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                                 Investigative Ophthalmology & Visual Science, Vol. 29, No. 10, October 1988
                                          Copyright © Association for Research in Vision and Ophthalmology




    Pathogenesis of Blepharoconjunctivitis Complicating
       13-cis-Retinoic Acid (Isotretinoin) Therapy in a
                      Laboratory Model
                                          Robert W. Lambert ond Ronald E. Smith

            Systemic treatment of adult male New Zealand albino rabbits with 13-cis-retinoic acid (isotretinoin)
            resulted in a reduction in the size of the meibomian gland. Clinical signs of toxicity included weight
            loss, alopecia, dry skin and mild conjunctiva! erythema with crusting on the eyelid margin. Histopath-
            ologic findings included thickening of duct and ductule epithelium, decrease in acinar tissue, accen-
            tuation of basaloid cells and evidence of periacinar fibrosis. The model presents the first experimental
            data to indicate that systemic 13-cis-retinoic acid effects meibomian gland structure in a laboratory
            model. Future functional studies of this model may yield important insights into the relationships
            between meibomian gland morphology, function, the ocular surface and the pathogenesis of blepharo-
            conjunctivitis. Invest Ophthalmol Vis Sci 29:1559-1564,1988



   Isotretinoin (13-cis-retinoic acid) is used for the                                             Materials and Methods
treatment of acne vulgaris and keratinizing derma-                               Eighteen male New Zealand albino rabbits were
toses.1'2 Therapeutic effects of the drug as used for                         treated with isotretinoin at the following doses: 1-2
dermatologic conditions include decreased sebum                               mg/kg/day (Group I, n = 6), 10 mg/kg/day (Group II,
production, changes in the surface lipid composition                          n = 6), and 20 mg/kg day (Group III, n = 6) for a
and inhibition of keratinization.23 One of the more                           period of 12 weeks. The low dose was chosen to ap-
common side effects of this therapy is blepharocon-                           proximate the clinical dose, while the medium and
junctivitis, which has been reported in 20-50% of                             higher doses were chosen based on the data of
such patients. 12 ' 4 Although Fraunfelder and col-                           Kamm.8 The drug was administered by oral intuba-
leagues2 suggested that meibomian gland dysfunction                           tion, using peanut oil as a vehicle. A control group of
may be implicated, to date there has been no evi-                             six additional animals received the vehicle only. Prior
dence to support this hypothesis. Since studies in pa-                        to initiation of treatment, the lids of each animal were
tients undergoing isotretinoin therapy for acne have                          evaluated by biomicroscopy.7 All meibomian glands
revealed a reduction in the size of skin sebaceous                            appeared normal.
glands,5'6 and since there are similarities between skin
sebaceous glands and the meibomian glands,7 we                                   13-cis-retinoic acid (RO 4-3780) was a gift from
studied animals fed 13-cis-retinoic acid to determine                         Hoffmann-La Roche, Inc. It was supplied as a pure
if pathologic changes occur in the meibomian gland.                           dry powder that was stored at —20°C. Prior to its use,
Herein we describe the histopathology of the rabbit                           the 13-cis-retinoic acid was brought to room temper-
meibomian gland after systemic treatment with Ac-                             ature and dissolved in a known quantity of the ve-
cutane® (Hoffman-La Roche, Inc., Nutley, NJ).                                 hicle.
                                                                                 At the end of the 12-week treatment period, the
                                                                              animals were killed and the eyelids were removed and
                                                                              placed in fixative for 24 hr. The tissue was then dis-
                                                                              sected into rectangular blocks containing two or three
  From the Department of Ophthalmology, University of South-
ern California School of Medicine, and Estelle Doheny Eye Insti-              glands per block and processed for histologic exami-
tute, Los Angeles, California.                                                nation. Only glands taken from the central portion of
  Supported in part by National Institutes of Health Core Center              the lipid were sectioned for morphometric analysis.
grant EY-03040 (Bethesda, Maryland) and by a grant from Re-                   This was done to minimize the error introduced by
search to Prevent Blindness, Inc.                                             regional differences in the size of the rabbit meibo-
  Submitted for publication: January 13, 1988; accepted April 7,
1988.
                                                                              mian glands from temporal to nasal.
  Reprint requests: Ronald E. Smith, MD, 1355 San Pablo Street,                  At least three glands per animal were serially sec-
Los Angeles, CA 90033.                                                        tioned (10 fim section thickness, 150-200 sections/


