Rapid onset of tolerance to the bronchoprotective effect of salmeterol.

INTRODUCTION

Twice-daily inhaled salmeterol for 4 weeks produces marked reduction in its acute bronchoprotective effect against methacholine. This investigation examined the onset of this effect over 5 days, and also assessed cross-tolerance with salbutamol.

SUBJECTS AND METHODS

Ten asthmatic volunteers who were able to withhold beta 2-agonist therapy for 4 weeks before and during the study participated in a double-blind, crossover, placebo-controlled study with two random-order treatment periods: inhaled salmeterol, 50 micrograms twice a day for seven doses, and placebo in similar fashion. Methacholine inhalation tests were done 1 h after doses 1, 3, 5, and 7, and then 24 h after the last dose of the study inhaler 10 minutes after 200 micrograms of salbutamol.

RESULTS

Baseline FEV1 value before doses 3, 5, and 7 of salmeterol (ie, 12 h after salmeterol) was significantly higher than all other (n = 7) values. Twenty-four hours after the last dose of salmeterol, the FEV1 was no different from that during the placebo period. The geometric mean methacholine concentration causing a 20% fall in FEV1 (PC20) after the first dose of salmeterol (6.1 mg/mL) was statistically similar to the value achieved 10 min after salbutamol after the placebo period (8.3 mg/mL), and these were significantly (analysis of variance, p < 0.00005) larger than the second, third, and fourth salmeterol days (3.4 mg/mL, 2.6 mg/mL, 1.9 mg/mL, respectively). The methacholine PC20 10 min after salbutamol measured after the salmeterol period was significantly lower than after placebo (2.3 mg/mL vs 8.3 mg/mL; p < 0.001).

CONCLUSIONS

Tolerance to the acute bronchoprotective effect of salmeterol was significant after the first two doses and progressively increased to the seventh dose. Tolerance to the acute bronchoprotective effect of salbutamol was significant after regular use of salmeterol for seven doses.