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Effect of the S-nitrosoglutathione reductase inhibitor N6022 on bronchial hyperreactivity in asthma.
Immun Inflamm Dis. 2018 06; 6(2):322-331.II

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 < 0.05) over the 7-day observation period. Furthermore, a significant treatment effect was observed in the change in PC20 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 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.

Authors+Show Affiliations

Departmentof Medicine, Duke University Health System, Durham, North Carolina, USA.Departmentof Medicine, Duke University Health System, Durham, North Carolina, USA.Departmentof Medicine, Duke University Health System, Durham, North Carolina, USA.Division of Allergy & Clinical Immunology, National Jewish Health, Denver, Colorado, USA.Nivalis Therapeutics Inc., Boulder, Colorado, USA.Nivalis Therapeutics Inc., Boulder, Colorado, USA.Nivalis Therapeutics Inc., Boulder, Colorado, USA.Departmentof Medicine, Duke University Health System, Durham, North Carolina, USA.Department of Medicine, College of Medicine, University of Arizona Health Sciences, Tucson, Arizona, USA.

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29642282

Citation

Que, Loretta G., et al. "Effect of the S-nitrosoglutathione Reductase Inhibitor N6022 On Bronchial Hyperreactivity in Asthma." Immunity, Inflammation and Disease, vol. 6, no. 2, 2018, pp. 322-331.
Que LG, Yang Z, Lugogo NL, et al. Effect of the S-nitrosoglutathione reductase inhibitor N6022 on bronchial hyperreactivity in asthma. Immun Inflamm Dis. 2018;6(2):322-331.
Que, L. G., Yang, Z., Lugogo, N. L., Katial, R. K., Shoemaker, S. A., Troha, J. M., Rodman, D. M., Tighe, R. M., & Kraft, M. (2018). Effect of the S-nitrosoglutathione reductase inhibitor N6022 on bronchial hyperreactivity in asthma. Immunity, Inflammation and Disease, 6(2), 322-331. https://doi.org/10.1002/iid3.220
Que LG, et al. Effect of the S-nitrosoglutathione Reductase Inhibitor N6022 On Bronchial Hyperreactivity in Asthma. Immun Inflamm Dis. 2018;6(2):322-331. PubMed PMID: 29642282.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of the S-nitrosoglutathione reductase inhibitor N6022 on bronchial hyperreactivity in asthma. AU - Que,Loretta G, AU - Yang,Zhonghui, AU - Lugogo,Njira L, AU - Katial,Rohit K, AU - Shoemaker,Steven A, AU - Troha,Janice M, AU - Rodman,David M, AU - Tighe,Robert M, AU - Kraft,Monica, Y1 - 2018/04/11/ PY - 2017/11/29/received PY - 2018/02/20/revised PY - 2018/02/22/accepted PY - 2018/4/12/pubmed PY - 2019/4/30/medline PY - 2018/4/12/entrez KW - N6022 KW - S-nitrosoglutathione KW - S-nitrosoglutathione reductase KW - mild asthma SP - 322 EP - 331 JF - Immunity, inflammation and disease JO - Immun Inflamm Dis VL - 6 IS - 2 N2 - 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 < 0.05) over the 7-day observation period. Furthermore, a significant treatment effect was observed in the change in PC20 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 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. SN - 2050-4527 UR - https://www.unboundmedicine.com/medline/citation/29642282/Effect_of_the_S_nitrosoglutathione_reductase_inhibitor_N6022_on_bronchial_hyperreactivity_in_asthma_ L2 - https://doi.org/10.1002/iid3.220 DB - PRIME DP - Unbound Medicine ER -