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Drugs

, Volume 53, Issue 3, pp 358–388 | Cite as

Current Use and Future Potential Role of Retinoids in Dermatology

  • Constantin E. Orfanos
  • Christos C. Zouboulis
  • Brigitte Almond-Roesler
  • Christoph C. Geilen
Review Article

Summary

Since their introduction 15 years ago, retinoids have been increasingly used for topical and systemic treatment of psoriasis and other hyperkeratotic and parakeratotic skin disorders, keratotic genodermatoses, severe acne and acne-related dermatoses, and also for therapy and/or chemoprevention of skin cancer and other neoplasia. Oxidative metabolites of vitamin A (retinol) are natural retinoids present at low levels in the peripheral blood. Synthetic retinoids are classified into 3 generations including nonaromatic, monoaromatic and polyaromatic compounds. They are detectable in plasma 30–60 minutes after systemic administration, and reach maximum concentrations 2 to 4 hours later. Elimination half-life is 10 to 20 hours for isotretinoin, 80 to 175 days for etretinate and 2 to 4 days for trans-acitretin; the latter, however, partially converts into etretinate. Retinoid concentrations in skin are rather low in contrast to subcutaneous fat tissue.

Intracellularly, retinoids interact with cytosolic proteins and specific nuclear receptors. Two classes of nuclear receptors have been suggested to mediate retinoid activity at the molecular level, RARs and RXRs. The expression of retinoid receptors is tissue specific; skin mainly espresses RARγ and RXRα. Retinoids affect epidermal cell growth and differentiation as well as sebaceous gland activity and exhibit immunomodulatory and anti-inflammatory properties.

Current retinoid research targets the development of receptor-selective retinoids for tailoring and/or improving their therapeutic profile. Currently, tretinoin is used systemically for acute promyelocytic leukaemia, etretinate and acitretin for psoriasis and related disorders, as well as other disorders of keratinisation, and isotretinoin for seborrhoea, severe acne, rosacea and acneiform dermatoses. Systemic retinoids are also applied for chemoprevention of epithelial skin cancer and cutaneous T cell lymphoma. The major adverse effect of retinoids is teratogenicity; all other adverse effects are dose-dependent and controllable. Contraception is, therefore, essential during retinoid treatment in women of child-bearing age. Clinical monitoring requires physical examination for adverse effects every 3 to 4 weeks and proper laboratory investigations, also including analysis of retinoid bioavailability in selected cases. Topical retinoids are rapidly developing at present and seem promising for the future; their clinical application includes acne, aging, photodamage, precanceroses, skin cancer and disorders of skin pigmentation. The development of receptor-specific retinoids for topical treatment of psoriasis and/or acne may lead to interesting new compounds based on our current concepts of retinoid function.

Keywords

Psoriasis Acne Retinoid Dermatol Isotretinoin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    IUPAC-IUB Joint Commission on Biochemical Nomenclature. Eur J Biochem 1982; 129: 1–5Google Scholar
  2. 2.
    Orfanos CE, Schuppli R. Oral retinoids in dermatology. Proc. Workshop XVth International Congress of Dermatology 1977, Mexico City. Dermatologica 1978; 157 Suppl. 1: 1–64Google Scholar
  3. 3.
    Orfanos CE. Oral retinoids: present status. Br J Dermatol 1980; 103: 473–81PubMedGoogle Scholar
  4. 4.
    Voorhees JJ, Orfanos CE. Oral retinoids. Broad spectrum dermatologic therapy for the 1980s. Arch Dermatol 1981; 117: 418–21PubMedGoogle Scholar
  5. 5.
    Gollnick H, Rinck G, Bitterling T, et al. Pharmakokinetik von Etretinat, Acitretin und 13-cis-Acitretin: neue Ergebnisse und Nutzen der Blutspiegel-orientierten klinischen Anwendung. Z Hautkr 1990; 65: 40–50PubMedGoogle Scholar
  6. 6.
    Safavi K. Serum vitamin A levels in psoriasis: results from the first national health and nutrition examination survey. Arch Dermatol 1992; 128: 1130–1PubMedGoogle Scholar
  7. 7.
    Tang G, Russel RM. 13-cis-retinoic acid is an endogenous compound in human serum. J Lipid Res 1990; 31: 175–82PubMedGoogle Scholar
  8. 8.
    Matsuoka LY, Wortsman J, Tang G, et al. Are endogenous retinoids involved in the pathogenesis of acne? Arch Dermatol 1991; 127: 1072–3PubMedGoogle Scholar
  9. 9.
    Biesalski HK. Comparative assessment of the toxicology of vitamin A and retinoids in man. Toxicology 1989; 57: 117–61PubMedGoogle Scholar
  10. 10.
    Dawson MI, Hobbs PD. The synthetic chemistry of retinoids. In: Sporn MB, Roberts AB, Goodman DS, editors. The retinoids. Biology, chemistry, and medicine. 3rd ed. New York: Raven Press, 1994: 5–178Google Scholar
  11. 11.
    Orfanos CE, Stadler R, Gollnick H, et al. Current developments of oral retinoid therapy with three generations of drugs. Recent Developments in Clinical Research. Curr Probl Dermatol 1985; 13: 33–49PubMedGoogle Scholar
  12. 12.
    Vahlquist A, Rollman O. Etretinate and the risk for teratogenicity: drug monitoring in a pregnant woman for 9 months after stopping treatment. Br J Dermatol 1990; 123: 31Google Scholar
  13. 13.
    Bernard BA. Adapalene, a new chemical entity with retinoid activity. Skin Pharmacol 1993; 6 Suppl. 1: 61–9PubMedGoogle Scholar
  14. 14.
    Verschoore M, Langner A, Wolska H, et al. Efficacy and safety of topical CD 271 alcoholic gels. A new treatment candidate for acne vulgaris. Br J Dermatol 1991; 124: 368–71PubMedGoogle Scholar
  15. 15.
    Esgleyes-Ribot T, Chandraratna RA, Lew-Kaya DA, et al. Response of psoriasis to a new topical retinoid, AGN 190168. J Am Acad Dermatol 1994; 30: 581–90PubMedGoogle Scholar
  16. 16.
    Chandraratna RAS, Johnson AT, Thatcher SM, et al. Retinoid agonists, neutral antagonists and inverse agonists; novel retinoids for the treatment of psoriasis [abstract]. Br J Dermatol 1996; 135: 837Google Scholar
  17. 17.
    Chalker DK, Lesher JL Jr, Smith JG Jr, et al. Efficacy of topical isotretinoin 0.05% gel in acne vulgaris: results of a multicenter, double-blind investigation. J Am Acad Dermatol 1987; 17: 251–4PubMedGoogle Scholar
  18. 18.
    Hughes BR, Norris JFB, Cunliffe WJ. A double-blind evaluation of topical isotretinoin 0.05%, benzoyl peroxide gel 5% and placebo in patients with acne. Clin Exp Dermatol 1992; 17: 165–8PubMedGoogle Scholar
  19. 19.
    Shalita A, Weiss JS, Chalker DK, et al. A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris. A multicenter trial. J Am Acad Dermatol 1996; 34: 482–5PubMedGoogle Scholar
  20. 20.
    Schumacher A, Stüttgen G. Vitamin-A-Säure bei Hyperkeratosen, epithelialen Tumoren und Akne. Dtsch Med Wochenschr 1971; 96: 1547–51PubMedGoogle Scholar
  21. 21.
    Allen JG, Bloxham DP. The pharmacology and pharmacokinetics of the retinoids. Pharmacol Ther 1989; 40: 1–27PubMedGoogle Scholar
  22. 22.
    Larsen FG, Jakobsen P, Eriksen H, et al. The pharmacokinetics of acitretin and its 13-cis-metabolite in psoriatic patients. J Clin Pharmacol 1991; 31: 477–83PubMedGoogle Scholar
  23. 23.
    Larsen FG, Nielsen-Kudsk F, Jakobsen P, et al. Pharmacokinetics and therapeutic efficacy of retinoids in skin diseases. Clin Pharm 1994; 23: 42–61Google Scholar
  24. 24.
