To evaluate the pharmacodynamic effects of darifenacin (a muscarinic M3 selective receptor antagonist) and dicyclomine (an M1 selective receptor antagonist) in healthy male volunteers.
To evaluate the pharmacodynamic effects of darifenacin (a muscarinic M3 selective receptor antagonist) and dicyclomine (an M1 selective receptor antagonist) in healthy male volunteers.
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 heart rate variability were made on day 7 in each treatment period.
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.
Darifenacin did not affect cognitive, cardiac or visual function in healthy volunteers, a profile that may reflect its relative M3 receptor selectivity and M1/M2 sparing properties.
visual analogue scales
relative beta ratio
relative theta ratio
relative delta ratio
Overactive bladder (OAB), defined as urinary urgency (with or without urge incontinence) usually with frequency of micturition and nocturia , is a chronic illness that has a debilitating effect on the daily life of affected individuals . 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 . However, in addition to antagonizing cholinergic stimulation of muscarinic M3 receptors (the subtype responsible for normal and involuntary bladder contractions) , current antimuscarinics tend to block other muscarinic receptor subtypes that are distributed in many body tissues . Of particular concern is the untargeted antagonism of brain M1 receptors, which are important in certain cognitive functions, including learning and memory. In addition, antagonism of M1 receptors may block activity in salivary glands and sympathetic ganglia . Notably, maximum salivary secretion requires activation of both M1 and M3 receptors , with M1 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 M2 receptors are the predominant subtype in the heart, and are also found in smooth muscle organs and caudal formations of the brain . Antagonism of cardiac M2 receptors may give rise to tachycardia . 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 , 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 . 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. ). Thus, there is a real need for an effective OAB therapy that is well tolerated and, more importantly, which minimizes CNS and cardiac safety-related side-effects. In the absence of clear differences in the safety profiles of antimuscarinic treatments, healthcare providers have not previously included safety in their criteria for treatment selection. However, the development of a more specific, targeted therapy might provide prescribers or healthcare providers with additional choice and allow safety issues to come to the forefront. Darifenacin is a novel M3 selective receptor antagonist developed for treating OAB; it is highly selective for the M3 receptor, with a mean binding affinity at M3 receptors that is 9.3 times that at M1 receptors, 59 times that at M2 or M4 receptors, and 12 times that at M5 receptors (all P < 0.001) . Given the pivotal role of M3 receptors in detrusor muscle contraction, the selectivity of darifenacin for this receptor subtype is expected to provide clinical efficacy in treating OAB, with fewer adverse events and safety concerns related to blocking other muscarinic receptor subtypes.
In the present study we evaluated the pharmacodynamic effects of darifenacin in healthy volunteers, with particular focus on cognitive and cardiac function. Dicyclomine, an antimuscarinic agent that is selective for the M1 receptor subtype (35-fold selectivity for M1 over M2 receptors) , was used as a positive control for CNS effects.
This was a randomized, placebo-controlled, double-blind, double-dummy, four-way crossover study in 27 healthy male volunteers with a mean (range) age of 28 (19–44) years. Men were excluded if they had taken any prescribed or over-the-counter drug other than acetaminophen (paracetamol, ≤ 3 g/day) within the previous 3 weeks, or any experimental drug in the previous 4 months. Men with, or a close family history of, narrow-angle glaucoma, and men with a peak urinary flow of <15 mL/s were also excluded.
The primary objectives were to investigate the effects of darifenacin and dicyclomine on cognitive function, and the power spectrum of a quantitative electroencephalogram (EEG). The study was conducted in compliance with the Good Clinical Practice Guidelines originating from the Declaration of Helsinki, and the protocol was approved by a local independent Ethics Committee. Written informed consent was obtained from each volunteer before screening or any study-related activity.
