Effect of Pharmacotherapy for Overactive Bladder on the Incidence of and Factors Related to Urinary Tract Infection: A Systematic Review and Meta-analysis.

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.

Study design of a phase 4, real-world study (COMPOSUR) to evaluate vibegron in patients with overactive bladder.

BACKGROUND: Overactive bladder (OAB) is defined as urinary urgency accompanied by frequency and nocturia, with or without urge urinary incontinence (UUI). Vibegron, a selective ß3-adrenergic receptor agonist approved in the US in December 2020, demonstrated efficacy in reducing symptoms of OAB and was safe and well tolerated in the 12-week EMPOWUR trial and its 40-week, double-blind extension trial. The goal of the COMPOSUR study is to evaluate vibegron in a real-world setting to assess patient treatment satisfaction, tolerability, safety, duration of treatment, and persistence. METHODS: This is a 12-month, prospective, observational, real-world study, with an optional 12-month extension to 24 months, in the US assessing adults ≥ 18 years old starting a new course of vibegron. Patients must be previously diagnosed with OAB with or without UUI, symptomatic for ≥ 3 months before enrollment, and receive prior treatment with an anticholinergic, with mirabegron, or with a combination of an anticholinergic and mirabegron. Enrollment is performed by the investigator following exclusion and inclusion criteria guided by US product labeling, reinforcing a real-world approach. Patients complete the OAB Satisfaction with Treatment Questionnaire (OAB-SAT-q) monthly and the OAB Questionnaire short form (OAB-q-SF) and Work Productivity and Activity Impairment Questionnaire (WPAI:US) at baseline and monthly for 12 months. Patients are followed up via phone call, in-person visits, or telehealth (ie, virtual) visits. The primary endpoint is patient treatment satisfaction as determined by the OAB-SAT-q satisfaction domain score. Secondary endpoints include percent positive responses to individual OAB-SAT-q questions, additional OAB-SAT-q domain scores, and safety. Exploratory endpoints include adherence and persistence. DISCUSSION: OAB leads to a significant decrease in quality of life, as well as impairment of work activities and productivity. Persistence with OAB treatments can be challenging, often due to lack of efficacy and adverse effects. COMPOSUR is the first study to provide long-term, prospective, pragmatic treatment data for vibegron in the US and the resultant effect on quality of life among patients with OAB in a real-world clinical setting. Trial registration ClinicalTrials.gov identifier: NCT05067478; registered: October 5, 2021.

ß3-Adrenoceptor Agonist for the Treatment of Bladder Dysfunction in Children: A Systematic Review and Meta-Analysis.

PURPOSE: ß3-adrenergic receptor agonists (ß3 agonists) have been used in treatment of overactive bladder (OAB) and neurogenic detrusor overactivity (NDO) in adults. However, their use in children has only recently been approved by the U.S. Food and Drug Administration for patients with NDO. As in adults, the role of ß3 agonists in children may include conditions such as OAB. This systematic review and meta-analysis aims to understand the intended use, efficacy and safety of ß3 agonists in the pediatric population. MATERIALS AND METHODS: A literature search was performed in February 2021 across MEDLINE®, Embase®, Scopus®, the Cochrane Library and ClinicalTrials.gov. No language restrictions were placed. All records describing the clinical use of ß3 agonists in pediatric patients (<18 years of age) were included, regardless of the methodological design or outcomes assessed. The identified records were screened by 2 independent authors. The reporting was compliant with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Data extraction was performed by 2 independent reviewers, blinded to each other's extractions. The data were pooled using the fixed effects model. RESULTS: Of 367 records identified, 8 studies were included in the review (3 prospective and 5 retrospective). ß3 agonists led to improvements in both urodynamics parameters and self-reported outcomes such as incontinence. Commonly reported side effects were headaches (3%‒5.9%), constipation (3.5%‒5.7%), rhinitis/nasopharyngitis (1.7%‒5.8%) and blurred vision (1.7%‒2.9%). Clinically meaningful changes in safety outcomes (blood pressure, heart rate, electrocardiogram-related changes, liver function) were rare. Before and after ß3 agonist use, pooled effect estimates for maximum cystometric capacity for 171 patients were mean difference of +98.84 ml (95% CI 74.72, 122.96); for complete dryness, assessment of 235 patients showed a Peto odds ratio of 8.68 (95% CI 5.22, 14.45). CONCLUSIONS: ß3 agonists appear to be a promising, effective and safe alternative/adjunctive therapy in management of pediatric NDO or OAB, with improvements in both objective urodynamics parameters and subjective patient-reported outcomes following their use.

