© 2 0 0 5 B J U I N T E R N A T I O N A L | 9 6 , 1 0 5 5 – 1 0 6 2 | doi:10.1111/j.1464-410X.2005.05745.x 1055 Original Article PHARMACODYNAMIC EFFECTS OF DARIFENACIN FOR OVERACTIVE BLADDER KAY and WESNES Pharmacodynamic effects of darifenacin, a muscarinic M 3 selective receptor antagonist for the treatment of overactive bladder, in healthy volunteers GARY G. KAY and KEITH A. WESNES† Washington Neuropsychological Institute, Washington DC, USA and †Cognitive Drug Research Ltd, Goring-on-Thames, UK Accepted for publication 10 June 2005 heart rate variability were made on day 7 in each treatment period. RESULTS Compared with placebo, neither dose of darifenacin affected cognitive function, whereas dicyclomine impaired performance on five of the 12 variables 2 h after dosing; simple reaction time (P = 0.009), speed of numeric (P = 0.012) and spatial (P = 0.048) working memory, and speed (P = 0.04) and sensitivity (P = 0.03) of picture recognition. These cognitive changes were accompanied by slowing of the EEG for dicyclomine. Darifenacin showed no clinically relevant effect on EEG. Darifenacin 7.5 and 15 mg once daily did not differ from placebo in effects on visual nearpoint, heart rate or heart rate variability. By contrast, dicyclomine significantly increased the maximum visual nearpoint, decreased heart rate and increased heart rate variability, relative to placebo. Both agents decreased salivary flow rate vs placebo. Treatment-related adverse events were comparable in all groups, the most common being dry mouth; none led to treatment discontinuation. CONCLUSIONS Darifenacin did not affect cognitive, cardiac or visual function in healthy volunteers, a profile that may reflect its relative M 3 receptor selectivity and M 1 /M 2 sparing properties. KEYWORDS darifenacin, dicyclomine, overactive bladder, cognitive function, heart rate OBJECTIVE To evaluate the pharmacodynamic effects of darifenacin (a muscarinic M 3 selective receptor antagonist) and dicyclomine (an M 1 selective receptor antagonist) in healthy male volunteers. SUBJECTS AND METHODS In this double-blind, four-way crossover study, 27 healthy men (aged 19–44 years) were randomized to receive darifenacin 7.5 mg or 15 mg once daily, dicyclomine 20 mg four times daily or matching placebo. Each 7-day treatment period was separated by a 7-day washout. Multiple assessments of cognitive function, quantitative electroencephalogram (EEG) recordings, salivation, visual nearpoint, heart rate and INTRODUCTION Overactive bladder (OAB), defined as urinary urgency (with or without urge incontinence) usually with frequency of micturition and nocturia [1], is a chronic illness that has a debilitating effect on the daily life of affected individuals [2]. Antimuscarinic drugs have become the ‘gold standard’ treatment for OAB, reducing detrusor reflexivity, frequency and strength of the involuntary detrusor contractions, and thus helping to lessen symptom severity [3]. However, in addition to antagonizing cholinergic stimulation of muscarinic M 3 receptors (the subtype responsible for normal and involuntary bladder contractions) [4], current antimuscarinics tend to block other muscarinic receptor subtypes that are distributed in many body tissues [5]. Of particular concern is the untargeted antagonism of brain M 1 receptors, which are important in certain cognitive functions, including learning and memory. In addition, antagonism of M 1 receptors may block activity in salivary glands and sympathetic ganglia [5]. Notably, maximum salivary secretion requires activation of both M 1 and M 3 receptors [6], with M 1 receptors involved in the control of high-viscosity lubricating secretions; thus any agent that only blocks one of the receptor subtypes might reduce the incidence and/or severity of dry mouth in the clinical setting. The M 2 receptors are the predominant subtype in the heart, and are also found in smooth muscle organs and caudal formations of the brain [5]. Antagonism of cardiac M 2 receptors may give rise to tachycardia [5]. These cognitive, CNS and cardiac side-effects are infrequently reported, but can have serious consequences. The CNS-related effects can include, e.g. hallucinations and confusion, particularly in elderly patients with other neurocognitive problems. Although such CNS effects would be of concern for any age group, they are particularly important in elderly individuals. This population is not only more likely to have OAB [2], but also to have several comorbidities, which might predispose them to neurocognitive problems. Moreover, elderly patients are often treated with multiple medications (including anticholinergics), and tend to be more susceptible to antimuscarinic side-effects [7]. Such patients have an increased anticholinergic burden and are at risk of anticholinergic toxicity. Although many signs of this toxicity are well recognized, more subtle CNS effects can be obscured by other symptoms or general age-related declines in an individual’s condition. In particular, muscarinic receptor antagonists can impair memory in the absence of any awareness of this by the patient, and indeed there have been case reports of such events (e.g. [8]). Thus, there is a real need for an effective OAB