Comparison of mirabegron and vibegron for clinical efficacy and safety in female patients with overactive bladder: a multicenter prospective randomized crossover trial.

PURPOSE: To compare the efficacy and safety of mirabegron and vibegron in female OAB patients. METHODS: We conducted a multicenter, prospective, randomized crossover study of female patients with OAB. The patients were assigned to Group MV (mirabegron for 8 weeks, followed by vibegron for 8 weeks) or group VM (vibegron for 8 weeks, followed by mirabegron for 8 weeks). The primary endpoint was the change in OABSS from baseline, and the secondary endpoint was the change in FVC parameters. After completion of the study, each patient was asked which drug was preferable. RESULTS: A total of 83 patients were enrolled (40 and 43 in groups MV and VM, respectively). At 8th and 16th week, 33 and 29 in Group MV and 34 and 27 in Group VM continued to receive the treatment. The change in PVR was not significantly different between treatment with mirabegron and vibegron. The changes in OABSS, nighttime frequency, mean, and maximum voided volume were similar between mirabegron and vibegron. The mean change in the daytime frequency was greater in the vibegron than in the mirabegron. Of the 56 patients, 15 (27%) and 30 (53%) preferred mirabegron and vibegron, respectively. The remaining 11 patients (20%) showed no preference. The change in the urgency incontinence score during vibegron was better in patients who preferred vibegron to mirabegron. CONCLUSION: The efficacies of mirabegron and vibegron in female patients was similar. The patients' preference for vibegron could depend on the efficacy of vibegron for urgency incontinence.

Efficacy of transcutaneous electrical nerve stimulation combined with mirabegron therapy compared with mirabegron monotherapy for overactive bladder: a prospective randomized controlled study.

PURPOSE: The objective was to evaluate the efficacy of transcutaneous electrical nerve stimulation (TENS) combined with mirabegron therapy compared with mirabegron monotherapy in the treatment of female patients with overactive bladder (OAB). METHODS: In this randomized controlled study, 100 female outpatients with OAB were screened. Among these patients, 86 who met the inclusion criteria were randomly divided into the TENS combined with mirabegron treatment group and mirabegron monotherapy treatment group, with 43 patients in each group. The voiding diary, Overactive Bladder Symptom Score (OABSS), Overactive Bladder Questionnaire Symptom Bother Score (OAB-q SBS), total health-related quality of life (OAB-q HRQoL), and treatment satisfaction-visual analog scale (TS-VAS) score before and after treatment were recorded to evaluate the efficacy of OAB treatment. Seventy-nine of the 86 patients (40 in the TENS plus mirabegron group and 39 in the mirabegron monotherapy group) completed 12 weeks of treatment. RESULTS: TENS combined with mirabegron therapy was superior to mirabegron monotherapy in improving the primary endpoints, including the daily number of micturition episodes and the daily MVV/micturition and secondary endpoints, including the daily number of urgency episodes, the OABSS, the OAB-q SBS, the HRQoL score and TS-VAS score. There were no statistically significant differences in urgency urinary incontinence and nocturia between the groups. Some minor adverse effects were observed, including muscle pain, local paresthesia and constipation. CONCLUSIONS: The combination of TENS and mirabegron was more effective than mirabegron alone in the treatment of female patients with OAB. TRIAL REGISTRATION NUMBER: ChiCTR2400080528 (31.01.2024, retrospectively registered).

Lessons learned from a multi-data source research collaboration: The mirabegron post-authorization safety study program.

BACKGROUND: Many factors contribute to developing and conducting a successful multi-data source, non-interventional, post-authorization safety study (NI-PASS) for submission to multiple health authorities. Such studies are often large undertakings; evaluating and sharing lessons learned can provide useful insights to others considering similar studies. OBJECTIVES: We discuss challenges and key methodological and organizational factors that led to the delivery of a successful post-marketing requirement (PMR)/PASS program investigating the risk of cardiovascular and cancer events among users of mirabegron, an oral medication for the treatment of overactive bladder. RESULTS: We provide context and share learnings, including sections on research program collaboration, scientific transparency, organizational approach, mitigation of uncertainty around potential delays, validity of study outcomes, selection of data sources and optimizing patient numbers, choice of comparator groups and enhancing precision of estimates of associations, potential confounding and generalizability of study findings, and interpretation of results. CONCLUSIONS: This large PMR/PASS program was a long-term commitment from all parties and benefited from an effective coordinating center and extensive scientific interactions across research partners, scientific advisory board, study sponsor, and health authorities, and delivered useful learnings related to the design and organization of multi-data source NI-PASS.

