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                                                          A    RIIVIIiW

                                               A.    C. lVY,        N{.I)., Prr.D.

                                                F.   R.       COETZL,       Ps.D.
                                                              CI I ICJAGO

                      This revierv has been prepared becaused-desoxyephedrine                  hyclro-
               chlori<le is apparently being r.rsedby the Gennan armed forces arrd
               l :c c a rrs a rc v i c rv o f th e l i tcrature on the pharnracol ogy tl re cl rtrgl ras
               t t o t l , c ' c ' r ru l r l i s l r c < 1 .

                                           CIIDMISTRY     AND          NOMENCLATUIiE

                    I)esoxvelrheclrirre first preparecl Ogata I in 1919 as d-desoxy-
                                              ivas                  by
               ephedrinehyclrochloride,             rvhich he called d-plreuylisopropylmethylanrine
               h1'clrochloriclc.       r\ltotrt ten 1'earslater l}nclc 3 couverte<l      d-pseucloephe-
               drine to the corre:sponcling             chloridc arrci tlrrough catalytic recluction
               obtainecll-clcsoxt'ephedrine            ancl thus establishcdthe strnctttre of ephe-
               drine. No attention was paid to clesoxycpheclrine                   trntil 1938, rvheu
               several Gen.nanauthors claimed that d-clesoxl'ephedrine                   hydrochloricle,
               tvhich in its action was closely rclatecl to amphetamiue srtllate, was
               s u p e ri o r to tl re l a ttc r i n th;rt i ts central euphori c atrrl rval ti rtgcl fects
               could lle obtainecl        lvithout causingundesirablesiclereactions. This mav
               account for the preferential study and use tlie clrug lias received by
               Gernran investigators.
                    The svnolrynrso{ clesoxyephedrine,               wliich tnay be obtained chetrii-
               callf in the clextrorotatory, levorotatory or racenric fortrt, are :
               N-metliylphenylisol>r'opylamine             ; 1-phenyl-2-methylaminopropatre         (clex-
               trorotaiory), melting point 173 C. ; r/-pherrvlisopropyhnethylamine                        ;
               rnethl'lbenzeclritre       ancl nrethylisomyn.
                    J-he chenrical relation of r/-11csox1'spheclrine epheclrirreancl to
               anrplietanrinc show'trby the following forurulas:
                    Il p h e c l ri n e
                                      :               C uIIo C IIOH          C fI (C i 13) N I{ (C Il ,)
                    t/-D e s o x v e p h e c l ri ne: C oH , C H ,           C I{(C I-I3) N II(C I-IB )
                    -' \n rp h e ta mi n:e            C oII, C FI,           C H (C H r)   N II"

                    Ijronr the Department of Physiology and Pharmacology, Northrvestern IJni-
               versitl' I'[edical Sclrool.
                    1. Ogata, A.: J. Pharm, Soc. Japan 451t751, 1919; abstracteclChem. Abstr.
               14 :7{.(, 1910.
                    L ilnrrlc, JJ. :      Ilelvet. chem. acta 12:265, 1929.


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                                                                                                              a                     {?|{.ffiFr
                                I V Y_GO]J7'ZL*d-DESOXY IiI'I'I EDRI NE,                          6I

             Dultz 3 and Richter n clescribed method for the cletection
                                                     a                          and estimation
             of petvitin.
                 I)csox1'cphedrine      has usually been aclrnitristered d-desoxycl>lre-
             clrine hyclrochlorirle(pervitin [Tremniler], the product rnost freqtrently
             rrs e ciln Ge rn ra n y ;me th e d ri neIB urroughs W el l corne& C o.l ).

                                           TOXICI-TY AND       DOSE

                 To:"'icilyin, LozuarAnhn,als.-A largc nunrberof rc1>orts the lctlra.l
             closeof anrphetaniinecxist in tlre litcrature, but otre is not favor;rl-rly
             impressedby nrost of thcnr, because     the variations found are relativcly
             large. One gains the irnpressionthat the LD50 dose of ampltetauiine
             sulfate given by injection to diffcrent animals is 20 to 40 nrg. per liilo-
             gram. Younger aninials are nlore tolerant as a rule. An extensive
             strrclyon the LD50 dose of r1-clesoxyephedrine    hyclrochloriclen,as rnacle
             b1' l-l.11rchilcl.n Jiive hurrdreclrats were useci, ar-rdthe I,D50 iutrir-
             peritoncaltlosevarieclfrom 15 to 25 nrg. per kilograru, the averagebcing
              17 ntg, pcr l<ilogram,and the average LD50 oral closewas 37 rrg. pcr
             icilograni. Kiessig's0 study on nrice indicatedthat d-desoxyephedrine     is
             about trvice as toxic as amphetamine (table). I(ohn-Richards,Twho
             compared amphetamirre      and d-clesoxyephedrine,  was unwilling to con-
             cluclefrom his rvork and from the literature that one conrpouncl more
             toxic than the other. When the trvo have beerl conrparedby the sante
             person, d-clesoxyephedrine been fourrclto be somervhatnrore toxic,
             though it is diflrctrlt,if not irnpossible,even in the satne laboratorl, to
             reproducethe LD50 dose obtained at a fornrer date rvith the acclrracy
             ustrallv attained r,vith other chemicals. It should be pointed out that
             r/-desoxt'ephedrine   hydrochlorideis nruch lnore activethan /-clesoxyephe-
             drine ; the d-l form is intermediatein activity. Chronic toxicity studies
             in animals have been conducted only by l(ohn-Richards, Fle fotrrrd
             d-dgsoxyephderine to be more toxic than arrrphetamine,but too ferv
             experimentsrvere done to establishthe ratio of toxicity.
                 Tacliypnea, excitement, piloerection and mydriasis are the cl-rief
             effects of overdosage. Paralysis of the respiratory system, frequently
             plecededby convulsions,is the carlseof death.
                  Comment: If there is any difference in toxicity between the trvo
             drugs, it would appear from the evidenceavailable that d-desoxyephe-
              drine hydrochloride per nrilligranr of rveight is somelvhat more toxic

                 3. Dultz, G.: Ztschr. f. anal. Chem. 120:84, 1940.
                 4 . R i c h t e r ,D . : B i o c h e m . . 3 2 : 1 7 6 3 , 1 9 3 8 .
                 5. Hauschild, F.: (o) Arch. f. exper. Path. u. Pharmal<ol.             191:465, 1939;
             (b) Klin. Wchnschr. 17:1257, 1938.
                 6. Kiessig, H.J.:             Arcl.r.f. exper. Path. u. Pharmakol. 197:384, 1941.
                 7. Kohn-Richarcls,           R.: Unpublishecl           data.


                            tltan amphetatuinesulfate. It is of interest to note tlrat d-desoxl'ephe-                                         arty clata, r
                            drine hydrochloricle clispensed Germany in 3 nrg. tablets ancl in thc
                                                is          in                                                                                12 nrg. pri,
                            Unitc<I Stateszrmphetamine sulfate is usually dispensed 5 n.rg.tal-rlets.
                                                                                    in                                                        unr est ,nct
                                 Toricity in IvIan.-No dcaths or instancesof acute sevcre intoxica-                                           out using t
                            tion fronr r/-clesoxvepheclrine                  hydrochloride have becn rcportecl.                               catrse ct'r:
                                 Issel<trtz tool< 200 nrs. of r/-clesoxyepheclrine                          hyclrochloricle rvith             elf ect s sir ,
                            alcolrolanclcoffeecluring oue everring'. A conrpanion                            tooli 60 nrg. l-loth             tcred. I\l
                            nlt tri l c s tc rls l c c p l c s s rrc src,s tl c s s ncss, cl l < ncss,
                                                                       s                w             nrydri i rsi s,sonrcnrrus(' :r          ( ntuul-rel r
                            and v o n ri ti n g , c l y s p n c a , c h y c arrl i a(a ratc of 150 per nri ntrte) anrl
                                                                      ta                                                                       ( nunt bcr r
                            ar r h y th n i i a . L a rg e c l o ss o I ani phctauri neprocl uce si nri l ar c1fects.1'
                                                                       e                                                                      closesbtrt
                            Pcrsons u,ho, becauseof the clevelopnrent toleranceto the euphoric   of                                           r epor t ed t r
                            effect, gradually increasethe daily dose of either drug manifest hyper-                                           obser ve<l,    t
                            glycen-ria, high rnetabolic ratc, cardiovasculardisturbances,erythro-
                                               a                                                                                              m ended ir
                            cytosisaucl                                                                                      lvhonr 15
                                 ' l ' rv o                                                                                                    wcre cllrs,
                                            i rrs ta l tc c s l ' a p p a rc rrticl i osyncrasy
                                                             o                                      havc l l ecn rcportc< 1, th
                                        of            15
                            closes 12 ar-rd mg. rcspcctivclyof r/-clesoxyephcdrine                                   Piillen," ,
                            Urticaria occurt'ecl 1 patient, although in both the rlose o[ the drug
                                                              irr                                                                              on 4@ sr r
                            was e x c e s s i v e .                                                                                            st im ulat it ,
                                 TherapeuticDose f or Man.-Seifert 12gave 25, 35 arrd 45 mg. doses                                             times catr
                                                                  h1'clrochloride several pliysiciansand obscrved
                                                                                       to                                                      avoidatrct
                            of d-tlesox;'eplrcdritrc
                                                                                                                                               in tl-resc   ,i
                            their objective ancl sul-rjective                    reactions. Ccntral stimtrlation u'ithout
                            distu rb i n g s i c l c re a c ti o n sw a s o b scrvccl uri ng the cl a1' after the rl rug
                                                                                            cl                                                 latter is t
                            n'as adrninisterecl.During the night clesire                         for slcep rv;rsabscnt and the                      G er t t t ,
                                                                                                          'I'ire                               ephedrirr.
                            subiectsexperienced itrcrczrsccl    an                  desire to rvork.             following day a
                            sensationof fulness in the l-reacl,                      anorcxia ar-rcl   tirechress   werc expcri-                doses [ t,
                            enced. Drinking of coffec increased                        the elTectof the drug. Neunranr-r        t3              out sidc r',
                                                                                                                                                colrlparat   r
                            perspired unduly rvhen he took 33 mg. of the clrug per clay; 5-[ nrg.
                            caused perspiration, xerostomia and anorexia. He statecl,u'ithout                                                   support ri
                            presenting any clata,that unclesirable                        siclc effects did not occur in his
                                                                                                                                                d- desox1
                            patientsuntil 18 mg. or r-r1ore day was tal<en. Seifert 13 stated that
                                                                                                                                                cat ed sig,
                            trnrlesirable        synrptours       resultedwhen 12 to 15 mg. of d-clcsoxyepheclrine
                                                                                                                                                dose fot' ,
                            hydrochloridewas taken. In 15 per cent of cases(apparently 9 lrcalthy
                                                                                                                                                side efft,.
                            personswere useclas subjects) such synrptomsas sensationof heat ancl
                            colcl, sweating, thirst, headaches,                      twitching of e1'es,grincling of teeth                         Corn1
                            and unrest were rnanifested                    cluring the prolonged adrninistration (three                         and Arttl
                            nrontlrs) of 6 to 72 :lg. two to four tinres a rveel<. (IJe did not inclucle                                            14.Sti,
                                                                                                                                                    1 5 .\ ' 1 r r
                                   8. Issekutz, B. : Samml. v. Vergiftungsf. 10:85, 1939.
                                                                                                                                                    16. H..
                                   9. Ivy, A. C., and Krasno,L. R.: Arnphetamine                            (Benzedrine)   Sulfate: Revierv         17.R;,,
                            of Its Pharmacology,              War l{ed. 1:15 (Jan.) I94I.
                                                                                                                                                    1 8 .I I ,
                                 10. Greving, H.: Nervenarzt 14:395, 1941.
                                 11. (o) Agnoli and Galli: Samml. v. Vergifturrgsf.102773,1939. (b) Munt-                                            1 9 .I ' r
                            n e r , S . : S c h r v e i zm e d . W c h n s c h r .6 9 : 1 3 3 3 ,1 9 3 9 .
                                                                                                                                                1 1 : 4 8 5 ,l
                                 1 2 . S e i f e r t ,W . : D e u t s c h e r e d .W c h n s c h r .6 5 : 9 1 3 ,1 9 3 9 .                           2 0 .L ,
                                 13. Ncnnrann, E. : tr{ Wchn,;r:trr.86:72(t6, 1939.

