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Purpose: The aim of this meta-analysis was to investigate the effect of pharmacotherapy for overactive bladder on the pathogenesis of urinary tract infection. Materials and Methods: A comprehensive search was performed in MEDLINE and the Cochrane Library using terms for overactive bladder, antimuscarinic agents, and beta 3eadrenoceptor agonists. The primary end point was the emergence of urinary tract infection after pharmacotherapy for overactive bladder. The secondary end point was the emergence of urinary retention, dysuria, and/or increased residual urine volume after overactive bladder treatment. Metaanalyses were conducted using random-effects models. Results: A total of 35,939 patients in 33 trials (29 trials of antimuscarinic agents vs placebo, and 9 trials of beta 3eadrenoceptor agonists vs placebo) that included patients with overactive bladder were identified. At 1-3 months after treatment, the incidence of urinary tract infections was statistically significantly higher in the patients treated with antimuscarinic agents (RR: 1.23, 95% CI: 1.04, 1.45; P [ .013) than in the placebo control group. The incidence of urinary tract infections was not increased in the patients treated with beta 3eadrenoceptor agonists (RR: 1.04, 95% CI: 0.76, 1.42; P [ .796). Antimuscarinic agents also statistically significantly increased the risks of urinary retention, dysuria, and/or increased residual urine volume (RR: 2.88, 95% CI: 1.79, 4.63; P < .001), whereas beta 3eadrenoceptor agonists did not (RR: 1.26, 95% CI: 0.38, 4.14; P [ .708). Conclusions: This meta-analysis showed that antimuscarinic agents statistically significantly increased the incidences of urinary tract infection and lower urinary tract symptoms and dysfunction, but beta 3eadrenoceptor agonists did not. To prevent urinary tract infection emergence, beta 3eadrenoceptor agonists might be safer than antimuscarinic agents. [ABSTRACT FROM AUTHOR]

Purpose: We evaluate the efficacy and safety of combining antimuscarinics with alpha-blockers to treat storage symptoms in men with benign prostatic hyperplasia. Materials and Methods: Searches were carried out on PubMed, MEDLINE, EMBASE, and Cochrane databases to identify randomized, placebo-controlled trials published before February 15, 2022, assessing the efficacy or safety of antimuscarinics in men with benign prostatic hyperplasia treated with alpha-blockers. Further meta-analyses were performed using standardized mean difference and risk ratio. Results: A total of 12 randomized trials were included in the systematic review. The meta-analysis showed no impact of antimuscarinics on the number of urgencies per day (SMD -0.23 [95%CI: -0.64; -0.17]; P = .21). However, the use of antimuscarinics was associated with a small reduction of micturition episodes per day (SMD -0.19 [95%CI: -0.37; -0.01]; P=.045). With regard to side effects, post-void residual increased slightly in patients treated with antimuscarinics (SMD 0.26 [95% CI: 0.15; 0.37]; P < .01). In addition, there was a higher risk of acute urinary retention (RR 3.26 [95%CI: 1.35; 7.86]; P = .02), dry mouth (RR 3.43 [95%CI: 1.86; 6.32]; P < .001), and constipation (RR 2.92 [95%CI: 1.48; 5.73]; P < .001) with the use of antimuscarinics. Finally, the risk of treatment interruption due to adverse events was higher for the patients treated with antimuscarinics (RR 1.74 [95%CI: 1.27; 2.38]; P < .01). Conclusions: The addition of antimuscarinics to alpha-blockers was not associated with a substantial reduction in urgencies and micturition episodes in benign prostatic hyperplasia patients with storage symptoms. In addition, the toxicity profile was not in favor of antimuscarinic use in these patients. [ABSTRACT FROM AUTHOR]

Purpose: We investigated the efficacy and safety of high-dose vitamin D supplementation (VDS) plus standard urotherapy (SU) in managing overactive bladder dry in children., Materials and Methods: A 3-arm, randomized clinical trial was performed at an academic center in China between January 2023 and June 2023. Eligible patients (n=303) were randomized to receive 8 weeks of high-dose VDS (vitamin D3 drops encapsulated as soft capsules, 2400 IU/d) plus SU (VDS + SU group; n=100), solifenacin (5-10 mg/d) plus SU (SOL + SU group; n=102), or SU alone (SU group; n=101). Reduction in voiding frequency was the primary outcome. Secondary outcomes encompassed improvement in urgency, nocturia, quality of life score, pediatric lower urinary tract symptom score, and participant satisfaction. Treatment-emergent adverse events were recorded within each group., Results: Participants had a median age of 82.0 months and their baseline mean vitamin D level was 22.64 ng/mL. The VDS + SU group showed greater improvements in voids/d than the SOL + SU group (median difference 3.0; 95% CI, 2.0 to 3.5; P < .001) and the SU group (median difference 4.0; 95% CI, 3.0 to 5.0; P < .001) after intervention. The VDS + SU group also showed the greatest improvement in quality of life and pediatric lower urinary tract symptom scores. Patient satisfaction was similar between the SOL + SU and SU groups. The VDS + SU group did not exhibit a heightened risk of treatment-emergent adverse events compared to the other groups., Conclusions: High-dose VDS plus SU was effective and well-tolerated in managing overactive bladder dry in children, suggesting its potential as a novel therapeutic option for this population.

Purpose A recent study demonstrated improvement in nocturnal urgency in patients with overactive bladder when treated with fesoterodine. In the current study we aimed to determine which bladder diary parameters predict the response to fesoterodine in these patients. Materials and Methods Patients with nocturnal urgency completed a 2-week, single-blind placebo run-in followed by 1:1 double-blind randomization to 12 weeks of fesoterodine or placebo. We analyzed bladder diary parameter changes from baseline to week 12, including the actual number of night voids (total number of nocturia episodes), maximum voided volume, nocturnal bladder capacity, Nocturnal Bladder Capacity Index (NBCi) (actual number of night voids – nocturnal urine volume/maximum voided volume – 1), nocturnal urine volume, the nocturia index (nocturnal urine volume/maximum voided volume) and the nocturnal polyuria index (nocturnal urine volume/24-hour volume). Additionally, we analyzed OAB-q (Overactive Bladder Questionnaire) changes. Results There was a linear relationship between the likelihood of being a responder for NBCi and the nocturia index. Responders had a significant decrease in nocturnal urine volume relative to baseline (–181.7 ml, p <0.01). Neither group showed a significant change in maximum voided volume relative to baseline. There was a significant decrease in NBCi and the nocturia index in responders (–0.82 and –0.61, respectively, each p <0.01). Responders demonstrated improvement in the OAB-q concern, coping, sleep, bother and total score metrics. Conclusions Patients with nocturnal urgency secondary to overactive bladder syndrome and low nocturnal bladder capacity with a mismatch between nocturnal urine production and bladder capacity may benefit from fesoterodine. Symptom improvement appears to be mediated by increases in typical rather than maximum nocturnal voided volumes. Symptom improvement was associated with improved quality of life. [ABSTRACT FROM AUTHOR]