Persistence of overactive bladder pharmacological treatment in women as reflected from large-scale real-world data of prescription claims: A retrospective cohort study.

INTRODUCTION AND OBJECTIVES: Medical treatments for overactive bladder (OAB) have proven efficacy in controlled trials. However, 1-year treatment persistence is reported to be as low as 25% for anticholinergics and 40% for ß3 agonists. Real-world data on treatment continuation and treatment sequence is limited. Therefore, we aimed to study treatment persistence trends in women initiated on OAB medications. MATERIALS AND METHODS: We used advanced data-mining techniques to query the largest regional provider's medication purchase database, dispensing for patients, for all women initiating OAB pharmacotherapy between 2010 and 2020. Treatment persistence was measured as days in which the patient was in possession of medication and nonpersistence was defined as prescription nonrefilling for 90 days. We employed a Sankey diagram to explore trends in OAB medication acquisition and treatment sequence. We compared treatment persistence using Kaplan-Meier survival curves and pairwise log-rank analysis. RESULTS: Here, 46 079 women made 791 681 unique claims of OAB medications. Only 39% of the patients tried more than one OAB formulation, including dose change. The overall persistence rate for all drugs was 55% in 30 days, 46% in 90 days, and 37% per year. The persistence rate for Mirabegron at 30 days was 54%, 42% at 90 days, and 17% at 1 year. Overall, persistence rates were unchanged when stratifying by the time Mirabegron insurance acceptance into coverage (p > 0.05). CONCLUSIONS: Real-world OAB pharmacotherapy persistence rates are lower than previously reported. The introduction of Mirabegron did not seem to improve these rates or affect the treatment sequence.

A treatment prediction strategy for overactive bladder using a machine learning algorithm that utilized data from the FAITH study.

AIMS: To use machine learning algorithms to develop a model to accurately predict treatment responses to mirabegron or antimuscarinic agents in patients with overactive bladder (OAB), using real-world data from the FAITH registry (NCT03572231). METHODS: The FAITH registry data included patients who had been diagnosed with OAB symptoms for at least 3 months and were due to initiate monotherapy with mirabegron or any antimuscarinic. For the development of the machine learning model, data from patients were included if they had completed the 183-day study period, had data for all timepoints and had completed the overactive bladder symptom scores (OABSS) at baseline and end of study. The primary outcome of the study was a composite outcome combining efficacy, persistence, and safety outcomes. Treatment was deemed "more effective" if the composite outcome criteria for "successful," "no treatment change," and "safe" were met, otherwise treatment was deemed "less effective." To explore the composite algorithm, a total of 14 clinical risk factors were included in the initial data set and a 10-fold cross-validation procedure was performed. A range of machine learning models were evaluated to determine the most effective algorithm. RESULTS: In total, data from 396 patients were included (266 [67.2%] treated with mirabegron and 130 [32.8%] treated with an antimuscarinic). Of these, 138 (34.8%) were in the "more effective" group and 258 (65.2%) were in the "less effective" group. The groups were comparable in terms of their characteristic distributions across patient age, sex, body mass index, and Charlson Comorbidity Index. Of the six models initially selected and tested, the decision tree (C5.0) model was chosen for further optimization, and the receiver operating characteristic of the final optimized model had an area under the curve result of 0.70 (95% confidence interval: 0.54-0.85) when 15 was used for the min n parameter. CONCLUSIONS: This study successfully created a simple, rapid, and easy-to-use interface that could be further refined to produce a valuable educational or clinical decision-making aid.

Does metabolic syndrome influence the efficacy of mirabegron treatment in female patients with overactive bladder?

