Functional antagonism with formoterol and salmeterol in asthmatic patients expressing the homozygous glycine-16 beta(2)-adrenoceptor polymorphism.
BACKGROUND
Formoterol and salmeterol differ in their relative intrinsic activity at airway beta(2)-adrenoceptors, with formoterol being a full agonist. The homozygous glycine-16 polymorphism of the beta(2)-adrenoceptor occurs in approximately 40% of patients and is known to predispose to agonist-induced downregulation and desensitization.


OBJECTIVE
To evaluate possible differences in intrinsic beta(2)-adrenoceptor agonist activity between salmeterol and formoterol in terms of their functional antagonism against methacholine-induced bronchoconstriction (the primary end point) in genetically susceptible patients who exhibited the homozygous glycine-16 polymorphism.


METHODS
Eighteen patients with mild-to-moderate persistent asthma receiving inhaled corticosteroid who expressed the homozygous glycine-16 genotype were randomized to completion (mean [SEM] age, 35.8 [3.2] years; mean FEV(1), 76.9 [2. 5]% predicted). Patients received three different treatments for 1 week in randomized, double-blind, crossover fashion, with a 1-week washout period between treatments: formoterol, 12 microg bid; salmeterol, 50 microg bid; and placebo. For each of the randomized treatment periods, there were three separate methacholine challenges: baseline after washout, 12 h after the first dose, and 12 h after the last dose.


RESULTS
Both salmeterol and formoterol exhibited significantly (p < 0.05) greater bronchoprotection than placebo for their effects after single or repeated dosing, although there was no significant difference between the two drugs. The geometric mean fold protection vs placebo (95% confidence interval [CI]) for the first dose was 1.6-fold (95% CI, 1.1 to 2.2) for salmeterol and 1.9-fold (95% CI, 1.1 to 3.2) for formoterol, and for last dose was 1.6-fold (95% CI, 1.2 to 2.3) for salmeterol and 1. 9-fold (95% CI, 1.2 to 2.8) for formoterol. Salmeterol and formoterol produced significant (p < 0.05) increases in FEV(1) and forced expiratory flow after 25 to 75% of vital capacity has been expelled, after the first but not the last dose compared to placebo, while there were significant (p < 0.05) improvements in domiciliary peak flows during treatment with both drugs.


CONCLUSIONS
Our results showed no difference between formoterol and salmeterol in the degree of functional antagonism against methacholine-induced bronchoconstriction at the end of a 12-h dosing interval in patients who expressed the homozygous glycine-16 genotype. There was a significant residual degree of bronchoprotection after 1 week of treatment, which was not significantly different compared to the first-dose effect.
Lipworth
B J
BJ
Asthma and Allergy Research Group, Department of Clinical Pharmacology & Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Scotland, UK. b.j.lipworth@dundee.uk
Dempsey
O J
OJ
Aziz
I
I
D000280:Administration, Inhalation; D000293:Adolescent; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage*; D000328:Adult; D000368:Aged; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects; D016085:Bronchoconstrictor Agents / Q000037:antagonists & inhibitors; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004983:Ethanolamines / Q000008:administration & dosage*; D005260:Female; D000068759:Formoterol Fumarate; D005998:Glycine / Q000235:genetics*; D006801:Humans; D008297:Male; D016210:Methacholine Chloride / Q000037:antagonists & inhibitors; D008875:Middle Aged; D011110:Polymorphism, Genetic; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D000068299:Salmeterol Xinafoate; D016896:Treatment Outcome
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D016085:Bronchoconstrictor Agents; D004983:Ethanolamines; D018343:Receptors, Adrenergic, beta-2; D016210:Methacholine Chloride; D000068299:Salmeterol Xinafoate; D000420:Albuterol; D005998:Glycine; D000068759:Formoterol Fumarate