Fil*Br.'ifBi?:|   ft'l!f'

         any clata,ancl tltcrc \\'rrc no controls.) Of 15 laborers who reccivcd
         12 mg. prior to a clay's worl<, l had a headaclre                            and anotlter reportccl
         ruurest,   nervorlsness          and dizziness. Stiecla,la           obscrving 60 subjectsrvith-
         out using tests,           reporteclthat 6 rng. of d-desoxyepheclrine                  h1'drochloride
         caused central stirriulation without "hang-over" and disturl-ring side
         clfccts; such s1'mptr-rrrrs swcating arrclrestlcssness re rarcly cncoull-
                                                as                                      we
         t c r ec l. [ I iil l e r-]l o n rr ' 5 g a v e .] n rg . o f tl i e cl rtrg to rai l road engi necrs
          ( nur nber n o t s ta tt:c l )rv i tl to u t o l l ta i n i n g any si dc efi ccts; i n pati cnts
          (number not staterl) sidc cffects \r'ere not observeclu'ith 3 to 6 rng.
         dos esbut n ' c re s o rn e ti n rc s o te c lw i th 9 to 15 nrg. cl oscs. H ei netrt0
         reporteclthat sicle eflccts are sccn orrly in "labile" persons. Rarrke17
         observed side effects rvith 3 to 6 n-rg.closes the clrug and recom-       of
         r ner r c ler ls u s e fo r th e p c rs o n n c l o f n rotori zcd uni ts. In runncrs to
         whorl 15 rng. hacl been givcr-rbelore a race side effects after the race
         r v er eobs e rv c c tl ro trg l rth c p c rfo n l ra n c c trri ngthe racc nas i ncreased.18
                                   l,                                  cl
         Piillcrt,lt'rvho obscn'ccltlrc cffects of d-cleso-xycphcdrine                          hydrochloride
         on 400 subjects,conclurlcrlthat 3 to 6 mg. o[ the clrug callsescentral
         stinrulationrvithout provoking sicleeffects,'*'hereas to 15 mg. some-           9
         tinres catlsesside effects, the optimal closefor ccntral stimulation and                                                     *
         avoidanceof side effccts bcing 6 to 9 mg. FIe stated that this clrug                                                         ll

         in thcse closesis plefcrable to arnl>hetamine,                          l.recausc action of thc
         latter is too unpredictableas to duration.                                                                                   fr'
               German authors hAve conrmonly expressedthe view that d-clesoxy-                                                        l,
         epheclrine       hydrochlorideis superior to arnphetarnine                     sulfatel.recausesmall                         I'

         dosesof the fornrer drug (3 to 6 mg.) produce ccntral stimulation with-
         out side reactions,            which is not so true of the latter compound. No goocl
         comparative data are actually available in the Gernran literature to
         support this vierv.
               Cornment: The Gerrnan literature has established the dose of
         d-desoxyephedrine                hydrochlorideto be 3 to 6 rng., since no report indi-
         cated significantundesirirble                  sicleeffectsrvith such a close. The optirnal
         close   for central stinrulationappearsto be 6 to 9 mg.; 9 rng. nray cause
               C ornparative D oses and E fJects of d -D eso:t:y phedrin e II ydro clilorid e
         and Aurpltetantiue Sulfate.--Leurmcl ancl l{artlvig 20 reported the only
           14. Stieda,lf.: Deutschemed. Wchnschr. 652682,1939.
           1 5 . M i i l l e r - B o n n ,F I . : t r I e c l W e l t 1 3 : 1 3 1 5 ,1 9 3 9 .
           1 6 . H e i n e n ,W . : I { e d . W e l t t 2 : I 6 3 7 , 1 9 3 8 .
           17. Ranke,C. F. D.: Deutsch.                         mil.-zirztl.    Ztschr.4:147, L939.
           18. Heyrodt, H., and Weisenstein,                           I{.: Arch. f. exper. Path. u. Pharmalcol.
         195:273, 1940.
           1 9 . P i i l l e n , C . : ( o ) I U i i n c h e nm e d . W c h n s c h r .8 6 : 1 0 0 1 ,1 9 3 9 ; ( b ) C h i r u r g
           20. Lemrnel,G., and Hartwig, J.: Deutsches                                 Arch. f. klin. tr{ed.185:626,1940.

              64                                           II/,4R A.INDICIN]i

              data in the Gernrar-r              literature pcrtaining to a comparison of the two
              clrugsin nran.                    carefully stuclied     psyclionrotor         activity in 5 srrl-rjects
              and foturd that 3 to 6 nrg. of d-desoxyeplieclrine                                             is
                                                                                         hydrochloricle optinral
              for inrproving ps1'chomotor                                                                                                        clrl,
                                                          activity of certain types ancl that 9 rng. is
              likelv to clecrease           concentrationancl to increaseerrors. They rnade no
              sigrrificant         rernarltsregarclirrg     such sir,le  rcactionsas p;rlpitation,dizziness
                                                                                             2t                                                  cll,
              a n c ls w c a ti n g . J a c o b s t' uW ol l stci n :trrcl hri stcuscn nracl e extettsi ve
                                                      ,                  C                                an
              study zurdcornparcci              the effectsof 15 nrg. <loses anrphetarnineo[                      strllate
                                                                                                                                                 Sllt I
              rvith those of 15 lrg. doses of racemic clesoxyephedrine                                      ancl othcr
              ceplialotropicamines; tlrr:y incluclecl control series of da1,5in tlrcir
              stucly. They founcl that the results in regard to elevationof nrooclancl
              sicleeffects slightl-vfavored amphetaminearrclthat all the amines rvith
              the central effccts of arnphetatnine                   causedunclesirable            sidc eiTectsin a
              ferv subjects. Both drugs causedthe sarne.sideeffects, the chief ones
              b e i n g u n c a s i n e s s n d te nsi on, I)oor :rl )pcti te,hot and col d scrrsati ons,
              lreavinessof head, hcaclaches                 and clizziressancl clisttrrbanccof sleep the
              niglrt after tlre clrug rvas tal<cn in the rnorning. Hauschilcl!! pointed                                                          t))t

              out that the rlose ernployecl Jacobsenand l'ris co-rvorl<ers
                                                          by                                                 'rvaslarge                          ll l(
                                                                                                                                                  t ti r
              and that the dextrorotatory forrn of clesoxyephedrine nrore active tlian         is
              the racernicfornr and reiterateclthe vietv that 3 to 6 mg. of r/-desoxy-
                                                                                                                                                  f r rr
              ephedrine hydrochloriclegives the desired central stimulatiorr without
                                     'Jlhc                                                                                                        irr
              side effects.                               of
                                            statcments expericncccited in the Geruran litcrature
              anclthe resultsobtaincdrvith thc nrerrtal                   arr<lpst'chonrotor          test of Lcrnrncl
              and Flartrvig 20 tend to bcar out l-Iauschiltl's clainrs.                                         vicn' of
              Flauschildis also borne out by ccrtain conclusionsof Golla, Blackburn                                                               ltl r
              ancl Graham,28            rvho compared the trvo clrugs. They stated that 10 rng.

