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Retinoids at a Glance
  • The biologic functions and actions of retinoids (excluding vision) include:
    • Reproduction, embryonic growth, and morphogenesis.
    • Modulation of proliferation and differentiation of epithelia.
    • Decrease in sebaceous gland size (isotretinoin).
    • Immunologic and anti-inflammatory effects.
    • Tumor prevention and treatment.
    • Effect on extracellular matrix components.
  • Four types of oral retinoids and the major indications for their use are isotretinoin (acne), alitretinoin (chronic hand eczema), acitretin/etretinate (psoriasis, keratinizing disorders), and bexarotene (cutaneous T-cell lymphoma). Contraindications to their use include pregnancy, breastfeeding, and nonadherence to contraceptive regimen. Retinoids should always be taken with food or milk to enhance intestinal absorption. Dosing once a day is usually sufficient.
  • Mucocutaneous side effects (cheilitis, xerosis, skin peeling, conjunctivitis) are common, as are reversible abnormal results on laboratory tests [hyperlipidemia, increased liver enzyme levels, and hypothyroidism (bexarotene)]. Musculoskeletal and central nervous system side effects are rare.

Retinoids include both naturally occurring molecules and synthetic compounds that have specific biologic activities that resemble those of vitamin A or bind to the nuclear receptors for retinoids. Vitamin A from natural sources was already being used in the 1930s in high dosages to treat certain hyperkeratotic diseases, often with toxic side effects. Three generations of synthetic retinoids have since been developed (Fig. 228-1).

Figure 228-1

Chemical structure of three generations of retinoids. Isotretinoin is first generation; in second-generation (e.g., acitretin) the β-ionone ring, is replaced with an aromatic structure. Bexarotene is an example of a third-generation retinoid.

First generation: All-trans-retinoic acid (tretinoin, ATRA), a naturally occurring metabolite of retinol, was the first retinoid synthesized but had no significant advantages over vitamin A in treatment of dermatologic diseases. It is used as a differentiation-inducing agent to treat acute promyelocytic leukemia.

Isotretinoin (13-cis-retinoic acid), clinically available since the 1970s, was found to cause prolonged remissions in patients with previously treatment-resistant cystic acne [it has been approved by the US Food and Drug Administration (FDA) for this indication since 1982].1

The latest approved systemic retinoid is alitretinoin (9-cis-retinoic acid), which is approved in several European countries and Canada for treatment of chronic hand eczema.

Second generation: Through replacement of the β-ionone ring in ATRA with an aromatic structure, newer retinoids with better therapeutic margins were synthesized in the 1970s. Etretinate and its free acid metabolite, acitretin, showed a therapeutic index ten times more favorable than that of ATRA. Etretinate (approved in Europe 1983 and by the FDA in 1987) and acitretin (approved 1987 and 1997, respectively) became a standard treatment for psoriasis. Acitretin has replaced etretinate in most countries, but not in Japan and a few other countries.

Third generation: The discovery of retinoic acid receptors (RARs)2,3 allowed research directed toward receptor-specific, third-generation retinoids with a safer ...

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