Purpose Mirabegron (β3 adrenoreceptor agonist) is a new molecule with a mechanism of action distinct from antimuscarinics. Combination therapy with solifenacin was recently studied in an adult population. We evaluated the efficacy and safety of mirabegron as add-on therapy to treat urinary incontinence in children with idiopathic overactive bladder refractory/intolerant to antimuscarinics. Materials and Methods A prospective off-label study using add-on regimens of mirabegron was conducted in pediatric patients presenting with no symptom improvement while undergoing intensive behavioral and medical therapies and/or significant side effects while undergoing antimuscarinic dose escalation. Our primary outcome was better reported efficacy than with the use of prior antimuscarinic monotherapy. Secondary end points were tolerability, safety and satisfaction. Efficacy and tolerability were assessed based on voiding diaries, post-void residuals, urine cultures, electrocardiograms and vital signs. Families were questioned regarding continence, side effects and compliance. Wilcoxon signed-rank test was used for statistical analysis. Results A total of 35 patients were recruited at a median age of 10.3 years and were administered add-on mirabegron for a median of 16.4 months. Median bladder capacity improved from 50% to 74% expected bladder capacity (p <0.001). Continence improved in all patients, with 12 being completely dry. Post-void residual was increased in 2 patients and 1 urinary tract infection was reported. Seven patients reported mild or moderate side effects, with 2 withdrawals because of side effects (1 patient) and post-void residual (1). Conclusions Add-on mirabegron appears to be a safe alternative for children with refractory overactive bladder. Dual therapy is well tolerated and adjusted dose regimen appears safe in this first pediatric study. [ABSTRACT FROM AUTHOR]

Purpose: We investigated the safety and efficacy of peroneal electrical transcutaneous neuromodulation using the URIS neuromodulation system in a home-based setting in comparison with standard treatment using solifenacin in treatment-naïve female patients with overactive bladder., Materials and Methods: A total of 120 patients were screened, of whom 77 were randomized in a 2:1 ratio to 12 weeks of treatment with daily peroneal electrical transcutaneous neuromodulation or solifenacin 5 mg. The primary endpoint was safety; efficacy assessments included proportion of responders, defined as subjects with ≥50% reduction in bladder diary-derived variables; Overactive Bladder-Validated 8-question Screener, and European Quality of Life-5 Dimensions questionnaire; and treatment satisfaction after 12 weeks of therapy., Results: Seventy-one out of 77 randomized patients completed the study. In the peroneal electrical transcutaneous neuromodulation group 6/51 (12%) patients reported a treatment-related adverse event vs 12/25 (48%) in the solifenacin group ( P < .001). No clinically significant changes were observed in any other safety endpoint. The proportions of responders in the peroneal electrical transcutaneous neuromodulation group vs the solifenacin group were 87% vs 74% with respect to Patient Perception of Intensity of Urgency Scale grade 3 urgency episodes, 87% vs 75% with respect to grade 3+4 urgency episodes, and 90% vs 94% with respect to urgency incontinence episodes. In post hoc analyses we observed significant improvement over time in multiple efficacy variables in both treatment arms., Conclusions: Peroneal electrical transcutaneous neuromodulation is a safe and effective method for overactive bladder treatment associated with a significantly lower incidence of treatment-related adverse events compared to solifenacin and a considerably better benefit-risk profile.

Purpose: The aim of this meta-analysis was to investigate the effect of pharmacotherapy for overactive bladder on the pathogenesis of urinary tract infection., Materials and Methods: A comprehensive search was performed in MEDLINE and the Cochrane Library using terms for overactive bladder, antimuscarinic agents, and beta 3-adrenoceptor agonists. The primary end point was the emergence of urinary tract infection after pharmacotherapy for overactive bladder. The secondary end point was the emergence of urinary retention, dysuria, and/or increased residual urine volume after overactive bladder treatment. Meta-analyses were conducted using random-effects models., Results: A total of 35,939 patients in 33 trials (29 trials of antimuscarinic agents vs placebo, and 9 trials of beta 3-adrenoceptor agonists vs placebo) that included patients with overactive bladder were identified. At 1-3 months after treatment, the incidence of urinary tract infections was statistically significantly higher in the patients treated with antimuscarinic agents (RR: 1.23, 95% CI: 1.04, 1.45; P = .013) than in the placebo control group. The incidence of urinary tract infections was not increased in the patients treated with beta 3-adrenoceptor agonists (RR: 1.04, 95% CI: 0.76, 1.42; P = .796). Antimuscarinic agents also statistically significantly increased the risks of urinary retention, dysuria, and/or increased residual urine volume (RR: 2.88, 95% CI: 1.79, 4.63; P < .001), whereas beta 3-adrenoceptor agonists did not (RR: 1.26, 95% CI: 0.38, 4.14; P = .708)., Conclusions: This meta-analysis showed that antimuscarinic agents statistically significantly increased the incidences of urinary tract infection and lower urinary tract symptoms and dysfunction, but beta 3-adrenoceptor agonists did not. To prevent urinary tract infection emergence, beta 3-adrenoceptor agonists might be safer than antimuscarinic agents.

Purpose We investigated improvements in overactive bladder and patient reported outcomes in patients with overactive bladder and refractory incontinence treated with mirabegron 50 mg plus solifenacin 5 mg vs solifenacin 5 or 10 mg. Materials and Methods Patients with overactive bladder who were incontinent despite 4 weeks of single-blind daily solifenacin 5 mg were randomized 1:1:1 to a double-blind daily combination of mirabegron 50 mg/solifenacin 5 mg, or solifenacin 5 or 10 mg for 12 weeks. The mirabegron dose was increased from 25 to 50 mg after week 4. Symptom bother, health related quality of life and patient perception of bladder condition were assessed by OAB-q (Overactive Bladder Questionnaire) and the PPBC (Patient Perception of Bladder Condition) questionnaire, respectively. Responder rates were based on a 50% reduction in daily incontinence, zero incontinence episodes and fewer than 8 micturitions per 24 hours with minimal important differences in OAB-q and PPBC. Results Overall 2,174 patients with a median age of 59 years were randomized, including 727 to the combination, 728 to solifenacin 5 mg and 719 to solifenacin 10 mg. Symptom bother, total health related quality of life and its subscales (coping, concern and social), and PPBC were significantly improved with combination vs solifenacin monotherapy (p <0.05). The odds of achieving clinically meaningful improvements in incontinence, micturition frequency, symptom bother, health related quality of life and PPBC were significantly higher for combination than solifenacin monotherapy. The odds of becoming continent was 47% and 28% higher for combination vs solifenacin 5 and 10 mg (OR 1.47, 95% CI 1.17–1.84, p = 0.001 and OR 1.28; 95% CI 1.02–1.61, p = 0.033, respectively). Conclusions Significantly more patients on the combination achieved clinically meaningful improvements in incontinence and micturition frequency. Improvements were accompanied by similar improvements in PPBC, symptom bother and health related quality of life. [ABSTRACT FROM AUTHOR]

Purpose: To our knowledge no group has evaluated antimuscarinic efficacy in patients with de novo overactive bladder after mid urethral sling placement. We assessed solifenacin efficacy in women with de novo overactive bladder after obturator tension-free vaginal tape placement compared to a control group. Materials and Methods: We prospectively considered all women with de novo overactive bladder symptoms at a 3-month followup visit after placement of obturator tension-free vaginal tape. Patients with overactive bladder preoperatively and those with obstructive symptoms or signs were excluded from analysis. Women who satisfied inclusion and exclusion criteria (group 1) were compared with a series of consecutive naïve patients with overactive bladder symptoms without a previous surgical procedure for stress urinary incontinence (group 2). We prescribed 12-week antimuscarinic therapy with oral solifenacin 5 mg once daily. Objective outcomes included changes from baseline in 3-day voiding diary data. Subjective efficacy was evaluated using the Overactive Bladder Questionnaire Short Form, Urgency Severity Scale and Patient Global Impression of Improvement questionnaires. Results: A total of 110 patients with de novo overactive bladder after obturator tension-free vaginal tape placement completed solifenacin treatment and were included in group 1. They were compared with 120 consecutive naïve women with overactive bladder (group 2). Group 1 presented at the 3-month followup visit with significantly less benefit in the mean decrease in urgency and urgency urinary incontinence episodes daily (−1.1 vs −2.3 and −0.2 vs −1.1, respectively, each p <0.0001). In group 1 we also found a lower subjective solifenacin effect. Previous obturator tension-free vaginal tape placement was an independent predictor of failed solifenacin treatment. Conclusions: Antimuscarinic treatment with solifenacin had significantly lower efficacy in women with de novo overactive bladder after mid urethral sling placement than in controls. [ABSTRACT FROM AUTHOR]