Once-Daily Vibegron 75 mg for Overactive Bladder: Long-Term Safety and Efficacy from a Double-Blind Extension Study of the International Phase 3 Trial (EMPOWUR).

PURPOSE: The long-term safety, tolerability and efficacy of vibegron in adults with overactive bladder were evaluated in the 40-week phase 3 EMPOWUR extension study. MATERIALS AND METHODS: Patients who completed 12 weeks of once-daily vibegron 75 mg or tolterodine 4 mg extended release in EMPOWUR continued double-blind treatment; patients who completed 12 weeks of placebo were randomly assigned 1:1 to receive double-blind vibegron or tolterodine. The primary outcome was safety, measured by incidence of adverse events. Secondary outcomes included change from baseline at week 52 in average daily number of micturitions and urgency episodes (all patients), and urge and total urinary incontinence episodes (patients with overactive bladder wet) based on 7-day diary data. RESULTS: Of 506 patients randomized 505 received ≥1 dose of medication, and 430 (85%) completed the study. A total of 12 patients (2.4%) discontinued owing to adverse events. The most common adverse events with vibegron/tolterodine (>5% in either group) were hypertension (8.8%/8.6%), urinary tract infection (6.6%/7.3%), headache (5.5%/3.9%), nasopharyngitis (4.8%/5.2%) and dry mouth (1.8%/5.2%). Improvements in efficacy end points were maintained for patients receiving vibegron for 52 weeks; least squares mean change from baseline to week 52 in micturitions was ‒2.4 for vibegron vs ‒2.0 for tolterodine; in urge urinary incontinence episodes ‒2.2 vs ‒1.7 (p <0.05); in urgency episodes ‒3.4 vs ‒3.2; and in total incontinence episodes ‒2.5 vs ‒1.9 (p <0.05). Among patients with overactive bladder wet 61.0% receiving vibegron experienced ≥75% reduction in urge urinary incontinence episodes after 52 weeks of treatment vs 54.4% with tolterodine, while 40.8% vs 34.2% experienced a 100% reduction. CONCLUSIONS: Vibegron demonstrated favorable long-term safety, tolerability and efficacy in patients with overactive bladder, consistent with results of the 12-week study.

International Phase III, Randomized, Double-Blind, Placebo and Active Controlled Study to Evaluate the Safety and Efficacy of Vibegron in Patients with Symptoms of Overactive Bladder: EMPOWUR.

PURPOSE: We assessed efficacy, safety and tolerability of vibegron, a novel, potent, highly selective ß3-adrenoceptor agonist, administered 12 weeks at 75 mg once daily to patients with overactive bladder in an international phase III trial with placebo and active control. MATERIALS AND METHODS: Adult patients with overactive bladder with 8.0 or more micturitions per day were randomized 5:5:4 to 75 mg vibegron, placebo or extended-release 4 mg extended-release tolterodine. Up to 25% of patients could have dry overactive bladder (less than 1.0 urge incontinence episode per day). Patients completed 7-day voiding diaries at baseline and weeks 2, 4, 8 and 12. RESULTS: Of 1,518 randomized patients 90.4% completed the trial. At 12 weeks micturitions decreased by an adjusted mean of 1.8 episodes per day for vibegron vs 1.3 for placebo (p <0.001, co-primary end point) and 1.6 for tolterodine. Among incontinent patients urge incontinence episodes decreased by an adjusted mean 2.0 episodes per day for vibegron vs 1.4 for placebo (p <0.0001, co-primary end point) and 1.8 for tolterodine. Moreover, vibegron was statistically significantly superior to placebo for key secondary measures of number of urgency episodes, volume per micturition and proportion of incontinent patients with a 75% or greater reduction in urge incontinence episodes (all p <0.01). Among vibegron treated patients 1.7% discontinued treatment because of adverse events vs 1.1% for placebo and 3.3% for tolterodine. Incidence of hypertension was 1.7% for vibegron and for placebo. CONCLUSIONS: Once daily 75 mg vibegron provided statistically significant reductions in micturitions, urgency episodes and urge incontinence, and increased the volume per micturition. Treatment was well tolerated with a favorable safety profile.

