benzofurans and Xerostomia

Drug therapy for overactive bladder (OAB) most commonly includes antimuscarinic agents, which work by relaxing bladder smooth muscle through inhibition of acetylcholine receptors in the bladder. The major adverse effects with existing antimuscarinic agents are anticholinergic in nature (e.g., dry mouth, constipation, blurred vision). Oxybutynin and tolterodine have been used for several years for treatment of OAB; both are available in immediate- and extended-release formulations. Fewer or less severe adverse effects are reported with the extended- versus the immediate-release formulations, with little or no difference in efficacy. Oxybutynin is also available as a transdermal patch. Trospium, which was recently approved for use in the United States, has efficacy and an incidence of dry mouth similar to existing agents but does not cross the blood-brain barrier. It requires twice-daily dosing. Two new antimuscarinic agents--darifenacin and solifenacin--are in development. Both show significantly better efficacy compared with placebo for key symptoms of OAB, including urgency. The incidence of dry mouth at the lowest effective dose is 19% for darifenacin and 8% and 14% for solifenacin (2 studies).

Topics: Benzhydryl Compounds; Benzilates; Benzofurans; Constipation; Cresols; Delayed-Action Preparations; Humans; Mandelic Acids; Muscarinic Antagonists; Nortropanes; Phenylpropanolamine; Pyrrolidines; Quinuclidines; Solifenacin Succinate; Tetrahydroisoquinolines; Tolterodine Tartrate; Treatment Outcome; Urinary Incontinence; Vision Disorders; Xerostomia

Antimuscarinics, used commonly to treat overactive bladder, may differ in their potential to increase heart rate via effects on cardiac muscarinic M2 receptors. This prospective, 3-way crossover, randomized, double-blind study assessed the heart rate effects of 7 days' exposure to a nonselective M2/M3 receptor blocker (tolterodine; 4 mg/d), a highly selective M3 receptor blocker (darifenacin; 15 mg/d), and placebo in 162 healthy participants > or = 50 years. Heart rate was measured by 24-hour Holter monitoring. Tolterodine significantly increased heart rate versus darifenacin and heart rate versus placebo, while darifenacin did not affect heart rate versus placebo. The proportion of participants with an increase in mean heart rate per 24 hours of > or =5 beats per minute was higher with tolterodine than with darifenacin (P = .0004) or with placebo (P = .0114) but did not differ between darifenacin and placebo. The results show that antimuscarinics exert differential effects on heart rate depending on their muscarinic receptor profile. This should be considered when selecting a treatment.

Topics: Age Factors; Aged; Aged, 80 and over; Benzhydryl Compounds; Benzofurans; Constipation; Cresols; Cross-Over Studies; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Female; Heart Rate; Humans; Male; Middle Aged; Muscarinic Antagonists; Phenylpropanolamine; Prospective Studies; Pyrrolidines; Time Factors; Tolterodine Tartrate; Xerostomia

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

To examine, in a 2-year, non-comparative, open-label extension study, the safety, tolerability and efficacy of darifenacin controlled-release (CR) 7.5/15 mg once daily in patients with overactive bladder (OAB) who completed two 12-week randomized, double-blind, placebo-controlled 'feeder' studies.. Patients entering the extension received darifenacin 7.5 mg once daily for 2 weeks, after which a voluntary increase in dose to 15 mg was permitted. Thereafter, patients could adjust the dose (either 7.5 or 15 mg). Safety and tolerability were assessed from adverse events (AEs) and discontinuations. Efficacy was determined using various endpoints.. In all, 716 patients entered the extension (mean age 57.3 years; 85.1% women) and 475 (66.3%) completed it (1089.9 patient-years of exposure). Darifenacin was well tolerated with no significant safety concerns. The most commonly reported AEs were dry mouth and constipation (all-causality rates 23.3% and 20.9%, respectively), leading to discontinuation in 1.3% and 2.4% of patients, respectively. Constipation infrequently required intervention, and analysis of bowel-habit questionnaires revealed that the reporting of constipation was related to minor changes in bowel habit rather than true constipation. The efficacy of darifenacin was maintained, including significant improvements in the number of incontinence episodes/week (median change -84.4% at 2 years, P < 0.001 vs feeder-study baseline). After 2 years, > 40% of patients achieved a > or = 90% reduction in incontinence episodes/week.. In the first published 2-year, open-label study of a CR antimuscarinic agent, darifenacin 7.5/15 mg once daily had a favourable safety, tolerability and efficacy profile during the long-term treatment of OAB. As such, darifenacin represents a valuable therapeutic option for OAB.

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Constipation; Delayed-Action Preparations; Double-Blind Method; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Pyrrolidines; Treatment Outcome; Urinary Incontinence; Xerostomia

We assessed the effect of darifenacin, an M3 selective receptor antagonist, on the warning time associated with urinary urgency.. In this multicenter, double-blind study subjects with urinary urgency for 6 months or greater and episodes of urgency 4 times or greater daily were randomized to darifenacin controlled release tablets (30 mg once daily) or placebo. Warning time was defined as the time from the first sensation of urgency to voluntary micturition or incontinence. Data were collected using electronic event recorders during 6-hour clinic visits or 3 urge-void cycles, if shorter, at baseline and at treatment end.. A total of 72 subjects entered the study and 67 were included in the primary efficacy analysis (darifenacin in 32 and placebo in 35). Darifenacin treatment resulted in a significant increase in mean warning time with a median increase of 4.3 minutes compared with placebo (p = 0.003). Overall 47% of darifenacin treated subjects compared with 20% receiving placebo achieved a 30% increase or greater in mean warning time (OR 5.6, p = 0.009). Median and minimum warning times were also significantly increased following darifenacin treatment vs placebo (p = 0.004 and 0.017, respectively). The median difference in minimum warning time was 1.9 minutes in favor of darifenacin vs placebo.. To our knowledge this is the first study to evaluate change in warning time, which is potentially important to individuals with symptoms associated with overactive bladder. Darifenacin increases mean, median and minimum warning time compared with placebo, allowing subjects more time to reach a toilet and potentially avoiding the embarrassing experience of incontinence.

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Constipation; Delayed-Action Preparations; Double-Blind Method; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Placebos; Pyrrolidines; Receptor, Muscarinic M3; Safety; Time Factors; Treatment Outcome; Urinary Incontinence; Urination; Xerostomia

Darifenacin (Enablex) and solifenacin (VESIcare) are 2 new oral anticholinergics available for once-daily symptomatic treatment of overactive bladder. Overactive bladder is a common condition in older patients. The 5 drugs currently approved for treatment are modestly effective but also cause anticholinergic adverse effects such as dry mouth and constipation and can cause confusion in the elderly. In some experimental studies, the new drugs particularly target bladder receptors, but the clinical significance of these findings is unknown.

Topics: Benzofurans; Drug Interactions; Humans; Intestinal Obstruction; Pyrrolidines; Quinuclidines; Solifenacin Succinate; Tetrahydroisoquinolines; Urinary Incontinence; Xerostomia