The volunteers attended two pre-study visits where their medical history was assessed and a full medical examination was completed, involving blood pressure, pulse rate, 12-lead electrocardiogram (ECG) and urinary flow measurements. Eligible men then had two training sessions in which they were given a computer-based cognitive function test battery (Table 1), to familiarise them with the testing procedure and to reduce the effects of practice. Two more training sessions were conducted on the first day of the first period of treatment. The men participated in four randomized treatment sequences, in an order established using a balanced Latin square design. A pseudorandom code using permuted blocks was used to allocate subjects to one of the four treatment sequences. Treatments comprised: darifenacin controlled-release tablets 7.5 mg once daily; darifenacin controlled-release tablets 15 mg once daily; dicyclomine 20 mg capsules four times daily; and matching placebo. Each treatment period lasted 7 days and was separated by a 7-day washout period that, given the elimination half-lives of the drugs, was sufficient to prevent a carry-over effect. Blinding was maintained by the double-dummy technique. Study drugs (morning doses) were taken under supervision by study personnel, with a mouth check to ensure compliance.
|Primary measure||Supportive measure|
|Immediate word recall||Subject presented with a list of 15 words to memorise at a rate of one every 2 s. Subject is then given 1 min to recall as many words as possible||% of words recalled||Errors, intrusions|
|Picture presentation||A series of 20 pictures is presented on the monitor at a rate of one every 3 s for the subject to remember.|
|Simple reaction time||Subject presses the ‘Yes’ response as quickly as possible every time the word ‘Yes’ is presented on the monitor screen; 50 stimuli are presented with a varying inter-stimulus interval||Speed (ms)|
|Digit vigilance task||A target digit is randomly selected and constantly displayed on the right-hand side of the monitor screen. A series of digits is then displayed in the centre of the screen at 150/min and the subject presses ‘Yes’ every time the digit in the series matches the target digit. There are 45 targets in this task||Speed (ms) and % targets detected||Number of false responses|
|Choice reaction time||Either the word ‘No’ or ‘Yes’ is presented on the monitor screen and the subject must press the corresponding button as quickly as possible. There are 50 trials, for each of which the stimulus word is chosen randomly with equal probability and with a varying inter-stimulus interval||Speed (ms)||Accuracy|
|Visual tracking||Subject uses a joystick to track a randomly moving target on the monitor screen for 1 min and the average off-target distance per second is recorded||Average distance from target (mm)|
|Spatial working memory||A picture of a house is presented on the monitor screen with four of its nine windows lit. The subject must memorise the position of the lit windows. For each of 36 subsequent presentations of the house, the subject must decide whether or not the one window that is lit was also lit in the original presentation by responding ‘Yes’ or ‘No’||Scanning sensitivity† and speed (ms)|
|Numeric working memory||A series of 5 digits is presented for the subject to memorise. This is followed by a series of 30 probe digits, for each of which the subject must decide whether or not it was in the original series and responds ‘Yes’ or ‘No’. This procedure is repeated twice, each time with a different five and 30 digit series||Scanning sensitivity† and speed (ms)|
|Delayed word recall||Subject given 1 min to recall as many words as possible that were presented as part of the immediate recall test||% of words recalled||Errors, intrusions|
|Delayed word recognition||Original words, plus 15 distracter words, are presented one-at-a-time in a randomized order. For each, the subject indicates whether the word is from the original list by responding ‘Yes’ or ‘No’||Recognition sensitivity† and speed (ms)||Recognition speed|
|Delayed picture recognition‡||Original pictures, plus 20 distracter pictures, are presented one-at-a-time in a randomized order. For each, the subject indicates whether the picture is from the original list by responding ‘Yes’ or ‘No’||Recognition sensitivity† and speed (ms)|
|Critical flicker fusion threshold||The subject monitors the flickering of a light source. The frequency at which the light can no longer be perceived to be flickering is identified||Critical flicker fusion threshold (Hz)|
