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Background: Combining the β3-adrenoceptor agonist mirabegron and the antimuscarinic (AM) agent solifenacin may improve efficacy in the treatment of overactive bladder (OAB) while reducing the AM side effects., Objective: The primary objective was to evaluate the efficacy of combinations of solifenacin/mirabegron compared with solifenacin 5mg monotherapy. The secondary objective was to explore the dose-response relationship and the safety/tolerability compared with placebo and monotherapy., Design, Setting, and Participants: A phase 2, factorial design, randomised, double-blind, parallel-group, placebo- and monotherapy-controlled trial, conducted at 141 sites in 20 European countries. Male and female patients were aged ≥18 yr with symptoms of OAB for ≥3 mo., Intervention: A total of 1306 patients (66.4% female) were randomised to 12 wk of treatment in 1 of 12 groups: 6 combination groups (solifenacin 2.5, 5, or 10 mg plus mirabegron 25 or 50 mg), 5 monotherapy groups (solifenacin 2.5, 5, or 10 mg, or mirabegron 25 or 50 mg), or placebo., Outcome Measurements and Statistical Analysis: Change from baseline to end of treatment in mean volume voided per micturition (MVV) (primary end point) and mean numbers of micturitions per 24 h, incontinence episodes per 24 h, and urgency episodes per 24 h were analysed using an analysis of covariance model. Safety assessments included treatment-emergent adverse events (TEAEs), blood pressure, pulse rate, postvoid residual (PVR) volume, and laboratory and electrocardiography (ECG) parameters., Results and Limitations: Compared with solifenacin 5 mg monotherapy, all combinations with solifenacin 5 or 10 mg significantly improved MVV, with adjusted differences ranging from 18.0 ml (95% confidence interval [CI], 5.4-30.0) to 26.3 ml (95% CI, 12.0-41.0). Three combination groups significantly reduced micturition frequency compared with solifenacin 5 mg, ranging from -0.80 (95% CI, -1.39 to -0.22) to -0.98 (95% CI, -1.68 to -0.27). Five of six combinations significantly reduced urgency episodes compared with solifenacin 5 mg, ranging from -0.98 (95% CI, -1.78, to -0.18) to -1.37 (95% CI, -2.03 to -0.70). No dose-related trends in TEAEs, blood pressure, pulse rate, PVR volume, or laboratory or ECG parameters were observed between combination and monotherapy groups, although the incidence of constipation was slightly increased with combination therapy., Conclusions: Combination therapy with solifenacin/mirabegron significantly improved MVV, micturition frequency, and urgency compared with solifenacin 5 mg monotherapy. All combinations were well tolerated, with no important additional safety findings compared with monotherapy or placebo., Patient Summary: To improve treatment of overactive bladder (OAB), mirabegron/solifenacin in combination was compared with each drug alone and placebo. Combination therapy improved OAB symptoms and had similar safety and acceptability., Trial Registration: Clinical trials.gov: NCT01340027., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction and Hypothesis: The Actionable Bladder Symptom Screening Tool (ABSST) was initially developed to identify patients with multiple sclerosis (MS) who could benefit from lower urinary tract assessment and treatment. Assessment of the measurement properties of the ABSST, including its ability to identify patients experiencing bladder symptoms related to overactive bladder (OAB), was undertaken in a general female population., Methods: One hundred women completed the ABSST, OAB Questionnaire Short Form (OAB-q SF), and a patient global impression of severity (PGI-S) scale. Half of the sample had urgency urinary incontinence (UUI), while the other half did not. Descriptive statistics, reliability, and validity were examined, as was sensitivity and specificity of the previous cut-off score established in MS., Results: Fifty-three women with UUI/OAB and 47 controls took part (71.0 % Caucasian). Patients with UUI/OAB were older (54.6 vs 40.4 years), had a higher body mass index (31.1 vs 26.4 kg/m(2)), and more comorbid conditions. The Cronbach's alpha reliability of ABSST was 0.90. High correlations with OAB-q SF Symptom Bother and Health Related Quality of Life (r = 0.83 and -0.81 respectively) supported concurrent validity. Using the PGI-S severity scores as a reference, the ABSST was able to distinguish patients with differing severity levels (known-group validity). Physician assessment of the need for further evaluation/treatment showed sensitivity (79 %) and specificity (98 %), supporting a cut-off score of ≥3., Conclusions: The previous MS ABSST scoring algorithm was validated in a non-neurogenic female population. ABSST is a reliable, valid, and sensitive tool for screening women with UUI/OAB.

