Comparison of Different Types of Therapy for Overactive Bladder: A Systematic Review and Network Meta-Analysis

To compare the efficacy and safety of different interventions (including Antimuscarinics, Mirabegron, OnabotulinumtoxinA, sacral neuromodulation (SNM) and peripheral tibial nerve stimulation (PTNS)) on idiopathic overactive bladder (OAB). PubMed, Embase, Cochrane library, and other sources were searched for randomized controlled trials (RCTs) comparing interventions of OAB from 1 January 2000 to 19 April 2021. A systematic review and network meta-analysis were performed by two authors independently. 55 RCTs involving 32,507 patients were included in this network. Overall, Antimuscarinics, Mirabegron, OnabotulinumtoxinA, SNM, and PTNS were more efficacious than placebo and SNM showed the best effect for reducing micturition frequency, urgency episodes and urgency urinary incontinence episodes. OnabotulinumtoxinA was the best in achieving reduction of 100% and ≥50% in the number of urinary incontinence episodes /day and PTNS was the best in reducing urinary incontinence episodes. The efficacy of Antimuscarinics, Mirabegron and PTNS were similar in reducing micturition frequency, urinary incontinence episodes and urgency urinary incontinence episodes. The results revealed that all interventions included in the network were efficacious in managing adult OAB syndrome compared with placebo. Furthermore, SNM and OnabotulinumtoxinA were the most efficient treatments for overactive bladder.

Remyelination Improves Voiding Dysfunction in a Mouse Model of Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Of note, over 80% of MS patients have urinary symptoms as one of their earliest symptoms. Since MS patients often live into older age, urinary incontinence and retention are significant problems affecting their quality of life. Although several studies show that inflammatory-demyelinating animal models of MS develop bladder dysfunction, the confounding influence of systemic inflammation in these models limits potential interpretation on the contribution of CNS-myelination to bladder dysfunction. We sought to address this knowledge gap using the cuprizone model of demyelination and remyelination. C57Bl/6 mice were treated with dietary cuprizone (0.2%w/w) for four weeks to induce demyelination. One group was allowed four additional weeks for recovery and remyelination. We performed voiding spot assay (VSA), urethane-anesthetized cystometry, and CNS-histology to assess demyelination-induced differences in urinary performance. We observed that cortical demyelination causes significant aberrance in voiding behavior (conscious cortical control) characterized by increased micturition frequency and reduced volume per micturition. Interestingly, remyelination restored healthy bladder function. However, there were no significant changes in the cystometric parameters (brainstem reflex) between the treatment groups. While MS is not classically considered a disease of aging, extending the longevity of these patients has not been reciprocated with improved treatments for their most-bothersome conditions, notably urinary symptoms that persist throughout life. Our data represent a novel compelling connection and strong correlation between CNS-myelination and cortical control of bladder function, which has potential implications in MS, aging, and aging-associated neurological disorders.

Voiding defects in acute radiation cystitis driven by urothelial barrier defect through loss of E-cadherin, ZO-1 and Uroplakin III

Long term-side effects from cancer therapies are a growing health care concern as life expectancy among cancer survivors increases. Damage to the bladder is common in patients treated with radiation therapy for pelvic cancers and can result in radiation (hemorrhagic) cystitis (RC). The disease progression of RC consists of an acute and chronic phase, separated by a symptom-free period. Gaining insight in tissue changes associated with these phases is necessary to develop appropriate interventions. Using a mouse preclinical model, we have previously shown that fibrosis and vascular damage are the predominant pathological features of chronic RC. The goal of this study was to determine the pathological changes during acute RC. We identified that radiation treatment results in a temporary increase in micturition frequency and decrease in void volume 4–8 weeks after irradiation. Histologically, the micturition defect is associated with thinning of the urothelium, loss of urothelial cell–cell adhesion and tight junction proteins and decrease in uroplakin III expression. By 12 weeks, the urothelium had regenerated and micturition patterns were similar to littermate controls. No inflammation or fibrosis were detected in bladder tissues after irradiation. We conclude that functional bladder defects during acute RC are driven primarily by a urothelial defect.

Potential Targets for Overactive Bladder in Older Men Based on Urinary Analysis of Metabolomics