              ofd-desoxyephedrinelryc1roclrlorideisanl".,.tffi                                                                                    l,_l
              ampli-elamine           strllate is eqtraltfn its effect to 5 mg. of d-desoxyepliedrine                                             l(,

              liycliochl oiia; fit ttr ii-'elariiiii'r1iln                                                                                        clr
                                                                           ;L scepffility aoTIie ceiitia-l Cnci
                                               "i                                             ---...-.-------.._--                                 (;
              t ti e u n ile-s-i?abl ff ect s-=dThETwo-d:ugs-is th€--sail1e.
                ------.----?-.---\                                              ---l-r-r                                                           .t
                      ConrmenT: It u'o-irltlappear thaf airy one [akiiift trrore than 6 rng. of                                                   ta

              d-desoxycl>l-redrine            h1'clrochloride 10 mg. of amphetaminesulfate runs
              the risk of the unclesirable              effectscounteractingthe benefitsof the eleva-                                              i.
                                                                                                                                                   I t   t
              tion in mood and the au'al<ening                  effect for rvhich the drug is tal<en. No
              one seemsto have compared the effects of 3 mg. of d-desoxyephedrine
              hydrochloride follou'ed in trvo hours with the sarre dose and the efTects
              of 5 mg. dosesof amphetaminetal<enat similar intcrvals.
                 2I. (a) Jacobsen, and Wollstein, A.: Acta med. Scandinav.
                                              E.,                                                                100:159,1939.
              (b) Jacobsen,          E.: ibid. 100:188, 1939. (c) Jacobsen,                        E.; Wollstein, A., and                           't.
              Christensen, T.: Klin. Wchnschr. 17:1580, 1938. (d) Wollsteirr, A.: Acta
              med. Scandinav.100:203, 1939.
                 22. Hauschild, F. : I(tin. Wchnschr. 17:1695, 1938.
                 2 3 . G o l l a ,F . C . ; R l a c k b u r n ,J . M . , a n d G r a h a m L . : J . \ 4 e n t .S c . 8 6 : 4 8 ,1 9 4 0 .

    l" r"''

                                  I I')'-GOD'I'ZL-d-DESOXYEPIIEDRIN                                t:        65

                     ]IF'IIECT     ON      NIIiNT.,\L       AN]]      I'SYCIIOITOTOR            ACTIVITIES

             All authors seem to be in agreementthat d-clesoxyephedrine                          hydro-
         chloride,lilie arrrphetanrine        strlfate,elevates      the moocl,incrcases     the urge
         to vi'ork ancl counteractsslecpinessancl the feelirrg of fatigue in the
         majoritl'of persons. As rvith arnphetamine, euphoricanclthe rval<ing
         efiect clccrcase      rvith protracteclnreclication          bccauseoi the accunrtrlatiott
         of t l rtrrrc e dfo r rc s t.s r A s rc g ri r rl sthc l att:rrt1-rcri ocl acti t-xr, ci fcrt rr
                                                                                 of          S
         stated tLrat tlre cllcct oI z/             hyclrocltlorideon rnood is
         experiencccl       ten to trverrty trritrtrtesaftcr oral adrrrinistration other       ;
         authorshave reported thirty to sixty nrinutesas the latent period.
         duration of action of 6 to 12 nrg. r'aries from six to thirty-six hours,
         tusually    being six to twelve hotrrs,26            though Jacobsenand co-rvorl<ers          to
         found sleep to be disturbed in a nunr'Lrcr subjects the night after
         15 nrg. of the drug was talien at breakfast.
              It has been used favorably, or its use recorllmended                    for the afore-
         rnentionedeffects, for railroad engineers (3 mS.),tu the prersonnel                          of
         rnotorizecl     units,'7personstaking long autorrrobile             drives (3 to 6 mg.),1'
         nig h t l v a tc h me n(3 to 6 rn g .) 1 2anclhi l < ers marchers (12 mg.).1'
              Practicallyevery Gerrrranclinician rvriting on the subject has spoken
         favorablyoi the value of d-clesoxyephedrine                  hyclrochloride(3 to 12 ng.)
         in elevatingthe nrood of paticnts after opcration or of personssuffering
         from chronic disease inoperirble
                                      or                   trrmor.
              X,[ental artrl Psycltontotor Actiaity.-Wollstein 21d founcl anrphet-
         aurinc ancl racemic desoxyephedrine have no effect on "intelligcnce
         scores"  as testcd by the Bourclon test and the missing word test of
         Ebbirrghaus. Graf 28 observedincreasedefficiencyin placing pearls in
         rows in 4 srrbjectsafter a closeof 9 mg. of d-desoxyephedrine      hydro-
         chloride  and increased speed and acctlracy of calculation in 2 subjects.
         Golla, Blackburn and Graham 23con-rpared    the effects of 5 to 10 mg. of
         d-desoxyepl-redrine  hydrochloride with those of.20 rng. of ampl'retamine
         strlfate and 15 grains (0.97 G-.) of caffeine with sodium benzoate.
         Amphetamine and. d-desoxyephedrinetended to speed the rate of pcr-
         formancein writing, drawing and aclditiontests and increasecl   attention;
         caffeine in a relatively large dose had no effect except that, as with the
         other two drugs, attention was improved. In throwing darts, amphet-
         arnine and d-desoxyepheclrinedicl not improve the score; caffeine
         inrpaired the score, bnt this might be attributed to unsteadiness,  rvhicli

           24. (a) Bruns, O. : Fortschr. d. Therap. 17 237, 7941. (1,) Specknran, :
         Nervenarzt12:350, 1939.
           25. Seifert.l2 Stieda.rr Miiller-Bonn.r6
           26. Jacobsen and Wollstein.zla Jacobsen.2lb
                                                     Jacobsen,Wollstein and Christen-
            2 7 . ( a ) G o r d o n o f f T . : P r a x i s 3 0 : 5 5 7 ,1 9 4 1 . ( b ) R a n k e . t z
            28. Gral, O.: Arbeitsphysiol.                 10:692, 1939.

            oo                                       IY.,1R MEI)ICIND

            caffeineis knorvn to increase.g Lemmel arrcl}lartwig'o testecl.5 sulr-                                                       the l,'t'l
            jects ratlrer intensively,conrparingthe effect of l to 3 tablets (5 to 15                                                    in that
            r n g .) o [ a n i p h e ta n ri n e u l fa te rvi th that of 1to 3 tabl ets (3 to 9 nrg.)
                                                  s                                                                                      llerVOti
            of d-cle     soxl'spheclrine hydrochloricle. In the Bourclorr-Sterzinger                                                     I)rcscrl
            abstlactiontest ancl calculationtests, r/-clesoxyephcclrine                         incrcascrlspccrl                         t-ltlrcrl
            n ro re th a n a n rp h c ta rn i n ew i t horrt dccreasi rrg
                                                        ,                            attcnti otr, concctttrati ott                                1l'"
                                 'l'hc                                                                                                   n t t t s cr I
            ol' accurac-\/.              atrthors fourrcld-tlcso-x1'ephedrirre procluccr! nrore
            "junrpy," r,rrirregul;tr, learning crlrve than arrrphetaurirre. testing the           L-r                                    tnitttrl.,
            eli'ects the clrugsorr the rccogriitionof the meaning of form (tacliisto-
                      of                                                                                                                 242 1t,"
            scope), d-clesox),cPheclrile                was fotrrrclto ililtroye oltservatiorl,collcell-                                 artd rr ,
            tration ancl imagination rnore than amphetarnine. The drugs did not                                                          ti -dest,
            clift'er in their influence on the completiorr of tralf-finished drarvirtgs                                                  llOtll    lt't

             (Sander test). They did not influenceauclitory or visrral reaction tinre.                                                   coutlll;,
                  Cornment: Some improvenrentin speecl work lvithout change in    of                                                     achc :rr
            accrlracysccrnsto lre clerivecl                 florr-rlroth clrtrgs. Becauseof v:rriatiortitt                               It rv:r.
            d o s a g c n rl v a ri a b i l i ty i n s u s c epti l ;i l i ty, cl ataavai l abl care too nl cagcr
                       a                                                    the                                                          WilS tt,'

            to wArrirnt a gcncralizationas to rvhetircr one clnrg is bettcr tharr tlrc                                                   lte rt't',

            other in irnproving psychomotor perfnrnrance.                                                                                       I l : ,r
                                                                                                                                         cau l;r'
                F a ti q ttc a n tl l :' h 5 ,s i c o l rf onnonca.-Graf,38 i thout presenti ugan)'
                                                    Pc                       w
                                                                                                                                         arrd I i
            evi<lencc,     statccl tlrat d-clesoryephcclrine         hy<lroclrloricle  dccreasccltlie
                                                                                 'fhe                                                    brain i
            feelins of fatigue in the interest of a higher goal.                       clrug has becn
                                                                                                                                         r / - des,
            useclto increascthe physical perfornliulce of the German nteclranizecl
                                                                                                                                         is ttror
            forces.s?nSeifert 1?gave 12 mg. of d-clesoxl'epheclrine                                to
                                                                                                                                         socliur      l
            1 5 l a b o re rsi n th e mo rn i n g ;a t the en< lof tl i e cl ay 13 of the 15 reportecl
                                                                                                                                         clr lor ir     I
            that tlrev felt fresh and not tired. Of the renraining2, 7 hacla heaclache
            anclthe other felt uneasy,nervous and clizzy. Seifert also gave 12 ntg,
            to 10 of.20 marchersrvith full pack before they started on a 25 l<ilorneter                                                   d-des,
            r.narch. Five of the 10 not receiving the drug fell out, and the other                                                        &fe l't l;
            5 reported that they felt the same as after any such march. Eiglrt of                                                         clecrcu
            those tal<ingd-desoxyephedrine                   hydrochloriclereported they felt much                                        the orr
            l-.retter than nsual, particularly cluring the latter half of the nrarch, ancl                                                T l r e ri
            2 sztid   they fclt as they usually clid after such a rn:rrch. Similar rcsults                                                ttt lll() 5 i

