Bronchodilator subsensitivity after chronic dosing with eformoterol in patients with asthma

Abstract

Purpose: The aim of the present study was to evaluate in vivo and in vitro beta 2-adrenoceptor responsiveness after chronic inhaled therapy with the long-acting beta 2-agonist eformoterol or placebo, given twice daily, in patients with mild to moderate asthma.

Patients and methods: Seven asthmatic patients, age 34 +/- 5 years were evaluated. Mean forced expiratory volume in 1 second (FEV1) (% predicted) at entry was 58 +/- 5%. After at least 2 weeks run-in without beta 2-agonist therapy, patients were randomized to receive regular treatment with eformoterol 24 micrograms twice daily or placebo twice daily given by metered-dose inhaler for 4 weeks, in a double-blind, crossover design. Dose-response curves (DRC) to eformoterol (cumulative dose 6 micrograms to 126 micrograms) for airways and systemic beta 2-responses were constructed at the end of each treatment period. Responses were measured at baseline, 30 minutes after each dose, and for 6 hours after the last dose. In addition, in vitro parameters of lymphocyte beta 2-receptor function were evaluated prior to the DRC after each treatment period.

Results: There was a nonsignificant trend towards higher baseline values after eformoterol compared with placebo for FEV1: 0.16 L (95% CI -0.04 to 0.36) and forced expiratory flow (FEF25-75): 0.27 L/sec (95% CI -0.08 to 0.62). The peak bronchodilator response from the DRC and response 6 hours after the last dose were both significantly (P < 0.05) attenuated after chronic therapy with eformoterol compared with placebo. The mean differences between eformoterol and placebo for delta FEV1 were as follows: peak: 0.26 L (95% CI 0.09 to 0.43), and at 6 hours: 0.39 L (95% CI 0.20 to 0.58). Corresponding values for delta FEF25-75 were as follows: peak: 0.41 L/sec (95% CI 0.10 to 0.71), 6 hours 0.52 L/sec (95% CI 0.22 to 0.82). Systemic responses were likewise significantly blunted after eformoterol treatment compared with placebo. There was also subsensitivity of lymphocyte beta 2-adrenoceptor function after treatment with eformoterol compared with placebo.

Conclusions: Our results suggest that chronic therapy with eformoterol produces (1) tachyphylaxis to its bronchodilator response, which was greatest at 6 hours after the last dose, (2) tachyphylaxis of extrapulmonary beta 2-mediated responses, and (3) subsensitivity of in vitro beta 2-adrenoceptor function.