Mirabegron as a treatment for overactive bladder symptoms in men (MIRACLE study): Efficacy and safety results from a multicenter, randomized, double-blind, placebo-controlled, parallel comparison phase IV study.

AIMS: To evaluate the efficacy and safety of mirabegron in males with overactive bladder (OAB) symptoms. METHODS: In total, 464 males with OAB symptoms were enrolled from 14 institutes and were sorted into either the mirabegron 50 mg (n = 310) or placebo (n = 154) groups. The change in (i) the mean number of 24-h micturition episodes; (ii) OAB Symptom Scale (OABSS); and (iii) International Prostate Symptom Score (IPSS) from baseline to 12 weeks of treatment were compared between the two groups. Safety assessments included treatment-emergent adverse events, blood pressure, pulse rate, postvoid residual volume, and maximum urinary flow rate. After 12 weeks, the study was extended for 14 additional weeks by administering mirabegron 50 mg to both groups. RESULTS: The reduction in the mean number of 24-h micturition episodes from baseline to 12 weeks of treatment was similar between the two groups. However, significantly greater changes from baseline to 12 weeks were observed in total OABSS, OABSS urgency incontinence score (Q4), IPSS storage subscore (Q2 + Q4 + Q7), and IPSS urgency score (Q4) in the mirabegron group (P = 0.01 for all). According to the extended study, the changes of all efficacy variables from baseline to 26 weeks were similar between both groups. The safety assessment results were also similar between the two groups at 12 and 26 weeks. CONCLUSION: A daily 50 mg dose of mirabegron for 12 weeks reduced OAB symptoms in men, and no significant adverse events compared to the placebo group were noted.

Mirabegron escalation to 50 mg further improves daily urgency and urgency urinary incontinence in Asian patients with overactive bladder.

PURPOSE: To investigate the efficacy and safety of mirabegron dose escalation from 25 to 50 mg in Asian patients with overactive bladder (OAB). METHODS: A total of 242 patients (mean age: 67 years) with OAB were randomized to two groups: M25 (mirabegron 25 mg daily for 12 weeks) and M50 (mirabegron 25 mg daily for 4 weeks + 50 mg daily for 8 weeks). The primary endpoint was the percentage of patients without urgency or with a reduction of ≥2 in daily urgency episodes after treatment. Secondary endpoints included OAB symptom scores and other voiding parameters. Chi-squared and Wilcoxon signed-rank tests were used for data comparison. RESULTS: All OAB symptom scores in both groups improved significantly at 4 and 12 weeks. Both groups showed similar numbers of patients who reached the primary endpoint after treatment (M25: 64.6%, 42/65; M50: 64.9%, 50/77; p = 0.554). Patients in the M50 group with residual daily urgency or urgency urinary incontinence (UUI) episodes after 4 weeks of mirabegron 25 mg had a significantly higher rate of reduction in daily urgency episodes (60.9% vs. 34.5%, p = 0.034) and daily UUI episodes (87.5% vs. 37.5%, p = 0.021). Adverse event (AE) rates were similar between the groups. CONCLUSION: Mirabegron 25 mg for 12 weeks and mirabegron dose escalation from 25 to 50 mg exerted similar therapeutic effects. However, the dose escalation further improved the daily urgency and UUI episodes in patients with residual urgency or UUI after the initial treatment with mirabegron 25 mg.

