Roflumilast attenuates pulmonary inflammation upon segmental endotoxin challenge in healthy subjects: A randomized placebo-controlled trial

RATIONALE: 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. OBJECTIVES: 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 500mug once daily or placebo. At day 29, a baseline bronchoalveolar lavage was performed, followed by segmental endotoxin challenge (4ng/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.