Purpose: Antimuscarinic drug treatment is known to have side effects and, consequently, poor adherence in therapeutic regimens. In this systematic review we study the long-term (greater than 6 months) adherence to antimuscarinic drugs in daily clinical practice, and identify factors contributing to poor adherence and persistence. Materials and Methods: This systematic review was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A literature search was performed using PubMed® and Embase™ using synonyms for incontinence, overactive bladder and antimuscarinics combined with synonyms for medication adherence. We chose to include only pharmaceutical database studies (using prescription/insurance claim data) and patient self-report studies, using established pharmacoepidemiological parameters such as persistence rate and medication possession rate. Results: A total of 1,245 titles were screened, of which 102 abstracts were assessed. Fourteen studies were ultimately included, comprising 190,279 unique patients (mean age 69.5 years). Regardless of which specific antimuscarinic drug is studied, persistence rates are usually poor. Considering all drugs together, median persistence rates were 12.0% to 39.4% (with an outlier of 75.5%) at 12 months, 8.0% to 15.0% at 18 months and 6.0% to 12.0% at 24 months. At 36 months persistence rates ranged from 0.0% (darifenacin) to 16.0% (trospium). Mean reported medication possession rates were also low, with a mean of 0.37 at 12 months. Risk factors for discontinuation were identified, with the most important being younger age group, use of oxybutynin and use of immediate release formulations. Conclusions: Improvement in adherence and persistence with antimuscarinic medication should be an important goal in the development of new drugs for overactive bladder and urinary incontinence. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated the efficacy and safety of flexible dose fesoterodine in medically complex vulnerable elderly subjects with urgency urinary incontinence. Materials and Methods: In this 12-week, randomized, double-blind, flexible dose, placebo controlled trial, subjects were community dwelling men and women 65 years old or older. Subjects had scores of 3 or more on the VES-13 (Vulnerable Elders Survey) and 20 or more on the MMSE (Mini-Mental State Examination), and 2 to 15 urgency urinary incontinence episodes and 8 or more micturitions per 24 hours on 3-day baseline diaries. Subjects randomized to fesoterodine received 4 mg once daily for 4 weeks and could then increase to 8 mg based on discussion with the investigator. Subjects receiving 8 mg could decrease the dose to 4 mg at any time (sham escalation and de-escalation for placebo). The primary outcome measure was change in daily urgency urinary incontinence episodes. Secondary outcomes included changes in other diary variables and patient reported quality of life measures. Safety evaluations included self-reported symptoms and post-void residual volume. Results: A total of 562 patients were randomized (mean age 75 years, 50.4% age 75 years or greater). Subjects had high rates of comorbidities, polypharmacy and functional impairment. At week 12 the fesoterodine group had significantly greater improvements in urgency urinary incontinence episodes per 24 hours (–2.84 vs –2.20, p = 0.002) and most other diary variables and quality of life, as well as a higher diary dry rate (50.8% vs 36.0%, p = 0.002). Adverse effects were generally similar to those of younger populations including risk of urinary retention. Conclusions: To our knowledge this is the first antimuscarinic study in a community based, significantly older, medically complex elderly population with urgency urinary incontinence. Flexible dose fesoterodine significantly improved urgency urinary incontinence episodes and other outcomes vs placebo, and was generally well tolerated. [ABSTRACT FROM AUTHOR]

Purpose: We explored possible associations between long-term antimuscarinic use and behavioral problems in children with spinal dysraphism and neurogenic bladder. Materials and Methods: Children with open and closed spinal dysraphism were recruited from 2 pediatric hospitals, 1 in Amsterdam and 1 in Utrecht, The Netherlands. At the Amsterdam facility antimuscarinics were prescribed in selected patients with detrusor overactivity. At the Utrecht facility antimuscarinics were prescribed from birth onward in patients with spinal dysraphism beginning in the early 1990s. Parents of study participants were asked to fill out a Child Behavior Checklist. Demographics, data on level and type(s) of lesion, and presence of hydrocephalus with a drain (and, if applicable, number of drain revisions) were retrieved for each patient. Cases and controls (8 boys and 8 girls per group) were matched on a 1-to-1 basis. Results: Data on 32 children were analyzed. Median age was 10.6 years in cases and 10.5 years in controls (p = 0.877). In each group 9 of 16 patients had hydrocephalus with a drain. No significant difference in Child Behavior Checklist scores for total problems was found between cases and controls (median 52.0 vs 59.5, p = 0.39). No differences were found between the groups on any subdomain of the Child Behavior Checklist. Conclusions: No significant differences in behavior were found between children with spinal dysraphism with and without long-term use of antimuscarinics. [ABSTRACT FROM AUTHOR]

Purpose: The bladder effects of isoprenaline, and selective β1 and β2-adrenoceptor agonists reported in early studies suggest that bladder β-adrenoceptors are atypical. Since there is a lack of alternatives to antimuscarinics in the treatment of overactive bladder symptoms, there has been an intensive search for new drug targets. Discovery of the β3-adrenoceptor with high expression in the bladder suggested that this receptor, which mediates detrusor relaxation, could be a target for overactive bladder symptoms. Materials and Methods: An overview of the published literature on β-adrenoceptor and the bladder was performed using MEDLINE®. The United States Food and Drug Administration website, clinicaltrials.gov and controlled-trials.com online trial registries were searched for English language articles containing the terms β3-adrenoceptors and β3-adrenoceptor agonists. In addition, abstracts from recent international scientific meetings were searched for randomized, controlled trials of β3-adrenoceptor agonists. Results: Stimulation of β3-adrenoceptors relaxes detrusor smooth muscle, decreases afferent signaling from the bladder, improves bladder compliance upon filling and increases bladder capacity. Randomized, controlled trials show that the selective β3-adrenoceptor agonist mirabegron, for which most information is available and which is approved in Japan, the United States and Europe, decreases the number of micturitions and incontinence episodes in a 24-hour period compared with placebo. The most common adverse effects recorded are dry mouth (placebo level) and gastrointestinal disturbances, rated as mild to moderate. Small increases in mean heart rate (1 beat per minute) and blood pressure (1 mm Hg) were noted in patients with overactive bladder. Conclusions: Available information suggests that β3-adrenoceptor agonists may be a promising alternative to antimuscarinics in the treatment of overactive bladder. However, further clinical experience outside clinical trials and information on long-term use in terms of efficacy, safety and tolerability are warranted to optimally characterize the position of β3-adrenoceptor agonists in the treatment algorithm for overactive bladder. [ABSTRACT FROM AUTHOR]

