HIV-2, SIV, and
                           zidovudine-resistant strains of HIV-1 in
                           vitro. After treatment of HIV-infected CEM
                           cells with SC-52151, the virus core of
                           infectious extracellular virus particles was
                           absent. A four-arm, phase I/II clinical study
                           using the highest previously tested daily
                           dose of SC-52151, 2250 mg, was conducted in
                           49 patients. One patient developed
                           hypertriglyceridemia, and one had fever and
                           dyspnea. Although SC-52151 was well tolerated
                           and one formulation used resulted in plasma
                           concentrations above the IC90 for viral
                           replication, no antiviral activity was
                           produced. The manufacturer has announced that
                           development of their two protease inhibitors,
                           SC-52151 & SC-55389A, has ceased. [NIAID ACTG
                           282; AmFAR Tx Dir 1995;7(4); J Acquir Immune
                           Defic Syndr Hum Retrovirol. 1997 May 1;15(1)]
DISEASES STUDIED/TREATED   Primary HIV infection. [NIAID ACTG 282]
CLASSIFICATION CODE        Protease inhibitor [NIAID ACTG 282]
CLASSIFICATION CODE        Antiretroviral [NIAID ACTG 282]
CONTRAINDICATIONS          Contraindicated in pregnant or nursing women,
                           since safety has not been determined. [NIAID
                           ACTG 282]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Urea-based peptidomimetic.
                           [NIAID ACTG 282]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C33H44N6O5 [USAN 1997]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 604.75 [USAN 1997]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 175 ml amber glass bottles of
                           elixir or SEDDS (self-emulsifying drug
                           delivery system) formulation. [NIAID ACTG
                           282]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [NIAID ACTG 282]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Store at room
                           temperature. [NIAID ACTG 282]
MANUFACTURERS              G D Searle & Company; 4901 Searle Parkway;
                           Skokie, IL 60077
REFERENCES                 MED/97323587. Yuan JH, Stolzenbach JC,
                           Salamon CM, Snook SS, Schoenhard GL.
                     Improvement of bioavailability of the HIV
                     protease inhibitor SC-52151 in the beagle dog
                     by coadministration of the CYP3A4 inhibitor,
                     ketoconazole. Xenobiotica. 1997 May; 27(5):
                     489-97.
REFERENCES           MED/97358555. Fischl MA, Richman DD, Flexner
                     C, Para MF, Haubrich R, Karim A, Yeramian P,
                     Holden-Wiltse J, Meehan PM. Phase I/II study
                     of the toxicity, pharmacokinetics, and
                     activity of the HIV protease inhibitor
                     SC-52151. J Acquir Immune Defic Syndr Hum
                     Retrovirol. 1997 May 1; 15(1): 28-34.
REFERENCES           MED/97275173. Lazdins JK, Mestan J, Goutte G,
                     Walker MR, Bold G, Capraro HG, Klimkait T. In
                     vitro effect of alpha1-acid glycoprotein on
                     the anti-human immunodeficiency virus (HIV)
                     activity of the protease relevant HIV
                     protease inhibitors. J Infect Dis. 1997 May;
                     175(5): 1063-70.
REFERENCES           MED/96202332. Rose RE, Gong YF, Greytok JA,
                     Bechtold CM, Terry BJ, Robinson BS, Alam M,
                     Colonno RJ, Lin PF. Human immunodeficiency
                     virus type 1 viral background plays a major
                     role in development of resistance to protease
                     inhibitors. Proc Natl Acad Sci U S A. 1996
                     Feb 20: 93(4): 1648-53.
REFERENCES           MED/96109417. Bryant M, Getman D, Smidt M,
                     Marr J, Clare M, Dillard R, Lansky D,
                     DeCrescenzo G, Heintz R, Houseman K, et al.
                     SC-52151, a novel inhibitor of the human
                     immunodeficiency virus protease. Antimicrob
                     Agents Chemother. 1995 Oct; 39(10): 2229-34.
REFERENCES           MED/96234098. Moutouh L, Corbeil J, Richmann
                     DD. Recombination leads to the rapid
                     emergence of HIV-1 dually resistant mutants
                     under selective drug pressure. Proc Natl Acad
                     Sci U S A. 1996 Jun 11;93(12):6106-11.
REFERENCES           AIDS/96920156. Potts KE, Smid ML, Tucker SP,
                     Stiebel TR, McDonald JJ, Stegman RA,
                     Stallings WC, Wiegand RC. Characterization of
                     human immunodeficiency virus type 1 (HIV-1)
                     isolates with reduced sensitivity to
                     hydroxyethylurea isostere containing protease
                     inhibitors in vitro. 3rd Conf Retro and
                     Opportun Infect. 1996 Jan 28-Feb 1;:81.
REFERENCES           AIDS/95920218. Fischl MA, Richman DD, Flexner
                     C, Meehan P, Para MF, Haubrich R, Cook J,
                     Wood K, Karim A. Phase I study of two
                     formulations and dose schedules of SC-521151,
                     a protease inhibitor. Natl Conf Hum
                     Retroviruses Relat Infect (2nd). 1995 Jan
                     29-Feb 2;:88.
REFERENCES           MED/93140133. Getman DP, DeCrescenzo GA,
                     Heintz RM, Reed KL, Talley JJ, Bryant ML,
                     Clare M, Houseman KA, Marr JJ, Mueller RA, et
                     al. Discovery of a novel class of potent
                     HIV-1 protease inhibitors containing the
                     (R)-(hydroxyethyl)urea isostere. J Med Chem.
                     1993 Jan 22;36(2):288-91.
ENTRY MONTH          199408
LAST REVISION DATE   19980512
92
UNIQUE IDENTIFIER          DRG-0215
NAME OF SUBSTANCE          935U83 [FDA 237A]
REGISTRY NUMBER            119644-22-3
STANDARD CHEMICAL NAME     Uridine, 5-chloro-2', 3'-dideoxy-3'-fluoro-
                           [Antimicrob Agents Chemother 1994 July;38(7)]
SYNONYMS                   5-Chloro-2',3'-dideoxy-3'-fluorouridine
                           [Antimicrob Agents Chemother 1994 July;38(7)]
SYNONYMS                   Raluridine [USAN 1997]
SYNONYMS                   Fddclurd [CHEMID]
PROTOCOL ID NUMBERS        FDA 237A
PHARMACOLOGICAL ACTION     MODE OF ACTION: 935U83 (also called BW935U83)
                           is a nucleoside reverse transcriptase
                           inhibitor. When tested in
                           phytohemagglutinin-stimulated normal human
                           peripheral blood lymphocytes against fresh
                           clinical isolates of HIV-1 obtained from
                           patients naive to AZT, 935U83 inhibited virus
                           growth with an average 50% inhibitory
                           concentration. Importantly, 935U83 retained
                           activity against HIV strains that were
                           resistant to AZT, ddI, or ddc. Testers were
                           unable to generate virus which was resistant
                           to 935U83 by passaging either HXB2
                           (AZT-sensitive) or RTMC (AZT-resistant)
                           strains in the presence of high
                           concentrations of 935U83. The anabolic
                           profile of 935U83 was similar to that of AZT,
                           and 935U83 triphosphate was a potent
                           inhibitor of HIV-1 reverse transcriptase.
                           Pharmacokinetic evaluation showed good oral
                           bioavailability (86% in mice and 60% in
                           monkeys) and less extensive metabolism to the
                           glucuronide relative to AZT. 935U83 showed
                           low toxicity. In monkeys dosed orally with up
                           to 700 mg/kg/day for 1 and 6 months, the only
                           possible treatment-related finding was
                           cataracts in 1 of 12 animals given the
                           intermediate dose of 225 mg/kg/day. At the
                           highest doses in mice and monkeys, maximal
                           concentrations in plasma were more than
                           100-fold the anti-HIV IC50s against clinical
                           isolates. This safety profile in animals
                           compares very favorably with that of any of
                           the anti-HIV drugs approved to date (i.e.,
                           1994). A phase I trial of a single dose of
                           935U83 revealed excellent tolerance, oral
                           bioavailability, and a half-life of 1.2
                           hours. [Antimicrob Agents Chemother 1994
                           July;38(7); Prog Abst Intersci Conf
                           Antimicrob Agents Chemother 1994 Oct]
DISEASES STUDIED/TREATED   Primary HIV infection. Drug development
                           discontinued per company. [FDA 237A; Glaxo
                           Wellcome 4/96]
CLASSIFICATION CODE        Antiretroviral [FDA 237A]
CONTRAINDICATIONS          Contraindicated in pregnant women. [FDA 237A]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: A 3'-fluoropyrimidine
                           nucleoside. [Antimicrob Agents Chemother 1994
                           July;38(7)]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C9H1OClFN2O4 [USAN 1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 264.64 [USAN 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral. [FDA 237A]
MANUFACTURERS             Glaxo Wellcome; 5 Moore Drive / PO Box 13398;
                          Research Triangle Park, NC 27709
REFERENCES                AIDS/95920300. Bartlett JA, McMahon D. A
                          phase I trial of BW935U83 in HIV infected
                          persons. Natl Conf Hum Retroviruses Relat
                          Infect (2nd). 1995 Jan 29-Feb 2;:104.
REFERENCES                AIDS/95920790. Joyner SS, Novak P, Dornsife
                          RE, Dev IK. Molecular basis for the increased
                          hematopoietic toxicity of FLT compared to AZT
                          and 935U83. Program Abstr Intersci Conf
                          Antimicrob Agents Chemother. 1994 Oct
                          4-7;:93.
REFERENCES                AIDS/95920848. Bartlett JA, Fife KH. A phase
                          I trial of BW935U83 in HIV infected persons.
                          Program Abstr Intersci Conf Antimicrob Agents
                          Chemother. 1994 Oct 4-7;:133.
REFERENCES                MED/95070022. Daluge SM, Purifoy DJ, Savina
                          PM, St Clair MH, Parry NR, Dev IK, Novak P,
                          Ayers KM, Reardon JE, Roberts GB, et al.
                          5-Chloro-2',3'-dideoxy-3'-fluorouridine
                          (935U83), a selective anti-human
                          immunodeficiency virus agent with an improved
                          metabolic and toxicological profile.
                          Antimicrob Agents Chemother. 1994
                          Jul;38(7):1590-603.
REFERENCES                AIDS/9592600. Riddler SA, McMahon DK,
                          Bartlett JA, Savina PM, Wang LH, Dunn JA,
                          Mellors JW. A phase I single-dose trial to
                          evaluate the safety and pharmacokinetics (PK)
                          of 5-chloro-2'3'-dideoxy-3'fluorouridine
                          (935U83). Natl Conf Hum Retroviruses Relat
                          Infect (1st). 1993 Dec 12-16;:160.
ENTRY MONTH               199408
LAST REVISION DATE        19980413

93
UNIQUE IDENTIFIER         DRG-0214
NAME OF SUBSTANCE         Sulfadiazine [USAN 1997]
REGISTRY NUMBER           68-35-9
STANDARD CHEMICAL NAME    Benzenesulfonamide, 4-amino-N-2-pyrimidinyl-
                          [USAN 1997]
SYNONYMS                  Adiazine [Merck Index 1996]
SYNONYMS                  Debenal [Merck Index 1989]
SYNONYMS                  Delvoprim [Merck Index 1989]
SYNONYMS                  Diazyl [Merck Index 1996]
SYNONYMS                  Eskadiazine [USAN 1996]
SYNONYMS                  Pyrimal [Merck Index 1989]
SYNONYMS                  Sterazine [Merck Index 1989]
SYNONYMS                  Sulfolex [Merck Index 1996]
SYNONYMS                  Ultradiazin [Merck Index 1989]
SYNONYMS                  Sulphadiazine [USAN 1997]
SYNONYMS                  Coco-Diazine [USAN 1997]
SYNONYMS                  Cremodiazine [CHEMLINE]
SYNONYMS                  Deltazine [CHEMLINE]
SYNONYMS                  Diazolone [CHEMLINE]
SYNONYMS                  Diazovit [CHEMLINE]
SYNONYMS                  Honey Diazine [CHEMLINE]
SYNONYMS                  Lipo-Diazine [CHEMLINE]
SYNONYMS                  Lipo-Levazine [CHEMLINE]
SYNONYMS                   Liquadiazine [CHEMLINE]
SYNONYMS                   Microsulfon [CHEMLINE]
SYNONYMS                   Neazine [CHEMLINE]
SYNONYMS                   N1-2-Pyrimidinylsulfanilamide [CHEMLINE]
SYNONYMS                   Piridisir [CHEMLINE]
SYNONYMS                   Sanodiazine [CHEMLINE]
SYNONYMS                   SDA [CHEMLINE]
SYNONYMS                   Solfadiazina [CHEMLINE]
SYNONYMS                   Sulfacombin [CHEMLINE]
SYNONYMS                   Spofadrizine [CHEMLINE]
SYNONYMS                   Sulfadiazina [CHEMLINE]
SYNONYMS                   Sulfapyrimidine [Merck Index 1996]
SYNONYMS                   Theradiazine [CHEMLINE]
PROTOCOL ID NUMBERS        NIAID 98 I-0153
PROTOCOL ID NUMBERS        NIAID ACTG 237
SECONDARY SOURCE ID        AI3-01047 [CHEMLINE]
SECONDARY SOURCE ID        RP 2616 [CHEMLINE]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Sulfonamides are
                           broad-spectrum, bacteriostatic,
                           anti-infectives. They are structural analogs
                           of para-aminobenzoic acid (PABA) and
                           competitively inhibit a bacterial enzyme,
                           dihydropteroate synthetase, that is
                           responsible for incorporation of PABA into
                           dihydrofolic acid, the immediate precursor of
                           folic acid. This blocks the synthesis of
                           dihydrofolic acid and decreases the amount of
                           metabolically active tetrahydrofolic acid, a
                           cofactor for the synthesis of purines,
                           thymidine, and DNA. Susceptible bacteria are
                           those that must synthesize folic acid.
                           Sulfadiazine is readily absorbed from the GI
                           tract. After a single 2-gram dose, peak
                           plasma concentrations of 60 microgram/mL were
                           reached within 4 hours. Sulfadiazine is
                           distributed into most body tissues; the drug
                           appears to cross cell membranes freely. The
                           drug is excreted largely in the urine.
                           Urinary sulfadiazine concentrations usually
                           are 10-25 times those attained in serum.
                           About 15-40% of the sulfadiazine in the urine
                           is in the N-4 acetylated form; about 43-60%
                           is excreted unchanged. [USP DI 1997; AHFS
                           Drug Information 1997]
DISEASES STUDIED/TREATED   Toxoplasmic encephalitis. [NIAID ACTG 237;
                           AHFS Drug Information 1997]
CLASSIFICATION CODE        Antibacterial (tuberculostatic) [USAN 1997]
OTHER MAJOR USES           Gram positive and gram negative infections,
                           excluding urinary tract infections, unless
                           other sulfonamides have failed.
                           Toxoplasmosis, as an adjunct to pyrimethamine
                           therapy, malaria, trachoma, nocardiosis and
                           chancroid. [PDR 1995; USP DI 1997]
SUBSTANCE INTERACTIONS     The effects of oral anticoagulants (coumarin
                           or indanedione derivatives) and methotrexate
                           may be increased by sulfadiazine.
                           Sulfonylurea hypoglycemic agents, thiazide
                           diuretics and uricosuric agents may be
                           potentiated. Agents such as indomethacin,
                           probenecid, and salicylates may displace the
                           sulfa from plasma albumin and increase the
                           concentrations of free drug in the plasma.
                           Interactions have also been reported with
                           hemolytics, hepatotoxic medications and
                           methenamine. [PDR 1995; USP DI 1997; AHFS
                           Drug Information 1997]
ADVERSE EFFECTS            Adverse effects include crystalluria
                           (crystals in the urine), hematuria, kidney
                           stones, kidney failure, hypersensitivity
                           reactions, and anemia. [NIAID ACTG 237; PDR
                           1995; AHFS Drug Information 1997]
CONTRAINDICATIONS          Contraindicated in patients with
                           hypersensitivity to sulfonamides, in infants
                           less than 2 months of age and in pregnant
                           women at term and during nursing. [PDR 1995;
                           AHFS Drug Information 1997]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Dihydrofolate synthetase
                           inhibitor; a synthetic derivative of
                           p-amino-benzenesulfonamide. [NIAID ACTG 237;
                           AHFS Drug Information 1995]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: A white or slightly
                           yellow, odorless or nearly odorless powder.
                           [AHFS Drug Information 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR FORMULA: C10H10N4O2S [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR WEIGHT: 250.28 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MELTING POINT: 252-256 C [Merck Index 1989]
CHEMICAL/PHYSICAL   DATA   ELEMENTAL COMP: C47.99%, H4.03%, N22.39%,
                           O12.79%, S512.81%. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     SOLUBILITY: Sparingly soluble in water at 37
                           C and in alcohol or acetone. Soluble at 1
                           g/620 ml human serum at 37 C. Freely soluble
                           in dilute mineral acids and in solutions of
                           potassium and sodium hydroxides and in
                           ammonia water. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     STABILITY: Stable in air but darkens on
                           exposure to light. [AHFS Drug Information
                           1997]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 500 mg tablets. [NIAID ACTG 237;
                           PDR 1995]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [NIAID ACTG 237; PDR
                           1995]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Store at 15-30 C.
                           Protect from light. [NIAID ACTG 237; PDR
                           1995]
MANUFACTURERS              EON Labs Manufacturing; 227-15 North Conduit;
                           Laurelton, NY 11413
REFERENCES                 MED/96320354. Becker K, Jablonowski H,
                           Haussinger D. Sulfadiazine-associated
                           nephrotoxicity in patients with the acquired
                           immunodeficiency syndrome. Medicine
                           (Baltimore). 1996 Jul;75(4):185-94.
REFERENCES                 MED/96303152. Wei ME, Campbell SH, Taylor C.
                           Precipitous visual loss secondary to optic
                           nerve toxoplasmosis as an unusual
                           presentation of AIDS. Aust N Z J Ophthalmol.
                           1996 Feb;24(1):75-7.
REFERENCES                 MED/96369158. Diaz F, Collazos J, Mayo J,
                           Martinez E. Sulfadiazine-induced multiple
                           urolithiasis and acute renal failure in a
                           patient with AIDS and Toxoplasma
                           encephalitis. Ann Pharmacother. 1996
                           Jan;30(1):41-2.
REFERENCES               AIDS/96343499. Kamaurulzaman A, Hoy J. Effect
                         of folinic acid on haematological toxicity
                         during treatment of cerebral toxoplasmosis in
                         patients with AIDS. Annu Conf Australs Soc
                         HIV Med. 1995 Nov 16-19;768 (abstract no.
                         68).
REFERENCES               AIDS/96343496. Marriott DJ, Miliken S,
                         Harkness JL, Brew B, Maitland D, Canning E,
                         Kench J, Field A. Myositis in an HIV-infected
                         patient caused by new microsporidian species.
                         Annu Conf Australas Soc HIV Med 1995 Nov
                         16-19;7:67 (abstract no. 65).
REFERENCES               MED/97278534 de Diego JA, Penin P, Arribas
                         JR, Vazquez E, Vazquez JJ. A
                         clinical-parasitological monotherapy cure in
                         the treatment of experimental infection by a
                         highly virulent strain of Toxoplasma gondii.
                         Folia Microbiol (Praha). 1996; 41(6): 513-6.
REFERENCES               MED/97196897. Mir N, O'Farrell N, Creagh TA,
                         Knowles C. Obstructive renal failure
                         requiring surgical intervention in an AIDS
                         patient being treated with sulphadiazine. Int
                         J STD AIDS. 1997 Jan; 8(1): 61-2.
REFERENCES               MED/97138617. Ebrahimzadeh A, Bottone EJ.
                         Persistent diarrhea caused by Isospora belli:
                         therapeutic response to pyrimethamine and
                         sulfadiazine. Diagn Microbiol Infect Dis.
                         1996 Oct; 26(2): 87-9.
REFERENCES               MED/97030415. Laing RB, Flegg PJ, Brettle RP,
                         Leen CL, Burns SM. Clinical features, outcome
                         and survival from cerebral toxoplasmosis in
                         Edingburgh AIDS patients. Int J STD AIDS.
                         1996 Jul; 7(4): 258-64.
REFERENCES               de Sequera P, Albalate M, Hernandez J,
                         Vazquez A, Abad J, Ramiro E, Fernandez
                         Guerrero M, Caramelo C, Casado S, Ortiz A,
                         Acute renal failure due to sulphadiazine
                         crystalluria in AIDS patients. Postgrad Med
                         J. 1996 Sep; 72(851): 557-58.
ENTRY MONTH              199408
LAST REVISION DATE       19980507

94
UNIQUE IDENTIFIER        DRG-0213
NAME OF SUBSTANCE        Isotretinoin [USAN 1997]
REGISTRY NUMBER          4759-48-2
STANDARD CHEMICAL NAME   Retinoic acid, 13-cis- [USAN 1997]
SYNONYMS                 Accutane [USAN 1997]
SYNONYMS                 Isotrex [USAN 1997]
SYNONYMS                 13-cis-Retinoic acid [CHEMLINE]
SYNONYMS                 Teriosal [Merck Index 1989]
SYNONYMS                 13-RA [CHEMLINE]
SYNONYMS                 3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexen--
                         1-yl)2- cis-4-
                         trans-6-trans-8-trans-nonatetraenoic acid.
                         [USAN 1997]
SYNONYMS                 Roaccutane [Merck Index 1996]
SYNONYMS                 13-cis-Vitamin A acid [CHEMLINE]
SYNONYMS                 Tasmar [USAN 1997]
PROTOCOL ID NUMBERS      NIAID ACTG 293
PROTOCOL ID NUMBERS      NIAID ACTG 216
SECONDARY SOURCE ID        Ro 4-3780 [USAN 1997]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Inhibits sebaceous gland
                           function and keratinization. Isotretinoin is
                           99% bound in human plasma almost exclusively
                           to albumin. Terminal elimination half-life
                           ranges from 10 to 20 hours from oral
                           administration of 80 mg (capsules). The major
                           identifiable metabolite in blood is
                           4-oxo-isotretinoin, which has a mean
                           elimination half-life of 25 hours (range
                           17-50 hours). Oral absorption of isotretinoin
                           increases when taken with food or milk. [PDR
                           1997]
DISEASES STUDIED/TREATED   Treatment of anal neoplasia secondary to
                           anogenital human papillomavirus infection.
                           [NIAID ACTG 216; AmFAR Tx Dir 1997;8(3)]
CLASSIFICATION CODE        Keratolytic [USAN 1997]
OTHER MAJOR USES           Treatment of acne vulgaris, cystic acne, and
                           several other skin diseases. [AHFS Drug
                           Information 1997; PDR 1997]
SUBSTANCE INTERACTIONS     Concurrent use of etretinate, tretinoin or
                           vitamin A may result in additive toxic
                           effects; concurrent tetracyclines may
                           increase the potential for the development of
                           pseudotumor cerebri. [USP DI 1997]
ADVERSE EFFECTS            Adverse effects include major fetal
                           abnormalities, cheilitis, conjunctivitis,
                           pseudotumor cerebri (benign intracranial
                           hypertension), skeletal hyperostosis,
                           musculoskeletal symptoms including
                           arthralgia, decreased night vision, corneal
                           opacities, inflammatory bowel disease,
                           changes in serum lipid levels,
                           hepatotoxicity, transient chest pain, rash,
                           and thinning of hair. Less frequent adverse
                           effects include peeling of palms and soles,
                           skin infections, nonspecific urogenital
                           findings and gastrointestinal symptoms,
                           fatigue, headache, depression, and increased
                           susceptibility to sunburn. CNS reactions
                           (seizures, emotional instability, dizziness,
                           nervousness, drowsiness, malaise, etc.) have
                           been reported but may not be related to
                           therapy. [PDR 1997]
CONTRAINDICATIONS          Strongly contraindicated in pregnant and
                           nursing women and in those who may become
                           pregnant while on therapy. Also
                           contraindicated in patients with sensitivity
                           to parabens, to vitamin A, and to other
                           retinoids. [PDR 1997; AHFS Drug Information
                           1997]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Isotretinoin, a synthetic
                           retinoid, is the 13-cis-isomer of naturally
                           occurring all-trans-retinoic acid
                           (tretinoin). [AHFS Drug Information 1997]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: Yellow-orange to orange
                           crystalline powder. [PDR 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR FORMULA: C20H28O2 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR WEIGHT: 300.44 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MELTING POINT: 174-175 C [Merck Index 1996]
CHEMICAL/PHYSICAL   DATA   SOLUBILITY: Insoluble in water, sparingly
                          soluble in alcohol. [AHFS Drug Information
                          1997]
CHEMICAL/PHYSICAL DATA    STABILITY: Photosensitive and degrades when
                          exposed to light; capsules are stable for two
                          years. [AHFS Drug Information 1997]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: 10, 20, and 40 mg soft gelatin
                          capsules. [PDR 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral. [PDR 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store at 15-30 C (59-86
                          F). Protect from light. [PDR 1997]
MANUFACTURERS             Hoffmann - La Roche Incorporated; 340
                          Kingsland Street; Nutley, NJ 07110-1199
REFERENCES                96087477. Sass JO, Masgrau E, Saurat JH, Nau
                          H. Metabolism of oral 9-cis-retinoic acid in
                          the human. Identification of
                          9-cis-retinoyl-beta-glucuronide and
                          9-cis-4-oxo-retinoyl-beta-glucuronide as
                          urinary metabolites. Drug Metab Dispos 1995
                          Sep;23(9):887-91.
REFERENCES                MED/95390704. Otley CC, Avram MR, Johnson RA.
                          Isotretinoin treatment of human
                          immunodeficiency virus-associated
                          eosinophilic folliculitis. Results of an
                          open, pilot trial. Arch Dermatol. 1995
                          Sep:131(9):1047-50.
REFERENCES                ICDB/95613987. Lewi D, Reboredo G, Jauregui
                          Rueda H, Monticelli A, Losso M, Vujacich C,
                          Litovska S, Marantz A, De la Torre A, Politi
                          P. Phase II trial of 13-cis-retinoic acid
                          (CRA) in AIDS-related Kaposi's sarcoma (KS)
                          (Meeting abstract). Proc Annu Meet Am Assoc
                          Cancer Res;14:A835 1995.
REFERENCES                94265797. Markowska J, Nowak M, Niecewicz R,
                          Breborowicz J, Wiese E, Zengteler G. Results
                          of topical treatment of HPV infection in the
                          uterine cervix using interferon beta,
                          13-cis-retinoic acid and TFX. Eur J Gynaecol
                          Oncol. 1994;15(1):65-9.
REFERENCES                MED/94305011. Birley HD, Luzzi GA, Walker MM,
                          Ryait B, Taylor-Robinson D, Renton AM. The
                          association of human papillomavirus infection
                          with balanoposthitis: a description of five
                          cases with proposals for treatment. Int J STD
                          AIDS. 1994 Mar-Apr;5(2):139-41.
REFERENCES                Digiovanna JJ. Therapy of skin cancer,
                          psoriasis, keratinization disorders, and
                          cystic acne. Crisp Data Base National
                          Institutes of Health.
REFERENCES                94355255. Lippman SM, Hong WK.
                          13-cis-retinoic acid plus interferon-alpha in
                          solid tumors: keeping the cart behind the
                          horse [editorial]. Ann Oncol. 1994
                          May;5(5):391-3.
REFERENCES                MED/97359623. Yen A, Sanchez RL, Raimer SS.
                          Papular mucinosis associated with AIDS:
                          response to isotretinoin. J Am Acad Dermatol.
                          1997 Jul; 37(1): 127-8.
REFERENCES                MED/96308893. Kellock DJ, Parslew R,
                          Mendelsohn SS, O'Mahony CP. Non-specific
                          urethritis--possible association with
                          isotretinoin therapy. Int J STD AIDS. 1996
                           Mar-Apr; 7(2): 135-6.
REFERENCES                 MED/96258893. Maeda Y, Miyatake J, Sono H,
                           Matsuda M, Tatsumi Y, Horiuchi F, Irimajiri
                           K, Horiuchi A. 13-cis retinoic acid inhibits
                           growth of adult T cell leukemia cells and
                           causes apoptosis; possible new indication for
                           retinoid therapy [see comments]. Intern Med.
                           1996 Mar; 35(3): 180-4.
REFERENCES                 MED/96315407. Bergbrant IM. Seborrheic
                           dermatitis and Pithyrosporum yeasts. Curr Top
                           Med Mycol. 1995; 6: 95-112.
ENTRY MONTH                199407
LAST REVISION DATE         19980506

95
UNIQUE IDENTIFIER          DRG-0212
NAME OF SUBSTANCE          Microparticulate Monovalent HIV-1 Peptide
                           Vaccine [NIAID VEU 018]
PROTOCOL ID NUMBERS        FDA 091
PROTOCOL ID NUMBERS        NIAID VEU 018
PROTOCOL ID NUMBERS        NIAID VEU 023
PHARMACOLOGICAL ACTION     MODE OF ACTION: Consists of eight PND-derived
                           peptides attached to a lysine core to form
                           radial-octamers. The PND peptides are the
                           immunogenic portion of the multiple antigen
                           peptide; the lysine core matrix is not
                           immunogenic. The antigen is entrapped in
                           biodegradable microparticles that may protect
                           it from acid and proteolytic digestion in the
                           gastrointestinal tract. Microparticles are
                           taken up into the Peyer's patches following
                           oral administration, phagocytosed by
                           macrophages, and degraded over time, thus
                           inducing both mucosal and systemic immunity.
                           [NIAID VEU 018]
DISEASES STUDIED/TREATED   Prevention of HIV infection. [NIAID VEU 018]
CLASSIFICATION CODE        Vaccine [NIAID VEU 018]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: HIV-1 MN branched peptide
                           entrapped in polymeric microparticles. [NIAID
                           VEU 018]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: Freeze-dried white
                           powder entrapped in microparticles prepared
                           from polymers. [NIAID VEU 018]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Biodegradable microparticles.
                           [NIAID VEU 018]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [NIAID VEU 018]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Store at 2-8 C
                           (35.6-46.4 F). [NIAID VEU 018]
MANUFACTURERS              United Biomedical Incorporated; 25 Davids
                           Drive; Hauppauge, NY 11788
REFERENCES                 MED/97304082. Cleland JL. Protein delivery
                           from biodegradable microspheres. Pharm
                           Biotechnol. 1997;10:1-43.
REFERENCES                 MED/97410431. Ben-Yedidia T, Arnon R. Design
                           of peptide and polypeptide vaccines. Curr
                           Opin Biotechnol. 1997Aug;8(4):442-8.
REFERENCES                 AIDS/97920735. Burnett PR, VanCott TC, van
                           Hamont JE, Loomis-Price LD, Cox JH, Mascola
                           JR, Birx DL. Immunogenicity of parenterally
                           administered microencapsulated HIV-1 gp160.
                           Conf Adv AIDS Vaccine Dev. 1996 Feb
                           11-15;:161[Poster 41].
REFERENCES                 MED/95120365. Wassef NM, Alving CR, Richards
                           RL. Liposomes as carriers for vaccines.
                           Immunomethods. 1994 Jun;4(3):217-22.
REFERENCES                 AIDS/95921127. Grek V, Zgoulli S, Zinner S,
                           Thonart P. Microencapsulation of antigens
                           using a spray-drying technique: potential
                           application to HIV vaccines. Natl Conf Hum
                           Retroviruses Relat Infect (1st). 1993 Dec
                           12-16;:72.
ENTRY MONTH                199407
LAST REVISION DATE         19971111

96
UNIQUE IDENTIFIER          DRG-0211
NAME OF SUBSTANCE          Levocarnitine [USAN 1997]
REGISTRY NUMBER            541-15-1
STANDARD CHEMICAL NAME     1-Propanaminium,
                           3-carboxy-2-hydroxy-N,N,N-trimethyl-,
                           hydroxide, inner salt, (R)- [USAN 1997]
SYNONYMS                   L-carnitine [CHEMLINE]
SYNONYMS                   Vitamin BT [Merck Index 1996]
SYNONYMS                   Cardiogen [Merck Index 1996]
SYNONYMS                   Carnitene [Merck Index 1996]
SYNONYMS                   Carnicor [Merck Index 1996]
SYNONYMS                   Carnitor [USAN 1997]
SYNONYMS                   Carrier [Merck Index 1996]
SYNONYMS                   Levocarnil [Merck Index 1989]
SYNONYMS                   Metina [Merck Index 1989]
SYNONYMS                   VitaCarn Liquid [Drug Evaluations Annual
                           1995]
SYNONYMS                   Carnitine (L-Form) [CHEMLINE]
SYNONYMS                   Miocor [Merck Index 1996]
SYNONYMS                   Miotonal [Merck Index 1996]
SYNONYMS                   Vitacarn [Merck Index 1996]
PROTOCOL ID NUMBERS        FDA 232G
PROTOCOL ID NUMBERS        FDA 246N
PROTOCOL ID NUMBERS        NIAID ACTG 398
PROTOCOL ID NUMBERS        NIAID CPCRA 039
PROTOCOL ID NUMBERS        NINDS 93 N-30
PROTOCOL ID NUMBERS        FDA 232D
PROTOCOL ID NUMBERS        FDA 232E
PROTOCOL ID NUMBERS        NIAID ACTG 359
PROTOCOL ID NUMBERS        NIAID ACTG 372
PHARMACOLOGICAL ACTION     MODE OF ACTION: Carrier molecule in the
                           transport of long chain fatty acids across
                           the inner mitochondria, delivering substrate
                           for oxidation and subsequent energy
                           production. Fatty acids are utilized as an
                           energy substrate in all tissues except the
                           brain. The mean distribution half-life for a
                           20 mg/kg IV dose was 0.585 h and the mean
                           apparent terminal elimination half-life of
                           total levocarnitine was 17.4 h. Mean body
                           clearance was about 4.0 L/h. [PDR 1997]
DISEASES STUDIED/TREATED   Zidovudine-induced myopathy resulting from
                           carnitine deficiency. [NINDS 93 N-30]
CLASSIFICATION CODE        Antihyperlipoproteinemic [Merck Index 1996]
OTHER MAJOR USES           Acute and chronic treatment of inborn errors
                           of metabolism that result in carnitine
                           deficiency. [PDR 1997]
SUBSTANCE INTERACTIONS     Levocarnitine can be competitively inhibited
                           by D,L-carnitine; requirements for
                           levocarnitine may be increased in patients
                           receiving valproic acid. [Drug Evaluations
                           Annual 1992; USP DI 1997]
ADVERSE EFFECTS            Adverse effects include mild gastrointestinal
                           complaints, including transient nausea and
                           vomiting, abdominal cramps, and diarrhea; and
                           drug-related body odor. [PDR 1997]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Naturally occurring
                           essential cofactor of fatty acid metabolism.
                           Used as a nutritional supplement for
                           treatment of primary or secondary carnitine
                           deficiencies. [Drug Evaluations Annual 1992]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: White powder. [PDR
                           1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR FORMULA: C7H15NO3 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR WEIGHT: 161.20 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MELTING POINT: 197 - 198 C [Merck Index 1996]
CHEMICAL/PHYSICAL   DATA   SOLUBILITY: Soluble in water, hot alcohol.
                           Practically insoluble in acetone, ether,
                           benzene. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     STABILITY: Very hygroscopic solid. [Merck
                           Index 1996]
CHEMICAL/PHYSICAL DATA     DRUG PHYSICAL COMMENT: pH 6-8 (solution); pKa
                           3.8. [PDR 1997]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 330 mg tablets; oral solution, 5
                           ml ampuls (1 g/5 ml) for intravenous
                           injection. [PDR 1997]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral; intravenous. [PDR
                           1997]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Tablets, injections and
                           oral solutions; store at 25 C (77 F). Protect
                           ampules from light. [PDR 1997]
MANUFACTURERS              Drugs are provided by each participating unit
                           site
REFERENCES                 MED/97222555. Di Marzio L, Alesse E,
                           Roncaioli P, Muzi P, Moretti S, Marcellini S,
                           Amicosante G, De simone C, Cifone MG.
                           Influence of L-carnitine on CD95
                           cross-lining-induced apoptosis and ceramide
                           generation in human cell lines: correlation
                           with its effects on purified acidic and
                           neutral sphingomyelinases in vitro. Pro Assoc
                           Am Physicians. 1997 Mar; 109(2): 154-63.
REFERENCES                 MED/97222554. Cifone MG, Alesse E, Di Marzio
                           L, Ruggeri B, Zazzeroni F, Moretti S,
                           Famularo G, Steinberg SM, Vullo E, De Simone
                           C. Effect of L-carnitine treatment in vivo on
                           apoptosis and ceramide generation in
                           peripheral blood lymphocytes from AIDS
                           patients. Proc Assoc Am Physicians. 1997 Mar;
                           109(2): -53.
REFERENCES                 MED/96347288. Virmani MA, Biselli R, Spadoni
                           A, Rossi S, Corsico N, Calvani M, Fattorossi
                           A, De Simone C, Arrigoni-Martelli E.
                           Protective actions of L-carnitine and
                           acetyl-L-carnitine on the neurotoxicity
                           evoked by mitochondrial uncoupling or
                           inhibitors. Pharmacol Res. 1995 Dec; 32(6):
                           383-9.
REFERENCES               MED/96155690. Mintz M. Carnitine in human
                         immunodeficiency virus type 1
                         infection/acquired immune deficiency
                         syndrome. J Child Neurol. 1995 Nov;10 Suppl
                         2:S40-4.
REFERENCES               MED/95298176. Famularo G, De Simone C. A new
                         era for carnitine? Immunol Today. 1995
                         May;16(5):211-3.
REFERENCES               96049855. Vitale G, Parente R, Melotti C.
                         Carnitine supplementation in human idiopathic
                         asthenospermia: clinical results. Drugs Exp
                         Clin Res 1995;21(4):157-9.
REFERENCES               MED/94315860. Semino-Mora MC, Leon-Monzon ME,
                         Dalakas MC. Effect of L-carnitine on the
                         zidovudine-induced destruction of human
                         myotubes. Part I: L-carnitine prevents the
                         myotoxicity of AZT in vitro. Lab Invest. 1994
                         Jul;71(1):102-12.
REFERENCES               MED/95057042. Semino-Mora MC, Leon-Monzon ME,
                         Dalakas MC. The effect of L-carnitine on the
                         AZT-induced destruction of human myotubes.
                         Part II: Treatment with L-carnitine improves
                         the AZT-induced changes and prevents further
                         destruction. Lab Invest. 1994
                         Nov;71(5):773-81.
REFERENCES               MED/94338602. De Simone C, Famularo G,
                         Tzantzoglou S, Trinchieri V, Moretti S,
                         Sorice F. Carnitine depletion in peripheral
                         blood mononuclear cells from patients with
                         AIDS: effect of oral L-carnitine. AIDS. 1994
                         May;8(5):655-60.
REFERENCES               MED/94206021. Dalakas MC, Leon-Monzon ME,
                         Bernardini I, Gahl WA, Jay CA.
                         Zidovudine-induced mitochondrial myopathy is
                         associated with muscle carnitine deficiency
                         and lipid storage. Ann Neurol. 1994
                         Apr;35(4):482-7.
REFERENCES               MED/93195254. De Simone C, Tzantzoglou S,
                         Famularo G, Moretti S, Paoletti F, Vullo V,
                         Delia S. High dose L-carnitine improves
                         immunologic and metabolic parameters in AIDS
                         patients. Immunopharmacol Immunotoxicol. 1993
                         Jan;15(1):1-12.
REFERENCES               MED/93113914. Grau JM, Casademont J, Pedrol
                         E, Fernandez-Sola J, Cardellach F, Barros N,
                         Urbano-Marquez A. Chronic fatigue syndrome:
                         studies on skeletal muscle. Clin Neuropathol.
                         1992 Nov-Dec;11(6):329-32.
REFERENCES               med/92215480. De Simone C, Tzantzoglou S,
                         Jirillo E, Marzo A, Vullo V, Martelli EA.
                         L-carnitine deficiency in AIDS patients.
                         AIDS. 1992 Feb;6(2):203-5.
ENTRY MONTH              199405
LAST REVISION DATE       19980506

