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A dual CysLT1/2 antagonist attenuates allergen-induced airway responses in subjects with mild allergic asthma.
Allergy. 2016 12; 71(12):1721-1727.A

Abstract

BACKGROUND

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 cysLT1/2 antagonist, ONO-6950, against allergen-induced airway responses.

METHODS

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.

RESULTS

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 FEV1 and 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.

CONCLUSIONS

Attenuation of EAR, LAR, and airway inflammation is consistent with cysLT1 blockade. Whether dual cysLT1/2 antagonism offers additional benefit for treatment of asthma requires further study.

Authors+Show Affiliations

Department of Medicine, McMaster University, Hamilton, ON, Canada.Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, QC, Canada.Department of Medicine, University of British Columbia, Vancouver, BC, Canada.Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.Department of Medicine, University of Calgary, Calgary, AB, Canada.ONO Pharmaceutical Co., Ltd., Osaka, Japan.ONO Pharmaceutical Co., Ltd., Osaka, Japan.ONO Pharmaceutical Co., Ltd., Osaka, Japan.ONO Pharmaceutical Co., Ltd., Osaka, Japan.Department of Medicine, McMaster University, Hamilton, ON, Canada.

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial

Language

eng

PubMed ID

27444660

Citation

Gauvreau, G M., et al. "A Dual CysLT1/2 Antagonist Attenuates Allergen-induced Airway Responses in Subjects With Mild Allergic Asthma." Allergy, vol. 71, no. 12, 2016, pp. 1721-1727.
Gauvreau GM, Boulet LP, FitzGerald JM, et al. A dual CysLT1/2 antagonist attenuates allergen-induced airway responses in subjects with mild allergic asthma. Allergy. 2016;71(12):1721-1727.
Gauvreau, G. M., Boulet, L. P., FitzGerald, J. M., Cockcroft, D. W., Davis, B. E., Leigh, R., Tanaka, M., Fourre, J. A., Tanaka, M., Nabata, T., & O'Byrne, P. M. (2016). A dual CysLT1/2 antagonist attenuates allergen-induced airway responses in subjects with mild allergic asthma. Allergy, 71(12), 1721-1727. https://doi.org/10.1111/all.12987
Gauvreau GM, et al. A Dual CysLT1/2 Antagonist Attenuates Allergen-induced Airway Responses in Subjects With Mild Allergic Asthma. Allergy. 2016;71(12):1721-1727. PubMed PMID: 27444660.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A dual CysLT1/2 antagonist attenuates allergen-induced airway responses in subjects with mild allergic asthma. AU - Gauvreau,G M, AU - Boulet,L-P, AU - FitzGerald,J M, AU - Cockcroft,D W, AU - Davis,B E, AU - Leigh,R, AU - Tanaka,M, AU - Fourre,J A, AU - Tanaka,M, AU - Nabata,T, AU - O'Byrne,P M, Y1 - 2016/08/09/ PY - 2016/07/17/accepted PY - 2016/7/23/pubmed PY - 2017/11/29/medline PY - 2016/7/23/entrez KW - CysLT1/2 antagonist KW - ONO-6950 KW - allergen challenge KW - allergic asthma KW - eosinophils SP - 1721 EP - 1727 JF - Allergy JO - Allergy VL - 71 IS - 12 N2 - BACKGROUND: 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 cysLT1/2 antagonist, ONO-6950, against allergen-induced airway responses. METHODS: 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. RESULTS: 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 FEV1 and 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. CONCLUSIONS: Attenuation of EAR, LAR, and airway inflammation is consistent with cysLT1 blockade. Whether dual cysLT1/2 antagonism offers additional benefit for treatment of asthma requires further study. SN - 1398-9995 UR - https://www.unboundmedicine.com/medline/citation/27444660/A_dual_CysLT1/2_antagonist_attenuates_allergen_induced_airway_responses_in_subjects_with_mild_allergic_asthma_ L2 - https://doi.org/10.1111/all.12987 DB - PRIME DP - Unbound Medicine ER -