Purpose: Intravesical injection of onabotulinumtoxinA is effective for idiopathic detrusor overactivity refractory to antimuscarinics. However, safety is a major concern, especially in elderly individuals. We investigated the efficacy and safety of intravesical onabotulinumtoxinA injection for refractory idiopathic detrusor overactivity in the frail elderly population. Materials and Methods: A total of 166 patients with urodynamic idiopathic detrusor overactivity refractory to previous antimuscarinics for more than 3 months received 1 intravesical 100 U onabotulinumtoxinA injection from 2004 to 2009. Frail elderly was defined as age greater than 65 years and 3 or more of certain criteria, including unintentional weight loss, self-reported exhaustion, weakness, slow walking speed and/or low physical activity. Treatment results were assessed by the Patient Perception of Bladder Condition, voiding diary, urodynamic parameters and Kaplan-Meier estimates of survival plots. Results: We evaluated 61 frail elderly patients, 63 who were elderly without frailty and 42 younger than 65 years. Large post-void residual urine volume (greater than 150 ml) after onabotulinumtoxinA injection was significantly higher in the frail elderly group than in the other groups (60.7% vs 39.7% and 35.7%, respectively, p = 0.018). Urinary retention developed in 7 frail elderly patients (11.5%), 4 (6.3%) who were elderly without frailty and 1 younger patient (2.4%) (p = 0.203). Recovery duration was significantly longer in frail elderly patients. The cumulative success rate was significantly lower in the frail elderly group than in the other 2 groups (p = 0.009). Conclusions: Although safety and efficacy were similar between elderly patients without frailty and younger patients, an increased risk of large post-void residual urine volume and a lower long-term success rate in frail elderly patients were noted after intravesical onabotulinumtoxinA injection for refractory idiopathic detrusor overactivity. [Copyright &y& Elsevier]

Purpose: Awakening from sleep to urinate is the hallmark of nocturia, a condition that impacts several facets of health related quality of life and for which current therapy is suboptimal. Given the paucity of prospective data on antimuscarinics for the management of nocturia, we investigated the efficacy and safety of flexible dose fesoterodine for the treatment of nocturnal urgency in subjects with nocturia and overactive bladder. Materials and Methods: Subjects with 2 to 8 nocturnal urgency episodes per 24 hours began a 2-week, single-blind, placebo run-in followed by 1:1 randomization to 12 weeks of double-blind treatment with fesoterodine (4 mg daily for 4 weeks with an optional increase to 8 mg) or placebo using predefined criteria for nocturnal urgency episodes, nocturnal urine volume voided and total 24-hour urine volume voided. The primary end point was change from baseline to week 12 in the mean number of micturition related nocturnal urgency episodes per 24 hours. Results: Overall 963 subjects were randomized from 2,990 screened, and 82% of subjects treated with fesoterodine and 84% of those treated with placebo completed the study. Significant improvements in the primary end point (–1.28 vs –1.07), in nocturnal micturitions per 24 hours (–1.02 vs –0.85) and in nocturnal frequency urgency sum (–4.01 vs –3.42) were observed with fesoterodine vs placebo (all p ≤0.01). Health related quality of life measures (overactive bladder questionnaire Symptom Bother –20.1 vs –16.5, sleep 22.3 vs 19.9 and other domains; all p <0.05) were improved with fesoterodine. Conclusions: To our knowledge this is the first prospective study to assess antimuscarinic efficacy for reducing nocturnal urgency. Flexible dose fesoterodine significantly reduced nocturnal urgency episodes vs placebo in subjects with overactive bladder. [ABSTRACT FROM AUTHOR]

Purpose: Bladder augmentation by enterocystoplasty or detrusorectomy might prevent renal damage, help achieve dryness and decrease the need for antimuscarinics. We compared the long-term outcomes of enterocystoplasty and detrusorectomy in adults with spina bifida. Materials and Methods: A retrospective study using the hospital electronic database was performed. We identified 47 patients with spina bifida (median age at followup 26.8 years) who underwent either enterocystoplasty or detrusorectomy between 1988 and 2004. Median followup was 13.1 years in the detrusorectomy group and 15.3 years in the enterocystoplasty group. Results: In the detrusorectomy group 4 patients with treatment failure were identified. All 4 patients underwent secondary enterocystoplasty. No reoperation was necessary in the enterocystoplasty group. Preoperative bladder volume was approximately 100 ml higher in the detrusorectomy group (not significant). There was a significantly greater improvement of median bladder volume in the enterocystoplasty group (increase of 300 vs 77.5 ml, p = 0.006). No differences in continence rate, antimuscarinic use or condition of the upper tract were found. Conclusions: In this series of 47 patients long-term outcomes were good after enterocystoplasty and detrusorectomy, although bladder volume exhibited a greater increase in the enterocystoplasty group. No differences were observed among the other outcomes. If preoperative bladder volume is sufficient, detrusorectomy can be considered before enterocystoplasty is done. [ABSTRACT FROM AUTHOR]

Purpose: We investigated urinary levels of nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in healthy individuals and patients with overactive bladder. Materials and Methods: Urine from 40 healthy volunteers, half of them male and half female, was collected in the morning, afternoon and evening on 2 occasions 3 months apart. Morning urine samples were collected from 37 female naïve patients with overactive bladder. A total of 24 patients were followed. Urine was collected after a 3-month lifestyle intervention and after 3-month antimuscarinic treatment (oxybutynin 10 mg, extended release). Urinary nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor concentrations were measured by enzyme-linked immunosorbent assay and normalized to creatinine. Patients completed a 7-day bladder diary combined with an urgency severity scale. The number of urgency episodes per week was counted. Results: In healthy individuals urinary levels of neurotrophic factors were stable. In patients with overactive bladder the nerve growth factor-to-creatinine (mean ± SD 488.5 ± 591.8 vs 188.3 ± 290.2, p = 0.005) and brain-derived neurotrophic factor-to-creatinine (mean 628.1 ± 590.5 vs 110.4 ± 159.5, p <0.001) ratios were significantly higher than in healthy women. No significant differences were found in the glial cell line-derived neurotrophic factor-to-creatinine ratio. After lifestyle intervention the nerve growth factor-to-creatinine and brain-derived neurotrophic factor-to-creatinine ratios decreased to a mean of 319.7 ± 332.3 and 432.5 ± 589.0 (vs baseline p = 0.318 and 0.033, respectively). After antimuscarinic treatment the nerve growth factor-to-creatinine and brain-derived neurotrophic factor-to-creatinine ratios further decreased to a mean of 179.8 ± 237.9 and 146.6 ± 264.9 (vs baseline p = 0.008 and <0.001, respectively). There was no significant variation in the glial cell line-derived neurotrophic factor-to-creatinine ratio at any time point. The reduction in the number of urgency episodes per week correlated with the brain-derived neurotrophic factor-to-creatinine variation (Pearson product-moment correlation coefficient r = 0.607, p = 0.006) but not with the nerve growth factor-to-creatinine ratio (r = 0.396, p = 0.094). Conclusions: The urinary nerve growth factor-to-creatinine and brain-derived neurotrophic factor-to-creatinine ratios are increased in patients with overactive bladder. These findings may have pathophysiological and clinical implications. [Copyright &y& Elsevier]