Cognitive function, EEG analysis, visual nearpoint and salivary flow were assessed at the beginning (before the dose) and end of each 7-day treatment period. Cognitive function tests and EEG recordings on the seventh day were done before the medication dose and at 2, 4, 6, 8, 10 and 12 h after dosing. The computer-assisted tests, devised by Cognitive Drug Research (http://www.cdr.org.uk) to measure cognitive processes such as the ability to access short-term memory, to concentrate, and to respond rapidly, are listed in Table 1. The sensitivity of these tests to muscarinic blockade with scopolamine has been shown in both young  and elderly volunteers . The tests were done in the order shown in Table 1. For EEG analysis, Ag/AgCl electrodes were positioned on the scalp according to the 10/20 system (impedances adjusted to ≤ 5 M Ω) on the morning of study days; the following montage was used: (1) Fp1–Fz; (2) T4–C4; (3) O2–P4; and (4) T6–Pz. Channel 1 determined eye movements during data selection and, if artefact-free, was used for analysis; channels 2 and 4 provided transverse data, and channel 3 anterior-posterior data. EEG recordings were made over a 5-min monitoring period, with subjects completing a mental arithmetic task to maintain vigilance (eyes closed), at each time. Recordings were subsequently analysed quantitatively using spectral analysis. In addition, a computerized questionnaire comprising 16 visual analogue scales (VAS), recommended by Bond and Lader , was completed to assess changes in self-rated alertness, calmness and contentment. Visual nearpoint and salivary flow were measured before the morning dose on the first day. Further measurements were made before the morning dose and at 1, 3, 5, 7, 9 and 11 h after the morning dose on the seventh day. Visual nearpoint (cm) was determined using a British Royal Air Force nearpoint rule, and the maximum decrease in the distance on the seventh day relative to baseline was derived and statistically analysed. Salivary flow was evaluated by asking subjects to swallow all saliva and then suck on a candy (of a specific brand and flavour) for 1 min; saliva was then carefully collected to determine salivary flow (mL/min). On the seventh day of each treatment period, quantitative 12-lead ECG recordings, lasting for 15 min, were made before assessments at 4 h after the medication dose. The mean heart rate and heart rate variability were calculated for the middle 5 min of the monitoring period using a validated method for the Mortara Cardio ‘Prodigy’ analyser (Mortara Instrument, Milwaukee, USA).
Adverse events (observed or volunteered through non-leading questioning) were evaluated in terms of seriousness, intensity and causal relationship. Routine laboratory tests, including haematology, biochemistry and urine analysis, were carried out at screening, on the seventh study day, and at follow-up (7–10 days after the final dose). Samples were analysed by Biorim Laboratory (Brussels, Belgium). Vital signs and a 12-lead ECG were also taken to evaluate safety at screening and follow-up. The study was powered to find differences in cognitive function tests only. The inclusion of 24 men (six per group) was considered sufficient to detect a difference from placebo in choice reaction time and subjective alertness similar to that expected with the antimuscarinic agent hyoscine (also known as scopolamine), assuming 80% power testing at the 5% level of significance. Changes from baseline on measures of cognitive functioning, visual nearpoint (maximal increase), salivary flow (area under the salivary flow-time curve, 0–11 h after medication dose), heart rate and heart-rate variability were investigated between groups using split-plot repeated-measures of analysis of variance (anova). EEG data were analysed using an analysis of covariance model (using the baseline value before the medication dose on the first day as covariate).
Of the 27 volunteer men randomized into the study, none were identified as having a medical condition at the start of the study and none were taking any medication of clinical significance. Twenty-three men completed the study and were included in the analysis of cognitive function tests; two were withdrawn because of protocol violations due to detection of drugs of abuse, and two because of withdrawal of consent. For each measure from the cognitive tests and for each volunteer, the assessment before medication on the first day of each treatment period was used as a baseline and subtracted from the data from the seventh day to compute ‘difference from baseline’ scores. Compared to placebo, neither 7.5 nor 15 mg of darifenacin produced a detectable effect on the battery of cognitive function tests performed throughout the 12-h after medication on Day 7. By contrast, compared with placebo, dicyclomine was associated with significant impairment on five of 12 cognitive function measures on Day 7, with the most marked impairment at 2 h after the dose in simple reaction time, speed of spatial and numeric working memory, sensitivity of picture recognition and speed of picture recognition (Fig. 1). Compared with placebo, 2 h after dosing with dicyclomine, simple reaction time on the seventh day was prolonged (P = 0.0085). This was accompanied by decreases in the mean speed of spatial working memory (P = 0.0484), speed of numeric working memory (P = 0.0119), decreased sensitivity of picture recognition (P = 0.0296) and worsening speed of picture recognition (P = 0.0403). No other effects on cognitive function were detected during the study that could be reliably differentiated from chance. There were no clear differences between groups or time points in the Bond-Lader VAS measures of self-rated alertness, calmness or contentment.
