Effects of adding a leukotriene antagonist or a long-acting beta(2)-agonist in asthmatic patients with the glycine-16 beta(2)-adrenoceptor genotype.
OBJECTIVE
In the United Kingdom, about 40% of patients with asthma are homozygous for the glycine-16 beta(2)-adrenoceptor polymorphism, which predisposes 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 microg twice daily) or a leukotriene receptor antagonist (oral zafirlukast, 20 mg twice daily) to inhaled corticosteroid therapy in patients with this genotype.


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 formoterol in addition to inhaled corticosteroids) for 1 week each in a crossover fashion, separated by a 1-week placebo run-in and washout period. Measurements of bronchoprotection (measured as the provocative dose of methacholine 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 of each treatment.


RESULTS
Both formoterol and zafirlukast were equally effective in maintaining asthma control compared with placebo: the geometric mean-fold difference in the methacholine provocative dose was 1.5-fold (95% confidence interval [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 significant suppression in exhaled nitric oxide (1.7-fold difference in geometric mean values, 95% CI: 1.1- to 2.6-fold) but formoterol did not (1.2-fold difference, 95% CI: 0.8- to 1.9-fold). Diary cards showed significant (P <0.05) improvements in the peak flow with formoterol (morning and evening) and zafirlukast (evening) as compared with placebo.


CONCLUSIONS
Formoterol and zafirlukast maintained asthma control in patients who might be genetically predisposed to fare worse with long-acting beta(2)-agonists. The reduction in exhaled nitric oxide with zafirlukast suggests that it may have anti-inflammatory effects in addition to those seen with inhaled corticosteroids.
Lipworth
B J
BJ
Asthma and Allergy Research Group, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK.
Dempsey
O J
OJ
Aziz
I
I
Wilson
A M
AM
D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics; D001507:Beclomethasone / Q000008:administration & dosage / Q000627:therapeutic use; D016535:Bronchial Hyperreactivity / Q000188:drug therapy; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use; D016001:Confidence Intervals; D018592:Cross-Over Studies; D004983:Ethanolamines / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D000068759:Formoterol Fumarate; D005838:Genotype; D005938:Glucocorticoids / Q000008:administration & dosage / Q000627:therapeutic use; D005998:Glycine / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007211:Indoles; D020024:Leukotriene Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D048448:Phenylcarbamates; D010919:Placebos; D011110:Polymorphism, Genetic / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D013449:Sulfonamides; D014105:Tosyl Compounds / Q000008:administration & dosage / Q000627:therapeutic use
D000318:Adrenergic beta-Agonists; D018927:Anti-Asthmatic Agents; D001993:Bronchodilator Agents; D004983:Ethanolamines; D005938:Glucocorticoids; D007211:Indoles; D020024:Leukotriene Antagonists; D048448:Phenylcarbamates; D010919:Placebos; D018343:Receptors, Adrenergic, beta-2; D013449:Sulfonamides; D014105:Tosyl Compounds; D009569:Nitric Oxide; D001507:Beclomethasone; D005998:Glycine; D000068759:Formoterol Fumarate; C062735:zafirlukast