Long-term effects of a long-acting beta 2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma.
BACKGROUND
Asthma is characterized by hyperresponsiveness of the airways to bronchoconstrictive stimuli. Long-acting beta 2-adrenoceptor agonists have been introduced as a new therapeutic approach, but there is growing concern about whether control of asthma may deteriorate with the regular use of these agents. We investigated the long-term effects of the beta 2 agonist salmeterol on bronchodilation and on airway hyperresponsiveness to the bronchoconstrictive agent methacholine in mild asthma.


METHODS
In a parallel, double-blind study, 24 patients with mild asthma were randomly assigned to treatment with either inhaled salmeterol (50 micrograms, twice daily) (n = 12) or placebo (n = 12) during an eight-week trial. Methacholine challenge was performed before, during, and after the treatment period. Methacholine responsiveness was measured as the provocative concentration (PC20) that caused a 20 percent decrease in the forced expiratory volume in one second (FEV1).


RESULTS
There was a significant increase in FEV1 one hour after the inhalation of salmeterol (P = 0.006), which did not differ significantly on days 0, 28, and 56 of the treatment period (increase, 9.8, 9.4, and 8.8 percent of predicted FEV1, respectively; P = 0.91). On the first treatment day, salmeterol afforded significant protection against methacholine-induced bronchoconstriction, as shown by a 10-fold increase in the PC20 as compared with the value at entry (P less than 0.001). After four and eight weeks of treatment, however, the salmeterol-induced change in the PC20 was significantly attenuated (P less than 0.001) to only a twofold increase. Two and four days after treatment ended, the PC20 was not significantly different from the value before treatment (P = 0.15).


CONCLUSIONS
Regular treatment of patients with mild asthma with salmeterol leads to tolerance to its protective effects against a bronchoconstrictor stimulus, in this case inhaled methacholine, despite well-maintained bronchodilation. This finding raises concern about the effectiveness of prolonged therapy with long-acting beta 2-adrenoceptor agonists in asthma.
Cheung
D
D
Department of Pulmonology, University Hospital Leiden, The Netherlands.
Timmers
M C
MC
Zwinderman
A H
AH
Bel
E H
EH
Dijkman
J H
JH
Sterk
P J
PJ
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage* / Q000009:adverse effects; D000328:Adult; D000420:Albuterol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D001249:Asthma / Q000188:drug therapy*; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D004361:Drug Tolerance; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D016210:Methacholine Chloride; D000068299:Salmeterol Xinafoate
D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D016210:Methacholine Chloride; D000068299:Salmeterol Xinafoate; D000420:Albuterol