Selective inducible nitric oxide synthase inhibition has no effect on allergen challenge in asthma

Research output: Contribution to journalArticle

  • Authors:
  • Dave Singh
  • Duncan Richards
  • Richard G. Knowles
  • Sheila Schwartz
  • Ashley Woodcock
  • And 2 others
  • External authors:
  • Steve Langley
  • Brian J. O'Connor

Abstract

Rationale: Exhaled breath nitric oxide (FENO) is increased in asthma. NO is produced predominantly by inducible nitric oxide synthase (iNOS). Objectives: We evaluated the selective and potent iNOS inhibitor GW274150 in asthma. Methods: Twenty-eight steroid-naive patients with asthma participated in a double-blind, randomized, double-dummy, placebo-controlled, three-period cross-over study. Subjects received GW274150 (90 mg), montelukast (10 mg), or placebo once daily for 14 days. FENO was assessed predose on Days 1, 7, 10, and 14. Adenosine 5′-monophosphate (AMP) challenge was performed on Day 10, allergen challenge on Day 14 followed by methacholine challenge (MCh) 24 hours later, and then bronchoscopy. Measurements and Main Results: GW274150 reduced predose FENO by 73, 75, and 71% on Days 7, 10, and 14, respectively, compared with placebo. Montelukast did not reduce FNO. GW274150 did not inhibit AMP reactivity whereas for montelukast there was a trend toward inhibition: the mean doubling dose difference versus placebo was 0.64 (95% confidence interval [95% CI], 0 to 1.28). GW274150 did not inhibit early (EAR) and late (LAR) asthmatic responses to allergen, or MCh reactivity, despite reduced FENO levels. Montelukast inhibited EAR and LAR FEV1; the mean difference versus placebo for minimal FEV1 was 0.37 L (95% CI, 0.19 to 0.55) and 0.18 L (95% CI, 0.04 to 0.32), respectively. MCh reactivity was inhibited by montelukast (mean doubling dose difference vs. placebo, 0.51; 95% CI, 0.02 to 1.01). GW271540 also had no effect on inflammatory cell numbers in bronchoalveolar lavage fluid after allergen challenge. Conclusions: Selective iNOS inhibition effectively reduces FE NO but does not affect airway hyperreactivity or airway inflammatory cell numbers after allergen challenge in subjects with asthma.

Bibliographical metadata

Original languageEnglish
Pages (from-to)988-993
Number of pages5
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume176
Issue number10
DOIs
Publication statusPublished - 15 Nov 2007

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