Purpose: Conservative therapy and antimuscarinic agents are first line therapies for overactive bladder. Patients refractory to treatment are candidates for neuromodulation therapy. We estimated the costs and cost-effectiveness of percutaneous tibial nerve stimulation and sacral nerve stimulation. Materials and Methods: A Markov model was constructed to simulate the total costs and effectiveness of percutaneous tibial and sacral nerve stimulation during 2 years. Cost data used average Medicare national physician payments, and ambulatory payment classification and diagnosis related group payments for hospital based care and office visits. Clinical effectiveness, and the rates of patient adherence to treatment and adverse events were estimated by a review of the literature. Results: The costs of initial therapy were $1,773 for 12 weekly percutaneous tibial nerve stimulation treatments and $1,857 for test sacral nerve stimulation. For ongoing therapy the cost of the sacral nerve stimulation surgical implant was $22,970. Cumulative discounted 2-year costs were $3,850 for percutaneous tibial nerve stimulation and $14,160 for sacral nerve stimulation, including those who discontinued therapy. Of the patients 48% and 49%, respectively, remained on therapy. The incremental cost-effectiveness ratio was $573,000 per additional patient on sacral nerve stimulation. When considering only patients who completed initial stimulation successfully, the costs were $4,867 and $24,342 for percutaneous tibial and sacral nerve stimulation with 71% and 90%, respectively, remaining on therapy for an incremental cost-effectiveness ratio of $99,872. Conclusions: Percutaneous tibial nerve stimulation and sacral nerve stimulation are safe, effective neuromodulation therapies for overactive bladder. In this economic model percutaneous tibial nerve stimulation had substantially lower cost. An additional 1% of patients would remain on therapy at 2 years if sacral nerve stimulation were used rather than percutaneous tibial nerve stimulation but the average cost per additional patient would be more than $500,000. [Copyright &y& Elsevier]

Purpose: We analyzed the effects of baseline symptom severity and placebo response magnitude on the decision to dose escalate in a 12-week, randomized, double-blind, flexible dose antimuscarinic trial of subjects with overactive bladder symptoms. Materials and Methods: Data from the placebo arm of the trial were used for this post hoc analysis. Subjects could elect dose escalation at week 2. Those in the placebo arm received sham escalation. Results: Most placebo treated subjects who continued to week 2 elected dose escalation (75% or 325 of 435). Overactive bladder symptoms at baseline were similar between placebo escalators and nonescalators. Nonescalators showed a significantly larger placebo response than escalators, as measured by improvements in bladder diary end points and patient reported outcomes, and by the incidence rate of adverse events before and after sham escalation. Conclusions: These findings suggest that the decision to dose escalate among placebo treated subjects is independent of baseline symptom severity but may be influenced by the placebo response magnitude for efficacy assessment and adverse events. Placebo nonescalators showed a rapid, large placebo response while placebo escalators showed a smaller placebo response even after sham escalation. These observations may have important implications for the design and interpretation of flexible dose trials using a placebo control. [Copyright &y& Elsevier]

Purpose: The combination of muscarinic receptor and α1-adrenoceptor antagonists is increasingly used for benign prostatic hyperplasia related lower urinary tract symptoms. In addition to the well established peripheral site of action, little is known about the central effects of muscarinic receptor antagonists and muscarinic receptor/α1-adrenoceptor antagonist combinations on bladder function, partly due to poor brain penetration after systemic administration. We assessed the effects of intrathecal 5-hydroxymethyl tolterodine, an active metabolite of fesoterodine, in obstructed and nonobstructed rats, and of combined intrathecal 5-hydroxymethyl tolterodine/doxazosin in a rat model of partial urethral obstruction. Materials and Methods: We used 80 male Sprague-Dawley® rats to test various doses of intrathecal 5-hydroxymethyl tolterodine and/or intrathecal doxazosin on urodynamic parameters. Urodynamic evaluation without anesthesia was done 3 days after bladder and intrathecal catheterization. Two weeks before urodynamics 40 rats underwent partial urethral obstruction. Results: Intrathecal 5-hydroxymethyl tolterodine had no urodynamic effects in nonobstructed rats. Compared to controls obstructed rats had increased bladder pressure and weight, and voiding frequency. In obstructed rats 5-hydroxymethyl tolterodine restored urodynamic parameters to those seen in nonobstructed animals. Doxazosin had effects similar to those of intrathecal 5-hydroxymethyl tolterodine. When the 2 drugs were combined, at the doses used only small additional effects were observed. Conclusions: Urodynamic changes in obstructed rats can be normalized by intrathecal 5-hydroxymethyl tolterodine and by intrathecal doxazosin. The central pathways on which the 2 drugs act seem to be up-regulated with partial urethral obstruction and less relevant under normal conditions. [Copyright &y& Elsevier]

Purpose: Neurokinin-1 receptor dependent mechanisms may regulate urinary frequency and urgency. We conducted this study to assess the efficacy and tolerability of the neurokinin-1 receptor antagonist serlopitant vs placebo or tolterodine in patients with overactive bladder. Materials and Methods: This randomized, double-blind, 69-center trial enrolled adults with overactive bladder (8 or more average daily micturitions and 1 or more daily urge incontinence episodes). After a 1-week placebo run-in the patients were randomized to 8 weeks of daily 0.25, 1 or 4 mg serlopitant, 4 mg tolterodine extended release or placebo. Patients kept 7-day voiding diaries. The primary end point was change from baseline in micturitions per day. Secondary end points included urgency, total incontinence, urge incontinence episodes and incidence of dry mouth. Results: Of 557 patients randomized 476 completed the trial and had valid efficacy data for analysis. Mean change from baseline in daily micturitions was significantly greater for 0.25 (–1.1) and 4 mg (–1.1) serlopitant, and for tolterodine (–1.5) than for placebo (–0.5), but not for 1 mg serlopitant (–0.8). No serlopitant dose response was demonstrated. Tolterodine was numerically superior to all doses of serlopitant in mean micturitions per day and secondary end points. The incidence of dry mouth on serlopitant (3.3%) was comparable to placebo (4.6%) and lower than tolterodine (8.8%). Serlopitant was generally well tolerated. Conclusions: Serlopitant (0.25 and 4 mg) significantly decreased the primary end point of daily micturitions but not the secondary end points compared with placebo. Serlopitant was generally well tolerated. Thus, NK-1 receptor antagonists may have a role in the treatment of overactive bladder but this compound does not offer advantages in efficacy compared to tolterodine. [Copyright &y& Elsevier]

Purpose: Anticholinergic medications are commonly used to treat urinary urgency and frequency. Muscarinic receptors are located in areas beyond the detrusor muscle. In this study we measured changes in central nervous system activity in patients with lower urinary tract symptoms treated with tolterodine or a placebo. Materials and Methods: A total of 20 female patients with urinary frequency were randomized to 4 weeks of treatment with tolterodine or a placebo. Functional magnetic resonance imaging based on blood oxygenation level dependant imaging of the brain during bladder filling was performed before and after treatment. For each patient the bladder was filled by a urethral catheter and emptied 5 times. Results: Multiple brain areas showed significant activation with bladder filling compared to the empty state and many areas also showed deactivation. Overall brain activation with bladder filling was decreased after treatment in both groups. After treatment 2 areas of the parietal cortex (precuneus and postcentral gyrus) showed significantly greater activity in patients treated with tolterodine vs placebo. Two areas of the cerebellum (anterior lobe and culmen) showed significantly greater activity in the placebo group, and these were also areas of significant deactivation in the tolterodine group. Conclusions: Brain activity changes as well as the areas of activation after treatment of lower urinary tract symptoms in patients with an anticholinergic medication or placebo are different in the 2 groups. Whether this finding represents action at the central nervous system or the bladder level is not known. [Copyright &y& Elsevier]