INTRODUCTION AND HYPOTHESIS: We aimed to determine whether the presence of metabolic syndrome (MS) affects the efficacy of mirabegron in treatment-naïve women with overactive bladder (OAB). METHODS: Women being treated with mirabegron 50 mg were allocated to MS and non-MS groups, and the efficacy of treatment of OAB was compared using the OAB symptom score (OABSS) and a 3-day voiding diary before and 12 weeks after starting treatment. The Wilcoxon signed-rank and Mann-Whitney U tests and multivariate logistic regression were used for statistical analyses, and a p-value < 0.05 was considered to represent statistical significance. RESULTS: Of the 197 patients who completed the trial, 43 (23.9%) had MS. After 12 weeks of mirabegron treatment, both the MS and non-MS groups showed significant improvements in OABSS score, the number of incontinence episodes/24 h, the number of micturition episodes/24 h, and the number of episodes of urgency/24 h. The factors associated with clinically important differences in OABSS were the presence of hyperglycemia (odds ratio 2.43, 95% confidence interval [CI] 1.05-5.60) and OABSS score at baseline (odds ratio 1.23, 95% CI 1.09-1.39). CONCLUSIONS: Mirabegron is effective in patients with and without MS, and comorbid hyperglycemia and severe OAB symptoms before treatment are predictors of the efficacy of mirabegron treatment.

Tamsulosin vs. Tadalafil as medical expulsive therapy for distal ureteral stones: a systematic review and meta-analysis.

PURPOSE: Medical expulsive therapy (MET) is recommended for distal ureteral stones from 5 to 10 mm. The best drug for MET is still uncertain. In this review, we aim to compare the effectiveness of tadalafil and tamsulosin for distal ureteral stones from 5 to 10 mm in terms of stone expulsion rate (SER), stone expulsion time (SET) and the side effect profile. MATERIALS AND METHODS: A comprehensive literature search was conducted on MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Scopus and Web of Science, from inception until April 2023. Only randomized controlled trials were included in the analysis. RESULTS: Eleven publications with 1,330 patients were included. We observed that tadalafil has a higher SER (OR 0.55, CI 95% 0.38;0.80, p=0.02, I2=52%) and the same efficacy in SET (MD 1.07, CI 95% -0.25; 2.39, p=0.11, I2=84%). No differences were found when comparing side effects as headache, backache, dizziness, and orthostatic hypotension. CONCLUSION: Tadalafil has a higher stone expulsion rate than tamsulosin as a medical expulsive therapy for patients with distal stones from 5 to 10 mm without differences in side effects.

[Assessment of prescribing practices in overactive bladder pharmacotherapy across different specialties of India: a prescription trend analysis].

PURPOSE: To assess the prescribing practices for overactive bladder (OAB) pharmacotherapy based on the prescription trend analysis across different specialties of India. METHOD: s: IQVIA (Quintiles and IMS Health) secondary sales audit (SSA), as well as a prescription audit for antimuscarinics and beta-3 adrenoceptor agonists (mirabegron) from 2014 to 2021, were analyzed. The data includes SSA data of various antimuscarinics like solifenacin, oxybutynin, tolterodine, darifenacin, trospium and mirabegron change in the prescription trend of antimuscarinics and mirabegron across different specialties; prescribers overlap analysis for solifenacin and mirabegron among Indian urologists were also analyzed. RESULTS: Urologists prescription rates of OAB drugs were 65% in 2016 and 54% in 2021. The rate of OAB medication prescription by non-urologist was highest from the surgeon (11%), followed by gynecologists (9%) and consultant physicians (8%) in 2021. In addition, among OAB medication prescription rates for antimuscarinics were 100% in 2016 and 58% in 2021 whereas for mirabegron, it was 0% in 2016 and 42% in 2021. Solifenacin was most frequently prescribed anticholinergics, followed by oxybutynin, tolterodine, darifenacin, and trospium. The proportion of prescribers of OAB medication among urologists was 38% in 2016 and 33% in 2021. Exclusive prescribers of solifenacin were 748 in 2018 and 739 in 2021 at the urologist, whereas for mirabegron, it was 961 in 2018 and 934 in 2021. The compound annual growth rate for prescription of the last 6 years (from 2016-2021) for solifenacin and mirabegron was -3% and 8% respectively. CONCLUSIONS: Urology remained a top prescribing specialty for OAB drugs, although prescription share increased at surgeon and consultant physician. OAB medicines prescriptions by urologists are shifting from leading antimuscarinic solifenacin to beta-agonist mirabegron. Data from this study will ultimately lead to the OAB medication preference by the specialist that could lead to more advanced OAB management.