                                                                       1559




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1560                          INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / October 1988                                        Vol. 29




         B
   Fig. 1. (A) Normal rabbit eyelid. The central duct (*) extends the length of the gland and connects to acini by means of short ductules
(arrowhead). C - conjunctiva. Original magnification X50, hematoxylin and eosin. (B) Tracing of an outline of the meibomian gland
illustrated above.

gland); every tenth section was stained with hema-                      Morphometric Analysis
toxylin and eosin, assessed by light microscopy and
subjected to morphometric analysis.                                       The Micro-Plan II Digitizer (Donsanto Corp.) was
  This study conformed to the ARVO Resolution on                        used to determine cross-sectional area. The section
the Use of Animals in Research.                                         was projected onto a digitizing tablet and an outline




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No. 10                                    ISOTRETINOIN COMPLICATIONS / Lamberr and Smith                             1561




   Fig. 2. Acini from normal
rabbit meibomian gland
containing cells at various
stages of holocrine differen-
tiation. A single layer of
nondifferentiated basaloid
cells is present at the pe-
riphery of acini (arrow-
head). Original magnifica-
tion X250, hematoxylin and
eosin.




of the entire gland was traced with a cursor (Fig. 1).              topathologic examination of the control tissue re-
The following parameters were determined:                           vealed no structural abnormalities. The "normal"
                                                                    rabbit meibomian gland is a simple branched acinar
   1. Cross-sectional area (Ax) in mm2 for every tenth              gland that extends the approximate length of the tar-
      section of a serially sectioned gland.                        sal plate (Fig. 1). A central duct courses throughout
   2. Mean cross-sectional area (A) as the mean of all              the length of the gland and connects with individual
      cross sectional areas measured for a particular               acini by short ductules. Acinar cells can be identified
      group.                                                        at various stages of holocrine differentiation (Fig. 2).
   3. Meibomian gland volume (Vx) in mm3 for each                      Animals treated with 13-cis-retinoic acid showed a
      serially sectioned gland, according to the De-                marked reduction in the size of the meibomian
      lesse principle9:                                             glands (Fig. 3); this was confirmed by morphometric
         Vx = SAXT                                                  analysis. The mean cross-sectional surface area of the
                                                                    meibomian gland was reduced by 15% in Group I, by
       2AX = sum of all cross-sectional areas for gland             21% in Group II and by 26% in Group III. This was
           T = thickness of tissue section represented by           reflected in a similar reduction of the meibomian
               a single slide, ie, T = 0.1 mm as every              gland volume; ie, mean volumes were reduced by
               tenth section was sectioned.                          18% in Group I, by 25% in Group II and by 28% in
                                                                    Group III. Results are presented in Table 1.
   4. Mean meibomian gland volume (V) as the
                                                                       Meibomian acinar tissue appeared to be dimin-
      mean of all gland volumes calculated for a par-               ished and histopathologic changes were observed in
      ticular group.                                                all experimental animals treated with isotretinoin.
                                                                    These changes included thickening of the epithelium
                                Results                             lining the ducts and ductules, decrease in the number
  At the time of sacrifice, all animals treated with                and size of acini and a reduction in the frequency of
13-cis-retinoic acid showed signs of systemic toxicity.             lipid-laden acinar cells (Fig. 3). Meibomian glands of
These included weight loss, alopecia of the chest, ab-              animals treated with a high dose of isotretinoin
domen and distal extremities, dry skin and mild ery-                (Group III) showed evidence of a periacinar fibroblas-
thema with crusting on the eyelid margins. Animals                  tic activity replacing acinar tissue (Fig. 4). Casts of
in the control group showed no signs of toxicity. His-              acinar cells were frequently observed in the acinar