            were said to have been olrtairredrvith night watchnrenancl autonrobile
            drivers, though no data were sr-rppliecl.I-ehmann, Straub and Szakall 2e                                                          llI u
            gave 3 yorlng adult subjects 5 to 15 *g.of d-desoxyephedrine    hydro-                                                        amine
            chloride ancl worked them on a bicycle ergometer. They stated that                                                            pr essr
            the work output was increased,tl-rorrghno clata were provided. They                                                           signit r
            concluded that d-clesoxyepheclrinehydrochloride does not increase the                                                                r
                                                                                                                                          eplie lr
            rvork capacity of a person but that it rvears it out by using up all
            reserves. They pointed otrt that therein lies the danger of the drtrg-
            a statementu'hich is probably true but one which is unsupporteclby                                                                    JJ.
            actual evidence. Szal<all later briefecltlie prececlingworl< ancl statecl                                                      ancl I I
                 29. Lehmann,G.; Straub, H., and Szakall, A. : Arbeitsphysiol.                                    10:680, 1939.
                 3 0 . S z a k a l l ,A . : M i i n c h c n .r n c d .W c h r r s r : h r8 6 : 1 3 . 1 41 9 3 9 .
                                                                                          .             ,



hccrr   E
                           IVY-GOLTZL-d-DItSOXyEPII                              DDRI N n                                 ()/

the l-relief      that d-desoxyephecirine                     hl,drochloride is lretter than caffeine                                {
in that rvhenenoughcaffeine is useclto obtain stimulation of the central                                                             t

ncr\,oLls      s1'stern       nuclesirable           sicle etfects result, though no eviclenceis
presentcd. Severalauthols have reported that ca{feine and r/-desoxy-                                                                 ii,
ephedrine          are s)'nergistic.31
       I-IcyrodtanctWeisenstein,l8                       studying 1 runueL, observecl                         that intra-
nrrrscular       injcctionof 15 rng. of r/-rlcsoxyephcdrirtc                                h_yclrochloridc          trvcnty
r r r inut cllc f o rca rrl l r i rrc rc l s c cll rc p l ry s i c r rl
               's                                                             pcr' l ornrnr)cLr to 15i and
242 per ccrrt. 1'he pulserate, blooclprcssureanclclectrocurdiogranr                                                     rvitlr
:rnd rvitlroutd-clesoxyepheclrine                        hyclrocliloride\\'crc the sanre. Without
r/-clesoxl'epheclrine               dyspneaancl heavinessof the {eet u'ere more pro-
nouncecl        than rvith tlre drug. Rut sometinres                                after the run the subject
c or nplained h c a rt b u rn , a b c l o n ri n a l a i n s,di zzi ncss,
                    of                                                                          restl essness,         head-
aclrcarrrlhot zrncl              cokl scnsations,             l'lrich \\'ere rclicvcclbrr aminopvrine.
 I t iv asc onc l u rl etl rl t th e s ti rn rrl a ti o o I r/-rl csoxycphr< l ri nc l rochl ori dc
                                rl                                 n                                    hy<
 w : r st t ) oc o s t l t ' l o l - l cu s c t l .                       r
                                                           r ' r r n r r cc o r r l ctlc l l s u b j c c t i v c l y v h c t h c r
he received placebo the clrug.
                    a                   or                                                                                           ii',
       Ranke3?statedtliat the depressant
                                                                      cllects of fatigue on performance
can be repeatedly                                       33
                                 counteracted over a perioclof tu'o rveel<s. Griittner
and Bonl<Alo reportecl3a                    that the recluctionof the amplitucleof the alpha
brain \\,Aves fatigue statt:scan bc cotrntcractccl                                           u'itli 3 to 15 mg. of
 t/-desoxyel>hctlrine              lryclrochloridc.                     effect of srrcha close this drug     of
is nrorelastingand greater tharr that of 200 to 300 rng. of caffeinewith
socliuru      betizoate. The subjective effects of d-desoxyephedrine                                                 hyclro-
chloricle      occur before the encephalographic                               changesare apparent.
       Contnrctrt: It is obvious that the scientific clata on the eflect of
d-dcsoxyeplrcdrine                  hyclrochloriclc fatiguc ancl physical performance
are relativelymcager,though there is little reasonto cloubtthat the drug
clecreases sertse fatigue in most sultjects. It therelty may increase
                  the               of
the output of physicalwork at the expenseof expenditure of reserves.
Tlre clmg vcr.y lilcely increasesthe lvillingness to cxert oneself to the
ut m os t .
                  EFFDCT ON             BLOOD PRESSURE AND                          HEART         RATE

   Man.-Golla, Blackburn and Grairanr33comparedthe effect of arnphet-
amine sulfate and tlrat of d-clesoxyephedrine                       hydrochloricle on blood
pressure   anclon heart rate in a small scriesof subjects. They found no
significant differencein tl-re                   of
                                      efJects the trvo drugs, except that d-desoxy-
ephc r lr ine h o u l cb e u s e c li n s n ra l l e r a n ro nrrts. Of 14 srrbj ects, mg.
            s          l                                                             10

    . 3 1A g n o l i n n d G ' 1 l i . 1 1 8 S e i f e r t . l 2 M i i l l e r - B o n n . r 5
    3 J . R a n k e ,C . t r . D . : \ I e d . W e l t 1 5 : 1 9 8 , 1 9 1 1 .
    33. (o) Siegmund,                 B.: Deutsche        med. Wchnschr. 65:754, 1939. ( D ) I ' e m m e l
a n c lI l a r t i v i g . 3 o ( c ) R m n s , O . : F o r t s c h r .c l . T h c r a p . 1 7 : 9 0 , 1 9 4 1 ,
    34. Clriittner,           R,, and Ilonl<alo, : Ilsyclriat.-neuro1.
                                                      A.                                     \\'clrnsclrr.42:243, 1940.
                 68                               WAII     lt"tnDlCINE

                 of d-desoxyephedrine                 hydrochloricleincreasecl    the pulse rate and ttrc       S
                 blood pressurein 8 and 11 respectively,and redtrce<l                     thent in 3 and 1      d
                 respectively, maxirnunr rise of blooclpressurebeing 18 nrtn. of nrer-
                                      the                                                                       lr
                 cury. Frank 35founcl that amphetaminesulfate hacl no signi{icantelfect                         r
                 on blood pressrlrein 10 rng. dosesrvlrereas rnc. incrcaserlit for five
                                                                              20                                L

                 to scvcn horrrs. Six milligranrs oI d-clesoxyephcclrirre                    hydrochloriclc     I.
                 catrsccl irritial rlccrease blood pressrlrein 14 of 30 .strlljccts; 1
                             an                           in                                             irr    it
                 subject the blood prcssure was elevated 10 to 20 urnr. of nrcrcnry for                         rl
                 tlvo or three hours. Piillen 30 stuclieclttre effect of r/-clesoxl'epheclrine                  tr
                 hyclrochloricle,         mal<ingover 400 determinationsof blooclprcssr.u'c an        on
                 unstated      nurnberof subjects. In the group he calleclnornral and healthy,                  I
                 6 .g. of the drrrg increased                the blooclpressure5 to 10 rlur. of nrercury.
                 Larger doscs rarcll' czrusecl rise o[ over 20 nrm., the rnaxinrum rise
                 being reachccl two ht-rurs
                                         in                 and the uormal systolic pressurein eight to         I
                 ten hours. The irulserate increasecl                only slightly. Irr a group of subjects
                                                                                                                    { i

