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

Abstract

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Objectives: The aim of this study was to explore the anti-inflammatory properties of roflumilast in a human model of segmental bronchial endotoxin challenge. A c c e p t e d m a n u s c r i p tMethods: In a randomized, placebo-controlled, double-blind, single-center parallelgroup study, 37 healthy subjects of either sex were treated for 28 days with either oral roflumilast 500 µg 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 24 h, 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. (Word count: 240 words)

Differential Inflammatory Response to Inhaled Lipopolysaccharide Targeted Either to the Airways or the Alveoli in Man

“…A novel human airway inflammation study limiting LPS challenge to the airways used segmental endotoxin challenge in healthy subjects during bronchoscopy [27]. This model gives limited systemic but only local inflammatory responses and is invasive to the subjects.…”

PDE4-inhibitors: A novel, targeted therapy for obstructive airways disease

“…The mortality due to COPD was similar in both treatment-arms in both studies The mechanism of the improvements in lung function, exacerbation rates and quality of life scores cannot be attributed to a direct bronchodilating action of this drug class, as we have previously discussed for cilomilast. It is more likely that these beneficial actions are secondary to an anti-inflammatory activity of roflumilast, although the reduction in pro-inflammatory cell numbers found in two other studies was modest, reflecting a 30-50% suppression of inflammatory cell numbers [43,44] and reduced the number of airway CD8+ T lymphocytes and CD68+ macrophages by approximately 40-50% [30]. Other evidence of an anti-inflammatory mechanism stems from in vitro studies which reported that cilomilast reduced the level of TNF-alpha (25% decrease), GMCSF (46% decrease) and neutrophil chemotactic factors (35% decrease) with no effect on IL-8 released by epithelial cells from COPD patients [45].…”

Design, Synthesis and Biological Evaluation of Novel Quinazoline-Based Anti-inflammatory Agents Acting as PDE4B Inhibitors

“…[14][15][16][17][18] A breakthrough of PDE4 inhibitors as anti-inflammatory agents came up with second generation Roflumilast (3) Dexas ® by Merck Sharp & Dohme, a selective, long-acting inhibitor of the enzyme PDE4B. [19][20][21][22] Continuous efforts in this era lead to the discovery of Cilomilast (4) Ariflo ® , the most advanced PDE4 inhibitor developed by GSK. 10) Many quinoline based PDE4B inhibitors were also reported in literature among which SCH 351591(5) and SCH 365351 (6).…”