Subsensitivity to bronchoprotection against adenosine monophosphate challenge following regular once-daily formoterol.
Regular treatment with inhaled long-acting beta2-agonists leads to subsensitivity to their bronchoprotective effects, although the effect of dosing frequency on this subsensitivity is not known. The aim of this study was to assess whether a once-daily dosing regimen with formoterol might be associated with a lesser degree of subsensitivity. In a randomized placebo-controlled double-blind, double-dummy crossover study 10 asthmatics treated with inhaled steroids (mean age 31 yrs, forced expiratory volume in one second (FEV1) 82% predicted) received 1 week of treatment with: formoterol dry powder 24 microg twice daily (08:00 and 20:00 h); formoterol 24 microg once daily (20:00 h); or identical placebo. Adenosine monophosphate (AMP) bronchial challenge was performed 12 h after the first and the last dose of each treatment. There was significant loss of protection with formoterol twice daily between the first and last dose (geometric mean provocative concentration causing a 20% fall in FEV1 (PC20)): 475 versus 129 mg x mL(-1) (a 3.7-fold loss, p=0.006) and with formoterol once daily: 367 versus 127 mg x mL(-1) (a 2.9-fold loss, p=0.005), compared with placebo: 71 versus 75 mg x ml(-1) (nonsignificant). There was no significant difference in the degree of loss of protection between formoterol once and twice daily. For first-dose protection there was a significant difference between active treatments and placebo, but after the last dose the residual protection between active treatments and placebo was not significant. Thus, in patients taking inhaled corticosteroids, regular formoterol 24 micreog once daily induces a similar degree of subsensitivity to adenosine monophosphate bronchial challenge as with formoterol 24 microg twice daily. This in turn suggests that even with a 24-h dosing interval there is the development of tolerance to formoterol by prolonged occupancy of airway beta2-adrenoceptors.
Dept of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, UK.
I
I
Aziz
K S
KS
Tan
I P
IP
Hall
M M
MM
Devlin
B J
BJ
Lipworth
D000249:Adenosine Monophosphate; D000284:Administration, Oral; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage*; D000328:Adult; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy*; D001980:Bronchi / Q000187:drug effects; D016535:Bronchial Hyperreactivity / Q000517:prevention & control*; D001985:Bronchial Provocation Tests; D016001:Confidence Intervals; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D004983:Ethanolamines / Q000008:administration & dosage*; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D000068759:Formoterol Fumarate; D005838:Genotype; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D011943:Receptors, Adrenergic, beta / Q000235:genetics; D016896:Treatment Outcome
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D011943:Receptors, Adrenergic, beta; D000249:Adenosine Monophosphate; D000068759:Formoterol Fumarate