97
UNIQUE IDENTIFIER        DRG-0210
NAME OF SUBSTANCE        Vesnarinone [USAN 1997]
REGISTRY NUMBER          81840-15-5
STANDARD CHEMICAL NAME   Piperazine,
                         1-(3,4-dimethoxybenzoyl)-4-(1,2,3,4-tetrahydr-
                           o -2-oxo-6-quinolinyl)- [USAN 1997]
SYNONYMS                   3,4-Dihydro-6-(4-(3,4-dimethoxybenzoyl)-1-pip-
                           erazinyl)- 2(1H)-quinolinone [CHEMLINE]
SYNONYMS                   Arkin-Z [Index Nominum 16th ed.]
SYNONYMS                   Piteranometozine [Merck Index 1996]
SYNONYMS                   Arkin [Merck Index 1996]
PROTOCOL ID NUMBERS        FDA 234A
PROTOCOL ID NUMBERS        FDA 234B
PROTOCOL ID NUMBERS        FDA 234C
PROTOCOL ID NUMBERS        FDA 234D
SECONDARY SOURCE ID        OPC-8212 [USAN 1997]
SECONDARY SOURCE ID        OPC 8212 [CHEMLINE]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Inhibits both nucleoside and
                           nucleobase transport in mammalian cells.
                           Inhibits replication of HIV-1 in a peripheral
                           blood lymphocytes model and in chronically
                           infected macrophages at clinically achieved
                           concentrations. Vesnarinone has no direct
                           inhibitory activity against the reverse
                           transcriptase of HIV-1, syncytium formation
                           in short term assays, or retroviral protease.
                           In addition, vesnarinone inhibits production
                           of TNF-alpha and IL-6 by human peripheral
                           blood mononucleated cells stimulated with
                           lipopolysaccharide (LPS). Preliminary results
                           from a phase I clinical trial in asymptomatic
                           HIV+ patients treat with 60 or 90 mg
                           vesnarione daily showed no significant effect
                           on plasma RNA viremia,CD4 or CD8 counts, TNF,
                           IL-6, or beta-2-microglobulin. [Biochem
                           Biophys Res Commun 1993 Sep 30;195(3); Life
                           Sci 1995 Jun 30;57(6); AmFAR Tx Dir
                           1997;8(3)]
DISEASES STUDIED/TREATED   Under investigation in the US as a treatment
                           for HIV and Kaposi's sarcoma. [FDA 234A;
                           AmFAR Tx Dir 1997;8(3)]
CLASSIFICATION CODE        Antiretroviral [Biochem Biophys Res Commun
                           1993 Sep 30;195(3)]
CLASSIFICATION CODE        Cardiotonic [USAN 1997]
OTHER MAJOR USES           Used in Japan as a treatment for mild to
                           moderate congestive heart failure. [Biochem
                           Biophys Res Commun 1993 Sep 30;195(3); AmFAR
                           Tx Dir 1997;8(3)]
SUBSTANCE INTERACTIONS     Possibly interacts with nucleoside analog
                           antiretroviral agents such as AZT, ddI, and
                           ddC. [FDA 234A]
ADVERSE EFFECTS            In patients with heart failure, neutropenia
                           and agranulocytosis have been reported.
                           [AmFAR Tx Dir 1997;8(3)]
CONTRAINDICATIONS          Contraindicated in pregnant women. [FDA 234A]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Synthesized quinolinone
                           derivative. An inotropic phosphodiesterase
                           inhibitor. [Circulation 1994 Mar;89(3); Eur J
                           Pharmacol 1993 Aug 10;240(1)]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C22H25N3O4 [USAN 1996]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 395.46 [USAN 1996]
CHEMICAL/PHYSICAL DATA     MELTING POINT: 238.1 -239.5 C [Merck Index
                           1996]
CHEMICAL/PHYSICAL DATA     ELEMENTAL COMP: C66.82%, H6.37%, N10.63%,
                           O16.18% [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     SOLUBILITY: Practically insoluble in water;
                          slightly soluble in glacial acetic acid,
                          chloroform, benzyl alcohol. [Merck Index
                          1996]
CHEMICAL/PHYSICAL DATA    DRUG PHYSICAL COMMENT: Odorless, tasteless,
                          pale yellow, crystalline powder. [Merck Index
                          1996]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Tablets. [FDA 234A]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral. [FDA 234A]
MANUFACTURERS             Otsuka America Pharmaceutical Incorporated;
                          1290 Page Mill Road / Suite 200; Palo Alto,
                          CA 94304
REFERENCES                ICA11/96923453. Kaneko H, Sekigawa I, Takeda
                          N, Neoh LP, Ogasawara H, Yamaguchi K,
                          Hishikawa T, Takasaki Y, Iida N, Hashimoto H,
                          et al. Vesnarinone inhibits
                          TNF-alpha-mediated T cell activation induced
                          by HIV-1 gp120-bound macrophage. Int Conf
                          AIDS. 1996 Jul 7-12;11(2):72 (abstract no.
                          We.A.3091).
REFERENCES                MED/96203800. Oyaizu N, McCloskey TW, Than S,
                          Pahwa S. Inhibition of CD4
                          cross-linking-induced lymphocytes apoptosis
                          by vesnarinone as a novel immunomodulating
                          agent: vesnarinone inhibits Fas expression
                          and apoptosis by blocking cytokine secretion.
                          Blood. 1996 Mar 15;87(6):2361-8.
REFERENCES                AIDS/96920138. Kiat R, Tirawatnapong S,
                          Ubolyam S, Suthapinthu P, Nookhai S, Aihara
                          K, Ohi H, Adachi M, Phanuphak. A Phase I
                          trial of vesnarinone in HIV-infected persons
                          with CD4+ cells counts greater than 200
                          cells/microliter. 3rd Conf Retro and Opportun
                          Infect. 1996 Jan 28-Feb 1;:78.
REFERENCES                95387276. Zhan X, Yin G, Liu S. Kinetic study
                          on the photostability of solid vesnarinone
                          and the equivalent relationship between
                          daylight and lamplight. J Pharm Sci 1995
                          May;84(5):624-6.
REFERENCES                MED/95349329. Kumakura T, Takase K, Terada N,
                          Gelfand EW. Vesnarinone inhibits nucleoside
                          and nucleobase transport. Life Sci.
                          1995;57(6):PL75-81.
REFERENCES                ICA10/94370922. Mitsuyasu R, Bort L, Miles
                          SA, Hardy WD, Petit RG. Preliminary results
                          of a phase I study of vesnarinone (OPC-8212)
                          in HIV-infected persons with CD4 > 300
                          cells/MM3. Int Conf AIDS. 1994 Aug
                          7-12;10(1):8 (abstract no. 005B).
REFERENCES                ICA10/94369695. Maruyama Y, Kobayachi N,
                          Maruyama I, Osame M. Vesnarinone; a
                          preliminary therapeutic approach to HIV-1
                          infection. Int Conf AIDS. 1994 Aug
                          7-12;10(1):203 (abstract no. PBO241).
REFERENCES                ICA10/94371029. Maruyama I, Nakajima T,
                          Kitajima I, Osame M, Zhao JQ, Chen IS, Aihara
                          K, Nakai S, Ikeda M, Adachi M. Vesnarionone,
                          a quinolinone derivative, inhibits the
                          replication of HIV-1 in cultured cells. Int
                          Conf AIDS. 1994 Aug7-12;10(2):107 (abstract
                          no. PA0307).
REFERENCES                ICA10/943689543. Petit RG, Miles S, Magpantay
                         L, Mitsuyasu R. Vesnarinone inhibits AIDS-KS
                         cells in culture. Inf Conf AIDS. 1994 Aug
                         7-12;10(1):169 (abstract no. PB0104).
REFERENCES               MED/94029956. Maruyama I, Maruyama Y,
                         Nakajima T, Kitajima I, Osame M, Zhao JQ,
                         Chen IS, Nakai S, Ikeda M, Yabu-uchi Y, et
                         al. Vesnarinone inhibits production of HIV-1
                         in cultured cells. Biochem Biophys Res
                         Commun. 1993 Sep 30;195(3):1264-71.
ENTRY MONTH              199405
LAST REVISION DATE       19980127

98
UNIQUE IDENTIFIER        DRG-0209
NAME OF SUBSTANCE        Adefovir dipivoxil (oral prodrug of PMEA)
                         [NIAID ACTG 310]
STANDARD CHEMICAL NAME   9-[2-(bispivaloyloxymethyl)phosphonylmethoxye-
                         thyl]-adenine [FDA 232A]
SYNONYMS                 Bis(pom)PMEA [Antimicrob Agents Chemother
                         1993 Oct;37(10)]
SYNONYMS                 Bis(pivaloyloxymethyl) PMEA [Antiviral Res
                         1992 Sep;19(3)]
SYNONYMS                 bis-POM PMEA [FDA 232A]
SYNONYMS                 GS 840 [AmFAR Tx Dir 1997;8(3)]
SYNONYMS                 Preveon [AmFar Tx Dir December, 1997]
SYNONYMS                 BisPom PMEA [AmFar Tx Dir December, 1997]
SYNONYMS                 bis(pivaloyloxymethyl)-9-(2-phosphonyl-methox-
                         yethyl) adenine [AmFar Tx Dir December, 1997]
PROTOCOL ID NUMBERS      FDA 232F
PROTOCOL ID NUMBERS      FDA 232G
PROTOCOL ID NUMBERS      FDA 232H
PROTOCOL ID NUMBERS      FDA 232J
PROTOCOL ID NUMBERS      FDA 246N
PROTOCOL ID NUMBERS      FDA 299A
PROTOCOL ID NUMBERS      NIAID ACTG 398
PROTOCOL ID NUMBERS      NIAID CPCRA 039
PROTOCOL ID NUMBERS      FDA 232A
PROTOCOL ID NUMBERS      FDA 232B
PROTOCOL ID NUMBERS      FDA 232C
PROTOCOL ID NUMBERS      FDA 232D
PROTOCOL ID NUMBERS      FDA 232E
PROTOCOL ID NUMBERS      NCI 95 C-83
PROTOCOL ID NUMBERS      NIAID ACTG 310
PROTOCOL ID NUMBERS      NIAID ACTG 359
PROTOCOL ID NUMBERS      NIAID ACTG 364
PROTOCOL ID NUMBERS      NIAID ACTG 372
SECONDARY SOURCE ID      GS-840 [FDA 232A]
PHARMACOLOGICAL ACTION   MODE OF ACTION: bis-POM PMEA exhibited in
                         vitro antiviral activity against HIV and HCMV
                         that was equipotent with the parent compound,
                         PMEA. Metabolic studies of both compounds
                         suggested a > 100-fold increase in the
                         cellular uptake of the bis-POM derivative and
                         formation of active diphosphorylated
                         metabolite; however, bis-POM derivatives were
                         chemically unstable and highly susceptible to
                         serum-mediated hydrolysis, factors that limit
                         their potential utility for intracellular
                         drug delivery. In human trials,
                         bioavailability of adefovir dipivoxil was
                         45.10 percent, 39.10 percent, and 36.50
                           percent with daily oral doses of 125, 250,
                           and 500 mg, respectively, based on renal
                           excretion. A randomized, double-blind,
                           placebo-controlled, dose-escalation study of
                           adefovir dipivoxil was conducted in 36 HIV+
                           subjects to evaluate its anti-HIV activity,
                           safety, and pharmacokinetics. Median
                           decreases in serum p24 antigen of 31% and 30%
                           occurred in each drug-treated group, compared
                           with an increase of 17% in the placebo group.
                           Median decreases in serum HIV RNA of 0.4-0.6
                           log10 copies/mL occurred in the drug-treated
                           groups, compared with no change in the
                           placebo group. Gastrointestinal complaints
                           and reversible liver transaminase elevations
                           were the most frequently noted adverse
                           events. Decreases in serum free carnitine
                           occurred in each drug-treated group during
                           treatment. After 14 days of dosing, adefovir
                           dipivoxil demonstrated anti-HIV activity and
                           was best tolerated at 125 mg daily, the
                           lowest dosage studied. [Antiviral Res 1992
                           Sep;19(3); Antimicrob Agents Chemother 1993
                           Oct;37(10); J Infect Dis. 1997 Aug;176(2)]
DISEASES STUDIED/TREATED   Primary HIV infection. [FDA 232A]
CLASSIFICATION CODE        Antiretroviral [Antiviral Res 1992 Sep;19(3)]
ADVERSE EFFECTS            Adverse effects in adults have included grade
                           2 nausea, anorexia, vomiting, diarrhea,
                           transaminase increase, and abdominal
                           discomfort, primarily at daily doses of 250
                           and 500 mg. [NIAID ACTG 310]
CONTRAINDICATIONS          Contraindicated in pregnant and lactating
                           women. [FDA 232A]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: The bis(pivaloyloxymethyl)
                           derivative of the nucleotide analog PMEA;
                           ester prodrug of PMEA acetylated with
                           chloromethyl pivalate. [Antiviral Res 1992
                           Sep;19(3); Antimicrob Agents Chemother 1993
                           Oct;37(10)]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 501.48 [NIAID ACTG 310]
CHEMICAL/PHYSICAL DATA     SOLUBILITY: Low aqueous solubility. [Pharm
                           Res 1994 Jun;11(6)]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Granules. [FDA 232A]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [FDA 232A]
MANUFACTURERS              Gilead Sciences Incorporated; 353 Lakeside
                           Drive; Foster City, CA 94404
REFERENCES                 MED/973799383. Barditch-Crovo P, Toole J,
                           Hendrix CW, Cundy KC, Ebeling D, Jaffe HS,
                           Lietman PS. Anti-human immunodeficiency virus
                           (HIV) activity, safety, and pharmacokinetics
                           of adefovir dipivoxil
                           (9-[2-(bis-pivaloyloxymethyl)-phosphonylmetho-
                           xyethyl]adenine) in HIV-infected patients. J
                           Infect Dis. 1997 Aug;176(2):406-13.
REFERENCES                 AIDS/97290233. Hepatitis B and adefovir
                           depivoxil. AIDS Patient Care STDS. 1997
                           Apr;11(2):103.
REFERENCES                 AIDS/97926548. Cherrington JM, Fuller MF,
                           Lalezari JP, Miner R, Chen MS, Drew WL. In
                           vitro antiviral susceptibilities of isolates
                           from CMV retinitis patients receiving first
                         or second line cidofovir therapy:
                         relationship to clinical outcome. 4th Conf
                         Retro and Opportun Infect.1997 Jan 22-26;:120
                         (abstract no. 304).
REFERENCES               AIDS/97926544. Cherrington JM, Mulato AS,
                         Lamy PL, Hellmann NS, Chen MS. Genotypic
                         characterization of HIV-1 variants isolated
                         from AIDS patients treated with adefovir
                         dipivoxil (bis-POM PMEA). 4th Conf Retro and
                         Opportun Infect. 1997 Jan 22-26;:104
                         (abstract no. 216).
REFERENCES               AIDS/97702375. James JS. GS 840 (adefovir
                         dipivoxil): broad-spectrum antiviral trial,
                         CD4 count under 100. AIDS Treat News. 1997
                         Feb 7;(No 264):4-5.
REFERENCES               AIDS/96920632. McKinney RE Jr. Ongoing and
                         future trials of antiretroviral therapy in
                         the pediatric AIDS clinical trials group
                         (PACTG). 3rd Conf Retro and Opportun Infect.
                         1996 Jan 28-Feb 1;:173.
REFERENCES               MED/96139529. Cundy KC, Barditch-Crovo P,
                         Walker RE, Collier AC, Ebeling D, Toole J,
                         Jaffe HS. Clinical pharmacokinetics of
                         adefovir in human immunodeficiency virus type
                         1-infected patients. Antimicrob Agents
                         Chemother. 1995 Nov;39(11):2401-5.
REFERENCES               MED/95174749. Robbins BL, Connelly MC,
                         Marshall DR, Srinivas RV, Fridland A. A human
                         T lymphoid cell variant resistant to the
                         acyclic nucleoside phosphonate
                         9-(2-phosphonylmethoxyethyl)adenine shows a
                         unique combination of a phosphorylation
                         defect and increased efflux of the agent. Mol
                         Pharmacol. 1995 Feb;47(2)391-7.
REFERENCES               AIDS/95920519. Barditch-Crovo PA, Cundy KC,
                         Wachsman M, Toole J, Burgee H, Ebeling D.
                         Pharmacokinetic profile of
                         9-[2-(bispivaloyloxy-methyl)
                         phosphonylmethoxy]adenine (bis-POM PMEA), an
                         orally bioavailable prodrug of the antiviral
                         nucleotide, PMEA. Natl Conf Hum Retroviruses
                         Relat Infect (2nd). 1995 Jan 29-Feb 2;:145.
REFERENCES               MED/94293304. Starrett JE Jr, Tortolani DR,
                         Russell J, Hitchcock MJ, Whiterock V, Martin
                         JC, Mansuri MM. Synthesis, oral
                         bioavailability determination, and in vitro
                         evaluation of prodrugs of the antiviral agent
                         9-[2-(phosphonomethoxy)ethyl]adenine (PMEA).
                         J Med Chem. 1994 Jun 10;37(12):1857-64.
ENTRY MONTH              199405
LAST REVISION DATE       19980415

99
UNIQUE IDENTIFIER        DRG-0208
NAME OF SUBSTANCE        524W91 [FDA 233A]
REGISTRY NUMBER          143491-54-7
STANDARD CHEMICAL NAME   2(1H)-Pyrimidinone,
                         4-amino-5-fluoro-1-(2-(hydroxymethyl)-1,3-
                         oxa-thiolan-5-yl)-, cis-(+-)- [CHEMID]
SYNONYMS                 ddFTC [AIDS Therapies 1995 Sep]
SYNONYMS                 cis-2',3'-Dideoxy-5-fluoro-3'-thiacytidine [J
                           Pharm Sci 1994 Aug;83(8)]
SYNONYMS                   FTC [Antimicrob Agents Chemother 1992
                           Dec;36(12)]
SYNONYMS                   2',3',5-Ftc [CHEMID]
SYNONYMS                   2',3'-Dideoxy-5-fluoro-3'-thiacytidine
                           [CHEMID]
PROTOCOL ID NUMBERS        FDA 298A
PROTOCOL ID NUMBERS        FDA 233A
PHARMACOLOGICAL ACTION     MODE OF ACTION: 524W91 is a nucleoside analog
                           with potent anti-human immunodeficiency virus
                           and anti-human hepatitis B virus activities
                           in vitro. The pharmacokinetics and
                           bioavailability of 524W91 after oral dosing
                           were studied in mice by the oral and
                           intravenous routes and in cynomolgus monkeys.
                           In both species, the clearance of 524W91 was
                           rapid, via the kidney, and was independent of
                           dose. The metabolism of orally administered
                           (tritium labeled) 524W91 was studied in
                           cynomolgus monkeys, which excreted 41% (+/-
                           6%) of the radioactive dose in the 0- to 72-h
                           urine, 33% (+/- 10%) in the feces, and 10%
                           (+/- 7%) in the cage wash. Unchanged 524W91
                           was 64% of the total radiolabeled drug
                           recovered in the urine. [Antimicrob Agents
                           Chemother 1994 Dec;38(12)]
DISEASES STUDIED/TREATED   Primary HIV infection. Drug development
                           discontinued per company. [FDA 233A; Glaxo
                           Wellcome 4/96]
CLASSIFICATION CODE        Antiretroviral [FDA 233A]
CONTRAINDICATIONS          Contraindicated in pregnant or nursing women.
                           [FDA 233A]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Nucleoside analog.
                           [Antimicrob Agents Chemother 1994 Dec;38(12)]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C8H10FN3O3S [CHEMLINE]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Capsules. [FDA 233A]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [FDA 233A]
MANUFACTURERS              Glaxo Wellcome; 5 Moore Drive / PO Box 13398;
                           Research Triangle Park, NC 27709
REFERENCES                 MED/96431833. Condreay LD, Condreay JP,
                           Jansen RW, Paff MT, Averett DR.
                           (-)-cis-5-fluoro-1-[2(hydroxymethyl)-1,3-oxat-
                           hiolan-5-yl]cytosine (524W91) inhibits
                           hepatitis B virus replication in primary
                           human hepatocytes. Antimicrob Agents
                           Chemother. 1996 Feb;40(2):520-3.
REFERENCES                 MED/96283736. St. Clair MH, Millard J, Rooney
                           J, Tisdale M, Parry N, Sadler BM, Blum MR,
                           Painter G. In vitro antiviral activity of
                           141W94 (VX-478) in combination with other
                           antiretroviral agents. Antiviral Res. 1996
                           Jan;29(1):53-6.
REFERENCES                 MED/95209293. Frick LW, Lambe CU, St John L,
                           Taylor LC, Nelson DJ. Pharmacokinetics, oral
                           bioavailability, and metabolism in mice and
                           cynomolgus monkeys of
                           (2'R,5'S-)-cis-5-fluoro-1-[2-(hydroxymethyl)--
                           1,3-oxathiolan-5-y] cytosine, an agent active
                           against human immunodeficiency virus and
                           human hepatitis B virus. Antimicrob Agents
                           Chemother. 1994 Dec;38(12);2722-9.
REFERENCES               MED/94379807. Lacey SF, Larder BA. Novel
                         mutation (V75T) in human immunodeficiency
                         virus type 1 reverse transcriptase confers
                         resistance to
                         2',3'-didehydro-2',3'dideoxythymidine in cell
                         culture. Antimicrob Agents Chemother. 1994
                         Jun;38(6):1428-32.
REFERENCES               MED/94263171. Condreay LD, Jansen RW,
                         Powdrill TF, Johnson LC, Selleseth DW, Paff
                         MT, Daluge SM, Painter GR, Furman PA, Ellis
                         MN, et al. Evaluation of the potent
                         anti-hepatitis B virus agent (-)
                         cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathio-
                         lan-5-yl]cytosine in a novel in vivo model.
                         Antimicrob Agents Chemother. 1994
                         Mar;38(3):616-9.
REFERENCES               MED/94079369. Mathez D, Schinazi RF, Liotta
                         DC, Leibowitz J. Infection amplification of
                         wild-type human immunodeficiency virus from
                         patients' lymphocytes and modulation by
                         reverse transcriptase inhibitors in vitro.
                         Antimicrob Agents Chemother. 1993
                         Oct;37(10):2206-11.
REFERENCES               MED/94028810. Wilson JE, Martin JL,
                         Borroto-Esoda K, Hopkins S, Painter G, Liotta
                         DC, Furman PA. The 5'-triphosphates of the
                         (-) and (+) enantiomers of
                         cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathio-
                         lane-5-yl] cytosine equally inhibit human
                         immunodeficiency virus type 1 reverse
                         transcriptase. Antimicrob Agents Chemother.
                         1993 Aug;37(8):1720-2.
REFERENCES               MED/93263665. Schinazi RF, Lloyd RM Jr,
                         Nguyen MH, Cannon DL, McMillan A, Ilksoy N,
                         Chu CK, Liotta DC, Bazmi HZ, Mellors JW.
                         Characterization of human immunodeficiency
                         viruses resistant to oxathiolane-cytosine
                         nucleosides. Antimicrob Agents Chemother.
                         1993 Apr;37(4):875-81.
ENTRY MONTH              199405
LAST REVISION DATE       19980406

100
UNIQUE IDENTIFIER        DRG-0207
NAME OF SUBSTANCE        Ifosfamide [USAN 1997]
REGISTRY NUMBER          3778-73-2
STANDARD CHEMICAL NAME   2H-1,3,2-Oxazaphosphorin-2-amine,
                         N,3-bis(2-chloroethyl)tetrahydro-, 2-oxide
                         [USAN 1997]
SYNONYMS                 Ifex [USAN 1997]
SYNONYMS                 Iphosphamid(e) [Merck Index 1996]
SYNONYMS                 Isoendoxan [Merck Index 1996]
SYNONYMS                 Isophosphamide [Merck Index 1996]
SYNONYMS                 Cyfos [Merck Index 1989]
SYNONYMS                 Holoxan [Merck Index 1996]
SYNONYMS                 Mitoxana [Merck Index 1996]
SYNONYMS                 Naxamide [Merck Index 1989]
PROTOCOL ID NUMBERS      NCI 93 C-207
SECONDARY SOURCE ID      MJF-9325 [USAN 1997]
SECONDARY SOURCE ID      Z-4942 [USAN 1997]
SECONDARY SOURCE ID      NSC-109724 [USAN 1997]
SECONDARY SOURCE ID        A4942 [Merck Index 1996]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Ifosfamide, like
                           cyclophosphamide, requires transformation in
                           the liver by mixed-function oxidases
                           (cytochrome P-450 system) before it can exert
                           its cytotoxic effect. After conversion to
                           active metabolites, ifosfamide functions as
                           an alkylating agent, interfering with DNA
                           replication and transcription of RNA, and
                           ultimately resulting in disruption of nucleic
                           acid functions. Ifosfamide is cycle-phase
                           nonspecific. Ifosfamide exhibits
                           dose-dependent pharmacokinetics in humans. At
                           single doses of 3.8-5.0 g/m2, the plasma
                           concentrations decay biphasically and the
                           mean terminal elimination half-life is about
                           15 hours. At doses of 1.6-2.4 g/m2/day, the
                           plasma decay is monoexponential and the
                           terminal elimination half-life is about 7
                           hours. Ifosfamide is extensively metabolized
                           in humans and the metabolic pathways appear
                           to be saturated at high doses. After
                           administration of doses of 5 g/m2 of
                           14C-labeled ifosfamide, from 70% to 86% of
                           the dosed radioactivity was recovered in the
                           urine, with about 61% of the dose excreted as
                           parent compound. At doses of 1.6-2.4 g/m2
                           only 12% to 18% of the dose was excreted in
                           the urine as unchanged drug within 72 hours.
                           Two different dechloroethylated derivatives
                           of ifosfamide, 4-carboxyifosfamide,
                           thiodiacetic acid and cysteine conjugates of
                           chloroacetic acid have been identified as the
                           major urinary metabolites of ifosfamide in
                           humans and only small amounts of
                           4-hydroxyifosfamide and acrolein are present.
                           Small quantities (nmole/ml) of ifosfamide
                           mustard and 4-hydroxyifosfamide are
                           detectable in human plasma. Metabolism of
                           ifosfamide is required for the generation of
                           the biologically active species and while
                           metabolism is extensive, it is also quite
                           variable among patients. Enzymatic oxidation
                           of the chloroethyl side chains and subsequent
                           dealkylation produces the major urinary
                           metabolites, dechloroethyl ifosfamide and
                           dechloroethyl cyclophosphamide. The alkylated
                           metabolites of ifosfamide have been shown to
                           interact with DNA. [PDR 1997; AHFS Drug
                           Information 1997]
DISEASES STUDIED/TREATED   Treatment of AIDS-related non-Hodgkin's
                           lymphoma. [NCI 93 C-207]
CLASSIFICATION CODE        Antineoplastic (adjunct) [USAN 1997]
OTHER MAJOR USES           Germ cell testicular cancer. [PDR 1997]
SUBSTANCE INTERACTIONS     Precautions should be observed if
                           coadministered with bone marrow depressants,
                           live virus vaccines, radiation therapy or
                           drugs affecting microsomal enzymes. [USP DI
                           1997; AHFS Drug Information 1997]
ADVERSE EFFECTS            In patients receiving ifosfamide as a single
                           agent, the dose-limiting toxicities are
                          myeleosuppression and urotoxicity. Alopecia
                          occurred in many of the patients treated.
                          Nausea and vomiting also were common
                          occurrences in patients receiving ifosfamide
                          (Ifex). Hematuria occurred in 6% to 92% of
                          patients treated with Ifex. CNS side effects
                          most commonly seen were somnolence,
                          confusion, depressive psychosis, and
                          hallucinations. Other adverse reactions
                          observed in less than 1% of patients include
                          stomatitis, salivation, pulmonary symptoms,
                          polyneuropathy, malaise, hypotension,
                          hypertension, fatigue, diarrhea, dermatitis,
                          constipation, coagulopathy, cardiotoxicity,
                          anorexia, allergic reaction, fever,
                          phlebitis, and liver dysfunction and
                          infections. [PDR 1997]
CONTRAINDICATIONS         Continued use of ifosfamide is
                          contraindicated in patients with severely
                          depressed bone marrow function and in
                          patients who have demonstrated a previous
                          hypersensitivity to it. [PDR 1997]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: Alkylating agent that is
                          chemically related to the nitrogen mustards
                          and is a synthetic analog of
                          cyclophosphamide. [PDR 1997; USP DI 1997]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: A white crystalline
                          powder. [PDR 1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C7H15Cl2N2O2P [USAN 1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 261.09 [USAN 1997]
CHEMICAL/PHYSICAL DATA    ELEMENTAL COMP: C32.20%, H5.79%, Cl27.16%,
                          N10.73%, O12.26%, P11.86%. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    SOLUBILITY: Soluble in water. [PDR 1997]
CHEMICAL/PHYSICAL DATA    STABILITY: Constituted or constituted and
                          further diluted solutions of IFEX (Ifosfamide
                          for intravenous use) should be refrigerated
                          and used within 24 hours. [PDR 1997]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: 1 and 3 g single dose vials;
                          available in combination packages with the
                          uroprotective agent mesna. [PDR 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Intravenous. [PDR 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: The dry powder may be
                          stored at room temperature, preferably
                          between 15-30 C. Storage above 40 C should be
                          avoided. [PDR 1995; USP DI 1997]
MANUFACTURERS             Bristol - Myers Squibb Company; PO Box 4500;
                          Princeton, NJ 08543-4500
REFERENCES                97418078. Joqueviel C, Gilard V, Martino R,
                          Malet-Martino M, Niemeyer U. Urinary
                          stability of carboxycyclophosphamide and
                          carboxyifosfamide, two major metabolites of
                          the anticancer drugs cyclophosphamide and
                          ifosfamide. Cancer Chemother Pharmacol
                          1997;40(5):391-9.
REFERENCES                97418075. Goren MP, McKenna LM, Goodman TL.
                          Combined intravenous and oral mesna in
                          outpatients treated with ifosfamide. Cancer
                          Chemother Pharmacol 1997;40(5):371-5.
REFERENCES                97341808. Rossi R. Nephrotoxicity of
                          ifosfamide--moving towards understanding the
                          molecular mechanisms [editorial]. Nephrol
                         Dial Transplant 1997 Jun;12(6):1091-2.
REFERENCES               96087018. Dincol D, Icli F, Karaoguz H, Cay
                         F, Arican A, Demirkazik A, Akbulut H.
                         Mesna/ifosfamide, mitoxantrone, etoposide,
                         bleomycin, vincristine, prednisone (MINE-BOP)
                         combination chemotherapy in the treatment of
                         refractory and relapsed non-Hodgkin's
                         lymphoma. Acta Oncol 1995;34(7):937-40.
REFERENCES               95222325. De Lena M, Ditonno P, Lorusso V,
                         Brandi M, Timurian A, Marzullo F, Ventrella
                         V, Pellecchia A. CEOP-B alternated with VIMB
                         in intermediate-grade and high-grade
                         non-Hodgkin's lymphoma: a pilot study. J Clin
                         Oncol 1995 Apr;13(4):953-60.
REFERENCES               ICA9/93335239. Hentrich M, Brack N, Sander R,
                         Lutz L, Jager H, Hartenstein R. Testicular
                         germ cell tumors (GCT) and HIV infection: 2
                         case reports. Int Conf AIDS. 1993 Jun
                         6-11;9(1):412 (abstract no. PO-B15-1660).
REFERENCES               93089742. Quezado ZM, Wilson WH, Cunnion RE,
                         Parker MM, Reda D, Bryant G, Ognibene FP.
                         High-dose ifosfamide is associated with
                         severe, reversible cardiac dysfunction. Ann
                         Intern Med. 1993 Jan 1;118(1):31-6.
REFERENCES               ICDB/94695626. Gisselbrecht C, Lepage E,
                         Tirelli U, Oksenhendler E, Gabarre J, Farcet
                         JP, Gastaldi R, Coiffier B, Thyss A, Rapahel
                         M, et al. Human immunodeficiency
                         virus-related lymphoma treatment with
                         intensive combination chemotherapy (Meeting
                         abstract). Proc Annu Meet Am Soc Clin Oncol;
                         12:A1227 1993.
REFERENCES               TOXBIB/93/030841. Cabanillas F. Non-Hodgkin's
                         lymphomas: a review of the M.D. Anderson
                         experience. Semin Oncol. 1992 Feb;19(1 Suppl
                         1):11-3.
REFERENCES               TOXBIB/93/134390. Goss PE. New perspectives
                         in the treatment of non-Hodgkin's lymphoma.
                         Semin Oncol. 1992 Dec;19(6 Suppl 12):23-9.
REFERENCES               ICA7/3237091. Northfelt DW, Kahn JO,
                         Volberding PA, Kaplan LD.
                         Ifosfamide/etoposide for AIDS-related
                         non-Hodgkin's lymphoma (AIDS-NHL). Int Conf
                         AIDS. 1991 Jun 16-21;7(2):274 (abstract no.
                         W.B.2370).
REFERENCES               ICDB/93689059. Cabanillas F. Malignant
                         lymphomas. Hematology; 14:299-334 1991.
ENTRY MONTH              199404
LAST REVISION DATE       19980413

101
UNIQUE IDENTIFIER        DRG-0206
NAME OF SUBSTANCE        TBC-3B Vaccine [NIAID VEU 014]
SYNONYMS                 TBC-3B [NIAID VEU 014]
SYNONYMS                 Recombinant vaccinia HIV-1 III B env/gag/pol
                         vaccine [NIAID VEU 014]
PROTOCOL ID NUMBERS      NIAID VEU 014A/B
PROTOCOL ID NUMBERS      NIAID VEU 014C
PHARMACOLOGICAL ACTION   MODE OF ACTION: Insertion of the HIV-1
                         (strain IIIB) env, gag, and pol genes, each
                         under the transcriptional direction of a
                           vaccinia promoter element, into the genome of
                           this parental virus resulted in the
                           generation of a multivalent recombinant virus
                           that efficiently expresses fully processed,
                           authentically configured HIV-1 polypeptides
                           encoded by those genes. In animal studies,
                           this vaccine presented multiple conserved and
                           variable HIV-1 epitopes to the immune system,
                           and elicits both humoral and cell mediated
                           immune responses to the expressed
                           polypeptides. [NIAID VEU 014]
DISEASES STUDIED/TREATED   Prevention of HIV infection. [NIAID VEU 014]
CLASSIFICATION CODE        Vaccine [NIAID VEU 014]
ADVERSE EFFECTS            Adverse effects include possible tenderness,
                           redness, and swelling at site of vaccination.
                           [NIAID VEU 014]
CONTRAINDICATIONS          Contraindicated in pregnant and lactating
                           women. [NIAID VEU 014]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Live recombinant vaccinia
                           virus that expresses the env, gag, and pol
                           genes of HIV-1 (IIIB strain). [NIAID VEU 014]
CHEMICAL/PHYSICAL DATA     STABILITY: Stable for 12 months at -75 to -85
                           C. [NIAID VEU 014]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Vials containing 3 billion
                           PFU/ml. [NIAID VEU 014]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Scarification by bifurcated
                           needle. [NIAID VEU 014]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Freeze at -75 to -85 C.
                           Can remain thawed at 4 C for 4 days. [NIAID
                           VEU 014]
MANUFACTURERS              Therion Biologics Corporation; 76 Rogers
                           Street; Cambridge, MA 02142
REFERENCES                 AIDS/97927089. Richmond JF, Mustafa F, Lu S,
                           Fenyo EM, Hurwitz JL, Montefiori DC, Robinson
                           HL. Screening of HIV-1 env glycoproteins for
                           the ability to raise neutralizing antibody
                           using DNA immunization and recombinant
                           vaccinia virus boosting. Conf Adv AIDS
                           Vaccine Dev. 1997 May 4-7;:125 (Poster 20).
REFERENCES                 MED/97288304. Richmond JF, Mustafa F, Lu S,
                           Santoro JC, Weng J, O'Connell M, Fenyo EM,
                           Hurwitz JL, Montefiori DC, Robinson HL.
                           Screening of HIV-1 Env glycoproteins for the
                           ability to raise neutralizing antibody using
                           DNA immunization and recombinant vaccinia
                           virus boosting. Virology. 1997 Apr
                           14;230(2):265-74.
REFERENCES                 MED/97227578. Rencher SD, Lockey TD, Srinivas
                           RV, Owens RJ, Hurwitz JL. Eliciting HIV-1
                           envelope-specific antibodies with mixed
                           vaccinia virus recombinants. Vaccine. 1997
                           Feb;15(3):265-72.
REFERENCES                 MED/96071441. Abimiku AG, Franchini G,
                           Tartaglia J, Aldrich K, Myagkikh M, Markham
                           PD, Chong P, Klein M, Kieny MP, Paoletti E,
                           et al. HIV-1 recomibant poxvirus vaccine
                           induces cross-protection against HIV-2
                           challenge in rhesus macaques [see comments].
                           Nat Med. 1995 Apr;1(4):321-9.
REFERENCES                 MED/95376334. Perales MA, Schwartz DH, Fabry
                           JA, Lieberman J. A vaccinia-gp160-based
                         vaccine but not a gp160 protein vaccine
                         elicits anti-gp160 cytotoxic T lymphocytes in
                         some HIV-1 seronegative vaccines. J Acquir
                         Immune Defic Syndr Hum Retrovirol. 1995 Sep
                         1;10(1):27-35.
REFERENCES               MED/95016023. Graham BS, Gorse GJ, Schwartz
                         DH, Keefer MC, McElrath MJ, Matthews TJ,
                         Wright PF, Belshe RB, Clements ML, Dolin R,
                         et al. Determinants of antibody response
                         after recombinant gp160 boosting in
                         vaccinia-naive volunteers primed with
                         gp160-recombinant vaccinia virus. The
                         National Institute of Allergy and Infectious
                         Disease AIDS Vaccine Clinical Trials Network.
                         J Infect Dis. 1994 Oct;170(4):782-6.
REFERENCES               ICA8/92400000. Hesselton RM, Mazzara GP,
                         Panicali D, Sullivan JL. HIV-specific immune
                         responses in rabbits immunized with HIV-like
                         particles and recombinant vaccinia virus. Int
                         Conf AIDS. 1992 Jul 19-25;8(1):Mo13 (abstract
                         no. MoA 0045).
ENTRY MONTH              199404
LAST REVISION DATE       19971104

102
UNIQUE IDENTIFIER        DRG-0205
NAME OF SUBSTANCE        Multivalent HIV-1 Peptide Immunogen [NIAID
                         VEU 017]
PROTOCOL ID NUMBERS      NIAID VEU 017
PROTOCOL ID NUMBERS      NIAID VEU 023
PHARMACOLOGICAL ACTION   MODE OF ACTION: The antigenic principal
                         neutralizing determinant (PND) peptides are
                         the major immunogenic portion of this
                         multiple antigen peptide. Evaluation of the
                         safety and immunogenicity of a formulation of
                         HIV-1 gp120 principal neutralizing domain
                         branched synthetic peptides (in alum) from 15
                         different viral strains representing diverse
                         worldwide isolates given to healthy,
                         seronegative adult volunteers showed that
                         almost all vaccine recipients developed
                         active lymphocyte proliferation was seen in
                         the placebo group. After three vaccinations,
                         gamma interferon could be detected in 4 day
                         supernatants from one of five vaccinees, but
                         no antigen-specific interleukin 4 (IL4) was
                         seen. Il4 production to phytohemagglutinin
                         (PHA) was occasionally detectable at this
                         time. No antigen-specific cytokine production
                         was seen at baseline in subjects. LPA
                         responses did not predict the cytokine
                         pattern seen. By utilizing restimulation
                         protocols to allow for memory cells which
                         secrete IL4 to develop. TH1/TH2 (acquired
                         immune) responses can be seen following
                         vaccination which may be missed using shorter
                         in vitro culture techniques. Another series
                         of studies showed that for including HIV-1
                         specific immunity, immunization with DNA
                         vaccine followed by VCI (macromolecular
                         multicomponet peptide vaccine) boosting
                           produces better results than immunizing with
                           either vaccine alone. [NIAID VEU 017; 3rd
                           Conf Retro and Opportun Infect 1996; Vaccine.
                           1997 Jul;15(10)]
DISEASES STUDIED/TREATED   Prevention of HIV infection. [NIAID VEU 017]
CLASSIFICATION CODE        Vaccine [NIAID VEU 017]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Mixture of HIV-1 gp120
                           principal neutralizing domain (PND) branched
                           synthetic peptides from 15 viral strains
                           formulated in alum. Each strain component of
                           the vaccine consists of eight homologous
                           PND-derived peptides attached to a lysine
                           core to form radial-octamers. [NIAID VEU 017]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 0.5 ml vials. [NIAID VEU 017]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intramuscular. [NIAID VEU
                           017]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Store vials at 2-8 C.
                           Storage above or below the recommended
                           temperature may reduce potency. Do not freeze
                           since freezing may destroy potency. [NIAID
                           VEU 017]
MANUFACTURERS              United Biomedical Incorporated; 25 Davids
                           Drive; Hauppauge, NY 11788
REFERENCES                 MED/97414189. Okuda K, Xin KO, Tsuji T,
                           Bukawa H, Tanaka S, Koff WC, Okunda K, Honma
                           K, Kawamoto S. et al. DNA vaccination
                           followed by macromolecular multicomponet
                           peptide vaccination against HIV-1 induces
                           strong antigen-specific immunity. Vaccine.
                           1997 July;15(10):1049-56.
REFERENCES                 AIDS/97926165. Evans TG, Keefer MC, Wolff M,
                           Weinhold K, Excler Jl, Duliege AM, McNamara
                           J, McElrath JM, Graham BJ, Clements ML. et
                           al. Immunization of HIV-1 non-infected
                           volunteers with a canarypox recombinant
                           containing HIV-1 env, gag, pol, and nef genes
                           (vCP 300) given simultaneously or followed by
                           recombinant HIV-1 SF2 gp120. 4th Conf Retro
                           and Opportun Infect. 1997 Jan 22-26;:204
                           (abstract no. 754).
REFERENCES                 AIDS/96920471. Evans TG, Fitzgerald T,
                           Demeter L, Keefer M, Koff W. Cytokine
                           response to vaccination of HIV seronegative
                           volunteers with a multivalent HIV-1 peptide
                           immunogen. 3rd Conf Retro and Opportun
                           Infect. 1996 Jan 28-Feb 1;:141.
REFERENCES                 MED/94338751. Okuda K, Kaneko T, Shigematsu
                           T, Yamakawa T, Tanaka S, Yamamoto A, Hamajima
                           K, Nakajima K, Kawamoto S, Phanuphak P.
                           Strong immunogenicity of a multicomponent
                           peptide vaccine develope with the branched
                           lysine oligopeptide method for human
                           immunodeficiency virus infection. J Mol
                           Recognit, 1993 Sep;6(3):101-9.
ENTRY MONTH                199403
LAST REVISION DATE         19980217

