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Feasibility of Retinoids for the Treatment of Emphysema Study

2006; Elsevier BV; Volume: 130; Issue: 5 Linguagem: Inglês

10.1378/chest.130.5.1334

1931-3543

Michael D. Roth, John E. Connett, Jeanine D’Armiento, Robert Foronjy, Paul J. Friedman, Jonathan Goldin, Thomas A. Louis, Jenny T. Mao, Josephia R. Muindi, George O'connor, Joe Ramsdell, Andrew L. Ries, Steven M. Scharf, Neil W. Schluger, Frank C. Sciurba, M.A. Skeans, Robert Walter, Christine Wendt, Robert A. Wise,

Heme Oxygenase-1 and Carbon Monoxide

Background Retinoids promote alveolar septation in the developing lung and stimulate alveolar repair in some animal models of emphysema. Methods One hundred forty-eight subjects with moderate-to-severe COPD and a primary component of emphysema, defined by diffusing capacity of the lung for carbon monoxide (Dlco) [37.1 ± 12.0% of predicted] and CT density mask (38.5 ± 12.8% of voxels <− 910 Hounsfield units) [mean ± SD] were enrolled into a randomized, double-blind, feasibility study at five university hospitals. Participants received all-trans retinoic acid (ATRA) at either a low dose (LD) [1 mg/kg/d] or high dose (HD) [2 mg/kg/d], 13-cis retinoic acid (13-cRA) [1 mg/kg/d], or placebo for 6 months followed by a 3-month crossover period. Results No treatment was associated with an overall improvement in pulmonary function, CT density mask score, or health-related quality of life (QOL) at the end of 6 months. However, time-dependent changes in Dlco (initial decrease with delayed recovery) and St. George Respiratory Questionnaire (delayed improvement) were observed in the HD-ATRA cohort and correlated with plasma drug levels. In addition, 5 of 25 participants in the HD-ATRA group had delayed improvements in their CT scores that also related to ATRA levels. Retinoid-related side effects were common but generally mild. Conclusions No definitive clinical benefits related to the administration of retinoids were observed in this feasibility study. However, time- and dose-dependent changes in Dlco, CT density mask score, and health-related QOL were observed in subjects treated with ATRA, suggesting the possibility of exposure-related biological activity that warrants further investigation. Retinoids promote alveolar septation in the developing lung and stimulate alveolar repair in some animal models of emphysema. One hundred forty-eight subjects with moderate-to-severe COPD and a primary component of emphysema, defined by diffusing capacity of the lung for carbon monoxide (Dlco) [37.1 ± 12.0% of predicted] and CT density mask (38.5 ± 12.8% of voxels <− 910 Hounsfield units) [mean ± SD] were enrolled into a randomized, double-blind, feasibility study at five university hospitals. Participants received all-trans retinoic acid (ATRA) at either a low dose (LD) [1 mg/kg/d] or high dose (HD) [2 mg/kg/d], 13-cis retinoic acid (13-cRA) [1 mg/kg/d], or placebo for 6 months followed by a 3-month crossover period. No treatment was associated with an overall improvement in pulmonary function, CT density mask score, or health-related quality of life (QOL) at the end of 6 months. However, time-dependent changes in Dlco (initial decrease with delayed recovery) and St. George Respiratory Questionnaire (delayed improvement) were observed in the HD-ATRA cohort and correlated with plasma drug levels. In addition, 5 of 25 participants in the HD-ATRA group had delayed improvements in their CT scores that also related to ATRA levels. Retinoid-related side effects were common but generally mild. No definitive clinical benefits related to the administration of retinoids were observed in this feasibility study. However, time- and dose-dependent changes in Dlco, CT density mask score, and health-related QOL were observed in subjects treated with ATRA, suggesting the possibility of exposure-related biological activity that warrants further investigation.