    Lucek RW, Colburn WA. Clinical pharmacokinetics of the retinoids. Clin Pharmacokinet 1985; 10: 38–62PubMedGoogle Scholar
  25. 25.
    Benifla JL, Ville Y, Imbert MC, et al. Fetal tissue dosages of retinoids: experimental study concerning a case of isotretinoin (Roaccutan®) administration and pregnancy. Fetal Diagn Ther 1995; 10: 189–91PubMedGoogle Scholar
  26. 26.
    Reiners J, Lofberg B, Kraft JC, et al. Transplacental pharmacokinetics of teratogenic doses of etretinate and other aromatic retinoids in mice. Reprod Toxicol 1988; 2: 19–29PubMedGoogle Scholar
  27. 27.
    Chalmers RJ. Retinoid therapy — a real hazard for the developing embryo. Br J Obstet Gynaecol 1992; 99: 276–8PubMedGoogle Scholar
  28. 28.
    DiGiovanna JJ, Zech LA, Ruddel ME, et al. Etretinate. Persistent serum levels after long-term therapy. Arch Dermatol 1989; 125: 246–51PubMedGoogle Scholar
  29. 29.
    Rollmann O, Phil-Lundin I. Acitretin excretion into human breast milk. Acta Derm Venereol 1990; 70: 487–90Google Scholar
  30. 30.
    Rollmann O, Vahlquist A. Retinoid concentrations in skin, serum and adipose tissue of patients treated with etretinate. Br J Dermatol 1983; 109: 439–47Google Scholar
  31. 31.
    McNamara PJ, Jewell RC, Jensen BK, et al. Food increases the bioavailability of acitretin. J Clin Pharmacol 1988; 28:1051–5PubMedGoogle Scholar
  32. 32.
    Brindley C. An overview of recent clinical pharmacokinetic studies with acitretin (Ro 10-1670, etretin). Dermatologica 1989; 178: 79–87PubMedGoogle Scholar
  33. 33.
    Pilkington T, Brogden RN. Acitretin: a review of its pharmacology and therapeutic use. Drugs 1992; 43: 597–627PubMedGoogle Scholar
  34. 34.
    Vane FM, Buggé CJL, Rodriguez LC, et al. Human biliary metabolites of isotretinoin: identification, quantification, sythesis and biological activity. Xenobiotica 1990; 20: 193–207PubMedGoogle Scholar
  35. 35.
    Rubio F, Jensen BK, Henderson L, et al. Disposition of [14C] acitretin in humans following oral administration. Drug Metab Dispos 1994; 22: 211–15PubMedGoogle Scholar
  36. 36.
    Geiger J-M, Brindley CJ. Cis-trans interconversion of acitretin in man. Skin Pharmacol 1988; 1: 230–6PubMedGoogle Scholar
  37. 37.
    Stuck AE, Brindley CJ, Busslinger A, et al. Pharmacokinetics of acitretin and its 13-cis-metabolite in patients with haemodialysis. Br J Clin Pharmacol 1989; 27: 301–4PubMedGoogle Scholar
  38. 38.
    Gollnick H, Bauer R, Brindley CJ, et al. Acitretin versus etretinate in psoriasis. Clinical and pharmacokinetic results of a German multicenter study. J Am Acad Dermatol 1988; 19: 458–69PubMedGoogle Scholar
  39. 39.
    Gollnick H, Zaun H, Ruzicka T, et al. Relapse rate of severe generalized psoriasis after treatment with acitretin or etretinate. Eur J Dermatol 1993; 3: 442–6Google Scholar
  40. 40.
    Kingston TP, Matt LH, Lowe NJ. Etretin therapy for severe psoriasis. Evaluation of clinical responses. Arch Dermatol 1987; 123: 55–8PubMedGoogle Scholar
  41. 41.
    Kraemer KH, Di Giovanna JJ, Moshella AN, et al. Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 1988; 318: 1633–7PubMedGoogle Scholar
  42. 42.
    Larsen FG, Jakobsen P, Knudsen J, et al. Conversion of acitretin to etretinate in psoriatic patients is influenced by ethanol. J Invest Dermatol 1993; 100: 623–7PubMedGoogle Scholar
  43. 43.
    Chou RC, Wyss R, Huselton CA, et al. A potentially new metabolic pathway: ethyl esterification of acitretin. Xenobiotica 1992; 8: 993–1002Google Scholar
  44. 44.
    Almond-Roesler B, Orfanos CE. Trans-Acitretin wird in Etretinat rückmetabolisiert. Bedeutung für die orale Retinoidtherapie. Hautarzt 1996; 47: 173–7PubMedGoogle Scholar
  45. 45.
    Larsen FG. Pharmacokinetics of etretinate and acitretin with special reference to treatment of psoriasis. Acta Derm Venereol 1995; 190: 1–33Google Scholar
  46. 46.
    Rollmann O, Vahlquist A. Oral isotretinoin (13-cis-retinoic acid) therapy in severe acne: drug and vitamin A concentrations in serum and skin. J Invest Dermatol 1986; 86: 384–9Google Scholar
  47. 47.
    Laugier JP, Berbis P, Brindley C, et al. Determination of acitretin and 13-cis acitretin in skin. Skin Pharmacol 1989; 2: 181–6PubMedGoogle Scholar
  48. 48.
    Larsen FG, Vahlquist C, Andersson E, et al. Oral acitretin in psoriasis: drug and vitamin A concentrations in plasma, skin and adipose tissue. Acta Derm Venereol 1992; 72: 84–8PubMedGoogle Scholar
  49. 49.
    Giguère V. Retinoic acid receptors and cellular retinoid binding proteins: complex interplay in retinoid signaling. Endocr Rev 1994; 15: 61–79PubMedGoogle Scholar
  50. 50.
    Vieira AV, Schneider WJ, Vieira PM. Retinoids: transport, metabolism, and mechanisms of action. J Endocrinol 1995; 146: 201–7PubMedGoogle Scholar
  51. 51.
    Fisher GJ, Talwar HS, Xiao J-H, et al. Immunological identification and functional quantitation of retinoic acid and retinoid X receptor proteins in human skin. J Biol Chemistry 1994; 269: 20629–35Google Scholar
  52. 52.
    Ross AC. Cellular metabolism and activation of retinoids: roles of cellular retinoid-binding proteins. FASEB J 1993; 7: 317–27PubMedGoogle Scholar
  53. 53.
    Apfel C, Crettaz M, Siegenthaler G, et al. Synthetic retinoids: differential binding to retinoic acid receptors. In: Saurat J-H, editor. Retinoids 10 years on. Karger: Basel, 1991: 110–20Google Scholar
  54. 54.
    Törmä H, Rollmann O, Vahlquist A. Detection of mRNA transcripts for retinoic acid, vitamin D3, and thyreoid hormone (e-erb-A) nuclear receptors in human skin using reverse transcription and polymerase chain reaction. Acta Derm Venereol 1993; 73: 102–7PubMedGoogle Scholar
  55. 55.
    Mangelsdorf DJ, Umesono K, Evans RM. The retinoid receptors. In: Sporn MB, Roberts AB, Goodman DS, editors. The retinoids. Biology, chemistry, and medicine. New York: Raven Press, 1994: 319–49Google Scholar
  56. 56.
    Brand N, Petkovich M, Krust A, et al. Identification of a second human retinoic acid receptor. Nature 1988; 332: 850–3PubMedGoogle Scholar
  57. 57.
    Krust A, Kastner P, Petkovich M, et al. A third human retinoic acid receptor, hRAR-gamma. Proc Natl Acad Sci USA 1989; 86: 5310–4PubMedGoogle Scholar
  58. 58.
    Petkovich M, Brand NJ, Krust A, et al. A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature 1987; 330: 444–50PubMedGoogle Scholar
  59. 59.
    Mangelsdorf DJ, Burgmeyer U, Heyman RA, et al. Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Genes Dev 1992; 6: 329–44PubMedGoogle Scholar
  60. 60.