<b><i>Objective:</i></b> We investigated the association between overactive bladder (OAB) and urinary metabolites in men. <b><i>Methods:</i></b> This prospective observational study included 42 men aged 65–80 years. The 3-day frequency volume chart (FVC), International Prostate Symptom Score (IPSS), and quality of life score were adapted to assess the micturition behavior. Participants with IPSS urgency score ≥2 were included in the OAB group, and those with IPSS urgency score &#x3c;2 were included in the control group. We performed a comprehensive metabolomic analysis using urine samples. Metabolites were compared between the groups using an unpaired <i>t</i> test and Fisher’s exact test in a nonadjusted analysis. Multivariable logistic regression analysis was performed to investigate the association between OAB and the metabolites. <b><i>Results:</i></b> Overall, 23 men were included in the OAB group and 19 in the control group. There were no differences in the background factors except age between the groups. FVC analysis demonstrated that nocturnal urine volume, 24-h micturition frequency, and nocturnal micturition frequency were significantly higher, and the maximum voided volume was significantly lower in the OAB group than in the controls. Metabolomic analysis revealed 14 metabolites that were differentially expressed between the groups. Multivariate analysis indicated that an increase in the levels of 5-iso prostaglandin F2α-VI (5-iPF2a-VI) and 5-methoxyindoleacetic acid was associated with OAB. <b><i>Conclusion:</i></b> Abnormal urinary metabolites, including metabolites in the tryptophan (5-methoxyindoleacetic acid, 3-indoleacetonitrile, and 3-hydroxyanthranilic acid) and arachidonic acid (5-iPF2a-VI) pathways, play a role in the pathogenesis of OAB in older men.

THE EFFICACY COMPARISON OF MIRABEGRON AS A MONOTHERAPY VERSUS ITS COMBINATION WITH SOLIFENACIN IN OVERACTIVE BLADDER: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Objective: This review aimed to evaluate the efficacy and safety of mirabegron as monotherapy and its combination with solifenacin for patients with overactive bladder (OAB). Material & Methods: A systematic search was conducted in PubMed, Google Scholar, and Science Direct using the keywords Overactive bladder or OAB and mirabegron or beta-3 agonist or β3 adrenoreceptor agonist and solifenacin or antimuscarinic based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guideline to include relevant randomized controlled trials (RCT)s. The included studies were assessed for their risks of bias using the Cochrane risk of bias tool for randomized controlled trials. Quantitative analysis using forest plot was performed in Review Manager 5.4. Results: A total of 4 RCTs were included from 227 studies. A fixed-effects model was chosen due to the low level of heterogeneity between the studies (I2 = 0%). The average micturition volume of patients in the combination group is higher compared to the monotherapy group (MD 17.13, 95% CI 12.78 - 21.48, p < 0.00001). The mean micturition frequency (MD - 0.54, 95% CI - 0.73 - -0.34, p < 0.00001) and incontinence incidence (MD -0.30, 95% CI -0.48 - -0.12, p = 0.001) in the combined group are significantly lower compared to the monotherapy group. Conclusion: The combination of mirabegron and solifenacin has better efficacy compared to mirabegron as monotherapy for OAB patients with a therapy duration of less than 12 weeks based on the micturition volume, micturition frequency, and incontinence incidence. The administration of combination therapy would not increase adverse event incidence compared to monotherapy.

Preliminary findings from stimulated spontaneous reporting of adverse drug reactions during COVID-19 pandemic: an experience from Ghana

Background: The novel coronavirus disease 2019 (COVID-19) is an ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There is limited information on the safety of drugs used for the treatment of COVID-19.Objective: Objective of this study is to describe the pattern of stimulated spontaneous adverse drug reaction (ADR) reports received from healthcare professionals for SARS-CoV-2 positive patients in Ghana and lessons learnt particularly for low- and middle-income countries.Methods: This is a study of individual case safety reports (ICSRs) received from healthcare professionals between 1st April 2020 to 31st July 2020 in SARS-CoV-2 positive patients in Ghana. The ICSRs were retrieved from the SafetyWatch System and descriptive statistics used to describe the ADRs by System Organ Classification and Preferred Term.Results: Information was received from 40 COVID-19 Treatment Centres across the country with 9 centres submitting a total of 53 ICSRs containing 101 ADRs; approximately two ADRs per ICSR. Females accounted for 29(54.7%) of the ICSRs and males 24(45.3%). Newly reported ADRs of interest were one report each of tremor for doxycycline; scrotal pain, dyspnoea, gait disturbances and dysgeusia for chloroquine; and dry throat, hyperhidrosis, restlessness and micturition frequency increased for hydroxychloroquine. A strong spontaneous system with the availability of focal persons at the Treatment Centres played a key role in reporting ADRs during the pandemic.Conclusion: This is the first experience with spontaneous reporting during COVID-19 pandemic in Ghana. The profile of most of the ADRs reported appears consistent with what is expected from the summary of product characteristics. A study with a larger sample size with well-defined denominator in future studies is paramount in determining the relative risk of these medications in SARS-CoV-2 positive patients.

Mirabegron a novel approach in the management of overactive bladder

Many prescriptions are available for the therapy of the overactive bladder, yet assessing and choosing the correct medication is essential. The study was carried to examine whether Mirabegron could be the drug that can be used effectively in treating overactive bladder. To assess the effectiveness of Mirabegron, the field survey for this project was conducted through a structured questionnaire form the doctors in Bengaluru for about two months with the Support of Micro Labs Pvt. Ltd by involving 44 leading Doctors in the City from February- March 2020. The Survey population was chosen based on convenient random sampling. The analysis was done based on the occurrence of overactive bladder observed in their clinical practice every month, the age group, and the gender, who are being affected. It evaluated Mirabegron as a treatment option for incontinence episode and micturition frequency. Results showed noteworthy improvement in the quantity of incontinence episode and the quantity of micturition recurrence by utilising Mirabegron. The study outcomes indicated that Mirabegron promising effect in the management of overactive bladder.

