Subsensitivity of bronchodilator and systemic β2 adrenoceptor responses after regular twice daily treatment with eformoterol dry powder in asthmatic patients

Abstract

Background - There is controversy as to the role of long acting β2 agonists such as eformoterol and, in particular, whether bronchodilator tolerance occurs during continuous therapy. The purpose of this study was to extend previous observations of bronchodilator subsensitivity with metered dose eformoterol aerosol in order to assess whether tolerance also occurs with a dry powder formulation ofthe same drug. Methods - Sixteen asthmatic patients of mean age 33 (range 18-53) years and FEV1 (%/o predicted) of 64 (3)%, ofwhom 13 were receiving inhaled corticosteroids, received regular treatment with eformoterol 24 ttg twice daily or placebo twice daily (without β2 agonists) given concurrently for four weeks in a randomised double blind crossover design. An initial two week run-in was used when β2 agonists were withdrawn and substituted with ipratropium bromide. Dose-response curves to eformoterol (cumulative dose 6-102 μg) for airways and systemic β2 responses were constructed at the end of each treatment period. Results - Baseline values for airways and systemic responses were similar. The peak delta FEV1 response fromthe dose-response curve (as change from baseline) and the delta response for FEV1 and FEF2575 at six hours after the last dose were attenuated after eformoterol compared with placebo: peak delta FEV1 response I 00 1 with placebo v 0.841 with eformoterol (95% CI 004 to 0.28); at six hours 0-931 with placebo v 0-581 with eformoterol (95% CI 0-20 to 0.50); and for delta FEF25-75 at six hours 1 291/s with placebo v 0-871Vs with eformoterol (95% CI 015 to 0.69). Morning peak expiratory flow rate was significantly improved during treatment with eformoterol (451 /min) compared with placebo (399 1min) (95% CI 21 to 82). Systemnic β2 responses were blunted after eformoterol, together with a reduction in lymphocyte β2 receptor binding density. Conclusions - Regular twice daily eformoterol dry powder may produce bronchodilator subsensitivity in terms of both peak and duration of response to cumulative repeated doses of eformoterol. Systemic β2-mediated adv,erse effects also showed tolerance, which was mirrored by downregulation of lymphocyte β2 adrenoceptors.