    Mangelsdorf DJ, Ong ES, Dyck JA, et al. Nuclear receptor that identifies a novel retinoic acid response pathway. Nature 1990; 345: 224–9PubMedGoogle Scholar
  61. 61.
    Elder J, Åström A, Pettersson U, et al. Differential regulation of retinoic acid receptors and binding proteins in human skin. J Invest Dermatol 1992; 98: 573–679Google Scholar
  62. 62.
    Leid M, Kastner P, Lyons R, et al. Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell 1992; 68: 377–95PubMedGoogle Scholar
  63. 63.
    Boylan JF, Goudas LJ. Overexpression of the cellular retinoic acid-binding protein-I (CRABP-I) results in a reduction in differentiation-specific gene expression in F9 teratocarcinoma cells. J Cell Biol 1991; 112: 965–79PubMedGoogle Scholar
  64. 64.
    Schüle R, Evans RM. Cross-coupling of signal transduction pathways: zink finger meets leucine zipper. Trends Genet 1991; 7: 377–81PubMedGoogle Scholar
  65. 65.
    Fanjul A, Dawson MI, Hobbs PD, et al. A new class of retinoids with selective inhibition of AP-1 inhibits proliferation. Nature 1994; 372: 107–11PubMedGoogle Scholar
  66. 66.
    Tong PS, Horowitz NN, Wheeler LA. Trans-retinoic acid enhances the growth response of epidermal keratinocytes to epidermal growth factor and transforming growth factor beta. J Invest Dermatol 1990; 94: 126–31PubMedGoogle Scholar
  67. 67.
    Zheng Z-S, Polakowska R, Johnson A, et al. Transcriptional control of epidermal growth factor receptor by retinoic acid. Cell Growth Differ 1992; 3: 225–32PubMedGoogle Scholar
  68. 68.
    Asselineau D, Darmon M. Retinoic acid provokes metaplasia of epithelium formed by adult human epidermal keratinocytes. Differentiation 1995; 58: 297–306PubMedGoogle Scholar
  69. 69.
    Griffiths CEM, Dabelsteen E, Voorhees JJ. Topical retinoic acid changes the epidermal cell surface glycosylation pattern towards that of a mucosal epithelium. Br J Dermatol 1996; 134: 431–6PubMedGoogle Scholar
  70. 70.
    Rosenthal DS, Griffiths CEM, Yuspa SH, et al. Acute or chronic topical retinoic acid treatment of human skin in vivo alters the expression of epidermal transglutaminase, loricrin, involucrin, filaggrin, and keratins 6 and 13 but not keratins 1, 10, and 14. J Invest Dermatol 1992; 98: 343–50PubMedGoogle Scholar
  71. 71.
    Asselineau D, Bernard BA, Bailly C, et al. Retinoic acid improves epidermal morphogenesis. Dev Biol 1989; 133: 322–35PubMedGoogle Scholar
  72. 72.
    Asselineau D, Cavey MT, Shroot B, et al. Control of epidermal differentiation by a retinoid analogue unable to bind to cytosolic retinoid acid-binding proteins (CRABP). J Invest Dermatol 1992; 98: 128–34PubMedGoogle Scholar
  73. 73.
    Geiger J-M, Hommel L, Harms M, Saurat J-H. Oral 13-cis retinoic acid is superior to 9-cis retinoic acid in sebosuppression in human beings. J Am Acad Dermatol 1996; 34: 513–5PubMedGoogle Scholar
  74. 74.
    Hommel L, Geiger J-M, Harms M, et al. Sebum excretion rate in subjects treated with oral all-trans-retinoic acid. Dermatology 1996; 193: 127–30PubMedGoogle Scholar
  75. 75.
    Shapiro SS, Hurley J, Vane FM, et al. Evaluation of potential therapeutic entities for the treatment of acne. In: Reichert U, Shroot B, editors. Pharmacology of retinoids in the skin. Basel: Karger, 1989: 104–12Google Scholar
  76. 76.
    Zouboulis ChC, Korge B, Akamatsu H, et al. Effects of 13-cis-retinoic acid, all-trans-retinoic acid, and acitretin on the proliferation, lipid synthesis and keratin expression of cultured human sebocytes in vitro. J Invest Dermatol 1991; 96: 792–7PubMedGoogle Scholar
  77. 77.
    Zouboulis ChC, Xia L, Korge B, et al. Cultivation of human sebocytes in vitro. Cell characterization and influence of synthetic retinoids. In: Saurat J-H, editor. Retinoids 10 years on. Basel: Karger, 1991: 254–73Google Scholar
  78. 78.
    Zouboulis ChC, Krieter A, Gollnick H, et al. Progressive differentiation of human sebocytes in vitro is characterized by increased cell size and altered antigenic expression and is regulated by culture duration and retinoids. Exp Dermatol 1994; 3: 151–60PubMedGoogle Scholar
  79. 79.
    Bauer R, Orfanos CE. Trimethoxyphenylretinoic acid (Ro 10-1670) inhibits mitogen-induced DNA-synthesis in peripheral blood lymphocytes in vitro. Br J Dermatol 1981; 105: 19–24PubMedGoogle Scholar
  80. 80.
    Bauer R, Orfanos CE. Effects of synthetic retinoids on human peripheral blood lymphocytes and polymorphonuclears in vitro. In: Cunliffe WJ, Miller A, editors. Retinoid therapy. Lancaster: MTP Press, 1984: 201–18Google Scholar
  81. 81.
    Bauer R, Schütz R, Orfanos CE. Impaired motility and random migration of vital polymorphonuclears in vitro after therapy with aromatic retinoid in psoriasis. Int J Dermatol 1984; 23: 72–7PubMedGoogle Scholar
  82. 82.
    Bécherel P-A, Mossalayi MD, Le Goff L, et al. Mechanism of anti-inflammatory action of retinoids on keratinocytes. Lancet 1994; 344: 1570–1PubMedGoogle Scholar
  83. 83.
    Dubertret L, Lebreton C, Touraine R. Inhibition of neutrophil migration by etretinate and its main metabolite. Br J Dermatol 1982; 107: 681–5PubMedGoogle Scholar
  84. 84.
    Orfanos CE, Bauer R. Evidence for antinflammatory activities of oral synthetic retinoids: experimental findings and clinical experience. Br J Dermatol 1983; 109 Suppl. 25: 55–60PubMedGoogle Scholar
  85. 85.
    Imcke E, Ruszczak Zb, Mayer-da-Silva A, et al. Cultivation of human dermal microvascular endothelial cells in vitro: immunocytochemical and ultrastructural characterization and effect of treatment with three synthetic retinoids. Arch Dermatol Res 1991; 283: 149–57PubMedGoogle Scholar
  86. 86.
    Buck J, Derguini F, Levi E, et al. Intracellular signaling by 14-hydroxy-4,14-retro-retinol. Science 1991; 254: 1654–6PubMedGoogle Scholar
  87. 87.
    Halliday GM, Ho KK, Barnetson RS. Regulation of the skin immune system by retinoids during carcinogenesis. J Invest Dermatol 1992; 99: 83S–86SPubMedGoogle Scholar
  88. 88.
    Prabhala RH, Maxey V, Hicks MJ, et al. Enhancement of the expression of activation markers on human peripheral blood mononuclear cells by in vitro culture with retinoids and carotenoids. J Leukoc Biol 1989; 45: 249–54PubMedGoogle Scholar
  89. 89.
    Bollag W. Retinoid and interferon: a new promising combination? Br J Haematol 1991; 79 Suppl. 1: 87–91PubMedGoogle Scholar
  90. 90.
    Halewy O, Arazy Y, Melamed D, et al. Retinoic acid receptor-alpha gene expression is modulated by dietary vitamin A and by retinoic acid in chicken T lymphocytes. J Nutrition 1994; 124: 2139–46Google Scholar
  91. 91.
    Wozel G, Chang A, Zultak M, et al. The effect of topical retinoids on the leukotriene-B4-induced migration of polymorphonuclear leukocytes into human skin. Arch Dermatol Res 1991; 283: 158–61PubMedGoogle Scholar
  92. 92.