103
UNIQUE IDENTIFIER          DRG-0204
NAME OF SUBSTANCE          WF 10 [CHEMLINE]
REGISTRY NUMBER            92047-76-2
SYNONYMS                   TCDO [MeSH]
SYNONYMS                   Tetrachlorodecaoxide [MeSH]
SYNONYMS                   Tetrachlorodecaoxygen [MeSH]
SYNONYMS                   Ryoxon [MeSH]
SYNONYMS                   Oxoferin [MeSH]
PROTOCOL ID NUMBERS        FDA 222A
PROTOCOL ID NUMBERS        FDA 222B
PHARMACOLOGICAL ACTION     MODE OF ACTION: In previous in vitro
                           experiments, WF 10 appeared to inactivate HIV
                           particles directly, but had no influence on
                           the intracellular replicative machinery of
                           HIV. [AIDS 1993 Sep;7(9)]
DISEASES STUDIED/TREATED   Primary HIV infection. [FDA 222A]
CLASSIFICATION CODE        Antiretroviral [FDA 222A]
OTHER MAJOR USES           Promotion of wound healing, including ulcer
                           wounds. [Lancet 1986 Apr 12; Vol 1; The Extra
                           Pharmacopoeia 1993]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Chlorite-oxygen reaction
                           product. [AIDS 1993 Sep;7(9)]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Solution. [FDA 222A]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intravenous. [FDA 222A]
MANUFACTURERS              Oxo Chemie GmbH / R Hamer Associates; 100
                           East 15th Street / Water Gardens Place /
                           Suite 320; Fort Worth, TX 76102
REFERENCES                 95060572. Kempf SR, Blaszkiewitz K, Port RE,
                           Ivankovic S. Influence of
                           tetrachlorodecaoxide (Ryoxon) on the
                           development of leukemia after total-body
                           gamma-irradiation. Oncology 1994
                           Nov-Dec;51(6):510-4.
REFERENCES                 ICA10/94369698. Busch HW, Christensen S,
                           Reichelt D, Jahn S, Zidek W. Treatment of
                           HIV-infected patients with advanced
                           symptomatic disease with WF10 solution
                           (TCDO). Int Conf AIDS. 1994 Aug
                           7-12;10(1):204 (abstract no. PB0245).
REFERENCES                 MED/94030751. Ennen J, Werner K, Kuhne FW,
                           Kurth R. Inactivation of HIV infectivity by
                           the chlorite-oxygen reaction product
                           tetrachlorodecaoxygen. AIDS. 1993
                           Sep;7(9):1205-12.
REFERENCES                 94268079. Wolin MS, Kleber E, Mohazzab KM,
                           Elstner EF Tetrachlorodecaoxygen, a wound
                           healing agent, produces vascular relaxation
                           through hemoglobulin-dependent inactivation
                           of serotonin and norepinephrine. J Cardiovasc
                           Pharmacol 1994 Apr;23(4):664-8.
REFERENCES                 93185419. Stoll P, Huber H, Pelz K, Weingart
                           D. Antimicrobial effects of the
                           tetrachlorodecaoxygen-anion complex on
                           oropharyngeal bacterial flora: an in vitro
                           study. Chemotherapy 1993;39(1):40-7.
ENTRY MONTH                199403
LAST REVISION DATE         19980417

104
UNIQUE IDENTIFIER          DRG-0203
NAME OF SUBSTANCE          Diethylhomospermine [AmFAR Tx Dir 1995;7(4)]
REGISTRY NUMBER            119422-08-1
STANDARD CHEMICAL NAME     1,4-Butanediamine,
                           N,N'-bis(4-(ethylamino)butyl)- [CHEMLINE]
SYNONYMS                   N(1),N(14)-bis(ethyl)homospermine [MeSH]
SYNONYMS                   BEHSpm [MeSH]
SYNONYMS                   BE-4-4-4 [MeSH]
SYNONYMS                   1,14-Bis(ethylamino)-5,10-diazatetradecane
                           [MeSH]
SYNONYMS                   N(1),N(14)-diethylhomospermine [MeSH]
SYNONYMS                   DEHSPM [MeSH]
SYNONYMS                   N1 N14-bis(ethyl)norspermine [MeSH]
PROTOCOL ID NUMBERS        FDA 223A
PHARMACOLOGICAL ACTION     MODE OF ACTION: In a previous experiment to
                           determine the antiproliferative effects of
                           diethylhomospermine in human transitional
                           cell carcinoma lines, the drug suppressed the
                           activity of the biosynthetic enzymes
                           ornithine decarboxylase and
                           S-adenosylmethionine decarboxylase. The
                           substantial antiproliferative activity of
                           this polyamine analog was believed to result
                           from mechanisms other than polyamine
                           depletion. However, other experiments using
                           HeLa cells demonstrated that
                           diethylhomospermine depleted polyamines. [J
                           Urol 1993;150; Biochemistry 1993;32]
DISEASES STUDIED/TREATED   Under investigation for refractory
                           AIDS-related diarrhea. [AmFAR Tx Dir
                           1997;8(3)]
CLASSIFICATION CODE        Antidiarrheal [AmFAR Tx Dir 1995;7(4)]
OTHER MAJOR USES           Inhibited growth of tumor cells in culture.
                           [Biochemistry 1993;32]
ADVERSE EFFECTS            Constipation. [AmFAR Tx Dir 1995;7(4)]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Synthetic polyamine analog.
                           [AmFAR Tx Dir 1995;7(4)]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C16H38N4 [CHEMLINE]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intravenous. [FDA 223A]
MANUFACTURERS              Gainesville Veterans Administration Medical
                           Center; Gastroenterology Section 111-C;
                           Gainesville, FL 32608
REFERENCES                 95361048. Bergeron CJ, Basu HS, Marton LJ,
                           Deen DF, Pellarin M, Feuerstein BG. Two
                           polyamine analogs(BE-4-4-4 and BE-4-4-4-4)
                           directly affect growth, survival, and cell
                           cycle progression in two human brain tumor
                           cell lines. Cancer Chemother Pharmacol
                           1995;36(5)411-7.
REFERENCES                 95152339. Fernandez CO, Frydman B, Samejima
                           K. Interactions between polyamine analogs
                           with antiproliferative effects and tRNA: a
                           15N NMR analysis. Cell Mol Biol
                           (Noisy-le-grand) 1994 Nov;40(7):933-44.
REFERENCES                 97133458. Bergeron RJ, Weimar WR, Wu Q, Feng
                           Y, McManis JS, Polyamine analogue regulation
                           of NMDA MK-801 binding: a structure-activity
                           study. J Med Chem 1996 Dec 20;39(26):5257-66.
REFERENCES                 96265145. Bergeron RJ, Yao GW, Yao H, Weimar
                           WR, Sninsky CA, Raisler B, Feng Y, Wu Q, Gao
                           F. Metabolically programmed polyamine
                           analogue antidiarrheals. J Med Chem 1996 Jun
                           21;39(13):2461-71.
REFERENCES                 96417634. Bergeron RJ, Weimar WR, Luchetta G,
                           Sninsky CA, Wiegand J, Metabolism and
                           pharmacokinetics of
                           N1,N14-diethylhomospermine. Drug Metab Dispos
                           1996 Mar;24(3):334-43.
REFERENCES                 96120801. Bergeron RJ, Wiegand J, Sninsky CA,
                           Katovich MJ. The impact of polyamine
                           analogues on the blood pressure of
                           normotensive and hypertensive rats. Clin Exp
                           Hypertens 1995 Nov;17(8):1197-217.
ENTRY MONTH                199403
LAST REVISION DATE         19980506

105
UNIQUE IDENTIFIER          DRG-0202
NAME OF SUBSTANCE          MDL 28574 [CHEMLINE]
REGISTRY NUMBER            121104-96-9
STANDARD CHEMICAL NAME     Butanoic acid,
                           octahydro-1,7,8-trihydroxy-6-indolizinyl
                           ester,
                           (1S-(1alpha,6beta,7alpha,8beta,8abeta))-
                           [CHEMLINE]
SYNONYMS                   MDL 28,574 [MeSH]
SYNONYMS                   MDL-28574 [MeSH]
SYNONYMS                   6-O-butanoylcastanospermine [MeSH]
SYNONYMS                   MDL 28574A (hydrochloride salt) [FDA 221B]
PROTOCOL ID NUMBERS        FDA 221A
PROTOCOL ID NUMBERS        FDA 221B
PROTOCOL ID NUMBERS        FDA 221C
PHARMACOLOGICAL ACTION     MODE OF ACTION: Demonstrates inhibitory
                           effect on glucosidases and has antiviral
                           activity against HIV-1 and against Moloney
                           murine leukemia virus (MOLV). In previous
                           studies, MDL 28574 had an IC50 of 0.3 mcg/ml
                           against HIV-induced syncytial formation in
                           HeLa T4+ cells and an IC50 of 0.15 mcg/ml
                           against productive infection in JM cells
                           infected with HIV-1. In both cases, MDL 28574
                           was more potent than castanospermine. The
                           IC50 was 0.05 mcg/ml against MOLV. MDL 28574
                           also showed equivalent activity to AZT and
                           was more potent than castanospermine in
                           inhibiting FLV-induced splenomegaly in mice.
                           MDL 28574 was tested alone or in combination
                           with AZT orally in groups of AIDS patients
                           with CD4+ counts between 100 and 500
                           cells/microliter. Preliminary efficacy
                           measures showed good results for about one
                           third of the patients, stable results for a
                           third, and rather poor results for another
                           third of the patients. [Ann N Y Acad Sci
                           1990;616; Biochem Biophys Res Commun 1995 Mar
                           8;208(1); Int Conf AIDS 1996 Jul
                           7-12;11(1):18]
DISEASES STUDIED/TREATED   Primary HIV infection. [FDA 221A]
CLASSIFICATION CODE        Antiretroviral [Ann N Y Acad Sci 1990;616]
CLASSIFICATION CODE        Alpha glucosidase I inhibitor [Ann N Y Acad
                           Sci 1990;616]
ADVERSE EFFECTS            Bloody diarrhea and flatulence are the
                           primary dose-limiting toxicities reported in
                           one phase I and two phase II studies. [AmFAR
                           Tx Dir 1997;8(3)]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Analogue of the glucosidase
                           I inhibitor, castanospermine. [Ann N Y Acad
                          Sci 1990;616; Glycobiol 1995 Mar;5(2); AmFAR
                          Tx Dir 1997;8(3)]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C12H21NO5 [CHEMLINE]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Solution. [FDA 221A]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral. [FDA 221A]
MANUFACTURERS             Hoechst - Marion - Roussel Incorporated; 9300
                          Ward Parkway; Kansas City, MO 64114
REFERENCES                ICA11/96921187. Arasteh K, Czerwinska R,
                          Scholote F, Fatkenheuer G, Jessen H, Moll A,
                          Gehring P, Ulmer A, Hamedani P, McPherson M.
                          A randomized, double-blind, dose-ranging
                          phase II European study of the safety and
                          efficacy of chornically administered
                          butanoyl-castanospermine (MDL 28,574A)
                          HIV-infected patients. Int Conf AIDS. 1996
                          Jul 7-12;11(1):75 (abstract no. Mo.B.1121).
REFERENCES                ICA11/96922324. Roth H, McPherson M, Hamedani
                          P, Herrmann WM, Sidarous E, Frampton M,
                          Maddern J, Dieterich A. Phase I tolerance and
                          pharmockinetics of a new castanospermine
                          derivative, MDL 28,574A. Int Conf AIDS. 1996
                          Jul 7-12;11(1):284. (abstract no. Tu.B.2117).
REFERENCES                ICA11/96921393. Stoltz ML, McPherson M,
                          Frampton M, Sidarous E, Jacobs M, Roth H.
                          Pharmacokinetics of castanospermine in
                          asymptomatic HIV-positive patients treated
                          with MDL 28,574A during phase I trials. Int
                          Conf AIDS. 1996 Jul 7-12;11(1):112 (abstract
                          no. Mo.B.1329).
REFERENCES                ICA11/96921211. Richmond GJ, Zolnouni P,
                          Stall J, McPherson M, Hamedani P, Cross V,
                          Sidarous E, Stoltz M. Efficacy and safety of
                          MDL 28,574A in HIV-positive patients with
                          baseline CD4 values of 301-500. Int Conf
                          AIDS. 1996 Jul 7-12;11(1):80 (abstract no.
                          Mo.B.1145).
REFERENCES                ICA11/96921204. Zolnouni P, Berger DS, Perez
                          G, Hamedani P, Frampton M, Gibson C, Sidarous
                          E, Stoltz M. Efficacy and safety of MDL
                          28,574A in HIV-positive patients with
                          baseline CD4 values of 100-300. Int Conf
                          AIDS. 1996 Jul 7-12;11(1):78 (abstract no.
                          Mo.B.1138).
REFERENCES                MED/96285861. Kang MS. Uptake and metabolism
                          of BuCast: a glycoprotein processing
                          inhibitor and potential anti-HIV drug.
                          Glycobiology. 1996 Mar;6(2):209-16.
REFERENCES                MED/95328860. Brennan TM, Taylor DL, Bridges
                          CG, Leyda JP, Tyms AS. The inhibition of
                          human immunodeficiency virus type 1 in vitro
                          by a non-nucleoside reverse transcriptase
                          inhibitor MKC-442, alone and in combination
                          with other anti-HIV compounds. Antiviral Res.
                          1995 Mar;26(2):173-87.
REFERENCES                MED/95299228. Bridges CG, Taylor DL, Kang MS,
                          Brennan TM, Tyms AS. Treatment with the
                          alpha-glucosidase 1 inhibitor 6-O-butanoyl
                          castanospermine reduces the detection of
                          LFA-1 (CD18/CD11a) by monoclonal antibodies.
                          Glycobiology. 1995 Mar;5(2):243-7.
REFERENCES                95299229. Bridges CG, Ahmed SP, Kang MS, Nash
                         RJ, Porter EA, Tyms AS. The effect of oral
                         treatment with 6-0-butanoyl castanospermine
                         (MDL 28,574) in the murine zosteriform model
                         of HSV-1 infection. Glycobiology 1995
                         Mar;5(2):249-53.
REFERENCES               95194418. Ahmed SP, Nash RJ, Bridges CG,
                         Taylor DL, Kang MS, Porter EA, Tyms AS.
                         Antiviral activity and metabolism of the
                         castanospermine derivative MDL 28,574, in
                         cells infected with herpes simplex virus type
                         2. Biochem Biophys Res Commun 1995 Mar
                         8;208(1):267-73.
ENTRY MONTH              199403
LAST REVISION DATE       19980114

106
UNIQUE IDENTIFIER        DRG-0201
NAME OF SUBSTANCE        Streptomycin sulfate [USAN 1997]
REGISTRY NUMBER          3810-74-0
STANDARD CHEMICAL NAME   D-Streptamine, O-2-deoxy-2(methylamino)-
                         alpha-L-glucopyranosyl-
                         (1-->2)-O-5-deoxy-3-C-formyl-alpha-L-lyxo-fur-
                         anosyl- (1-->4)-N,N'-bis(aminoiminomethyl)-,
                         sulfate(2:3) (salt) [USAN 1997]
SYNONYMS                 Strycin [USAN 1997]
SYNONYMS                 Agri Strep [Merck Index 1996]
SYNONYMS                 Streptobrettin [Merck Index 1996]
SYNONYMS                 Vetstrep [Merck Index 1996]
SYNONYMS                 Agrimycin 17 [CHEMLINE]
SYNONYMS                 Streptomycin [MeSH]
PROTOCOL ID NUMBERS      NIAID ACTG 238
PHARMACOLOGICAL ACTION   MODE OF ACTION: The pharmacokinetics of
                         streptomycin are similar to those of the
                         other aminoglycosides. Aminoglycosides are
                         usually bactericidal in action. Although the
                         exact mechanism of action has not been fully
                         elucidated, the drugs appear to inhibit
                         protein synthesis in susceptible bacteria by
                         irreversibly binding to 30S ribosomal
                         subunits. Following intramuscular
                         administration of streptomycin in adults with
                         normal renal functions, peak plasma
                         concentrations are attained within 1-2 hours
                         and are reported to range from 25-50 ug/ml
                         after a single 1-g dose. Streptomycin is
                         distributed into most body tissues and fluids
                         except the brain. Substantial amounts of the
                         drug reportedly are found in pleural fluid
                         and tuberculous cavities. The drug crosses
                         placenta; serum concentrations in cord blood
                         are similar to maternal serum concentrations.
                         Small amounts of streptomycin are distributed
                         into milk. The plasma elimination half-life
                         of streptomycin is usually 2-3 hours in
                         adults with normal renal functions. In adults
                         with normal renal function, approximately
                         30-90% of a single intramuscular dose of
                         streptomycin is excreted unchanged by
                         glomerular filtration within 24 hours with
                         the major portion being excreted within the
                         first 12 hours. [AHFS Drug Information 1997]
DISEASES STUDIED/TREATED   Treatment of HIV-associated multi-drug
                           resistant pulmonary tuberculosis. [NIAID ACTG
                           238]
CLASSIFICATION CODE        Antibacterial (tuberculostatic) [USAN 1996]
OTHER MAJOR USES           Streptomycin is indicated for the treatment
                           of individuals with moderate to severe
                           infections caused by susceptible strains of
                           microorganisms in the specific conditions
                           listed below: Mycobacterium tuberculosis,
                           non-tuberculosis infections with Pasteurella
                           pestis (plague), Francisella tularensis
                           (tularemia), Brucella, Calymmatobacterium
                           granulomatis (donovanosis, granuloma
                           inguinale), H. ducreyi (chancroid), H.
                           influenzae (in respiratory, endocardial, and
                           meningeal infections-concomitantly with
                           another antibacterial agent), K. pneumonia
                           (concomitantly with another antibacterial
                           agent), E. coli, Ptoteus, A. aerogenes, K.
                           pneumoniae, and Enterococcus faecalis in
                           urinary tract infections, Streptococcus
                           viridans, Enterococcus faecalis (in
                           endocardial infections-concomitantly with
                           penicillin). [PDR 1997]
SUBSTANCE INTERACTIONS     Ototoxic effects are potentiated by
                           ethacrynic acid, furosemide, mannitol and
                           possibly other diuretics. [PDR 1997]
ADVERSE EFFECTS            Common adverse reactions include vestibular
                           ototoxicity (nausea, vomiting and vertigo),
                           paresthesia of face, rash, fever, urticaria,
                           angioneurotic edema, and eosinophilia. Less
                           frequent adverse effects include cochlear
                           ototoxicity (deafness), exfoliative
                           dermatitis, anaphylaxis, azotemia,
                           leucopenia, thrombocytopenia, pancytopenia,
                           hemolytic anemia, muscular weakness and
                           amblyopia. [PDR 1997]
CONTRAINDICATIONS          Contraindicated in patients with
                           hypersensitivity to streptomycin or to other
                           aminoglycosides. [PDR 1997]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Aminoglycoside antibiotic
                           obtained from cultures of Streptomycin
                           griseus. [AHFS Drug Information 1997]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: White to light gray or
                           pale buff powder with faint amine-like odor.
                           [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: (C21H39N7O12)2*3H2SO4
                           [USAN 1997]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 1457.41 [USAN 1997]
CHEMICAL/PHYSICAL DATA     SOLUBILITY: Very soluble in water, but almost
                           insoluble in alcohol, chloroform, or ether.
                           [Merck Index 1996]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Ampules containing streptomycin
                           sulfate equivalent to 1-g of streptomycin in
                           2.5 ml. [PDR 1997]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intramuscular injection.
                           [PDR 1997]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Store under
                           refrigeration at 2 to 8 C (36 to 46 F). [PDR
                           1997]
MANUFACTURERS              Pfizer Incorporated / USPG; 235 East 42nd
                     Street; New York, NY 10017-5755
REFERENCES           MED/94328758. Heym B, Honore N,
                     Truffot-Pernot C, Banerjee A, Schurra C,
                     Jacobs WR Jr. van Embden JD, Grosset JH, Cole
                     ST. Implications of multidrug resistance for
                     the future of short-course chemotherapy of
                     tuberculosis: a molecular study {see
                     comments}. Lancet. 1994 Jul 30;
                     344(8918):293-8.
REFERENCES           MED/94305146. Luo C, Chintu C, Bhal G,
                     Ravigliont M, Diwan V, DuPont HL, Zumla A.
                     Human immunodeficiency virus type-1 infection
                     in Zambian children with tuberculosis:
                     changing seroprevalence and evaluation of a
                     thioacetazone-free regimen. Tuber Lung Dis.
                     1994 Apr;75(2):110-5.
REFERENCES           MED/97221882. Peloquin CA. Mycobacterium
                     avium complex infection. Pharmacokinetic and
                     pharmacodynamic considerations that may
                     improve clinical outcomes. Clin
                     Pharmacokinet. 1997 Feb; 32:2, 132-44.
REFERENCES           MED/97215051. Pozniak A. Tuberculous
                     meningitis [letter]. Int J STD AIDS. 1997
                     Feb; 8:2, 139-40.
REFERENCES           MED/97015631. Espinal MA, Reingold AL, Perez
                     G, Camilo E, Soto S, Cruz E, Matos N,
                     Gonzalez G. Human immunodeficiency virus
                     infection in children with tuberculosis in
                     Santo Domingo, Dominican Republic:
                     prevalence, clinical findings, and response
                     to antituberculosis treatment. J Acquir
                     Immune Defic Syndr Hum Retrovirol. 1996 Oct
                     1; 13:2, 155-9.
REFERENCES           MED/97048231. Humma LM. Prevention and
                     treatment of drug resistant tuberculosis. Am
                     J Health Syst Pharm. 1996 Oct 1; 53:19,
                     2291-8; quiz 2335-6.
REFERENCES           MED/96423967. Guay DR. Nontuberculous
                     mycobacterial infections. Ann Pharmacother.
                     1996 Jul-Aug; 30:7-8, 819-30.
REFERENCES           MED/96341176. Grosset J. Current problems
                     with tuberculosis treatment. Res Microbiol.
                     1996 Jan-Feb; 147:1-2, 10-6.
REFERENCES           MED/95165491. Elliott AM, Halwiindi B, Hayes
                     RJ, Luo N, Mwinga AG, Tembo G, Machiels L,
                     Teenburgen G, Pobee JO, Nunn PP, et al. The
                     impact of human immunodeficiency virus in
                     response to treatment and recurrence rate in
                     patients treated for tuberculosis: two-year
                     follow-up of a cohort in Lusaka, Zambia. J
                     Trop Med Hyg. 1995 Feb; 98:1, 9-21.
REFERENCES           MED/95266133. Elliot AM, Halwiindi B, Hayes
                     RJ, Luo N, Mwinga AG, Tembo G, Machiels L,
                     Steenbergen G, Pobee JO, Nunn P. The impact
                     of human immunodeficiency virus on mortality
                     of patients treated for tuberculosis in a
                     cohort study in Zambia [see comments]. Trans
                     R Soc Trop Med Hyg. 1995 Jan-Feb; 89:1,
                     78-82.
ENTRY MONTH          199403
LAST REVISION DATE   19980506
107
UNIQUE IDENTIFIER        DRG-0200
NAME OF SUBSTANCE        Aminosalicylic acid [USAN 1997]
REGISTRY NUMBER          65-49-6
STANDARD CHEMICAL NAME   4-Amino-2-hydroxybenzoic acid [Merck Index
                         1996]
SYNONYMS                 PAS [Merck Index 1996]
SYNONYMS                 4-Aminosalicylic acid [Merck Index 1996]
SYNONYMS                 p-Aminosalicylic acid [Merck Index 1996]
SYNONYMS                 Deapasil [Merck Index 1996]
SYNONYMS                 Apas [Merck Index 1996]
SYNONYMS                 Apacil [Merck Index 1996]
SYNONYMS                 Pamacyl [Merck Index 1996]
SYNONYMS                 Parasal [Merck Index 1996]
SYNONYMS                 Pascorbic [Merck Index 1989]
SYNONYMS                 Pasolac [Merck Index 1996]
SYNONYMS                 Parasalicil [Merck Index 1996]
SYNONYMS                 Parasalindon [Merck Index 1996]
SYNONYMS                 Propasa [Merck Index 1996]
SYNONYMS                 Rezipas [Merck Index 1996]
SYNONYMS                 Para-Pas [Merck Index 1996]
SYNONYMS                 para-Aminosalicylic acid [CHEMLINE]
SYNONYMS                 Paser Granules [PDR 1997]
SYNONYMS                 Enteropas [Merck Index 1996]
SYNONYMS                 Lepasen [Merck Index 1996]
SYNONYMS                 Paramycin [Merck Index 1996]
SYNONYMS                 Pasalon [Merck Index 1996]
SYNONYMS                 PASER [Merck Index 1996]
PROTOCOL ID NUMBERS      NIAID ACTG 238
SECONDARY SOURCE ID      NSC-2083 [CHEMLINE]
SECONDARY SOURCE ID      HSDB 3203 [CHEMLINE]
PHARMACOLOGICAL ACTION   MODE OF ACTION: Bacteriostatic in action.
                         Mechanism of action is similar to that of
                         sulfonamides. Prevents the synthesis of folic
                         acid in susceptible organisms by
                         competitively blocking the conversion of
                         aminobenzoic acid to dihydrofolic acid. The
                         activity of aminosalicylic acid is partially
                         blocked by aminobenzoic acid. Active only
                         against M. tuberculosis. Resistant strains of
                         initially susceptible organisms develop
                         rapidly if aminosalicylic acid is used alone
                         in the treatment of clinical tuberculosis.
                         This can be delayed or prevented by
                         concurrent treatment with other
                         antituberculosis drugs. Inhibits the onset of
                         resistance to streptomycin and isoniazid.
                         Aminosalicylic acid is readily absorbed from
                         the gastrointestinal tract. Following
                         administration with food of a single 4-g oral
                         dose of the drug as enteric-coated granules
                         in healthy adults, peak serum concentration
                         of 2 ug/ml was achieved in 2 hours and
                         maintained for an average of 7.9 hours. The
                         drug is distributed into various tissues and
                         fluids in concentrations approximately equal
                         to plasma concentrations of the drug. The
                         drug is 50-73% bound to plasma proteins. The
                         plasma half-life of aminosalicylic acid is
                         approximately 1 hour. The drug is inactivated
                           in the intestinal mucosa and liver primarily
                           by acetylation. Aminosalicyclic acid and its
                           metabolites are excreted in urine by
                           glomerular filtration and tubular secretion.
                           Aminosalicylic acid and its acetyl metabolite
                           accumulate in patients with severe renal
                           disease. [AHFS Drug Information 1997]
DISEASES STUDIED/TREATED   Treatment of multi-drug resistant pulmonary
                           tuberculosis. [NIAID ACTG 238]
CLASSIFICATION CODE        Antibacterial (tuberculostatic) [USAN 1997]
OTHER MAJOR USES           Aminosalicyclic acid is indicated for the
                           treatment of tuberculosis in combination with
                           other active agents. It is most commonly used
                           in patients with Multi-drug Resistant
                           tuberculosis or in situations when therapy
                           with isoniazid and rifampin is not possible
                           due to a combination of resistance and/or
                           intolerance. [PDR 1997]
SUBSTANCE INTERACTIONS     Aminosalicylic acid has been reported to
                           interact with probenecid, diphenhydramine,
                           digoxin, oral anticoagulants, ammonium
                           chloride, and isoniazid; therefore,
                           concurrent administration of aminosalicylic
                           acid and these drugs should be avoided. [AHFS
                           Drug Information 1997; PDR 1997]
ADVERSE EFFECTS            Adverse effects include the following,
                           gastrointestinal system (most common):
                           nausea, vomiting, diarrhea, and abdominal
                           pain; hypersensitivity reactions: fever, skin
                           eruptions of various types including
                           exfoliative dermatitis, infectious
                           mononucleosis-like or lymphoma-like syndrome,
                           leukopenia, agranulocytosis,
                           thrombocytopenia, Coombs' positive hemolytic
                           anemia, jaundice, hepatitis, pericarditis,
                           hypoglycemia, optic neuritis, encephalopathy,
                           Leofflers's syndrome, and vasculitis, and a
                           reduction in prothrombin. Other adverse
                           reaction includes crystalluria. [PDR 1997]
CONTRAINDICATIONS          Contraindicated in patients with impaired
                           renal or hepatic functions and in patients
                           with gastric ulcers. Also contraindicated in
                           patients who are hypersensitive to
                           aminosalicylic acid and its congeners. [AHFS
                           Drug Information 1997]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: A synthetic analog of
                           aminobenzoic acid. [AHFS Drug Information
                           1997]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: Off-white tan colored
                           granules with an average diameter of 1.5 mm.
                           [PDR 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR FORMULA: C7H7NO3 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR WEIGHT: 153.14 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MELTING POINT: 150-151 C [Merck Index 1996]
CHEMICAL/PHYSICAL   DATA   ELEMENTAL COMP: C54.90%, H4.61%, N9.15%,
                           O31.34%. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     SOLUBILITY: Soluble in water, alcohol, dilute
                           nitric acid, dilute sodium hydroxide.
                           Slightly soluble in ether. Practically
                           insoluble in benzene. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     STABILITY: With heat, aminosalicylic acid is
                          decarboxylated to produce CO2 and
                          m-aminophenol. It is also rapidly degraded in
                          acid media. [PDR 1997]
CHEMICAL/PHYSICAL DATA    DRUG PHYSICAL COMMENT: pKa 3.25. [Merck Index
                          1996]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: 4 g packets. [PDR 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral. [PDR 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store below 15 C (59 F)
                          in a refrigerator or freezer. Avoid excessive
                          heat. [PDR 1997]
MANUFACTURERS             Jacobus Pharmaceutical Company; 37 Cleveland
                          Lane / PO Box 5290; Princeton, NJ 08540
REFERENCES                MED/97048231. Humma LM. Prevention and
                          treatment of drug-resistant tuberculosis. Am
                          J Health Syst Pharm. 1996 Oct 1; 53:19,
                          2291-8; quiz 2335-6.
REFERENCES                ICA11/96923717. Arbulu MM; Weisburd G;
                          Biglione J; Terrazzino JC. Multidrug
                          resistant tuberculosis in AIDS patients in
                          the infectious diseases service - Sala
                          1-Pol.I. Carrasco-Rosario-Argentina. Int Conf
                          AIDS. 1996 Jul 7-12; 11:2, 121 (abstract no.
                          We.B.3368).
REFERENCES                MED/96341176. Grosset J. Current problems
                          with tuberculosis treatment. Res Microbiol.
                          1996 Jan-Feb; 147:1-2, 10-6.
REFERENCES                MED/96341176. Grosset J. Current problems
                          with tuberculosis treatment. Res Microbiol.
                          1996 Jan-Feb; 147(1-2):10-6.
REFERENCES                MED/95277953. Chaloner C, Segal I, Hassan H,
                          McIntosh J, Gut A, Rahme M, Braganza JM. A
                          preliminary report on urinary BT-PABA/PAS
                          excretion index, serum pancreatic isoamylase
                          and faecal chymotrypsin tests of pancreatic
                          dysfunction in Sowetan Africans. Clin Chim
                          Acta. 1995 Jan 16; 233(1-2):89-99.
REFERENCES                94211681. Peloquin CA, Henshaw TL, Huitt GA,
                          Berning SE, Nitta AT, James GT.
                          Pharmacokinetic evaluation of
                          para-aminosalicylic acid granules.
                          Pharmacotherapy. 1994 Jan-Feb; 14(1):40-6.
REFERENCES                95063425. Heifets LB. Antimycobacterial
                          drugs. Semin Respir Infect. 1994 Jun;
                          9(2):84-103.
REFERENCES                MED/94048413. Peloquin CA. Pharmacology of
                          the antimycobacterial drugs. Med Clin North
                          Am. 1993 Nov; 77(6):1253-62.
REFERENCES                MED/92266347. el-Chaar GM, Schwenk MH,
                          Bardini J, Caliendo G, Frank C, Profeta LM,
                          Talbot KA, Cohen H. New drugs on the horizon.
                          Clin Podiatr Med Surg. 1992 Apr;
                          9(2):481-501.
ENTRY MONTH               199403
LAST REVISION DATE        19980403

108
UNIQUE IDENTIFIER         DRG-0199
NAME OF SUBSTANCE         Capreomycin sulfate [USAN 1997]
REGISTRY NUMBER           1405-37-4
STANDARD CHEMICAL NAME    Capreomycin sulfate [USAN 1997]
SYNONYMS                  Capastat Sulfate [PDR 1997]
SYNONYMS                   Caprocin [USAN 1997]
SYNONYMS                   Capostatin [Merck Index 1989]
SYNONYMS                   Ogostal [Merck Index 1996]
PROTOCOL ID NUMBERS        NIAID ACTG 238
SECONDARY SOURCE ID        34977 [USAN 1997]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Active against strains of
                           Mycobacterium tuberculosis found in humans.
                           Not absorbed in significant quantities from
                           the gastrointestinal tract and must be
                           administered parenterally. In previous
                           studies using 1 g capreomycin (IM), peak
                           serum concentrations were achieved 1 to 2
                           hours after administration, and average peak
                           levels reached were 28 and 32 mcg/ml,
                           respectively. Frequent cross-resistance
                           occurs between capreomycin and viomycin. No
                           cross-resistance has been observed between
                           capreomycin and isoniazid, aminosalicylic
                           acid, cycloserine, streptomycin, ethionamide,
                           or ethambutol. The plasma half-life of
                           capreomycin in patients with normal renal
                           function is 4-6 hours. Plasma concentrations
                           of capreomycin are higher and the half-life
                           is prolonged in patients with impaired renal
                           function. Capreomycin is excreted mainly
                           unchanged in urine by glomerular filtration.
                           Following a single 1-g intramuscular dose of
                           the drug in adults with normal renal funcion,
                           approximately 57% of the dose is excreted in
                           urine within 24 hours. [PDR 1997; AHFS Drug
                           Information 1997]
DISEASES STUDIED/TREATED   Used as second-line therapy in combination
                           with other antituberculosis drugs for
                           pulmonary tuberculosis. [PDR 1997]
CLASSIFICATION CODE        Antibacterial (tuberculostatic) [USAN 1997]
OTHER MAJOR USES           Capreomycin is to be used concomitantly with
                           other appropriate antituberculosis agents, is
                           indicated in pulmonary infection caused by
                           capreomycin-susceptible strains of
                           Mycobacterium tuberculosis when the primary
                           agents (isoniazid, rifampin, ethambutol,
                           aminosalicyclic acid and streptomycin) have
                           been ineffective or cannot be used because of
                           toxicity or the presence of resistant
                           tubercle bacilli. [PDR 1997]
SUBSTANCE INTERACTIONS     Since there is some evidence that nephrotoxic
                           and/or ototoxic effects may be additive, the
                           concurrent or sequential use of capreomycin
                           and other nephrotoxic and/or ototoxic drugs
                           including aminoglycosides, colistin,
                           polymyxin B, and vancomycin should be
                           avoided. [AHFS Drug Information 1997]
ADVERSE EFFECTS            Adverse effects include the following,
                           nephrotoxicity: elevation of BUN above 20
                           mg/ml, depression of PSP excretion, abnormal
                           urine sediment; ototoxicity: subclinical
                           auditory loss, clinically apparent hearing
                           loss, tinnitus, and vertigo; Liver: decrease
                           in BSP excretion without change in AST (SGOT)
                           or ALT(SGPT) in preexisting liver disease
                           patients, abnormal results in liver function
                          tests in patients receiving capreomycin
                          concurrently with other antituberculosis
                          agents known to cause changes in hepatic
                          function; blood: leukocytosis, leukopenia,
                          pain and induration at the injection site,
                          excessive bleeding at the injection site,
                          sterile abscesses, thrombocytopenia rarely;
                          hypersensitivity; urticaria, maculopapular
                          skin rashes associated in some cases with
                          febrile reactions in cases when capreomycin
                          and other antituberculosis drugs were given
                          concomitantly. [PDR 1997]
CONTRAINDICATIONS         Should be used with extreme caution in
                          patients with renal insufficiency or auditory
                          impairment. Contraindicated in patients who
                          are hypersensitive to capreomycin. Safe use
                          in children has not been established. Should
                          be used in pregnant women only if the
                          potential benefits outweigh the potential
                          risk to the fetus. [AHFS Drug Information
                          1997]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: Cyclic peptide antibiotic
                          similar to viomycin; produced by Streptomyces
                          capreolus; complex of four microbiologically
                          active components which have been
                          characterized in part. [Merck Index 1996; PDR
                          1997]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: White or practically
                          white, amorphous powder. [AHFS Drug
                          Information 1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C25H44N14O8.2H2SO4 [PDR
                          1997]
CHEMICAL/PHYSICAL DATA    SOLUBILITY: Freely soluble in water. [AHFS
                          Drug Information 1997]
CHEMICAL/PHYSICAL DATA    STABILITY: Reconstituted capreomycin sulfate
                          solutions are stable for 48 hours at room
                          temperature or 14 days at 2-8 C. Solutions
                          may develop a pale straw color and darken;
                          however this does not affect potency. [AHFS
                          Drug Information 1997]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Sterile capreomycin sulfate
                          equivalent to 1g of capreomycin activity
                          supplied in 10 ml-size vials. [PDR 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Intramuscular injection.
                          [PDR 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store at controlled
                          room temperature 15-30 C (59-86 F) prior to
                          reconstitution. [PDR 1997]
MANUFACTURERS             Eli Lilly and Company; 307 East McCarty
                          Street; Indianapolis, IN 46285
REFERENCES                MED/97048231. Humma LM. Prevention and
                          treatment of drug-resistant tuberculosis. Am
                          J Health Syst Pharm. 1996 Oct 1; 53:19,
                          2291-8; quiz 2335-6.
REFERENCES                ICA11/96923714. Breaux K; Graviss E; Lahart
                          C, Is there a potential benefit of
                          intermittent antimycobacterial use in
                          HIV-infected patients at risk for DMAC? Int
                          Conf AIDS. 1996 Jul 7-12; 11:2 120 (abstract
                          no. We.B.3365).
REFERENCES                96144260. Thiara AS, Cundliffe E. Analysis of
                         two capreomycin-resistance determinants from
                         Streptomyces capreolus and characterization
                         of the action of their products. Gene 1995
                         Dec 29;167(1-2):121-6.
REFERENCES               AIDS/95920152. Bonomo RA, Briggs JM, Graham
                         RG, Ward AL, Hassan M. Mycobacterium celatum
                         sp. nov. infection in the acquired
                         immunodeficiency syndrome (AIDS): description
                         of a new opportunistic pathogen. Natl Conf
                         Hum Retroviruses Relat Infect (2nd). 1995 Jan
                         29-Feb 2;:76.
REFERENCES               94166069. Wank H, Rogers J, Davies J,
                         Schroeder R. Peptide antibiotics of the
                         tuberactinomycin family as inhibitors of
                         group I intron RNA splicing. J Mol Biol 1994
                         Mar 4;236(4):1001-10
REFERENCES               94139393. Nolan CM, Sandblom RE, Thummel KE,
                         Slattery JT, Nelson SD. Hepatotoxicity
                         associated with acetaminophen usage in
                         patients receiving multiple drug therapy for
                         tuberculosis. Chest 1995 Feb;105(2):408-11.
REFERENCES               MED/95031533. Weltman AC, Rose DN.
                         Tuberculosis susceptibility patterns,
                         predictors of multidrug resistance, and
                         implications for initial therapeutic regimens
                         at a New York City hospital. Arch Intern Med.
                         1994 Oct 10;154(19):2161-7.
REFERENCES               MED/94048413. Peloquin CA. Pharmacology of
                         the antimycobacterial drugs. Med Clin North
                         Am. 1993 Nov;77(6):1253-62.
REFERENCES               MED/93160311. Cowling P, Glover S, Reeves DS.
                         Mycobacterium malmoense type II bacteraemia
                         contributing to death in a patient with AIDS.
                         Int J STD AIDS. 1992 Nov-Dec;3(6):445-6.
REFERENCES               MED/90024999. Heifets L, Lindholm-Levy P.
                         Comparison of bactericidal activities of
                         streptomycin, amikacin, kanamycin, and
                         capreomycin against Mycobacterium avium and
                         M. tuberculosis. Antimicrob Agents Chemother.
                         1989 Aug;33(8):1298-301.
ENTRY MONTH              199403
LAST REVISION DATE       19980403

