Subsensitivity of bronchodilator and systemic beta 2 adrenoceptor responses after regular twice daily treatment with eformoterol dry powder in asthmatic patients.
BACKGROUND
There is controversy as to the role of long acting beta 2 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 of the same drug.


METHODS
Sixteen asthmatic patients of mean age 33 (range 18-53) years and FEV1 (% predicted) of 64 (3)%, of whom 13 were receiving inhaled corticosteroids, received regular treatment with eformoterol 24 micrograms twice daily or placebo twice daily (without beta 2 agonists) given concurrently for four weeks in a randomised double blind cross-over design. An initial two week run-in was used when beta 2 agonists were withdrawn and substituted with ipratropium bromide. Dose-response curves to eformoterol (cumulative dose 6-102 micrograms) for airways and systemic beta 2 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 from the dose-response curve (as change from baseline) and the delta response for FEV1 and FEF25-75 at six hours after the last dose were attenuated after eformoterol compared with placebo: peak delta FEV1 response 1.001 with placebo v 0.841 with eformoterol (95% CI 0.04 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 1.29 1/s with placebo v 0.87 1/s with eformoterol (95% CI 0.15 to 0.69). Morning peak expiratory flow rate was significantly improved during treatment with eformoterol (451 1/min) compared with placebo (399 1/min) (95% CI 21 to 82). Systemic beta 2 responses were blunted after eformoterol, together with a reduction in lymphocyte beta 2 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 beta 2-mediated adverse effects also showed tolerance, which was mirrored by downregulation of lymphocyte beta 2 adrenoceptors.
Newnham
D M
DM
Department of Clinical Pharmacology, University of Dundee, Ninewells Hospital and Medical School, UK.
Grove
A
A
McDevitt
D G
DG
Lipworth
B J
BJ
D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage*; D000328:Adult; D000336:Aerosols; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D001980:Bronchi / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D004983:Ethanolamines / Q000008:administration & dosage*; D005260:Female; D000068759:Formoterol Fumarate; D006801:Humans; D008297:Male; D008875:Middle Aged; D010366:Peak Expiratory Flow Rate; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D012680:Sensitivity and Specificity
D000318:Adrenergic beta-Agonists; D000336:Aerosols; D001993:Bronchodilator Agents; D004983:Ethanolamines; D018341:Receptors, Adrenergic, alpha-2; D000068759:Formoterol Fumarate