Mirabegron vs. solifenacin in control of endoscopically inserted ureteral stent-related symptoms.

PURPOSE: We aimed to assess the efficacy and safety of Mirabegron vs. solifenacin to treat LUTS resulting from DJ-stent insertion. METHODS: A total of 97 patients who had DJ-stent inserted for urinary stone disease were randomly divided into three groups according to received treatment. Group A took Mirabegron 50 mg daily, group B took solifenacin 5 mg daily from the 4th day after stent placement until the stent was removed, and group C only was hydrated well. All patients were evaluated by USSQ and IPSS at 4th day post-insertion of ureteral stent, follow-up day before removing of stent and post-removal of stent. RESULTS: The USSQ urinary symptom scores at day 4 comparing to day of removal of stent showed significant difference in between study groups (32 ± 6-13 ± 6 vs. 31 ± 6-14 ± 4 in Mirabegron and solifenacin, respectively) and without significant difference in control group. The USSQ body pain score significantly decreased in both Mirabegron and solifenacin groups at day of stent removal comparing to day 4 post-insertion of DJ with insignificant decreasing in the control group. Quality of life scores showed significant improving in Mirabegron and solifenacin group, and there was no difference in control group at 4 and 14 days after treatment. No severe complications were observed in either group. DISCUSSION/CONCLUSION: In our series, we indicate that Mirabegron and solifenacin can be used to improve symptoms caused by the insertion of DJ-stent without significant difference.

Utilization rate and long-term persistence of combination pharmacotherapy with ß3-agonists and antimuscarinics for overactive bladder refractory to monotherapy in a real-world setting.

AIM: To assess real-world treatment profiles, including utilization rate, time to and reasons for discontinuation of combination pharmacotherapy with ß3 -agonists and antimuscarinics for refractory overactive bladder (OAB) through a retrospective chart review. METHODS: We retrospectively reviewed the records of OAB patients who received ß3 -agonists or antimuscarinics at our hospital between 2012 and 2020 and analyzed the clinical course of patients who progressed to combination therapy. Data on age, sex, major complaints, OAB symptom score at the initiation of combination therapy, treatment persistence, and reasons for discontinuation were collected. Treatment persistence was assessed with respect to the median time to discontinuation and persistence rate at 12 months. RESULTS: Of the 2163 patients receiving ß3 -agonists or antimuscarinics, only 84 (3.8%) progressed to combination therapy with both drug classes. At therapy initiation, most (98%) of these patients had moderate to severe OAB symptoms. Median treatment duration and 12-month persistence rate for combination therapy were 595 days and 64.0%, respectively. The reasons for discontinuation were insufficient treatment efficacy followed by adverse effects including voiding impairment in nearly 10% of the patients. None of the baseline parameters was independently associated with persistence in the multivariate analysis. CONCLUSION: While underutilized among OAB patients refractory to monotherapy, combination pharmacotherapy showed a greater persistence rate than published mirabegron or antimuscarinic monotherapy when applied to patients with moderate to severe symptoms. Treatment-emergent voiding impairment is a concern associated with this mode of therapy. A small sample size at a single institution is the limitation of this study.

Mirabegron and antimuscarinic use in frail overactive bladder patients in the United States Medicare population.

INTRODUCTION: Overactive bladder (OAB) and frailty are independently associated with patient burden. However, economic burden and treatment-taking behavior have not been well characterized among frail patients with OAB, which, given the varying safety and tolerability profiles of available treatments, is crucial. OBJECTIVES: To assess costs, health care resource utilization, treatment-taking behavior (persistence and adherence) to OAB medication in older, frail OAB patients. METHODS: This was a retrospective cohort study using international business machines MarketScan Medicare Supplemental claims data. Eligible frail patients (per Claims-based Frailty Index score) initiating mirabegron were 1:2 propensity score matched (based on age, sex, and other characteristics) with those initiating antimuscarinics and were followed up to 1 year. All-cause, per-person, per-month costs, health care encounters, persistence (median days to discontinuation assessed using Kaplan-Meier methods) and adherence (≥80% of proportion of days covered at Day 365) were compared. RESULTS: From 2527 patients with incident mirabegron (21%) or antimuscarinic (79%) dispensations, 516 incident mirabegron users (median age: 82 years, 64% female) were matched to 1032 incident antimuscarinic users (median age: 81 years, 62% female). Median cost was higher in mirabegron group ($1581 vs. $1197 per month); this was primarily driven by medication cost. There was no difference in medical encounters. Adherence (39.1% vs. 33.8%) and persistence (103 vs. 90 days) were higher in mirabegron users. CONCLUSIONS: Among frail older adults with OAB, mirabegron use was associated with higher costs and potential improvements in treatment-taking behaviors, particularly with respect to treatment adherence, versus those initiating antimuscarinics.