Medical treatment of female overactive bladder syndrome and treatment-related effects.

The age-adjusted prevalence of overactive bladder syndrome (OAB) in Taiwan is approximately 16.9%. Currently, a variety of treatments are available for female OAB. However, different treatments have different treatment-related effects that may lead to significant adverse effects and ineffective treatment. In this article, we reviewed the tools that can be used to evaluate the efficacy of OAB treatments, such as a variety of questionnaires, serum or urine biomarkers, bladder diaries and urodynamic studies. In addition, we reviewed the medications used for female OAB treatment, such as antimuscarinics, beta-3 agonists, onabotulinumtoxinA intradetrusor injections, topical vaginal estrogen therapy and bladder instillation of liposome-encapsulated onabotulinumtoxinA. We focused on their efficacy and any treatment-related effects. The information in this review should be useful as a guide to the treatment of female OAB patients.

Safety and efficacy of beta-3 adrenergic agonists in treating neurogenic lower urinary tract dysfunction: A systematic review and meta-analysis.

PURPOSE: To evaluate efficacy and safety of beta-3 adrenergic agonists in adults with neurogenic lower urinary tract dysfunction. MATERIALS AND METHODS: According to a protocol (CRD42022350079), we searched multiple data sources for published and unpublished randomized controlled trials (RCTs) up to 2nd August 2022. Two review authors independently screened studies and abstracted data from the included studies. We performed statistical analyses by using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We used GRADE guidance to rate the certainty of evidence (CoE). RESULTS: We found data to inform two comparisons: beta-3 adrenergic agonists versus placebo (4 RCTs) and anticholinergics (2 RCTs). Only mirabegron was used for intervention in all included studies. Compared to placebo, beta-3 adrenergic agonists may have a clinically unimportant effect on urinary symptoms score (mean difference [MD] -2.50, 95% confidence interval [CI] -4.78 to -0.22; I²=92%; 2 RCTs; 192 participants; low CoE) based on minimal clinically important difference of 3. We are very uncertain of the effects of beta-3 adrenergic agonists on quality of life (MD 10.86, 95% CI 1.21 to 20.50; I²=41%; 2 RCTs; 98 participants; very low CoE). Beta-3 adrenergic agonists may result in little to no difference in major adverse events (cardiovascular adverse events) (risk ratio 0.57, 95% CI 0.14 to 2.37; I²=0%; 4 RCTs; 310 participants; low CoE). Compared to anticholinergics, no study reported urinary symptom scores and quality of life. There were no major adverse events (cardiovascular adverse events) in either study group (1 study; 60 participants; very low CoE). CONCLUSIONS: Compared to placebo, beta-3 adrenergic agonists may have similar effects on urinary symptom scores and major adverse events. There were uncertainties about their effects on quality of life. Compared to anticholinergics, we are either very uncertain or have no evidence about urinary symptom scores, quality of life, and major adverse events.

Real-World Adherence to and Persistence with Vibegron in Patients with Overactive Bladder: A Retrospective Claims Analysis.