    Gollnick H, Ehlert R, Rinck G, et al. Retinoids: an overview of pharmacokinetics and therapeutic value. Methods Enzymol 1990; 190: 291–304PubMedGoogle Scholar
  93. 93.
    Orfanos CE, Ehlert R, Gollnick H. The retinoids: a review of their clinical pharmacology and therapeutic use. Drugs 1987; 34: 459–503PubMedGoogle Scholar
  94. 94.
    Peck GL, Coats-Walton DA. Retinoids in dermatology. Current usage. In: Sober AJ, Fitzpatrick ThB, editors. The Year Book of Dermatology. St Louis: Mosby, 1995: 1–32Google Scholar
  95. 95.
    Orfanos CE, Schmidt HW, Mahrle G, et al. Retinoic acid in psoriasis: its value for topical therapy with and without corticosteroids. Clinical, histological and electron microscopical studies on forty-four hospitalized patients with extensive psoriasis. Br J Dermatol 1973; 88: 167–82PubMedGoogle Scholar
  96. 96.
    Orfanos CE, Schmidt HW, Mahrle G. Runne U Die Wirksamkeit von Vitamin-A-Säure bei Psoriasis. Topische Kombinationsbehandlung mit Corticoiden. Zwei neue VAS-Präparate zur peroralen Therapie. Arch Dermatol Forsch 1972; 244: 424–6PubMedGoogle Scholar
  97. 97.
    Runne U, Orfanos CE, Gartmann H. Perorale Applikation zweier Derivate der Vitamin A-Säure zur internene Psoriasis-Therapie. 13-cis-beta-Vitamin-A-Säure und Vitamin A-Säure-aethylamid. Arch Derm Forsch 1973; 247: 171–80Google Scholar
  98. 98.
    Lauharanta J, Geiger JM. A double-blind comparison of acitretin and etretinate in combination with bath PUVA in the treatment of extensive psoriasis. Br J Dermatol 1989; 121: 107–12PubMedGoogle Scholar
  99. 99.
    Lowe NL, Prystowsky J, Bourget T, et al. Acitretin plus UVB therapy for psoriasis. J Am Acad Dermatol 1991; 24: 591–4PubMedGoogle Scholar
  100. 100.
    Ruzicka T, Sommerburg C, Braun-Falco O, et al. Efficiency of acitretin in combination with UV-B in the treatment of severe psoriasis. Arch Dermatol 1990; 126: 482–6PubMedGoogle Scholar
  101. 101.
    Orfanos CE, Landes E, Bloch PH. Traitément du psoriasis pustuleux par un nouveaux rétinoide aromatique (Ro 10-9359). Ann Dermatol Venereol 1978; 103: 807–11Google Scholar
  102. 102.
    Lassus A, Geiger JM. Acitretin and etretinate in the treatment of palmoplantar pustulosis: a double-blind comparative trial. Br J Dermatol 1988; 119: 755–9PubMedGoogle Scholar
  103. 103.
    Borok M, Lowe N. Pityriasis rubra pilaris. J Am Acad Dermatol 1990; 22: 792–5PubMedGoogle Scholar
  104. 104.
    Dicken CH. Treatment of classic pityriasis rubra pilaris. J Am Acad Dermatol 1994; 31: 997–1001PubMedGoogle Scholar
  105. 105.
    Gollnick HPM, Orfanos CE. Clinical efficacy of etretinate and acitretin. European experience. In: Psoriasis, Roenigk HH, Maibach HI, editors. New York: Marcel Dekker, 1991: 725–48Google Scholar
  106. 106.
    Hartmann D, Mosberg H, Weber W. Lack of effect of acitretin on the hypoprothrombinemic action of phenprocumon in healthy volunteers. Dermatologica 1989; 178: 33–6PubMedGoogle Scholar
  107. 107.
    Berbis P, Bun H, Geiger JM, et al. Acitretin (Ro 10-1670) and oral contraceptives: interaction study. Arch Dermatol Res 1988; 6: 388–9Google Scholar
  108. 108.
    Saurat J-H, Geiger J-M, Amblard P, et al. Randomized double-blind multicenter study comparing acitretin-PUVA, etretinate-PUVA and placebo-PUVA in the treatment of severe psoriasis. Dermatologica 1988; 177: 218–24PubMedGoogle Scholar
  109. 109.
    Tanew A, Guggenbichler A, Hoenigsmann H, et al. Photochemotherapy for severe psoriasis without or in combination with acitretin: a randomized, double-blind comparison study. J Am Acad Dermatol 1991; 25: 682–4PubMedGoogle Scholar
  110. 110.
    Wright S, Baker H, Warin AR Treatment of psoriasis vulgaris with a combination of etretinate and hydroxyurea. J Dermatol Treat 1990; 1: 211–3Google Scholar
  111. 111.
    Geiger J-M, Czarnetzki BM. Acitretin (Ro 10-1670, etretin): overall evaluation of clinical studies. Dermatologica 1988; 176: 182–90PubMedGoogle Scholar
  112. 112.
    Lambert WE, De Leenheer AP, De Bersaques JP, et al. Persistent etretinate levels in plasma after changing the therapy to acitretin. Arch Dermatol Res 1990; 282: 343–4PubMedGoogle Scholar
  113. 113.
    Steijlen PM, Van Dooren-Greebe RJ, van de Kerkhof PCM. Acitretin in the treatment of lamellar ichthyosis. Br J Dermatol 1994; 130: 211–4PubMedGoogle Scholar
  114. 114.
    Jensen BK, Chaws CL, Huselton CA. Clinical evidence that acitretin is esterified to etretinate when administered with ethanol [abstract]. FASEB J 1992; 6: A1570Google Scholar
  115. 115.
    Laugier JP, De Sousa G, Bun H, et al. Acitretin biotransformation into etretinate: role of ethanol on in vitro hepatic metabolism. Dermatology 1994; 188: 122–5PubMedGoogle Scholar
  116. 116.
    Blanchet-Bardon C, Nazzaro V, Rognin C, et al. Acitretin in the treatment of severe disorders of keratinization. Results of an open study. J Am Acad Dermatol 1991; 24: 982–6PubMedGoogle Scholar
  117. 117.
    Happle R, Van de Kerkhof PCM, Traupe H. Retinoids in disorders of keratinization: their use in adults. Dermatologica 1987; 175 Suppl. 1: 107–24PubMedGoogle Scholar
  118. 118.
    Peck GL, Yoder FW. Treatment of lamellar ichthyosis and other keratinising disorders with an oral synthetic retinoid. Lancet 1976; II: 1172–3Google Scholar
  119. 119.
    Peck GL, Yoder FW, Olsen TG, et al. Treatment of Darier’s disease, lamellar ichthyosis, pityriasis rubra pilaris, and basal cell carcinoma with oral 13-cis retinoic acid. Dermatologica 1978: 11S-12SGoogle Scholar
  120. 120.
    Christophersen J, Geiger JM, Danneskiold-Samsoe P, et al. A double-blind comparison of acitretin and etretinate in the treatment of Darier’s disease. Acta Derm Venereol 1992; 72: 150–2PubMedGoogle Scholar
  121. 121.
    Lauharanta J, Kanerva L, Turjanmaa K, et al. Clinical and ultrastructural effects of acitretin in Darier’s disease. Acta Derm Venereol 1988; 68: 492–8PubMedGoogle Scholar
  122. 122.
    Ridden J, Ferguson D, Kealy T. Organ maintenance of human sebaceous glands: invitroeffects of 13-cis retinoic acid and testosterone. J Cell Sci 1990; 95: 125–36PubMedGoogle Scholar
  123. 123.
    Harms M, Philippe I, Radeff B, et al. Arotinoid Ro 13-6298 and etretin: two new retinoids inferior to isotretinoin in sebum suppression and acne treatment. Acta Derm Venereol 1986; 66: 149–54PubMedGoogle Scholar
  124. 124.
    Geiger J-M. Retinoids and sebaceous gland activity. Dermatology 1995; 191: 305–10PubMedGoogle Scholar
  125. 125.