The significant impairment of cognitive function measures at 2 h after dicyclomine dosing was paralleled by a statistically significant cluster of EEG changes (Table 2). The effect was mainly posterior and transverse, with some impact on the anterior channel. For example, at 2 h after the dose, in channels 1 and 4 the spectral power of beta, relative beta ratio (Rbeta), and beta2 declined, while relative theta ratio (Rtheta) power increased relative to placebo. An increase in power of the relative delta ratio (Rdelta) was also apparent on channel 4 at this timepoint. In all, dicyclomine resulted in nine significant EEG changes at 2 h. An effect of dicyclomine on EEG was still apparent at 6 and 8 h after the dose, when there were four and two significant changes, respectively (Table 2). By contrast, there were no significant EEG effects at 2 and 4 h after 7.5 mg darifenacin, although there were five significant changes at 6 h after dosing; these changes were in the beta frequencies and on channel 4 (Table 2). Administration of 15 mg darifenacin once daily significantly decreased beta frequencies on channels 1 and 4 (three significant changes) at 2 h after dosing, which were not maintained for the remainder of the monitoring period. Some effects were noted in channels 2 and 3 (four significant changes at 6 h) but in different frequency bands (Table 2). Neither dose of darifenacin produced a significant effect on visual nearpoint vs placebo. In contrast, the estimated difference (95% CI) between dicyclomine and placebo for the maximum increase in visual nearpoint observed over time on the seventh day was 1.53 (0.11–2.96) cm (P = 0.0349). For the area under the salivary flow-time curve to 12 h after the dose on the seventh day, both darifenacin and dicyclomine reduced salivary flow compared to placebo. The estimated difference (95% CI) between drug and placebo was − 274 (−425.5 to −123) mL for 7.5 mg darifenacin (P = 0.0006); −696 (−848 to − 544) mL for 15 mg darifenacin (P < 0.0001); and − 180 (−332 to −28) mL for dicyclomine (P = 0.0213). Neither dose of darifenacin significantly affected heart rate or heart-rate variability at 4 h after the dose compared with placebo (Fig. 2). By contrast, dicyclomine was associated with a reduction in mean heart rate of 4.8 beats/min vs placebo (mean heart rates 55.8 and 60.6 beats/min, respectively; P = 0.0028). Dicyclomine was also associated with an increase in heart rate variability of 11.9% compared with placebo (P = 0.0049; Fig. 2).