109
UNIQUE IDENTIFIER        DRG-0198
NAME OF SUBSTANCE        Benztropine mesylate [USAN 1997]
REGISTRY NUMBER          132-17-2
STANDARD CHEMICAL NAME   3-(diphenylmethoxy)-8-methyl-,
                         8-azabicyclo(3.2.1) octane, methanesulfonate
                         [Merck Index 1996]
SYNONYMS                 Cogentin [PDR 1997]
SYNONYMS                 Benzatropine methanesulfonate [MeSH]
SYNONYMS                 Benztropine mesilate [CHEMLINE]
SYNONYMS                 Benzotropine mesylate [CHEMLINE]
SYNONYMS                 Benzotropine methanesulfonate [CHEMLINE]
SYNONYMS                 Cogentin methanesulfonate [CHEMLINE]
SYNONYMS                 Tropine benzohydryl ether methanesulfonate
                         [Merck Index 1996]
SYNONYMS                 1alphaH,5alphaH-Tropane,
                         3alpha-(diphenylmethoxy)-, methanesulfonate
                         [CHEMLINE]
SYNONYMS                   Cobrentin methanesulfonate [Merck Index 1996]
SYNONYMS                   3-Diphenylmethoxytropane mesylate [CHEMLINE]
SYNONYMS                   Cogentinol [Merck Index 1996]
SYNONYMS                   3 alpha-(diphenylmethoxy)-1 alpha H, 52
                           H-tropane methanesulfonate [Merck Index 1996]
SYNONYMS                   Bensylate [Physicians GenRx 97]
SYNONYMS                   Glycopyrrolate [Physicians GenRx 97]
SYNONYMS                   Phatropine [Physicians GenRx 97]
PROTOCOL ID NUMBERS        NIAID ACTG 242
PHARMACOLOGICAL ACTION     MODE OF ACTION: The anticholinergic activity
                           of benztropine is about equal to that of
                           atropine. The antihistaminic activity is
                           similar to that of pyrilamine maleate.
                           Benztropine does not produce as much central
                           stimulation as does trihexyphenidyl.
                           Benztropine effects are cumulative and may
                           not be evident until 2 or 3 days after start
                           of treatment. [AHFS Drug Information 1997]
DISEASES STUDIED/TREATED   As an active placebo to mimic the side
                           effects of study drugs. [NIAID ACTG 242]
CLASSIFICATION CODE        Anticholinergic [Merck Index 1996]
CLASSIFICATION CODE        Antiparkinsonian [USAN 1997]
OTHER MAJOR USES           Adjunct in therapy for parkinsonism; useful
                           in control of extrapyramidal disorders
                           (except tardive dyskinesia) due to
                           neuroleptic drugs. [PDR 1997]
SUBSTANCE INTERACTIONS     Interacts with antipsychotic drugs such as
                           phenothiazines or haloperidol, and with
                           tricyclic antidepressants. [PDR 1997]
ADVERSE EFFECTS            The adverse effects within the following
                           category are listed in order of decreasing
                           severity, cardiovascular effects:
                           tachycardia; digestive system: paralytic
                           ileus, constipation, vomiting, nausea, dry
                           mouth; nervous system: toxic psychosis
                           including confusion, disorientation, memory
                           impairment, visual hallucinations,
                           exacerbation of preexisting psychotic
                           symptoms, nervousness, depression,
                           listlessness, numbness of fingers; special
                           senses: blurred vision, dilated pupils;
                           urogenital: urinary retention, dysuria;
                           metabolic/immune or skin effects:
                           occasionally, an allergic reaction, e.g.,
                           skin rash, develops. Other adverse effects
                           may include heat stroke, hyperthermia, and
                           fever. [AHFS Drug Information 1997]
CONTRAINDICATIONS          Contraindicated in children under 3 years of
                           age and in patients with hypersensitivity to
                           the drug or to any compenent of the injection
                           solution. Use with caution in older children.
                           [PDR 1997]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: A synthetic tertiary amine
                           containing sturctural features found in
                           atropine and diphenydramine. [PDR 1997; AHFS
                           Drug Information 1997]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: Crystalline white
                           powder, odorless, slightly hygroscopic. [PDR
                           1997; AHFS Drug Information 1997]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C22H29NO4S [Merck Index
                           1996]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 403.54 [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     MELTING POINT: 143 C [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     ELEMENTAL COMP: C65.48%, H7.24%, N3.47%,
                           O15.86%, S7.95%. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     SOLUBILITY: Soluble in water. [Merck Index
                           1996]
CHEMICAL/PHYSICAL DATA     DRUG PHYSICAL COMMENT: pH 6. [Merck Index
                           1996]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 0.5, 1, and 2 mg tablets; 1
                           mg/ml sterile solution for injection. [PDR
                           1997]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral; intravenous;
                           intramuscular. [PDR 1997]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Tablets and injection
                           solution should be stored at a temperature
                           less than 40 C, preferably between 15-30 C;
                           freezing of the injection solution should be
                           avoided. Tablets should be stored in
                           well-closed containers. [AHFS Drug
                           Information 1997]
MANUFACTURERS              Merck and Company Inc; P.O. Box 4; West
                           Point, PA 19486
REFERENCES                 ICA5/00258889. Holmes VF. Rapid progression
                           of organic delusional syndrome to dementia in
                           AIDS. Int Conf AIDS. 1989 Jun 4-9;5:499
                           (abstract no. B.611).
ENTRY MONTH                199403
LAST REVISION DATE         19980127

110
UNIQUE IDENTIFIER          DRG-0197
NAME OF SUBSTANCE          Mexiletine hydrochloride [USAN 1997]
REGISTRY NUMBER            5370-01-4
STANDARD CHEMICAL NAME     2-Propanamine, 1-(2,6-dimethylphenoxy)-,
                           hydrochloride [USAN 1997]
SYNONYMS                   Mexitil [PDR 1997]
SYNONYMS                   Katen [Merck Index 1996]
SYNONYMS                   Ritalmex [Merck Index 1996]
SYNONYMS                   1-Methyl-2-(2,6-xyloxy)ethylamine
                           hydrochloride [USAN 1997]
PROTOCOL ID NUMBERS        NIAID ACTG 242
SECONDARY SOURCE ID        Ko 1173 Cl [USAN 1997]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Inhibits the inward sodium
                           current, thus reducing the rate of rise of
                           the action potential, Phase 0. Mexiletine
                           hydrochloride is well absorbed (approximately
                           90%) from the gastrointestinal tract. Its
                           first-pass metabolism is low. Peak blood
                           levels are reached in 2-3 hours. In normal
                           subjects, plasma elimination half-life is
                           10-12 hours. The drug is 50-60% bound to
                           plasma protein, with a volume of distribution
                           of 5-7 liters/kg. Mexiletine hydrochoride is
                           metabolized by the liver, and approximately
                           10% is excreted unchanged by the kidney.
                           Acidification accelerates the rate of
                           excretion of the drug, and alkalinization
                           retards it. Mexiletine plasma levels of at
                           least 0.5 mcg/ml are generally required for
                           therapeutic response. [PDR 1997]
DISEASES STUDIED/TREATED   Relief or reduction of pain in HIV-associated
                           peripheral neuropathy. [NIAID ACTG 242]
CLASSIFICATION CODE        Analgesic [NIAID ACTG 242]
CLASSIFICATION CODE        Cardiac depressant (anti-arrhythmic) [USAN
                           1997]
CLASSIFICATION CODE        Antiarrhythmic [Merck Index 1996]
OTHER MAJOR USES           Treatment of documented ventricular
                           tachycardia that are life threatening. [PDR
                           1997]
SUBSTANCE INTERACTIONS     No interactions were observed with commonly
                           employed antianginal, antihypertensives, and
                           anticoagulant drugs. Lowered mexiletine
                           plasma levels were reported for concurrent
                           use with some hepatic enzyme inducers such as
                           rifampin, phenytoin, or phenobarbital.
                           Concurrent use with theophylline may increase
                           plasma theophylline levels. Concurrent
                           administration of dimetidine and mexiletine
                           has been reported to increase, decrease, or
                           leave unchanged mexiletine plasma levels.
                           [PDR 1997]
ADVERSE EFFECTS            Commonly produces reversible gastrointestinal
                           and nervous system adverse reactions but is
                           otherwise well tolerated. Adverse effects may
                           include gastrointestinal distress, dizziness
                           or lightheadedness, tremor, and coordination
                           difficulties. [PDR 1997]
CONTRAINDICATIONS          Contraindicated in cardiogenic shock, or
                           pre-existing second or third degree AV block
                           (if no pacemaker is present). Should be used
                           with caution in patients with structural
                           heart disease hypotension and severe
                           congestive heart failure, liver diseases, and
                           patients with known seizure disorder. [PDR
                           1997]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Class 1B antiarrhythmic
                           compound, with electrophysiologic properties
                           in man similar to lidocaine. [PDR 1997]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: White to off-white
                           crystalline powder with slightly bitter
                           taste. [PDR 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR FORMULA: C11H18ClNO [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR WEIGHT: 215.72 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MELTING POINT: 203-205 C [Merck Index 1996]
CHEMICAL/PHYSICAL   DATA   SOLUBILITY: Freely soluble in water and in
                           alcohol. [PDR 1997]
CHEMICAL/PHYSICAL DATA     DRUG PHYSICAL COMMENT: pKa 9.2. [PDR 1997]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 150, 200, and 250 mg gelatin
                           capsules. [PDR 1997]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [PDR 1997]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Store at room
                           temperature 20-25 C (68-77 F). [PDR 1997]
MANUFACTURERS              Boehringer Ingelheim Pharmaceuticals
                           Incorporated; 900 Ridgebury Road / PO Box
                           368; Ridgefield, CT 06877
REFERENCES                 96132021. Kwok DW, Kerr CR, McErlane KM.
                           Pharmacokinetics of mexiletine enantiomers in
                           healthy human subjects. A study of the in
                           vivo serum protein binding, salivary
                           excretion and red blood cell distribution of
                           the enantiomers. Xenobiotica 1995
                           Nov;25(10):1127-42.
REFERENCES               95386737. Morita H, Hirabayashi K, Nozaki S,
                         Ohmori K, Yoshikawa K, Matsuo H. Chronic
                         effect of oral mexiletine administration on
                         left ventricular contractility in patients
                         with congestive heart failure: a study based
                         on mitral regurgitant flow velocity measured
                         by continuous-wave Doppler echocardiography.
                         J Clin Pharmacol 1995 May;35(5);478-83.
REFERENCES               AIDS/95700461. Lein B. Potential therapy for
                         painful neuropathy. PI Perspect. 1995 May;(no
                         16):11.
REFERENCES               95272094. Murakawa Y, Inoue H, Kuo TT, Sezaki
                         K, Nakajima T, Usui M, Yamashita T, Ajika K,
                         Oikawa N, Sugimoto T, et al. Prolongation of
                         intraventricular conduction time associated
                         with fatal [correction of fetal] impairment
                         of defibrillation efficiency during treatment
                         with class I antiarrhythmic agents. J
                         Cardiovasc Pharmacol 1995 Feb;25(2):194-9.
REFERENCES               AIDS/95920655. Kemper CA, Ganer A, Kent G,
                         Deresinski S. Double-blind
                         placebo(P)-controlled cross-over study fails
                         to show benefit of mexiletine (MX) in painful
                         neuropathy. Natl Conf Hum Retroviruses Relat
                         Infect (2nd). 1995 Jan 29- Feb 2;:171.
REFERENCES               95123881. Kempton J, Manoukian A, Levine B,
                         Smialek J. A mexiletine intoxication. J Anal
                         Toxicol 1994 Oct;18(6):346-7.
REFERENCES               95123883. Rohrig TP, Harty LE. Postmortem
                         distribution of mexiletine in a fatal
                         overdose. J Anal Toxicol 1994
                         Oct;18(6):354-6.
REFERENCES               92197862. Chabal C, Jacobson L, Mariano A,
                         Chaney E, Britell CW. The use of oral
                         mexiletine for the treatment of pain after
                         peripheral nerve injury. Anesthesiology. 1992
                         Apr;76(4):513-7.
REFERENCES               93105769. Stracke H, Meyer UE, Schumacher HE,
                         Federlin K. Mexiletine in the treatment of
                         diabetic neuropathy. Diabetes Care. 1992
                         Nov;15(11):1550-5.
REFERENCES               ICA7/1206891. Kent GP, Ganer A, Deresinski
                         SC. The safety and efficacy of mexiletine in
                         HIV-associated painful peripheral neuropathy
                         (PPN). Int Conf AIDS. 1991 Jun 16-21;7(1):199
                         (abstract no. M.B.2068).
ENTRY MONTH              199403
LAST REVISION DATE       19980127

111
UNIQUE IDENTIFIER        DRG-0196
NAME OF SUBSTANCE        Ethionamide [USAN 1997]
REGISTRY NUMBER          536-33-4
STANDARD CHEMICAL NAME   2-Ethyl-4-pyridinecarbothioamide [Merck Index
                         1996]
SYNONYMS                 Amidazine [Merck Index 1996]
SYNONYMS                 Ethioniamide [Merck Index 1996]
SYNONYMS                 Bayer 5312 [Merck Index 1996]
SYNONYMS                 1314 Th [Merck Index 1996]
SYNONYMS                 Nisotin [Merck Index 1996]
SYNONYMS                 Trescatyl [Merck Index 1996]
SYNONYMS                   Aetina [Merck Index 1996]
SYNONYMS                   Ethimide [Merck Index 1996]
SYNONYMS                   Iridocin [Merck Index 1996]
SYNONYMS                   Tio-Mid [Merck Index 1996]
SYNONYMS                   Trecator-SC [PDR 1997]
SYNONYMS                   2-Ethylthioisonicotinamide [USAN 1997]
SYNONYMS                   3-Ethylisothionicotinamide [Merck Index 1996]
SYNONYMS                   2-Ethyl-4-thiocarbamoylpyridine [Merck Index
                           1996]
SYNONYMS                   2-Ethylisonicotinoylthioamide [Merck Index
                           1996]
SYNONYMS                   Ethatyl [Physicians GenRx 97]
SYNONYMS                   Etiocidan [Physicians GenRx 97]
SYNONYMS                   Tubermin [Physicians GenRx 97]
PROTOCOL ID NUMBERS        NIAID ACTG 238
PHARMACOLOGICAL ACTION     MODE OF ACTION: May be bacteriostatic or
                           bactericidal in action depending on drug
                           concentration at the site of infection and
                           the susceptibility of the infecting organism.
                           Appears to inhibit peptide synthesis in
                           susceptible organisms. Active only against
                           organisms of the genus Mycobacterium, such as
                           M. tuberculosis, M. bovis, M. kansasii, and
                           some strains of M. avium and M.
                           intracellulare. Resistant strains of
                           initially susceptible M. tuberculosis develop
                           rapidly if ethionamide is used alone in the
                           treatment of clinical tuberculosis. There is
                           no evidence of cross resistance between
                           ethionamide and other antituberculosis agents
                           used in the US. Approximately 80% of an oral
                           dose of ethionamide is rapidly absorbed from
                           the gastrointestinal tract. Following a
                           single 1-g oral dose in adults, peak plasma
                           concentrations of ethionamide averaging 20
                           ug/ml are attained within 3 hours. The drug
                           is widely distributed into body tissues and
                           fluids; concentrations in plasma and various
                           organs are approximately equal. Ethionamide
                           is 10% bound to plasma proteins. The drug
                           readily crosses the placenta. The plasma
                           half-life of ethionamide is approximately 3
                           hours. It is extensively metabolized to
                           active and inactive metabolites, probably in
                           the liver. The major active metabolite is the
                           sulfoxide, which may be converted back to
                           ethionamide in vivo. Within 24 hours, 1-5% of
                           an oral dose of ethionamide is excreted in
                           urine as active drugs and metabolites; the
                           remainder is excreted in urine as inactive
                           metabolites. The gastrointestinal
                           disturbances are the most frequent adverse
                           reactions of ethionamide; they appear to be
                           dose related and may be minimized by
                           decreasing dosage or changing the time of
                           drug administration. [AHFS Drug Information
                           1997; Drug Evaluations Annual 1995]
DISEASES STUDIED/TREATED   Used as a second-line agent against
                           tuberculosis in the HIV-infected person. It
                           should be given only with other effective
                           antituberculosis drugs. [NIAID ACTG 238; Drug
                           Evaluations Annual 1995]
CLASSIFICATION CODE        Antibacterial (tuberculostatic) [USAN 1997]
OTHER MAJOR USES           Tuberculosis; leprosy. [PDR 1997; AHFS Drug
                           Information 1995]
ADVERSE EFFECTS            Adverse effects include the following,
                           gastrointestinal effects: nausea, vomiting,
                           abdominal pain, diarrhea, excessive
                           salivation, metallic taste, anorexia, and
                           weight loss; nervous system and special
                           senses effects: mental depression,
                           restlessness, drowsiness, dizziness,
                           headache, postural hypotension, asthenia
                           (occasionally), and peripheral neuritis,
                           paresthesia, seizures, tremors, a
                           pellagra-like syndrome, hallucinations,
                           diplopia, optic neuritis, blurred vision,
                           olfactory disturbances (rarely); hepatic
                           effects: transient increase in serum
                           bilirubin, AST (SGOT), and ALT (SPGT)
                           concentrations, and hepatitis. Other rare
                           adverse effects include hypersensitivity
                           reactions including rash, stomatitis,
                           photosensitivity, thrombocytopenia, and
                           purpura; goiter (with or without
                           hypothyroidism), hypoglycemia, gynecomastia,
                           impotence, menorrhagia, joint pain, acute
                           rheumatic symptoms, and acne. [AHFS Drug
                           Information 1997]
CONTRAINDICATIONS          Contraindicated in patients who develop
                           severe hypersensitivity reactions and severe
                           hepatic damage. [PDR 1997]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: A synthetic, isonicotinic
                           acid-derivative antituberculosis agent. [AHFS
                           Drug Information 1997]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: Ethionamide is a
                           yellow, crystalline, nonhygroscopic compound
                           with a faint-to-moderate sulfide odor. [PDR
                           1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR FORMULA: C8H10N2S [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MOLECULAR WEIGHT: 166.25 [USAN 1997]
CHEMICAL/PHYSICAL   DATA   MELTING POINT: 162 C [PDR 1997]
CHEMICAL/PHYSICAL   DATA   ELEMENTAL COMP: C57.80%, H6.06%, N16.85%,
                           S19.29% . [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     SOLUBILITY: Very sparingly soluble in water
                           and ether. Sparingly soluble in methanol,
                           ethanol, propylene glycol. Soluble in hot
                           acetone, dichlorethane. Freely soluble in
                           pyridine. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA     STABILITY: Stable at ordinary temperatures
                           and humidities. [PDR 1997]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 250 mg tablets. [PDR 1997]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [PDR 1997]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Store in well-closed
                           containers at a temperature less than 40 C,
                           preferably between 15-30 C. [PDR 1997; AHFS
                           Drug Information 1997]
MANUFACTURERS              Wyeth - Ayerst Laboratories; PO Box 8299;
                           Philadelphia, PA 19101
REFERENCES                 MED/97048231. Humma LM. Prevention and
                           treatment of drug-resistant tuberculosis. Am
                           J Health Syst Pharm, 1996 Oct 1,
                         53;19:2291-8; quiz 2335-6.
REFERENCES               ICA11/96924695. Phadtare JM, Saple DG, Banka
                         RB. Multiple drug resistant tuberculosis and
                         mycobacteriosis in HIV infection. Int Conf
                         AIDS.1996 Jul 7-12; 11(2):304 (abstract no.
                         Th.B.4306).
REFERENCES               ICA11/96922556. Valencia ME, Moreno V,
                         Soriano V, Laguana F, Ortega A, March J, Cobo
                         G, Lahoz J. Hepatic and/or splenic abscesses
                         formation in patients with tuberculosis (TB)
                         and AIDS. Int Conf AIDS. 1996 Jul
                         7-12;11(1):326 (abstract no. Tu.B.2354).
REFERENCES               ICA11/96921374. Mellado MJ, M-Fontelos P,
                         Cilleruelo MJ, Garcia M, Barreiro G, P-Jurado
                         ML, Ortega A, Villota J. Nosocomial outbreak
                         of multidrug resistant tuberculosis in
                         HIV-infected children. Int Conf AIDS. 1996
                         Jul 7-12;11 (1):108 (abstract no. Mo.B.1310.
REFERENCES               95349686. Stone MM, Vannier AM, Storch SK,
                         Peterson C, Nitta AT, Zhang Y. Brief report:
                         meningitis due to iatrogenic BCG infection in
                         two immunocompromised children. N Eng J Med
                         1995 Aug 31;333(9):561-3.
REFERENCES               MED/94328758. Heym B, Honore N,
                         Truffot-Pernot C, Banerjee A, Schurra C,
                         Jacobs WR Jr, van Embden JD, Grosset JH, Cole
                         ST. Implications of multidrug resistance for
                         the future of short-course chemotherapy of
                         tuberculosis: a molecular study [see
                         comments]. Lancet. 1994 Jul
                         30;344(8918):293-8.
REFERENCES               95063425. Heifets LB. Antimycobacterial
                         drugs. Semin Respir Infect. 1994
                         Jun;9(2):84-103.
REFERENCES               94112548. Banerjee A, Dubnau E, Quemard A,
                         Balasubramanian V, Um KS, Wilson T, Collins
                         D, de Lisle G, Jacobs WR Jr. inhA, a gene
                         encoding a target for isoniazid and
                         ethionamide in Mycobacterium tuberculosis
                         [see comments]. Science 1994 Jan
                         14;263(5144):227-30.
REFERENCES               ICA9/93335937. Rose DN, Weltman A. Antibiotic
                         sensitivity pattern of Mycobacterium
                         tuberculosis in a population with high
                         prevalence of AIDS and antibiotic resistance;
                         implications for choosing therapeutic
                         regimens. Int Conf AIDS. 1993 Jun
                         6-11;9(1):52 (abstract no. WS-B09-5).
ENTRY MONTH              199402
LAST REVISION DATE       19980506

112
UNIQUE IDENTIFIER        DRG-0195
NAME OF SUBSTANCE        Cycloserine [USAN 1997]
REGISTRY NUMBER          68-41-7
STANDARD CHEMICAL NAME   3-Isoxazolidinone,4-amino [USAN 1997]
SYNONYMS                 Orientomycin [Merck Index 1996]
SYNONYMS                 PA-94 [Merck Index 1996]
SYNONYMS                 106-7 [Merck Index 1996]
SYNONYMS                 Closina [Merck Index 1996]
SYNONYMS                 Farmiserina [Merck Index 1996]
SYNONYMS                   Micoserina [Merck Index 1996]
SYNONYMS                   Oxamycin [Merck Index 1996]
SYNONYMS                   Seromycin [USAN 1997]
PROTOCOL ID NUMBERS        NIAID ACTG 238
PHARMACOLOGICAL ACTION     MODE OF ACTION: Inhibits cell-wall synthesis
                           in susceptible strains of gram-positive and
                           gram-negative bacteria and in Mycobacterium
                           tuberculosis. After oral administration,
                           cycloserine is readily absorbed from the
                           gastrointestinal tract, with peak blood
                           levels occurring in 4 to 8 hours. Blood
                           levels of 25 to 30 mg/ml can generally be
                           maintained with the usual dosage of 250 mg
                           twice a day, although the relationship of
                           plasma levels to dosage is not always
                           consistent. Concentrations in the
                           cerebrospinal fluid, pleural fluid, fetal
                           blood, and mother's milk approach those found
                           in the serum. Detectable amounts are found in
                           ascitic fluid, bile, sputum, amniotic fluid,
                           and lung and lymph tissues. Approximately 65%
                           of a single dose of cycloserine can be
                           recovered in the urine within 72 hours after
                           oral administration. The remaining 35% is
                           apparently metabolized to unknown substances.
                           The maximum excretion rate occurs 2 to 6
                           hours after administration, with 50% of the
                           drug eliminated in 12 hours. [PDR 1997]
DISEASES STUDIED/TREATED   Used in the treatment of active pulmonary and
                           extrapulmonary tuberculosis (including renal
                           disease). When the causative organisms are
                           susceptible to the drug and when treatment
                           with primary medications (streptomycin,
                           isoniazid, rifampin and ethambutol) has
                           proved inadequate. Should be administered
                           with other effective chemotherapy and not as
                           the sole therapeutic agent. [PDR 1997]
CLASSIFICATION CODE        Antibacterial (tuberculostatic) [USAN 1997]
OTHER MAJOR USES           Pulmonary and extrapulmonary tuberculosis,
                           and acute urinary tract infections. [PDR
                           1997]
SUBSTANCE INTERACTIONS     Concurrent administration of ethionamide has
                           been reported to potentiate neurotoxic side
                           effects. Alcohol and cycloserine are
                           incompatible. Concurrent administration of
                           isoniazid may result in increased incidence
                           of CNS effects such as dizziness or
                           drowsiness. [PDR 1997]
ADVERSE EFFECTS            Most adverse effects occuring during
                           seromycin therapy involve the nervous system.
                           Adverse effects include convulsions,
                           drowsiness and somnolence, headache, tremor,
                           dysarthria, vertigo, confusion and
                           disorientation with loss of memory, psychoses
                           (possibly with suicidal tendencies),
                           character changes, hyperirritability,
                           aggression, paresis, hyperreflexia,
                           paresthesia, seizures, coma, allergy, skin
                           rash, and sudden development of congestive
                           heart failure (in patients receiving 1 to 1.5
                           grams). [PDR 1997]
CONTRAINDICATIONS         Contraindicated in patients with seizure
                          disorders, depression, severe anxiety or
                          psychosis, renal insufficiency, excessive use
                          of alcohol, and hypersensitivity. [PDR 1997]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: A broad-spectrum antibiotic
                          that is produced by a strain of Streptomyces
                          orchidaceus and has also been synthesized.
                          [PDR 1997]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: White to off-white
                          powder. [PDR 1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C3H6N2O2 [USAN 1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 102.09 [USAN 1997]
CHEMICAL/PHYSICAL DATA    MELTING POINT: 155-156 C (decomposes) [Merck
                          Index 1996]
CHEMICAL/PHYSICAL DATA    ELEMENTAL COMP: C35.29%, H5.92%, N27.44%,
                          O31.34%. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    SOLUBILITY: Cycloserine is soluble in water
                          and alkaline solutions. [PDR 1997]
CHEMICAL/PHYSICAL DATA    STABILITY: Forms salts with acids and bases.
                          Neutral or acid solutions are unstable.
                          Aqueous solution buffered to pH 10 with
                          sodium carbonate can be stored without loss
                          of potency for one week at refrigerator
                          temperatures. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    DRUG PHYSICAL COMMENT: Aqueous solutions have
                          a pH around 6. [Merck Index 1996]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: 250 mg capsules. [AHFS Drug
                          Information 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral. [PDR 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store at controlled
                          room temperature, 15 to 30 C. [PDR 1997]
MANUFACTURERS             Eli Lilly and Company; 307 East McCarty
                          Street; Indianapolis, IN 46285
REFERENCES                ICA11/96924695. Phadtare JM, Saple DG, Banka
                          RB. Multiple drug resistant tuberculosis and
                          mycobacteriosis in HIV infection. Int Conf
                          AIDS. 1996 Jul 7-12;11(2):304 (abstract no.
                          Th.B.4306).
REFERENCES                MED/96183051. Tamma SL, Sundaram SK, Lev M,
                          Coico RK. Inhibition of sphingolipid
                          synthesis down-modulates CD4 expression by
                          peripheral blood T lymphocytes and T lymphoma
                          cells. Biochem Biophys Res Commun. 1996 Mar
                          27;220(3):916-21.
REFERENCES                MED/96147313. Mizrachi Y, Lev M, Harish Z,
                          Sundaram SK, Rubinstein A. L-cycloserine, an
                          inhibitor of sphingolipid biosynthesis
                          inhibits HIV-1 cytopathic effects,
                          replication, and infectivity. J Acquir Immune
                          Defic Syndr Hum Retrovirol. 1996 Feb
                          1;11(2):137-41.
REFERENCES                MED/94248078. Katz MH. Effect of HIV
                          treatment on cognition, behavior, and
                          emotion. Psychiatr Clin North Am. 1994
                          Mar;17(1):227-30.
REFERENCES                95063425. Heifets LB. Antimycobacterial
                          drugs. Semin Respir Infect. 1994
                          Jun;9(2):84-103.
REFERENCES                MED/93331228. Rastogi N, David HL. Mode of
                          action of antituberculous drugs and
                          mechanisms of drug resistance in
                           Mycobacterium tuberculosis. Res Microbiol.
                           1993 Feb;144(2):133-43.
REFERENCES                 MED/94048413. Peloquin CA. Pharmacology of
                           the antimycobacterial drugs. Med Clin North
                           Am. 1993 Nov;77(6):1253-62.
REFERENCES                 MED/87053027. Rodriguez JL, Barrio JL,
                           Pitchenik AE. Pulmonary nocardiosis in the
                           acquired immunodeficiency syndrome. Diagnosis
                           with bronchoalveolar lavage and treatment
                           with non-sulphur containing drugs. Chest.
                           1986 Dec;90(6):912-4.
ENTRY MONTH                199402
LAST REVISION DATE         19980407

113
UNIQUE IDENTIFIER          DRG-0194
NAME OF SUBSTANCE          Glutamic acid hydrochloride [Facts and
                           Comparisons 1995]
REGISTRY NUMBER            138-15-8
STANDARD CHEMICAL NAME     L-glutamic acid, hydrochloride [CHEMLINE]
SYNONYMS                   Feracid [NIAID ACTG 183]
SYNONYMS                   Acidulin [Merck Index 1996]
SYNONYMS                   Acidoride [Merck Index 1996]
SYNONYMS                   Hypochylin [Merck Index 1996]
SYNONYMS                   Antalka [Merck Index 1996]
SYNONYMS                   Aciglumin [Merck Index 1996]
SYNONYMS                   Pepsdol [Merck Index 1996]
SYNONYMS                   Glutamidin [Merck Index 1996]
SYNONYMS                   Acidogen [Merck Index 1996]
SYNONYMS                   Aclor [Merck Index 1996]
SYNONYMS                   Gastuloric [Merck Index 1996]
SYNONYMS                   Glutan-HC1 [Merck Index 1996]
SYNONYMS                   Hydrionic [Merck Index 1996]
SYNONYMS                   Muriamic [Merck Index 1996]
SYNONYMS                   Glutasin [Merck Index 1996]
PROTOCOL ID NUMBERS        NIAID ACTG 183
PHARMACOLOGICAL ACTION     MODE OF ACTION: A high incidence of
                           hypochlorhydria has been reported in AIDS
                           patients, but the cause is uncertain. An
                           unselected group of 43 AIDS patients, who
                           underwent endoscopy and biopsy, were studied
                           for hypochlorhydria. It was concluded that
                           intragastric buffering of acid by refluxed
                           alkaline duodenal contents may be a cause of
                           apparent hypochlorhydria. Gastric
                           hypochlorhydria in patients with HIV/AIDS
                           also is associated with a significantly
                           higher probability of systemic mycobacterium
                           avium complex (MAC) infection, independent of
                           CD4 count. Furthermore, the absorption of
                           rifampin and rifabutin are impaired in an
                           alkaline environment, potentially limiting
                           their efficacy. [Int Conf AIDS 1996 Jul
                           7-12;11(1); Int Conf AIDS 1996 Jul
                           7-12;11(1)]
DISEASES STUDIED/TREATED   Prevention of hypochlorhydria, in order to
                           enhance absorption of oral ganciclovir.
                           [NIAID ACTG 183]
CLASSIFICATION CODE        Gastric acidifier [Facts and Comparisons
                           1995]
OTHER MAJOR USES           Gastric acidifier. [Facts and Comparisons
                          1995]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C5H10ClNO4 [Merck Index
                          1996]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 183.59 [Lancaster Research
                          Chemical]
CHEMICAL/PHYSICAL DATA    MELTING POINT: 214 F [Merck Index 1996]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: 340 mg capsules. [NIAID ACTG
                          183; Facts and Comparisons 1995]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral. [NIAID ACTG 183]
MANUFACTURERS             Major Pharmaceuticals Incorporated; 8330
                          Arjons Drive; San Diego, CA 92126
REFERENCES                94188289. Russell TL, Berardi RR, Barnett JL,
                          O'Sullivan TL, Wagner JG, Dressman JB.
                          pH-related changes in the absorption of
                          dipyridamole in the elderly. Pharm Res. 1994
                          Jan;11(1):136-43.
REFERENCES                94250008. Carver PL, Berardi RR, Knapp MJ,
                          Rider JM, Kauffman CA, Bradley SF, Atassi M.
                          In vivo interaction of ketoconazole and
                          sucralfate in healthy volunteers. Antimicrob
                          Agents Chemother. 1994 Feb;38(2):326-9.
REFERENCES                ICA11/96920889.Koch J, Scott MK, Morgan D,
                          Steuerwald M, Lor E, Cello JP. Gastric
                          hypochlorhydria is associated with
                          mycobacterium avium complex (MAC) infection
                          in patients with HIV/AIDS. Int Conf AIDS.
                          1996 Jul 7-12;11(1):18(abstract no.Mo.B.118).
REFERENCES                ICA8/92403593. Stollman N, Rotterdam H,
                          Kotier DP. Gastric histopathology in AIDS.
                          Int Conf AIDS. 1992 Jul
                          19-24;8(3):137(abstract no. PuB 7529).
REFERENCES                92174500. Knapp MJ, Berardi RR, Dressman JB,
                          Rider JM, Carver PL. Modification of gastric
                          pH with oral glutamic acid hydrochloride.
                          Clin Pharm. 1991 Nov;10(11):866-9.
ENTRY MONTH               199402
LAST REVISION DATE        19980402

114
UNIQUE IDENTIFIER         DRG-0193
NAME OF SUBSTANCE         SC-49483 [NIAID ACTG 259]
REGISTRY NUMBER           131262-82-3
SYNONYMS                  Grycovir [CHEMID]
SYNONYMS                  Perbutylated-N-butyl-1-deoxynojiromycin
                          [Toxicol Pathol. 1996 Sep-Oct; 24(5)]
PROTOCOL ID NUMBERS       NIAID ACTG 259
PHARMACOLOGICAL ACTION    MODE OF ACTION: SC-49483 does not have any
                          inherent anti-HIV activity but is converted
                          to SC-48334 in the intestinal wall. SC-48334,
                          an alpha glucosidase I inhibitor, when used
                          with AZT does appear to suppress HIV-1 in
                          vitro. A major problem with SC-48334 is
                          diarrhea with associated weight loss, thus
                          SC-49483 was developed to avoid this problem.
                          The mean oral bioavailability of SC-48334
                          from single doses of the SC-49483 was
                          estimated to be about 30% relative to the
                          single oral dose of SC-48334. SC-49483 was
                          administered orally to rats and cynomolgus
                          monkeys for 4 weeks. At dosages which gave
                          clinically meaningful plasma SC-48334
                           concentrations (8-10 mcg/ml), no diarrhea or
                           clinically severe toxicity was observed. A
                           6-month clinical study of patients receiving
                           SC-48334 plus AZT, or AZT alone showed no
                           significant difference in mean peak increase
                           in CD4 cells between the two treatment
                           groups. No further development of SC-48334 is
                           anticipated. [NIAID ACTG 259; AmFAR Tx Dir
                           1995;7(4)]
DISEASES STUDIED/TREATED   Primary HIV infection. [NIAID ACTG 259]
CLASSIFICATION CODE        Antiretroviral [NIAID ACTG 259]
ADVERSE EFFECTS            Mild adverse effects noted include headache,
                           rash, abdominal pain, diarrhea, flatulence,
                           nausea, vomiting, temperature elevation, and
                           dizziness. [NIAID ACTG 259]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 499.65 [NIAID ACTG 259]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 1 g capsules. [NIAID ACTG 259]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Oral. [NIAID ACTG 259]
MANUFACTURERS              G D Searle & Company; 4901 Searle Parkway;
                           Skokie, IL 60077
REFERENCES                 MED/96386611. Fischer PB, Karlsson GB,
                           Butters TD, Dwek RA, Platt FM.
                           N-butyldeoxynojirimycin-mediated inhibition
                           of human immunodeficiency virus entry
                           correlates with changes in antibody
                           recognition of the V1/V2 region of gp120. J
                           Virol. 1996 Oct;70(10):7143-52.
REFERENCES                 MED/96386612. Fischer PB, Karlsson GB, Dwek
                           RA, Platt FM.
                           N-butyldeoxynojirimycin-mediated inhibition
                           of human immunodeficiency virus entry
                           correlates with impaired gp120 shedding and
                           gp41 exposure. J Virol. 1996
                           Oct;70(10):7153-60.
REFERENCES                 MED/97082437. Khan KN, Snook SS, Semler DE,
                           Baron DA, Alden CL. Pathology of
                           perbutylated-N-butyl-1-deoxynojirimycin (an
                           alpha-glucosidase-1 inhibitor) in
                           Sprague-Dawley rats. Toxicol Pathol. 1996
                           Sep-Oct;24(5):531-8.
REFERENCES                 MED/96142217. Tierney M, Pottage J, Kessler
                           H, Fischl M, Richman D, Merigan T, Powderly
                           W, Smith S, Karim A, Sherman J, et al. The
                           tolerability and pharmacokinetics of
                           N-butyl-deoxynojirimycin in patients with
                           advanced HIV disease (ACTG100). The AIDS
                           Clinical Trials Group (ACTG) of the National
                           Institute of Allergy and Infectious Diseases.
                           J Acquir Immune Defic Syndr Hum Retrovirol
                           1995 Dec 15;10(5):549-53.
REFERENCES                 MED/95363994. Fischer PB, Collin M, Karlsson
                           GB, James W, Butters TD, Davis SJ, Gordon S,
                           Dwek RA, Platt FM. The alpha-glucosidase
                           inhibitor N-butyldeoxynojirimycin inhibits
                           human immunodeficiency virus entry at the
                           level of post-CD4 binding. J Virol 1995
                           Sep;69(9):5791-7.
REFERENCES                 96118653. Kiso M, Ando K, Inagaki H, Ishida
                           H, Hasegawa A. Synthetic and structural
                           studies of alpha-sialyl-(2-->6) and
                           alpha-sialyl-(2-->3) 1-deoxynojirimycin
                         derivatives potentially useful for biomedical
                         applications. Carbohydr Res 1995 Aug
                         11;272(2):159-78.
REFERENCES               MED/96021491. Cook CS, Karabatsos PJ,
                         Schoenhard GL, Karim A. Species dependent
                         esterase activities for hydrolysis of an
                         anti-HIV prodrug glycovir and bioavailability
                         of active SC-48334. Pharm Res 1995
                         Aug;12(8);1158-64.
REFERENCES               MED/94133083. Fischl MA, Resnick L, Coombs R,
                         Kremer AB, Pottage JC Jr, Fass RJ, Fife KH,
                         Powderly WG, Collier AC, Aspinall RL, et al.
                         The safety and efficacy of combination
                         N-butyl-deoxynojirimycin (SC-48334) and
                         zidovudine in patients with HIV-1 infection
                         and 200-500 CD4 cells/mm3. J Acquir Immune
                         Defic Syndr. 1994 Feb;7(2);139-47.
REFERENCES               ICA9/93334689. Bryant M, Mueller R, Smidt M,
                         Tiemeier D, Jacobs G, Platt F, Butters T,
                         Karlsson N, Houseman K, Marr J. Anti-HIV
                         properties of alpha-glucosidase inhibitor
                         SC-48334, the active component of prodrug
                         SC-49483. Int Conf AIDS. 1993 Jun
                         6-11;9(1):33 (abstract no. WS-A17-6).
ENTRY MONTH              199402
LAST REVISION DATE       19980330

