Abstract
<h4>Rationale</h4>Patients with asthma demonstrate depletion of the endogenous bronchodilator
GSNO and upregulation of GSNOR.<h4>Objectives</h4>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.<h4>Methods</h4>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.<h4>Measurements
and main results</h4>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 < 0.05) over the 7-day observation
period. Furthermore, a significant treatment effect was observed in the change in
PC<sub>20</sub> FEV1 from baseline averaged over the 7-day observation period (mean
change: +0.82 mg/ml [N6022] from 1.34 mg/ml [baseline] vs -0.18 mg/ml [placebo] from
1.16 mg/ml [baseline], P = 0.023). N6022 was well tolerated in mild asthmatics. In
vitro studies demonstrated enhanced eosinophilic apoptosis with N6022.<h4>Conclusions</h4>In
this early phase exploratory proof of concept trial in asthma, N6022 did not significantly
alter methacholine PC20 FEV1 at 24 h, but did have a treatment effect at 7 days compared to baseline. Further
investigation of the efficacy of S-nitrosoglutathione reductase inhibition in a patient
population with eosinophilic asthma is warranted.
Published Version (Please cite this version)
10.1002/iid3.220
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