Effect of the S-nitrosoglutathione reductase inhibitor N6022 on bronchial hyperreactivity in asthma.

ABSTRACT: RATIONALE:Patients with asthma demonstrate depletion of the endogenous bronchodilator GSNO and upregulation of GSNOR. OBJECTIVES:An exploratory proof of concept clinical study of N6022 in mild asthma to determine the potential bronchoprotective effects of GSNOR inhibition. Mechanistic studies aimed to provide translational evidence of effect. METHODS:Fourteen mild asthma patients were treated with intravenous N6022 (5?mg) or placebo and observed for 7 days, with repeated assessments of the provocative dose of methacholine causing a 20% fall in FEV1 (methacholine PC20 FEV1), followed by a washout period and crossover treatment and observation. In vitro studies in isolated eosinophils investigated the effect of GSNO and N6022 on apoptosis. MEASUREMENTS AND MAIN RESULTS:This was a negative trial as it failed to reach its primary endpoint, which was change from baseline in methacholine PC20 FEV1 at 24?h. However, our exploratory analysis demonstrated significantly more two dose-doubling increases in PC20 FEV1 for N6022 compared with placebo (21% vs 6%, P?

SUBMITTER: Que LG 

PROVIDER: S-EPMC5946144 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature