title: Efficacy and safety of the long-acting muscarinic antagonist GSK233705 delivered once daily in patients with COPD.
abstract: BACKGROUND
  GSK233705 is a recently developed inhaled anticholinergic being investigated for the potential treatment of chronic obstructive pulmonary disease (COPD).
  
  
  OBJECTIVE
  This dose-ranging, parallel-group, double-blind study compared the bronchodilator efficacy, safety and pharmacokinetics of GSK233705 with placebo in patients with moderate-to-severe COPD.
  
  
  METHODS
  Patients were randomised to receive 12.5 µg, 25 µg, 50 µg, 100 µg or 200 µg of GSK233705 or placebo once daily for 28 days. The primary endpoint was change from baseline in trough forced expiratory volume in 1 s (FEV(1)) on day 29.
  
  
  RESULTS
  The intent-to-treat population consisted of 576 patients (mean predicted FEV(1) 51%; mean age 62 years). Treatment with GSK233705 produced statistically significant improvements in pulmonary function compared with placebo. Only the 200 µg dose exceeded the predefined target threshold of 130-mL difference compared with placebo for the primary endpoint of change from baseline in trough FEV(1) on day 29. No clear pattern of dose response was observed for the other doses. Serial FEV(1) (0-24 h) showed a peak effect around 2 h postdose and tended to decline to clinically insignificant levels compared with placebo at 23 and 24 h. Each dose of GSK233705 was well tolerated. The incidence of adverse events was low and similar across all treatment groups. There were no clinically significant effects on laboratory parameters, vital signs or electrocardiograms.
  
  
  CONCLUSIONS
  All doses of GSK233705 demonstrated bronchodilatory activity and were well tolerated. Although the onset of bronchodilation was rapid, it was not sustained over 24 h making it unsuitable for once-daily dosing.
authors.affiliation: Department of Medicine, University of Cape Town, Cape Town, South Africa. eric.bateman@uct.ac.za
authors.forename: Eric
authors.initials: E
authors.lastname: Bateman
authors.forename: Gregory
authors.initials: G
authors.lastname: Feldman
authors.forename: Sally
authors.initials: S
authors.lastname: Kilbride
authors.forename: Jean
authors.initials: J
authors.lastname: Brooks
authors.forename: Rashmi
authors.initials: R
authors.lastname: Mehta
authors.forename: Stephanie
authors.initials: S
authors.lastname: Harris
authors.forename: Claire
authors.initials: C
authors.lastname: Maden
authors.forename: Glenn
authors.initials: G
authors.lastname: Crater
mesh_terms: D000280:Administration, Inhalation; D000368:Aged; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D016001:Confidence Intervals; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage*; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000188:drug therapy*; D012016:Reference Values; D012129:Respiratory Function Tests; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D016896:Treatment Outcome
chemical_list: D001993:Bronchodilator Agents; D003692:Delayed-Action Preparations; D018727:Muscarinic Antagonists