Whilst symptoms of bladder outlet obstruction (BOO) and post micturition symptoms are more commonly reported in men a significant number of women may also complain of voiding dysfunction. However, despite the recent advances in the standardisation of terminology of lower urinary tract dysfunction there remains a lack of consensus regarding a precise diagnosis and definition of voiding abnormalities in women. In addition voiding symptoms may co-exist with storage symptoms as well as those associated with urinary incontinence. Consequently many patients present with a spectrum of different urinary symptoms, related to both storage and voiding, which may be multifactorial in origin or be related to one another. The purpose of this paper is to review the current literature in order to accurately define and classify female voiding dysfunction including causes and aetiology. In addition to reviewing the investigation and management of those women with voiding dysfunction recommendations are proposed for management in clinical practice as well as suggestions for future research., (Copyright © 2012 Wiley Periodicals, Inc.)

Aims: To characterize the response to fesoterodine treatment for overactive bladder (OAB) in subjects who did or did not choose to dose escalate in a flexible-dose study., Methods: Subjects were randomized to fesoterodine 4  mg or placebo. At week 2, subjects could remain on 4  mg (non-escalators) or choose to increase to 8  mg (escalators) for the remaining 10 weeks (sham escalation for placebo). Subjects completed 3-day bladder diaries at baseline, week 2 and week 12 noting micturitions, urgency episodes, and urgency urinary incontinence (UUI) episodes., Results: Sixty-three per cent of 438 subjects randomized to fesoterodine and 73% of 445 randomized to placebo dose escalated. At baseline, fesoterodine escalators had significantly more micturitions and urgency episodes than fesoterodine non-escalators (P < 0.001); at week 2, before dose escalation, diary-dry rate and improvement in micturitions and urgency episodes were significantly greater among fesoterodine non-escalators versus escalators (P < 0.001); and by week 12, after dose escalation, diary-dry rate and improvements in micturitions and UUI episodes were similar between fesoterodine non-escalators and escalators (P > 0.05). The placebo escalator group did not demonstrate a similar response over placebo non-escalators following the dose escalation decision point., Conclusion: A rapid and robust response to fesoterodine 4  mg was demonstrated in non-escalators. Subjects who chose to dose escalate to fesoterodine 8  mg at week 2 showed significant improvement by week 12 versus baseline and week 2 (prior to escalation), as well as versus placebo. Dose escalation to 8  mg fesoterodine provided subjects with efficacy and tolerability similar to those who were satisfied with the 4-mg dose., (Copyright © 2011 Wiley Periodicals, Inc.)

Aims: To report the conclusions of the Think Tank on mechanisms of incontinence and surgical cure in female and male SUI: surgical research initiatives during the ICI-RS meeting in 2010., Methods: The sub-group considered five areas for future research in stress urinary incontinence (SUI); (i) epidemiology and public health efforts in SUI, (ii) the basic sciences examining the physiology and pathophysiology of the continence mechanism, (iii) diagnostic techniques and clinical assessment of SUI, (iv) the future of treatment and surgical cure, and (v) the separate issue of male SUI., Results: Roadblocks to progress were identified for each of the five directions., Conclusions: Future research directions are suggested for each of these areas., (Copyright © 2011 Wiley-Liss, Inc.)

Extended voiding cystometry was performed to elucidate the true detrusor function in a patient originally misdiagnosed during standard fill cystometry. This methodology allows for observation of an extended period of bladder activity and eliminates the artifacts of classical fill cystometry, which are detrusor instability and noncompliance. A chronically elevated intravesical pressure between contractions (inter-contraction pressure) representing high pressure residual urine, as well as frequent, high amplitude, long duration detrusor contractions during the storage phase and a large post-void residual urine volume were documented. These urodynamic abnormalities are known to precipitate hydroureteronephrosis in the absence of vesicoureteral reflux.

A retrospective urodynamic study of 50 parkinsonian patients was done to determine the incidence and causes of post-prostatectomy incontinence. At presentation 22 per cent of the patients were incontinent. In 36 patients who underwent transurethral prostatectomy the incontinence rate was 17 per cent preoperatively and 28 per cent postoperatively. There was a clear association between normal voluntary sphincter control and urinary continence. After transurethral prostatectomy 5 of 6 patients continent preoperatively (83 per cent) who had abnormal sphincter control became incontinent compared to 1 of 24 (4.2 per cent) who had normal sphincter control. We conclude that the major risk of incontinence following prostatectomy in the parkinsonian patient is associated with lack of voluntary sphincter control.

The anticholinergic and musculotropic relaxant properties of desmethylimipramine (DMI) on smooth muscle were investigated utilizing cholinergic radioligand receptor binding and in-vitro muscle bath techniques. Receptor binding studies revealed the direct antimuscarinic potency of DMI to be 1/480th that of atropine. Muscle bath studies characterized discrete antimuscarinic and musculotropic actions. An initial, competitive antimuscarinic action could be separated from a delayed onset, noncompetitive musculotropic action by altering the time between the addition of DMI and the addition of bethanechol to the smooth muscle bath.

Experimental models to represent the surgical methods of bladder transection in humans were performed on dogs and rabbits. The effects on vesical neurophysiology were studied by cystometry with bethanechol supersensitivity testing; by in vitro pharmacological responsiveness; by determination of autonomic receptor densities using radioligand binding and by autonomic neurohistochemical staining. Analysis revealed that transection with or without neurovascular preservation resulted in an alpha-adrenergic denervation and cholinergic decentralisation. A comparison with the surgical models is presented and proposed mechanisms of action are discussed in relation to the experimental results.

Bladder capacity and stability were determined among 171 incontinent geriatric patients (mean age 80 years) with 2 techniques: a simple procedure for cystometry involving incremental bladder filling by gravity and a continuous water filling multichannel cystometrogram. Bladder capacities measured by both methods in 164 patients were correlated significantly by simple linear regression (r equals 0.75, p equals 0.0001) and they were not significantly different by paired t tests (t equals 1.20, p equals 0.23). Of the patients 110 (64 per cent) had detrusor motor instability or hyperreflexia on the multichannel cystometrogram, and simple cystometry had a sensitivity of 75 per cent, specificity of 79 per cent and positive predictive value of 85 per cent for this finding. The simple procedure was practical, well tolerated and helped to provide information for management decisions that would have been difficult to obtain from many of these geriatric patients without a formal and more complex urodynamic evaluation. When performed with other simple tests of lower urinary tract function and interpreted in conjunction with a few straightforward clinical criteria, simple cystometry can be helpful to assess bladder function among incontinent geriatric patients in settings in which formal urodynamics are either unavailable or impractical.

Jeffrey Frankel,1 David Staskin,2 Susann Varano,3 Michael J Kennelly,4 Rachael A Jankowich,5 Cornelia Haag-Molkenteller5 1Seattle Urology Research Center, Seattle, WA, USA; 2Tufts University School of Medicine, Boston, MA, USA; 3Clinical Research Consulting, Milford, CT, USA; 4Carolinas Medical Center, Charlotte, NC, USA; 5Urovant Sciences, Irvine, CA, USACorrespondence: Jeffrey Frankel, PO Box 1192, Mercer Island, WA 98040, USA, Tel +1 206 972 2775, Email jmfrankel@comcast.netAbstract: Pharmacologic treatment for overactive bladder (OAB), which is characterized by bothersome symptoms such as urgency and urge urinary incontinence (UUI), includes anticholinergics and β3-adrenergic receptor agonists. Anticholinergics are associated with adverse effects including dry mouth, constipation, cognitive impairment, and increased risk of dementia. Therefore, the drug class of β3-adrenergic receptor agonists may represent an effective, safe treatment option. Vibegron, a β3-adrenergic receptor agonist, was approved for use in Japan (2018) and the United States (2020). Over the past 3 years, 2 phase 3 trials (EMPOWUR, EMPOWUR extension) have been conducted with once-daily vibegron 75 mg for the treatment of OAB, and additional secondary and subgroup analyses have detailed the efficacy and safety of vibegron. In the international phase 3 EMPOWUR trial, treatment with vibegron was associated with significant improvements compared with placebo in efficacy outcomes of micturition frequency, UUI episodes, urgency episodes, and volume voided as early as week 2 that were sustained throughout the 12-week trial. The 40-week EMPOWUR extension study, following the 12-week treatment period, demonstrated sustained efficacy in patients receiving vibegron for 52 weeks. Treatment with vibegron was also associated with improvements in patient-reported measures of quality of life. Across studies, vibegron was generally safe and well tolerated. A separate, dedicated ambulatory blood pressure monitoring study showed that treatment with vibegron was not associated with clinically meaningful effects on blood pressure or heart rate. Across all studies, vibegron was efficacious, safe, and well tolerated and thus represents a valuable treatment option for patients with OAB. Here, nearly 1 year after US approval, we review the published data on efficacy and safety of vibegron 75 mg for the treatment of OAB.Keywords: adrenergic agonist, β-adrenergic receptor, urinary bladder overactive, urinary incontinence, vibegron