Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects.
BACKGROUND
Phosphodiesterase 4 (PDE4) inhibitors increase intracellular cyclic adenosine monophosphate (cAMP), leading to regulation of inflammatory cell functions. Roflumilast is a potent and targeted PDE4 inhibitor. The objective of this study was to evaluate the effects of roflumilast on bronchoconstriction, airway hyperresponsiveness (AHR), and airway inflammation in mild asthmatic patients undergoing allergen inhalation challenge.


METHODS
25 subjects with mild allergic asthma were randomized to oral roflumilast 500 mcg or placebo, once daily for 14 days in a double-blind, placebo-controlled, crossover study. Allergen challenge was performed on Day 14, and FEV1 was measured until 7 h post challenge. Methacholine challenge was performed on Days 1 (pre-dose), 13 (24 h pre-allergen), and 15 (24 h post-allergen), and sputum induction was performed on Days 1, 13, 14 (7 h post-allergen), and 15.


RESULTS
Roflumilast inhibited the allergen-induced late phase response compared to placebo; maximum % fall in FEV1 (p = 0.02) and the area under the curve (p = 0.01). Roflumilast had a more impressive effect inhibiting allergen-induced sputum eosinophils, neutrophils, and eosinophil cationic protein (ECP) at 7 h post-allergen (all p = 0.02), and sputum neutrophils (p = 0.04), ECP (p = 0.02), neutrophil elastase (p = 0.0001) and AHR (p = 0.004) at 24 h post-allergen.


CONCLUSIONS
This study demonstrates a protective effect of roflumilast on allergen-induced airway inflammation. The observed attenuation of sputum eosinophils and neutrophils demonstrates the anti-inflammatory properties of PDE4 inhibition and supports the roles of both cell types in the development of late phase bronchoconstriction and AHR.


BACKGROUND
ClinicalTrials.gov: NCT01365533.
Department of Medicine, McMaster University, Hamilton, Ontario, Canada. gauvreau@mcmaster.ca
Gail M
GM
Gauvreau
Louis-Philippe
LP
Boulet
Christine
C
Schmid-Wirlitsch
Johanne
J
Côté
Mylinh
M
Duong
Kieran J
KJ
Killian
Joanne
J
Milot
Francine
F
Deschesnes
Tara
T
Strinich
Richard M
RM
Watson
Dirk
D
Bredenbröker
Paul M
PM
O'Byrne
D000293:Adolescent; D000328:Adult; D000485:Allergens / Q000633:toxicity*; D000631:Aminopyridines / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D001549:Benzamides / Q000627:therapeutic use*; D018592:Cross-Over Studies; D003521:Cyclopropanes / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D058988:Phosphodiesterase 4 Inhibitors / Q000627:therapeutic use*; D011014:Pneumonia / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D011657:Pulmonary Eosinophilia / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D055815:Young Adult
D000485:Allergens; D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; C424423:Roflumilast