In vivo effect of albuterol on methacholine-contracted bronchi in conjunction with salmeterol and formoterol

Background: It has been shown in vitro that prior treatment with salmeterol and formoterol antagonizes the relaxant effect of albuterol in carbachol-contracted human bronchi. Objectives: The primary aim of this study was to evaluate whether there is a potential in vivo interaction between long- and short-acting beta(2)-agonists in the presence of increased airway tone induced by methacholine, In addition,a post hoc analysis was made, to evaluate the effects of beta(2)-adrenoceptor polymorphisms. Methods: Sixteen asthmatic subjects (mean age [+/-SD], 39 [13] years; FEV1, 81% [17%] of predicted value), all taking inhaled corticosteroids and having methacholine PD20 values of less than 500 mu g, were randomized in double-blind, double-dummy, cross-over fashion to receive single doses of inhaled placebo, inhaled formoterol 12 mu g, or inhaled salmeterol 50 mu g followed 12 hours later by a single dose of inhaled albuterol 400 mu g (low dose) or 1600 mu g (high dose). Methacholine challenges were performed on each of 6 separate occasions 1 hour after albuterol, Results: There was a greater numerical difference in geometric mean PD20 values between low- and high-dose albuterol after placebo dosing (671 mu g vs 1080 mu g, a 1.61-fold difference; P < .05) compared with low- and high-dose albuterol after formoterol dosing (660 mu g vs 799 mu g, a 1.21-fold difference; P = .4). or after salmeterol dosing (568 mu g vs 847 mu g, a 1.49-fold difference; P = .055). PD20 values with high-dose albuterol in combination with formoterol or salmeterol were numerically Lower than those found with high-dose albuterol in combination with placebo, but they were not significantly different, There was a significant difference between PD20 values with low-dose albuterol after dosing with formoterol (PD20 = 660 mu g, a 1.6-fold difference; P < .05) or with salmeterol (PD20 = 568 mu g, a 19-fold difference; P < .05) compared with PD20 with high-dose albuterol after placebo dosing (PD20 = 1080 mu g). Post hoc polymorphism analysis for pooled pretreatment with formoterol and salmeterol (excluding placebo pretreatment) showed significantly (P < .05) lower PD20 values with homozygous glycine-16 compared with heterozygous glycine/arginine-16 and significantly (P < .05) lower PD20 values with homozygous glutamate-27 compared with either heterozygous glutamate/glutamine-27 or homozygous glutamine-27, Conclusion: Compared with placebo, both salmeterol and formoterol caused a significant degree of antagonism of albuterol-induced bronchorelaxation in methacholine-contracted bronchi in vivo. This interaction could be caused by prolonged occupancy of airway beta(2)-adrenoceptors by long-acting beta(2)-agonists or by early tachyphylaxis 12 hours after a single-dose exposure. The degree of albuterol protection was also related to beta(2)-adrenoceptor polymorphism.