darifenacin and Urination-Disorders

Antimuscarinic drug therapy has been shown to be effective in the management of patients with symptoms of the overactive bladder syndrome (OAB), but the bothersome antimuscarinic adverse effects of dry mouth, constipation, somnolence and blurred vision often affect compliance with medication. The development of bladder selective M3 specific antagonists offers the possibility of increasing efficacy whilst minimising adverse effects. The M3 specific antagonist solifenacin has recently been marketed, and darifenacin will soon be available. The purpose of this article is to review the pharmacology and clinical trial data available for darifenacin, in addition to examining its role in the treatment of the OBS.

Topics: Absorption; Benzofurans; Central Nervous System Diseases; Drug Interactions; Drug Tolerance; Heart Rate; Humans; Muscarinic Antagonists; Pyrrolidines; Receptors, Muscarinic; Treatment Outcome; Urinary Bladder Diseases; Urination Disorders

Limitations exist with regard to the array of available agents for the pharmacologic therapy of overactive bladder, including issues of efficacy and tolerability. It is clear that the ideal agent for this condition has not been identified. However, several new pharmacologic treatments, including some with novel approaches to drug delivery, have emerged in clinical development over the past few years. These agents include a variety of anticholinergics and others. In initial studies, some of the agents appear to compare favorably with existing therapies. Whether these promising results will hold up when subjected to large-scale, well-controlled clinical trials is unclear.

Topics: Administration, Cutaneous; Administration, Intravesical; Administration, Oral; Adrenergic beta-3 Receptor Antagonists; Benzhydryl Compounds; Benzilates; Benzofurans; Botulinum Toxins; Cresols; Dosage Forms; Dose-Response Relationship, Drug; Drug Compounding; Drug Evaluation; Duloxetine Hydrochloride; Humans; Mandelic Acids; Muscarinic Antagonists; Nortropanes; Phenylpropanolamine; Pyrrolidines; Thiophenes; Tolterodine Tartrate; Treatment Outcome; Urinary Bladder Diseases; Urination Disorders

This study evaluated the efficacy, tolerability, and safety of darifenacin, an M3 selective receptor antagonist (M3 SRA), in patients with overactive bladder (OAB). In a multicenter, double-blind, placebo-controlled dose-ranging study, 439 adult OAB patients (85.4% female) were randomized to darifenacin controlled-release tablets 7.5 mg (n = 108), 15 mg (n = 107) or 30 mg (n = 115) qd, or placebo (n = 109) for 12 weeks. Darifenacin significantly reduced the median number of incontinence episodes/week (-68.7, -76.5, and -77.3% from baseline at 7.5, 15, and 30 mg, respectively, vs -46% with placebo, all p < 0.01) and dose relatedly improved micturition frequency, frequency and severity of urgency, nocturia, and bladder capacity. Darifenacin was well tolerated. Adverse events were commonly mild to moderate dry mouth and constipation. There were no safety concerns. Darifenacin is effective and well tolerated in the treatment of OAB, with 7.5 and 15 mg doses offering flexibility of dosing for optimal treatment outcome.

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Constipation; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Placebos; Pyrrolidines; Receptor, Muscarinic M3; Safety; Tablets; Treatment Outcome; Urinary Bladder; Urinary Incontinence; Urination; Urination Disorders; Xerostomia

The aim of the study was to establish a methodology whereby ambulatory urodynamic monitoring (AUM) may be used in the assessment of the effects of darifenacin on urodynamic measures of detrusor function and symptoms associated with detrusor instability. Six patients (one man and five women) with detrusor instability (DI) on conventional urodynamic monitoring were recruited into this placebo-controlled crossover study. The study was divided into two periods of 7 days of treatment with either darifenacin 5 mg t.d.s. or placebo with the patient crossing over to the alternative treatment after a washout period of 7 days. On the 7th day of each treatment, AUM was carried out. Parameters used to quantify detrusor activity on AUM were the number, amplitude, and duration of detrusor contractions and the total area under the detrusor pressure/time curve. "Events" recorded were urge, leakage episodes, voids, and pain. Six comparable hours of AUM for each treatment period could be analyzed in four patients and 4 hr in one. In three of the five patients, reduction in activity on AUM while on darifenacin was apparent. Symptom data closely matched the changes in detrusor activity measured on AUM. This is the first study reporting the use of AUM in the development of a drug with an effect on detrusor activity. AUM has clear advantages over conventional cystometry, which can only measure surrogate urodynamic parameters at a single time point. The optimal duration of monitoring in this context appears to be 6 hr with prolongation of monitoring time beyond this being unlikely to yield additional useful information. Correlation between symptoms and findings on AUM is good with changes in parameters recorded on AUM relating closely to the improvement in symptoms.

Topics: Benzofurans; Cholinergic Antagonists; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Monitoring, Ambulatory; Patient Acceptance of Health Care; Prospective Studies; Pyrrolidines; Urinary Bladder; Urination Disorders; Urodynamics