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Accutane: Thoughts and Ramblings

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May 2, 2008

Accutane: Thoughts and Ramblings

  1. Lowell A. Goldsmith, MD, MPH

A thorny question about optimization testing of 13-cis retinoic acid for acne therapy

  1. Lowell A. Goldsmith, MD, MPH

The Journal of Clinical Investigation recently published the results of an important clinical study on the mechanism of action of 13-cis retinoic acid in acne therapy. Of equal importance to the study’s scientific value is the question it raises of whether clinical research into the treatment of severe acne is stagnating.

First the facts: Investigators analyzed biopsy samples of the back skin of six patients receiving 0.50 or 0.67 mg/kg/day of 13-cis retinoic acid for severe acne; skin was biopsied before treatment and 1 week after the start of therapy. A reduction in the size of the sebaceous glands was of borderline significance (P=0.16), but apoptosis increased markedly in sebaceous cells (and not in epidermal cells). Using gene arrays, with data confirmed by real-time PCR, the investigators noted a sevenfold increase in message RNA for the lipocalin-2 gene (LCN2), which encodes the protein NGAL (neutrophil gelatinase–associated lipocalin) in the sebaceous glands and increases NGAL protein in sebocytes. NGAL initiates apoptosis in cultured sebocytes, and in vitro, LCN2-induced changes can be abrogated by siRNA for LCN2.

Comment

Let’s take as a given that oral 13-cis retinoic acid is a very effective treatment for severe cystic acne. I suggest that little is being done to optimize its clinical use. If apoptosis in the sebaceous glands eliminates sebaceous stem cells, or follicle cells that are sebaceous gland precursors, or both, this action could be the basis for 13-cis retinoic acid’s long-term effects. Better clinical optimization of 13-cis retinoic acid is needed, but how will it be possible in the current climate for clinical research and the I-Pledge program? The several manufacturers of 13-cis retinoic acid are unlikely to fund serious studies; they will be satisfied with the 5-month courses of therapy currently in use. If apoptosis is the key mechanism, serial studies to determine both optimum treatment duration and dose for inducing apoptosis would be important. The trials reported were short, and the doses were less than 1 mg/kg/day. Might quick bursts at higher dosages lead to much-shorter courses? Are inadequate doses necessitating more-prolonged treatment or repeated courses of therapy? Could other drugs potentiate the pro-apoptotic effect of 13-cis retinoic acid? Any changes in treatment regimens would have to address safety concerns.

Therapy using 13-cis retinoic acid still needs rational, mechanistically based dosing. If investigators do not continue to obtain more data from consciously planned and conscientiously performed tests of hypotheses, the old cookbook method will be the default approach. This problem surely arises elsewhere, and drugs other than 13-cis retinoic acid have protocols that have been optimized for FDA approval but not for maximal efficacy.

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