title: Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics.
abstract: We defined the contribution of histamine and leukotrienes to allergen-induced airway obstruction in asthmatics; 12 subjects with allergic asthma underwent identical allergen bronchoprovocations on four occasions. At a control session, all subjects displayed early (EAR) and late asthmatic (LAR) reactions. The mean (+/- SE) drop in FEV1 during EAR (0-2 h) and LAR (2-12 h) was 29 +/- 2% and 28 +/- 4%, respectively. Thereafter, the influence of 1 wk randomized pretreatment with the leukotriene receptor antagonist zafirlukast (Accolate) (80 mg twice daily), the antihistamine loratadine (10 mg twice daily), and the combination of both antagonists was assessed. Expressed as AUC FEV1 in percent of the control reaction, zafirlukast reduced the response during EAR and LAR by 62 +/- 11% and 55 +/- 12%, respectively (p < 0.05 versus control). Loratadine inhibited EAR and LAR by 25 +/- 14% and 40 +/- 16%, respectively (p < 0.05 versus control). Zafirlukast was significantly more effective than loratadine during EAR but not during LAR. The combination of zafirlukast and loratadine reduced the AUC FEV1 during EAR and LAR further, by 75 +/- 8% and 74 +/- 14%, respectively (p < 0.05 versus control). The combination was significantly (p < 0.05) more effective than either drug alone during the LAR. The findings indicate that leukotrienes and histamine together mediate the major part of both the EAR and the LAR following exposure of asthmatics to allergen. Combination of leukotriene antagonism and antihistamines may represent a new strategy for treatment of airway obstruction in asthma.
authors.affiliation: Department of Medicine at Karolinska Hospital, Experimental Asthma and Allergy Research, Institute of Environmental Medicine, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Roquet
authors.forename: B
authors.initials: B
authors.lastname: Dahlén
authors.forename: M
authors.initials: M
authors.lastname: Kumlin
authors.forename: E
authors.initials: E
authors.lastname: Ihre
authors.forename: G
authors.initials: G
authors.lastname: Anstrén
authors.forename: S
authors.initials: S
authors.lastname: Binks
authors.forename: S E
authors.initials: SE
authors.lastname: Dahlén
mesh_terms: D000293:Adolescent; D000328:Adult; D000402:Airway Obstruction / Q000276:immunology* / Q000503:physiopathology; D000485:Allergens / Q000276:immunology*; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use; D001249:Asthma / Q000276:immunology* / Q000503:physiopathology; D004359:Drug Therapy, Combination; D005260:Female; D005541:Forced Expiratory Volume; D006633:Histamine Antagonists / Q000627:therapeutic use*; D006634:Histamine H1 Antagonists / Q000627:therapeutic use; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D006969:Hypersensitivity, Immediate / Q000276:immunology; D007211:Indoles; D020024:Leukotriene Antagonists; D017336:Loratadine / Q000627:therapeutic use; D008297:Male; D048448:Phenylcarbamates; D013449:Sulfonamides; D014105:Tosyl Compounds / Q000627:therapeutic use
chemical_list: D000485:Allergens; D018927:Anti-Asthmatic Agents; D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists; D007211:Indoles; D020024:Leukotriene Antagonists; D048448:Phenylcarbamates; D013449:Sulfonamides; D014105:Tosyl Compounds; D017336:Loratadine; C062735:zafirlukast