title: An inhaled glucocorticoid does not prevent tolerance to the bronchoprotective effect of a long-acting inhaled beta 2-agonist.
abstract: There is increasing evidence for the development of tolerance to the protective effects of inhaled beta 2-agonists against bronchoconstrictor stimuli. Animal studies have suggested that glucocorticoids protect against the down-regulation of beta 2-receptors after chronic exposure to beta 2-agonists. In a double-blind placebo-controlled crossover study in 12 patients with mild asthma, we investigated the effect of inhaled budesonide or identical placebo on the protection conferred by albuterol (200 micrograms) against methacholine-induced bronchoconstriction before and after treatment with the long-acting beta 2-agonist salmeterol. Patients were randomized to be treated for 3 wk with inhaled budesonide (800 micrograms twice a day) or placebo; salmeterol (50 micrograms twice a day) was added during the third week. Airway responsiveness to methacholine was measured 15 min after albuterol, both before and exactly 12 h [corrected] after the last salmeterol dose. Mean FEV1 increased significantly after 2 wk of budesonide (p < 0.05) and increased further after salmeterol (p < 0.05) compared with placebo. After 2 wk, the bronchoprotective effect of albuterol against methacholine was significantly greater with budesonide than with placebo (3.4 versus 2.4 doubling dilutions; p < 0.05), consistent with an improvement in airway hyperresponsiveness with budesonide therapy. However, regular salmeterol treatment for 1 wk significantly diminished the protection conferred by albuterol against methacholine challenge, both with budesonide and with placebo (-1.1 +/- 0.42 and -1.41 +/- 0.30 doubling dilutions, respectively). There was no significant difference in the loss of bronchoprotection seen with salmeterol between budesonide and placebo treatment periods. Our study suggests that even a high dose of an inhaled glucocorticoid fails to prevent the loss of bronchoprotection produced by regular beta 2-agonist therapy.
authors.affiliation: Department of Thoracic Medicine, National Heart and Lung Institute, London, United Kingdom.
authors.forename: D H
authors.initials: DH
authors.lastname: Yates
authors.forename: S A
authors.initials: SA
authors.lastname: Kharitonov
authors.forename: P J
authors.initials: PJ
authors.lastname: Barnes
mesh_terms: D000280:Administration, Inhalation; D000287:Administration, Topical; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage*; D000328:Adult; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy*; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D019819:Budesonide; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004361:Drug Tolerance; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D011282:Pregnenediones / Q000008:administration & dosage; D000068299:Salmeterol Xinafoate
chemical_list: D000318:Adrenergic beta-Agonists; D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; D005938:Glucocorticoids; D011282:Pregnenediones; D016210:Methacholine Chloride; D019819:Budesonide; D000068299:Salmeterol Xinafoate; D000420:Albuterol