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

Pulm Pharmacol Ther. 2008 Aug;21(4):616-23. doi: 10.1016/j.pupt.2008.02.002. Epub 2008 Feb 21.

Abstract

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 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aminopyridines / adverse effects
  • Aminopyridines / pharmacology*
  • Anti-Inflammatory Agents / adverse effects
  • Anti-Inflammatory Agents / pharmacology*
  • Benzamides / adverse effects
  • Benzamides / pharmacology*
  • Bronchoalveolar Lavage
  • Cyclopropanes / adverse effects
  • Cyclopropanes / pharmacology
  • Endotoxins
  • Eosinophils / drug effects
  • Eosinophils / metabolism
  • Female
  • Humans
  • Inflammation / drug therapy
  • Inflammation / pathology
  • Lung / drug effects*
  • Lung / pathology
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Phosphodiesterase Inhibitors / adverse effects
  • Phosphodiesterase Inhibitors / pharmacology*
  • Young Adult

Substances

  • Aminopyridines
  • Anti-Inflammatory Agents
  • Benzamides
  • Cyclopropanes
  • Endotoxins
  • Phosphodiesterase Inhibitors
  • Roflumilast