INTRODUCTION: Vibegron is a ß3-adrenergic receptor agonist approved for overactive bladder (OAB). This analysis assessed real-world adherence and persistence with vibegron in patients with OAB, along with demographics and clinical characteristics associated with adherence and persistence. METHODS: This retrospective study used the Optum Research Database to identify patients treated with vibegron from April 2021 to August 2022 (identification period). Patients had ≥ 60 days of continuous pharmacy coverage in a commercial or Medicare Advantage plan following the index fill (follow-up). Adherence was assessed as proportion of days covered (PDC) from index to end of follow-up and was defined as PDC ≥ 80%. Persistence was measured as days to discontinuation of therapy (30-day gap) or end of follow-up. Data for adherence and persistence are presented descriptively. Characteristics associated with adherence and persistence were analyzed using multivariable models among patients with medical and pharmacy benefits during the 90 days before index (baseline). RESULTS: Overall, 9992 patients had a vibegron claim during the identification period; 9712 had ≥ 2 months of follow-up. Mean (SD) age was 74.2 (10.7) years; 68.2% were female. Mean (SD) PDC was 0.64 (0.34). Median (95% confidence interval) persistence was 142 (132-153) days. Of the 5073 patients who were ≥ 18 years old with continuous baseline pharmacy and medical benefits ≥ 90 days before index, 2497 (49.2%) were adherent. Patients were more likely to be adherent and persistent if they received a greater days' supply for the index fill and had baseline medication count ≥ 6. Patients were more likely to discontinue if their index copay was > $45. CONCLUSION: Nearly half of the patients initiating vibegron were adherent. Factors associated with adherence and persistence were more likely to be related to prescribing practices than patient characteristics. These results suggest it may be best to follow up with patients approximately 4 to 5 months after initiating treatment with vibegron.

Vibegron is a newer drug for treating overactive bladder. Vibegron was safe and worked well in clinical trials. However, there is no information on use of vibegron in a real-world population that is not a clinical trial. This study looked at how consistently and how long patients took vibegron after starting it. It also looked at what was common in patients who took vibegron consistently. To do this, the study used pharmacy prescription data from April 2021 to August 2022. It examined adherence to the study medication for each patient. Adherence is how many days patients had medication on hand compared to how long they were followed. The study also looked at persistence to the study medication. Persistence is how long a patient takes a medication before they stop taking it. Researchers then examined if there were reasons a patient may or may not take vibegron as prescribed. The study included prescription data for 9712 patients. The average age was 74 years and 68% of patients were female. Patients had their medication 64% of the time (adherence). On average, patients took their medication for 142 days before stopping (persistence). Patients had better adherence and persistence if they received a larger supply of medication at the pharmacy when first prescribed the medication and if they had more medications overall. Patients' age and gender did not affect adherence and persistence. Vibegron may be a good option for patients with overactive bladder. Follow-up with a provider may be considered 4 to 5 months after starting vibegron.

TReating Incontinence for Underlying Mental and Physical Health (TRIUMPH): a study protocol for a multicenter, double-blinded, randomized, 3-arm trial to evaluate the multisystem effects of pharmacologic treatment strategies for urgency-predominant urinary incontinence in ambulatory older women.

BACKGROUND: Urgency-type urinary incontinence affects one in four older community-dwelling women and overlaps with other common aging-associated health syndromes such as cognitive impairment, physical mobility impairment, and depression. Observational studies have raised concern about potentially higher rates of delirium and dementia in older adults taking anticholinergic bladder medications, but few prospective data are available to evaluate the effects of these and other pharmacologic treatments for urgency incontinence on cognition and other multisystem functional domains important to older women. METHODS: The TRIUMPH study is a randomized, double-blinded, 3-arm, parallel-group trial comparing the multisystem effects of anticholinergic versus beta-3-adrenergic agonist bladder therapy and versus no active bladder anti-spasmodic pharmacotherapy in older women with urgency incontinence. Women aged 60 years and older (target N = 270) who have chronic urgency-predominant urinary incontinence and either normal or mildly impaired cognition at baseline are recruited from the community by investigators based in northern California, USA. Participants are randomized in equal ratios to take identically encapsulated oral anticholinergic bladder therapy (in the form of tolterodine 2 mg extended release [ER]), oral beta-3 adrenergic agonist bladder therapy (mirabegron 25 mg ER), or placebo daily for 24 weeks, with the option of participant-directed dose titration (to tolterodine 4 mg ER, mirabegron 50 mg ER, or matching placebo daily). Participants also receive patient-oriented information and instructions about practicing first-line behavioral management strategies for incontinence. The primary outcome is change in composite cognitive function over 24 weeks assessed by a comprehensive battery of cognitive tests, with a secondary exploration of the persistence of change at 36 weeks. Secondary outcomes include changes over 24 and 36 weeks in domain-specific cognitive function; frequency, severity, and impact of urgency-associated urinary symptoms; physical function and balance; sleep quality and daytime sleepiness; psychological function; and bowel function. DISCUSSION: The TRIUMPH trial addresses the need for rigorous evidence to guide counseling and decision-making for older women who are weighing the potential multisystem benefits and risks of pharmacologic treatments for urgency incontinence in order to preserve their day-to-day functioning, quality of life, and independence in older age. TRIAL REGISTRATION: ClinicalTrials.gov NCT05362292. Registered on May 5, 2022.

