Systemic and topical drugs for aging skin

Journal of Drugs in Dermatology, August, 2003 by Michael Kockaert, Martino Neumann

There is still no consensus about the dose of tretinoin that offers maximal therapeutic effects with minimal toxicities. The global effects of topical retinoids on sundamaged and intrinsically (chronologically) aged skin are concentration-dependent. It is clear that a concentration of 0.05% tretinoin significantly decreases photodamage, and therefore this concentration is most commonly used in clinical trials. A concentration of 0.025% has the same effects on the fine wrinkles and roughness and produces less irritation, but requires a longer period of time in order to achieve clinical efficacy. A concentration of 0.1% was used in a study for the treatment of actinic keratoses with good results (5). A concentration of less than 0.01% tretinoin is not effective on sundamaged skin.

In general, it is recommended that patients start applying tretinoin 0.025% every other evening. When the patient demonstrates tolerance, the concentration can be increased to 0.05% and the frequency to every night. Nightly application should be continued for one year; lifelong maintenance therapy with 2-3 applications a week is generally sufficient thereafter (10,11). The response to topical retinoids varies based on genetic factors, the degree of photodamage, individual skin quality, and the concentration of retinoids.

Oral isotretinoin (13-cis RA) is also effective for photodamaged skin. As isotretinoin does not bind the retinoid receptors, it is thought that this retinoid is effective only after it is metabolized into tretinoin, its active form.

To reduce the side effect of retinoid dermatitis, there has been increased interest in evaluating pro-drugs such as retinol (ROL), retinaldehyde (RAL), and retinyl palmitate (RYL). Kang et al. studied the effects of retinol on volunteers, where ROL was applied to the skin under occlusion. The same histological effects seen in patients treated with tretinoin were seen in patients treated with ROE, but these patients did not develop cutaneous side effects such as erythema, burning, and scaling. ROL at a concentration of 1.6% was found to have the same effects as 0.025% tretinoin (7). Although ROL itself is 20-fold less effective than tretinoin, it is metabolized to tretinoin in the skin. However, the overall cutaneous concentration of tretinoin is 1000-fold less with topically applied ROL than with topically applied tretinoin, avoiding non-specific cutaneous toxicities while preserving a supply of tretinoin to the nucleus of keratinocytes (6,12).

Topical RAL activates CRABP-II in the same way as tretinoin does. Vitamin A esters (such as RYL palmitate) in a dose of 2000 to 5000 IE/ml effectively promote elastin regeneration and thickening of the nucleated epidermis, without causing irritation (13).

Retinoids are also effective in the treatment of aged skin without significant sun damage. An explanation for this could be that chronologically aged skin contains fewer retinoids. New studies are required to further investigate this issue.

Systemic Retinoids