Rapid Onset of Tolerance to the Bronchoprotective Effect of Salmeterol

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. Ten asthmatic volunteers who were able to withhold ß2-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 pg 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 pg of salbutamol. 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