title: Salbutamol tolerance to bronchoprotection: course of onset.
abstract: BACKGROUND
  Regular use of inhaled β-agonist leads to tolerance to its bronchoprotective effect. This occurs within 12 hours with salmeterol and has been documented at 1 week for salbutamol. The course of onset after introduction of salbutamol has not been investigated.
  
  
  OBJECTIVE
  To determine the course of onset of tolerance to the bronchoprotective effect of salbutamol against methacholine.
  
  
  METHODS
  Thirteen individuals with mild asthma completed a randomized, double-blind, placebo-controlled, cross-over study. Each treatment period consisted of 7 twice-daily doses (2 puffs of 100 μg of salbutamol or placebo). Methacholine challenges were conducted 24 hours apart on 4 consecutive days, 10 minutes after the first, third, fifth, and seventh doses. The 2 treatment periods were separated by at least 14 days.
  
  
  RESULTS
  Methacholine provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20% (PC(20)) values during the 4 days of placebo treatment did not significantly differ (analysis of variance P = .79). A single dose of salbutamol shifted the methacholine PC(20) approximately 5-fold from a geometric mean of 2.1 mg/mL to a geometric mean of 10.7 mg/mL. Maximal bronchoprotection after the active treatment occurred on day 2 after the third dose, which was significantly higher than on day 1 after the first dose (P = .04). After the fifth dose the methacholine PC(20) was trending downward, and on day 4 the bronchoprotective effect of salbutamol had significantly decreased from its peak protection (P = .001).
  
  
  CONCLUSIONS
  The detrimental effects on bronchoprotection after regular use of salbutamol manifest after 5 doses and are significantly reduced from peak protection after 7 doses.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01338311.
authors.affiliation: Department of Medicine, Division of Respirology, Critical Care, and Sleep Medicine, University of Saskatchewan, Saskatoon, Canada.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Stewart
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Martin
authors.forename: Beth E
authors.initials: BE
authors.lastname: Davis
authors.forename: Donald W
authors.initials: DW
authors.lastname: Cockcroft
mesh_terms: D000318:Adrenergic beta-Agonists / Q000627:therapeutic use; D000328:Adult; D000420:Albuterol / Q000008:administration & dosage* / Q000009:adverse effects; D001249:Asthma / Q000188:drug therapy*; D001985:Bronchial Provocation Tests / Q000379:methods; D016084:Bronchoconstriction / Q000187:drug effects*; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004361:Drug Tolerance; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D009241:Ipratropium / Q000627:therapeutic use; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000318:Adrenergic beta-Agonists; D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D016210:Methacholine Chloride; D009241:Ipratropium; D000420:Albuterol