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Selective Inducible Nitric Oxide Synthase Inhibition Has No Effect on Allergen Challenge in Asthma

Dave Singh¹, Duncan Richards², Richard G. Knowles², Sheila Schwartz², Ashley Woodcock¹, Steve Langley^1, and Brian J. O'Connor³

¹ Medicines Evaluation Unit, South Manchester University Hospitals Trust, University of Manchester, Manchester, United Kingdom; ² GlaxoSmithKline, Stevenage, United Kingdom; and ³ Department of Asthma, Allergy, and Respiratory Science, Guy's, King's and St. Thomas' School of Medicine, King's College Hospital, London, United Kingdom

Correspondence and requests for reprints should be addressed to Dave Singh, M.D., Medicines Evaluation Unit, South Manchester University Hospitals Trust, University of Manchester, Southmoor Road, Manchester M23 9LT, UK. E-mail: dsingh{at}meu.org.uk

Rationale: Exhaled breath nitric oxide (FE_NO) 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. FE_NO 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 FE_NO by 73, 75, and 71% on Days 7, 10, and 14, respectively, compared with placebo. Montelukast did not reduce FE_NO. 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 FE_NO 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.

Clinical trial registered with www.clinicaltrials.gov (NCT00273013).

Key Words: nitric oxide • bronchial hyperreactivity

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Exhaled nitric oxide (NO) is produced by inducible nitric oxide synthase (iNOS), and levels are high in asthma. iNOS is therefore a potential therapeutic target in asthma. What This Study Adds to the Field Administration of a selective iNOS inhibitor to patients with asthma reduced NO levels, but had no effect on allergen responsiveness. Targeting NO may not be an effective intervention in asthma.

 

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