Purpose: Although antimuscarinic treatment is indicated for overactive bladder, many patients discontinue it because of dry mouth. Of available antimuscarinics oxybutynin is associated with the highest dry mouth rate. We compared the safety and tolerability of 5 mg solifenacin vs 15 mg oxybutynin immediate release. Materials and Methods: At 12 Canadian centers a total of 132 patients with overactive bladder symptoms (greater than 1 urgency episode per 24 hours, and 8 or greater micturitions per 24 hours) were randomized to 5 mg solifenacin once daily or 5 mg oxybutynin 3 times daily for 8 weeks. The primary end point was the incidence and severity of dry mouth reported after direct questioning. Efficacy end points (3-day diary documented changes in urgency, frequency, incontinence, nocturia and voided volume), and changes on the Patient Perception of Bladder Condition scale and the Overactive Bladder Questionnaire were evaluated secondarily. Results: Of patients on solifenacin vs oxybutynin immediate release 35% vs 83% reported dry mouth (p <0.0001). Of patients reporting dry mouth severity was graded moderate by 13% and 42% of those on solifenacin and oxybutynin immediate release, and severe by 13% and 28%, respectively (p = 0.001). Patients in each group showed improvements in efficacy end points, and Patient Perception of Bladder Condition scale and Overactive Bladder Questionnaire scores from baseline to treatment end. Conclusions: Significantly fewer patients on 5 mg solifenacin once daily reported dry mouth vs those receiving 5 mg oxybutynin immediate release 3 times daily. Significantly fewer patients on solifenacin reported moderate/severe dry mouth. Significantly fewer patients on solifenacin withdrew from study due to dry mouth and there were significantly fewer overall adverse events. Solifenacin and oxybutynin immediate release were efficacious in decreasing efficacy end points, and improved Patient Perception of Bladder Condition scale and Overactive Bladder Questionnaire results from baseline to treatment end. [Copyright &y& Elsevier]

Purpose: We examined overactive bladder medication compliance in a health care system in which patients do not pay for medication. Materials and Methods: Pharmacy dispensing records were reviewed for antimuscarinic agents from January 2003 to December 2006 for the United States Military Health System National Capital Region. Medication nonpersistence, switching and adherence were examined. Kaplan-Meier survival analysis was done to compare medication persistence duration. Results: Overactive bladder medications were dispensed to 7,879 adults. Tolterodine extended release (4,716 patients or 60%) and oxybutynin immediate release (2,003 or 25.5%) were most commonly prescribed. The medication nonpersistence rate, defined as the proportion of patients who never refilled a prescription for antimuscarinics during the study period, was 35.1% (2,760 of 7,858). Of 5,098 patients who refilled a prescription 1,305 changed the medication or dose at least once for a medication switch rate of 25.6%. The overall median medication possession ratio, defined as the total days of medication dispensed except for the last refill divided by the number of days between the first dispense date and the last refill date, was 0.82 in all cases. Men had a significantly higher median medication possession ratio than women (0.86 vs 0.81, p <0.001). Of patients who obtained at least 1 refill women remained on medication longer than men (median 606 vs 547 days, p = 0.01). Patients on tolterodine extended release had a higher medication nonpersistence rate than those on oxybutynin immediate release (0.89 vs 0.68, p <0.01). There was no difference between extended release medications. Conclusions: In a health care system in which patients do not pay for medications 35% of patients did not refill a prescription for overactive bladder medication, similar to previous reports. However, other measures of medication compliance were higher than those published previously in systems with copays. [Copyright &y& Elsevier]

Purpose: VICTOR was a 12-week, double-blind, placebo controlled trial assessing the safety and tolerability of solifenacin plus tamsulosin in men with residual overactive bladder symptoms after tamsulosin monotherapy. Efficacy of solifenacin plus tamsulosin vs placebo plus tamsulosin was also evaluated. Materials and Methods: A total of 398 men 45 years old or older were randomized to 12 weeks of solifenacin plus tamsulosin or placebo plus tamsulosin once daily. The study population had 8 or more micturitions per 24 hours and 1 or more urgency episode per 24 hours after taking tamsulosin for 4 or more weeks, a total International Prostate Symptom Score of 13 or greater, a Patient Perception of Bladder Condition score of 3 or greater, a post-void residual of 200 ml or less and a peak flow rate of 5 ml per second or greater. Adverse events were monitored throughout the study. The primary efficacy end point was mean change from baseline to week 12 in micturitions per 24 hours. Secondary measures included mean change in urgency episodes per 24 hours, and changes in Patient Perception of Bladder Condition, Urgency Perception Scale and total International Prostate Symptom Scores. Results: The most frequent adverse events in the solifenacin plus tamsulosin and placebo plus tamsulosin groups were dry mouth (7% and 3%, respectively) and dizziness (3% and 2%, respectively). Of the patients on solifenacin plus tamsulosin 7 (3%) reported retention and 3 required catheterization. No patients on placebo plus tamsulosin reported retention. Patients on solifenacin plus tamsulosin vs placebo plus tamsulosin showed larger reductions in frequency but not of statistical significance (−1.05 vs −0.67, p = 0.135). However, patients on solifenacin plus tamsulosin vs placebo plus tamsulosin did show statistically significant reductions in urgency (−2.18 vs −1.10, p <0.001). Patient reported outcome measures showed no significant between group differences. Conclusions: Solifenacin plus tamsulosin was well tolerated. There was a low incidence of urinary retention requiring catheterization. At week 12 solifenacin plus tamsulosin decreased daily micturitions and urgency episodes. Only urgency reached statistical significance vs placebo plus tamsulosin. [Copyright &y& Elsevier]

Purpose: We evaluated the efficacy and safety of transdermal and oral oxybutynin in children with neurogenic detrusor overactivity. Materials and Methods: Children with neurogenic detrusor overactivity 6 to 15 years old and previously receiving oxybutynin were assigned randomly at a 3:1 ratio to treatment with transdermal or oral oxybutynin. Initial dosages (transdermal 1.3, 2.9 or 3.9 mg daily; oral 5, 10 or 15 mg daily), based on pre-study dosages, were adjusted after 2 weeks and then maintained for 12 weeks. The primary efficacy end point was change from baseline to last observation in average urine volume collected by clean intermittent catheterization. Results: A total of 57 patients were randomized to receive transdermal (41) or oral (16) oxybutynin. Safety data were available for 55 patients and efficacy data were available for 52. Mean ± SD urine volume increased from 95 ± 64 ml to 125 ± 74 ml (p <0.001) with transdermal oxybutynin and from 114 ± 75 ml to 166 ± 92 ml (p = 0.002) with oral oxybutynin. Transdermal oxybutynin resulted in significant improvement in all measured urodynamic parameters. Similar trends and a significant increase in maximal cystometric bladder capacity were observed in the smaller oral oxybutynin group. There were 12 treatment related adverse events noted with transdermal oxybutynin (mild skin reaction) and 1 with oral oxybutynin (vasodilatation). The ratio of N-desethyloxybutynin-to-oxybutynin plasma concentrations was substantially lower with transdermal (1.4) than with oral (6.7) oxybutynin. Conclusions: Transdermal oxybutynin was a well tolerated and effective alternative to oral oxybutynin in treating neurogenic detrusor overactivity in children who previously tolerated oxybutynin. [Copyright &y& Elsevier]

