title: A dual CysLT1/2antagonist attenuates allergen-induced airway responses in subjects with mild allergic asthma.
abstract: The cysteinyl leukotrienes (cysLTs) play a key role in the pathophysiology of asthma. In addition to functioning as potent bronchoconstrictors, cysLTs contribute to airway inflammation through eosinophil and neutrophil chemotaxis, plasma exudation, and mucus secretion. We tested the activity of the dual cysLT1/2antagonist, ONO-6950, against allergen-induced airway responses.
  
  
  
  Subjects with documented allergen-induced early (EAR) and late asthmatic response (LAR) were randomized in a three-way crossover study to receive ONO-6950 (200 mg) or montelukast (10 mg) or placebo q.d. on days 1-8 of the three treatment periods. Allergen was inhaled on day 7 two hours postdose, and forced expiratory volume in 1 s (FEV1) was measured for 7 h following challenge. Sputum eosinophils and airway hyperresponsiveness were measured before and after allergen challenge. The primary outcome was the effect of ONO-6950 vs placebo on the EAR and LAR.
  
  
  
  Twenty-five nonsmoking subjects with mild allergic asthma were enrolled and 20 subjects completed all three treatment periods per protocol. ONO-6950 was well tolerated. Compared to placebo, ONO-6950 significantly attenuated the maximum % fall in FEV1and area under the %FEV1/time curve during the EAR and LAR asthmatic responses (P < 0.05) and allergen-induced sputum eosinophils. There were no significant differences between ONO-6950 and montelukast.
  
  
  
  Attenuation of EAR, LAR, and airway inflammation is consistent with cysLT1blockade. Whether dual cysLT1/2antagonism offers additional benefit for treatment of asthma requires further study.
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: G M
authors.initials: GM
authors.lastname: Gauvreau
authors.affiliation: Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, QC, Canada.
authors.forename: L-P
authors.initials: LP
authors.lastname: Boulet
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: J M
authors.initials: JM
authors.lastname: FitzGerald
authors.affiliation: Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
authors.forename: D W
authors.initials: DW
authors.lastname: Cockcroft
authors.affiliation: Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
authors.forename: B E
authors.initials: BE
authors.lastname: Davis
authors.affiliation: Department of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Leigh
authors.affiliation: ONO Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: ONO Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: J A
authors.initials: JA
authors.lastname: Fourre
authors.affiliation: ONO Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: ONO Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nabata
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: P M
authors.initials: PM
authors.lastname: O'Byrne
mesh_terms: D000328:Adult; D000485:Allergens / Q000276:immunology*; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D002087:Butyrates / Q000494:pharmacology / Q000627:therapeutic use; D045853:Exhalation; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D020024:Leukotriene Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D018077:Receptors, Leukotriene / Q000378:metabolism*; D012129:Respiratory Function Tests; D013183:Sputum / Q000166:cytology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000485:Allergens; D002087:Butyrates; D007211:Indoles; D020024:Leukotriene Antagonists; D018077:Receptors, Leukotriene; D009569:Nitric Oxide; C000603360:gemilukast; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor
keywords: CysLT1/2 antagonist; ONO-6950; allergen challenge; allergic asthma; eosinophils