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Am. J. Respir. Crit. Care Med., Volume 165, Number 5, March 2002, 718-723

A Pilot Study of All-trans-Retinoic Acid for the Treatment of Human Emphysema

JENNY T. MAO, JONATHAN G. GOLDIN, JOHN DERMAND, GRACE IBRAHIM, MATHEW S. BROWN, ALETHA EMERICK, MICHAEL F. MCNITT-GRAY, DAVID W. GJERTSON, FRANCINE ESTRADA, DONALD P. TASHKIN, and MICHAEL D. ROTH

Pulmonary and Critical Care Medicine, Radiologic Sciences, and the Department of Pathology and Laboratory Medicine, UCLA School of Medicine, Los Angeles, California

Emphysema results from progressive destruction of alveolar septae and was considered irreversible until all-trans-retinoic acid (ATRA) was shown to reverse anatomic and physiologic signs of emphysema in a rat model. To evaluate the feasibility of ATRA as a clinical therapy, 20 patients with severe emphysema were enrolled into a randomized, double-blind, placebo-controlled pilot study. Participants included 16 male and 4 female former smokers, two with alpha 1-antitrypsin deficiency. Patients were treated with either 3 mo of ATRA (50 mg/m2/d) or 3 mo of placebo, followed by a 3-mo crossover phase. Plasma drug levels were followed and outcome measures included serial pulmonary function tests, blood gases, lung compliance, computed tomography (CT) imaging, and quality of life questionnaires. In general, treatment was well tolerated and associated with only mild side effects including skin changes, transient headache, hyperlipidemia, transaminites, and musculoskeletal pains. Plasma drug levels varied considerably between subjects and decreased significantly over time in 35% of the participants. Physiologic and CT measurements did not change appreciably in response to therapy. We conclude that ATRA is well tolerated in patients with emphysema, and trials evaluating higher doses, longer treatment, or different dosing schedules are feasible.




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