Selective inducible nitric oxide synthase inhibition has no effect on allergen challenge in asthma.
Am J Respir Crit Care Med
; 176(10): 988-93, 2007 Nov 15.
Article
em En
| MEDLINE
| ID: mdl-17717202
ABSTRACT
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 MAINRESULTS:
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).
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Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Asma
/
Sulfetos
/
Hiper-Reatividade Brônquica
/
Óxido Nítrico Sintase Tipo II
Tipo de estudo:
Clinical_trials
/
Etiology_studies
Limite:
Adult
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Am J Respir Crit Care Med
Assunto da revista:
TERAPIA INTENSIVA
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Reino Unido