Purpose: We determined whether men treated with oral antimuscarinics are at increased risk for acute urinary retention. Materials and Methods: In this population based, retrospective cohort study using a nested case-control design we analyzed data from a large primary care database containing patient information entered by general practitioners in the United Kingdom. Our study cohort comprised men 20 to 84 years old. Cases of acute urinary retention were identified by reviewing diagnostic codes and were confirmed in a random sample through questionnaires sent to the treating physician. Results: The overall incidence of acute urinary retention in the study cohort (1,844) was 1.0 per 1,000 person-years, with the incidence rate increasing with age. The first 30 days (early treatment) of antimuscarinic use was associated with a relative risk of acute urinary retention of 8.3 (95% CI 4.8–14.2) and with longer term use (more than 30 days) the relative risk was 2.0 (95% CI 1.2–3.1). The relative risk of acute urinary retention was similar for low/medium and high antimuscarinic doses (relative risk 2.8 vs 3.0, 95% CI 2.1–3.8 and 1.3–6.8, respectively). The relative risk of acute urinary retention was highest during early treatment for a urogenital indication (relative risk 14.2, 95% CI 6.8–29.6). The risk of acute urinary retention was not increased when antimuscarinics were used as antispasmodics or for drug induced parkinsonism. Conclusions: Men prescribed antimuscarinics, particularly for a urogenital condition, should be closely monitored during the first 30 days of treatment for signs or symptoms of urinary retention. [Copyright &y& Elsevier]

Purpose: The definitions of acute and chronic urinary retention remain empirical and subject to wide interpretation. Standardized criteria have not been established and many questions remain unanswered. Moreover, the definition of significant post-void residual urine is unclear. We reviewed several aspects of urinary retention that require clarification with the objective of stimulating discussion among urologists to establish an accurate and coherent definition of urinary retention and significant post-void residual urine, and clarify risk factors. Materials and Methods: A MEDLINE® search for articles written in English and published before April 2007 was done using a list of terms related to urinary retention. Articles not directly relevant to urinary retention or post-void residual urine were excluded. Results: The term urinary retention lacks precise clinical or urodynamic meaning. Use of this term to describe a symptom, a sign, and a condition further complicates the issue. Many factors can contribute to the development of retention, including bladder outlet obstruction, detrusor underactivity, and neurogenic bladder conditions. Community based studies and clinical trials in patients with benign prostatic enlargement and/or lower urinary tract symptoms yield different estimates of the incidence of retention and only provide information on the epidemiology of acute urinary retention. However, age, previous retention episodes, lower urinary tract symptoms, chronic inflammation, serum prostate specific antigen level, prostate size, and urodynamic variables appear to be predictors of acute urinary retention. α-Receptor antagonists and 5α-reductase inhibitors may be useful in preventing urinary retention episodes and progressive benign prostatic enlargement. Clinical trials on the short-term use of antimuscarinics have not provided evidence that these agents increase the risk of retention; data on longer term administration are needed. Conclusions: Clinicians are adopting less invasive approaches (eg pharmacology or catheterization) to treating patients who present with the symptoms, sign, and condition of urinary retention. Faced with an abundance of new data on acute urinary retention, urologists need to reach a consensus about the risks of urinary retention; this may promote movement toward patient centered prevention strategies with tailored treatment options. [Copyright &y& Elsevier]

Purpose: We evaluated the efficacy, tolerability and safety of the new antimuscarinic agent fesoterodine relative to placebo for overactive bladder syndrome. Materials and Methods: This was a randomized, double-blind, placebo controlled, multicenter trial performed in the United States. Overall 836 subjects with urinary frequency, urinary urgency or urgency urinary incontinence were randomized to placebo (274), 4 mg fesoterodine (283) or 8 mg fesoterodine (279) once daily for 12 weeks. The primary efficacy end point was the change in the number of micturitions per 24 hours. Co-primary end points were the change in the number of urgency urinary incontinence episodes per 24 hours and the treatment response. Secondary efficacy end points were other bladder diary variables, such as the change in mean voided volume per micturition, number of continent days and number of urgency episodes per 24 hours. Tolerability and safety were assessed by evaluating adverse events, electrocardiograms, post-void residual urine volume, laboratory parameters and treatment withdrawals. Results: Treatment with 4 or 8 mg fesoterodine resulted in statistically significant and clinically relevant improvements from baseline to end of treatment for the primary and co-primary end points compared with placebo (p <0.05). Results for most secondary end points, including mean voided volume per micturition, number of continent days and number of urgency episodes per 24 hours, were also significantly improved vs placebo. The adverse events reported more frequently with fesoterodine than with placebo were dry mouth, constipation and urinary tract infection. Conclusions: The 2 doses of fesoterodine were well tolerated and they statistically significantly improved overactive bladder symptoms. [Copyright &y& Elsevier]

Purpose: Antimuscarinic drugs increase bladder capacity without prominent side effects such as urinary retention even when administered to patients with mild to moderate bladder outlet obstruction. Some mechanisms might exist in the urethra to compensate for the emptying function of the detrusor after the administration of antimuscarinic drugs. We investigated the influence of the antimuscarinic drug propiverine (Taiho Pharmaceutical, Tokyo, Japan) on urethral function. Materials and Methods: Urethral pressure and rhythmic bladder pressure were simultaneously monitored in urethane anesthetized female Sprague-Dawley rats. Prostaglandin E2 was continuously administered intravesically or intraurethrally to induce detrusor overactivity. To eliminate the influence of bladder activity and monitor urethral baseline pressure isovolumetric pressure of the urethra was then recorded after cystectomy and ligation of the external urethral meatus. Furthermore, in vitro contractile responses of the urethral circular smooth muscle to field stimulation were examined in the presence of propiverine, tamsulosin (Taiho Pharmaceutical), verapamil, ω-conotoxin and atropine (Sigma®). Results: Intravesical or intraurethral administration of prostaglandin E2 significantly decreased the bladder contraction interval by 10.7% and 36.0%, respectively. Intra-arterial administration of 2 × 102 nM/kg propiverine significantly increased the bladder contraction interval in rats receiving intraurethral prostaglandin E2 by 81.8% but it had no marked effect on rats receiving intravesical prostaglandin E2. Significant decreases in urethral baseline pressure were found after propiverine administration. Field stimulation induced contraction was inhibited by propiverine and verapamil but not by tamsulosin, ω-conotoxin or atropine. Conclusions: These results suggest that the inhibitory effects of propiverine are more prominent in rats with detrusor overactivity induced by intraurethral prostaglandin E2 than by intravesical prostaglandin E2. Propiverine may compensate for detrusor function by decreasing urethral resistance in the voiding phase. [Copyright &y& Elsevier]