Symptom improvement with mirabegron treatment is associated with urobiome changes in adult women.

INTRODUCTION AND HYPOTHESIS: Mirabegron, a beta-3 agonist, is prescribed for urgency urinary incontinence (UUI). We assessed the correlation of symptom improvement with urobiome characteristics in adult women participants prescribed mirabegron for UUI treatment. METHODS: We enrolled participants seeking UUI treatment who selected mirabegron and agreed to participate in this 12-week, open label study conducted at the Female Pelvic Medicine and Reconstructive Surgery Center at Loyola University Medical Center. Following eligibility screening and research consent, participants completed the overactive bladder questionnaire (OAB-Q) and provided a catheterized urine sample at baseline, 4, 8, and 12 weeks. The primary outcome, symptom improvement at 12 weeks, was based on the validated Patient Global Symptom Control questionnaire score to dichotomize symptom response (responder vs nonresponder [PGSC score ≤3]). Urine samples were processed by the Expanded Quantitative Urine Culture (EQUC) protocol. RESULTS: Eighty-three participants (mean age 68 years) completed baseline assessment. Of the 47 participants with primary outcome data and samples analysis, there were 16 responders and 31 nonresponders; responder groups were similar demographically. Living microbes were detected in most participants. There were no significant differences in alpha diversity (within sample) at baseline between groups. However, at the 12-week follow-up, the responder urobiome became significantly richer, with a larger number of genera (p = 0.027) and was significantly more diverse than the nonresponders. CONCLUSIONS: Longitudinal urobiome changes are associated with symptom improvement in adult women being treated with mirabegron for UUI. The mechanism for symptoms improvement may relate to the detected changes in the urobiome and warrants further study.

Mirabegron for overactive bladder in frail patients 80 years or over (HOKUTO study).

BACKGROUND: We assessed the efficacy and safety of mirabegron, a ß3-adrenoceptor agonist, in older adults (≥ 80 years old) with overactive bladder (OAB). METHODS: OAB patients aged ≥ 80 years were enrolled in this prospective, single-arm observational study. OAB was diagnosed based on the OAB symptom score (OABSS); i.e., a total score of ≥ 3 points and an urgency score of ≥ 2 points. Patients who received 50 mg mirabegron once daily were evaluated at the baseline and at 4, 8, and 12 weeks. The changes from the baseline in the OABSS, International Prostate Symptom Score (IPSS), OAB questionnaire (OAB-q) score, and Vulnerable Elders Survey (VES-13) score were determined. Adverse events, laboratory tests, 12-lead electrocardiography, the QT interval according to Fridericia's formula (QTcF), uroflowmetry, the post-void residual urine volume (PVR), and the Mini-Mental State Examination (MMSE) score were used to assess safety. RESULTS: Forty-three patients (median age: 84 years, range: 80-96 years) were examined. They had high rates of comorbidities and polypharmacy. Mirabegron significantly improved in total score of the OABSS, including urgency and urge incontinence. The total IPSS, IPSS quality-of-life (QOL) index, and OAB-q scores also significantly improved. Mirabegron improved in the VES-13 score. There were no significant changes in laboratory test values, uroflowmetry findings, PVR, the QTcF, or MMSE score. Two patients (4.7%) withdrew from the study after experiencing adverse events. CONCLUSIONS: Mirabegron was well tolerated and significantly improved in OAB symptoms, and QOL in older patients. Trial registration The present clinical study was approved by University of Yamanashi Institutional Review Board prior to study initiation (ID1447) and was retrospectively registered with the UMIN Clinical Trials Registry (UMIN-CTR), Japan (UMIN000045996) on Nov 6, 2021.