115
UNIQUE IDENTIFIER        DRG-0192
NAME OF SUBSTANCE        F105 human monoclonal antibody [NIAID ACTG
                         232]
SYNONYMS                 F105 [J Acquir Immune Defic Syndr. 1993
                         Jan;6(1)]
SYNONYMS                 F105 mAb [J Clin Invest 1992 Oct;90(4)]
SYNONYMS                 mAb F105 [J Clin Invest 1992 Oct;90(4)]
SYNONYMS                 Human mAb [J Immunol 1991 Jun 15;146(12)]
SYNONYMS                 HmAb [J Immunol 1991 Jun 15;146(12)]
SYNONYMS                 Monoclonal antibody F105 [J Clin Invest 1995
                         Feb;95(2)]
PROTOCOL ID NUMBERS      NIAID ACTG 232
PHARMACOLOGICAL ACTION   MODE OF ACTION: F105 is a human monoclonal
                         antibody that binds to the CD4 binding site
                         of human immunodeficiency virus type 1 gp120
                         and neutralizes clinical and laboratory
                         isolates of the human immunodeficiency virus.
                         F105 neutralizes the IIIB, SF2 and MN strains
                         of HIV at concentrations readily achievable
                         in man (1.50 - 10 mcg/ml). The F105 antibody
                         does not neutralize some strains of virus at
                         fairly high doses in vitro assays.
                         Nonetheless, F105 does react with GP 120 from
                         these non-neutralized strains and also
                         promotes cellular immunity in the form of
                         antibody dependent cellular cytotoxicity
                         against diverse viral strains. The F105
                         epitope on GP120 is a conformational epitope
                         and overlaps significantly the CD4 binding
                         region on GP120. Other CD4 binding site Hmab
                         overlap with F105 and have similar
                         neutralization profiles. F105 offers a
                         potential alternative to RCD4-IgG as a
                           biological treatment for HIV infection
                           because it reacts with an immunogenic epitope
                           on GP120 and avoids the problems related to
                           the possible normal functions of CD4 within
                           the immune system, and lacks the potential
                           immunogenicity and instability of the
                           nonbinding structures of the CD4 portion of
                           the artificial construct. In a study
                           investigating the disposition of the antibody
                           in humans, F105 was administered over a
                           60-minute period at two dose levels, 100 and
                           500 mg/m2. Blood samples were obtained for up
                           to 56 days. The clearance of the antibody was
                           0.33 ml/min with a corresponding half-life of
                           approximately 13 days. Peak concentrations
                           achieved at the higher dose level were 216.19
                           +/- 9.62 micrograms/ml. It was concluded that
                           F105 can be administered as a bolus dose
                           every 21 days. [NIAID ACTG 232; J Clin Invest
                           1995 Feb;95(2); Clin Pharmacol Ther. 1996
                           Jun; 59(6)]
DISEASES STUDIED/TREATED   Inhibition of tumor necrosis factor
                           production in HIV infection. [NIAID ACTG 232]
CLASSIFICATION CODE        Immunomodulator [NIAID ACTG 232]
ADVERSE EFFECTS            Adverse effects include mild headache and
                           backache. F105 was well tolerated both(100 or
                           500 mg/square meta) dosing levels. [AIDS
                           Therapies 1995 Sep; AmFAR Tx Dir 1997;8(3)]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Human monoclonal antibody,
                           F105, is an IgG1 kappa antibody produced by a
                           hybridoma constructed from an
                           Epstein-Barr-virus transformant fused with a
                           human myeloma analogue. [NIAID ACTG 232;
                           AmFAR Tx Dir 1997;8(3)]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Single use 10 ml glass vials
                           containing 5.0 mg/ml of F105. [NIAID ACTG
                           232]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intravenous. [NIAID ACTG
                           232]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Should be stored at 2-8
                           C. [NIAID ACTG 232]
MANUFACTURERS              Centocor Incorporated; 200 Great Valley
                           Parkway; Malvern, PA 19355-1307
REFERENCES                 97353800. Turbica I, Simon F, Besnier JM,
                           LeJeune B, Choutet P, Goudeau A, Barin F.
                           Temporal development and prognostic value of
                           antibody response to the major neutralizing
                           epitopes of gp120 during HIV-1 infection. J
                           Med Virol. 1997 Jul;52(3):309-15.
REFERENCES                 97360027. McInerney TL, McLain L, Armstrong
                           SJ, Dimmock NJ. A human IgG1 (b12) specific
                           for the CD4 binding site of HIV-1 neutralizes
                           by inhibiting the virus fusion entry process,
                           but b12 Fab neutralizes by inhibiting a
                           postfusion event. Virology. 1997 Jul
                           7;233(2):313-26.
REFERENCES                 MED/97018136. Chen JD, Yang Q, Yang AG,
                           Marasco WA, Chen SY. Intra- and extracellular
                           immunization against HIV-1 infection with
                           lymphocytes transduced with an AAV vector
                           expressing a human anti-gp120 antibody. Hum
                         Gene Ther. 1996 Aug 20;7(13):1515-25.
REFERENCES               MED/96290506. Wolfe EJ, Cavacini LA, Samore
                         MH, Posner MR, Kozial C, Spino C, Trapnell
                         CB, Ketter N, Hammer S, Gambertoglio JG.
                         Pharmacokinetics of F105, a human monoclonal
                         antibody, in persons infected with human
                         immunodeficiency virus type 1. Clin Pharmacol
                         Ther. 1996 Jun;59(6):662-7.
REFERENCES               MED/96016013. Cavacini LA, Emes CL, Power J,
                         Desharnais FD, Duval M, Montefiori D, Posner
                         MR. Influence of heavy chain constant regions
                         on antigen binding and HIV-1 neutralization
                         by a human monoclonal antibody. J Immunol.
                         1995 Oct 1;155(7):3638-44.
REFERENCES               MED/95164706. Khouri YF, McIntosh K, Cavacini
                         L, Posner M, Pagano M, Tuomala R, Marasco WA.
                         Vertical transmission of HIV-1. Correlation
                         with maternal viral load and plasma levels of
                         CD4 binding site anti-gp120 antibodies. J
                         Clin Invest. 1995 Feb;95(2):732-7.
REFERENCES               MED/95063934. Burton DR, Pyati J, Koduri R,
                         Sharp SJ, Thornton GB, Parren PW, Sawyer LS,
                         Hendry RM, Dunlop N, Nara PL, et al.
                         Efficient neutralization of primary isolates
                         of HIV-1 by a recombinant human monoclonal
                         antibody. Science. 1994 Nov
                         11;266(5187):1024-7.
REFERENCES               MED/94179837. Cavacini LA, Emes CL, Power J,
                         Duval M, Posner MR. Effect of antibody
                         valency on interaction with cell-surface
                         expressed HIV-1 and viral neutralization. J
                         Immunol. 1994 Mar 1;152(5):2538-45.
REFERENCES               MED/94015913. Cavacini LA, Emes CL, Power J,
                         Underdahl J, Goldstein R, Mayer K, Posner MR.
                         Loss of serum antibodies to a conformational
                         epitope of HIV-1/gp120 identified by a human
                         monoclonal antibody is associated with
                         disease progression. J Acquir Immune Defic
                         Syndrome. 1993 Oct;6(10):1093-102.
REFERENCES               MED/93108253. Posner MR, Cavacini LA, Emes
                         CL, Power J, Byrn R. Neutralization of HIV-1
                         by F105, a human monoclonal antibody to the
                         CD4 binding site of gp120. J Acquir Immune
                         Defic Syndr. 1993 Jan;6(1):7-14.
ENTRY MONTH              199401
LAST REVISION DATE       19980406

116
UNIQUE IDENTIFIER        DRG-0191
NAME OF SUBSTANCE        Anti-Rh antibodies [NCI 93 C-155]
SYNONYMS                 Anti-D [NCI 93 C-155]
SYNONYMS                 WinRho [Blood. 1997 Apr 15;89(8)]
SYNONYMS                 WinRHO SD [Blood. 1997 Apr 15;89(8)]
PROTOCOL ID NUMBERS      NCI 93 C-155
PHARMACOLOGICAL ACTION   MODE OF ACTION: Patients with classic immune
                         thrombocytopenic pupura (ITP) or HIV-related
                         thrombocytopenia and acute or chronic disease
                         at the time of the intial anti-D treatment
                         were studied. The group with the best results
                         is HIV- children, but all patient groups
                         respond and the effect lasts more than 21
                           days in 50% of the responders. Duration of
                           response is not influenced by HIV status;
                           futhermore, HIV+ patients show no adverse
                           effects on hemoglobin decrease or HIV disease
                           progression. Other studies also showed that
                           Anti-Rh(D) immunoglobulin is a safe and
                           easily administered treatment, at low cost
                           and slightly lower in efficacy compared with
                           i.v.IG (intravenous immunoglobulin). [Blood.
                           1997 Apr 15;89(8); Pediatr Med Chir. 1993
                           Jul-Aug;15(4)]
DISEASES STUDIED/TREATED   HIV-associated thrombocytopenia. [NCI 93
                           C-155]
CLASSIFICATION CODE        Immunomodulator [NCI 93 C-155]
ADVERSE EFFECTS            Anti-D is a safe treatment providing a
                           hemostatic platelet increase in greater than
                           70% of the Rh+ non-splenectomized patients.
                           [Blood. 1997 Apr 15;89(8)]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intravenous. [NCI 93 C-155]
MANUFACTURERS              Drugs are provided by each participating unit
                           site
REFERENCES                 MED/97261972. Scaradavou A, Woo B, Woloski
                           BM, Cunningham-Rundles S, Ettinger LJ,
                           Aledort LM, Bussel JB. Intravenous anti-D
                           treatment of immune thrombocytopenic purpura:
                           experience in 272 patients. Blood. 1997 Apr
                           15;89(8):2689-700.
REFERENCES                 MED/94089497. Mascarin M, Trovo MG, Ventura
                           A. [Anti-Rh(D): an efficacious therapeutic
                           alternative in autoimmune hemocytopenias].
                           Pediatr Med Chir. 1993 Jul-Aug;15(4):349-52.
REFERENCES                 ICA8/92403493. Pinier Y, Pradier C, Bernard
                           E, Durant J, Dellamonica P. Interest of
                           anti-D immunoglobulins (IgG) for treatment of
                           AIDS or ARC patients with severe
                           thrombopenia. Int Conf AIDs. 1992 Jul
                           19-24;8(3):121 (abstract no. PuB 7437).
REFERENCES                 MED/92256204. Gringeri A, Cattaneo M,
                           Santagostino E, Mannucci PM. Intramuscular
                           anti-D immunoglobulins for home treatment of
                           chronic immune thrombocytopenic purpura. Br J
                           Haematol. 1992 Mar;80(3):337-40.
REFERENCES                 97406385. Smith NA, Boughton BJ. The
                           treatment of autoimmune thrombocytopaenic
                           purpura with anti-D immunoglobulin: similar
                           platelet responses in homozygous and
                           heterozygous Rh(D) positive patients.
                           Transfus Med. 1991 Sep;1(3):183-5.
REFERENCES                 ICA7/1234091. Gringeri A, Santagostino E,
                           Cattaneo M, Simoni L, Tradati F. Anti-D
                           immunoglobulins (IgG) for long-term treatment
                           of patients with HIV-related or idiopathic
                           immune thrombocytopenic purpura (ITP). Int
                           Conf AIDS. 1991 Jun 16-21;7(1):267 (abstract
                           no. M.B.2340).
REFERENCES                 MED/91208398. Bussel JB, Graziano JN,
                           Kimberly RP, Pahwa S, Aledort LM. Intravenous
                           anti-D treatment of immune thrombocytopenic
                           purpura: analysis of efficacy, toxicity, and
                           mechanism of effect [see comments]. Blood.
                           1991 May 1;77(9):1884-93.
REFERENCES                 ICA6/20052190. Santagostino E, Cattaneo M,
                           Capitanio A, Gringeri A, Tradati F, Mannucci
                           PM. Anti-D immunoglobulin for treatment of
                           immune thrombocytopenic purpura (ITP):
                           comparison between HIV-related ITP and
                           idiopathic ITP. Int Conf AIDS. 1990 Jun
                           20-23;6(2):208 (abstract no. F.B.521).
REFERENCES                 MED/90264050. Babu PG, Cherian T, Jairaj PK,
                           Jayakumari H, John TJ. Lack of evidence for
                           seroconversion to human immunodeficiency
                           virus in recipients of anti-D immunoglobulin
                           containing HIV antibody. Indian J Med Res.
                           1990 Mar;91:81-3.
ENTRY MONTH                199311
LAST REVISION DATE         19980330

117
UNIQUE IDENTIFIER          DRG-0190
NAME OF SUBSTANCE          Paclitaxel [USAN 1997]
REGISTRY NUMBER            33069-62-4
STANDARD CHEMICAL NAME     Tax-11-en-9-one,
                           5beta,20-epoxy-1,2alpha,4,7beta,10beta,
                           13alpha-a-hexahydroxy-, 4,10-diacetate
                           2-benzoate, 13-ester with
                           (2R,3S)-N-benzoyl-3-phenylisoserine. [CHEMID]
SYNONYMS                   Taxol [USAN 1997]
SYNONYMS                   Taxol A [Merck Index 1989]
PROTOCOL ID NUMBERS        FDA 273A
PROTOCOL ID NUMBERS        NCI 93 C-193
SECONDARY SOURCE ID        NSC-125973 [USAN 1997]
SECONDARY SOURCE ID        BMS-181339-01 [USAN 1997]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Promotes the assembly of
                           microtubules and inhibits the tubulin
                           disassembly process. Following IV doses,
                           paclitaxel plasma levels decline in a
                           biphasic manner. The initial rapid decline
                           represents distribution to the peripheral
                           compartment and elimination of the drug.
                           After IV doses of 15-275 mg/m2 as 1, 6 or 24
                           h infusions, mean values for cumulative
                           urinary recovery of unchanged drug ranged
                           from 1.3% to 12.6% of the dose, indicating
                           extensive nonrenal clearance. High drug
                           concentrations have been reported in the
                           bile. The efficacy of paclitaxel in treating
                           AIDS-related Kaposi's sarcoma was evaluated
                           in clinical trials by assessing cutaneous
                           tumor response and by seeking evidence of
                           clinical benefits in patients. The objective
                           response rate was 59% in patients with prior
                           systemic therapy. The median time to response
                           was 8.1 weeks and the median duration of
                           reponse was 10.4 months. Other patient
                           benefits included instances of improved
                           pulmonary function in patients with pulmonary
                           involvement, improved ambulation, or
                           resolution of ulcers. [PDR 1997;
                           MeadJohnson/Bristol-Myers Squibb Package
                           Insert 8/97]
DISEASES STUDIED/TREATED   FDA approved (8/5/97) for the second-line
                           treatment of AIDS-related Kaposi's sarcoma.
                         [MeadJohnson/Bristol-Myers Squibb Package
                         Insert 8/97]
CLASSIFICATION CODE      Antineoplastic (adjunct) [USAN 1997]
OTHER MAJOR USES         Breast cancer and metastatic carcinoma of the
                         ovary. [PDR 1997]
SUBSTANCE INTERACTIONS   Combinations involving any of the following
                         medications or therapies may interact with
                         this drug: blood dyscrasia-causing
                         medications, bone marrow depressants or
                         radiation therapy, killed virus vaccines,
                         live virus vaccines. When paclitaxel was
                         given as sequential infusion with cisplatin,
                         myelosuppression was more profound when
                         paclitaxel was given after cisplatin than
                         with the alternate sequence. In the absence
                         of formal clinical studies, caution should be
                         used when giving paclitaxel concomitantly
                         with substrates or inhibitors of the
                         cytochrome P 450 isoenzymes CYP2C8 and CYP3A4
                         (all involved in the metabolism of
                         paclitaxel). [USP DI 1997;
                         MeadJohnson/Bristol-Myers Squibb Package
                         Insert 8/97]
ADVERSE EFFECTS          Adverse effects include neutropenia,
                         peripheral neuropathy, mucositis, alopecia,
                         N/V, diarrhea, cardiotoxicity, and
                         hypotension. The adverse events profile of
                         paclitaxel in patients with advanced HIV
                         disease and poor-risk AIDS-related Kaposi's
                         sarcoma was generally similar to that seen in
                         patients with solid tumors. In this
                         immunosuppressed patient population, a
                         lower-dose intensity of paclitaxel and
                         supportive therapy including hematopoietic
                         growth factors are recommended. Patients with
                         AIDS-related Kaposi's sarcoma may have more
                         severe hematologic toxicities than patients
                         with solid tumors. [MeadJohnson/Bristol-Myers
                         Squibb Package Insert 8/97]
CONTRAINDICATIONS        Contraindicated in patients who have a
                         history of hypersensitivity reactions to
                         paclitaxel. Should not be used in patients
                         with AIDS-related Kaposi's sarcoma with
                         baseline neutrophil counts of <1000
                         cell/cubic mm. Patients with a history of
                         severe hypersensitivity reaction to products
                         containing Cremophor (polyoxyethylated castor
                         oil) should not be treated with paclitaxel.
                         [PDR 1997; MeadJohnson/Bristol-Myers Squibb
                         Package Insert 8/97]
CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: A natural or semisynthetic
                         diterpene extracted from the bark of the
                         Western (Pacific) yew (Taxus brevifolia) or
                         from needles and twigs of a more prevalant
                         yew (Taxus baccata). [AHFS Drug Information
                         1997]
CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: Clear colorless to
                         slightly yellow viscous solution or a white
                         to off-white crystalline powder. [PDR 1997]
CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C47H51NO14 [USAN 1997]
CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 853.92 [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    MELTING POINT: 213-216 C [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    ELEMENTAL COMP: C66.11% H6.02% N1.64%
                          O26.23%. [Merck Index 1996]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Single dose vials, 30 mg/5 mL,
                          100 mg/16.7 mL. [PDR 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Intravenous infusion. [PDR
                          1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store at 2-25 C (36-77
                          F) and protect from light. [PDR 1997]
MANUFACTURERS             Drugs are provided by each participating unit
                          site
REFERENCES                ICDB/97636617. Hausner P, Otterson G, McElroy
                          K, Curt GA. Performance status in clinical
                          oncology: different import in protocol and
                          non-protocol settings (Meeting abstract).
                          Proc Annu Meet Am Soc Clin Oncol;15:A1617
                          1996.
REFERENCES                ICDB/97635859. Mega A, Akhtar MS, Safran H,
                          Rich J, Sikov W, Flanigan T. Low dose weekly
                          paclitaxel for HIV associated Kaposi's
                          sarcoma (Meeting abstract). Proc Annu Meet Am
                          Soc Clin Oncol;15:A859 1996.
REFERENCES                ICDB/97635854. Gill PS, Tulpule A, Reynolds
                          T, Hadjenberg J, Mocharnuk R, Espina BM,
                          Bresnahan J, Cabriales S, Ilaw M, Shea K, et
                          al. Paclitaxel (Taxol) in the treatment of
                          relapsed or refractory advanced AIDS-related
                          Kaposi's sarcoma (Meeting abstract). Proc
                          Annu Meet Am Soc Clin Oncol;15:A854 1996.
REFERENCES                ICDB/97636258. Younes A, Romaguera J, Sarris
                          A, North L, Preti A, Hagemeister F,
                          McLaughlin P, Rodriguez MA, Cabanillas F.
                          Phase II trial of infusional taxol and high
                          dose cytoxan with granulocyte colony
                          stimulating factor (filgrastim) for the
                          treatment of relapsed/refractory intermediate
                          grade non-Hodgkin's lymphoma (NHL) (Meeting
                          abstract). Proc Annu Meet Am Soc Clin
                          Oncol;15:A1258 1996.
REFERENCES                MED/96140305. Sarris AH, Younes A, McLaughlin
                          P, Moore D, Hagemeister F, Swan F, Rodriguez
                          MA, Romaguera J, North L, Mansfield P,
                          Callendar D, Mesina O, Cabanillas F.
                          Cyclosporin A does not reverse clinical
                          resistance to paclitaxel in patients with
                          relapsed non-Hodgkin's lymphoma. J Clin
                          Oncol. 1996 Jan;14(1):233-9.
REFERENCES                MED/96228966. Arbuck SG. Paclitaxel: current
                          developmental approaches of the National
                          Cancer Institute. Semin Oncol. 1995 Dec;22(6
                          Suppl 15):55-63.
REFERENCES                MED/96050094. Sweet MJ, Hume DA. RAW264
                          macrophages stably transfected with an HIV-1
                          LTR reporter gene provide a sensitive
                          bioassay for analysis of signalling pathways
                          in macrophages stimulated with
                          lipopolysaccharide, TNF-alpha or taxol. J
                          Inflamm. 1995;45(2):126-35.
REFERENCES                MED/95326733. Saville MW, Lietzau J, Pluda
                          JM, Feuerstein I, Odom J, Wilson WH, Humphrey
                          RW, Feigal E, Steinberg SM, Broder S, et al.
                         Treatment of HIV-associated Kaposi's sarcoma
                         with paclitaxel. Lancet. 1995 Jul
                         1;346(8966):26-8.
REFERENCES               AIDS/95920166. Saville MW, Lietzau J, Pluda
                         JM, Wilson W, Bailey J, Cohen R, Feigal F,
                         Feuerstein I, Humphrey R, Broder S, et al.
                         Use of paclitaxel (Taxol(TM)) as therapy for
                         HIV-associated Kaposi's sarcoma (KS). Natl
                         Conf Hum Retroviruses Relat Infect (2nd).
                         1995 Jan 29-Feb 2;:79.
REFERENCES               ICDB/96615860. Saville MW, Lietzau J, Pluda
                         M, Wilson W, Bailey J, Cohen R, Feigal E,
                         Humphrey R, Broder S, Yarchoan R. Phase II
                         study of paclitaxel (Taxol) for the treatment
                         of HIV-associated Kaposi's sarcoma (KS)
                         (Meeting abstract). Blood;84(10,Suppl 1):248a
                         1994.
ENTRY MONTH              199310
LAST REVISION DATE       19980330

118
UNIQUE IDENTIFIER         DRG-0189
NAME OF SUBSTANCE         Tumor Necrosis Factor soluble
                          receptor-immunoadhesin complex [NIAID
                          93-I-206]
SYNONYMS                  rhu TNFR:Fc [NIAID 93-I-206]
SYNONYMS                  TNFR:Fc [NIAID 93-I-206]
PROTOCOL ID NUMBERS       NIAID ACTG 928
PROTOCOL ID NUMBERS       NIAID 93 I-206
PHARMACOLOGICAL ACTION    MODE OF ACTION: Tumor necrosis factor-alpha
                          (TNF-alpha) is a naturally occuring cytokine
                          with many functions in the human immune
                          system. TNF-alpha levels are elevated in HIV+
                          people, and TNF-alpha may play a role in the
                          pathogenesis of HIV disease. TNF-alpha may
                          also be implicated in the wasting syndrome
                          associated with HIV disease. In vitro,
                          TNFR:Fc (a TNF-alpha blocking agent) has been
                          shown to inhibit TNF-alpha induced expression
                          of HIV-1 and limit the activation of the
                          HIV-long terminal repeat transcription in
                          chronically infected human cell lines.
                          TNFR:Fc bind to TNF-alpha and TNF-gamma,
                          whereas anti-TNF antibodies bind largely to
                          TNF-alpha. A dose ranging safety study in
                          which TNFR:Fc was administered subcutaneously
                          twice weekly for 8 weeks to HIV+ subjects
                          with CD4 count <200 cells/cubic mm showed
                          that while the doses were well tolerated, no
improvement occurred in immunologic or
                          virologic parameters. [AmFAR Tx Dir
                          1997;8(3)]
DISEASES STUDIED/TREATED Inhibition of tumor necrosis factor
                          production in HIV infection. [AmFAR Tx Dir
                          1995;7(4)]
CLASSIFICATION CODE       Immunomodulator [AmFAR Tx Dir 1995;7(4)]
ADVERSE EFFECTS           Adverse effects include skin rash and chest
                          tightness (single IV dose). [AmFAR Tx Dir
                          1997;8(3)]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: A TNF blocking agent.
                          [NIAID 93-I-206]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: TNFR:Fc is a
                          recombinantly produced dimer composed of two
                          molecules of the tumor necrosis factor (TNF)
                          receptor linked by the Fc portion of
                          immunoglobulin. [AmFAR Tx Dir 1997;8(3)]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Subcutaneous. [NIAID
                          93-I-206]
MANUFACTURERS             Natl Inst of Allergy & Infect Dis / Cln Ctr;
                          9000 Rockville Pike / RM 11C304; Bethesda, MD
                          20892
REFERENCES                MED/97296311. Cope AP, Liblau RS, Yang XD,
                          Congia M, Laudanna C, Schreiber RD, Probert
                          L, Kollias G, McDevitt HO. Chronic tumor
                          necrosis factor alters T cell responses by
                          attenuating T cell receptor signaling. J Exp
                          Med. 1997 May 5;185(9):1573-84.
REFERENCES                MED/97107749. Lynch DH, Campbell KA, Miller
                          RE, Badley AD, Paya CV. FasL/Fas and TNF/TNFR
                          interactions in the regulation of immune
                          responses and disease. Behring Inst Mitt.
                          1996 Oct;(7):175-84.
REFERENCES                MED/97180787. Kreuzer KA, Rockstroh JK,
                          Jelkmann W, Theisen A, Spengler U, Sauerbruch
                          T. Inadequate erythropoietin response to
                          anaemia in HIV patients: relationship to
                          serum levels of tumor necrosis factor-alpha,
                          interleukin-6 and their soluble receptors. Br
                          J Haematol. 1997 Feb;96(2):235-9.
REFERENCES                MED/97085691. Rizzardi GP, Barcellini W,
                          Tambussi G, Lillo F, Malnati M, Perrin L,
                          Lazzarin A. Plasma levels of soluble CD30,
                          tumor necrosis factor (TNF)-alpha and TNF
                          receptors during primary HIV-1 infection:
                          correlation with HIV-1 RNA and the clinical
                          outcome. AIDS. 1996 Nov;10(13):F45-50.
REFERENCES                MED/96198880. Granowitz EV, Saget BM, Angel
                          JB, Wang MZ, Wang A, Dinarello CA, Skolnik
                          PR. Soluble tumor necrosis factor receptors
                          inhibit phorbol myristate acetate and
                          cytokine-induced HIV-1 expression in
                          chronically infected U1 cells. J Acquir
                          Immune Defic Syndr Hum Retrovirol. 1996 Apr
                          15;11(5):430-7.
REFERENCES                MED/95181808. Agostini C, Zambello R, Trentin
                          L, Cerutti A, Enthammer C, Facco M, Milani A,
                          Sancetta R, Garbisa S, Semenzato G.
                          Expression on TNF receptors by T cells and
                          membrane TNF-alpha by alveolar macrophages
                          suggests a role for TNF-alpha in the
                          regulation of the local immune responses in
                          the lung of HIV-1-infected patients. J
                          Immunol. 1995 Mar 15;154(6):2928-38.
REFERENCES                MED/95209276. Wilt SG, Milward E, Zhou JM,
                          Nagasato K, Patton H, Rusten R, Griffin DE,
                          O'Connor M, Dubois-Dalcq M. In vitro evidence
                          for a dual role of tumor necrosis
                          factor-alpha in human immunodeficiency virus
                          type 1 encephalopathy [see comments]. Ann
                          Neurol. 1995 Mar;37(3):381-94.
REFERENCES                MED/95318750. Puccioni-Sohler M, Rieckmann P,
                          Kitze B, Lange P, Albrecht M, Felgenhauer K.
                         A soluble form of tumour necrosis factor
                         receptor in cerebrospinal fluid and serum of
                         HTLV-1-associated myelopathy and other
                         neurological diseases. J Neurol. 1995
                         Mar;242(4):239-42.
REFERENCES               MED/94340806. Zangerle R, Fuchs D, Sarcletti
                         M, Gallati H, Reibnegger G, Wachter H,
                         Dierich MP, Most J. Increased concentrations
                         of soluble tumor necrosis factor receptor 75
                         but not of soluble intercellular adhesion
                         molecule-1 are associated with the decline of
                         CD4+ lymphocytes in HIV infection. Clin
                         Immunol Immunopathol. 1994 Sep;72(3):328-34.
REFERENCES               MED/93211956. Howard OM, Clouse KA, Smith C,
                         Goodwin RG, Farrar WL. Soluble tumor necrosis
                         factor receptor: inhibition of human
                         immunodeficiency virus activation. Proc Natl
                         Acad Sci USA. 1993 Mar 15;90(6):2335-9.
ENTRY MONTH              199309
LAST REVISION DATE       19980406

119
UNIQUE IDENTIFIER        DRG-0188
NAME OF SUBSTANCE        Paromomycin sulfate [USAN 1997]
REGISTRY NUMBER          1263-89-4
STANDARD CHEMICAL NAME   D-Streptamine,
                         O-2-amino-2-deoxy-alpha-D-glucopyranosyl-(1
                         to
                         4)-O-[O-2,6-diamino-2,6-dideoxy-beta-L-idopyr-
                         anosyl-(1 to 3)-beta-D-ribofuranosyl-(1 to
                         5)]-2-deoxy-, sulfate (salt) [USAN 1997]
SYNONYMS                 Humatin [USAN 1997]
SYNONYMS                 Amminosidin [Merck Index 1996]
SYNONYMS                 Catenulin [Merck Index 1996]
SYNONYMS                 Crestomycin [Merck Index 1996]
SYNONYMS                 Estomycin [Merck Index 1996]
SYNONYMS                 Hydroxymycin [Merck Index 1996]
SYNONYMS                 Monomycin A [Merck Index 1996]
SYNONYMS                 Neomycin E [Merck Index 1996]
SYNONYMS                 Paucimycin [Merck Index 1996]
SYNONYMS                 O-2,6-Diamino-2,6-dideoxy
                         -beta-L-idopyranosyl-(1 to 3)-O
                         -beta-D-ribofuranosyl- (1 to 5)-O-
                         [2-amino-2-deoxy-alpha-D-glucopyranosyl- (1
                         to 4)]-2-deoxystreptamine sulfate (salt)
                         [USAN 1993]
SYNONYMS                 Paromomycin I [Merck Index 1996]
SYNONYMS                 Aminosidine Sulfate [USAN 1996]
PROTOCOL ID NUMBERS      NIAID ACTG 192
PHARMACOLOGICAL ACTION   MODE OF ACTION: Under aerobic conditions, the
                         aminoglycosides are bactericidal, but their
                         exact mechanism of action is unknown. These
                         antibiotics must be actively transported
                         across the cytoplasmic membrane into
                         susceptible bacteria; two sequential
                         energy-dependent phases, called EDP-1 and
                         EDP-II and characterized by slow and very
                         rapid rates of uptake, respectively, have
                         been observed. Based on studies done
                         primarily of streptomycin, the bacterial
                         ribosome is considered to be the principal
                           target of the aminoglycosides. It is still
                           not known why the aminoglycosides are
                           bactericidal, while other antibiotics that
                           impair protein synthesis are usually only
                           bacteriostatic. Bacterial cell death does not
                           appear to correlate with the production of
                           faulty proteins due to misreading of the
                           genetic code. The lethal effect of the
                           aminoglycosides may result from their high
                           affinity for the 30S subunit that leads to
                           essentially irreversible binding, but other
                           mechanisms may be involved. Paromomycin is
                           active against many gram-negative bacilli,
                           principally members of the Enterobacteriaceae
                           (e.g., Escherichia coli). Pseudomonas
                           aeruginosa are resistant, however. Many
                           strains of Staphylococcus aureus are
                           susceptible, but most other gram-positive
                           bacteria are resistant. Paromomycin is a
                           luminal amebicide. Entamoeba histolytica, the
                           causative organism of amebiasis, Dentamoeba
                           fragilis, and various tapeworms, including
                           Taenia saginata, T. solium, Diphyllobothrium
                           latum, Dipylidium caninum, and Hymenolepis
                           nana, are susceptible to paromomycin.
                           Paromomycin is poorly absorbed in the
                           gastrointestinal tract, and most of a single
                           dose is eliminated in the feces.
                           Nevertheless, to avoid excessive absorption,
                           the drug should be used with caution in
                           patients with renal failure, intestinal
                           inflammation, or ulcerations. [Drug
                           Evaluations Annual 1992; AHFS Drug
                           Information 1997]
DISEASES STUDIED/TREATED   Currently being investigated for treatment of
                           cryptosporidiosis. [AmFAR Tx Dir 1997;8(3);
                           NIAID ACTG 192]
CLASSIFICATION CODE        Antibiotic [AHFS Drug Information 1997]
CLASSIFICATION CODE        Amebicidal [USAN 1997]
CLASSIFICATION CODE        Anthelmintic [Drug Evaluations Annual 1992]
OTHER MAJOR USES           Intestinal amebiasis- acute and chronic;
                           management of hepatic coma- as adjunctive
                           therapy; cestodiasis (tapeworm infections).
                           [AHFS Drug Information 1997]
SUBSTANCE INTERACTIONS     Penicillins (antipseudomonal penicillins),
                           ethacrynic acid, furosemide, bumentanide,
                           skeletal muscle relaxants, methoxyflurane,
                           amphotericin B, vancomycin, cisplatin,
                           cyclosporine, intravenous indomethacin,
                           cephalothin, and dimenhydrinate all have
                           reported interactions with the
                           aminoglycosides. [Drug Evaluations Annual
                           1992; Facts and Comparisons 1995]
ADVERSE EFFECTS            May cause nausea, abdominal cramps, and
                           diarrhea, particularly when doses exceed 3 g
                           daily. Overgrowth of non-susceptible
                           organisms and a malabsorption syndrome may
                           occur after prolonged administration.
                           Possibility of nephrotoxicity in patients
                           with ulcerative lesions. [Drug Evaluations
                           Annual 1992; AHFS Drug Information 1997]
CONTRAINDICATIONS         Contraindicated in patients with a history of
                          previous hypersensitivity to the drug. Also
                          contraindicated in those with intestinal
                          obstruction or ulcerative lesions. [AHFS Drug
                          Information 1997; Drug Evaluations Annual
                          1992]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: An aminoglycoside
                          antibiotic derived from Streptomyces rimosus
                          and structurally related to neomycin,
                          streptomycin and kanamycin. [AHFS Drug
                          Information 1997]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: Amorphous white powder.
                          [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C23H45N5O14.XH2SO4 [USAN
                          1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 615.65 [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    ELEMENTAL COMP: C44.87%, H7.37%, N11.38%,
                          O36.38%. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    SOLUBILITY: Soluble in water, moderately
                          soluble in methanol, sparingly soluble in abs
                          ethanol. [Merck Index 1996]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Capsules 250 mg. [AHFS Drug
                          Information 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral. [AHFS Drug
                          Information 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store in tightly closed
                          containers at 15-30 C. [AHFS Drug Information
                          1997]
MANUFACTURERS             Warner - Lambert Parke - Davis; 2800 Plymouth
                          Road; Ann Arbor, MI 48105
REFERENCES                MED/97416465. Clark RA, Bessinger R. Re:
                          Cryptosporidiosis among patients infected
                          with human immunodeficiency virus: factors
                          related to symptomatic infection and
                          survival [letter]. Am J Epidemiol. 1997 Aug
                          15;146(4):358-9.
REFERENCES                MED/97250598. Ventura G, Cauda R, Larocca LM,
                          Riccioni ME, Tumbarello M, Lucia MB. Gastric
                          cryptosporidiosis complicating HIV infection:
                          case report and review of the literature. Eur
                          J Gastroenterol Hepatol. 1997
                          Mar;9(3):307-10.
REFERENCES                MED/97215047. Blanshard C, Shanson DC,
                          Gazzard BG. Pilot studies of azithromycin,
                          letrazuril and paromomycin in the treatment
                          of cyptosporidiosis. Int J STD AIDS. 1997
                          Feb;8(2):124-9.
REFERENCES                AIDS/97926685. Hewitt RG, Yiannoutsos CT,
                          Carey J, Geiseler PJ, Soave R, Rosenberg R,
                          Vazquez GJ, Wheat J, Fass RJ, Higgs ES, et
                          al. A double-blind, placebo-controlled trial
                          of paromomycin (par) for the treatment of
                          cryptosporidiosis (cs) in patients with
                          advanced HIV disease and CD4 counts under 150
                          (ACTG 192). 4th Conf Retro and Opportun
                          Infect. 1997 Jan 22-26;:65 (abstract no. 4).
REFERENCES                MED/96202857. Flanigan TP, Ramratnam B,
                          Graeber C, Hellinger J, Smith D, Wheeler D,
                          Hawley P, Heath-Chiozzi M, Ward DJ, Brummitt
                          C, Turner J. Prospective trial of paromomycin
                          for cryptosporidiosis in AIDS. Am J Med. 1996
                         Mar;100(3):370-2.
REFERENCES               MED/96263610. Caramello P, Mazzucco G, Romeo
                         M, Ullio A, DeRosa G, Lucchini A, Forno B,
                         Brancale T, Macor A, Preziosi C, et al.
                         Clinical and microscopical features of
                         small-intestinal microsporidiosis in patients
                         with AIDS. Infection. 1995
                         Nov-Dec;23(6):362-8.
REFERENCES               MED/95226747. Tan WW, Chapnick EK, Abter EI,
                         Haddad S, Zimbalist EH, Lutwick LI.
                         Paromomycin-associated pancreatitis in
                         HIV-related cryptosporidiosis. Ann
                         Pharmacother. 1995 Jan;29(1):22-4.
REFERENCES               MED/95126196. Mohri H, Fujita H, Asakura Y,
                         Katoh K, Okamoto R, Tanabe J, Harano H,
                         Noguchi T, Inayama Y, Amano T, et al. Case
                         report: inhalation therapy of paromomycin is
                         effective for respiratory infection and
                         hypoxia by cryptosporidium with AIDS. Am J
                         Med Sci. 1995 Jan;309(1):60-2.
REFERENCES               MED/95052871. Scaglia M, Atzori C, Marchetti
                         G, Orso M, Maserati R, Orani A, Novati S,
                         Olliaro P. Effectiveness of aminosidine
                         (paromomycin) sulfate in chronic
                         Cryptosporidium diarrhea in AIDS patients: an
                         open, uncontrolled, prospective clinical
                         trial. J Infect Dis. 1994 Nov;170(5):1349-50.
ENTRY MONTH              199309
LAST REVISION DATE       19980406

120
UNIQUE IDENTIFIER        DRG-0187
NAME OF SUBSTANCE        Thymic humoral factor [Facts and Comparisons
                         1995]
SYNONYMS                 THF [AmFAR Tx Dir 1997;8(3)]
SYNONYMS                 THF-gamma 2 [FDA 136A]
PROTOCOL ID NUMBERS      FDA 136A
IND NUMBER               31,822
PHARMACOLOGICAL ACTION   MODE OF ACTION: THF is reported to increase
                         the number of T-lymphocytes and augment
                         cell-mediated immunity. A clinical trial to
                         evaluate efficacy and safety of a combined
                         zidovudine/THF therapy in HIV+ subjects was
                         conducted in 13 patients. Twenty-six patients
                         were included as controls receiving only
                         zidovudine. No significant difference was
                         observed between the two groups as far as
                         surrogate markets of HIV disease progression
                         are concerned, but patients receiving
                         zidovudine and THF showed a lower number of
                         opportunistic complications. Only one patient
                         in this group progressed to manifest AIDS
                         while 9 of 18 controls presented disease
                         progression. Survival time was increased in
                         the case group. The exact immunological
                         effect of thymus hormones in HIV infection
                         has still to be elucidated, but a possible
                         therapeutic role of these agents is
                         foreseeable. However, analysis (1995) of
                         another, multicenter study comparing THF
                         (i.m.) and AZT (oral) in HIV+ asymptotic
                           subjects, demonstrated no significant
                           differences between the two groups in terms
                           of CD4+ count increases and viral RNA
                           decreases. Future development of THF has been
                           discontinued in the US. [Int Conf AIDS 1993
                           Jun 6-11;9(1); AmFAR Tx Dir 1997;8(3)]
DISEASES STUDIED/TREATED   Enhancement of immune response in HIV
                           infection. [AmFAR Tx Dir 1995;7(4)]
CLASSIFICATION CODE        Immunomodulator [AmFAR Tx Dir 1995;7(4)]
ADVERSE EFFECTS            Mild fatigue and reduced mental acuity have
                           been reported. [AmFAR Tx Dir 1997;8(3)]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: THF is a natural peptide
                           hormone isolated from calf thymus. THF-gamma
                           2 is a member of the general class of
                           thymus-derived compounds and is a synthetic
                           octapeptide. This octapeptide has
                           demonstrated both in vitro and in vivo
                           immunomodulatory properties. [AmFAR Tx Dir
                           1993;6(4); AmFAR Tx Dir 1997;8(3)]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 500 ng and 40 micrograms. [FDA
                           136A]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intramuscular injection.
                           [AmFAR Tx Dir 1997;8(3)]
MANUFACTURERS              Pharmacia Incorporated; PO Box 16529;
                           Columbus, OH 43216-6529
REFERENCES                 MED/97191590. Maggiolo F, Taras A, Pravettoni
                           MG, Leone M, Ingrosso A, Suter F. Zidovudine
                           and thymus humoral factor gamma-2 in the
                           treatment of HIV infection: preliminary
                           clinical experience. Infection. 1997
                           Jan-Feb;25(1):35-8.
REFERENCES                 AIDS/95920738. Maggiolo F, Taras A,
                           Pravettoni MG, Caprioli S, Marchetti G, Suter
                           F. AZT and THF combined therapy in HIV
                           positive patients. Program Abstr Intersci
                           Conf Antimicrob Agents Chemother. 1994 Oct
                           4-7;:57.
REFERENCES                 ICA9/93334147. Clayette P, Chassard D, Marce
                           D, Toutain B, Thebault JJ, Lebeaut A, Dormont
                           D. THF-gamma 2 phase I study in healthy
                           volunteers. Int Conf AIDS. 1993 Jun
                           6-11;9(1):246 (abstract no. PO-A28-0671).
REFERENCES                 MED/94134981. Calenda V, Silvy F, Chermann
                           JC. Effects of thymus humoral factor gamma-2
                           (THF gamma 2) on lymphohaematopoietic
                           progenitor cells: an in vitro study. Res
                           Immunol. 1993 Jul-Sep;144(6-7):395-406.
REFERENCES                 ICA8/92401177. Kouttab N, Accetta G,
                           Calabresi P, Skowron G. Phase I trial of
                           intramuscular (IM) thymic humoral factor
                           (THF) in combination with zidovudine (ZDV) in
                           HIV infected individuals. Int Conf AIDS. 1992
                           Jul 19-24;8(2):B161 (abstract no. PoB 3447).
REFERENCES                 MED/90318423. Trainin N. Prospects of AIDS
                           therapy by thymic humoral factor, a thymic
                           hormone. Nat Immun Cell Growth Regul.
                           1990;9(3):155-9.
REFERENCES                 Luzi G, Pesce AM, De Luca S, Carlesimo M,
                           Aiuti F. VIRAL INFECTIONS AND THYMIC
                           HORMONES: A NEW THERAPEUTIC APPROACH. Serono
                           Symp Publ Raven Press. 1989;59:291-302.
REFERENCES               MED/87221086. Handzel ZT, Berner Y, Segal O,
                         Burstein Y, Buchner V, Pecht M, Levin S,
                         Burstein R, Milchan R, Bentwich Z, et al.
                         Immunoreconstitution of T-cell impairments in
                         asymptomatic male homosexuals by thymic
                         humoral factor (THF). Int J Immunopharmacol.
                         1987;9(2):165-73.
ENTRY MONTH              199309
LAST REVISION DATE       19980330

