Effects of adding a leukotriene antagonist or a long-acting beta(2)-agonist in asthmatic patients with the glycine-16 beta(2)-adrenoceptor genotype

PURPOSE: In the United Kingdom, about 40% of patients with asthma are homoz ygous for the glycine-16 beta(2)-adrenoceptor polymorphism, which predispos es them to agonist-induced down-regulation and desensitization of the beta( 2)-adrenoceptor. We assessed the effects of adding treatment with either a long-acting beta(2)-agonist (inhaled formoterol, 12 mu g twice daily) or a leukotriene receptor antagonist (oral zafirlukast, 20 mg twice daily) to in haled corticosteroid therapy in patients with this genotype. SUBJECTS AND METHODS: We enrolled 24 patients with mild to moderate asthma who were being treated with inhaled corticosteroids. Patients were randomly assigned to receive one of three treatments (placebo, zafirlukast, or form oterol in addition to inhaled corticosteroids) for 1 week each in a crossov er fashion, separated by a 1-week placebo run-in and washout period. Measur ements of bronchoprotection (measured as the provocative dose of methacholi ne that produced a 20% decline in forced expiratory volume in 1 second [FEV 1]), exhaled nitric oxide (a surrogate marker of airway inflammation), and symptoms were made before each treatment and 12 hours after the last dose o f each treatment. RESULTS: Both formoterol and zafirlukast were equally effective in maintain ing asthma control compared with placebo: the geometric mean-fold differenc e in the methacholine provocative dose was 1.5-fold (95% confidence interva l [CI]: 1.1- to 2.2-fold) for zafirlukast and 1.9-fold (95% CI: 1.2- to 2.9 -fold) for formoterol. As compared with placebo, zafirlukast caused a signi ficant suppression in exhaled nitric oxide (1.7-fold difference in geometri c mean values, 95% CT: 1.1- to 2.6-fold) but formoterol did not (1.2-fold d ifference, 95% Cl: 0.8- to 1.9-fold). Diary cards showed significant (P < 0 .05) improvements in the peak flow with formoterol (morning and evening) an d zafirlukast (evening) as compared with placebo. CONCLUSIONS: Formoterol and zafirlukast maintained asthma control in patien ts who might he genetically predisposed to fare worse with long-acting beta (2)-agonists. The reduction in exhaled nitric oxide with zafirlukast sugges ts that it may have anti-inflammatory effects in addition to those seen wit h inhaled corticosteroids. Am J Med. 2000;109:114-121. (C) 2000 by Excerpta Medica, Inc.