                 he calleclvagotonic,6                ng. causecl change; 9 to 15 mg. catrseci rise
                                                                   no                                  a
                 in pre.ssure 5 to 10of                nrm. oi nrercury rvith a return to a subnormal
                 l e v e l ;th c .p u l s e ra te i n creasccl to 15 per r-ni nrrte.In a thi rtl group of
                 subjects,      rvhclmhe desigrratcd           sympatheticotonic   and in wltottt tlrere rvas
                 incrcasecl       dcrnrographia ancl riscs in           l-rloodpl'essure\\'cre elicitcrl by
             j                                                                                                  t
             t   psycliicclisturbanccs, to 15 nrg. causeda steepancllong-lastingincrease.
             !                                                                                                  t
                 L r a h y p o te n s i v es u bgroul >(rvi th bl ood pressure 100 to 110 runr. of
         t       mercury) a sliglrt fall was followed by a rise of 10 to 20 nrm. ; in another
         tI                                                                                                     (.
                 srrlrgroup specialchange was noted. The pulse rate ancl respiratiorr
                 werc increased. In a fourth group, designated"vasolabile," the l,'loocl
                 pressrrre responseto 6 to 15 rng. shorveda steep rise (20 to .15nrnr.
 I                                                                                                              I
 I               of mercury) ancl tl"rena fall to trormal arrd another rise ovcr a pcriod
 i:                                                                                                             (
f,'              of four hours. In a fifth group, with fixed hypertension,6 to 15 rng.
iir              causeda 35 to 50 mm. sustainedrise in blood pressure,the larger rises
                 being due to the larger doses. Warstadt 3? stated that anrphetarnine
                 sulfate is more uncertain in its vascular effects than d-clesoxyepheclrine
                 hydrochloride and that when it is given repeatecllyin the presence of
                 hypertensiontacliyphylaxis results, so that even 20 to 30 mg. of d-desoxy-
                 ephedrinehydrocliloride causesonly a 10 to 20 mm. rise in blood pres-
                 sure. Seifert 12statedthat 3 to 5 nrg. of d-desoxyephedrine                 hydrochloride
                                                       an           in
                 taken orally ouly cattses increase pulserate of 10 per minute in a few
                 strbjects     after about ninety mirrutes; 15 mg. causesan increaseof 20 to
                 40 beats per minute during two to seven hours. Five milligrams in 2
                 of apparently 121 subjects caused a rise in blood pressure of 10 mnr.
                 of mercury, and 15 mg. caused a rise of 15 rnm. in rnost of the 121
                      ?q    Frank, lI.:   Klin. Wchnschr. 17:1695, 1938.
                      36. Piillen, C.: Ztschr. f. Kreislaufforsch.
                                                                 31:448, 1939.
                      Jl.   Warstadt: Wierr. med. \\rchnschr.88:1227. 1938.
                                                                                                                                       t, I 1.1r,,
                                                                                                                                         'f         'r.:
                                                                                                                                           '    tl
                                                                                                                                       i     .:"':';;;t,

                                                                                                                                              ri f
                                                                                                                                           , nrl:l*.,,

                             IVY_COD7'ZL-d.DESOXY EPI] EDRI NIJ                                                    69

        subjectsfor trvo hours. 1\.[ii11er-Bonn stated that 3 to 6 nrg. of the
        drug causesno peripheral elfect and that 9 to 15 mg. causesa rise in
        bloodpr e s s u re . W i th d o s e so f l e s s th an 5 mg. (3 subj ects) no si gni -
        ficantchangein blood pressrlreocctlrs,accordingto Lehnrann ancl asso-
        ciates; the same is true for pulse and blood pressure during rvork.
        Kneises8 reported that 3 to 6 nlg. is sufficient to improve circulatior-r
        ar r dr es p i ra ti o ni n p a ti c rrtsa fte r o p c r ati orr. S ti ccl a' { ol l gi vi rrg 6 nrg.
        daily for five lveeks obscrvcd the blooclpressrll'e be raiseclfrorn t t0to
        to 130 systolicancl from 70 to 80 diastolic.
             Anirnols.-In anesthetizedaninrals Springorum 3e observed tachy-
        phylaxis. Flauschilcl found that tacht'phylaxisoccurs or-rly                             rvith largc:
          closes the clrug or \r'hen the second closeis giverr l-lcforcthe bloocl
          pressurch:rs rcturned to the rrorrr-ral                   lcvr:I. lirgotamine, atropine attd
          cocaine lravc no significant effcct o11 thc vasopressor rcsl)or1se                             to
          r/-desoxyephedrine          liycliochloricle.s" According to Nlalorny and Orze-
          chowski,{0    the drug in relatively large dt-rses                   cansed taciryphylaxis to
          itself and also to similar clrugs, such as epinephrine. They discussed
          the theory of tachyphylaxis and expresseclthe belief that anrphetarnine
          sulfateand r/-dcsoxyc'pheclrinc                                   in
                                                        hydrochloricle large       ltlock synlpa-
                    nc                                              ?
          t lr et ic rv c c n tl i u g s . I(o l n r-l ti c l ra rd s al so obscrvccltachypl ryl rtxi s.In
          the cat 300 mg. of d-dcsoxyephcclrine                       hydrochloridc pcr l<ilogramprc-
          ventedthe blood pressurefronr falling in rcsponse 35 rng. of histanrineto
          dilrydrochlorideper kilogram. In anesthetizecl                         cats ancl rabbits, otre
          two-hundredthof the letlial dose causedthe blood pressureto rise 5 to
          15 mm. of mercury. Its major effect on the circulation is peripheral.ou
          Larsen{1 found that the vasoconstrictor effect of racemic desoxyephe-
          drine is one and a half times greater than that of racenricamplietarnine.
          This has been confirmecl.a? I-arsen a3 also observed that arnphetamine
          sulfateis somewhatmore active than is r/-desoxyephedrine                       hydroclrloride
          in decreasingthe minute volume output of the perfused frog heart.
          I(ohn-Richarcls recorded ectopic beats electrocariliographicallyafter 1
          mg. of amphetaminesulfate per kilogranr was administeredintravenously,
          but not with the same dose of /-desoxyepheclrine; he did not use
          d-desoxyephedrine.            Atropine preventedthe ectopicbeatsfrom occurring.
        '       Comrnent: The eviclence                availableindicatesthat a 3 to 6 mg. oral
          dose of d-clesoxyephedrine              hydrochloricle usually has little or no signifi-

           38. Kneise, G.: I)eutsche Ztschr. f. Chir. 2622664, 1939.
           39. Springorum,P. W.: Klin. Wchnschr. 19:33, 1940.
           40. (a) Malorny, G., and Orzechowski,G.: Arch. f. exper. Path. u. Pharmakol.
         1962245,7940. (b) Orzechowski,  G.: ibid. 198:27, 1941.
           41. Larsen,V. : Skanrlin;rv.Arch. f. Physiol. ?0:282, 1938.
           42. Domenjoz,R., and Fleisch,A.: Arch. f. exper. Path. u. Pharmakol.195:
         609, 1940.
           43. Larsen, B.: Skandinav.Arch. f. ['hysiol. 82:288, 1939.

--J__                                                                              q-   *,,1413   1*!cs**...$.*&        dr+   .+*.la
                                                       IT/AR A4NDICIND,

                      callt effect on blooclpressureor heart rat€ in normal persorts. It rvould
                      appear that 6 mg. of d-rlesoxyephedrine   hydrochloride has a circulatory
                      effect in a human subject that is equivalentto l0 or 15 r-ng.of anrphet-
                      amine sulfate,e  though the clataon the former drug are relatively nrcager
                      anclare not presentedso that a fairly accttratecotnparisotlcall l;e u-rade.

                             RESPIRATION,      }'TETABOLISM,       TEMPERATURIi,       BT,OOD   SUGAR,

                                              BI-OOD    PICTURI|     AND   DIUI{DSIS

                           Resfiratioru.-Seifert12 reported that 15 mg. of d-desox),cpheclrine
                      hydrochloride (he useclapparentlyonly 1 subject) increasedthe voltune
                      of pulmonary ventilation ancl clecreased                 the frecluency. The nraxirnum
                      change occurreclthree to               fotrr hours after tlte drug was givctr; 5 nrg.
                      had no effect. I'iillen 36 observed uo effect ou respiration itr trorrnal
                      strbjects receiving 6 rrig. of the drug; larger closes,rvhich cattsecla
                      significant increasc in bloocl pfcssurc, augtnerrted                 the rcspiratory rate.
                      Biissemakerand Sonnenberg,ar                  who    performed trventy-fc,urtests on 1
                      subject, found that 6, 9 ancl 12 mg. closeshacl no significant effect on
                      volurne and rate of respiration. The same result was obtained by
                      Lehrnann and co-rrvorl<ers,20 used 3 subjects. They accounted for
                      Seifert's results b]' assunringthat mouth breathing, as cmployed in the
                                                                                                   -1' he
                      e x p c ri u rc u ts c a u s c sl rypcrvcnti l ati orrrr sotre strl rj ccts.
                                            ,                              i                             drug rvas
                      a c h n i n i s te re c li th e r one or tw o hours before the tests. Il auschi l d 6o
                      found respiration to be inflrrencedin auimals only by relatively large
                      doses. The effect on vital capacityhas not been studied.
                         Metabolisrn.-The respiratory quotient was unchanged in Btisse-
                      maker and Sonnenberg's and I-ehmann's subjects, thorrgh Seifert
                      reported an increase. No one obse.rved signihcantchangein the basal
                      metabolic rate with orclirrarytherapeutic The respiratiorl was
                                                                          except in the 1 sub-
                      not influenced by the clrug during and after worl<,a8
                      ject in lvhom hyperverrtilation developed.21"
                         Bocly Temferatuvs.-F,sdy temperature is apparently unchanged by
                      orclinary therapeuticdoses,though l5 mg. of d-desoxyephedrine   hydro-
                      chloricleincreasesbody temperaturein human beings slightly, 0.5 degree
                      C.oI Schoena8founcl tltat 20 mg. o{ amphetamine sul{ate nray increase
                      body temperature by 1 clegreeC. I(iessig 6 observed that about one
                                                                    hyclrochloride caused a
                      sixth of the lethal dose of d-desoxyepl-redrine
                      decided rise in bocly temperature in mice and rabbits. By weight

                         44. Biissemaker, ancl Sonnenberg: Ztschr. f. d. ges. exper. I\{ed. 106:771,
                         45. Agnoli, R., and Galli, T.: Gior. di clin. med.20:943,1939.
                         46. Jacobsen, Wollstein and Christensen.2lc Riissemaker ancl Sonnenberg.a*
                         47. Seifert,l2 Piillen.30
                         48. Schoeu, R.: \/ cleutsch.         f.
                                                               Gesellsch. I(rcisl:rtrfforsch.,  p.
                                                                                            1938, 80.