Sestrin2 Regulates Beneficial ß3-Adrenergic Receptor-Mediated Effects Observed in Inguinal White Adipose Tissue and Soleus Muscle.

Sestrin2, a well-known adenosine monophosphate-activated protein kinase (AMPK) regulator, plays a protective role against metabolic stress. The ß3-adrenergic receptor (ß3AR) induces fat browning and inhibits muscle atrophy in an AMPK-dependent manner. However, no prior research has examined the relationship of sestrin2 with ß3AR in body composition changes. In this study, CL 316,243 (CL), a ß3AR agonist, was administered to wild-type and sestrin2-knockout (KO) mice for 2 weeks, and fat and muscle tissues were harvested. CL induced AMPK phosphorylation, expression of brown-fat markers, and mitochondrial biogenesis, which resulted in the reduction of lipid droplet size in inguinal white adipose tissue (iWAT). These effects were not observed in sestrin2-KO mice. In CL-treated soleus muscle, sestrin2-KO was related to decreased myogenic gene expression and increased levels of muscle atrophy-related molecules. Our results suggest that sestrin2 is associated with beneficial ß3AR-mediated changes in body composition, especially in iWAT and in the soleus.

Long-term efficacy and safety of vibegron versus mirabegron and anticholinergics for overactive bladder: a systematic review and network meta-analysis.

Background: Few randomized controlled trials evaluate the long-term efficacy and safety of pharmacotherapy for overactive bladder (OAB). This network meta- analysis compares the long-term (52-week) efficacy and safety of vibegron, mirabegron and anticholinergics for the treatment of OAB. Methods: A systematic literature review and network meta-analysis were conducted following PRISMA guidelines using MEDLINE, Embase and Cochrane Central Register of Controlled Trials and terms related to OAB. Efficacy outcomes included change from baseline to week 48-52 in mean daily total urinary incontinence (UI) episodes, mean daily number of micturitions and volume voided/micturition. Efficacy outcomes were analysed using Bayesian models. Commonly reported adverse events (AEs) are described. Results: Of 2098 hits retrieved, 5 publications and 1 study report describing 5 unique randomized controlled trials were included in the analyses. Mean (95% credible interval) change from baseline in total UI episodes for vibegron 75 mg (-2.2; -2.9 to -1.5) showed a significantly greater reduction than mirabegron 50 mg (-1.3; -1.9 to -0.8) and tolterodine 4 mg extended release (-1.6; -2.1 to -1.1). No significant differences were observed between vibegron and comparators for daily micturitions or volume voided/micturition. Within the manuscripts, the 4 most common AEs (range) for anticholinergics included dry mouth (5.2-90.0%), constipation (7.7-65.0%), blurred vision (3.8-35.0%) and hypertension (8.6-9.6%); the 4 most commonly reported AEs for ß3-adrenergic agonists included hypertension (8.8-9.2%), urinary tract infection (5.9-6.6%), headache (5.5%) and nasopharyngitis (4.8-5.2%). Conclusion: Vibegron was associated with significantly greater improvement in daily total UI episodes at 52 weeks than mirabegron and tolterodine. When reported, the most common AE for anticholinergics was dry mouth and for ß3-adrenergic agonists was hypertension. Hypertension incidence was similar between drug classes.

