Comparative trough effects of formoterol and salmeterol on lymphocyte beta(2)-adrenoceptor - regulation and bronchodilatation

Objectives: The primary aim of the present study was to evaluate comparativ e trough effects of formoterol and salmeterol on beta(2)-adrenoceptor regul ation and bronchodilator response after regular twice-daily treatment, with a secondary aim to evaluate any possible association with beta(2)-adrenoce ptor polymorphism. Methods: Sixteen asthmatic subjects, with mean (SD) age 33(9) years, all ta king inhaled corticosteroids and with a forced expiratory volume in 1 s (FE V1) 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 mu g twice daily, (2) salmeterol dry powder, 50 mu g twice dail y, or (3) placebo, twice daily. Spirometry and lymphocyte beta(2)-adrenocep tor 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 treatm ent. Results: There were no differences in beta(2)-adrenoceptor density (B-max) between the three treatments prior to the first dose; whereas, after the la st dose, B-max was lower with both active treatments than with placebo, but was significant for salmeterol only - a 1.2-fold geometric mean fold diffe rence (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 ha d a greater than 15% fall in B-max. Post-hoc trend analysis of polymorphism showed that the propensity for downregulation appeared to be related to th e occurrence of an allelic substitution of glycine at codon 16 - 8 of 13 fo r salmeterol versus 5 of 13 for formoterol with a greater than 15% fall com pared with placebo. There were no significant differences between salmetero l and formoterol in terms of mean or individual values for downregulation. There was evidence of persistent bronchodilator activity with both active t reatments compared with placebo; this was significant for forced expiratory flow rate between 25% and 75% of vital capacity (FEF25-75) - the mean diff erence versus salmeterol was 0.39 l/s (95% CI 0.06-0.70), P = 0.02, and ver sus formoterol was 0.35 l/s (95% CI 0.16-0.53), P = 0.001. These effects we re mirrored by significant improvements in morning peak flow rate compared with placebo - mean difference versus salmeterol was 24 l/min (95% CI 7-42) , P = 0.01, and versus formoterol was 36 l/min (95% CI 25-48), P < 0.0001. Conclusion: There were no differences between regular treatment with formot erol and salmeterol in their effects on lymphocyte beta(2)-adrenoceptor reg ulation 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 req uired in susceptible patients who have the homozygous glycine-16 polymorphi sm.