IgG4-related prostatitis manifesting as urinary obstruction in a 28-year-old male.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a systemic lymphoproliferative disorder characterized by elevated serum IgG4 levels and tumefactive lesions that can involve nearly every organ system. Involvement of the prostate is rare but has been reported in limited cases. CASE PRESENTATION: A 28-year-old man of Asian descent with a history of sinusitis and priapism presented to hospital with rigors and voiding symptoms. He was diagnosed with IgG4-RD one month prior to presentation, following pathological analysis of a submandibular mass that demonstrated chronic sclerosing sialadenitis. On presentation, white blood cell count, C-reactive protein, and prostate serum antigen levels were all within normal limits. Examination was notable for a large, firm prostate, and a foley catheter was inserted. Contrast CT of the abdomen was unremarkable. Further workup revealed elevated serum IgG4 levels (9.22 g/L) and he was subsequently started on prednisone 35 mg daily. Imaging to screen for systemic IgG4-RD involvement demonstrated paravertebral soft tissue involvement and he was given rituximab 1000 mg IV × 2 doses. MRI revealed diffuse prostatitis. Five days after starting prednisone and one day after his first dose of rituximab, he successfully passed trial of void and was discharged home. CONCLUSIONS: IgG4-related prostatitis is a rare and underrecognized manifestation of IgG4-RD. Our case highlights the need to consider IgG4-related prostatitis as an etiology of urinary obstruction in young individuals. Resolution of symptoms following treatment with steroids may be diagnostic of IgG4-related prostatitis, and may potentially avoid the need for invasive diagnostic procedures such as prostate biopsy.

The efficacy of a suppository based on Phenolmicin P3 and Bosexil (Mictalase®) in control of irritative symptoms in patients undergoing thulium laser enucleation of prostate: a single-center, randomized, controlled, open label, phase III study.

BACKGROUND: Several studies described post-operative irritative symptoms after laser enucleation of prostate, sometimes associated with urge incontinence, probably linked to laser-induced prostatic capsule irritation, and potential for lower urinary tract infections We aimed to evaluate the efficacy of a suppository based on Phenolmicin P3 and Bosexil (Mictalase®) in control of irritative symptoms in patients undergoing thulium laser enucleation of prostate (ThuLEP). METHODS: In this single-center, prospective, randomized, open label, phase-III study, patients with indication to ThuLEP were enrolled (Dec2019-Feb2021-Institutional ethics committee STS CE Lazio approval no.1/N-726-ClinicalTrials.gov NCT05130918). The report conformed to CONSORT 2010 guidelines. Eligible patients were 1:1 randomized. Randomization defined Group A: patients who were administered Mictalase® suppositories twice a day for 5 days, then once a day for other 10 days; Group B: patients who did not receive Mictalase® ("controls"). Study endpoints were evaluated at 15 and 30 days postoperation. Primary endpoint included evaluation of effects of the suppository on irritative symptoms by administering IPSS + QoL questionnaire. Secondary endpoint included evaluation of effects on urinary tract infections by performance of urinalysis with urine culture. RESULTS: 111 patients were randomized: 56 in Group A received Mictalase®. Baseline and perioperative data were comparable. At 15-days, no significant differences were found in terms of IPSS + QoL scores and urinalysis parameters. A significant difference in the rate of positive urine cultures favored Group A (p = 0.04). At 30-days follow-up, significant differences were found in median IPSS score (6 [IQR 3-11] versus 10 [5-13], Group A vs B, respectively, p = 0.02). Urinalysis parameters and rate of positive urine cultures were not significantly different. CONCLUSIONS: The present randomized trial investigated the efficacy of Mictalase® in control of irritative symptoms and prevention of lower urinary tract infections in patients undergoing ThuLEP. IPSS improvement 30-days postoperation was more pronounced in patients who received Mictalase®. Lower rate of positive urine culture favored Mictalase® group 15-days postoperatively. TRIAL REGISTRATION: The clinical trial has been registered on ClinicalTrials.gov on November 23rd, 2021-Registration number NCT05130918.

Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis.

Mirabegron (Myrbetriq) is a ß3-adrenoreceptor agonist approved for treating overactive bladder syndrome in human patients. This drug can activate brown adipose tissue (BAT) in adult humans and rodents through the ß3-adrenoreceptor-mediated sympathetic activation. However, the effect of the mirabegron, approved by the US Food and Drug Administration, on atherosclerosis-related cardiovascular disease is unknown. Here, we show that the clinical dose of mirabegron-induced BAT activation and browning of white adipose tissue (WAT) exacerbate atherosclerotic plaque development. In apolipoprotein E-/- (ApoE-/-) and low-density lipoprotein (LDL) receptor-/- (Ldlr-/-) mice, oral administration of clinically relevant doses of mirabegron markedly accelerates atherosclerotic plaque growth and instability by a mechanism of increasing plasma levels of both LDL-cholesterol and very LDL-cholesterol remnants. Stimulation of atherosclerotic plaque development by mirabegron is dependent on thermogenesis-triggered lipolysis. Genetic deletion of the critical thermogenesis-dependent protein, uncoupling protein 1, completely abrogates the mirabegron-induced atherosclerosis. Together, our findings suggest that mirabegron may trigger cardiovascular and cerebrovascular diseases in patients who suffer from atherosclerosis.

Therapeutic efficacy and cognitive adverse events of overactive bladder medication in patients with central nervous system Disorders-A cohort study.

PURPOSE: This cohort study evaluates therapeutic efficacy and adverse events (AEs) of various overactive bladder (OAB) medications for patients with central nervous system (CNS) disorders. METHODS: Patients with OAB and CNS disorders were prospectively enrolled. They were randomly allocated to 3 different treatment subgroups: (1) mirabegron 50 mg once daily (2) solifenacin 5 mg per day, and (3) combined solifenacin 5 mg and mirabegron 50 mg once daily. Efficacy and safety questionnaires and objective parameters were compared among the subgroups, and subgroups between baseline and 3 and 6 months after treatment. AEs, including cognitive dysfunction, were assessed using the Mini-Mental State Examination (MMSE). RESULTS: 102 patients (mean age, 71.8 ± 8.7 years) were enrolled, including 35, 36, and 31 patients received mirabegron monotherapy, solifenacin monotherapy, and combination therapy, respectively. OAB symptoms scores all significantly improved 3 months after treatment in different subgroup. However, PVR increased and VE decreased significantly after treatment in patients receiving solifenacin monotherapy and combination therapy. Dry mouth and constipation were the most common AEs, especially in the solifenacin and combination subgroups. Mild incidence of AEs was noted in patients receiving mirabegron monotherapy. No significant change in MMSE was noted among the subgroups after treatment. CONCLUSION: OAB medication had good therapeutic efficacy in patients who had OAB with CNS disorders, especially in cerebrovascular accident and parkinsonism. No OAB medication or their combination affected cognitive function, whereas minimal AEs were noted with mirabegron. Mirabegron could be recommended as the first choice for managing OAB in these patients.

Impact of Mirabegron Administration on the Blood Pressure and Pulse Rate in Patients with Overactive Bladder.

Background and Objectives: To determine changes in the blood pressure (BP) and pulse rate (PR) before and after the administration of mirabegron in real-world clinical practice for patients with overactive bladder (OAB). Materials and Methods: This study was conducted in patients newly diagnosed with OAB. Before and 12 weeks after mirabegron treatment, we evaluated the effects on BP and PR. An overall examination was conducted, and the patients were divided into two groups according to their age: a young group (<65 years old) and an old group (≥65 years old). Results: A total of 263 patients were enrolled in this study. In the overall and intragroup comparisons, the systolic BP (SBP) did not change significantly after mirabegron administration. However, an increase in SBP of ≥10 mmHg was observed in 53 (20.2%), 4 (7.4%), and 49 (23.4%) in the entire group, young group, and old group, respectively (p = 0.009). Regarding diastolic BP, a significant decrease after the treatment was detected in entire (71.2 ± 11.4 versus 69.8 ± 10.7 mmHg; p = 0.041) and old patients (71.5 ± 10.6 versus 69.5 ± 10.2 mmHg; p = 0.012). There was no significant change in PR in our study population. Further examination using a propensity match score revealed that age was the risk factor for the increase in SBP after mirabegron administration. Conclusions: Mirabegron does not have any adverse effects on BP and PR. However, since some patients in this study had elevated SBP after administration, we suggest regular BP monitoring during mirabegron treatment.