Purpose: This study was designed to test the power potential of a number of different clinical trial designs that could be deployed to test the efficacy of an antimuscarinic drug against bladder retraining. Materials and Methods: This was an observational cohort study. Data were collected prospectively from patients treated for an overactive bladder by antimuscarinic agents with bladder retraining, or by bladder retraining alone. At initiation and at followup data on frequency, incontinence, urgency and urge incontinence were collected. Data from visits up to 16 weeks of treatment were analyzed using the parametric methods.708 patients were studied, 44 males and 664 females, and their mean age was 54 (sd 22). 52 patients used pure bladder retraining and 656 used bladder retraining and an antimuscarinic agent. The drug was oxybutynin, tolterodine or imipramine combined with oxybutynin or tolterodine as combination therapy. Results: A between groups analysis demonstrated that bladder retraining was associated with a greater improvement in urinary frequency compared to antimuscarinic therapy (Z = -4.6, 95% CI of difference -3.3, -1.4, p <0.001) whereas antimuscarinic therapy was associated with a greater improvement in incontinence compared to bladder retraining (Z = -2.6, 95% CI of difference -0.93, -0.27, p = 0.024). The within group change in incontinence episodes in the bladder retraining group did not appear to show an effect (95% CI of change -0.19, 0.43). A subgroup showing greatest ΔInc was sought. Boxplots of ΔInc against age group, sex and the grading of symptoms were examined for maximum effect. Female sex, age group of 50 or greater and patients describing urge incontinence demonstrated the greatest ΔInc. Their mean daily frequency was 11.45 (sd 6.1) and incontinence 1.6 (sd 2.1). A sample with such characteristics would be most sensitive to treatment effect. The bladder retraining group had a higher daily frequency (Z = -3.2, p = 0.001, 95% CI for bladder retraining 10 to 11, 95% CI for antimuscarinic group 10 to 12) and a lower daily incontinence compared to the antimuscarinic group (Z = -3.4, p <0.001, 95% CI of median for bladder retraining 0.75, 0.85, 95% CI of median for antimuscarinic group 0.75, 1.75). Conclusions: Change in frequency is a poor outcome measure, ΔInc is significantly superior. An antimuscarinic tested against bladder retraining, using ΔInc for outcome, would probably compare favorably. [Copyright &y& Elsevier]

Purpose: We examined the relationship between self-reported health status data, subsequent antimuscarinic medication adherence and health care service use in older adults with OAB syndrome in a managed care setting. Materials and Methods: This was a longitudinal cohort study of older adults in the southeastern United States with OAB who completed a health status assessment, used antimuscarinic medications and were enrolled in an HMO continuously for 1 to 3 years. Demographic, clinical and use related economic variables were also retrieved from the administrative claims data of patient HMOs. Prescription refill patterns were used to measure medication adherence. Associations were examined with a sequential, mixed model regression approach. Results: A total of 275 patients were included. The severity of comorbidity (Charlson index), patient perception of quality of life (Short Form-12 scores) and total number of prescribed medications during the year prior to enrollment in a Medicare HMO were independently associated with decreased antimuscarinic MPRs after enrollment. After controlling for other variables increased antimuscarinic MPR remained the strongest predictor of decreased total annual health care costs (5.6% decrease in annual costs with every 10% increase in MPR, p <0.001). Conclusions: We found strong associations between decreased antimuscarinic medication adherence and increased health care service use in older adults with OAB in a managed care setting. Health status assessments completed at enrollment had the potential to identify enrollees at higher risk for nonadherent behaviors and poor health related outcomes. [Copyright &y& Elsevier]

Purpose: We characterized the binding affinities of several antimuscarinic agents in human muscarinic receptors. Materials and Methods: Competitive inhibitory effects of antimuscarinic agents on specific NMS [H] (PerkinElmer Life Sciences, Boston, Massachusetts) binding were examined in human tissue homogenates and in CHO-K1 cell membranes expressing human muscarinic receptor subtypes. Results: Oxybutynin, propiverine, tolterodine, the respective metabolites DEOB, DPr-P-4(N→O) and 5-HM, and darifenacin inhibited in concentration dependent fashion specific [3H]NMS binding in homogenates of the human bladder and parotid gland as well as in membranes of CHO-K1 cell lines expressing human muscarinic M1 to M5 receptor subtypes. Based on inhibition constant values the inhibitory effects of tolterodine, 5-HM and DPr-P-4(N→O) were 1.4 to 1.7 times greater in the bladder than in the parotid gland, whereas the inhibitory effects of oxybutynin, DEOB, propiverine and darifenacin were 2 to 10 times greater in the parotid gland. Consequently tolterodine, 5-HM and DPr-P-4(N→O) compared with oxybutynin, DEOB, propiverine and darifenacin were found to show 3 to 4 times greater affinity to muscarinic receptors in the human bladder than in the parotid gland. Tolterodine and 5-HM were 2-fold more potent for inhibiting specific [3H]NMS binding at cell membranes expressing the M2 vs the M3 subtype. Conversely oxybutynin, DEOB, propiverine, DPr-P-4(N→O) and darifenacin showed 2 to 22 times higher affinity to the M3 than to the M2 subtype. Conclusions: Compared with oxybutynin, tolterodine, 5-HM and DPr-P-4(N→O) may bind more selectively to muscarinic receptors in the human bladder than in the parotid gland. [Copyright &y& Elsevier]

ABSTRACT: Purpose:: Three exploratory studies were conducted to investigate the pharmacokinetics (PK) and safety of tolterodine in children 1 month to 15 years old with neurogenic detrusor overactivity. We urodynamically evaluated the dose and concentration effects of tolterodine to establish safe and effective dosing regimens. Materials and Methods:: Three open-label, dose escalating studies were conducted in children with stable neurological disease and detrusor overactivity. In studies 1 (patient aged 1 month to 4 years) and 2 (5 to 10 years) patients received 0.03, 0.06 and 0.12 mg/kg tolterodine solution day twice daily for 4 weeks each. In study 3 (patient age 11 to 15 years) patients received 2, 4 and 6 mg tolterodine extended-release capsules once daily for 4 weeks each. PK was assessed after 8 weeks, urodynamic assessments were conducted after each 4-week dosing period and 3-day micturition diaries were completed. Results:: Patients in studies 1 (19) and 2 (15) showed some dose related increases in volume to first detrusor contraction and cystometric bladder capacity. In study 3 (11 patients) there were no obvious dose-response relationships. PK results from studies 1 and 2 suggest that there was no apparent effect of age (≤10 y) on these parameters. In study 3 time of maximum observed serum concentration and apparent terminal half-life were delayed, which is consistent with the extended-release formulation. Tolterodine was well tolerated, and there was no apparent relationship between tolterodine dose and adverse events in any study. Conclusions:: These results support the safety of age and body weight adjusted dosing regimens for further clinical evaluation of tolterodine in children with neurogenic detrusor overactivity. [Copyright &y& Elsevier]

Purpose: Williams-Beuren syndrome is a chromosomal disorder caused by a deletion at region 7q11.23. Lower urinary tract symptoms are highly prevalent and significantly affect quality of life. We assessed the long-term outcomes of lower urinary tract symptoms in children with Williams-Beuren syndrome., Materials and Methods: From February 2001 to July 2016, 90 patients with Williams-Beuren syndrome were evaluated in our hospital, of whom 31 (20 boys) had at least 5 years of followup. Baseline evaluation included a history of lower urinary tract symptoms, frequency-volume chart and the impact on quality of life measured on a scale of 0 (delighted) to 6 (terrible). Pharmacological therapy with oxybutynin or doxazosin was offered to symptomatic patients. We present the outcome of lower urinary tract symptoms after 5 and 10 years of followup., Results: At baseline 27 (87.1%) patients were symptomatic. Median duration of followup was 10 (range 6-13) years. Pharmacological therapy was started for 25 (92.6%) symptomatic patients at baseline, including oxybutynin for 19 (76.0%), doxazosin for 1 (4.0%) and a combination of the 2 agents for 5 (20.0%). Medical therapy was still in use by 61.2% after 5 years and 52.9% after 10 years (p=0.043). Median duration of pharmacological treatment was 7 (range 6-11) years. A significant improvement of lower urinary tract symptoms was observed over time, with 35.5% and 29.5% patients considered symptomatic after 5 years and 10 years, respectively (p <0.001). Quality of life was also markedly improved over time (p <0.001)., Conclusions: This long-term study showed significant improvement of lower urinary tract symptoms in children and adolescents with Williams-Beuren syndrome over time. Long-term pharmacological treatment was needed in most patients.