121
UNIQUE IDENTIFIER        DRG-0186
NAME OF SUBSTANCE        Chimeric anti-TNF monoclonal antibody [NIAID
                         93 I-182]
SYNONYMS                 Chimeric A2 [NIAID 93 I-182]
SYNONYMS                 cA2 [NIAID 93 I-182]
PROTOCOL ID NUMBERS      NIAID 93 I-182
PROTOCOL ID NUMBERS      NIAID 95 I-133
PHARMACOLOGICAL ACTION   MODE OF ACTION: Tumor necrosis factor-alpha
                         (TNF-alpha), a proinflammatory cytokine known
                         to stimulate human immunodeficiency virus
                         type 1 (HIV-1) replication, has been
                         implicated in the pathogenesis of HIV-1
                         infection. Inhibition of TNF-alpha by a
                         chimeric humanized monoclonal antibody, cA2,
                         was investigated. A murine-human chimeric
                         monoclonal antibody was constructed by
                         cloning the heavy and light chain variable
                         region genomic domains of A2 and joining them
                         to the respective heavy and light chain
                         genomic domains of human gamma1 constant
                         regions. The resulting mouse-human chimeric
                         IgG monoclonal antibody, designated cA2, was
                         expressed from a stably transfected SP2/0
                         murine hybridoma cell line. Incorporating
                         human constant region structure into the
                         chimeric construct might also be expected to
                         improve allogenic antibody effector function
                         and increase serum circulating half-life in
                         human subjects. To date, experience with cA2
                         has been gained in two phase I/II studies. In
                         a phase I/II trial in healthy human
                         volunteers, 9 volunteers received cA2 alone
                         in ascending doses of 0.1, 1, 5 or 10
                         milligrams per kilogram bodyweight. cA2 was
                         well tolerated by all volunteers. Tumor
                         necrosis factor-alpha (TNF-alpha) is a
                         monocyte-derived cytokine shown to be
                         important in killing both tumor cells and
                         target cells infected with certain viruses.
                         Sustained blood levels of TNF have been found
                         in studies of patients with sepsis and TNF
                         levels above 540 pg/ml have been associated
                         with a fatal outcome. Elevated serum TNF
                         levels increase with the advancing stage of
                         infection. TNF-alpha has also been
                         demonstrated to enhance HIV replication in
                         chronically infected T lymphocytic and
                         promonocytic cell lines when administered
                         alone. A recent study has shown that
                         treatment of primary blood monocyte-derived
                           macrophages with recombinant TNF-alpha
                           enhanced HIV replication fivefold or more
                           above control. Thus TNF-alpha appears to be
                           one of multiple inflammatory cytokines that
                           may serve to upregulate HIV expression and
                           thereby accelerate clinical progression of
                           HIV disease. TNF-alpha also functions
                           biologically in the control of nutritional
                           homeostasis and indeed derives its other
                           name, cachetin, from the dysregulation that
                           may be associated with excessive levels or
                           activity of this cytokine. The desire to
                           block the actions of TNF-alpha in producing
                           enhanced HIV expression and cachexia thus
                           serves as an important rationale for the
                           development and clinical testing of an
                           anti-TNF antibody. [NIAID 93 I-182; J Infect
                           Dis. 1996 Jul; 174(1)]
DISEASES STUDIED/TREATED   Inhibition of tumor necrosis factor
                           production in HIV infection. [NIAID 93 I-182]
CLASSIFICATION CODE        Immunomodulator [NIAID 93 I-182]
SUBSTANCE INTERACTIONS     Infusions of Interleukin-2 (IL-2) produce
                           increases in CD4 counts in a majority of
                           HIV-1 infected patients with baseline CD4
                           greater than 200. In pilot studies,
                           dose-limiting constitutional symptoms and
                           transient increases in viral load paralleled
                           increases in serum levels of TNF-alpha. A
                           study was done to determine in TNF inhibition
                           during IL-2 treatment would reduce IL-2
                           associated adverse events and ablate viral
                           activation. Patients with CD4=200-500 were
                           randomized to receive IL-2 alone, IL-2 plus
                           cA2, or IL-2 plus thalidomide. At the doses
                           studied, IL-2 administered with cA2 or
                           thalidomide was safe. Further evaluation at
                           higher doses of cA2 on TNF blockade will be
                           necessary to assess the contribution of TNF
                           to IL-2 treatment toxicity. [PDR 1997]
ADVERSE EFFECTS            Chimeric A2 has been well tolerated in phase
                           I/II clinical trials. [NIAID 93 I-182]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Chimeric A2 (cA2) is an
                           anti-TNF (tumor necrosis factor) mouse-human
                           monoclonal antibody. [NIAID 93 I-182]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 10 mg/kg in 150 ml of saline
                           from original glass vial containing 300 mg of
                           cA2 in a buffer solution (pH 7.2). [NIAID 93
                           I-182]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intravenous infusion.
                           [NIAID 93 I-182]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: The vials must be
                           stored refrigerated at 2 to 8 C. [NIAID 93
                           I-182]
MANUFACTURERS              Centocor Incorporated; 200 Great Valley
                           Parkway; Malvern, PA 19355-1307
REFERENCES                 AIDS/97926254. Walker RE, Hahn B, Kelly GG,
                           Miller K, Piscitelli S, Figg WD, Davey RT,
                           Falloon J, Kovacs JA, Polis MA, et al.
                           Effects of TNF-alpha antagonists thalidomide
                           and monoclonal anti-TNF antibody (cA2) on
                           reducing IL-2 associated toxicities: a
                         randomized, controlled trial. 4th Conf Retro
                         and Opportun Infect. 1997 Jan 22-26;:71
                         (abstract no.36).
REFERENCES               MED/96261994. Walker RE, Spooner KM, Kelly G,
                         McCloskey RV, Woody JN, Falloon J, Baseler M,
                         Piscitelli SC, Davey RT Jr, Polis MA, Kovacs
                         JA, Masur H, Lane HC. Inhibition of
                         immunoreactive tumor necrosis factor-alpha by
                         a chimeric antibody in patients infected with
                         human immunodeficiency virus type 1. J Infect
                         Dis. 1996 Jul;174(1):63-8.
REFERENCES               96070209. Maini RN, Elliott MJ, Brennan FM,
                         Williams RO, Chu CQ, Paleolog E, Charles PJ,
                         Taylor PC, Feldman M. Monoclonal anti-TNF
                         alpha antibody as a probe of pathogenesis and
                         therapy of rheumatoid disease. Immunol Rev
                         1995 Apr;144:195-223.
REFERENCES               95386252. Elliott MJ, Feldmann M, Maini RN.
                         TNF alpha blockade in rheumatoid arthritis:
                         rationale, clinical outcomes and mechanisms
                         of action. Int J Immunopharmacol 1995
                         Feb;17(2):141-5.
REFERENCES               AIDS/95920744. Walker RE, Kelly GG, Kilgariff
                         CE, Woody JN, Falloon J, Polis MA, Davey RT,
                         Kovacs JA, Masur H, Lane HC. A pilot study of
                         the safety and antiviral activity of a
                         chimeric anti-TNF antibody in HIV infected
                         patients. Program Abstr Intersci Conf
                         Antimicrob Agents Chemother. 1994 Oct
                         4-7;:58.
REFERENCES               ICA6/30031790. Vyakarnam A, Matear P, Meager
                         A, Shultz T, Loveday C, Beverley P.
                         Inhibition of HIV-1 replication in CD4+ T
                         cell subsets with anti-TNF neutralizing
                         antibodies. Int Conf AIDS. 1990 Jun
                         20-23;6(3):161 (abstract no. S.A.317).
ENTRY MONTH              199308
LAST REVISION DATE       19980330

122
UNIQUE IDENTIFIER        DRG-0185
NAME OF SUBSTANCE        Doxorubicin hydrochloride (liposomal) [PDR
                         1997]
SYNONYMS                 DOX-SL [AIDS Treatment News]
SYNONYMS                 DOXIL [PDR 1997]
PROTOCOL ID NUMBERS      FDA 134A
PROTOCOL ID NUMBERS      FDA 134B
PROTOCOL ID NUMBERS      FDA 134C
PROTOCOL ID NUMBERS      FDA 134D
PROTOCOL ID NUMBERS      NIAID ACTG 286
PHARMACOLOGICAL ACTION   MODE OF ACTION: Doxorubicin hydrochloride,
                         the active ingredient of this formulation, is
                         thought to bind DNA and inhibit nucleic acid
                         synthesis. There is rapid cell penetration
                         and perinuclear chromatin binding, rapid
                         inhibition of mitotic activity and nucleic
                         acid synthesis and induction of mutagenesis
                         and chromosomal aberrations. Encapsulation in
                         long-circulating liposomes (i.e.,
                         phospholipid bilayers formulated with
                         surface-bound methoxypolyethylene glycol)
                           increases blood circulation time. These
                           liposomes have a half-life of ca. 55 hours in
                           humans; they are stable in blood, and direct
                           measurement shows that at least 90% of the
                           drug remains encapsulated during circulation.
                           Because of their small size the liposome
                           particles may be able to penetrate the
                           altered and often compromised vasculature of
                           tumors. Encapsulation of doxorubicin
                           hydrochloride alters the pharmacokinetics of
                           the drug with resultant decreased
                           distribution into peripheral compartments,
                           increased distribution into Kaposi's sarcoma
                           (KS) lesions, and decreased plasma clearance.
                           Following IV infusion over 15 minutes of a
                           40-mg/square meter dose of the liposomal
                           injection in adults with KS, peak plasma
                           concentration averaged 20.1 microgram/ml.
                           Plasma clearance was slow with a mean
                           clearance value of 0.041 L/h/square meter at
                           a dose of 20 mg/square meter. Liposomal
                           doxorubicin may cause regression of KS via 2
                           different mechanisms: (1) by highly specific
                           inhibition of KS spindle cell proliferation
                           and (2) by induction of monocyte
                           chemoattractant protein-1 expression in KS
                           spindle cells, which may result in increased
                           recruitment of phagocytic cells into the
                           lesions. [PDR 1997; AHFS Drug Information
                           1997; Res Virol 1994 May-Aug;145(3-4)]
DISEASES STUDIED/TREATED   Treatment of AIDS related Kaposi's sarcoma.
                           FDA approved 11/17/95 for the treatment of
                           Kaposi's sarcoma in AIDS patients with
                           disease that has progressed on prior
                           combination chemotherapy or in patients who
                           are intolerant to such therapy. [PDR 1997;
                           FDA Bulletin]
CLASSIFICATION CODE        Antineoplastic (adjunct) [AmFAR Tx Dir
                           1997;8(3)]
SUBSTANCE INTERACTIONS     Although the AIDS patient with KS population
                           using this drug is on various antiviral
                           medications, drug-drug interactions of this
                           drug and the antiviral drugs have not been
                           evaluated. However, drugs known to interact
                           with nonencapsulated doxorubicin
                           hydrochloride should be considered also to
                           interact with the encapsulated formulation.
                           [PDR 1997; AHFS Drug Information 1997]
ADVERSE EFFECTS            Side effects can include stomatitis, hair
                           loss, nausea, and hematological toxicity. One
                           case of fatal hepatic failure in a patient
                           with a history of symptom free hepatitis B
                           was attributed to liposomal doxorubicin.
                           Special attention must be given to possible
                           cardiac toxicity, an effect exhibited by
                           doxorubicin hydrochloride. The principle
                           dose-limiting toxicity of the encapsulated
                           drug in AIDS patients with KS has been
                           myelosuppression. [AmFAR Tx Dir 1997;8(3);
                           PDR 1997; AHFS Drug Information 1997]
CONTRAINDICATIONS          Contraindicated in patients who have a
                          history of hypersensitivity to conventional
                          formulations of doxorubicin hydrochloride.
                          [PDR 1997]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: An intravenous formulation
                          of doxorubicin that has been encapsulated in
                          liposomes. [PDR 1997]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Doxorubicin hydrochloride
                          liposome injection (Doxil) is supplied as a
                          sterile, translucent, red liposomal
                          dispersion in 10 mL glass, single use vials.
                          Each vial contains 20 mg doxorubicin
                          hyrochloride at a concentration of 2 mg/ml.
                          [PDR 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Intravenous infusion of a
                          dose of 20mg/square meter over 30 minutes.
                          [PDR 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Refrigerate at 2-8 C
                          (35.6 - 46.6 F). Avoid freezing. [PDR 1997]
MANUFACTURERS             Sequus Pharmaceutical Incorporated; 960
                          Hamilton Court; Menlo Park, CA 94025
REFERENCES                MED/97238119. Amantea MA, Forrest A,
                          Northfelt DW, Mamelok R. Population
                          pharmacokinetics and pharmacodynamics of
                          pegylated-liposomal doxorubicin in patients
                          with AIDS-related Kaposi's sarcoma. Clin
                          Pharmacol Ther. 1997 Mar;61(3):301-11.
REFERENCES                MED/97228822. Coukell AJ, Spencer CM.
                          Polyethylene glycol-liposomal doxorubicin. A
                          review of its pharmacodynamic and
                          pharmacokinetic properties, and therapeutic
                          efficacy in the management of AIDS-related
                          Kaposi's sarcoma. Drugs. 1997 Mar;
                          ;53(3):520-38.
REFERENCES                MED/97178757. Northfelt DW, Dezube BJ,
                          Thommes JA, Levine R, Von Roenn JH, Dosik GM,
                          Rios A, Krown SE, DuMond C, Mamelok RD.
                          Efficacy of pegylated-liposomal doxorubicin
                          in the treatment of AIDS-related Kaposi's
                          sarcoma after failure of standard
                          chemotherapy. J Clin Oncol. 1997
                          Feb;15(2):653-9.
REFERENCES                AIDS/97926746. Northfelt D, Stewart S. DOXIL
                          (pegylated liposomal doxorubicin) as
                          first-line therapy of AIDS-related Kaposi's
                          sarcoma (KS): integrated efficacy and safety
                          results from two comparative trials. 4th Conf
                          Retro and Opportun Infect. 1997 Jan
                          22-26;:200 (abstract no.736).
REFERENCES                AIDS/97926623. Medve M, Manegold C, Hussinger
                          D, Jablonowski H. Long term experience with
                          liposomal doxorubicin as treatment for
                          AIDS-related Kaposi's sarcoma. 4th Conf Retro
                          and Opportun Infect. 1997 Jan 22-26;:194
                          (abstract no.704).
REFERENCES                ASHM8/97153607. Newell M, Milliken S, Chipman
                          M, Cebon J, Lewis C, Goldstein D, Cooper DA.
                          DOX-SL (stealth liposomal doxorubicin HCL)
                          maintenance therapy after response in
                          AIDS-related Kaposi's sarcoma. Annu Conf
                          Australas Soc HIV Med. 1996 Nov 14-17;8:48
                          (abstract no.27).
REFERENCES                ICA11/97926902. Stewart S, Jablonowski H,
                          Goebel FD, L'Age M, Spittle M, Luthy R.
                          Randomized comparative trial of DOXIL vs.
                          Bleomycin and Vincristine in the treatment of
                          AIDS-Related KS. Int Conf AIDS. 1996 Jul
                          7-12;11 (Program Supplement):27 (abstract
                          no.LB.B.6026).
REFERENCES                MED/96200418. Goebel FD, Goldstein D, Goos M,
                          Jablonowski H, Stewart JS. Efficacy and
                          safety of Stealth liposomal doxorubicin in
                          AIDS-related Kaposi's sarcoma. The
                          International SL-DOX Study Group. Br J
                          Cancer. 1996 Apr;73(8):989-94.
REFERENCES                MED/96265821. Porche DJ, Liposomal
                          doxorubicin (Doxil). J Assoc Nurses AIDS
                          Care. 1996 Mar-Apr;7(2):55-9.
REFERENCES                MED/97086350. Northfelt DW, Martin FJ,
                          Working P, Volberding PA, Russell J, Newman
                          M, Amantea MA, Kaplan LD. Doxorubicin
                          encapsulated in liposomes containing
                          surface-bound polyethylene glycol:
                          pharmacokinetics, tumor localization, and
                          safety in patients with AIDS-related Kaposi's
                          sarcoma. J Clin Pharmacol. 1996
                          Jan;36(1):55-63.
ENTRY MONTH               199307
LAST REVISION DATE        19980406

123
UNIQUE IDENTIFIER         DRG-0184
NAME OF SUBSTANCE         Thalidomide [USAN 1997]
REGISTRY NUMBER           50-35-1
STANDARD CHEMICAL NAME    1H-Isoindole-1,3 (2H)-dione
                          2-(2,6-dioxo-3-piperidinyl)- [CHEMID]
SYNONYMS                  N-(2,6-Dioxo-3-piperidinyl) phthalimide
                          [Merck Index 1996]
SYNONYMS                  Alpha-phthalimidoglutarimide [Merck Index
                          1996]
SYNONYMS                  3-phthalimidoglutarimide [Merck Index 1996]
SYNONYMS                  2,6-dioxo-3-phthalimidopiperidine [Merck
                          Index 1996]
SYNONYMS                  N-phthalylglutamic acid imide [Merck Index
                          1996]
SYNONYMS                  N-phthaloylglutamimide [Merck Index 1996]
SYNONYMS                  K-17 [Merck Index 1996]
SYNONYMS                  Distaval [Merck Index 1996]
SYNONYMS                  Softenon [Merck Index 1996]
SYNONYMS                  Sedalis [Merck Index 1996]
SYNONYMS                  Talimol [Merck Index 1996]
SYNONYMS                  Pantosediv [Merck Index 1996]
SYNONYMS                  Neurosedyn [Merck Index 1996]
SYNONYMS                  Kevadon [USAN 1997]
SYNONYMS                  Contergan [Merck Index 1996]
PROTOCOL   ID   NUMBERS   FDA 279A
PROTOCOL   ID   NUMBERS   NCI 96 C-0004
PROTOCOL   ID   NUMBERS   NIDR 96 D-0095
PROTOCOL   ID   NUMBERS   FDA 133A
PROTOCOL   ID   NUMBERS   FDA 230A
PROTOCOL   ID   NUMBERS   FDA 230B
PROTOCOL   ID   NUMBERS   FDA 262A
PROTOCOL   ID   NUMBERS   NIAID 95 I-133
PROTOCOL ID NUMBERS        NIAID ACTG 251
PROTOCOL ID NUMBERS        NIAID ACTG 267
SECONDARY SOURCE ID        NSC-66847 [USAN 1997]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Thalidomide probably has a
                           direct effect on the immune system since it
                           has no antibacterial activity yet seems to be
                           effective against some bacterial infections.
                           The immunomodulatory effect of thalidomide is
                           currently unknown. The possibility that the
                           administration of this compound will
                           accelerate the deterioration of the
                           immunologic status of HIV patients cannot be
                           excluded. It has been shown in vitro that
                           thalidomide suppresses HIV and Toxic Necrosis
                           FactOR (TNF)-alpha expression in stimulated,
                           chronically infected promonocytic U1 cells
                           and in PMBC (Peripheral Blood Mononuclear
                           Cells) isolated from HIV+ patients. Effective
                           concentrations of thalidomide range from 5-50
                           microgram/mL depending on the HIV-1 inducer
                           used. The anti-TNF activity of thalidomide is
                           also being studied as a treatment for
                           AIDS-related wasting syndrome. [Drug Saf 1992
                           Mar-Apr;7(2); AmFAR Tx Dir 1997;8(3)]
DISEASES STUDIED/TREATED   Currently being studied for possible
                           treatment of mycobacterium infection and
                           wasting syndrome in HIV infection. Successful
                           results have been reported in treatment of
                           various ulcerations including recurrent
                           aphthous stomatitis (RAS). [DICP 1990 Nov;
                           Vol 24 No 11; FDA 133A, FDA 230A; AIDS
                           Therapies 1995 Sep]
CLASSIFICATION CODE        Immunomodulator [Merck Index 1996]
CLASSIFICATION CODE        Sedative [Merck Index 1996]
CLASSIFICATION CODE        Hypnotic [Merck Index 1996]
OTHER MAJOR USES           Previously used drug that was withdrawn from
                           market because of association with fetal
                           abnormalities. Orphan drug indication for
                           treatment of graft vs. host disease and
                           transplant rejection. Thalidomide is the
                           treatment of choice for type 2 leprosy
                           reactions and is available only for this
                           investigational use in the U.S. [Facts and
                           Comparisons 1995; Drug Saf 1992 Mar-Apr;7(2);
                           USP DI 1997]
ADVERSE EFFECTS            Thalidomide can induce severe congenital
                           abnormalities in developing fetuses. The most
                           common side effects are sedation and
                           constipation; it can also induce peripheral
                           neurotoxicity. [AmFAR Tx Dir 1997;8(3); Drug
                           Saf 1992 Mar-Apr;7(2); Arch Dermatol
                           1990;126]
CONTRAINDICATIONS          Except under unusual circumstances,
                           thalidomide is contraindicated in women of
                           child bearing age who might conceive during
                           therapy. Should not be used in patients with
                           pre-existing HIV related peripheral
                           polyneuropathy, polyradiculopathy, or
                           encephalopathy. [Drug Saf 1992 Mar-Apr;7(2)]
CHEMICAL/PHYSICAL DATA     MOLECULAR FORMULA: C13H10N2O4 [USAN 1997]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 258.23 [USAN 1997]
CHEMICAL/PHYSICAL DATA    MELTING POINT: 269-271 C [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    ELEMENTAL COMP: C60.46% H3.90% N10.85%
                          O24.78%. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    SOLUBILITY: Sparingly soluble in water,
                          methanol, ethanol, acetone, ethyl acetate,
                          butyl acetate, glacial acetic acid. Very
                          soluble in dioxane, DMF, and pyridine.
                          Practically insoluble in ether, chloroform,
                          and benzene. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    DRUG PHYSICAL COMMENT: UV max (neutral
                          solution) 200, 300 nm. [Merck Index 1996]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral. [AmFAR Tx Dir
                          1995;7(4)]
MANUFACTURERS             Celgene Corporation; 7 Powder Horn Drive;
                          Warren, NJ 07059
MANUFACTURERS             Andrulis Pharmaceuticals Corporation; 11800
                          Baltimore Avenue; Beltsville, MD 20705
REFERENCES                MED/97314548. Stirling D, Sherman M, Strauss
                          S. Thalidomide. A surprising recovery. J Am
                          Pharm Assoc (Wash). 1997
                          May-Jun;NS37(3):306-13.
REFERENCES                MED/97338527. Haslett P, Tramontana J,
                          Burroughs M, Hempstead M, Kaplan G. Adverse
                          reactions to thalidomide in patients infected
                          with human immunodeficiency virus. Clin
                          Infect Dis. 1997 Jun;24(6):1223-7.
REFERENCES                MED/97322018. Sharpstone D, Rowbottom A,
                          Francis N, Tovey G, Ellis D, Barrett M,
                          Gazzard B. Thalidomide: a novel therapy for
                          microsporidiosis. Gastroenterolgy. 1997
                          Jun;112(6):1823-9.
REFERENCES                MED/97282675. Jacobson JM, Greenspan JS,
                          Spritzler J, Ketter N, Fahey JL, Jackson JB,
                          Fox L, Chernoff M, Wu AW, MacPhail LA, et al.
                          Thalidomide for the treatment of oral
                          aphthous ulcers in patients with human
                          immunodeficiency virus infection. National
                          Institute of Allergy and Infectious Diseases
                          AIDS Clinical Trials Group. N Engl J Med.
                          1997 May 22;336(21):1487-93.
REFERENCES                MED/97276239. Shannon EJ, Sandoval F,
                          Krahenbuhl JL. Hydrolysis of thalidomide
                          abrogates its ability to enhance mononuclear
                          cell synthesis of IL-2 as well as its ability
                          to suppress the synthesis of TNF-alpha.
                          Immunopharmacology. 1997 Apr;36(1):9-15.
REFERENCES                MED/97225056. Alexander LN, Wilcox CM. A
                          prospective trial of thalidomide for the
                          treatment of HIV-associated idiopathic
                          esophageal ulcers. AIDS Res Hum Retroviruses.
                          1997 Mar 1;13(4):301-4.
REFERENCES                AIDS/97926735. Quinones F, Sierra-Madero J,
                          Calva-Mercado JJ, Ruiz-Palacios GM.
                          Thalidomide in patients with HIV infection
                          and chronic diarrhea: double blind placebo
                          controlled clinical trial. 4th Conf Retro and
                          Opportun Infect. 1997 Jan 22-26;:190
                          (abstract no. 682).
REFERENCES                AIDS/97926254. Walker RE, Hahn B, Kelly GG,
                          Miller K, Piscitelli S, Figg WD, Davey RT,
                          Falloon J, Kovacs JA, Polis MA, et al.
                         Effects of TNF-alpha antagonists thalidomide
                         and monoclonal anti-TNF antibody (cA2) on
                         reducing IL-2-associated toxicities: a
                         randomized, controlled trial. 4th Conf Retro
                         and Opportun Infect. 1997 Jan 22-26;:71
                         (abstract no. 36).
REFERENCES               MED/97133672. Bellomo A, Schorr-Lesnick B.
                         Thalidomide treatment for idiopathic
                         esphageal ulcers in patients with HIV.
                         Gastrointest Endosc. 1996 Dec;44(6):729-31.
REFERENCES               AIDS/97229451. Thalidomide effective in
                         treating AIDS-related mouth ulcers [news].
                         AIDS Patients Care STDS. 1996 Feb;10(1):51.
ENTRY MONTH              199307
LAST REVISION DATE       19980330

124
UNIQUE IDENTIFIER        DRG-0183
NAME OF SUBSTANCE        Trimetrexate glucuronate [USAN 1997]
REGISTRY NUMBER          82952-64-5
STANDARD CHEMICAL NAME   2,4-Quinazolinediamine,
                         5-methyl-6-(((3,4,5-trimethoxyphenyl)amino)me-
                         thyl)-, mono-D-glucuronate (9CI) [CHEMID]
SYNONYMS                 Trimetrexate D-glucuronate [Merck Index 1996]
SYNONYMS                 Neutrexin [Merck Index 1996]
SYNONYMS                 Oncotrex [Merck Index 1996]
PROTOCOL ID NUMBERS      FDA 132A
PROTOCOL ID NUMBERS      FDA 132B
PROTOCOL ID NUMBERS      FDA 132C
PROTOCOL ID NUMBERS      FDA 132D
PROTOCOL ID NUMBERS      FDA 224A
PROTOCOL ID NUMBERS      NIAID 88 CC-85
PROTOCOL ID NUMBERS      NIAID ACTG 018
PROTOCOL ID NUMBERS      NIAID ACTG 029
PROTOCOL ID NUMBERS      NIAID ACTG 030
PROTOCOL ID NUMBERS      NIAID ACTG 031
PROTOCOL ID NUMBERS      NIAID ACTG 039
PROTOCOL ID NUMBERS      NIAID NS 401
PROTOCOL ID NUMBERS      NIAID TX 301
SECONDARY SOURCE ID      NSC-352122 [Merck Index 1996]
PHARMACOLOGICAL ACTION   MODE OF ACTION: Trimetrexate is a potent
                         inhibitor of dihydrofolate reductase. It is
                         more lipophilic than methotrexate and this is
                         assumed to account for its better penetration
                         into P. carinii. In vitro studies have shown
                         that leucovorin provides a source of reduced
                         folates necessary for normal cellular
                         synthetic processes. Because the Pneumocystis
                         carinii organism lacks the reduced folate
                         carrier-mediated transport system, leucovorin
                         is prevented from entering the organism.
                         Therefore, at concentrations achieved with
                         therapeutic doses of trimetrexate plus
                         leucovorin, the selective transport of
                         trimetrexate, but not leucovorin, into the P.
                         carinii organism allows the concurrent
                         administration of leucovorin to protect
                         normal host cells from the cytotoxicity of
                         trimetrexate without hindering the
                         antifolate's inhibition of P. carinii. The
                         drug can produce considerable
                           myelosuppression due to its antifolate
                           action; however, administration with
                           leucovorin allows differential rescue of host
                           tissues without reversal of the
                           anti-protozoal effect. Trimetrexate has a
                           mean oral bioavailability of 44% (range, 19%
                           to 67%); therefore, it is administered
                           intravenously. The drug is extensively
                           protein bound (95%). Unlike methotrexate,
                           which is excreted mainly unchanged in the
                           urine, trimetrexate is extensively
                           metabolized by the liver. At least two
                           metabolites are active and two are conjugated
                           with glucuronic acid. The hepatic degradation
                           may account for the low and variable oral
                           absorption. The terminal elimination
                           half-life is 15-20 hours. [Drug Evaluations
                           Annual 1992; Facts and Comparisons 1995; PDR
                           1997]
DISEASES STUDIED/TREATED   For use with concurrent leucovorin
                           administration as an alternative therapy for
                           the treatment of moderate to severe
                           Pneumocystis carinii pneumonia (PCP) in
                           immunocompromised patients, including those
                           with AIDS, who are intolerant of, or are
                           refractory to, trimethoprim/sulfamethoxazole
                           (TMP-SMX), or for whom TMP-SMX is
                           contraindicated. [PDR 1997]
CLASSIFICATION CODE        Antifolate [US Bioscience drug insert
                           pamphlet on NeuTrexin]
CLASSIFICATION CODE        Antiprotozoal [Drug Evaluations Annual 1992]
CLASSIFICATION CODE        Antineoplastic (adjunct) [USAN 1997]
SUBSTANCE INTERACTIONS     Since trimetrexate is metabolized by a P450
                           enzyme system, drugs that induce or inhibit
                           this system may elicit important drug-drug
                           interactions that may alter trimetrexate
                           plasma concentrations. Agents that may be
                           coadministered with trimetrexate in AIDS
                           patients for other indications, that might
                           elicit this activity include: erythromycin,
                           rifampin, rifabutin, ketoconazole, and
                           fluconazole. Cimetidine may cause significant
                           reduction in trimetrexate metabolism, and
                           acetaminophen may alter the relative
                           concentration of trimetrexate metabolites.
                           [PDR 1997]
ADVERSE EFFECTS            Must be used with concurrent leucovorin to
                           avoid potentially serious or life-threatening
                           complications including bone-marrow
                           suppression, oral or gastrointestinal mucosal
                           ulceration, and renal and hepatic
                           dysfunction. Leucovorin therapy must be
                           extended 72 hours past the last dose of
                           trimetrexate glucuronate. Fluctuating
                           leukopenia and thrombocytopenia and transient
                           increases in serum concentrations of
                           aspartate and alanine aminotransferases are
                           observed commonly. No infections have
                           resulted from the leukopenia. Leukopenia and
                           thrombocytopenia respond promptly to lowering
                           the dose by 50%. Initial three- to five-fold
                          increases in serum concentrations of
                          aminotransferases gradually are reversed when
                          therapy is continued. Mucositis (stomatitis),
                          anemia, and skin rashes occur occasionally;
                          diarrhea, arthraglia, fever, bleeding,
                          anorexia, nausea, and vomiting are reported
                          even less frequently. [Drug Evaluations
                          Annual 1992; PDR 1997]
CONTRAINDICATIONS         Contraindicated in patients sensitive to
                          trimetrexate, leucovorin, or methotrexate.
                          [PDR 1997]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: A 2,4-diaminoquinazoline,
                          non-classical to late antagonist. [PDR 1997]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: Trimetrexate
                          glucuronate for injection is a pale
                          greenish-yellow powder or cake. [PDR 1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C19H23N5O3.C6H10O7 [USAN
                          1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 563.57 [USAN 1997]
CHEMICAL/PHYSICAL DATA    SOLUBILITY: Solubility in water: greater than
                          50 mg/ml [PDR 1997]
CHEMICAL/PHYSICAL DATA    STABILITY: Precipitates if reconstituted with
                          solutions containing chloride ions or
                          leucovorin. [PDR 1995]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Supplied as a sterile
                          lyophilized powder in 5 ml, single dose
                          vials. Each 5 ml bottle contains trimetrexate
                          glucuronate equivalent to 25 mg of
                          trimetrexate. [PDR 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Administered at a dose of
                          45 mg/m2 once daily by intravenous infusion
                          over 60-90 minutes. Leucovorin must be
                          administered daily during treatment with
                          NeuTrexin and for 72 hours past the last
                          dose. [PDR 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Reconstituted solutions
                          are stable for 24 h at room temperature or
                          under refrigeration. [PDR 1997]
MANUFACTURERS             United States Bioscience Incorporated; 100
                          Front Street / One Tower Bridge; West
                          Conshohocken, PA 19428
REFERENCES                MED/97339118. Deresinski SC. Treatment of
                          Pneumocystis carinii pneumonia in adults with
                          AIDS. Semin Respir Infect. 1997
                          Jun;12(2):79-97.
REFERENCES                AIDS/97229478. Blanchet KD. Current
                          management pratices in the treatment of
                          Pneumocystis carinii pneumonia (PCP). AIDS
                          Patient Care STDS. 1996 Apr;10(2):116-21.
REFERENCES                AIDS/97229561. Harris PJ. Trimetrexate
                          glucuronate associated with anti-Kaposi
                          sarcoma effect. AIDS Patient Care STDS. 1996
                          Oct;10(5):280-1.
REFERENCES                MED/96342537. Nusbaum NJ, Abraham T. AZT
                          modulation of trimetrexate myelotoxicity:
                          evidence from an HL60 model. Res Commun Mol
                          Pathol Pharmacol. 1995 Dec;90(3):403-12.
REFERENCES                MED/96185167. Korraa H, Saadeh C. Options in
                          the management of pneumonia caused by
                          Pneumocystis carinii in patients with
                          acquired immune deficiency syndrome and
                         intolerance to trimethoprim/sulfamethoxazole.
                         South Med J. 1996 Mar;89(3):272-7.
REFERENCES               MED/96008522. Drugs for AIDS and associated
                         infections. Med Lett Drugs Ther. 1995 Oct
                         13;37(959):87-94.
REFERENCES               MED/95387369. Chan JH, Hong JS, Kuyper LF,
                         Baccanari DP, Joyner SS, Tansik RL, Boytos
                         CM, Rudolph SK. Selective inhibitors of
                         Candida albicans dihydrofolate reductase:
                         activity and selectivity of
                         5-(arylthio)-2,4-diaminoquinazolines. J Med
                         Chem. 1995 Sep 1;38(18):3608-16.
REFERENCES               AHA/95393336. Wooten JM, Chase K, O'Connor
                         MC, Henry RB. Dosing guidelines for foscarnet
                         and trimetrexate. Formulary. 1995
                         Jun;30(6):349-52. 1994 Jul;170(1):165-72.
REFERENCES               MED/95309143. Fulton B, Wagstaff AJ, McTavish
                         D. Trimetrexate. A review of its
                         pharmacodynamic and pharmacokinetic
                         properties and therapeutic potential in the
                         treatment of Pneumocystis carinii pneumonia.
                         Drugs. 1995 Apr;49(4):563-76.
ENTRY MONTH              199307
LAST REVISION DATE       19990311

125
UNIQUE IDENTIFIER        DRG-0182
NAME OF SUBSTANCE        RMP-7 [AmFAR Tx Dir 1995;7(4)]
REGISTRY NUMBER          159768-75-9
STANDARD CHEMICAL NAME   L-Prolinamide, L-arginyl-L-prolyl-trans-4-
                         hydroxy-L-prolyl-3-(2- thienyl)-L-alanylglycl
                         -L-seryl-N-(2-((4-((aminoiminomethyl)amino)-1-
                         -carboxybutyl)
                         amino)-1-((4-methoxyphenyl)methyl)ethyl)-,
                         (S-(R*,R*))- [CHEMID]
PROTOCOL ID NUMBERS      FDA 131A
PHARMACOLOGICAL ACTION   MODE OF ACTION: RMP-7 is believed to cause
                         increased cerebrovascular permeability (i.e.,
                         increases permeability across blood-brain
                         barrier) by the activation of B2 receptors on
                         the vascular endothelium. The dose of
                         ganciclovir used to treat cytomegalovirus
                         (CMV) retinitis is restricted by its systemic
                         toxicity and the hydrophilicity which limits
                         its distribution across blood-ocular
                         barriers. The effect of the bradykinin
                         agonist, RMP-7, which increases the
                         permeability of the anatomically similar
                         blood-brain and blood tumor barriers, on the
                         distribution of ganciclovir to various eye
                         compartments in the guinea-pig was studied.
                         RMP-7 significantly increased the delivery of
                         ganciclovir to the lens and retina,
                         indicating the potential therapeutic benefit.
                         A placebo-controlled dose-ranging study of
                         the effect of RMP-7 on retinal permeability
                         is underway in volunteers and patients with
                         AIDS with or without CMV retinitis. [J
                         Pharmacol Exp Ther 1994 Oct;271(1); AmFAR Tx
                         Dir 1997;8(3); Natl Conf Hum Retroviruses
                         Relat Infect (2nd) 1995]
DISEASES STUDIED/TREATED   Under investigation in combination with
                           amphotericin B in patients with cryptococcal
                           meningitis. [AmFAR Tx Dir 1997;8(3)]
CLASSIFICATION CODE        Antifungal [FDA 131A]
ADVERSE EFFECTS            In clinical trials, RMP-7 has been well
                           tolerated by patients with AIDS or glioma.
                           [Natl Conf Hum Retroviruses Relat Infect
                           (2nd) 1995]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: A bradykinin analog with
                           the amino acid sequence:
                           Arg-Pro-Hyp-Gly-Thi-Ser-Pro-Tyr
                           (Me)-psi(CH2NH)-Arg. [FDA 131A; J Pharmacol
                           Exp Ther 1994 Oct;271(1)]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intravenous injection.
                           [AmFAR Tx Dir 1993;6(4)]
MANUFACTURERS              Alkermes Incorporated; 64 Sidney Street;
                           Cambridge, MA 02139
REFERENCES                 AIDS/95920310. Elliot PJ, Mackic JB, Graney
                           WF, Zlokovic BV. Intravenous RMP-7 elevates
                           ocular ganciclovir levels. Natl Conf Hum
                           Retroviruses Relat Infect (2nd). 1995 Jan
                           29-Feb 2;:106.
REFERENCES                 95303800. Straub JA, Akiyama A, Parmar P,
                           Musso GF. Chemical pathways of degradation of
                           the bradykinin analog, RMP-7. Pharm Res 1995
                           Feb; 12(2):305-8.
REFERENCES                 95175472. Straub JA, Akiyama A, Parmar P. In
                           vitro plasma metabolism of RMP-7. Pharm Res
                           1994 Nov;11(11):1673-6.
REFERENCES                 95039694. Straub JA, Akiyama A, Parmar P,
                           Musso GF. Limited enzymatic digestion for the
                           determination of the quantities of minor
                           diastereomeric impurities in preparation of
                           RMP-7, a peptide containing a reduced peptide
                           bond. J Chromatogr A. 1994 Sep
                           9;679(1):85-91.
ENTRY MONTH                199307
LAST REVISION DATE         19971030