Beta 3 Adrenoreceptor Agonist for the Management of Lower Urinary Tract Symptoms in Men With Benign Prostatic Hyperplasia: A Systematic Review.

Beta-3 adrenoceptor (B3AR) agonist which mediate detrusor relaxation has been tried as a new treatment modality for men with benign prostatic hyperplasia (BPH). However, it remains unclear whether the B3AR agonist has more clinical benefits and fewer adverse effects in men with BPH than in women. We performed a comprehensive search using multiple databases, trials registries, other sources of grey literature, and conference proceedings regardless of language or publication status and included randomized controlled trials. Two review authors independently screened the literature, extracted data, and assessed risk of bias. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. Primary outcomes were urologic symptom scores, quality of life (QoL), and overall adverse events. We found 4 randomized controlled trials with 1,105 participants in 3 comparisons. All studies reported short-term outcomes (ranged from 8 weeks to 12 weeks). Mirabegron, tamsulosin, silodosin, fesoterodine, and tadalafil were administrated as intervention. While B3AR agonist can improve the patient-important outcomes within group (before and after treatment), B3AR agonist combination therapy with current standard BPH treatment such as alpha blocker or anticholinergic may not have additional effects on urological symptom scores and QoL compared to alpha blocker or anticholinergic monotherapy. B3AR agonist therapy with phosphodiesterase 5 inhibitor (PDE5I) showed statistical improvement on urological symptom scores or QoL compared to PDE5I monotherapy. For safety profile, B3AR agonist in all 3 comparisons may not increase adverse event rate. While B3AR agonists may be used for the treatment of lower urinary tract symptoms in men with BPH if storage symptoms with standard BPH treatment are insufficient, B3AR agonists appear to have trivial or similar effects compared to current standard BPH treatment.

Effect of co-administration of two different phosphodiesterase inhibitors and a ß3-adrenoceptor agonist in an experimental model of detrusor overactivity.

The purpose of this study was to evaluate in vitro the effect of the combination of BRL 37344 (ß3-adrenoceptor agonist) with tadalafil (phosphodiesterase type 5 inhibitor) or rolipram (phosphodiesterase type 4 inhibitor) in an experimental model of detrusor overactivity. The experiments were carried out in two phases using bladder strips of mice. In the first phase, on the top of 40 mM potassium-induced contraction, strips isolated from control mice were exposed to increasing concentrations of each study drug. In another series of experiments, prior to contraction, strips were incubated with either tadalafil or rolipram, followed by the addition of increasing concentrations of BRL 37344. In the second phase, the same protocols were performed with animals previously treated with L-NAME for 30 days. Chronic L-NAME administration leads to detrusor overactivity due to nitric oxide synthase inhibition. In phase one, preincubation with tadalafil enhanced relaxation response to BRL 37344 at two concentrations. Pretreatment with rolipram had no effect on BRL 37344-induced relaxation. In L-NAME-treated mice, rolipram induced more relaxation than the other drugs, enhancing relaxation response to BRL 37344 at almost all concentrations, but no synergistic effect with tadalafil was observed. The relaxant effect of BRL 37344 was enhanced by rolipram but not by tadalafil, suggesting that PDE4 inhibition, especially when associated with ß3-adrenoceptor stimulation, could represent a potential treatment for overactive bladder.

Patient and physician preferences for oral pharmacotherapy for overactive bladder: two discrete choice experiments.

