Roflumilast attenuates pulmonary inflammation upon segmental endotoxin challenge in healthy subjects: a randomized placebo-controlled trial.
BACKGROUND
Roflumilast, an investigational, targeted phosphodiesterase 4 inhibitor, reduces the in vitro and in vivo inflammatory activity of cells such as neutrophils, eosinophils, macrophages, and monocytes.


OBJECTIVE
The aim of this study was to explore the anti-inflammatory properties of roflumilast in a human model of segmental bronchial endotoxin challenge.


METHODS
In a randomized, placebo-controlled, double-blind, single-center parallel-group study, 37 healthy subjects of either sex were treated for 28 days with either oral roflumilast 500 microg once daily or placebo. At day 29, a baseline bronchoalveolar lavage was performed, followed by segmental endotoxin challenge (4 ng/kg) and saline control challenge. After 24h, bronchoalveolar lavage fluid was sampled from the challenged segments and cells were counted and differentiated.


RESULTS
After endotoxin challenge, influx of total cells (difference from baseline) in bronchoalveolar lavage of roflumilast-treated subjects was 36% lower than with placebo (p=0.02). Correspondingly, the influx of neutrophils and eosinophils of roflumilast-treated subjects was 39% (p=0.02) and 74% (p=0.01) lower than with placebo, respectively. In contrast, endotoxin-induced influx of monocytes was not different between roflumilast- and placebo-treated subjects. No significant differences existed between the groups pertaining to endotoxin-induced influx of macrophages and lymphocytes. Roflumilast was well tolerated. No unexpected or serious treatment-emergent signs and symptoms were observed.


CONCLUSIONS
Roflumilast attenuated the endotoxin-induced influx of neutrophils and eosinophils into the airways. This study demonstrates the anti-inflammatory properties of roflumilast on bronchoalveolar granulocytes in endotoxin-induced airway inflammation in healthy subjects.
Hohlfeld
Jens M
JM
Department of Clinical Airway Research, Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM), Nikolai-Fuchs-Street 1A, D-30625 Hannover, Germany. hohlfeld@item.fraunhofer.de
Schoenfeld
Kerstin
K
Lavae-Mokhtari
Mehyar
M
Schaumann
Frank
F
Mueller
Meike
M
Bredenbroeker
Dirk
D
Krug
Norbert
N
Hermann
Robert
R
D000284:Administration, Oral; D000328:Adult; D000631:Aminopyridines / Q000009:adverse effects / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000494:pharmacology*; D001549:Benzamides / Q000009:adverse effects / Q000494:pharmacology*; D018893:Bronchoalveolar Lavage; D003521:Cyclopropanes / Q000009:adverse effects / Q000494:pharmacology; D004731:Endotoxins; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D055815:Young Adult
D000631:Aminopyridines; D000893:Anti-Inflammatory Agents; D001549:Benzamides; D003521:Cyclopropanes; D004731:Endotoxins; D010726:Phosphodiesterase Inhibitors; C424423:Roflumilast