Comparative trough effects of formoterol and salmeterol on lymphocyte beta2-adrenoceptor--regulation and bronchodilatation.
OBJECTIVE
The primary aim of the present study was to evaluate comparative trough effects of formoterol and salmeterol on beta2-adrenoceptor regulation and bronchodilator response after regular twice-daily treatment, with a secondary aim to evaluate any possible association with beta2-adrenoceptor polymorphism.


METHODS
Sixteen asthmatic subjects, with mean (SD) age 33(9) years, all taking inhaled corticosteroids and with a forced expiratory volume in 1 s (FEV1) of 81(12)% predicted were recruited to take part in a randomised single-blind, three-way cross-over study. The subjects received three treatments each for 1 week, with 1-week washout periods in between: (1) formoterol dry powder, 12 microg twice daily, (2) salmeterol dry powder, 50 microg twice daily, or (3) placebo, twice daily. Spirometry and lymphocyte beta2-adrenoceptor parameters were measured before the first dose and 12 h after the last dose of each treatment, as well as domiciliary peak flow during each treatment.


RESULTS
There were no differences in beta2-adrenoceptor density (Bmax) between the three treatments prior to the first dose; whereas, after the last dose, Bmax was lower with both active treatments than with placebo, but was significant for salmeterol only--a 1.2-fold geometric mean fold difference (95% CI 1- to 1.4-fold), P = 0.04. Compared with placebo, there were n = 9 of 16 subjects with salmeterol and n = 6 of 16 with formoterol who had a greater than 15% fall in Bmax. Post-hoc trend analysis of polymorphism showed that the propensity for downregulation appeared to be related to the occurrence of an allelic substitution of glycine at codon 16-8 of 13 for salmeterol versus 5 of 13 for formoterol with a greater than 15% fall compared with placebo. There were no significant differences between salmeterol and formoterol in terms of mean or individual values for downregulation. There was evidence of persistent bronchodilator activity with both active treatments compared with placebo; this was significant for forced expiratory flow rate between 25% and 75% of vital capacity (FEF25-75)--the mean difference versus salmeterol was 0.39 1/s (95% CI 0.06-0.70), P = 0.02, and versus formoterol was 0.35 1/s (95% CI 0.16-0.53), P = 0.001. These effects were mirrored by significant improvements in morning peak flow rate compared with placebo--mean difference versus salmeterol was 24 1/min (95% CI 7-42), P = 0.01, and versus formoterol was 36 1/min (95% CI 25-48), P < 0.0001.


CONCLUSIONS
There were no differences between regular treatment with formoterol and salmeterol in their effects on lymphocyte beta2-adrenoceptor regulation at the end of a 12-h dosing interval, with both drugs exhibiting a residual degree of bronchodilator activity at the same time point. Further studies to evaluate receptor regulation and bronchodilator response are required in susceptible patients who have the homozygous glycine-16 polymorphism.
Aziz
I
I
Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Scotland, UK.
McFarlane
L C
LC
Lipworth
B J
BJ
D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D058666:Adrenergic beta-2 Receptor Agonists; D000328:Adult; D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D018592:Cross-Over Studies; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D000068759:Formoterol Fumarate; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011110:Polymorphism, Genetic; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D000068299:Salmeterol Xinafoate; D016037:Single-Blind Method
D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D004983:Ethanolamines; D018343:Receptors, Adrenergic, beta-2; D000068299:Salmeterol Xinafoate; D000420:Albuterol; D000068759:Formoterol Fumarate