126
UNIQUE IDENTIFIER          DRG-0181
NAME OF SUBSTANCE          ALVAC-RG rabies glycoprotein ( vCP65 ) [NIAID
                           VEU 012A]
SYNONYMS                   ALVAC RG [NIAID VEU 012A]
SYNONYMS                   ALVAC vCP65 rabies glycoprotein [NIAID VEU
                           012A]
SYNONYMS                   ALVAC RG (vCP65) [NIAID VEU 012A]
PROTOCOL ID NUMBERS        NIAID VEU 012A
PROTOCOL ID NUMBERS        NIAID VEU 022
PROTOCOL ID NUMBERS        NIAID VEU 022A
PROTOCOL ID NUMBERS        NIAID VEU 026
PROTOCOL ID NUMBERS        NIAID VEU 027
PROTOCOL ID NUMBERS        NIAID VEU 029
PHARMACOLOGICAL ACTION     MODE OF ACTION: ALVAC-RG has been safe and
                           immunogenic when administered to mice, dogs,
                           cats, rhesus macaques, chimpanzees, and human
                           volunteers. Protection against lethal rabies
                           challenge has been achieved in mice, dogs,
                           and cats using ALVAC vCP65 rabies
                           glycoprotein vaccine. The live recombinant
                           canarypox-rabies glycoprotein vaccine has
                           been tested in 15 adult volunteers in
                           Baltimore, MD., and in 15 volunteers in
                           France. The immune response following
                           vaccination appeared to be dose dependent,
                           with detection of protective levels of serum
                           antibody against rabies after two
                           immunizations in 90% of those who received
                           the two highest doses in Baltimore and in 77%
                           of the French volunteers. Cell-mediated
                           immune responses were also detected. [NIAID
                           VEU 012A; Lancet 1992 Jun 13;339(8807)]
DISEASES STUDIED/TREATED   Used as control in vaccine studies. [NIAID
                           VEU 012A]
CLASSIFICATION CODE        Vaccine [NIAID VEU 012A]
ADVERSE EFFECTS            Adverse effects include mild transient pain
                           at the inoculation site. [NIAID VEU 012A]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: A recombinant canarypox
                           virus bearing the rabies virus glycoprotein G
                           gene under transcriptional control of the
                           vaccinia virus H6 promoter. [NIAID VEU 012A;
                           Lancet 1992 Jun 13;339(8807)]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: Cream, homogeneous
                           powder (lyophilized product); clear liquid
                           (reconstituted product). [NIAID VEU 012A]
CHEMICAL/PHYSICAL DATA     STABILITY: Thermostable at ambient
                           temperatures. [NIAID VEU 012A]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Vaccine is supplied as a sterile
                           lyophilized product in single dose vials
                           containing 10 to the 5.5 TCID50 of ALVAC
                           vCP65. [NIAID VEU 012A]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Vaccine preparation is
                           given intramuscularly with a 22 gauge 1.5
                           inch needle into the right or left deltoid
                           muscle after preparation of the site with
                           alcohol. [NIAID VEU 012A]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Refrigerate at 3-5 C.
                           Do not freeze. [NIAID VEU 012A]
MANUFACTURERS              Pasteur Merieux Serums et Vaccins; 3 Avenue
                           Pasteur / BP 10; Marnes la Coquette,
                           France92430
REFERENCES                 97303208. Yusibov V, Modelska A, Steplewski
                           K, Agadjanyan M, Weiner D, Hooper DC,
                           Koprowski H. Antigens produced in plants by
                           infection with chimeric plant viruses
                           immunize against rabies virus and HIV-1. Proc
                           Natl Acad Sci USA. 1997 May 27;94(11):5784-8.
REFERENCES                 MED/95046924. Tartaglia J, Cox WI, Pincus S,
                           Paoletti E. Safety and immunogenicity of
                           recombinants based on the
                           genetically-engineered vaccinia strain,
                           NYVAC. Dev Biol Stand. 1994;82:125-9.
REFERENCES                 MED/95341166. Perkus ME, Tartaglia J,
                           Paoletti E. Poxvirus-based vaccine candidates
                           for cancer, AIDS, and other infectious
                           diseases. J Leukoc Biol. 1995 Jul;58(1):1-13.
REFERENCES                 96065461. Taylor J, Meignier B, Tartaglia J,
                           Languet B, VanderHoeven J, Franchini G,
                           Trimarchi C, Paoletti E. Biological and
                           immunogenic properties of a canarypox-rabies
                           recombinant, ALVAC-RG (vCP65) in non-avian
                           species. Vaccine 1995 Apr;13(6):539-49.
REFERENCES               MED/95317468. Plotkin SA, Cadoz M, Meignier
                         B, Meric C, Leroy O, Excler JL, Tartaglia J,
                         Paoletti E, Gonczol E, Chappuis G. The safety
                         and use of canarypox vectored vaccines. Dev
                         Biol Stand. 1995;84:165-70.
REFERENCES               Fries LF, Shahan J, Thumus B, Tartaglia J,
                         Taylor J, Meignier B, Paoletti E. Safety and
                         immunogenicity of a canarypox-rabies
                         glycoprotein recombinant in adult human
                         volunteers. 32nd ICAAC Meeting, Anaheim, CA
                         1992.
REFERENCES               92292760. Cadoz M, Strady A, Meignier B,
                         Taylor J, Tartaglia J, Paoletti E, Plotkin S.
                         Immunization with canarypox virus expressing
                         rabies glycoprotein [see comments]. Lancet.
                         1992;339:1429-1432.
REFERENCES               93001054. Ferguson M, Heath A. Report of a
                         collaborative study to assess the
                         determination of glycoprotein antigen content
                         of rabies vaccines for human use.
                         Biologicals. 1992 Jun;20(2):143-54.
REFERENCES               96329208. Fries LF, Tartaglia J, Taylor J,
                         Kauffman EK, Meignier B, Paoletti E, Plotkin
                         S. Human safety and immunogenicity of a
                         canarypox-rabies glycoprotein recombinant
                         vaccine: an alternative poxvirus vector
                         system. Vaccine 1996 Apr;14(5):428-34.
ENTRY MONTH              199307
LAST REVISION DATE       19980417

127
UNIQUE IDENTIFIER        DRG-0180
NAME OF SUBSTANCE        ALVAC-HIV gp160 MN ( vCP125 ) [NIAID VEU
                         012A]
SYNONYMS                 Recombinant canarypox-gp160 MN [NIAID VEU
                         012A]
SYNONYMS                 ALVAC gp160 MN recombinant [NIAID VEU 012A]
SYNONYMS                 ALVAC vCP125 HIV-1 gp160 MN [NIAID VEU 012A]
SYNONYMS                 ALVAC vectored HIV gp160 Vaccine (vCP125)
                         [NIAID VEU 012A]
SYNONYMS                 ALVAC-HIV (v CP125) [AIDS Res Hum
                         Retroviruses 1995 Mar;11(3)]
PROTOCOL ID NUMBERS      NIAID VEU 012A
PHARMACOLOGICAL ACTION   MODE OF ACTION: Like vaccinia virus,
                         canarypox can accommodate large amounts of
                         foreign DNA in its genome, infect mammalian
                         cells, and cause them to produce foreign
                         proteins. In contrast to vaccinia virus,
                         canarypox virus is host-range restricted.
                         That is, it goes through an abortive cycle of
                         replication and does not produce infectious
                         progeny virus in mammalian cells. Mice,
                         guinea pigs, and rabbits inoculated
                         intramuscularly with ALVAC gp160 10 to the
                         5.7th TCID50/ml at 0 and 4 weeks, produced
                         antibodies against gp160. Further, spleen
                         cells from mice inoculated twice with ALVAC
                         gp 160 demonstrated significant gp160
                         lymphoproliferative responses. In six
                         macaques injected intramuscularly with 0.5 ml
                         of ALVAC gp160 at 0 and 4 weeks, no toxicity
                           was observed, and one of the six produced
                           significant levels of HIV-1 gp160 specific
                           antibody. Results of test for acute toxicity
                           in mice or rats receiving 2.5 or 5 times the
                           human dose i.v. were negative. A vaccine
                           against human immunodeficieny virus (HIV)
                           should induce virus-specific cytotoxic T
                           lymphocyte (CTL) activity. Immunization of
                           uninfected volunteers with a canarypox virus
                           expressing HIV envelope was carried out. Two
                           injections of canarypox expressing HIV-1MN gp
                           160 (months 0 and 1) were followed by two
                           boosts of recombinant envelope protein
                           (months 3 and 6). HIV envelope-specific CTL
                           were detected in peripheral blood mononuclear
                           cells stimulated with autologous
                           HIV-1-infected blast cells. CTL were detected
                           at least once following immunization in 7
                           (39%) of 18 volunteers. This activity was
                           mediated by major histocompatibility complex
                           class I-restricted CD3+CD8+ T cells. The CTL
                           responses with this prime-boost regimen are
                           the best observed with any HIV vaccine tested
                           in humans. [NIAID VEU 012A; J Leukoc Biol
                           1995 Jul;58(1); J Infect Dis. 1996
                           Oct;174(4)]
DISEASES STUDIED/TREATED   Prevention of HIV infection. [NIAID VEU 012A]
CLASSIFICATION CODE        Vaccine [NIAID VEU 012A]
ADVERSE EFFECTS            Adverse effects may include mild to moderate
                           local and systemic reactions which resolve
                           within 72 h of immunization. Canarypox virus
                           is attenuated for canaries. In principle, it
                           is non-infectious for humans or other
                           mammals. [AIDS Res Hum Retroviruses 1995
                           Mar;11(3); Dev Biol Stand. 1995;84]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: A live canarypox
                           recombinant vaccine; produced by homologous
                           recombination between the plasmid pC5HIVMNE
                           and the genomic DNA of ALVAC (canarypox),
                           thereby substituting the gp160 gene for the
                           open reading frame C5. The gp160 gene is
                           under the control of the vaccinia H6
                           promoter. [NIAID VEU 012A; AIDS Res Hum
                           Retroviruses 1995 Mar;11(3)]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: White to cream,
                           homogeneous powder (lyophilized product);
                           pale rose-pink liquid, slightly opalescent
                           (reconstituted). [NIAID VEU 012A]
CHEMICAL/PHYSICAL DATA     STABILITY: Thermostable at ambient
                           temperatures. [NIAID VEU 012A]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Vaccine is supplied as a sterile
                           lyophilized product in single dose vials
                           containing 1,000,000 TCID50 of ALVAC vCP125.
                           [NIAID VEU 012A]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Vaccine preparation is
                           given intramuscularly with a 22 gauge 1.5
                           inch needle into the right or left deltoid
                           muscle after preparation of the site with
                           alcohol. [NIAID VEU 012A]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Refrigerate at 3-5 C.
                           Do not freeze. [NIAID VEU 012A]
MANUFACTURERS   Pasteur Merieux Serums et Vaccins; 3 Avenue
                Pasteur / BP 10; Marnes la Coquette,
                France92430
REFERENCES      AIDS/97926165. Evans TG, Keefer MC, Wolff M,
                Weinhold K, Excler JL, Duliege AM, McNamara
                J, McElrath JM, Graham BJ, Clements ML, et
                al. Immunization of HIV-1 non-infected
                volunteers with a canarypox recombinant
                containing HIV-1 env, gag, pol, and nef genes
                (vCP 300) given simultaneously or followed by
                recombinant HIV-1 SF2 gp120. 4th Conf Retro
                and Opportun Infect. 1997 Jan 22-26;:204
                (abstract no. 754).
REFERENCES      MED/97000067. Fleury B, Janvier G, Pialoux G,
                Buseyne F, Robertson MN, Tartaglia J,
                Paoletti E, Kieny MP, Excler JL, Riviere Y.
                Memory cytotoxic T lymphocyte responses in
                human immunodeficiency virus type 1
                (HIV-1)-negative volunteers immunized with a
                recombinant canarypox expressing gp 160 of
                HIV-1 and boosted with a recombinant gp160. J
                Infect Dis. 1996 Oct;174(4):734-8.
REFERENCES      ICA11/97926910. Excler JL, Duliege AM,
                Clements ML, Salmon D, McNamara J, Fast P,
                Meignier B, Klein M, Plotkin SA. Prime-boost
                protocols for vaccination against HIV. Int
                Conf AIDS. 1996 Jul 7-12;11(Program
                Supplement):29 (abstract no. LB.B.6034).
REFERENCES      ICA11/97926890. De Giuli MC, Gimelli M,
                Ghioni C, Radaelli A, Teeuwsen V, van Gils M,
                den Haaft P, Borgers W, Heeney JL.
                Immunogenic profile and efficacy testing in
                macaques immunized with an avipox/env (SF2)
                recombinant virus. Int Conf AIDS. 1996 Jul
                7-12;11(Program Supplement):24 (abstract no.
                LB.A.6013).
REFERENCES      MED/96389598. Fricker J. Canarypox as a
                vector for HIV vaccine [news]. Mol Med Today.
                1996 Jun;2(6):225.
REFERENCES      ICA11/96920847. Clements ML, Weinhold K,
                Siliciano R, Schwartz D, Matthews T, Graham
                B, Keefer M, McElrath J, Gorse G, Hsieh R, et
                al. HIV immunity induced by canarypox
                (ALVAC)-MN gp160, -SF2 rgp120 or both. Int
                Conf AIDS. 1996 Jul 7-12;11(1):10 (abstract
                no. Mo.A.281).
REFERENCES      MED/95317468. Plotkin SA, Cadoz M, Meignier
                B, Meric C, Leroy O, Excler JL, Tartaglia J,
                Paoletti E, Gonczol E, Chappuis G. The safety
                and use of canarypox vectored vaccines. Dev
                Biol Stand. 1995;84:165-70.
REFERENCES      96012510. Pincus S, Tartaglia J, Paoletti E.
                Poxvirus-based vectors as vaccine candidates.
                Biologicals 1995 Jun;23(2):159-64.
REFERENCES      MED/95306141. Pialoux G, Excler JL, Riviere
                Y, Gonzalez-Canali G, Feuillie V, Coulaud P,
                Gluckman JC, Matthews TJ, Meignier B, Kieny
                MP, et al. A prime-boost approach to HIV
                preventive vaccine using a recombinant
                canarypox virus expressing glycoprotein 160
                (MN) followed by a recombinant glycoprotein
                           160 (MN/LAI). The AGIS Group, and l'Agence
                           Nationale de Recherche sur le SIDA [published
                           erratum appears in AIDS Res Hum Retroviruses
                           1995 Jul:11(7):875]. AIDS Res Hum
                           Retroviruses. 1995 Mar;11(3):373-81.
REFERENCES                 MED/95287062. Egan MA, Pavlat WA, Tartaglia
                           J, Paoletti E, Weinhold KJ, Clements ML,
                           Siliciano RF. Induction of human
                           immunodeficiency virus type 1
                           (HIV-1)-specific cytolytic T lymphocyte
                           responses in seronegative adults by a
                           nonreplicating, host-range-restricted
                           canarypox vector (ALVAC) carrying the HIV-1MN
                           env gene. J Infect Dis. 1995
                           Jun;171(6):1623-7.
ENTRY MONTH                199307
LAST REVISION DATE         19980402

128
UNIQUE IDENTIFIER          DRG-0179
NAME OF SUBSTANCE          882C87 [FDA 130A]
REGISTRY NUMBER            84558-93-0
STANDARD CHEMICAL NAME     2,4(1H,3H)-Pyrimidinedione,
                           1-beta-D-arabinofuranosyl-5-(1-propynyl)-,
                           [CHEMID]
SYNONYMS                   BW882C87 [AmFAR Tx Dir 1995;7(4)]
SYNONYMS                   1-beta-D-Arabinofuranosyl-5-(1-propynyl)uraci-
                           l [USAN 1997]
SYNONYMS                   Netivudine [USAN 1997]
PROTOCOL ID NUMBERS        FDA 130A
PHARMACOLOGICAL ACTION     MODE OF ACTION: In vitro activity against
                           varicella zoster virus (VZV). Data from
                           pharmacokinetic studies in HIV negative
                           volunteers suggest that potential therapeutic
                           concentrations can be achieved with once
                           daily dosing; elimination is mostly renal.
                           Bioavailability and disposition of 882C87, an
                           anti-varicella zoster virus (VZV) agent, have
                           been investigated in healthy young and
                           elderly volunteers. The mean bioavailability
                           of a 200 mg tablet was 21.1% in the young and
                           24.6% in the elderly, which is sufficient to
                           achieve plasma concentrations well above the
                           IC50 for anti-VZV activity. Plasma
                           concentrations of 882C87 after 50 mg i.v.
                           were higher in the elderly than in the young,
                           associated with a significantly longer
                           half-life and decreased renal and total
                           clearance. After i.v. administration, the
                           main route of elimination of 882C87 was renal
                           with 81.6% recovered unchanged in urine in
                           the young and 71.2% in the elderly. The
                           pyrimidine base, 5-propynyluracil (5-PU) was
                           unquantifiable in plasma and only present in
                           trace amounts in urine. Experimental data
                           suggest that 5-PU is formed from unabsorbed
                           882C87 in the gut lumen and then absorbed and
                           excreted in urine. [AmFAR Tx Dir 1993;6(4);
                           AmFAR Tx Dir 1995;7(4); Br J Clin Pharmacol.
                           1995 Feb;39(2)]
DISEASES STUDIED/TREATED   Treatment of localized herpes zoster. [FDA
                          130A; AmFAR Tx Dir 1995;7(4)]
CLASSIFICATION CODE       Antiviral [FDA 130A]
OTHER MAJOR USES          882C87 is a potential once daily treatment
                          for shingles. [Br J Clin Pharmacol. 1995
                          Feb;39(2)]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: A nucleoside analog. [AmFAR
                          Tx Dir 1993;6(3)]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C12H14N2O6 [USAN 1997]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: 200 mg tablets. [FDA 130A]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral. [AmFAR Tx Dir
                          1995;7(4)]
MANUFACTURERS             Glaxo Wellcome; 5 Moore Drive / PO Box 13398;
                          Research Triangle Park, NC 27709
REFERENCES                97012635. Peck RW, Crome P, Wood MJ,
                          McKendrick MW, Bannister B, Mandal BK, Crooks
                          RJ. Multiple dose netivudine, a potent
                          anti-varicella zoster virus agent, in healthy
                          elderly volunteers and patients with
                          shingles. J Antimicrob Chemother. 1996
                          Mar;37(3):583-97.
REFERENCES                97120396. Le Roy F, Godin M, Legallicler B,
                          Fillastre JP, Bidault R, Posner J, Peck RW.
                          Pharmacokinetics of netivudine in
                          haemodialysis patients [letter]. J Antimicrob
                          Chemother. 1996 Nov;38(5):913-5.
REFERENCES                96346908. Fillastre JP, Godin M, Legallicier
                          B, Chretien P, Bidault R, Gillotin C, Wooton
                          R, Posner J, Peck RW. Pharmacokinetics of
                          netivudine, a potent anti-varicella zoster
                          virus drug, in patients with renal
                          impairment. J Antimicrob Chemother. 1996
                          May;37(5):965-74.
REFERENCES                96152187. Peck R, Wiggs R, Callaghan J,
                          Wooton R, Crome P, Fraser I, Frick L, Posner
                          J. Inhibition of dihydropyrimidine
                          dehydrogenase by 5-propynyluracil, a
                          metabolite of the anti-varicella zoster virus
                          agent netivudine. Clin Pharmacol Ther. 1996
                          Jan;59(1):22-31.
REFERENCES                MED/95377331. Andrei G, Snoeck R, Reymen D,
                          Liesnard C, Goubau P, Desmyter J, De Clercq
                          E. Comparative activity of selected antiviral
                          compounds against clinical isolates of
                          varicella-zoster virus. Eur J Clin Microbiol
                          Infect Dis 1995 Apr;14(4):318-29.
REFERENCES                95260647. Peck RW, Wootton R, Lee DR, Jackson
                          SH, Posner J. The bioavailability and
                          disposition of
                          1-(beta-D-arabinofuranosyl)-5-(1-propynyl)ura-
                          cil (882C87), a potent, new anti-varicella
                          zoster virus agent. Br J Clin Pharmacol 1995
                          Feb;39(2):143-9.
REFERENCES                95209347. Peck RW, Weatherley BC, Wootton R,
                          Crome P, Posner J, et al. Pharmacokinetics
                          and tolerability of single oral doses of
                          882C87, a potent, new anti-varicella-zoster
                          virus agent, in healthy volunteers.
                          Antimicrob. Agents Chemother.; VOL 39 ISS Jan
                          1995, P20-27, (REF 9).
REFERENCES                94341482. Darby G. Acyclovir--and beyond. J
                          Int Med Res. 1994;22 Suppl 1:33A-42A.
REFERENCES                 94065699. Wood MR, McKendrick MW, Bannister
                           B, Mandal BK, Peck RW, Crooks RJ. Preliminary
                           pharmacokinetics and safety of 882C87 in
                           patients with herpes zoster. J Med Virol.
                           1993;Suppl 1:154-7.
ENTRY MONTH                199306
LAST REVISION DATE         19980402

129
UNIQUE IDENTIFIER          DRG-0178
NAME OF SUBSTANCE          QS-21 [Ann NY Acad Sci 1995 May 31;754]
SYNONYMS                   QS21 [NIAID VEU 016]
PROTOCOL ID NUMBERS        NIAID AVEG 036
PROTOCOL ID NUMBERS        NIAID VEU 016
PROTOCOL ID NUMBERS        NIAID VEU 016A
PHARMACOLOGICAL ACTION     MODE OF ACTION: The potential and desired
                           effects of this adjuvant may include the
                           following: an increase in antibody responses
                           directed to neutralizing epitopes, a
                           reduction in the time interval needed to
                           achieve high neutralizing antibody titers, an
                           increase in the duration of the immune
                           responses, the induction of CD8+
                           MHC-restricted CTL, and a decrease in the
                           amount of immunogen needed in the vaccine
                           preparation. The saponin adjuvant, QS-21, has
                           been extensively tested in experimental
                           vaccine formulations in animals and in one
                           human trial, and results to date indicate
                           that this adjuvant may offer several of the
                           above desired effects in combination with a
                           subunit HIV-1 envelope vaccine. [NIAID VEU
                           016; AIDS Res Hum Retroviruses 1995
                           Feb;11(2); J of Immunol 1992 Mar 1;158(4)]
DISEASES STUDIED/TREATED   Primary HIV infection: as a vaccine adjuvant
                           for the enhancement of the immune response.
                           [NIAID VEU 016; AIDS Res Hum Retroviruses
                           1995 Feb;11(2)]
CLASSIFICATION CODE        Immunologic Adjuvant [AIDS Res Hum
                           Retroviruses 1995 Feb;11(2)]
CLASSIFICATION CODE        Immunostimulant [NIAID VEU 015]
ADVERSE EFFECTS            Adverse effects include tenderness at site of
                           intramuscular injection and mild flu-like
                           symptoms. [NIAID VEU 016]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: A nontoxic saponin derived
                           from the soapbark tree Quillaja saponaria.
                           The molecule contains 8 monosaccharides, 2
                           fatty acids, and a triterpene aldehyde (< 10
                           EU/mg), at C4. [NIAID VEU 016; AIDS Res Hum
                           Retroviruses 1992 Aug;8(8); Vaccine 1995;
                           13(15)]
CHEMICAL/PHYSICAL DATA     MOLECULAR WEIGHT: 1990 kD [NIAID VEU 016]
CHEMICAL/PHYSICAL DATA     DRUG PHYSICAL COMMENT: The amphipathic
                           molecule forms micelles at a concentration of
                           35 mcM at pH 7. [NIAID VEU 016]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: 3 ml vial containing 0.5 mg/ml
                           QS-21, 20 mM succinate pH 5.5, and 120 mM
                           NaCl. [NIAID VEU 016]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intramuscular injection.
                           [NIAID VEU 016]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Refrigerate at 2-8 C.
                [NIAID VEU 016]
MANUFACTURERS   Genentech Incorporated; 460 Point San Bruno
                Boulevard; South San Francisco, CA 94080
REFERENCES      97116205. Kensil CR, Soltysik S, Wheeler DA,
                Wu JY. Structure/function studies on QS-21, a
                unique immunological adjuvant from Quillaja
                saponaria. Adv Exp Med Biol 1996;404:165-72.
REFERENCES      97120481. Cleland JL, Barron L, Daugherty A,
                Eastman D, Kensil C, Lim A, Weissburg RP,
                Wrin T, Vennari J, Powell MF. Development of
                a single-shot subunit vaccine for HIV-1. 3.
                Effect of adjuvant and immunization schedule
                on the duration of the humoral immune
                response to recombinant MN gp120. J Pharm Sci
                1996 Dec;85(12):1350-7.
REFERENCES      MED/96402439. Cleland JL, Kensil CR, Lim A,
                Jacobsen NE, Basa L, Spellman M, Wheeler DA,
                Wu JY, Powell MF. Isomerization and
                formulation stability of the vaccine adjuvant
                QS-21. J Pharm Sci. 1996 Jan;85(1):22-8.
REFERENCES      96146013. Jacobsen NE, Fairbrother WJ, Kensil
                CR, Lim A, Wheeler DA, Powell MF. Structure
                of the saponin adjuvant QS-21 and its
                base-catalyzed isomerization product by 1H
                and natural abundance 13C NMR spectroscopy.
                Carbohydr Res 1996 Jan 4;280(1):1-14.
REFERENCES      MED/95260529. Powell MF, Eastman DJ, Lim A,
                Lucas C, Peterson M, Vennari J, Weissburg RP,
                Wrin T, Kensil CR, Newman MJ, et al. Effect
                of adjuvants on immunogenicity of MN
                recombinant glycoprotein 120 in guinea pigs.
                AIDS Res Hum Retroviruses. 1995
                Feb;11(2):203-9.
REFERENCES      96145955. Soltysik S, Wu JY, Recchia J,
                Wheeler DA, Newman MJ, Coughlin RT, Kensil
                CR. Structure/function studies of QS-21
                adjuvant: assessment of triterpene aldehyde
                and glucuronic acid roles in adjuvant
                function. Vaccine 1995;13(15):1403-10.
                96057700. Kensil CR, Wu JY, Soltysik S.
                Structural and immunological characterization
                of the vaccine adjuvant QS-21. Pharm
                Biotechnol 1995;6:525-41.
REFERENCES      95159643. Livingston PO, Adluri S, Helling F,
                Yao TJ, Kensil CR, Newman MJ, Marciani D.
                Phase 1 trial of immunological adjuvant QS-21
                with a GM2 ganglioside-keyhole limpet
                haemocyanin conjugate vaccine in patients
                with malignant melanoma. Vaccine 1994
                Nov;12(14):1275-80.
REFERENCES      MED/95078004. Newman MJ, Munroe KJ, Anderson
                CA, Murphy CI, Panicali DL, Seals JR, Wu JY,
                Wyand MS, Kensil CR. Induction of
                antigen-specific killer T lymphocyte
                responses using subunit SIVmac251 gag and env
                vaccines containing QS-21 saponin adjuvant.
                AIDS Res Hum Retroviruses. 1994
                Jul;10(7):853-61.
REFERENCES      95169484. Cleland JL, Powell MF, Lim A,
                Barron L, Berman PW, Eastman DJ, Nunberg JH,
                Wrin T, Vennari JC. Development of a
                           single-shot subunit vaccine for HIV-1. AIDS
                           Res Hum Retroviruses 1994;10 Suppl 2:S21-6.
ENTRY MONTH                199306
LAST REVISION DATE         19990318

130
UNIQUE IDENTIFIER          DRG-0177
NAME OF SUBSTANCE          Threonyl muramyl dipeptide [CHEMLINE]
REGISTRY NUMBER            66112-59-2
STANDARD CHEMICAL NAME     2-Acetamido-3-0-(((1R)-1-((1S,2R)-1-
                           (((1R)-1-carbamoyl-3-carboxypropyl)carbamoyl)-
                           -2-
                           hydroxypropyl)carbamoyl)ethyl)-2-deoxy-D-gluc-
                           opyranose [CHEMID]
SYNONYMS                   Threonyl MDP [NIAID VEU 015]
SYNONYMS                   RS-37449 [CHEMLINE]
SYNONYMS                   D-alpha-Glutamine,
                           N(2)-(N-(N-acetylmuramoyl)-L-threonyl)
                           [CHEMID]
SYNONYMS                   Temurtide [CHEMID]
SYNONYMS                   N-acetylmuramyl-L-threonyl-D-isoglutamine
                           [NIAID VEU 015]
SYNONYMS                   ThrMDP [Eur J Immunol 1992 Sep;22(9)]
SYNONYMS                   MDP [NIAID VEU 015]
PROTOCOL ID NUMBERS        NIAID VEU 015
PHARMACOLOGICAL ACTION     MODE OF ACTION: The mechanisms in which
                           adjuvants augment vaccine immunogenicity may
                           include 1) the prolongation of antigen
                           exposure to antigen-presenting cells by the
                           creation of a depot at the site of injection,
                           2) the activation of antigen-presenting
                           cells, such as monocytes or macrophages, to
                           release cytokines that can promote T-cell
                           help for B cell and CTL response, 3) the
                           introduction of antigen into the MHC Class I
                           processing pathway. As a result, the adjuvant
                           may induce a more favorable antibody response
                           with high titers, which appear earlier in the
                           course of immunization and persist over time,
                           as well as increase memory responses and CD8+
                           MHC Class I-restricted CTL. Among 130 analogs
                           of muramyl dipeptides tested on animals,
                           threonyl muramyl dipeptide showed the
                           greatest separation of potency as an adjuvant
                           from potency in the production of
                           side-effects. [NIAID VEU 015; Mol Immunol
                           1991 Mar;28(3); Ann NY Acad Sci 1995 May
                           31;754]
DISEASES STUDIED/TREATED   Primary HIV infection: as a vaccine adjuvant
                           for the enhancement of the immune response.
                           [NIAID VEU 015]
CLASSIFICATION CODE        Immunologic Adjuvant [Ann NY Acad Sci 1995
                           May 31;754]
CLASSIFICATION CODE        Immunostimulant [NIAID VEU 015]
ADVERSE EFFECTS            This formulation does not produce tissue
                           damage or elicit an inflammatory reaction at
                           injection sites, and no systemic reaction is
                           demonstrable (in monkeys). [Modern Approaches
                           to New Vaccines]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: A synthetic muramyl
                           dipeptide analog. [Semin Immunol 1990
                          Sep;2(5)]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: C20H34N4O12 [CHEMLINE]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Vial containing 0.5 ml. [NIAID
                          VEU 015]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Intramuscular injection.
                          [NIAID VEU 015]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Vials should be stored
                          at 5 C. [NIAID VEU 015]
MANUFACTURERS             BIOCINE Company; 4560 Horton Street;
                          Emeryville, CA 94608-2916
REFERENCES                97304250. Hjorth RN, Bonde GM, Piner ED,
                          Goldberg KM, Levner MH. The effect of Syntex
                          adjuvant formulation (SAF-m) on humoral
                          immunity to the influenza virus in the mouse.
                          Vaccine 1997 Apr;15(5):541-6.
REFERENCES                96342144. Gupta RK, Griffin P Jr, Chang AC,
                          Rivera R, Anderson R, Rost B, Cecchini D,
                          Nicholson M, Siber GR. The role of adjuvants
                          and delivery systems in modulation of immune
                          response to vaccines. Adv Exp Med Biol
                          1996;397:105-13.
REFERENCES                96155133. Gupta RK, Siber GR. Adjuvants for
                          human vaccines--current status, problems and
                          future prospects. Vaccine 1995
                          Oct;13(14):1263-76.
REFERENCES                94378704. Hjorth RN, Bonde GM, Piner ED,
                          Goldberg KM, Levner MH, Hung PP. Relevance of
                          the guinea-pig necrotic inflammation footpad
                          reaction to safety concerns with MDP-based
                          adjuvants. Vaccine. 1994 Jun;12(8):687-90.
REFERENCES                93190590. Gupta RK, Relyveld EH, Lindblad EB,
                          Bizzini B, Ben-Efraim S, Gupta CK.
                          Adjuvants-- a balance between toxicity and
                          adjuvanticity. Vaccine. 1993;11(3):293-306.
REFERENCES                91203949. Allison AC, Byars NE. Immunological
                          adjuvants: desirable properties and
                          side-effects. Mol Immunol. 1991
                          Mar;28(3):279-84.
REFERENCES                MED/92182252. Allison AC, Byars NE. Adjuvant
                          formulations and their mode of action. Semin
                          Immunol. 1990 Sep;2(5):369-74.
REFERENCES                MED/90069604. Murphey-Corb M, Martin LN,
                          Davison-Fairburn B, Montelaro RC, Miller M,
                          West M, Ohkawa S, Baskin GB, Zhang JY, Putney
                          SD, et al. A formalin-inactivated whole SIV
                          vaccine confers protection in macaques.
                          Science. 1989 Dec 8;246(4935):1293-7.
REFERENCES                ICDB/88647963. Allison AC, Byars NE.
                          Development of an adjuvant formulation that
                          can elicit protective immunity against
                          retroviruses. Vaccines 87. Modern Approaches
                          to New Vaccines: Prevention of AIDS and Other
                          Viral, Bacterial, and Parasitic Diseases.
                          Chanock RM et al, eds. New York, Cold Spring
                          Harbor Laboratory, p. 56-9, 1987.
ENTRY MONTH               199306
LAST REVISION DATE        19990311

131
UNIQUE IDENTIFIER         DRG-0176
NAME OF SUBSTANCE         MF59 [Int Conf AIDS 1993 Jun 6-11;9(1)]
SYNONYMS                   MF-59 [Ann NY Acad Sci 1995 May 31;754]
SYNONYMS                   MF-59 oil emulsion [MeSH]
PROTOCOL ID NUMBERS        NIAID VEU 028
PROTOCOL ID NUMBERS        NIAID ACTG 214
PROTOCOL ID NUMBERS        NIAID ACTG 233
PROTOCOL ID NUMBERS        NIAID VEU 015
PROTOCOL ID NUMBERS        NIAID VEU 024
PHARMACOLOGICAL ACTION     MODE OF ACTION: The mechanisms in which
                           adjuvants augment vaccine immunogenicity may
                           include 1) the prolongation of antigen
                           exposure to antigen-presenting cells by the
                           creation of a depot at the site of injection,
                           2) the activation of antigen-presenting
                           cells, such as monocytes or macrophages, to
                           release cytokines that can promote T-cell
                           help for B cell and CTL response, 3) the
                           introduction of antigen into the MHC Class I
                           processing pathway. As a result, the adjuvant
                           may induce a more favorable antibody response
                           with high titers, which appear earlier in the
                           course of immunization and persist over time,
                           as well as increase memory responses and CD8+
                           MHC Class I-restricted CTL. [NIAID VEU 015; J
                           Infect Dis 1994 Nov;170(5); Ann NY Acad Sci
                           1995 May 31;754]
DISEASES STUDIED/TREATED   Primary HIV infection: as a vaccine adjuvant
                           for the enhancement of the immune response.
                           Used as an emulsifier system in conjunction
                           with other adjuvants such as MTP-PE. [NIAID
                           VEU 015; J Infect Dis 1994 Nov;170(5); J
                           Infect Dis 1994 Nov;170(5)]
CLASSIFICATION CODE        Immunologic Adjuvant [Ann NY Acad Sci 1995
                           May 31;754]
CLASSIFICATION CODE        Immunostimulant [NIAID VEU 015]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: MF59 is a safe, practical,
                           and potent adjuvant for use with human
                           vaccines. The formulation is easily
                           manufactured, may be sterilized by
                           filtration, and is both compatible and
                           efficacious with all antigens tested to date.
                           MF59 has been shown to be a potent stimulator
                           of cellular and humoral responses to subunit
                           antigens in both animal models and clinical
                           studies. Toxicology studies in animal models
                           and Phase I-III studies in humans have
                           demonstrated the safety of MF59 with HSV,
                           HIV, and influenza vaccines. This emulsion
                           consists of 0.5% polysorbate 80 and 0.5%
                           sorbitan trioleate. Squalene (5.0%), a
                           metabolizable lipid, constitutes the oil
                           phase. [NIAID VEU 015]
CHEMICAL/PHYSICAL DATA     PHYSICAL DESCRIPTION: Emulsion. [Int Conf
                           AIDS 1996 Jul 7-12;11(1); NIAID VEU 015]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Vial with a fill volume of 0.65
                           ml and a withdrawable volume of 0.50 ml.
                           [NIAID VEU 015]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intramuscular injection.
                           [Int Conf AIDS 1993 Jun 6-11;9(1)]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Store refrigerated at
                           2-8 C. [NIAID VEU 015]
MANUFACTURERS              BIOCINE Company; 4560 Horton Street;
                Emeryville, CA 94608-2916
MANUFACTURERS   Chiron Vaccines; 5560 Horton Street;
                Emeryville, CA 94608
REFERENCES      AIDS/97926054. Barnett SW, Duliege AM,
                Sinangil F, Walker CM, Hansen L, Boggio K,
                Steimer KS. HIV vaccine efforts at Chiron:
                polynucleotide, protein subunit, and
                prime/boost approaches. 4th Conf Retro and
                Opportun Infect. 1997 Jan 22-26;:219
                (abstract no.S30).
REFERENCES      AIDS/97926200. Schooley RT, Spino C, Chiu S,
                DeGruttola V, Kuritzkes DR. Poor
                immunogenicity of HIV-1 envelope vaccines
                with alum or MF59 adjuvant in HIV-infected
                individuals: results of two randomized
                trials. 4th Conf Retro and Opportun Infect.
                1997 Jan 22-26;:204 (abstract no.756).
REFERENCES      MED/96301139. Graham BS, Keefer MC, McElrath
                MJ, Gorse GJ, Schwartz DH, Weinhold K,
                Matthews TJ, Esterlitz JR, Sinangil F, Fast
                PE. Safety and immunogenicity of a candidate
                HIV-1 vaccine in healthy adults: recombinant
                glycoprotein (rgp) 120. A randomized,
                double-blind trial. NIAID AIDS Vaccine
                Evaluation Group. Ann Intern Med. 1996 Aug
                15;125(14):270-9.
REFERENCES      ICA11/96923724. Duliege AM, Sinangil F,
                Walker C, Dekker C, Boggio K, Clements ML,
                McElrath J, Kahn J, Graham B, Excler JL, et
                al. Recombinant HIV subunit vaccines
                development: a collaborative effort. Int Conf
                AIDS. 1996 Jul 7-12;11(2):122 (abstract
                no.We.B.3376).
REFERENCES      ICA11/96920850. McElrath MJ, Montefiori D,
                Wolff M, Clements M, Gorse G, Keefer M,
                Graham B, Duliege AM, Francis D, Matthews T,
                et. al. Safety, immunity, and risk behavior
                in HIV-1-uninfected volunteers representing
                diverse risk populations following
                recombinant envelope vaccinations: a
                three-year followup. Int Conf AIDS, 1996 Jul
                7-12;11(1):10 (absract no. Mo.A.284).
REFERENCES      MED/96303587. Keefer MC, Graham BS, McElrath
                MJ, Matthews TJ, Stablein DM, Corey L, Wright
                PF, Lawrence D, Fast PE, Weinhold K, et al.
                Safety and immunogenicity of Env 2-3, a human
                immunodeficiency virus type 1 candidate
                vaccine, in combination with a novel
                adjuvant, MTP-PE/MF59. NIAID AIDS Vaccine
                Evaluation Group. AIDS Res Hum Retroviruses.
                1996 May 20;12(8):683-93.
REFERENCES      AIDS/97920758. Nitayaphan S, Khamboonruang C,
                Chiu J, Morgan P, Suriyanon V, Sirisophana N,
                Duleige A-M, Boggio K, McNeil J, Michael R.
                Post-immunization reactogenicity and toxicity
                of Biocine(R) HIV SF2 gp120/MF59 vaccine in
                seronegative Thai volunteers. Conf Adv AIDS
                Vaccine Dev. 1996 Feb 11-15;:186 [Poster 66].
REFERENCES      AIDS/97920787. McElrath MJ, Montefiori DM,
                Clements ML, Belshe RB, Dolin R, Graham BS,
                Duliege A-M, Francis D, Bolognesi DP,
                           Matthews TJ, et al. Longitudinal
                           vaccine-induced immunity and risk behavior of
                           study participants of AVEG phase II protocol
                           201. Conf Adv AIDS Vaccine Dev. 1996 Feb
                           11-15;:216 [Poster 96].
REFERENCES                 AIDS/97920686. Clements ML, Weinhold K,
                           Schwartz D, Siliciano R, Matthews T, Graham
                           B, Keefer M, McElrath J, Gorse G, Hsieh R, et
                           al. HIV immunity induced by canarypox
                           (ALVAC)-(MN)gp160, (SF2)gp120 or both. Conf
                           Adv AIDS Vaccine Dev. 1996 Feb 11-15;:91.
REFERENCES                 AIDS/95920551. Lambert JS, McNamara J, Katz
                           S, Livingston R, Fenton T, Geheb H, Duliege
                           AM, Francis D, Volvowitz F, Hawkins E, et al.
                           Safety and immunogenicity of recombinant
                           envelope HIV vaccines in asymptomatic HIV
                           infected children. Natl Conf Hum Retroviruses
                           Relat Infect (2nd). 1995 Jan 29-Feb 2;:151.
ENTRY MONTH                199306
LAST REVISION DATE         19990203

