RAPID ONSET OF TOLERANCE TO THE BRONCHOPROTECTIVE EFFECT OF SALMETEROL

Introduction: Twice-daily inhaled salmeterol for 4 weeks produces marked reducton 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 mu g 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 mu g of salbutamol. Results: Baseline FEV(1) value before doses 3, 5, and 7 of salmeterol tie, 12 h after salmeterol) was significantly higher than all other (n=7) values. Twenty-four hours after the last dose of salmeterol, the FEV(1) was no different from that during the placebo period. The geometric mean methacholine concentration causing a 20% fall in FEV(1) (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,vas 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.