    Strauss JS, Davey WP, Denton SJ, et al. Effect of an orally administered arotinoid, Ro 15-0778, on sebum production in man. Arch Dermatol Res 1988; 280: 152–4PubMedGoogle Scholar
  126. 126.
    Vane FM, Chari SS, Shapiro S, et al. Comparison of the plasma and sebum concentrations of the arotinoid Ro 15-0778 and isotretinoin in acne patients. In: Marks R, Plewig G, editors. Acne and related disorders. London: Dunitz, 1989: 183–9Google Scholar
  127. 127.
    Saurat J-H, Mérot Y, Borsky M. Arotinoid acid (Ro 13-7410): a pilot study in dermatology. Dermatologica 1988; 176: 191–9PubMedGoogle Scholar
  128. 128.
    Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis retinoic acid. N Engl J Med 1979; 300: 329–33PubMedGoogle Scholar
  129. 129.
    Ott F, Bollag W, Geiger J-M. Oral 9-cis-retinoic acid versus 13-cis-retinoic acid in acne therapy. Dermatology 1996; 193: 124–6PubMedGoogle Scholar
  130. 130.
    Goulden V, Layton AM, Cunliffe WJ. Long-term safety of isotretinoin as a treatment for acne vulgaris. Br J Dermatol 1994; 131: 360–3PubMedGoogle Scholar
  131. 131.
    Layton AM, Knaggs H, Taylor J, et al. Isotretinoin for acne vulgaris — 10 years later: a safe and successful treatment. Br J Dermatol 1993; 129: 292–6PubMedGoogle Scholar
  132. 132.
    Stainforth JM, Layton AM, Taylor JP, et al. Isotretinoin for the treatment of acne vulgaris: which factors may predict the need for more than one course? Br J Dermatol 1993; 129: 297–301PubMedGoogle Scholar
  133. 133.
    Orme M, Back DJ, Shaw MA, et al. Isotretinoin and contraception [letter]. Lancet 1984; II(8045): 752–3Google Scholar
  134. 134.
    Santana D, Bun H, Joachim J, et al. Plasma concentrations after three different doses of topical isotretinoin. Skin Pharmacol 1994; 7: 140–4PubMedGoogle Scholar
  135. 135.
    Karvonen SJ. Acne fulminans. Report of clinical findings and treatment of twenty-four patients. J Am Acad Dermatol 1993; 28: 572–9PubMedGoogle Scholar
  136. 136.
    Ertl GA, Levine N, Kligman AM. A comparison of the efficacy of topical tretinoin and low-dose oral isotretinoin in rosacea. Arch Dermatol 1994; 130: 319–24PubMedGoogle Scholar
  137. 137.
    Irvine C, Kumar P, Marks R. Isotretinoin in the treatment of rosacea and rhinophyma. In: Marks R, Plewig G, editors. Acne and related disorders. London: Dunitz, 1989: 301–5Google Scholar
  138. 138.
    Schmidt JB, Gebhardt W, Raff M, et al. 13-cis-retinoic acid in rosacea. Acta Derm Venereol 1984; 64: 15–21PubMedGoogle Scholar
  139. 139.
    Petiau P, Cribier B, Chartier C, et al. Acne necrotica varioliformis, resolution with isotretinoin. Eur J Dermatol 1994; 4: 608–10Google Scholar
  140. 140.
    Finkelstein E, Lazarov A, Cagnano M, et al. Oil acne: successful treatment with isotretinoin. J Am Acad Dermatol 1994; 30: 491–2PubMedGoogle Scholar
  141. 141.
    Scerri L, Zaki I, Millard LG. Severe halogen acne due to a trifluoromethylpyrazole derivative and its resistance to isotretinoin. Br J Dermatol 1995; 132: 144–8PubMedGoogle Scholar
  142. 142.
    Plewig G, Steger M. Acne inversa (alias acne triad, acne tetrad or hidradenitis suppurativa). In: Marks R, Plewig G, editors. Acne and related disorders. London: Dunitz, 1989: 345–57Google Scholar
  143. 143.
    Pfahl M. Nuclear receptor/AP-1 interaction. Endocr Rev 1993; 14: 651–8PubMedGoogle Scholar
  144. 144.
    Geilen CC, Bektas M, Wieder Th, Orfanos CE. The vitamin D3 analogue, calcipotriol, induces sphingomyelin hydrolysis in human keratinocytes. FEBS Lett 1996; 378: 88–92PubMedGoogle Scholar
  145. 145.
    Hannun YA, Obeid LM. Ceramide: an intracellular signal for apoptosis. Trends Biol Sci 1995; 20: 72–7Google Scholar
  146. 146.
    Kalén A, Borchardt RA, Bell RM. Elevated ceramide levels in GH4C1 cells treated with retinoic acid. Biochim Biophys Acta 1992; 1125: 90–6PubMedGoogle Scholar
  147. 147.
    Bollag W, Holdener EE. Retinoids in cancer prevention and therapy. Ann Oncol 1991; 3: 513–26Google Scholar
  148. 148.
    Gollnick H, Orfanos CE. Theoretical aspects of the use of retinoids as anticancer agents. In: Marks R, editor. Retinoids in cutaneous malignancy. Oxford: Blackwell, 1991: 41–65Google Scholar
  149. 149.
    Lippman SM, Brenner SE, Hong WK. Cancer chemoprevention. J Clin Oncol 1994; 12: 851–73PubMedGoogle Scholar
  150. 150.
    Berth-Jones J, Cole J, Lehmann AR, et al. Xeroderma pigmentosum variant: 5 years of tumour suppression by etretinate. J Royal Soc Med 1993; 86: 355–6Google Scholar
  151. 151.
    Hodak E, Ginzburg A, David M, et al. Etretinate treatment of the nevoid basal cell carcinoma syndrome. Int J Dermatol 1987; 26: 606–9PubMedGoogle Scholar
  152. 152.
    Goldberg L, Hsu S, Alcalay J. Effectiveness of isotretinoin in preventing the appearance of basal cell carcinomas in basal cell nevus syndrome. J Am Acad Dermatol 1989; 21: 144–5PubMedGoogle Scholar
  153. 153.
    Kelly JW, Sabto J, Gurr FW, et al. Retinoids to prevent skin cancer in organ transplant recipients. Lancet 1991; 338: 1407PubMedGoogle Scholar
  154. 154.
    Rook AH, Jaworsky C, Nguyen T, et al. Beneficial effect of low-dose systemic retinoid in combination with topical tretinoin for the treatment and prophylaxis of premalignant and malignant skin lesions in renal transplant recipients. Transplantation 1995; 59: 714–9PubMedGoogle Scholar
  155. 155.
    Stüttgen G. Zur Lokalbehandlung von Keratosen mit Vitamin A-Säure. Dermatologica 1962; 124: 65–80Google Scholar
  156. 156.
    Purcell SM, Pierce DK, Dixon SL, et al. Chemoprevention of actinic keratoses with topical all-transretinoic acid (RA) [abstract]. J Invest Dermatol 1986; 86: 501Google Scholar
  157. 157.
    Watson AB. Preventive effect of etretinate therapy on multiple actinic keratoses. Cancer Detect Prev 1986; 9: 161–5PubMedGoogle Scholar
  158. 158.
    Alirezai M, Dupuy P, Amblard P, et al. Clinical evaluation of topical isotretinoin in the treatment of actinic keratoses. J Am Acad Dermatol 1994; 30: 447–51PubMedGoogle Scholar
  159. 159.
    Misiewicz J, Sendagorta E, Golebiowska A, et al. Topical treatment of multiple actinic keratoses of the face with arotinoid methyl sulfone (Ro 14-9706) cream versus tretinoin cream: a double blind, comparative study. J Am Acad Dermatol 1991; 24: 448–51PubMedGoogle Scholar
  160. 160.
    Hong WK, Endicott J, Itri LM, et al. 13-cis retinoic acid in the treatment of oral leukoplakia. N Engl J Med 1986; 315: 1501–5PubMedGoogle Scholar
  161. 161.