|Channel||Time, h||Difference to placebo (95% CI)||P|
|R2†||2||0||−0.056 (−0.11, −0.003)||0.04|
|Beta||1||2||−2.045 (−3.441, −0.649)||0.01|
|Rtheta||1||2||1.23 (0.348, 2.113)||0.01|
|R1‡||3||2||0.089 (0.003, 0.175)||0.04|
|Beta||4||2||−2.451 (−4.387, −0.515)||0.01|
|Beta2||4||2||−0.775 (−1.521, −0.029)||0.04|
|R1‡||4||2||0.12 (0.016, 0.224)||0.03|
|Rbeta||4||2||−1.763 (−3.005, −0.522)||0.01|
|Rdelta||4||2||2.28 (−0.002, 4.561)||0.05|
|Rtheta||4||2||1.238 (0.166, 2.31)||0.02|
|Rdelta||3||4||2.568 (0.75, 4.386)||0.01|
|Beta||1||6||−1.597 (−3.062, −0.132)||0.03|
|R1‡||1||6||0.303 (0.038, 0.569)||0.03|
|R2†||1||6||0.134 (0.016, 0.253)||0.03|
|Rbeta||1||6||−1.909 (−3.495, −0.323)||0.02|
|Rtheta||1||8||−1.252 (−2.091, −0.413)||0.01|
|Theta||1||8||−1.788 (−3.507, −0.069)||0.04|
|Rbeta2||1||10||0.812 (0.056, 1.568)||0.04|
|Theta||3||10||−2.265 (−4.439, −0.092)||0.04|
|Darifenacin, 7.5 mg once daily|
|R2†||2||0||−0.067 (−0.124, −0.01)||0.02|
|Rtheta||3||0||−0.773 (−1.535, −0.011)||0.05|
|Beta1||4||6||0.925 (0.088, 1.761)||0.03|
|Beta2||4||6||0.721 (0.028, 1.414)||0.04|
|Rbeta||4||6||1.514 (0.238, 2.791)||0.02|
|Rbeta1||4||6||0.653 (0.01, 1.296)||0.05|
|Rbeta2||4||6||1.095 (0.335, 1.855)||0.01|
|R2†||1||8||−0.127 (−0.242, −0.011)||0.03|
|Rtheta||1||8||−0.958 (−1.859, −0.056)||0.04|
|Theta||1||8||−2.17 (−3.993, −0.347)||0.02|
|Theta||1||10||−1.847 (−3.687, −0.008)||0.05|
|Darifenacin, 15 mg once daily|
|R2†||1||0||−0.094 (−0.187, −0.001)||0.05|
|Theta||1||0||−2.028 (−3.612, −0.444)||0.01|
|Beta||1||2||−1.629 (−3.001, −0.258)||0.02|
|Beta1||4||2||−0.852 (−1.627, −0.077)||0.03|
|Beta2||4||2||−0.835 (−1.545, −0.125)||0.02|
|Delta||3||6||−2.397 (−4.662, −0.132)||0.04|
|R2†||2||6||−0.082 (−0.141, −0.024)||0.01|
|Rtheta||2||6||−0.965 (−1.959, 0.029)||0.06|
|Theta||3||6||−2.586 (−4.868, −0.304)||0.03|
|Ralpha||2||8||1.952 (0.295, 3.609)||0.02|
|Rbeta2||4||12||−0.709 (−1.269, −0.149)||0.01|
Both doses of darifenacin were generally well tolerated, with no adverse events resulting in treatment discontinuation or dose reduction. Treatment-related adverse events were typically mild or moderate. The most common adverse event was dry mouth, with a similar incidence across the active groups (Table 3). A total of 39 all-causality adverse events were reported by 21 men during the period on darifenacin 7.5 mg; 19 reported 38 adverse events during the period on darifenacin 15 mg; 19 reported 36 adverse events during the dicyclomine period; and 11 reported 20 adverse events during the placebo period. In all, 72 treatment-related adverse events were reported, i.e. 22 in 15 men with darifenacin 7.5 mg, 22 in 13 with darifenacin 15 mg, 19 in 15 during treatment with dicyclomine, and nine in six men on placebo. One serious adverse event (appendicitis) occurred 21 days after completing treatment and was not considered to be drug-related. Four laboratory abnormalities were reported, relating to changes in urine analysis (protein, glucose and haemoglobin), i.e. two on darifenacin 7.5 mg, one on darifenacin 15 mg and one in the placebo period.
|Adverse event, n||Darifenacin||Dicyclomine (24 men)||Placebo (24 men)|
|7.5 mg (27 men)||15 mg (25 men)|
|Abnormality of visual accommodation||1||1||2||0|
The present study showed that the administration of darifenacin, an antimuscarinic agent with relative selectivity for the M3 receptor subtype, did not adversely affect cognitive and cardiac function at clinically relevant doses, whereas dicyclomine, an antimuscarinic agent with relative selectivity for the M1 subtype, resulted in significant impairment of cognitive function, and a significant reduction in heart rate and increase in heart-rate variability. Unlike darifenacin, currently available agents are less selective in their binding profile, and have greater affinity for M1 and M2 receptors. The CNS-depressant effects of oxybutynin in particular are well established [15–17]. Typically, the more subtle CNS-depressant effects of OAB medications are incorrectly attributed to age-related functional decline. In the present study, darifenacin, an M3-selective receptor antagonist, was not associated with CNS adverse effects, highlighting its potential as a highly suitable pharmacological treatment for patients with OAB, many of whom are at risk of such events with other pharmacotherapies.