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1562                             INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / Ocrober 1988                               Vol. 2 9




   Fig. 3. Treated meibomian gland (Group II, 10 mg isotretinoin daily X12 weeks). Epithelium lining the duct and acini is thickened
(arrowhead) and acini are reduced in size. Original magnification X65, hematoxylin and eosin.



lumen and in the central duct of meibomian glands                    clinical dose (Group I) and progressed in severity to
from this group of animals (Fig. 5).                                 Group III, where all animals showed clinical signs
                                                                     similar to a generalized hypervitaminosis A. The his-
                            Discussion                               topathology and statistical analysis of gland volume
                                                                     showed clearly that systemic 13-cis-retinoic acid af-
  Treatment of adult New Zealand albino rabbits                      fects the morphology and reduces the size of the mei-
with 13-cis-retinoic acid (1-20 mg/kg daily for 12                   bomian gland at each dose studied. Isotretinoin ap-
weeks) resulted in clinical signs of toxicity in all ani-            pears to inhibit the ability of the meibomian acinar
mals. These were present in animals receiving the                    cell to differentiate, while stimulating the epithelium
                                                                     lining the ducts and acini to proliferate.
                                                                        Histopathologic changes observed in our animal
Table 1. Rabbit meibomian gland cross-section                        model are compatible with those of Landthaler and
areas (A) in mm2 and volume (V) in mm3 following                     associates,l0 who demonstrated an inhibitory effect of
oral administration of 13-cis-retinoic acid                           13-cis-retinoic acid on human skin sebaceous glands.
                                   A (mm2)          V (mm3)          In their model, 13-cis-retinoic acid appeared to exert
                                                                     its action by inhibiting the differentiation of seba-
Control                           1.85 ±0.07      3.93 ± 0.25        ceous gland acinar cells. This results in a diminution
Group I
  13-cis-retinoic acid                                               of skin sebaceous gland size and, presumably, de-
  1-2 mg/kg/bw                    1.55 ±0.04t     3.23 ± 0.4f        creases the production of sebum. In the sebaceous
Group II                                                             gland, a reduction in sebum production is believed to
  13-cis-retinoic acid
  10 mg/kg/bw                     1.50 ±0.07*     2.97 + 0.16*       be the therapeutic basis for the treatment of acne
Group III                                                            vulgaris.1' In our animal model, the consequence of a
  13-cis-retinoic acid                                               reduction in gland tissue may be mirrored in the ad-
  20 mg/kg/bw                     1.42 ±0.16*     2.87 ±0.15*
                                                                     verse ocular side effects associated with isotretinoin
  Data are mean ± SD, n = 6,                                         therapy, the most common being blepharoconjuncti-
  * P < 0.005 (paired t-test).
  t P < 0.01 (paired t-test).                                        vitis, which has been reported in 20 to 50% of pa-




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No. 10                             ISOmETINOIN COMPLICATIONS / Lamberr ond Smirh                           1563




      Fig. 4. Treated meibo-
   mian acini {20 mg isotretin-
   oin daily X12 weeks). A
   periacinar fibrosis appears
   to be replacing actnar tissue
   (arrowhead). Original mag-
   nification X35O, toluidine
   blue.




tients.12 Several hypotheses have been suggested to         type of blepharitis arises from abnormal meibomian
explain retinoic-induced blepharoconjunctivitis. Ac-        gland function. They suggest that treatment with 13-
cording to Fraunfelder, La Braico and Meyer,2 this          cis-retinoic acid results in a decrease in the meibo-




   Fig. 5. Treated meibo-
mian gland (20 mg isotre-
tinoin daily X12 weeks).
Casts of intact differentiated
holocrine cells are seen in
the lumen of the gland
(arrow). Original magnifica-
tion X425, toluidine blue.