    Toma S, Mangiante PE, Margarino G, et al. Progressive 13-cis-retinoic acid dosage in the treatment of oral leukoplakia. Oral Oncol Eur J Cancer 1992; 28B: 121–3Google Scholar
  162. 162.
    Shaw JC, White CR. Treatment of multiple keratoakanthomas with oral isotretinoin. J Am Acad Dermatol 1986; 15: 1079–82PubMedGoogle Scholar
  163. 163.
    Mensing H, Wagner G. Etretinate-Therapie bei solitären Keratoakanthomen. Z Hautkr 1988; 63: 234–6PubMedGoogle Scholar
  164. 164.
    Peck GL. Topical tretinoin in actinic keratosis and basal cell carcinoma. J Am Acad Dermatol 1986; 15: 829–35PubMedGoogle Scholar
  165. 165.
    Lippman SM, Parkinson DR, Itri LM, et al. 13-cis retinoic acid and interferon alpha-2a: effective combination therapy for advanced squamous cell carcinoma of the skin. J Natl Cancer Inst 1992; 84: 241–5PubMedGoogle Scholar
  166. 166.
    Toma S, Palumbo R, Vincenti M, et al. Efficiency of recombinant alpha-interferon 2a and 13-cis-retinoic acid in the treatment of squamous cell carcinoma. Ann Oncol 1994; 5: 463–5PubMedGoogle Scholar
  167. 167.
    Eisenhauer EA, Lippman SM, Kavanagh JJ, et al. Combination 13-cis-retinoic acid and interferon alpha 2a in the therapy of solid tumours. Leukemia 1994; 8: 1622–5PubMedGoogle Scholar
  168. 168.
    Schuchter LM, Guerry D, Hamilton R, et al. A phase II study of all-trans-retinoic acid in patients with metastatic melanoma. Proc Am Assoc Cancer Res 1994; 35: 410Google Scholar
  169. 169.
    Modiano M, Dalton W, Lippman SM, et al. Phase II study of fenretinide (n-(4-hydroxyphenylretinamide) in advanced breast cancer and melanoma. Invest New Drugs 1990; 8: 317–9PubMedGoogle Scholar
  170. 170.
    Dhingra K, Papadopoulos N, Lippman SM, et al. Phase II study of alpha-interferon and 13-cis-retinoic acid in metastatic melanoma. Invest New Drugs 1993; 11: 39–43PubMedGoogle Scholar
  171. 171.
    Kessler JF, Jones SE, Levine N, et al. Isotretinoin and cutaneous helper T-cell lymphoma (mycosis fungoides). Arch Dermatol 1987; 123: 201–4PubMedGoogle Scholar
  172. 172.
    Molin L, Thomsen K, Volden G, et al. Oral retinoids in mycosis fungoides and Sézary syndrome: a comparison of isotretinoin and etretinate. Acta Derm Venereol 1987; 67: 232–6PubMedGoogle Scholar
  173. 173.
    Molin L, Thomsen K, Volden G, et al. Retinoids and systemic chemotherapy in cases of advanced mycosis fungoides. Acta Derm Venereol 1987; 67: 179–82PubMedGoogle Scholar
  174. 174.
    Neely SM, Mehlmauer M, Feinstein DI. The effect of isotretinoin in six patients with cutaneous T-cell lymphoma. Arch Intern Med 1987; 147: 529–31PubMedGoogle Scholar
  175. 175.
    Zachariae H, Thestrup-Pedersen K. Interferon alpha and etretinate combination treatment of cutaneous T-cell lymphoma. J Invest Dermatol 1990; 95 Suppl.: 206–8Google Scholar
  176. 176.
    Tousignant J, Raymond GP, Light MJ. Treatment of cutaneous T-cell lymphoma with the arotinoid Ro 13-6298. J Am Acad Dermatol 1987; 16: 167–71PubMedGoogle Scholar
  177. 177.
    Jones G, McLean J, Rosenthal D, et al. Combined treatment with oral etretinate and electron beam therapy in patients with cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome). J Am Acad Dermatol 1992; 26: 960–7PubMedGoogle Scholar
  178. 178.
    Gollnick H, Tsambaos D, Orfanos CE. Risk factors promote elevations of serum lipids in acne patients under oral 13-cis-retinoic acid (isotretinoin). Arch Dermatol Res 1981; 271: 189–96Google Scholar
  179. 179.
    Thestrup-Petersen K, Hammer R, Kaltoft K, et al. Treatment of mycosis fungoides with recombinant interferon-alpha 2a alone and in combination with etretinate. Br J Dermatol 1988; 118: 811–8Google Scholar
  180. 180.
    Altomare GF, Capella GL, Pigatto PD, et al. Intramuscular low dose alpha-2b interferon and etretinate for treatment of mycosis fungoides. Int J Dermatol 1993; 32: 138–41PubMedGoogle Scholar
  181. 181.
    Dreno B, Celerier P, Litoux P. Roferon-A in combination with Tigason in cutaneous T-cell lymphomas. Acta Haematol 1993; 89: 28–32PubMedGoogle Scholar
  182. 182.
    Dreno B, Claudy A, Meynadier J, et al. The treatment of 45 patients with cutaneous T-cell lymphoma with low doses of interferon-alpha 2a and etretinate. Br J Dermatol 1991; 125: 456–9PubMedGoogle Scholar
  183. 183.
    Braathen LR, McFadden N. Successful treatment of mycosis fungoides with the combination of etretinate and human recombinant interferon alpha-2a. J Dermatol Treat 1989; 1: 29–32Google Scholar
  184. 184.
    Knobler RM, Trautinger F, Radaszkiewicz T, et al. Treatment of cutaneous T-cell lymphoma with combination of low-dose interferon alpha-2b and retinoids. J Am Acad Dermatol 1991; 24: 247–52PubMedGoogle Scholar
  185. 185.
    Von Roenn J, von Gunten C, Mullane M, et al. All-trans retinoic acid (TRA) in the treatment of AIDS-related Kaposis sarcoma: a phase II Illinois Cancer Center study [abstract]. Proc Am Soc Clin Oncol 1993; 12: 51Google Scholar
  186. 186.
    Bonhomme L, Fredj G, Ecstein E, et al. Treatment of AIDS-associated Kaposi’s sarcoma with oral tretinoin. Am J Hosp Pharm 1991; 51: 2417–9Google Scholar
  187. 187.
    Laurberg G, Geiger JM, Hjorth N, et al. Treatment of lichen planus with acitretin: a double-blind placebo controlled study in 65 patients. J Am Acad Dermatol 1991; 24: 434–7PubMedGoogle Scholar
  188. 188.
    Harth W, Richard G. Retinoide in der Therapie des Granuloma anulare disseminatum. Hautarzt 1993; 44: 693–8PubMedGoogle Scholar
  189. 189.
    Stavermann T, Adler M, Stadler R. Erfolgreiche Therapie des Granuloma anulare disseminatum mit Etretinat und Prednisolon. Akt Dermatol 1990; 16: 76–9Google Scholar
  190. 190.
    Roenigk HH Jr. Liver toxicity of retinoid therapy. J Am Acad Dermatol 1988; 19: 199–208PubMedGoogle Scholar
  191. 191.
    Sanchez MR, Ross B, Rotterdam H, et al. Retinoid hepatitis. J Am Acad Dermatol 1993; 28: 853–8PubMedGoogle Scholar
  192. 192.
    Vahlquist C, Olsson AG, Lindholm A, et al. Effects of gemfibrozil (Lopid®) on hyperlipidemia in acitretin-treated patients: results of a double-blind cross-over study. Acta Derm Venereol 1995; 75: 377–80PubMedGoogle Scholar
  193. 193.
    Colemann R, MacDonald D. Effects of isotretinoin on male reproductive system. Lancet 1994; 344: 198Google Scholar
  194. 194.
    Barth JH, MacDonald-Hull SP, Mark J, et al. Isotretinoin therapy for acne vulgaris: a re-evaluation of the need for measurements of plasma lipids and liver function tests. Br J Dermatol 1993; 129: 704–7PubMedGoogle Scholar
  195. 195.
