Feasibility of retinoids for the treatment of emphysema study.
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.
Roth
Michael D
MD
Division of Pulmonary and Critical Care, University of California, Los Angeles, CA 90095-1690, USA. mroth@mednet.ucle.edu
Connett
John E
JE
D'Armiento
Jeanine M
JM
Foronjy
Robert F
RF
Friedman
Paul J
PJ
Goldin
Jonathan G
JG
Louis
Thomas A
TA
Mao
Jenny T
JT
Muindi
Josephia R
JR
O'Connor
George T
GT
Ramsdell
Joe W
JW
Ries
Andrew L
AL
Scharf
Steven M
SM
Schluger
Neil W
NW
Sciurba
Frank C
FC
Skeans
Melissa A
MA
Walter
Robert E
RE
Wendt
Christine H
CH
Wise
Robert A
RA
D000368:Aged; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004646:Emphysema / Q000000981:diagnostic imaging / Q000188:drug therapy*; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D015474:Isotretinoin / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D007641:Keratolytic Agents / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D012129:Respiratory Function Tests; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014212:Tretinoin / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*
D007641:Keratolytic Agents; D014212:Tretinoin; D015474:Isotretinoin