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1564                    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / October 1988                                   Vol. 29



mian lipid component of the tear film which de-                                     References
creases tear break-up time and consequently destabi-       1. Milson J, Jones DH, King K, and Cunliffe WJ: Ophthalmolo-
lizes the tear film, leading to a "dry eye" syndrome.         gical effects of 13-cis-retinoic acid therapy for acne vulgaris. Br
   Our present study does not address the meibomian           JDermatol 107:491, 1982.
lipid component of the tear film; however, it seems        2. Fraunfelder FT, LaBraico JM, and Meyer SM: Adverse ocular
likely that the histopathologic changes observed in           reactions possibly associated with isotretinoin. Am J Ophthal-
                                                              mol 100:534, 1985.
retinoid treated rabbit meibomian glands might in-         3. Rismondo V and Ubels JL: Isotretinoin in lacrimal gland fluid
fluence this factor. Additional studies would be re-          and tears. Arch Ophthalmol 105:416, 1987.
quired to determine if our model provides a basis for      4. Blackman HJ, Peck GL, Olsen TG, and Bergsma DR: Blepha-
the hypothesis that changes in meibomian gland mor-           roconjunctivitis: A side effect of 13-cis-retinoic acid therapy for
phology result in decreased meibum excretion and a            dermatologic diseases. Ophthalmology 86:753, 1979.
                                                           5. Plewig G, Wagner A, Nikolowski J, and Landthaler M: Effects
subsequent reduction in the lipid component of the            of two retinoids in animal experiments and after clinical appli-
tear film. Alternatively, Rismondo and Ubels3 have            cation in acne patients: 13-cis-retinoic Ro 4-3780 and aromatic
detected the presence of 13-cis-retinoic acid in the          retinoid Ro 10-9359. In Retinoids: Advances in Basic Re-
tear fluid of patients undergoing retinoid therapy for        search and Therapy, Orfanos CE, Braun-Falco O, Farber EM,
acne. They suggested that a lipolytic action of the           Grupper C, Polano MK, Schuppli R, editors. New York,
                                                              Springer-Verlag, 1981, pp. 219-235.
retinoid may further destabilize the tear film, com-
                                                           6. Landthaler M, Kummermehr J, Wagner A, and Plewig G:
pounding the effects described by Fraunfelder and             Inhibitory effects of 13-cis-retinoic acid on human sebaceous
associates.2                                                  glands. Arch Dermatol Res 269:297, 1980.
   The experimental evidence we have presented indi-       7. Jester JV, Rife L, Nii D, Luttrull JK, Wilson L, and Smith RE:
                                                              In vivo biomicroscopy and photography of meibomian glands
cates that 13-cis-retinoic acid affects meibomian             in a rabbit model of meibomian gland dysfunction. Invest
gland structure in a laboratory model. This is not            Ophthalmol Vis Sci 22:660, 1982.
only of potential importance in understanding the          8. Kamm J: Toxicology, carcinogenicity, and teratogenicity of
pathogenesis of retinoid-induced blepharoconjuncti-           some orally administered retinoids. J Am Acad Dermatol
vitis, but also in contributing to our understanding of       6:652, 1982.
the relationship between the meibomian gland and           9. Weissmann A, Bowden J, Frank B, Horwitz SN, and Frost P:
                                                              Morphometric studies of the hamster flank organ: An im-
the complex question of lid margin disease. Future            proved model to evaluate pharmacologic effects on sebaceous
functional studies in our animal model may yield              glands. J Invest Dermatol 82:522, 1984.
important insights into the relationship between mei-     10. Landthaler M, Kummermehr J, Wagner A, and Plewig G:
bomian gland structure, function, and the ocular sur-          13-cis-retinoic acid inhibits sebaceous glands in animals and
face. Similar studies have not yet been performed to          humans: Planimetry and in-vitro-autoradiography. J Invest
                                                              Dermatol 74:453, 1980.
confirm our findings in man.                              11. Strauss JS, Stranieri AM, Farrell LN, and Downing DT: The
                                                              effect of marked inhibition of sebum production with 13-cis-
Key words: blepharoconjunctivitis, meibomian gland dys-       retinoic acid on skin surface lipid composition. J Invest Der-
function, morphometry, toxicity, hypervitaminosis A           matol 74:66-67, 1980.




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