    Olsen EA, Weed WW, Meyer CJ, et al. A double-blind, placebo-controlled trial of acitretin for the treatment of psoriasis. J Am Acad Dermatol 1989; 21: 681–6PubMedGoogle Scholar
  196. 196.
    Gupta AK, Goldfarb MT, Ellis CN, Voorhees JJ. Side-effect profile of acitretin therapy in psoriasis. J Am Acad Dermatol 1989; 20: 1088–93PubMedGoogle Scholar
  197. 197.
    Vahlquist C, Selinus I, Vessby B. Serum lipid changes during acitretin (etretin) treatment of psoriasis and palmo-plantar pustulosis. Acta Derm Venereol 1988; 68: 300–5PubMedGoogle Scholar
  198. 198.
    Ashley JM, Lowe NJ, Borok ME, et al. Fish oil supplementation results in decreased hypertrigliceridemia in patients with psoriasis undergoing etretinate or acitretin therapy. J Am Acad Dermatol 1988; 19: 76–82PubMedGoogle Scholar
  199. 199.
    Hohl D, Pelloni F, Sigg C, et al. Prospective study of skeletal changes during short-term acitretin therapy. Dermatology 1992; 185: 23–6PubMedGoogle Scholar
  200. 200.
    Silverman AK, Ellis CN, Voorhees JJ. Hypervitaminosis A syndrome: a paradigm of retinoid side effects. J Am Acad Dermatol 1987; 16: 1027–39PubMedGoogle Scholar
  201. 201.
    Glover MT, Peters AM, Atherton DJ. Surveillance for skeletal toxicity of children treated with etretinate. Br J Dermatol 1987; 116: 609–14PubMedGoogle Scholar
  202. 202.
    Mills CM, Marks R. Adverse reactions to oral retinoids: an update. Drug Saf 1993; 9: 280–90PubMedGoogle Scholar
  203. 203.
    Paige DG, Judge MR, Shaw DG, et al. Bone changes and their significance in children with ichthyosis on long-term etretinate therapy. Br J Dermatol 1992; 127: 387–91PubMedGoogle Scholar
  204. 204.
    Tangrea JA, Kilcoyne RF, Taylor PR, et al. Skeletal hyperostosis in patients receiving chronic, very-low-dose isotretinoin. Arch Dermatol 1992; 128: 921–5PubMedGoogle Scholar
  205. 205.
    Simpson KR, Rosenbach A, Lowe NJ. Etretinate for retinoid-responsive dermatoses: further observations of long-term therapy. J Dermatol Treat 1993; 4: 179–82Google Scholar
  206. 206.
    DiGiovanna JJ, Sollitto RB, Abangan DL, et al. Osteoporosis is a toxic effect of long-term etretinate therapy. Arch Dermatol 1995; 131: 1263–7PubMedGoogle Scholar
  207. 207.
    Callot V, Ochonisky S, Vabres P, et al. Arthrite aiguë au cours d’un traitement par l’isotrétinoïne. Ann Dermatol Venerol 1994; 121: 402–3Google Scholar
  208. 208.
    Kistler A. Limb bud cell cultures for estimating the teratogenic potential of compounds: validation of the test system with retinoids. Arch Toxicol 1987; 60: 403–14PubMedGoogle Scholar
  209. 209.
    Kochhar DM, Jiang H, Penner JD, et al. The teratogenic activity of 9-cis-retinoic acid [abstract]. Teratology 1993; 47: 439Google Scholar
  210. 210.
    Kochhar DM, Penner JD, Minutella LM. Biotransformation of etretinate and developmental toxicity of etretin and other aromatic retinoids in teratogenic bioassays. Drug Metab Dispos 1989; 17: 618–24PubMedGoogle Scholar
  211. 211.
    Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med 1985; 313: 837–41PubMedGoogle Scholar
  212. 212.
    Camera G, Pregliasco P. Ear malformation in baby born to mother using tretinoin cream. Lancet 1992; 339: 687PubMedGoogle Scholar
  213. 213.
    Jick SS, Terris BZ, Jick H. First trimester topical tretinoin and congenital disorders. Lancet 1993; 341: 1181–2PubMedGoogle Scholar
  214. 214.
    Willhite CC, Sharma RP, Allen PV, et al. Percutaneous retinoid absorption and embryotoxicity. J Invest Dermatol 1990; 95: 523–9PubMedGoogle Scholar
  215. 215.
    Loefberg B, Chahoud I, Bochert G, et al. Teratogenicity of the 13-cis and all-trans-isomers of the aromatic retinoid etretin: correlation to transplacental pharmacokinetics in mice during organogenesis after a single oral dose. Teratology 1990; 41: 707–16Google Scholar
  216. 216.
    Geiger J-M, Baudin M, Saurat J-H. Teratogenic risk with etretinate and acitretin treatment. Dermatology 1994; 189: 109–16PubMedGoogle Scholar
  217. 217.
    Rinck G, Gollnick H, Orfanos CE. Duration of contraception after etretinate. Lancet 1989; II: 845–6Google Scholar
  218. 218.
    Stockton DL, Palier AS. Drug administration to the pregnant or lactating woman: a reference for dermatologists. J Am Acad Dermatol 1990; 23: 87–103PubMedGoogle Scholar
  219. 219.
    Vahlquist A, Rollmann O. Clinical pharmacology of three generations of retinoids. Dermatologica 1987; 175: 20–7PubMedGoogle Scholar
  220. 220.
    Marsden JR. Lipid metabolism and retinoid therapy. Pharmacol Ther 1989; 40: 55–65PubMedGoogle Scholar
  221. 221.
    Fex GA, Aronsson A, Andersson A, et al. In vivo effects of 13-cis retinoic acid treatment on the concentration of proteins and lipids in serum. Eur J Clin Chem Clin Biochem 1996; 34: 3–7PubMedGoogle Scholar
  222. 222.
    Halkier-Sörensen L, Laurberg G, Andersen J. Bone changes in children on long-term treatment with etretinate. J Am Acad Dermatol 1987; 16: 999–1006PubMedGoogle Scholar
  223. 223.
    Orfanos CE. Retinoide: der neue Stand. Erhaltungstherapie, Resorptionsstörungen bei ‘non-responders’, Interaktionen und Interferenzen mit Medikamenten, Behandlung von Kindern und Knochentoxizität, Acitretin und 13-cis-Acitretin. Hautarzt 1989; 40: 123–9PubMedGoogle Scholar
  224. 224.
    Decker MA, Zimmermann CL. Simultaneous determination of etretinate, acitretin and their metabolites in perfusate, perfusate plasma, bile or hepatic tissue with reversed-phase high-performance liquid chromatography. J Chromat B Biomed Appl 1995; 667: 105–13Google Scholar
  225. 225.
    Leenheer De AP, Lambert WE. High-performance liquid Chromatographic determination of etretinate and all-trans- and 13-cis-acitretin in human plasma. J Chromatogr 1990; 500: 637–42Google Scholar
  226. 226.
    Wyss R. Chromatographic and electrophoretic analysis of biomedically important retinoids. J Chromatogr B Biomed Appl 1995; 671: 381–425PubMedGoogle Scholar
  227. 227.
    Jakobsen P. Simultaneous determination of the aromatic retinoids etretin and etretinate and their main metabolites by reversed-phase liquid chromatography. J Chromatogr 1987; 415: 413–8PubMedGoogle Scholar
  228. 228.
    Wyss R, Bucheli F. Quantitative analysis of retinoids in biological fluids by high-performance liquid chromatography using column switching: II. Simultaneous determination of etretinate, acitretin and 13-cis-acitretin in plasma. J Chromatogr B Biomed Appl 1988 431: 297–307Google Scholar
  229. 229.
    Sturkenboom MCJM, de Jong-Van Den Berg LTW, van Voorst-Vader PC, et al. Inability to detect plasma etretinate and acitretin is a poor predictor of the absence of these teratogens in tissue after stopping acitretin treatment. Br J Clin Pharmacol 1994; 38: 229–35PubMedGoogle Scholar
  230. 230.
    Craven NM, Griffiths CEM. Topical retinoids and cutaneous biology. Clin Exp Dermatol 1996; 21: 1–10PubMedGoogle Scholar
  231. 231.