OBJECTIVE: We examined patient and treating physician (general practitioners, urologists, and [uro]gynecologists) preferences for oral pharmacotherapy (antimuscarinics and beta-3 adrenoceptor agonists) for overactive bladder to gain a deeper understanding of which attributes drive their treatment decision-making and to quantify to what extent. RESEARCH DESIGN AND METHODS: Two separate discrete choice experiments were developed and validated using the input of patients and physicians. The patient experiment contained the following attributes: micturition frequency, incontinence, nocturia, urgency, dry mouth, constipation, increased heart rate, and increased blood pressure. The physician experiment contained two additional attributes: coping and atrial fibrillation. Both were fielded in five European countries. To allow for preference heterogeneity, utility functions were estimated using a mixed multinomial logit model. RESULTS: A total of 442 patient and 318 physician responses were analyzed. Patients ranked the attributes based on their largest potential impact on treatment value as follows: incontinence, nocturia, risk of an increased heart rate, urgency, frequency, risk of increased blood pressure, risk of constipation, and risk of dry mouth; and physicians as follows: incontinence, urgency, nocturia, frequency, risk of dry mouth, coping, risk of increased heart rate, risk of increased blood pressure, risk of atrial fibrillation, and risk of constipation. CONCLUSION AND LIMITATIONS: In their valuations, physicians put more emphasis on increasing benefits, whereas patients put more emphasis on limiting risks of side effects. Another contrast that emerged was that patients' valuations of side effects were found to be fairly insensitive to the presented risk levels (with the exception of risk of dry mouth), whereas physicians' evaluated all side effects in a risk-level dependent manner. The obtained utility functions can be used to predict whether, to what extent, and for which reasons patients and physicians would choose one oral pharmacotherapy over another, as well as to advance shared decision-making.

Determination of Mirabegron in rat plasma by UPLC-MS/MS after oral and intravenous administration

SUMMARY Mirabegron is a kind of β3 adrenergic receptor agonist which is an effective drug for the treatment of overactive bladder. In this research, a UPLC-MS/MS method is developed and validated for the study of mirabegron pharmacokinetic in rats. A protein precipitation method is applied for sample preparation with acetonitrile. m/z 397.3→379.6, m/z 326.4→121.0 for mirabegron, tolterodine (IS), respectively in the positive ion mode was performed for quantitation. The method is reliable and reproducible in our study (intra-day precision≤11.06%, inter-day precision≤11.43%) with concentration curves linear from 5 to 2500 ng/mL(R2>0.999). Stability studies demonstrated that mirabegron was stable under a variety of storage conditions. This method was successfully applied for determining mirabegron in rats after oral and intravenous administration.

RESUMO Mirabegron é um tipo de agonista do receptor adrenérgico beta 3 que demonstra eficácia no tratamento de bexiga hiperativa. Nesta pesquisa, o método UPLC-MS/MS é desenvolvido e validado para o estudo da farmacocinética mirabegron em ratos. Um método de precipitação de proteínas é aplicado para a preparação de amostras com acetonitrilo. 397.3 → 379.6 M / Z, M / Z 326.4 → 121.0 para mirabegron, tolterodina (IS), respectivamente, para o íon positivo foi realizado para quantificação. O método é fiável e reprodutível em nosso estudo (precisão intradia ≤ 11,06%; precisão entredia ≤ 11.43%), com curvas de concentração linear de 5 a 2 ng/ml (R2 > 0,999). Estudos de estabilidade demonstraram que mirabegron permanece estável sob uma variedade de condições de armazenamento. Este método foi aplicado com sucesso para a determinação de mirabegron em ratos após administração oral e intravenosa.

Diagnosis and office-based treatment of urinary incontinence in adults. Part two: treatment.

Urinary incontinence is a common problem in both men and women. In this review article we address treatment of the various forms of incontinence with conservative treatments, medical therapy, devices and surgery. The US Preventive Services Task Force, The Cochrane Database of Systematic Reviews, and PubMed were reviewed for articles focusing on urinary incontinence. Conservative therapy with education, fluid and food management, weight loss, timed voiding and pelvic floor physical therapy are all simple office-based treatments for incontinence. Medical therapy for incontinence currently is only available for urgency incontinence in the form of anticholinergic medication. Condom catheters, penile clamps, urethral inserts and pessaries can be helpful in specific situations. Surgical therapies vary depending on the type of incontinence, but are typically offered if conservative measures fail.