Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjectsReport as inadecuate




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Respiratory Research

, 12:140

First Online: 01 December 2011Received: 01 September 2011Accepted: 26 October 2011

Abstract

BackgroundPhosphodiesterase 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.

Methods25 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.

ResultsRoflumilast 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.

ConclusionsThis 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.

Trial RegistrationClinicalTrials.gov: NCT01365533

KeywordsAllergic asthma allergen challenge PDE4 inhibitor inflammation sputum neutrophils eosinophils List of abbreviationsAEadverse event

AHRairway hyperresponsiveness

AUCarea under the curve

cAMPcyclic adenosine monophosphate

cGMPcyclic guanosine monophosphate

COPDchronic obstructive pulmonary disease

EARearly asthmatic response

ECPeosinophil cationic protein

FEV1forced expiratory volume in one second

ILinterleukin

LARlate asthmatic response

MCCmetachromatic cells

PC20The provocative concentration of methacholine causing a 20% fall in FEV1

PDE4phosphodiesterase 4

PKpharmacokinetics

SEMstandard error of the mean.

Electronic supplementary materialThe online version of this article doi:10.1186-1465-9921-12-140 contains supplementary material, which is available to authorized users.

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Author: Gail M Gauvreau - Louis-Philippe Boulet - Christine Schmid-Wirlitsch - Johanne Côté - MyLinh Duong - Kieran J Killian -

Source: https://link.springer.com/







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