title: Use of propranolol blockade to explore the pharmacology of GSK961081, a bi-functional bronchodilator, in healthy volunteers: results from two randomized trials.
abstract: OBJECTIVE
  The objective of this study was to explore the pharmacology of GSK961081, a bi-functional bronchodilator, in healthy volunteers.
  
  
  METHODS
  Two randomized, double-blind, placebo-controlled studies were conducted. Following optimization of the propranolol dosing regimen (study 1), we conducted a five-period crossover study (study 2) in which subjects received the following treatments: dry powder inhaler (DPI) GSK961081 400 µg + oral placebo, DPI GSK961081 1,200 µg + oral placebo, DPI GSK961081 400 µg + oral propranolol 80 mg, DPI GSK961081 1,200 µg + oral propranolol 80 mg and DPI and oral placebo. GSK961081 (or inhaled placebo) was dosed at 0 h. Propranolol (or oral placebo) was dosed at -8, -2, 4, 10, and 16 h. The primary endpoint for both studies was bronchodilation, measured by specific airway conductance (sGaw), which was assessed at 0, 1, 4, 7, 12, 22, and 24 h in study 2. Tolerability and pharmacokinetics were secondary endpoints.
  
  
  RESULTS
  Studies 1 and 2 enrolled 18 and 23 subjects, respectively. In study 2, bronchodilation was seen for 24 h following GSK961081 400 and 1,200 μg. In the presence of β2 blockade, GSK961081 1,200 μg demonstrated bronchodilation in the first 4 h after dosing (treatment difference from placebo at 1 h: 1.206; 90% confidence interval [CI] 1.126-1.292; and at 4 h: 1.124; 90% CI 1.078-1.173) but not at 7 h onwards. In the presence of β2 blockade, GSK961081 400 μg demonstrated bronchodilation in the first 1 h after dosing (treatment difference from placebo: 1.193; 90% CI 1.117-1.274), but not at 4 h onwards. Adverse events were reported for 21 (study 1) and 15 subjects (study 2); none were serious, and there were no deaths.
  
  
  CONCLUSIONS
  The duration of bronchodilation as a result of receiving the muscarinic antagonist component alone was shorter than that from the muscarinic antagonist β2 agonist combination. Removing the β2 agonist component may underestimate the contribution of the muscarinic antagonist component to the bronchodilation of the combination.
authors.affiliation: GlaxoSmithKline, GSK House, 980 Great West Road, Brentford, Middlesex, TW8 9GS, UK, virginia.h.norris@gsk.com.
authors.forename: Virginia
authors.initials: V
authors.lastname: Norris
authors.forename: Claire
authors.initials: C
authors.lastname: Ambery
mesh_terms: D000280:Administration, Inhalation; D000284:Administration, Oral; D000293:Adolescent; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000328:Adult; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D002219:Carbamates / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D036501:Metered Dose Inhalers; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000494:pharmacology; D011433:Propranolol / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015363:Quinolones / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors; D055815:Young Adult
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D002219:Carbamates; D018727:Muscarinic Antagonists; D015363:Quinolones; C588122:batefenterol; D011433:Propranolol