Selective inducible nitric oxide synthase inhibition has no effect on allergen challenge in asthma.
BACKGROUND
Exhaled breath nitric oxide (Fe(NO)) is increased in asthma. NO is produced predominantly by inducible nitric oxide synthase (iNOS).


OBJECTIVE
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.


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).
Singh
Dave
D
Medicines Evaluation Unit, South Manchester University Hospitals Trust, University of Manchester, Manchester, United Kingdom. dsingh@meu.org.uk
Richards
Duncan
D
Knowles
Richard G
RG
Schwartz
Sheila
S
Woodcock
Ashley
A
Langley
Steve
S
O'Connor
Brian J
BJ
D000328:Adult; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D001944:Breath Tests; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D001985:Bronchial Provocation Tests; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D013440:Sulfides / Q000627:therapeutic use*
D013440:Sulfides; C409004:GW 274150; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II