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

Abstract

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 beta2-agonists in the presence of increased airway tone induced by methacholine. In addition, a post hoc analysis was made to evaluate the effects of beta2-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 micrograms, were randomized in double-blind, double-dummy, cross-over fashion to receive single doses of inhaled placebo, inhaled formoterol 12 micrograms, or inhaled salmeterol 50 micrograms followed 12 hours later by a single dose of inhaled albuterol 400 micrograms (low dose) or 1600 micrograms (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 micrograms vs 1080 micrograms, a 1.61-fold difference; P <.05) compared with low- and high-dose albuterol after formoterol dosing (660 micrograms vs 799 micrograms, a 1. 21-fold difference; P =.4), or after salmeterol dosing (568 micrograms vs 847 micrograms, 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 micrograms, a 1. 6-fold difference; P <.05) or with salmeterol (PD20 = 568 micrograms, a 1.9-fold difference; P <.05) compared with PD20 with high-dose albuterol after placebo dosing (PD20 = 1080 micrograms). 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 beta2-adrenoceptors by long-acting beta2-agonists or by early tachyphylaxis 12 hours after a single-dose exposure. The degree of albuterol protection was also related to beta2-adrenoceptor polymorphism.