Open AccessEffect of the S ‐nitrosoglutathione reductase inhibitor N6022 on bronchial hyperreactivity in asthma
Author(s) -
Que Loretta G.,
Yang Zhonghui,
Lugogo Njira L.,
Katial Rohit K.,
Shoemaker Steven A.,
Troha Janice M.,
Rodman David M.,
Tighe Robert M.,
Kraft Monica
Publication year - 2018
Publication title -
immunity, inflammation and disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 18
ISSN - 2050-4527
DOI - 10.1002/iid3.220
Subject(s) - methacholine , placebo , asthma , medicine , crossover study , bronchial hyperresponsiveness , bronchodilator , anesthesia , pharmacology , respiratory disease , pathology , lung , alternative medicine
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 PC 20 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 PC 20 FEV1 at 24 h. However, our exploratory analysis demonstrated significantly more two dose‐doubling increases in PC 20 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 20 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. Conclusions In this early phase exploratory proof of concept trial in asthma, N6022 did not significantly alter methacholine PC 20 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.