    Griffiths CEM, Voorhees JJ. Human in vivo pharmacology of topical retinoids. Arch Dermatol Res 1994; 287: 53–60PubMedGoogle Scholar
  232. 232.
    Lehmann PA, Malany AM. Evidence for percutaneous absoption of isotretinoin from the photo-isomerization of topical tretinoin. J Invest Dermatol 1989; 93: 595–9Google Scholar
  233. 233.
    Lehmann PA, Slattery JT, Franz TJ. Percutaneous absorption of retinoids: influence of vehicle, light exposure, and dose. J Invest Dermatol 1988; 91: 56–61Google Scholar
  234. 234.
    Schaefer H. Penetration and percutaneous absorption of topical retinoids. Skin Pharmacol 1993; 6 Suppl. 1: 17–23PubMedGoogle Scholar
  235. 235.
    Tavakkol A, Zouboulis ChC, Duell EA, et al. A retinoic acid-inducible skin-specific gene (RIS-1/psoriasin): molecular cloning and analysis of gene expression in human skin in vivo and cultured skin cells in vitro. Mol Biol Rep 1994; 20: 75–83PubMedGoogle Scholar
  236. 236.
    Duell EA, Åström A, Griffiths CEM, et al. Human skin levels of retinoic acid and cytochrome P-450-derived 4-hydroxyretinoic acid after topical application of retinoic acid in vivo compared to concentrations required to stimulate retinoic acid receptor-mediated transcription invitro. J Clin Invest 1992; 90: 1269–74PubMedGoogle Scholar
  237. 237.
    Sanquer S, Gilcherst BA. Characterization of human cellular retinoic acid-binding proteins-I and -II: ligand binding affinities and distribution in skin. Arch Biochem Biophys 1994; 311: 86–94PubMedGoogle Scholar
  238. 238.
    Elder JT, Cromie MA, Griffiths CEM, et al. Stimulus-selective induction of CRABP-II mRNA: a marker for retinoic acid action in human skin. J Invest Dermatol 1993; 100: 356–9PubMedGoogle Scholar
  239. 239.
    Surber C, Laugier JP, Geiger JM, et al. Distribution de l’acitretine dans la peau humaine. Ann Dermatol Venereol 1993; 120: 116–22PubMedGoogle Scholar
  240. 240.
    Lavker RM, Leyden JJ, Thorne EG. An ultrastructural study of the effects of topical tretinoin on microcomedones. Clin Ther 1992; 14: 773–80PubMedGoogle Scholar
  241. 241.
    Melnik B, Kinner T, Plewig G. Influence of oral isotretinoin treatment on the composition of comedonal lipids. Implications for comedogenesis in acne vulgaris. Arch Dermatol Res 1988; 280: 97–102PubMedGoogle Scholar
  242. 242.
    Griffiths CEM, Kang S, Ellis CN, et al. Two concentrations of topical tretinoin (retinoic acid) cause similar improvement of photoaging but different degrees of irritation. Arch Dermatol 1995; 131: 1037–44PubMedGoogle Scholar
  243. 243.
    Olsen EA, Katz HI, Levine N, et al. Tretinoin emollient cream: a new therapy for photodamaged skin. J Am Acad Dermatol 1992; 26: 215–24PubMedGoogle Scholar
  244. 244.
    Sendagorta E, Lesiewicz J, Armstrong RB. Topical isotretinoin for photodamaged skin. J Am Acad Dermatol 1992; 27: S15–18PubMedGoogle Scholar
  245. 245.
    Weinstein GD, Nigra TP, Pochi PE, et al. Topical tretinoin for treatment of photodamaged skin: a multicenter study. Arch Dermatol 1991; 127: 659–65PubMedGoogle Scholar
  246. 246.
    Weiss JS, Ellis CN, Headington JT, et al. Topical tretinoin improves photoaged skin: a double-blind, vehicle-controlled study. JAMA 1988; 159: 527–32Google Scholar
  247. 247.
    Griffiths CEM, Russman AN, Majmudar G, et al. Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid). New Engl J Med 1993; 329: 530–5PubMedGoogle Scholar
  248. 248.
    Woodley DT, Zelickson AS, Briggaman RA, et al. Treatment of photoaged skin with topical tretinoin increases epidermaldermal anchoring fibrils. JAMA 1990; 263: 3057–9PubMedGoogle Scholar
  249. 249.
    Levine N, Kligman AM. A sequential combination of topical tretinoin and a potent topical corticosteroid improves photodamaged facial skin. J Dermatol Treat 1996; 7: 23–7Google Scholar
  250. 250.
    Kligman AM, Dogadkina D, Lavker RM. Effects of topical tretinoin on non-sun-exposed protected skin of the elderly. J Am Acad Dermatol 1993; 29: 25–33PubMedGoogle Scholar
  251. 251.
    Griffiths CEM, Finkel LJ, Ditre CM, et al. Topical tretinoin (retinoic acid) improves melasma in a vehicle-controlled clinical trial. Br J Dermatol 1993; 129: 415–21PubMedGoogle Scholar
  252. 252.
    Bulengo-Ransby SM, Griffiths CEM, Kimbrough-Green CK, et al. Topical tretinoin (retinoic acid) therapy for hyper-pigmented lesions caused by inflammation of the skin of black patients. New Engl J Med 1993; 328: 1438–43PubMedGoogle Scholar
  253. 253.
    Lippman SM, Meyskens FL. Results of the use of vitamin A and retinoids in cutaneous malignancies. Pharmacol Ther 1989; 40: 107–22PubMedGoogle Scholar
  254. 254.
    Kubeyinje EP. Evaluation of the efficacy and safety of 0.05% tretinoin cream in the treatment of plane warts in Arab children. J Dermatol Treat 1996; 7: 21–2Google Scholar
  255. 255.
    Ehlert R, Orfanos CE. Lokale Anwendung von Vitamin-A-Säure bei chronischer aktinischer Cheilitis. Hautarzt 1989; 40: 728PubMedGoogle Scholar
  256. 256.
    Kang S, Kim KJ, Griffiths CEM, et al. Topical tretinoin (retinoic acid) improves early stretch marks. Arch Dermatol 1996; 132: 519–26PubMedGoogle Scholar
  257. 257.
    Buchan P, Eckhoff C, Caron D, et al. Repeated topical administration of all-trans-retinoic acid and plasma levels of retinoic acids in humans. J Am Acad Dermatol 1994; 30: 428–34PubMedGoogle Scholar
  258. 258.
    Nau H. Embryotoxicity and teratogenicity of topical retinoic acid. Skin Pharmacol 1993; 3 Suppl.: 35–44Google Scholar
  259. 259.
    Griffiths CEM, Elder JT, Bernard BA, et al. Comparison of CD 271 (adapalene) and all-trans retinoic acid in human skin: dissociation of epidermal effects and CRABP II mRNA expression. J Invest Dermatol 1993; 101: 325–8PubMedGoogle Scholar
  260. 260.
    Tsambaos D, Orfanos CE. Arotinoid: a new potent oral retinoid. Preliminary results. In Farber, et al., editors. Psoriasis. New York: Grune & Stratton, 1982: 515–20Google Scholar
  261. 261.
    Tsambaos D, Orfanos CE. Antipsoriatic activity of a new synthetic retinoid: the arotinoid Ro 13-6298. Arch Dermatol 1983; 119: 746–51PubMedGoogle Scholar
  262. 262.
    Brogden RN, Goa KL. Adapalene: a review of its pharmacological properties and clinical potential in the management of mild to moderate acne. Drugs 1997 Mar; 53(3): 511–9PubMedGoogle Scholar

Copyright information

© Adis International Limited 1997

Authors and Affiliations

  • Constantin E. Orfanos
    • 1
  • Christos C. Zouboulis
    • 1
  • Brigitte Almond-Roesler
    • 1
  • Christoph C. Geilen
    • 1
  1. 1.Department of DermatologyUniversity Medical Center Benjamin Franklin, The Free University of BerlinBerlinGermany

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