                 IV| -GOI:T Z L * d -D \' ' OX Y f PII E D IIIN E
                                                                        than d-desoxy-
amphetamine       sulfate cattsccllcss risc in tcurperatttrc
              h),clrochloricle,  rvhich coinciclccl      rvith l(icssig's obscrvatiorr
that the latter    clrug tvas trvo times l1lofe toxic tharr the
                                                        of  r/-clcsoxyephedrine   hydro-
      Corlmelt: It lpp.afs that an oral closc
                                                   elTecton     respiratiou' resplratory
chloride to 6 n-,j.^has sig'ifrcant
           up                  no
quotient,   basal   nrctallolicrate or body temllerature'
                                                            nrg. of d-desoxyephedrine
      Btood srtgar._!It is reporteclthat 6 to 15
 hydrochloridJ     taken orally has      tro effect on blooclsttgar'ae Large closes
 increase   blooclsttgar.lo
                               '2                                                 hydro-
      Btood, Ccl/s.-Seifert gave 3 to 6 rng. oI d-clesoxyephedrine
                                                           ancl observed    no change tn
 chloriclcthrcc tirlrcs rveel<lyfor live rnonths
                              of the btood' I-arge closes          claily were associated
 the cellularconstitttents
 rvith erythrocYtosis.l
      I ntestirtes.-Reiser u0observecl       that d-desoxyephedrine
  in a clilutionof 1 : 700,000 inhibits         the pcristalsis o[ isolatcclintestinal
  loolls lor scvclty secotlcls;      tfie clrug acts a littlc-quicl<crthan' attd
                                                             to Flalrschild,"o  d-desoxy-
  quite so long as, amphetamine. Accorcling
  ephedrine   lil,clroc|lori.le ir. a <lilution  of 1 : 100,000cottuteractsspasurclue
                                                               l3         that given clail-y
  to pilocarpine    anclbariuur cfiloride. Nerrmlrnu stated                                    fl
  the clrug tenclsto causeconstipation'                                                        u
                                                                                         to    il
       Tlrc cpithclialcells c-r[   tlie omentttnt of the guinea pig are cattsecl      'l'he    ti
                                          hyclrochloriclc,    as by epirrcphrirre't1
   contractby d-clesorveplreclrine
                                                                  has rlo effect on bloocl
   spleerr also is .^.tr..l to contract,'r2 a closetfiat
   pressure; rveightd-clesoxyephedrine
               by                                   hyclrochloricle nrore activetharr

   amphetamine      sulfatein this respect'
   had taken 15 mg. of arnphetatnine           sulfatc arrd in 28 per cent after tlrey
   hacltal<en15 mg. of r/-clesoxyephedrine
        (Jterus.-_It has been reportecltl-ratd-clesox1'epheclrine
                                               sulfate in increasing       the tone of the
    is more acti'e tha' zrrnphetamine
    rabbit tltertts.53
                                                            irr vitro by a fiftieth-rnolar
        Ert.syntes.*Amipe oxidase is iniribited
                                                     hydrochloride or amphetan-rine
    concentration of d-clesoxyep|e<1rine
                                   uo                         3s observecl that d-desoxy-
        Diuresis._Hauschild and Springortlln
                                                      florv of ttritie, the latter finding
     ephedrinehYdrochloride i.rcreases tl-ie

     49. Seifert.l2 Frank'3s
                                           u' Pharmakol' 195j'603'1940-
     50. Reiser,\{.: Arch' f' exper' Path'
     52. Jacobsen.2lb  Jacobsenand Wollstein'21c
72                                14/AR II,fLDICINE

that the drug increased renal blood florv and that even relatively large                          d e x t r - ,, ,
doses    did not decrease          renal blood florv. Springorum also rcporteclthat               eXp(ll'l
i n l 0 h u rn a n s u l tj e c ts tu d i e dby the V ol harclmethocl15 nrg. of the cl rng
                                 s                                                                t l t a t l ,,
given orally caused diuresis, the rnaxinltlnl increase in the output of                           epltc,lr
turinebeing 28 per cent.                                                                          notetl
                                                                                                  sttitltll    '
     Lo c i,,,
       zvr/,, ;)'"':             :il. ;-#ffi:                        ri e y -
                                                         : ;.."*p'e <Irr Ir dro                   l l t c tr : ,
chloriclchas a rval<ingeffect in aninralsuucler ttre inRuenceof variotts                          git'<: i
hypnotics,       such as clrloral lrydrate,barbituric acid, solubleb:rrbital (bar-                          tii
                                 "T'                                rvasachi evccl th orre-
b i ta l s o d i u rn ),p e rn o c to na nd al cohol ;tl i i s efTect               rvi            chlor i
fifticth to one-hundred-and-sixtieth the letlul closein rats and nrice.
                                                  of                                               solulrI
                and co-u,orl<ers found r/-desoxyephedrine                   hydrochloride to                ).t'
Jacobsen                                                                                           trl
have:r     grcatcr rvaking effect thatt autphetatrtitte            strlfatein r-nicerruclcrtlre    I)iill,
influenceof ethl'lallylbarbituric acid (cloriurn).                                 rvho used       e l r l r t, I
0.4 cc. of paralclehycle            pltrs 0.032 mg. of each of a serics o[ drtrgs rincl                    >r
20 micein eachgroup, founclthat d-de.soxycphedrine                      hydrochloridervorrkl        cltl,,r
waken the mice in eleven and a half minutes (average), amphctarnine                                 t t'itti, ,
sulfate in tlventy minutes and ephedrine in thirty-otre mitttttes; ho"v-                            thcr
ever, 0.5 nrg of nretrazol and 0.04 nlg. of picrotoxin werc bctter                                  tlr:rt :
a n a l e p ti c s .                                                                                if it
     Fless56studieclcarefully in grorrps of 10 rats the rvaking effects of                          tlrt' I
metrazol,coramine (a 25 per cent solutiorr of pyridirre betacarl"roxylic                            cl.illt,
acid diethylanride), cycliton (3. 5 dinrethylisoxazol-4-carboxylic                        acid      t\\'t't r
diethylarnide)and c/-desoxyepl-reclrine                hyclrochloridein alcohol and in              ;ttitl
chloralosc(chloral hydrate rvith clextrose) anesthesia. nll the drugs
were of value in alcohol anesthesia,              but the optinrum closevaried.
optimum waking dose of metrazol was 2.5 mg. per hundred grams, and
of coramine, 15 nrg. Five milligrams of the former drug and 30 mg.                                   11lt(',
of the latter cornpoundprolonged the alcohol anesthesia. Cvcliton had                                nll)lt
the sanre     effectzrs     coramine. d-I)esoxyepheclrine           hydroclrloridewas ideal          ( ' l t rI t
in that it tnd no optimum dose,the animals beirig awakenedfaster with                                lati,
larger doses and doses as small as 25 to 50 nricrograms per hundred                                   c lt t . ,
grarnsbeing effcctive. None of the drugs rvas ideal in sl-rortening                    chlora-
                                                                                                      tit'.. t
lose anesthesia. Coran-rine                and cycliton were toxic, and metrazol and
desoxyephedrine             prolonged the anesthesia. I(ohn-RichardsT observed
that /-desoxyephedrine              and arnphetanrine        are about equal in antihypnotic
effect on rabbits rvherr soluble pentobarbital or pentobarbital is used.
                                                                                                      Oll          t
The levorotatoryform of desoxyephedrine practically inactive. The

   54. (a) Jacobsen, Christensen, T.; Ericksen,F., and Hald, J.: Skandinav.
                    E.;             J.
Arch. f. Physiol. 79:258, 1938. (b) Jacobsen,
                                            Wollstein and Christensen.2le
  55. Trevan,-T.\V.: Proc. Roy. Soc. It{ed.32:391, 1939.
  56. Iless, _T. Arch. f. cxper. Path. u. Pharrnal<ol.
               :                                    197:204, 1941.                                       19?
                    I\/I/-GO E7'ZL-d-DDSOXYEPII              n DRI N l:.                    73

tlextrorotatory      form is sonrewhat          superior to amphetamine,        thougl'rlltore
ex lr c r i rn c nw o u l c lb c re q u i re dto e s ta bl i sh rel ati on. It i s i nteresti rrg
tlrat after the incluctior-r "sleep" arrrphctarnine
                                    of                               sulfate ancl d-dcsoxi'-
epheclrine     hydrochloricle       usuallyprolorrgcrl        the period of "slecp," as I'Iess
noted for chloralose anesthesia. J(ohn-Riclrards, oS did Trevarr,
expressed       the belief that arnphctarnineand t/-clesoxyephedrine                   arc not
suitallle adrrrinistratior-r analepticsin thr: rvay tliat picrotoxin an<l
             for                        as
tnetrazol     are usecl,in that the sympathominicticzrnclother side effects
givc therna too smztllnrargin o[ safety.
    X,Ian.--Seifcrt statedthat 6 to 9 mg. of d-desoxyephcclrinc                         liydro-
clrloride antrulsthc elfect of orclinar"y                         doses of barbital ancl
soluble  phcnobarbital(phenobarbitalsodirrrn). Jecel5? statecltl-rat 15
t o 25 mg . i n te rru p tsn a rc o s i si n c l u cecl i th a barbi turate (bunarken).
l)iillen10"an(l liratrl<3t rernarkeclon the ar-raleptic             elfcct of d-clcsoxy-
epheclrine  hydrochloridcon paticrrts.
    Siegmund anclWarstadt 37reportedthat d-desoxyephedrine
                3tu                                                              hydro-
cltloridc counteracts     alcclholic   intoxicatiou without aflecting the concen-
trationof alcoholin the blood arrd is useful in cornbating"hang-over";
the-v achninistered to 12 nrg. dosesof the drug. Siegmuncl stated
                      6                                                       334
tluit the greatestefl'ectof the clrug on alcoholic intoxication is exerted
ii it is tal<en  beforc clrinlting,thotrgh the effect is clcllnite if talien at
tlre height of alcoholic iutoxication. This is likely, since d-desoxy-
cphcdrine   hydroclrloridebegins to nlanifest its central action in about
nventynrinutes. It has beenuseclas alr arraleptic                after rnetrazoltherapv
arrrlother forurso[ shock theraov.os

