Salbutamol-induced increased airway responsiveness to allergen and reduced protection versus methacholine: Dose response

Background: Two adverse effects of inhaled beta(2)-agonists are increased airway responsiveness to allergen and tolerance to the bronchoprotective effect of beta(2)-agonists versus bronchoconstrictors (e.g., methacholine). Objective: We studied three doses of inhaled salbutamol, 200, 400, and 800 mu g/day, to determine dose-response curves for these two adverse effects. Methods: Ten atopic patients with mild, stable asthma free of all asthma medications, allergen exposure, and respiratory tract infection for at least 4 weeks participated in a double-blind random-order, crossover study. There were four 1-week treatment periods with a 1-week washout period: placebo, salbutamol 200 mu g 400 mu g and 800 mu g per day. After each treatment, we assessed FEV(1), bronchodilation 10 minutes after administration of 200 mu g of salbutamol, methacholine PC20, methacholine dose-shift after administration of 200 mu g of salbutamol, and allergen PC20. Results: There was no significant different in baseline FEV(1), bronchodilation, or methacholine PC20. The methacholine nose shift was maximum after the placebo (3.4 +/- 0.22 doubling doses) and was significantly greater (p < 0.01) than all salbutamol regimens (2.2 to 2.6), which were not significantly different from each other (p > 0.05). Allergen PC20 was significantly lower (p < 002) after salbutamol 800 mu g/day (geometric mean = 288 protein nitrogen units [PNU]/ml) than each of the other treatments (447 to 550 PNU/ml), which were not significantly different from each other (p > 0.05). Conclusion: Significant increase in ail-way responsiveness to allergen occurred only with the largest dose of inhaled salbutamol (800 mu g/d); however, tolerance to the acute bronchoprotective effect of salbutamol was observed with all the three salbutamol regimens, even 200 mu g/day. This suggests different mechanisms may be operative in producing these two effects.