It is well established that muscarinic M1 receptors have a central role in cognitive functions such as memory and learning, hence this receptor subtype is a therapeutic target for Alzheimer's disease , although the clinical effectiveness of M1 agonists remains to be confirmed. Consequently, disruption of cholinergic activity for patients with dementia disorders can be particularly problematic, and there are reports of dementia and the development of clinically significant delirium in patients taking a combination of acetylcholinesterase inhibitors and tolterodine .
For darifenacin, at the therapeutic doses of 7.5 and 15 mg once daily, there was no evidence of cognitive impairment; there was no deterioration on tests of short-term memory, concentration or speed of response compared with placebo. These findings are consistent with the agent's relative selectivity for the M3 receptor over the M1 subtype , and are in accord with preclinical studies in which darifenacin was nearly 50-fold less potent than atropine (a nonselective antimuscarinic agent) at inhibiting oxotremorine-induced tremor (an effect mediated by central M1 receptors) in the mouse . By contrast, in the present study, the M1 selective drug dicyclomine produced cognitive impairment consistent with central blockade of this receptor subtype. Thus, dicyclomine was associated with a significant decline in simple reaction time, deterioration in the speed of spatial and numeric working memory, decreased sensitivity of picture recognition and worsening speed of picture recognition, the overall effect being similar to that produced by 2–3 units of alcohol .
EEG data have often been reported as a physiological measure of the impact of medications on CNS function, including studies of OAB medications . However, in earlier studies, quantitative EEG findings were not correlated with performance on cognitive function tests. In the present study, dicyclomine produced a rapid and sustained effect on quantitative EEG that was associated with changes in cognitive test performance beginning 2 h after dosing and continuing for several hours. By contrast, darifenacin was associated with short-lived EEG changes that were delayed in onset (6 h after the dose) and which were not associated with cognitive changes. The EEG changes with darifenacin appeared to be related to somatosensory changes, e.g. through brain activity associated with treatment-induced effects on vision, dry mouth or sensations in the bladder. Many factors affect the potential of an antimuscarinic agent to mediate adverse effects on cognitive function. The ability to cross the blood–brain barrier and penetrate the CNS has been viewed as particularly relevant . Currently available antimuscarinics penetrate the CNS to varying degrees. For example, oxybutynin, a relatively lipophilic, uncharged and small molecule, is thought to cross the blood–brain barrier readily. Conversely, the CNS penetration of tolterodine is thought to be low, as is that of trospium chloride, a highly charged molecule . However, CNS penetration can be influenced by several factors that can alter the blood–brain barrier, allowing increased permeability to drugs that would otherwise have ‘restricted’ entry . Penetration into the CNS increases with age  and may also be increased by various disease states such as type-2 diabetes . However, no human studies have been conducted in which any of these factors have been reported to increase CNS adverse events associated with antimuscarinic agents. Another factor influencing CNS concentrations is whether the drug is a substrate for P-glycoprotein, which is involved in the active transport of molecules out of the brain . In this context, it is notable that darifenacin has been found to be a substrate for P-glycoprotein in preclinical studies . Consequently, CNS concentrations of the drug are likely to be very low, as found in animal studies of tissue distribution using [14C]-darifenacin . Thus, the combination of low brain concentrations of darifenacin coupled with a low affinity for M1 receptors are likely to contribute to darifenacin's relative lack of effect on cognitive function, as seen in the present study.
