Summary
With the introduction of the synthetic retinoids, oral therapy with an acceptable risk/ benefit ratio became possible for a variety of skin diseases including severe acne, psoriasis and numerous genodermatoses. This article reviews the clinical pharmacology, mechanisms of action and therapeutic use of the retinoids, particularly isotretinoin (13-cis-retinoic acid) and etretinate. The free aromatic acid of etretinate, etretin, and the new polyaromatic retinoid compounds (arotinoids) are also discussed.
Isotretinoin is used clinically for oral therapy of severe acne, but is also recommended for severe Gram- negative folliculitis and rosacea not responding to traditional therapy. The results of several studies have established that acne therapy should be started with 1.0 mg/kg/day for 2 to 3 months after which the daily dosage should be lowered to 0.2 to 0.5 mg/kg/day for another 2 to 3 months. This therapeutic regimen of isotretinoin has proven to be the most successful in preventing relapses.
Etretinate is particularly useful for oral therapy of widespread plaque- like, pustular and erythrodermic psoriasis, and of generalised lichen planus, Darier’s disease and severe congenital ichthyoses. Whereas pustular forms of psoriasis require a high daily dosage of 1.0 mg/kg/day, erythrodermic psoriasis should be treated with a lower dosage of 0.25 to 0.35 mg/kg/day. In chronic plaque- like psoriasis, a mean daily dosage of 0.5 mg/kg/day over several weeks to months, usually combined with photo(chemo)therapy, tar or dithranol, is recommended. Other indications for oral etretinate therapy are adequately treated with a moderate dosage of 0.4 to 0.75 mg/kg/day.
Etretin differs from etretinate in having a much shorter elimination half- life of 2 to 3 days, in contrast to 80 to 100 days after long term administration of etretinate. Moreover, it has not been shown to increase serum cholesterol levels. However, its clinical efficacy is not yet clearly established.
Among the arotinoids, arotinoid ethylester (Ro 13- 6298) has revealed the best anti- psoriatic and anti- inflammatory effects at extremely low dose levels. Furthermore, no significant elevations of serum lipids have been observed. Taking its prolonged elimination half- life and its efficacy/side effect ratio into account, the drug is comparable to etretinate. The free arotinoid carboxylic acid (Ro 13- 7410) is currently undergoing clinical investigation.
Another arotinoid, the parent compound Ro 15- 0778, has not demonstrated any convincing clinical efficacy in acne or psoriasis, but topical anti- inflammatory effects were evident in some models. Experimental studies in animals have not demonstrated any bone toxicity, suggesting that arotinoid sulphone (Ro 15- 1570) may be the first polyaromatic retinoid with the potential for not causing adverse effects on the skeletal system. Preliminary results have demonstrated some antipsoriatic efficacy when applied topically.
Among other synthetic retinoids tested clinically for topical use, only motretinide has shown similar therapeutic results in acne when compared with tretinoin. Due to its chemical instability to ultraviolet light, the topical application of isotretinoin in acne was therapeutically not clearly successful.
Oral therapy with the retinoids causes a variety of mostly tolerable and reversible mucocutaneous side effects; however, their use requires careful laboratory and clinical monitoring of each patient. In particular, bone toxicity, serum lipid elevations, dysmorphogenicity and embryotoxicity are the most unacceptable adverse effects of the synthetic retinoids.
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Orfanos, C.E., Ehlert, R. & Gollnick, H. The Retinoids. Drugs 34, 459–503 (1987). https://doi.org/10.2165/00003495-198734040-00003
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DOI: https://doi.org/10.2165/00003495-198734040-00003