Possible Involvement of Muscarinic Receptor Blockade in Mirabegron Therapy for Patients with Overactive Bladder.

The selective ß 3-adrenoceptor agonist mirabegron, an established alternative to antimuscarinic therapy for patients with overactive bladder, induces additional effects against receptors, transporters, and hepatic enzymes. The present study aimed to elucidate the effects of mirabegron on muscarinic receptors in the rat bladder using radioligand binding and functional assays. Mirabegron (0.1-100 µM) inhibited specific [N-methyl-3H]scopolamine methyl chloride binding in the bladder and other tissues of rats in a concentration-dependent manner. Binding affinity in the bladder was similar to that in the heart and significantly higher than those in the submaxillary gland and brain. Mirabegron induced the concentration-dependent relaxation of carbachol-induced contractions in the rat isolated bladder. Further analyses using a two-site model revealed that the relative quantities of high- and low-affinity components for mirabegron were 44.5% and 55.5%, respectively. Respective pEC50 values were 7.06 and 4.97. Based on the receptor binding affinity and pharmacokinetics of mirabegron, muscarinic receptor occupancy in the human bladder for 24 hours after the administration of a single oral dose of 50 mg mirabegron was 37%-76%. The present results demonstrate for the first time that mirabegron may relax the detrusor smooth muscle not only by ß 3-adrenoceptor activation but also muscarinic receptor blockade. SIGNIFICANCE STATEMENT: Mirabegron, the first selective ß 3-adrenoceptor agonist, represents an alternative to antimuscarinic agents for management of overactive bladder (OAB). The present study aimed to clarify whether mirabegron directly binds to muscarinic receptors and affects cholinergic agonist-induced contractions in rat urinary bladder and to predict muscarinic receptor occupancy in human bladder after oral administration of mirabegron. The results demonstrated that mirabegron therapy for patients with OAB may be due not only to ß 3-adrenoceptor activation but also muscarinic receptor blockade.

Determining the Safety Threshold for the Passage of a Ureteral Access Sheath in Clinical Practice Using a Purpose-Built Force Sensor.

PURPOSE: Ureteral injury is a frequent complication of ureteral access sheath deployment. We sought to define the safe threshold of force for the passage of a ureteral access sheath using a novel ureteral access sheath force sensor. MATERIALS AND METHODS: Ureteral access sheath-force sensor measurements were recorded in 210 renal units. A 16Fr ureteral access sheath was deployed initially based on a prior porcine study. If 6 N was reached, the surgeon was advised to downsize the 16Fr ureteral access sheath. In each case, a post-ureteroscopic lesion scale was recorded. Regression models were used to estimate the impact of adjusted variables on post-ureteroscopic lesion scale grade, 16Fr ureteral access sheath deployment, and peak force. RESULTS: A 16Fr ureteral access sheath was deployed in 127 (61%) renal units with a mean peak force of 5.7 N. Two high-grade ureteral injuries occurred; in both cases >6 N of force was recorded. Post-ureteroscopic lesion scale grade correlated directly with peak insertion force (p <0.01). Bacteriuria within 60 days of the procedure (OR 2.009, p=0.034), combination of preoperative stent plus oral tamsulosin (OR 2.998, p=0.045), and prior ipsilateral stone surgery (OR 2.13, p=0.01) were independent predictors of successful 16Fr ureteral access sheath deployment. Among patients with neither prior ipsilateral stone surgery nor preoperative stent, preoperative tamsulosin facilitated passage of a 16Fr ureteral access sheath (OR 2.750, p=0.034). CONCLUSIONS: Ureteral access sheath associated ureteral injury can be averted by limiting the insertion force to ≤6 N. Prior stone surgery, preoperative indwelling ureteral stent plus oral tamsulosin, and recently treated bacteriuria favored passage of a 16Fr ureteral access sheath. In the naïve, unstented patient, preoperative tamsulosin favored deployment of a 16Fr ureteral access sheath.