Another potential benefit of M3 receptor selectivity is a low risk of cardiac side-effects. The heart contains a predominance of M2 receptors that play a role in inducing bradycardia ; as such, drugs that antagonize M2 receptors may induce tachycardia. Prescribing information for several antimuscarinic agents lacking in relative selectivity for M3 over M2 receptors and used in treating OAB includes reports of tachycardia and palpitations in postmarketing surveillance studies (e.g. tolterodine, trospium). In addition, in a placebo-controlled study comparing the effects of trospium 20 mg twice daily and moxifloxacin 400 mg once daily in 170 healthy subjects, a mean increase of 9.1 beats/min in heart rate vs placebo was reported for trospium . In the present study we therefore evaluated the effect of darifenacin on heart rate, along with heart-rate variability. The latter measurement provides an additional assessment that has clear diagnostic impact and is predictive of more serious events such as arrhythmic complications and mortality .
Overall, darifenacin produced no effect on these variables, which is in accord with its high selectivity (59-fold) for the M3 receptor over the M2 subtype . That darifenacin had no effects on heart rate or heart-rate variability is clinically important, and is particularly relevant in reducing safety risks for patients predisposed towards (or suffering from) concomitant heart conditions. As many patients with OAB are elderly and are likely to have such comorbidities, a substantial proportion of patients could be spared the risks associated with nonselective antimuscarinic therapy.
Despite its relative M1 selectivity, dicyclomine (which is 35-fold selective for M1 over M2 receptors ) evoked a decrease in heart rate and increased heart-rate variability. This might be related to in vitro findings that carbachol-induced increases in calcium transients of ventricular myocytes are mediated by M1 receptors , which would be antagonized by dicyclomine.
Blurred vision is also a common side-effect of antimuscarinic therapy for OAB, as muscarinic receptors are important in visual accommodation. The human iris-ciliary muscle expresses both M3 and M5 receptors, and each subtype might be functionally important, based on investigations of the canine eye . Despite the importance of M3 receptors in visual accommodation, darifenacin was not associated with changes in visual nearpoint, relative to placebo, in the present study. Whether this reflects the fact that the eye is a privileged site protected by a blood-eye barrier, which might show limited penetration of darifenacin, remains to be established. By contrast, dicyclomine elicited a greater maximum increase in visual nearpoint than placebo, suggesting that dicyclomine penetrates the eye and acts upon muscarinic receptors involved in visual accommodation. While dicyclomine has reported selectivity for the M1 receptor subtype , it has similar affinity for M5 receptors , which might explain its effect on visual nearpoint in the present study.
Several muscarinic receptor subtypes regulate salivation. Thus, M3 receptors play a functional role in producing low-viscosity secretions by serous cells, while both M3 and M1 subtypes are important in producing lubricating secretions by mucous cells . Selective blockade of the M3 receptor was thus expected to affect salivary secretion, as found in the present study. However, with less effect on M1 receptors a significant proportion of lubricating function should remain. This probably explains why reports of dry mouth with darifenacin were rated as mild to moderate in severity and were not treatment-limiting, findings that are in agreement with the results of large clinical trials with darifenacin .
One possible limitation of extrapolating the present findings to the OAB population is that this was a relatively small study in healthy young men, whereas OAB tends to affect older individuals, many of whom have comorbidities. However, in another placebo-controlled study, darifenacin (up to 15 mg once daily) had no effect on cognitive function tests such as memory scanning sensitivity, choice reaction time and word recognition sensitivity, in a large sample of elderly volunteers . These findings suggest that darifenacin would have a low risk of cognitive impairment among the target population of patients with OAB.
In conclusion, darifenacin was not associated with adverse effects on cognitive and cardiac function in the present study. The relative selectivity for the M3 receptor of the drug probably explains the lack of cognitive and cardiac side-effects that are seen with other antimuscarinic agents. Such findings therefore highlight the potential of this agent for the pharmacological treatment of OAB.
Manuscript preparation was supported by an educational grant from Novartis Pharma AG. Editorial and project management services were provided by Thomson ACUMED®.
G. Kay is a consultant and speaker. Source of funding: Novartis, Pfizer.