title: Inhaled corticosteroids do not prevent the development of tolerance to the bronchoprotective effect of salmeterol.
abstract: BACKGROUND
  Twice-daily inhaled salmeterol produces rapid reduction in its acute bronchoprotective effect against methacholine in patients with mild asthma. This investigation examined this effect in patients with moderate asthma who were using inhaled corticosteroids.
  
  
  METHODS
  Eight asthmatic volunteers who required inhaled corticosteroids for control of their symptoms and who were able to withhold treatment with beta 2-agonists for 4 weeks before and during the study participated in a double-blind, crossover, placebo-controlled study with two random-order treatment periods: inhaled salmeterol, 50 microg twice a day for seven doses, and placebo in similar fashion, with a 7-day or greater washout between these periods. Methacholine inhalation tests were done 1 h after doses 1, 3, 5, and 7, and then 24 h after the last dose of the study inhaler, 10 min post-200 microg salbutamol.
  
  
  RESULTS
  Baseline FEV1 measurements before doses 3, 5, and 7 of salmeterol, ie, 12 h after salmeterol, were significantly higher than all other baseline values. Twenty-four hours after the last dose of salmeterol, the FEV1 was no different from that during the placebo period. The geometric mean methacholine concentration causing a 20% fall in FEV1 (PC20) following the third dose of salmeterol (6.8 mg/mL) was significantly lower than after the first dose of salmeterol (12.0 mg/mL; p=0.031), and this reduction of bronchoprotection persisted following doses 5 and 7. The methacholine PC20 10 min postsalbutamol measured after the salmeterol period was significantly lower than after placebo (5.6 vs 13.3 mg/mL; p<0.001).
  
  
  CONCLUSIONS
  Tolerance to the acute bronchoprotective effect of salmeterol was significant after the first two doses and persisted after the seventh dose. Tolerance to the acute bronchoprotective effect of salbutamol was also significant after regular use of salmeterol for seven doses. These effects, in subjects using inhaled corticosteroids regularly, were similar to the those previously seen in patients with mild asthma using as-required beta 2-agonists only, indicating that tolerance is not prevented by use of inhaled corticosteroids.
authors.affiliation: Division of Respiratory Medicine, Royal University Hospital, University of Saskatchewan, Saskatoon, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Kalra
authors.forename: V A
authors.initials: VA
authors.lastname: Swystun
authors.forename: R
authors.initials: R
authors.lastname: Bhagat
authors.forename: D W
authors.initials: DW
authors.lastname: Cockcroft
mesh_terms: D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy; D001507:Beclomethasone / Q000008:administration & dosage / Q000627:therapeutic use*; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects; D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D019819:Budesonide; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004361:Drug Tolerance; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D016210:Methacholine Chloride; D008875:Middle Aged; D010919:Placebos; D011282:Pregnenediones / Q000008:administration & dosage / Q000627:therapeutic use*; D000068299:Salmeterol Xinafoate; D013618:Tachyphylaxis
chemical_list: D000318:Adrenergic beta-Agonists; D018927:Anti-Asthmatic Agents; D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D010919:Placebos; D011282:Pregnenediones; D016210:Methacholine Chloride; D019819:Budesonide; D000068299:Salmeterol Xinafoate; D001507:Beclomethasone; D000420:Albuterol