                                   OTI{ER     EFFECTS

    Sensitivity to Pain.-I{iessig and Orzechowski 6e have performed
interestingexperimentson the effect of d-desoxyephedrine  hydrochloride,
arnphetamine  sulfateand related cornpouncls sensitivity of pain nerve
en<lings. They testedchiellv sensitivityof tooth pulp to electricalstimtr-
lation. They found that d-desoxyephedrine    hydroclrlorideper rnilligrarn was n'lore effective than amphetarninesulfate. To prove that the
decreased sensitivity was not due to distraction secoudary to cerebral
stimulation,they gave aminopyrine and acetylsalicylicacid, which also
stiurulate cerebrum. These drugs after sonretirne definitely rendered
tlic animalsmore sensitiveto pain. This effect of acetylsalicylicacid
on peripheralsensitivity to pain was previously observedby Mullin arrd

    57. Jecel, J.: ' Wchnschr. 87 2239,1940.
    58. (a) Dosios,  A., and tr{incia,I. : Wien. nred.\Vchnschr.912746,1941. (1,)
    59. Kiessig, J., and Orzechowski, : Arch. f. exper. Path. u. Pharnrakol.
                 H.                         G.

                                                              IV,4li   ItII:.DICINL

Luckhardt,0o        wlto found that in human beings the drug at first had no
effect on cutaneous          paiu but a{ter trvo or tLrrcehours rendered thc crrta-
neouspain nerves ntore sensitive.                         observationssuggested         that it
rnight be therapeuticallydesirable to cornbine d-clesoxyr:ltlrctlrine                     u,itlr
m o rp h i n eo r l v i th a cetyl sal i cyl iaci clfor the rel i ef of pai n. S trcl ra conr-
bination rnight be substitutecl rnorphine in tlie r.nalragelncnt pairr."l
                                          for                                      of
    Morfline.-Jecel            5? and Piillen10b both stated that d-desoxyephc-
drine hydrochloridecounteracts central depression
                                                the                       by
                                                                  caused ntorphine
w i tl to u t a ffe c ti n gi ts anal gcsi c operti cs. Other autl rorsnrcnti onedi ts
usefulness tltis rcgard in the managementof inoperable turrrors.
      Szal<all anci \Varstadt 3? stated that d-desoxyepheririnehydro-
c h l o ri d e i s o f v a l u e i n thc l l l anagentent nrorphi ni srn.

       IIARIT            FORMATION,                         TOLERANCE       AND       CUMULATIVI:   IaFI.ECTS

     S z a k a l l ,s o i e b e ndorfer,02 ei fert,l 2I(nei se" 8 and Jacel3r statcclthat
                      L                    S
d-desoxyephedrine              hydrochloride is not habit forming. Othcr authors
rvho have used it over prolongeclperiods have made no comments on
this subject. I'Iowever, in June 1941 the Cerman governrnent placed
d-desoxyephedrine             hydrochloricle,  amphetamine     sulfateand clolantin (thc
ethyl ester of 4-phenyl-1-rnethvlpiperidine-4-carborric                acid) rrnclcr the
n a rc o ti c ,o r p re s c ri p ti on,rrv.63 One caseof habi t forrnati oni s ci tcd for
d-dcsoxyephedrirte            hydrochloricle, 'w'hich
                                               in         apparently8,1rng. rvrs tal<err
daily. The article by Druclirey 63',\'aspublishedin IvIedi:ittiscltc              lilinilt
in August 1941 at the requestof the editor; though only 1 caseof habit
formation is cited, the statement is macle that in nlany irrstancesthe
three drugs proved to be habit fornring. Drucl<reyadcledthat the habit
occurs only in persons rvith lorv will porver, who, however, provitle a
good demonstrationof the danger of these drugs.
     Tolerance to the effect both of amphetaminesulfate and of d-desoxv-
ephedrinehydrochloride on rnooclis known to develop.l'b This is the
reason for spacecl            nrcclication. Tliis nray also cause certain persorrsto
increasethe dose until serious toxic sicle effects are observcd. Three
caseshave been reported in r,vhichthe daily dose of d-clesoxyepheclrirre
hydrochloride had been gradually increased to 84, 225 ancl 270 ng.,
respectively.6aOn withdrarval of the drug, the patients slept tu'o or
three days and coul<l not stay arvalie rvithout the drug. Three rveel<s
were required for all symptorrrs disappear. In another patient, toler-

   60. Mullin, F. J., and Lrrcl<hardt, B.: Arch. pharrnacol. de
                                                 A.                                                          et
   61. MLiller-Bonn.15Warstaclt.gz Jecel.0z
   62. Liebendiirfer: Miinchen. rnecl.Wchnschr. 87:7182, 1940.
   63. Druckrey, lI.: Med. Klin. 37:885, 1941.
   6 1 . ( a ) L o e w e n s t e i n ,O . : S a m m l . v . V e r g i { t u n g s f . 1 1 : 1 5 5 , 1 9 { 1 . ( 1 , )


              I   -irrsi.+st6ifllltr!q!t!t!E^?,         3
                                                            ': -                                           n'i8|Ft!p#F   --"lhrn-
                  II/V-GODTZL-d-DESOXLEPII]:DRIN E                           75

  ance  apparently  did not clevelopbut use of the <1rug had to be continucd
  to preventthe patient from falling rhis appearsto be the only
  typeof "addictiort"observed,                             05
                                 somecalling it aclcliction and others not.00
  Ranlte 32statedthat d-cleso-xyephedrine
                                            h1'6ro.tltoric1edoes not produce
  a trtte craving but that "rveak-rvilled" persol-rscontinue the use of the
 drug becattse the inrprovcment in moocl ancl perfr:rrnance
                 of                                                 ancl t6at
 rvithdrarval  symptomsarc absentwhen the clrtrghas been useclfor lnany
 months. He says that tolerance is not clevelopedancl interprets tfie
 apparent   toleranceto increasedneed for sleep aftcr the drug lras been
 usedto l<eep   otre arval<e trventy-four hours ; it is the increaseci
                            for                                           need
 for sleepthat requires a larger closeto r<eep    one alvalce,  ancl it is the
 largedoserecluiredthat producesthe unclesirable       circulator,yand meta-
 bolicef{ects. I-Ie points out that sonre morphine adclictsw6en cleprivecl
 of nrorphine   have substitutedd-desoxyepheclrine    hydrochloricle. bl1.r.
 obse rvations regarding tolcrance ancl ackliction arc sirnilar to tSosc
 reported anrphetamine
           for                sulfate.0

                   OTIIER   USES FOR I{U]\.IAN     BEINGS
     The literatureshows that d-dcsoxyephedrine      hy<lrochloricle been
 usedin tire treatmentof every condition for r,vhichaurp6etamine     sulfate
 has been used, for example, nettrocirculatoryasthenia, chronic illless,
postopcrative  rlepression,postoperative nauseaanclvonriting,nrilclclepres-
 sionin ill patients,collapse,shock, alcoholism,morpliinism, seasickness,
hypotention,  rnigraine,narcolepsy,etc., as r,vellas to shorten anesthesia
or narcosis  and to treat patients after the crisis in pneumonia,3, 6 ancl
9 mg. closesbeing employed at two or three hour intervals.o? Like
amphetamine    sulfate,d-desoxyephedrine   hydrochloricle  has been used in
tlte treatnrent enuresis.llb It has been useclwith favorable results in
the treattnentof hay fever.68 Flugel 6?&   reported sornefavorable results
from the use of the drug in the managementof various types of schizo-
phrenicstupor anclclepression   ancl "astheniccleprcssion"  but statecltliat
the results could not be relied on. Warstaclt37 stated that the drug
(30 nrg.) is of value in treating patients in catatonic stupor or with a
postencephalitic   Parkinson synclrome0ebut not for patients with a true
or arteriosclerotic Parkinson synclronre.

