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An oral selective M3 cholinergic receptor antagonist in COPD

¹ Depts of Respiratory and Allergy, and ² Biostatistics, Merck Research Laboratories, Rahway, NJ, USA.

CORRESPONDENCE: T. F. Reiss, Merck Research Laboratories, RY 34B-328, P.O. Box 2000, Rahway, NJ 07065, USA. Fax: 1 7325947830. E-mail: theodore_reiss{at}merck.com

Keywords: Anticholinergics, antimuscarinic agents, bronchodilators, chronic obstructive pulmonary disease, ipratropium bromide, muscarinic receptors

Received: October 28, 2005
Accepted June 26, 2006

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 µg 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.