132
UNIQUE IDENTIFIER          DRG-0175
NAME OF SUBSTANCE          Syntex adjuvant formulation [Vaccine
                           1993;11(3)]
SYNONYMS                   SAF/2 [NIAID VEU 015]
PROTOCOL ID NUMBERS        NIAID VEU 015
PHARMACOLOGICAL ACTION     MODE OF ACTION: The mechanisms in which
                           adjuvants augment vaccine immunogenicity may
                           include 1) the prolongation of antigen
                           exposure to antigen-presenting cells by the
                           creation of a depot at the site of injection,
                           2) the activation of antigen-presenting
                           cells, such as monocytes or macrophages, to
                           release cytokines that can promote T-cell
                           help for B cell and CTL response, 3) the
                           introduction of antigen into the MHC Class I
                           processing pathway. As a result, the adjuvant
                           may induce a more favorable antibody response
                           with high titers, which appear earlier in the
                           course of immunization and persist over time,
                           as well as increase memory responses and CD8+
                           MHC Class I-restricted CTL. Vaccines using
                           SAF have protected guinea pigs against
                           genital herpes simplex virus infections and
                           subhuman primates against Epstein-Barr virus
                           and simian immunodeficiency virus infections.
                           [NIAID VEU 015; Semin Immunol 1990 Sep;2(5)]
DISEASES STUDIED/TREATED   Primary HIV infection: as a vaccine adjuvant
                           for the enhancement of the immune response.
                           [NIAID VEU 015]
CLASSIFICATION CODE        Immunologic Adjuvant [Semin Immunol 1990
                           Sep;2(5)]
CLASSIFICATION CODE        Immunostimulant [NIAID VEU 015]
ADVERSE EFFECTS            Adverse effects include discomfort at the
                           site of injection; mild acute elevations in
                           white blood count, CPK and sedimentation rate
                           have been observed. [NIAID VEU 015]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: An emulsion consisting of
                           squalene, Pluronic L121 block polymer and
                           Tween 80 in phosphate-buffered saline. [NIAID
                          VEU 015; MeSH]
CHEMICAL/PHYSICAL DATA    DRUG PHYSICAL COMMENT: Properties of SAF are
                          compared with those of other adjuvants,
                          including lipopolysaccharide analogs,
                          ISCOM's, and liposomes. [Semin Immunol 1990
                          Sep;2(5)]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: 0.6 ml vial. [NIAID VEU 015]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Intramuscular injection.
                          [NIAID VEU 015]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store refrigerated at
                          2-8 C. [NIAID VEU 015]
MANUFACTURERS             BIOCINE Company; 4560 Horton Street;
                          Emeryville, CA 94608-2916
REFERENCES                MED/97304250. Hjorth RN, Bonde GM, Piner ED,
                          Goldberg KM, Levner MH. The effect of Syntex
                          adjuvant formulation (SAF-m) on humoral
                          immunity to the influenza virus in the mouse.
                          Vaccine. 1997 Apr;15(5):541-6.
REFERENCES                ICA11/96920819. Buge SL, Lubeck M, Kalyan N,
                          Cheng S, Richardson E, Markham P, Miller C,
                          Udem S, Robert-Guroff M. Adenovirus host
                          range mutant-SIV recombinant vaccine trial in
                          rhesus macaques. Int Cont AIDS. 1996 Jul
                          7-12;11(1):4 (abstract no.Mo.A.102).
REFERENCES                94209040. Allison AC. Adjuvants and immune
                          enhancement. Int J Technol Assess Health
                          Care. 1994 Winter;10(1):107-20.
REFERENCES                93190590. Gupta RK, Relyveld EH, Lindblad EB,
                          Bizzini B, Ben-Efraim S, Gupta CK.
                          Adjuvants--a balance between toxicity and
                          adjuvanticity. Vaccine. 1993;11(3):293-306.
REFERENCES                93067447. Allison AC, Byars NE. Syntex
                          adjuvant formulation. Res Immunol. 1992
                          Jun;143(5):519-25.
REFERENCES                96043088. Robuccio JA, Griffith JW,
                          Chroscinski EA, Cross PJ, Light TE, Lang CM.
                          Comparison of the effects of five adjuvants
                          on the antibody response to influenza virus
                          antigen in guinea pigs. Lab Anim Sci 1995
                          Aug;45(4);420-6.
REFERENCES                95272066. Houston L, Moncla BJ, Page R, Engel
                          D. Response of guinea pigs to a vaccine
                          containing a new adjuvant (SAF) and
                          gram-negative bacteria. Lab Anim Sci 1995
                          Feb;45(1):59-66.
ENTRY MONTH               199306
LAST REVISION DATE        19980416

133
UNIQUE IDENTIFIER         DRG-0174
NAME OF SUBSTANCE         Liposome-encapsulated monophosphoryl lipid A
                          [NIAID VEU 015]
PROTOCOL ID NUMBERS       NIAID VEU 015
PHARMACOLOGICAL ACTION    MODE OF ACTION: The mechanisms in which
                          adjuvants augment vaccine immunogenicity may
                          include 1) the prolongation of antigen
                          exposure to antigen-presenting cells by the
                          creation of a depot at the site of injection,
                          2) the activation of antigen presenting
                          cells, such as monocytes or macrophages, to
                          release cytokines that can promote T-cell
                           help for B cell and CTL response, 3) the
                           introduction of antigen into the MHC Class I
                           processing pathway. As a result, the adjuvant
                           may induce a more favorable antibody response
                           with high titers, which appear earlier in the
                           course of immunization and persist over time,
                           as well as increase memory responses and CD8+
                           MHC Class I-restricted CTL. Encapsulation of
                           poorly immunogenic circumsporozoite protein
                           repeat peptides in monophosphoryl lipid A
                           containing liposomes is a successful adjuvant
                           strategy in humans for inducing high levels
                           of specific antibody production. The
                           mechanism of the adjuvant action of liposomal
                           lipid A is partly due to increased antigen
                           presentation by macrophages and partly due to
                           the recruitment of an increased number of
                           macrophages serving as antigen-presenting
                           cells. [NIAID VEU 015; Proc Natl Acad Sci USA
                           1992 Jan 1;89(1); Infect Immun 1992
                           Jun;60(6)]
DISEASES STUDIED/TREATED   Primary HIV infection: as a vaccine adjuvant
                           for the enhancement of the immune response.
                           [NIAID VEU 015]
CLASSIFICATION CODE        Immunologic Adjuvant [Proc Natl Acad Sci USA
                           1992 Jan 1;89(1)]
CLASSIFICATION CODE        Immunostimulant [NIAID VEU 015]
ADVERSE EFFECTS            Moderate but acceptable transient local
                           reactogenicity was noted at high doses of the
                           vaccine formulation, but little or no
                           systemic toxicity was seen despite doses up
                           to 2200 mcg. [Proc Natl Acad Sci USA 1992 Jan
                           1;89(1)]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Liposomes made of
                           phospholipids and cholesterol that contain
                           monophosphoryl lipid A. [NIAID VEU 015]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Vial with 8.8 mg MPL per ml.
                           [NIAID VEU 015]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intramuscular injection.
                           [NIAID VEU 015]
SUBSTANCE DELIVERY DATA    STORAGE INSTRUCTIONS: Store at 4 C. [NIAID
                           VEU 015]
MANUFACTURERS              Walter Reed Army Institute of Research; 16th
                           Street and Georgia Avenue NW; Washington, DC
                           20307
REFERENCES                 ICA11/96923146. VanCott TC, Kaminski R, Lewis
                           M, Mascola J, Wassef N, Alving C, Ulrich T,
                           Richardson C, Lowell G, Burnett P, et al.
                           Mucosal and systemic immune responses to
                           parenteral and intranasal administration of
                           an oligomeric HIV-1 gp160 vaccine. Int Conf
                           AIDS. 996 Jul 7-12;11(2):13 (abstract
                           no.We.A.391).
REFERENCES                 MED/95351596. Alving CR. Liposomal vaccines:
                           clinical status and immunological
                           presentation for humoral and cellular
                           immunity. Ann N Y Acad Sci. 1995 May
                           31;754:143-52.
REFERENCES                 95120365. Wassef NM, Alving CR, Richards RL.
                           Liposomes as carriers for vaccines.
                           Immunomethods. 1994 Jun;4(3):217-22.
REFERENCES                 94226318. Hui GS. Liposomes, muramyl
                           dipeptide derivatives, and nontoxic lipid A
                           derivatives as adjuvants for human malaria
                           vaccines. Am J Trop Med Hyg. 1994;50(4
                           Suppl):41-51.
REFERENCES                 93322093. Alving CR. Lipopolysaccharide,
                           lipid A, and liposomes containing lipid A as
                           immunologic adjuvants. Immunobiology. 1993
                           Apr;187(3-5):430-46.
ENTRY MONTH                199306
LAST REVISION DATE         19971020

134
UNIQUE IDENTIFIER          DRG-0173
NAME OF SUBSTANCE          Monophosphoryl lipid A [Infect Immu 1990
                           Mar;58(3)]
SYNONYMS                   MPL [Infect Immu 1990 Mar;58(3)]
SYNONYMS                   Lipid A MP [MeSH]
SYNONYMS                   MPLA [Infect Immu 1986 Sep;53(3)]
PROTOCOL ID NUMBERS        NIAID VEU 015
PHARMACOLOGICAL ACTION     MODE OF ACTION: Monophosphoryl lipid A has
                           been shown to be a potent immunologic
                           adjuvant. The mechanism in which adjuvants
                           augment vaccine immunogenicity may include 1)
                           the prolongation of antigen exposure to
                           antigen-presenting cells by the creation of a
                           depot at the site of injection, 2) the
                           activation of antigen presenting cells, such
                           as monocytes or macrophages, to release
                           cytokines that can promote T-cell help for B
                           cell and CTL response, 3) the introduction of
                           antigen into the MHC Class I processing
                           pathway. As a result, the adjuvant may induce
                           a more favorable antibody response with high
                           titers, which appear earlier in the course of
                           immunization and persist over time, as well
                           as increase memory responses and CD8+ MHC
                           Class I-restricted CTL. Animal studies
                           suggest monophosphoryl lipid A increases
                           antibody formation by inducing the helper T
                           cell population to secrete interferon gamma.
                           The latter activates the macrophage to
                           secrete increased levels of interleukin 1,
                           thereby resulting in increased responsiveness
                           throughout the ensuing sequence of cellular
                           and molecular events leading to antibody
                           synthesis. [Adv Exp Med Biol 1990; No 256;
                           NIAID VEU 015]
DISEASES STUDIED/TREATED   Primary HIV infection: as a vaccine adjuvant
                           for the enhancement of the immune response.
                           [NIAID VEU 015]
CLASSIFICATION CODE        Immunologic Adjuvant [J Immunol 1991 Oct
                           1;147(7)]
CLASSIFICATION CODE        Immunostimulant [NIAID VEU 015]
OTHER MAJOR USES           An immunological adjuvant. Induction of
                           endotoxin tolerance with monophosphoryl lipid
                           A improves survival from peritonitis. [NIAID
                           VEU 015; J Lab Clin Med 1994 Jan;123(1)]
ADVERSE EFFECTS            Mild to moderate symptoms include headache,
                           chills, myalgia, and pain at the site of
                           injection. [NIAID VEU 015]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: A monophosphorylated lipid;
                          a non-toxic derivative of lipid A. [NIAID VEU
                          015; Infect Immun 1986 Apr;52(1)]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Vials containing 100 mcg per ml.
                          [NIAID VEU 015]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Intramuscular injection.
                          [NIAID VEU 015]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Vials should be stored
                          at 2-6 C. [NIAID VEU 015]
MANUFACTURERS             RIBI ImmunoChem Research Incorporated; PO Box
                          1409; Hamilton, MT 59840
REFERENCES                MED/97296236. VanCott TC, Mascola JR,
                          Kaminski RW, Kalyanaraman V, Hallberg PL,
                          Burnett PR, Ulrich JT, Rechtman DJ, Birx DL.
                          Antibodies with specificity to native gp120
                          and neutralization activity against primary
                          human immunodeficiency virus type 1 isolates
                          elicited by immunization with oligomeric
                          gp160. J Virol. 1997 Jun 71(6):4319-30.
REFERENCES                AIDS/97926186. VanCott TC, Lewis M, Kaminski
                          R, Mascola J, Kalyanaraman V, Veit SD, Lu Y,
                          Jenkins S, Richardson C, Ulrich T, Birx DL.
                          Protection of rhesus macaques from SHIV
                          challenge using oligomeric gp160 formulated
                          in MPL or polyphoshazene adjuvants. 4th Conf
                          Retro and Opportun Infect. 1997 Jan
                          22-26;:204 (abstract no.755).
REFERENCES                ICA11/96923146. VanCott TC, Kaminski R, Lewis
                          M, Mascola J, Wassef N, Alving C, Ulrich T,
                          Richardson C, Lowell G, Burnett P, et al.
                          Mucosal and systemic immune responses to
                          parenteral and intransal administration of an
                          oligomeric HIV-1 gp160 vaccine. Int Conf
                          AIDS. 1996 Jul 7-12;11(2):13 (abstract
                          no.We.A.391).
REFERENCES                95366230. Schultz N, Oratz R, Chen D,
                          Zeleniuch-Jacquotte A, Abeles G, Bystryn JC.
                          Effect of DETOX as an adjuvant for melanoma
                          vaccine. Vaccine 1995 Apr;13(5):503-8.
REFERENCES                95094547. Astiz ME, Rackow EC, Still JG,
                          Howell ST, Cato A, Von Eschen KB, Ulrich JT,
                          Rudbach JA, McMahon G, Vargas R, et al.
                          Pretreatment of normal humans with
                          monophosphoryl lipid A induces tolerance to
                          endotoxin: a prospective, double-blind,
                          randomized, controlled trial. Crit Care Med
                          1995 Jan;23(1):9-17.
REFERENCES                95077062. Hoffman SL, Edelman R, Bryan JP,
                          Schneider I, Davis J, Sedegah M, Gordon D,
                          Church P, Gross M, Silverman C, et al.
                          Safety, immunogenicity, and efficacy of a
                          malaria sporozoite vaccine administered with
                          monophosphoryl lipid A, cell wall skeleton of
                          mycobacteria, and squalane as adjuvant. Am J
                          Trop Med Hyg 1994 Nov;51(5):603-12.
REFERENCES                95007435. Johnson AG. Molecular adjuvants and
                          immunomodulators: new approaches to
                          immunization. Clin Microbiol Rev 1994
                          Jul:7(3):277-89.
ENTRY MONTH               199306
LAST REVISION DATE        19971020
135
UNIQUE IDENTIFIER          DRG-0172
NAME OF SUBSTANCE          Aluminum hydroxide [USAN 1997]
REGISTRY NUMBER            21645-51-2
STANDARD CHEMICAL NAME     aluminum hydrate [Merck Index 1996]
SYNONYMS                   Aluminum trihydrate [Merck Index 1996]
SYNONYMS                   Hydrated alumina [Merck Index 1996]
SYNONYMS                   Alhydrogel [NIAID VEU 015]
SYNONYMS                   Superfos [NIAID VEU 015]
SYNONYMS                   Amphojel [USAN 1997]
SYNONYMS                   Dialume [USAN 1997]
SYNONYMS                   Creamalin [Merck Index 1996]
SYNONYMS                   Cremorin [Merck Index 1996]
SYNONYMS                   ALternaGEL [Merck Index 1996]
SYNONYMS                   Al-U-Creme [Merck Index 1996]
SYNONYMS                   Alucol [Merck Index 1996]
SYNONYMS                   Merlium [Merck Index 1996]
SYNONYMS                   Aludrox [Merck Index 1996]
SYNONYMS                   Alkagel I.S. [Merck Index 1996]
SYNONYMS                   Aldrox [Merck Index 1996]
SYNONYMS                   Aludyal [Merck Index 1996]
SYNONYMS                   Pepsamar [Merck Index 1996]
SYNONYMS                   Gelumina [Merck Index 1996]
SYNONYMS                   Uracid [Merck Index 1996]
SYNONYMS                   Alumigel [CHEMLINE]
SYNONYMS                   Antidiar [Merck Index 1996]
PROTOCOL ID NUMBERS        NIAID VEU 028
PROTOCOL ID NUMBERS        FDA 98 I-0028
PROTOCOL ID NUMBERS        NIAID ACTG 214
PROTOCOL ID NUMBERS        NIAID VEU 015
PROTOCOL ID NUMBERS        NIAID VEU 016
PROTOCOL ID NUMBERS        NIAID VEU 016A
PROTOCOL ID NUMBERS        NIAID VEU 019
PHARMACOLOGICAL ACTION     MODE OF ACTION: The mechanisms in which
                           adjuvants augment vaccine immunogenicity may
                           include 1) the prolongation of antigen
                           exposure to antigen-presenting cells by the
                           creation of a depot at the site of injection,
                           2) the activation of antigen-presenting
                           cells, such as monocytes or macrophages, to
                           release cytokines that can promote T-cell
                           help for B cell and CTL response, 3) the
                           introduction of antigen into the MHC Class I
                           processing pathway. As a result, the adjuvant
                           may induce a more favorable antibody response
                           with high titers, which appear earlier in the
                           course of immunization and persist over time,
                           as well as increase memory responses and CD8+
                           MHC Class I-restricted CTL. [NIAID VEU 015]
DISEASES STUDIED/TREATED   Primary HIV infection: as a vaccine adjuvant
                           for the enhancement of the immune response.
                           [NIAID VEU 015]
CLASSIFICATION CODE        Immunologic Adjuvant [Merck Index 1996]
CLASSIFICATION CODE        Immunostimulant [NIAID VEU 015]
OTHER MAJOR USES           Alum has been used as an adjuvant since the
                           1920's and is the only adjuvant approved by
                           the FDA for use in human vaccines; aluminum
                           hydroxide is an antacid and a
                           antihyperphosphatemic. [USAN 1997; Merck
                           Index 1996; NIAID VEU 015]
CHEMICAL/PHYSICAL DATA    DRUG DESCRIPTION: Aluminum salt (alum).
                          [NIAID VEU 015]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: White, bulky, amorphous
                          powder. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: AL(OH)3 [USAN 1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 78.00 [USAN 1997]
CHEMICAL/PHYSICAL DATA    ELEMENTAL COMP: Al34.59%, H3.88%, O61.53%
                          [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    SOLUBILITY: Practically insoluble in water;
                          soluble in alkaline aqueous solution, HCl,
                          H2SO4, and other strong acids in the presence
                          of some water. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    STABILITY: Forms gels on prolonged contact
                          with water. Absorbs acids and CO2. [Merck
                          Index 1996]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Aluminum hydroxide (2mg) in
                          water (q.s. to 1 ml). [NIAID VEU 015]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Intramuscular injection.
                          [NIAID VEU 015]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store at 4 C. [NIAID
                          VEU 015]
MANUFACTURERS             Drugs are provided by each participating unit
                          site
REFERENCES                MED/96057687. Hem SL, White JL. Structure and
                          properties of aluminum-containing adjuvants.
                          Pharm Biotechnol. 1995;6:249-76.
REFERENCES                MED/96155148. Aggerbeck H, Fenger C, Heron I.
                          Booster vaccination against diphtheria and
                          tetanus in man. Comparison of calcium
                          phosphate and aluminium hydroxide as
                          adjuvants--II. Vaccine. 1995
                          Oct;13(14):1366-74.
REFERENCES                MED/96155133. Gupta RK, Siber GR. Adjuvants
                          for human vaccines--current status, problems
                          and future prospects. Vaccine. 1995
                          Oct;13(14):1263-76.
REFERENCES                MED/95386258. Vogel FR. The role of adjuvants
                          in retroviral vaccines. Int J
                          Immunopharmacol; VOL 17, ISS 2, 1995, P85-90
                          (REF: 43).
REFERENCES                MED/95351597. Vogel FR. Immunologic adjuvants
                          for modern vaccine formulations. Ann N Y Acad
                          Sci 1995 May 31;754:153-60.
REFERENCES                95397586. Men Y, Thomasin C, Merkle HP,
                          Gander B, Corradin G. A single administration
                          of tetanus toxoid in biodegradable
                          microspheres elicits T cell and antibody
                          responses similar or superior to those
                          obtained with aluminum hydroxide. Vaccine
                          1995 May;13(7):683-9.
REFERENCES                95066310. Ma J, Bulger PA, Davis DR,
                          Perilli-Palmer B, Bedore DA, Kensil CR, Young
                          EM, Hung CH, Seals JR, Pavia CS, et al.
                          Impact of the saponin adjuvant QS-21 and
                          aluminium hydroxide on the immunogenicity of
                          recombinant OspA and OspB of Borrelia
                          burgdorferi. Vaccine 1994 Aug;12(10):925-32.
REFERENCES                94025902. Goto N, Kato H, Maeyama J, Eto K,
                          Yoshihara S. Studies on the toxicities of
                          aluminium hydroxide and calcium phosphate as
                          immunological adjuvants for vaccines[see
                           comments]. Vaccine; VOL 11, ISS 9, 1993,
                           P914-8.
REFERENCES                 Nicklas W. Aluminum salts. Res Immunol. 1992
                           Jun;143(5):489-94.
REFERENCES                 MED/93090458. Bomford R, Stapleton M, Winsor
                           S, McKnight A, Andronova T. The control of
                           the antibody isotype response to recombinant
                           human immunodeficiency virus gp120 antigen by
                           adjuvants. AIDS Res Hum Retroviruses. 1992
                           Oct;8(1):1765-71.
ENTRY MONTH                199306
LAST REVISION DATE         19980402

136
UNIQUE IDENTIFIER          DRG-0171
NAME OF SUBSTANCE          Lentinan [AmFAR Tx Dir 1993;6(4)]
REGISTRY NUMBER            37339-90-5
PROTOCOL ID NUMBERS        FDA 126A
PROTOCOL ID NUMBERS        FDA 126B
SECONDARY SOURCE ID        LC-33 [Merck Index 1996]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Demonstrates immune
                           potentiating activity by stimulating the
                           T-cell mediated cytotoxic immune response and
                           also effecting nonspecific macrophage
                           mediated responses. Analysis of the cellular
                           antimetastatic activity of combinations of
                           lentinan and interleukin-2 revealed the
                           involvement of a tumor associated
                           antigen-specific delayed type
                           hypersensitivity response. It is suggested
                           that the life prolonging effect of the
                           combination is mediated by antigen-specific T
                           cells. Lentinan appears to represent Host
                           Defense Potentiators (HDPs), which can
                           restore or augment the ability of
                           responsiveness of the host to
                           lympho-cytokines or other intrinsic bioactive
                           factors through maturation, differentiation
                           or proliferation of the important cells for
                           host defense mechanisms. HDPs such as
                           lentinan are the most appropriate drugs to
                           prevent cancer occurrence or the
                           manifestations of AIDS symptoms in HIV
                           carriers. [Intl Conf AIDS 1990 Jun
                           20-23;6(3); Jpn J Cancer Res 1994 Dec;85(12);
                           Dev Biol Stand 1992;77]
DISEASES STUDIED/TREATED   Enhancement of immune function in HIV
                           infection. [FDA 126A]
CLASSIFICATION CODE        Immunomodulator [Merck Index 1996]
CLASSIFICATION CODE        Antineoplastic (adjunct) [Merck Index 1996]
OTHER MAJOR USES           Treatment of cancer. [Dev Biol Stand 1992;77]
ADVERSE EFFECTS            Adverse effects include acute lumbar pain,
                           anaphylaxis, rigors, vasovagal response, and
                           exacerbation of granulocytopenia. Elevated
                           liver function tests, rash and mild chest
                           pains occur in some cancer patients receiving
                           lentinan. [Intl Conf AIDS 1990 Jun
                           20-23;6(3); AmFAR Tx Dir 1995;7(4)]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Neutral polysaccharide
                           isolated from the edible mushroom, lentinus
                           edodes. Primary structure is a
                          beta-1,3-D-glucan having 2
                          beta-1,6-glucopyranoside branchings for every
                          5 beta-1,3- linear linkages. [Merck Index
                          1996]
CHEMICAL/PHYSICAL DATA    PHYSICAL DESCRIPTION: White powder. [Merck
                          Index 1996]
CHEMICAL/PHYSICAL DATA    MOLECULAR FORMULA: (C6H10O5)n [Merck Index
                          1996]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 400,000 - 800,000 [Merck
                          Index 1996]
CHEMICAL/PHYSICAL DATA    SOLUBILITY: Soluble in aqueous alkali, formic
                          acid; slightly soluble in hot water and DMSO;
                          insoluble in cold water, alcohol, ether,
                          chloroform, pyridine, and
                          hexamethylphosphoramide. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    STABILITY: Stable against sulfuric and
                          hydrochloric acids. [Merck Index 1996]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Intravenous. [FDA 126A]
MANUFACTURERS             AJI PHARMA USA Incorporated; 500 Frank Burr
                          Boulevard; Teaneck, NJ 07666
REFERENCES                ICA11/96920916. Chang RY, Kong XB.
                          Meta-survey of plant and herb material as a
                          treatment for HIV. Int Conf AIDS. 1996 Jul
                          7-12;11(1):22 (abstract no.Mo.B.303).
REFERENCES                96056222. Moriyama A, Murata I, Kuroda T,
                          Yoshikawa I, Tabaru A, Ogami Y, Otsuki M.
                          Pericardiac metastasis from advanced gastric
                          cancer. J Gastroenterol 1995 Aug;30(4):512-6.
REFERENCES                MED/95155164. Hamuro J, Takatsuki F, Suga T,
                          Kikuchi T, Suzuki M. Synergistic
                          antimetastatic effects of lentinan and
                          interleukin 2 with pre- and post-operative
                          treatments. Jpn J Cancer Res. 1994
                          Dec;85(12):1288-97.
REFERENCES                94185237. Suto T, Fukuda S, Moriya N,
                          Watanabe Y, Sasaki D, Yoshida Y, Sakata Y.
                          Clinical study of biological response
                          modifiers as maintenance therapy for
                          hepatocellular carcinoma. Cancer Chemother
                          Pharmacol 1994;33 Suppl:S145-8.
REFERENCES                ICA10/94369733. Kaneko Y, Mimura T, Guralnik
                          M, Baker M, Goodgame J, DeMarzo C, Pierce D,
                          Lang W, Gordon M. Phase II study of
                          combination of lentinan with ddI in
                          HIV-positive patients. Int Conf AIDS. 1994
                          Aug 7-12;10(1):212 (abstract no. PBO276).
REFERENCES                ICA10/94372558. Masihi KN, Chihara G, Kaneko
                          Y. Inhibition of TNF production by lentinan
                          and curdlan sulfate. Int Conf AIDS. 1994 Aug
                          7-12;10(2):95 (abstract no. PAO261).
REFERENCES                92394698. Arinaga S, Karimine N, Takamuku K,
                          Nanbara S, Inoue H, Nagamatsu M, Ueo H,
                          Akiyoshi T. Enhanced induction of
                          lymphokine-activated killer activity after
                          lentinan administration in patients with
                          gastric carcinoma. Int J Immunopharmacol.
                          1992 May;14(4):535-9.
REFERENCES                MED/93050820. Chihara G. Recent progress in
                          immunopharmacology and therapeutic effects of
                          polysaccharides. Dev Biol Stand.
                          1992;77:191-7.
REFERENCES                 ICA6/30048790. Abrams D, Greco M, Wong R,
                           Goosby E, Gorter R, Gordon M, Guralnik M,
                           Kaneko Y. Results of a phase I/II
                           placebo-controlled dose finding pilot study
                           of lentinan in patients with HIV infection.
                           Int Conf AIDS. 1990 Jun 20-23;6(3):207
                           (abstract no. S.B.487).
ENTRY MONTH                199305
LAST REVISION DATE         19980402

137
UNIQUE IDENTIFIER          DRG-0170
NAME OF SUBSTANCE          Curdlan sulfate [AmFAR Tx Dir 1995;7(4)]
REGISTRY NUMBER            115743-28-7
STANDARD CHEMICAL NAME     Curdlan, hydrogen sulfate [CHEMLINE]
SYNONYMS                   CRDS [AmFAR Tx Dir 1995;7(4)]
PROTOCOL ID NUMBERS        FDA 127A
PHARMACOLOGICAL ACTION     MODE OF ACTION: The activity of curdlan
                           sulfate is comparable to other sulfated
                           polysaccharides with anti-HIV activity in
                           vitro (e.g. dextran sulfate). These compounds
                           are thought to inhibit HIV by blocking virion
                           adsorption to target cell surfaces. [AmFAR Tx
                           Dir 1993;6(4); AIDS Res Hum Retroviruses 1991
                           Apr;7(4)]
DISEASES STUDIED/TREATED   Tested for the treatment of Cytomegalovirus
                           retinitis. [AmFAR Tx Dir 1995;7(4)]
CLASSIFICATION CODE        Antiviral [AmFAR Tx Dir 1995;7(4)]
CHEMICAL/PHYSICAL DATA     DRUG DESCRIPTION: Sulfated polysaccharide
                           compound with 1-6-beta-D-glucan as a main
                           chain. [AmFAR Tx Dir 1993;6(4)]
SUBSTANCE DELIVERY DATA    DOSAGE FORM: Sterile aqueous solution. [FDA
                           127A]
SUBSTANCE DELIVERY DATA    MODE OF DELIVERY: Intravenous infusion.
                           [AmFAR Tx Dir 1995;7(4)]
MANUFACTURERS              AJI PHARMA USA Incorporated; 500 Frank Burr
                           Boulevard; Teaneck, NJ 07666
REFERENCES                 ICA11/96924573. Sekigawa I, Takeda N, Neoh
                           LP, Ogasawara H, Kaneko H, Yamaguchi K,
                           Hishikawa T, Hashimoto H, Hirose S, Mimura T,
                           et al. The role of curdlan sulfate on the
                           binding of HIV-1 gp120 to CD4 molecules. Int
                           Conf AIDS. 1996 Jul 7-12;11(2):281 (abstract
                           no.Th.B.4179).
REFERENCES                 MED/96098544. Gordon M, Guralnik M, Kaneko Y,
                           Mimura T, Goodgame J, Lang W. Further
                           clinical studies of curdlan sulfate
                           (CRDS)--an anti-HIV agent. J Med.
                           1995;26(3-4):97-131.
REFERENCES                 MED/96073117. Yoshida T, Yasuda Y, Mimura T,
                           Kaneko Y, Nakashima H, Yamamoto N, Uryu T.
                           Synthesis of curdlan sulfates having
                           inhibitory effects in vitro against AIDS
                           viruses HIV-1 and HIV-2. Carbohydr Res. 1995
                           Oct 23;276(2):425-36.
REFERENCES                 MED/95088509. Gordon M, Guralnik M, Kaneko Y,
                           Mimura T, Baker M, Lang W. A phase I study of
                           curdlan sulfate--an HIV inhibitor. Tolerance,
                           pharmacokinetics and effects on coagulation
                           and on CD4 lymphocytes. J Med.
                           1994;25(3-4):163-80.
REFERENCES                MED/94303188. Jagodzinski PP, Wiaderkiewicz
                          R, Kurzawski G, Kloczewiak M, Nakashima H,
                          Hyjek E, Yamamoto N, Uryu T, Kaneko Y, Posner
                          MR, et al. Mechanism of the inhibitory
                          effects of curdlan sulfate on HIV-1 infection
                          in vitro. Virology. 1994 Aug 1;202(2):735-45.
REFERENCES                ICA10/94369696. Gordon M, Guralnik M, Lang W,
                          Baker M, Goodgame J, DeMarzo C, Mimura T,
                          Kaneko Y. Phase I/II study of curdlan
                          sulfate--an HIV inhibitor. Int Conf AIDS.
                          1994 Aug 7-12;10(1):204 (abstract no.
                          PBO244).
REFERENCES                ICA10/94372558. Masihi KN, Chihara G, Kaneko
                          Y. Inhibition of TNF production by lentinan
                          and curdlan sulfate. Int Conf AIDS. 1994 Aug
                          7-12;10(2):95 (abstract no. PAO261).
REFERENCES                MED/92304364. Uryu T, Ikushima N, Katsuraya
                          K, Shoji T, Takahashi N, Yoshida T, Kanno K,
                          Murakami T, Nakashima H, Yamamoto N. Sulfated
                          alkyl oligosaccharides with potent inhibitory
                          effects on human immunodeficiency virus
                          infection. Biochem Pharmacol. 1992 Jun
                          9;43(11): 2385-92.
REFERENCES                MED/92385163. Aoki T, Kaneko Y, Nguyen T,
                          Stefanski MS, Ting RC, Manak MM. Curdlan
                          sulfate and HIV-1: II. In vitro long-term
                          treatment of HIV-1 infection with curdlan
                          sulfate. AIDS Res Hum Retroviruses. 1992
                          May;8(5):605-12.
ENTRY MONTH               199305
LAST REVISION DATE        19971120

138
UNIQUE IDENTIFIER         DRG-0169
NAME OF SUBSTANCE         Amitriptyline hydrochloride [USAN 1997]
REGISTRY NUMBER           549-18-8
RELATED REGISTRY NUMBER   50-48-6
RELATED REGISTRY NUMBER   8058-15-9
STANDARD CHEMICAL NAME    1-Propanamine,
                          3-(10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5-
                          -ylidene) -N,N-dimethyl-, hydrochloride [USAN
                          1997]
SYNONYMS                  Amitid [USAN 1997]
SYNONYMS                  Amitril [USAN 1997]
SYNONYMS                  Elavil [PDR 1997]
SYNONYMS                  Endep [USAN 1997]
SYNONYMS                  Deprex [Merck Index 1996]
SYNONYMS                  Domical [Merck Index 1996]
SYNONYMS                  Euplit [Merck Index 1996]
SYNONYMS                  Lentizol [Merck Index 1996]
SYNONYMS                  Miketorin [Merck Index 1996]
SYNONYMS                  Saroten [Merck Index 1996]
SYNONYMS                  Sylvemid [Merck Index 1996]
SYNONYMS                  Tryptizol [Merck Index 1996]
SYNONYMS                  Adepril [Merck Index 1996]
SYNONYMS                  Amineurin [Merck Index 1996]
SYNONYMS                  Laroxyl [Merck Index 1996]
SYNONYMS                  Redomex [Merck Index 1996]
SYNONYMS                  Sarotex [Merck Index 1996]
SYNONYMS                  Tryptanol [Merck Index 1996]
SYNONYMS                  Triptizol [Merck Index 1996]
PROTOCOL ID NUMBERS        NIAID ACTG 242
PROTOCOL ID NUMBERS        NIAID CPCRA 022
SECONDARY SOURCE ID        Ro-4-1575 [Merck Index 1996]
PHARMACOLOGICAL ACTION     MODE OF ACTION: Inhibits the membrane pump
                           mechanism responsible for uptake of
                           norepinephrine and serotonin in adrenergic
                           and serotonergic neurons. Pharmacologically,
                           this action may potentiate or prolong
                           neuronal activity since reuptake of these
                           biogenic amines is important physiologically
                           in terminating transmitting activity. Since
                           norepinephrine and serotonin can carry pain
                           messages to the brain from other parts of the
                           body, reducing the reabsorption of these
                           substances can potentially decrease the pain
                           felt by a person. Amitriptyline is rapidly
                           absorbed from the GI tract and from
                           parenteral sites. Peak plasma concentrations
                           occur within 2-12 h after oral or IM therapy.
                           The plasma half-life ranges from 10-50 h.
                           About 25-50% of a dose is excreted as
                           inactive metabolites within 24 h. [PDR 1997;
                           NIAID CPCRA 022; AHFS Drug Information 1997]
DISEASES STUDIED/TREATED   Relief or reduction of pain caused by
                           HIV-associated peripheral neuropathy. [NIAID
                           CPCRA 022]
CLASSIFICATION CODE        Antidepressant [USAN 1997]
CLASSIFICATION CODE        Analgesic [NIAID ACTG 242]
OTHER MAJOR USES           Relief of symptoms of depression; relief of
                           neuropathic pain in various peripheral
                           neuropathies. [NIAID CPCRA 022; PDR 1997]
SUBSTANCE INTERACTIONS     Interacts with monoamine oxidase inhibitors,
                           cimetidine, drugs metabolized by cytochrom
                           p450 2D6, selective serotonin reuptake
                           inhibitors, ethchlorvynol, sympathomimetic
                           and anticholinergic agents. May block the
                           antihypertensive action of guanethidine or
                           similarly acting compounds. May potentiate
                           the effects of alcohol, barbiturates, and
                           other CNS depressants. [PDR 1997; AHFS Drug
                           Information 1997]
ADVERSE EFFECTS            Adverse reaction in order of decreasing
                           severity are listed in the following,
                           cardiovasuclar: myocardial infarction,
                           stroke, nonspecific ECG changes and changes
                           in AV conduction, heart block, arrhythmias,
                           hypotension (particularly orthostatic
                           hypotension), syncope, hypertension,
                           tachycardia, palpitation; CNS and
                           neuromuscular: coma, seizures,
                           hallucinations, delusions, confusional
                           states, disorientation, incoordination,
                           ataxia, tremors, peripheral neuropathy,
                           numbness, tingling, and paresthesias of the
                           extremities, extrapyramidal symptoms
                           including abnormal involuntary movements and
                           tardive dyskinesia, dysarthria, disturbed
                           concentration, excitement, anxiety, insomnia,
                           restlessness, nightmares, drowsiness,
                           dizziness, weakness, fatigue, headache,
                           syndrome of inappropriate antidiuretic
                         hormone secretion, tinnitus, alteration in
                         EEG patterns; anticholinergic: paralytic
                         ileus, hyperpyrexia, urinary retension,
                         dilatation of the urinary tract,
                         constipation, blurred vision, disturbance of
                         accommodation, increased ocular pressure,
                         mydriasis, dry mouth; allergic: skin rash,
                         urticaria, photosensitization, edema of face
                         and tongue; hematologic: bone marrow
                         depression including agranulocytosis,
                         leukopenia, thrombocytopenia, purpura,
                         eosinophilia; gastrointestinal: rarely
                         hepatitis (including altered liver function
                         and jaundice), nausea, epigastric distress,
                         vomiting, anorexia, stomatitis, peculiar
                         taste, diarrhea, parotid swelling, black
                         tongue; endocrine: testicular swelling and
                         gynecomastia in the male, breast enlargement
                         and galactorrhea in the female, increased or
                         decreased libido, impotence, elevation and
                         lowering of blood sugar levels. Other adverse
                         effects include alopecia, edema, weight gain
                         or loss, urinary frequency and increased
                         perspiration. After prolonged administration,
                         abrupt cessation of treatment may produce
                         nausea, headache, and malaise. Gradual dosage
                         reduction has been reported, within two
                         weeks, transient symptoms including
                         irritability, restlessness, and dream and
                         sleep disturbance. These symptoms are not
                         indicative of addiction. Rare instances have
                         been reported of mania or hypomania occurring
                         withing 2-7 days following cessation of
                         chronic therapy with tricyclic
                         antidepressants. [PDR 1997]
CONTRAINDICATIONS        Contraindicated in patients with prior
                         hypersensitivity to the drug and those in the
                         acute recovery phase following myocardial
                         infarction. Amitriptyline hydrochloride
                         should not be given concomitantly with
                         monoamine oxidase inhibitors. Hyperpyretic
                         crises, severe convulsions, and deaths have
                         occurred in patients receiving tricyclic
                         antidepressants and monoamine oxidase
                         inhibiting drugs simultaneously. When it is
                         desired to replace a monoamine oxidase
                         inhibitor with amitriptyline hydrochloride, a
                         minimum of 14 days should be allowed to
                         elapse after the former is discontinued. The
                         drug should then be initiated cautiously with
                         gradual increase in dosage until optimum
                         response is achieved. [PDR 1997]
CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION:
                         Dibenzocycloheptadiene-derivative tricyclic
                         antidepressant. [AHFS Drug Information 1997]
CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: White or pratically
                         white, odorless or pratically odorless,
                         crystalline powder or small crystals with a
                         bitter, burning taste. [PDR 1997; AHFS Drug
                         Information 1997]
CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C20H23NHCl [USAN 1997]
CHEMICAL/PHYSICAL DATA    MOLECULAR WEIGHT: 313.87 [USAN 1997]
CHEMICAL/PHYSICAL DATA    MELTING POINT: 196-197 C [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    SOLUBILITY: Freely soluble in water,
                          chloroform, and alcohol. [Merck Index 1996]
CHEMICAL/PHYSICAL DATA    DRUG PHYSICAL COMMENT: pKa 9.4. [Merck Index
                          1996]
SUBSTANCE DELIVERY DATA   DOSAGE FORM: Tablets (10, 25, 50, 75, 100,
                          and 150 mg); solution (10 mg/ml, 10 ml per
                          vial). [PDR 1997]
SUBSTANCE DELIVERY DATA   MODE OF DELIVERY: Oral; intramuscular
                          injection. [PDR 1997]
SUBSTANCE DELIVERY DATA   STORAGE INSTRUCTIONS: Store tablets and
                          solution at or below 30 C (86 F). Protect 10
                          mg tablets from light. Store tablets in
                          well-closed containers. Protect 10 mg
                          solution from freezing. [PDR 1997]
MANUFACTURERS             Drugs are provided by each participating unit
                          site
REFERENCES                AIDS/96701690. McGuire S. Fun in the sun?
                          Posit Aware. 1996 Jul/Aug;7(4):10-1.
REFERENCES                AIDS/95700461. Lein B. Potential therapy for
                          painful neuropathy. PI Perspect. 1995 May;:no
                          16(11).
REFERENCES                AIDS/95700101. Chavez C, Prickly business.
                          The finer points of acupuncture. Posit Aware.
                          1995 Jan/Feb;:14-5.
REFERENCES                MED/95126437. Holsboer F, Grasser A, Friess
                          E, Wiedemann K. Steroid effects on central
                          neurons and implications for psychiatric and
                          neurological disorders. Ann NY Acad Sci. 1994
                          Nov 30;746:345-59; discussion 359-61.
REFERENCES                95054645. Benoliel R, Eliav E, Elishoov H,
                          Sharav Y. Diagnosis and treatment of
                          persistent pain after trauma to the head and
                          neck. J Oral Maxillofac Surg. 1994
                          Nov;52(11):1138-47; discussion 1147-8.
REFERENCES                93263324. McQuay HJ, Carroll D, Glynn CJ.
                          Dose-response for analgesic effect of
                          amitriptyline in chronic pain. Anaesthesia.
                          1993 Apr;48(4):281-5.
REFERENCES                93211712. Kerrick JM, Fine PG, Lipman AG,
                          Love G. Low-dose amitriptyline as an adjunct
                          to opioids for postoperative orthopedic pain:
                          a placebo-controlled trial. Pain. 1993
                          Mar;52(3):325-30.
REFERENCES                92220132. Max MB, Lynch SA, Muir J, Shoaf SE,
                          Smoller B, Dubner R. Effects of desipramine,
                          amitriptyline, and fluoxetine on pain in
                          diabetic neuropathy [see comments]. N Engl J
                          Med. 1992 May 7;326(19):1250-6.
REFERENCES                92150091. Watson CP, Chipman M, Reed K, Evans
                          RJ, Birkett N. Amitriptyline versus
                          maprotiline in postherpetic neuralgia: a
                          randomized, double-blind, crossover trial.
                          Pain. 1992 Jan;48(1):29-36.
REFERENCES                93040556. Bowsher D. Acute herpes zoster and