Published ahead of print on August 23, 2007, doi:10.1164/rccm.200704-588OC
© 2007 American Thoracic Society doi: 10.1164/rccm.200704-588OC
Selective Inducible Nitric Oxide Synthase Inhibition Has No Effect on Allergen Challenge in Asthma 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 (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 FENO. 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 FENO 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
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