Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD.
BACKGROUND
Roflumilast is a targeted oral once-daily administered phosphodiesterase 4 (PDE4) inhibitor with clinical efficacy in chronic obstructive pulmonary disease (COPD). Results from in vitro studies with roflumilast indicate that it has anti-inflammatory properties that may be applicable for the treatment of COPD.


METHODS
In a crossover study, 38 patients with COPD (mean (SD) age 63.1 (7.0) years, post-bronchodilator forced expiratory volume in 1 s (FEV(1)) 61.0 (12.6)% predicted) received 500 microg roflumilast or placebo once daily for 4 weeks. Induced sputum samples were collected before and after 2 and 4 weeks of treatment. Differential and absolute cell counts were determined in whole sputum samples. Markers of inflammation were determined in sputum supernatants and blood. Spirometry was performed weekly.


RESULTS
Roflumilast significantly reduced the absolute number of neutrophils and eosinophils/g sputum compared with placebo by 35.5% (95% CI 15.6% to 50.7%; p = 0.002) and 50.0% (95% CI 26.8% to 65.8%; p<0.001), respectively. The relative proportion of sputum neutrophils and eosinophils was not affected by treatment (p>0.05). Levels of soluble interleukin-8, neutrophil elastase, eosinophil cationic protein and alpha(2)-macroglobulin in sputum and the release of tumour necrosis factor alpha from blood cells were significantly reduced by roflumilast compared with placebo treatment (p<0.05 for all). Post-bronchodilator FEV(1) improved significantly during roflumilast compared with placebo treatment with a mean difference between treatments of 68.7 ml (95% CI 12.9 to 124.5; p = 0.018).


CONCLUSIONS
PDE4 inhibition by roflumilast treatment for 4 weeks reduced the number of neutrophils and eosinophils, as well as soluble markers of neutrophilic and eosinophilic inflammatory activity in induced sputum samples of patients with COPD. This anti-inflammatory effect may in part explain the concomitant improvement in post-bronchodilator FEV(1).
Grootendorst
Diana C
DC
Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands. d.c.Grootendorst@lumc.nl
Gauw
Stefanie A
SA
Verhoosel
Renate M
RM
Sterk
Peter J
PJ
Hospers
Jeannette J
JJ
Bredenbröker
Dirk
D
Bethke
Thomas D
TD
Hiemstra
Pieter S
PS
Rabe
Klaus F
KF
D000368:Aged; D000631:Aminopyridines / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002452:Cell Count; D018592:Cross-Over Studies; D003521:Cyclopropanes / Q000627:therapeutic use; D004311:Double-Blind Method; D004804:Eosinophils; D005260:Female; D005541:Forced Expiratory Volume / Q000502:physiology; D006801:Humans; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D009504:Neutrophils; D058988:Phosphodiesterase 4 Inhibitors; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000473:pathology; D013183:Sputum / Q000166:cytology*
D000631:Aminopyridines; D001549:Benzamides; D015415:Biomarkers; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; C424423:Roflumilast