title: An oral selective M3 cholinergic receptor antagonist in COPD.
abstract: Cholinergic antagonists have been used since the early 1900s as bronchodilators for chronic obstructive pulmonary disease (COPD). The present study investigated whether an oral muscarinic M3-selective anticholinergic agent (OrM3) would provide an improved therapeutic advantage compared with an inhaled anticholinergic agent in patients with COPD. A 6-week, multicentre, randomised, placebo- and active-controlled, parallel-group study was performed at 56 sites in the USA. In total, 412 male and female patients (aged 35-86 yrs) with a clinical history consistent with COPD were randomised to receive OrM3 0.5, 2, 3 or 4 mg orally once daily, ipratropium bromide 36 mug by inhalation four times daily or placebo. OrM3 demonstrated a significant dose-related improvement in serial forced expiratory volume in one second and a trend for dose-related improvement in patient-reported symptoms compared with placebo. However, at a dose that provided efficacy less than that of ipratropium, the incidence of dose-related, mechanism-based side-effects for OrM3 exceeded those observed for ipratropium. In patients with chronic obstructive pulmonary disease, the oral M3-selective agent did not offer a therapeutic advantage over inhaled ipratropium. These results do not support the hypothesis that high selectivity for muscarinic M3 receptors over airway neuronal M2 receptors will represent a more effective therapy than current inhaled anticholinergics in obstructive airway disease.
authors.affiliation: Depts of Respiratory and Allergy, Rahway, NJ, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lu
authors.forename: D D
authors.initials: DD
authors.lastname: Parekh
authors.forename: O
authors.initials: O
authors.lastname: Kuznetsova
authors.forename: S A
authors.initials: SA
authors.lastname: Green
authors.forename: C A
authors.initials: CA
authors.lastname: Tozzi
authors.forename: T F
authors.initials: TF
authors.lastname: Reiss
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018680:Cholinergic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D009241:Ipratropium / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors*; D012129:Respiratory Function Tests
chemical_list: D018680:Cholinergic Antagonists; D018727:Muscarinic Antagonists; D043587:Receptor, Muscarinic M3; D009241:Ipratropium