    65. Villinger, W.: Nervenarzt 14:405, 1941.
    66. (a) Eichholtz,F.: Angerv. chernie ir:517, 1940. (D) Stieda.r+
    67. (a) Flugel, tr. E.: I{lin. wcl.u.rschr.
                                              !721286, 1939. (b) Sei{ert.rz (r)
trIiiller-Bonn.rc(d) (e) Speckman.z+b                 t
                                                    (D Warstadt.s (rD Jecel.rr
(l) Dosios   and Nfincia.b8a(i) Licbendcjrfer.€z ) Villinger.or (a) Brcsler, :
                                                 (i                         J.
Psychiat.-neurol. Wchnschr. 42 :466, 1940.
   68. Tropp, C.: Miinchen.rned. Wclrnschr.88:7g6, 1941.
   69. Specl<man.24b   Liebenclcirfer.G2
76                                                       I'VAR MLI)ICINE

                                                      CONTRAINDICATIONS                                                                                         costlyI
   Hypertension,cardiopathy,  advanced  age,thyrotoxicosisanclinsournia                                                                                         eplred
are usttaliy given as contrairrclications.I{orvever, Warstadt 3? statecl

   LD50 l)ose ol Aml>hctantine      and d-Desorye[,hcdrhe
                             Su.lfate                    Ilydrochloridc*
:\ultnul                        llrug                     Il.outo     Dosc, Mg./Iig                                A r rL l r o r                               chloric
Rut,               d-Dcsoxyephedrlne I n t r a p e r i t o n e a l    l5-25,sver-           I{auschild rr                                                       amine l
                                                                        age I7
nat                r\mphctnmine                  Subcutaneous         il5, ,10,
                                                                              35            Ilartung, W. H.: Chern. llcv.                                       I{ence,
                                                                                               U : 38,9,     1931. licbube, I', G.,
                                                                                               and llrt,skin, N.: Psychirtrlc                                   sulfate
                                                                                               QutrL. 1-1 : 26, l()-10.Ih!'ich,                                 frorn t
                                                                                               } V . - E . ,0 D d K r r l r n [ ) l r r r r r , ] i . l l , :
                                                                                               Artn. lDt,. ,\Ictl. l(t 3l$7{, 19.i7                             to 6 tr
r * o u n g r n t A r n p l r c tt m i r r e     Subcutnneotrs        200                   nhrlch, \q. Ii., uncl Krurrrl.rlrunL.
                                                                                               l i . l J . : A n n . I u t . I I c r l . . l0 :                 o[ t he
                                                                                               1874, t9i7
Il,at              d-Dcsoxycphetlrlno            Oral                 37                    Iluuschild 6a                                                        (elcva
llouso             rI-Dcsoxye  plrcdrine         Subcutaneous         1 5 o r 1 5 0( ? )    Iilcssig o
JI(-ruse           rl-Dr-.rrxyeDlredrine
                                                                                                                                                                in sctr
                                                 Srtl.rcutarteoug     9-20; avcr. l0        Xohn-Illchards r
                   r\rnyrlretaminc               Subcutarrcous        10-50                                                                                     produ(
-\Iouse            Amphctamine                   Subcut&Dcous         3 0 t o 3 0 0( ? )    E l e s s l go
]Iouse             Arnlrlretntrrine              Subcutancous         2 i r ,1 5 5( ? ) ,   nlrrich, W. E., and Krumblrtar,
                                                                                                                                                                on the
                                                                       280 (?)                 li. B.: Ann. Int. Ilcrl. lo:                                     careiu
                                                                                               I8?4,1937. Chukruvurti, ll.:
                                                                                               J. Pharmacol. 19 1,l.r1rer.
                                                                                               '1'lrcr&p. 1t7', 15.t, ltlij!. trIlrl'ri,                         subjec
                                                                                               l i . , u n r l I , ' r a n c e s c l r i r r i(,i . :                Nc
                                                                                               Arch. di sc. biol. ::; : 7, I!i.i'J
lllouse            tl-Ilesoxyephedrirre          Intrapcritoneal      22                    Kohn-llichllds r                                                     dose c
\Iouse             Aurphr'tumine                 Intraperitoneal      t5,120                d l l e s , G . A . : J . P l r t l r n a < : o l .&
                                                                                               Jixpcr. I'lterup. (i6: l, 1339.
                                                                                                                                                                 ( am pl
                                                                                                G u n n , J . A . : ( ' l u r r l ,I L l i . . u r r r l         a dose
                                                                                                Stcks, L: J. I'ltysiul. t)J :
                                                                                               4So, 1939                                                         casc o
-\{ouse            Amphetamlno                   Ornl                 2 5 ,4 6              Elrrjch, \V, n., anrl KrunrblrnRr,
                                                                                               n. IJ.: Ann. Itrl. \Ietl, lO:                                     drug I
                                                                                               1 8 7 4 ,1 9 : i 7 . S u t e r , U . , \ L , u r r r l
                                                                                               Weston, A. W.: J. ,\nr. Chcrn.                                        AI
                                                                                               $0c. $il r 60e, t94l
Mouse             Amphetamine                           Oral          15                    Kohn-Richards 7                                                      ephed
                  d-Dcsoxyephedrine Ortl                              20-90
B abbit           d - I ) c s o x y e p h e d r i r r e fntravenous
                                                                      I l-r-?5              Klessig o
Rabblt            d-f)esoxycpherlrine lntravenous                     15-30                 Kohn-Richards z                                                      in Jut
Ilabbit           Amphetulnine                          futravcnous   20-P5                 Ilnrtung, W.: Chem. 11ay.f):
                                                                                                389,1931. Ihrich, W. E., rrnrl                                   WAS S
                                                                                                 Xrumblraar, li. B.: Ann, lrrt.
                                                                                                I I e d . 1 O : 1 8 7 4 ,1 9 3 7                                 sician
Rnbblt             d-Desoxvcphedrino S u b c u t a n e o u s          7.5                   I ( r i h n - R l c l r n r d s?                                     tion tl
                   Atnythcu rnirrc   Su lrctttu rtcoue                il(i
Ilabblt            Arnlrhctrnrinc    Subcutaucous                     20                    Ehrlch, W, 8., antl I(rurnblrnirr,                                   that e
                                                                                             X. B.: Am. J. I\I. Sc. 11)8:
                                                                                             ?85, 1939                                                           patier
Young              Amphetamine                   Subcutaneous         50                    Ehrich, W. 8., and Knrmtrhnar,
rabbit                                                                                       E. B.: Am. J. lI. Sc. lt)Fi:
                                                                                             785, 1939                                                           in eff
Iiabblt            Amphctamine                   Oral                 85                    Rcifenstcln, D. O.: J. pharrna-
                                                                                             eol. & Ilxpcr. l.lrerup. (;t) ! t,
                                                                                                                                                                 that t
                                                                                                                                                                 are rr
   I You_n8 animols tolera_to anrphctamine sulf&te
,                                                      better tlron older nnirntls; such a study
has not been rrtatlo for- d-desoxyephedrinc' h-yrlror:hloriclc. I'hc acrrte teilrat Obse-oi irnrptrrt--                                                          o[ r er
amlne gulfato given by lnjection apDears to bo 20 to 40 rng. per kilogr&rn ior mriture animals
of va-rious species-:l5 to 25 nlg., or &n aver&ge of 1f mg., Der kiiogram is ttre iD50 clorc
of d-dcsoxyephctlrine ydrochloride for rats.

that hypertensivepatients manifest tachyphylaxis on prolonged admin-
istration of the clrug. Szakall30n'arned that the drug is not a substittlte
for rest and sleep,and He1'rocltand Weisenstein18stateclthat it is too
                                                                                                                    , ri I i"'R

                                                                                                                    t Y j
                                                                                                                    'j; I
                                                                                                                    . i i u[.'f
                                                                                                                    i"l ,
                                                                                                                    1 thd.
                                I L/Y_GOET Z I,-d- D ES OXY EP H E D R I N E,                                               t. ?

                                                                                                                    '[t Iil*
         costly physiologicallyfor athletesto use (tliey gave 15 nrg. of d-desoxy-                                    ::;1
         ephedrine hydrochloride intrarnuscularly).                                                                 jfi

               A review of the literature indicatcs that d-dcsoxyephedrine
         chloride ltas an action on man arrclon :rnimalssimilar to that of amphet-
                                                                                                          fiydro-   ffi{
         at r t it r c t r l [a tc . It i s n ro rc p o tc n t p c r rrri l l i grarn ran l unphctarrri ne fate.
                     s                                                              tl                   sul
         I'Ietrcc,it is usually dispensedin a 3 mg. tablct, whcrcas anrphcta.nrine
         sulfate is usually dispensed a 5 mg. tablet. Or-re
                                                       in                                 gains the impression
         froui the German literature that d-desoxyephedrine                                  liyclrochloridein 3
         to 6i nrg. dosesis preferable to amphetarninesulfate, in that srrch a close
         of tlre former drug is more iikely to produce the clesiredcereltraleffect
          (eler,;rtion mood, rvillinrnessto exert oneselfto the utrnost, decrease
         itr sctrse fatiguc anrl couutcraction boredom anclslecpiness)
                                                                     of                                 lvithout
         producing ttnclesiraltle               efi'ccts. Alnrost every Gertnan autlror rcporting
         on the drug has maclesuch a claim. The availabledata pertaining to a
         careful compari.son the effects of the tlvo chemicalson the same huntan
         subjcctsare meager. So it is conjectural',vhether claim made is trtre.         the
                No comtnettts are to be found in tlie literature regarding the
         clost:of scclativcrcrluircclor the hest scrlative to use to incluce sleep
          (anrphetatriine            sulfate<iisturbs      falling to slccp rlrore tharr sleeping) a{ter
         a closeof d-desoxyephedrine                      hydrochloride l-ras          been taken. As in the
         casc of arnphetamine                  strlfate,sleep,n-raybe disturlreclat night after the
         drug has been taken cluring the day, or six to trvelve hours later.
                .t\lthough a number of German authors have stated that r/-clcsoxy-
         ephedrirre hyclrochlorideis not habit {ornring, it, along ',vith arnphet-
         amine strlfate,            was placecl     under the German narcotic,or prescription,larv
         in June 1941. In the article announcingthe new legislativeruling 63it
         rvas stated: "The ruling regarding these drugs will support the phy-
         sician in exercisingcaution,Lrutit is not intendedto deny or even ques-
         tion tl'remedicalor clinicalusefulness the drugs." It is further stated
         tl-rat either drug produces                 .euphoriafollowed by depression,                forcing the
         patient to take more and more of the drug, and that as to the "waking"
         amines, one should not forget that they act not by causing a true increase
         in efficiency but indirectly by depressingcertain central inhibitions and
         that the extra exertion exhauststhe amounts of strength which norrnally
         are retained; {rence regainingof efficiency
                                            the                                    will require a longer period
         of r es t .


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