Tolerance to the bronchoprotective effect of beta2-agonists: comparison of the enantiomers of salbutamol with racemic salbutamol and placebo.
BACKGROUND
Regular use of racemic salbutamol results in the partial loss of its bronchoprotective effect. The 2 enantiomers of salbutamol, the bronchodilator R-salbutamol and nonbronchodilator S-salbutamol, are now available.


OBJECTIVE
We sought to compare the effect of regular use of S-salbutamol, R-salbutamol, racemic salbutamol, and placebo on the bronchoprotective effect of a single dose of racemic salbutamol against methacholine-induced bronchoconstriction.


METHODS
Eleven of 13 well-controlled beta2 -agonist-free asthmatic subjects completed a double-blind, randomized study comparing racemic salbutamol 2.5 mg, S-salbutamol 1. 25 mg, R-salbutamol 1.25 mg, and diluent placebo nebulized and inhaled 3 times daily for 6 days (>/=6-day washout period). Ten to 12 hours after the last dose, the subjects performed measurement of FEV1, methacholine PC20, and a repeat methacholine PC20 done 1 hour after the first methacholine test and 10 minutes after 2 puffs (200 microgram) of racemic salbutamol administered from a metered-dose inhaler. The primary endpoint was the methacholine PC20 dose shift (Deltalog PC20/log 2) from before to after administration of 200 microgram of racemic salbutamol.


RESULTS
The methacholine dose shift was 3.2 doubling doses (9-fold increase in methacholine PC20 after 200 microgram of racemic salbutamol) during the placebo treatment and was unaltered (3.2) after administration of S-salbutamol. The dose shift was significantly lower after both the R-salbutamol and racemic salbutamol treatments (2.2 and 2.6 doubling doses, respectively); there was no significant difference between R-salbutamol and racemic salbutamol. There was no treatment effect on baseline FEV1, baseline methacholine PC20, or bronchodilation.


CONCLUSIONS
Regular treatment with racemic salbutamol or R-salbutamol, but not S-salbutamol, results in a partial loss of bronchoprotection, without loss of bronchodilation, compared with placebo.
Cockcroft
D W
DW
Division of Respiratory Medicine, Department of Medicine, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan S7N 0W8, Canada.
Davis
B E
BE
Swystun
V A
VA
Marciniuk
D D
DD
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D000420:Albuterol / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects*; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D013237:Stereoisomerism
D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D010919:Placebos; D000420:Albuterol