C-Phycocyanin Alleviates Bladder Inflammation and Dysfunction in Cyclophosphamide-Induced Cystitis in a Mouse Model by Inhibiting COX-2 and EP4

Objective. To explore the effect of C-phycocyanin (C-PC) on voiding behavior and histological changes in cyclophosphamide- (CYP-) induced cystitis in mice. Methods. Sixty female mice were included. The mice in the C-PC group received C-PC (25 mg/kg, twice, i.p.) and then CYP (200 mg/kg, i.p.) two hours later, while the mice in the CYP group only received the equivalent CYP. Saline was injected in the mice in the control group. A voided stain on paper (VSOP) test was conducted to analyze the micturition. The bladders were harvested for histological evaluation and measurements of inflammatory factors. Results. C-PC reduced the micturition frequency in the mice with CYP-induced cystitis. The bladder/body weight ratio and edema were remarkably higher in the CYP group compared to the C-PC group. C-PC suppressed the expressions of COX-2, PGE2, and EP4 (prostaglandin E receptor 4) according to the ELISA assay. Immunohistochemical staining also indicated that C-PC reduced the expressions of COX-2 in urothelium and EP4 in smooth muscles. Conclusions. C-PC relieved symptoms associated with CYP-induced cystitis in mice by inhibiting bladder inflammation through COX-2 and EP4 expression.

Metabolomics analysis of blood identifies potential biomarkers and possible treatment targets for nocturia

Background: Our aim was to investigate the association between serum metabolites and nocturia. Methods: A total of 66 males aged 65–80 years were enrolled in this study and stratified according to micturition behavior, which was characterized in terms of the 24 h frequency volume chart (FVC) for 3 consecutive days, the International Prostate Symptom Score (IPSS), and quality-of-life score. The nocturia group included participants with any total IPSS and ⩾1.5 micturitions/night as the mean of 3 nights, while the control group included participants with total IPSS < 8 and <1.5 micturitions/night. We conducted a comprehensive capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) study of plasma metabolites. Between-group comparisons of metabolite levels employed the Welch t test. The relationship between nocturia and metabolite profiles was determined using multivariable logistic regression analysis. Results: Of 66 participants, 45 were included in the nocturia group and 21 in the control group. There were no differences in background factors between the two groups. FVC analysis revealed that urine production during night-time, as well as micturition frequency during daytime and night-time were significantly higher in the nocturia group. CE-TOFMS identified eight metabolites whose plasma levels differed between the two groups. Multivariate analysis indicated that increased levels of lauric acid and imidazolelactic acid, as well as decreased levels of thiaproline and glycerol, contribute to the etiology of nocturia in aged men. Conclusions: Our findings suggest that abnormal serum levels of metabolites in several pathways play a role in the pathogenesis of nocturia in aged men.

Efficacy and safety of daily mirabegron 50 mg in male patients with overactive bladder: a critical analysis of five phase III studies

Background: Oral pharmacotherapies to treat overactive bladder (OAB) are used less in men despite a similar prevalence of storage symptoms as women. The efficacy and safety of once-daily mirabegron 50 mg was evaluated in male OAB patients from five phase III studies that included placebo or antimuscarinic (tolterodine ER 4 mg or solifenacin 5 mg) as a comparator. Methods: Three pooled 12-week placebo-controlled studies (mirabegron 50 mg versus placebo) and one 12-week non-inferiority phase IIIb study (BEYOND; mirabegron 50 mg versus solifenacin 5 mg) were used for efficacy (daily micturition frequency, urgency and incontinence episodes) and safety analyses. An additional 52-week active-controlled phase III safety study (mirabegron 50 mg versus tolterodine ER 4 mg) was included in the safety analysis. Male patients aged ⩾18 years with OAB for ⩾3 months were included in the analyses. Patients may also have a history of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH)/benign prostatic enlargement (BPE) or concomitant use of α1-blockers. Results: In the pooled studies, mirabegron 50 mg demonstrated superiority versus placebo (treatment difference: −0.37 [95% confidence interval (CI): −0.74, −0.01]) for reducing micturition frequency; improvements in urgency and incontinence were not significantly different between mirabegron 50 mg and placebo. In BEYOND, mirabegron 50 mg was comparable with solifenacin 5 mg for reducing micturition frequency, urgency, and incontinence episodes. Mirabegron was well tolerated at 12 and 52 weeks and overall treatment-emergent adverse events (AEs) were similar to those with placebo. Conclusions: In a male OAB population with or without LUTS associated with BPH/BPE, mirabegron 50 mg provided similar improvements in urgency, frequency, and incontinence as solifenacin 5 mg, and is a well-tolerated alternative to antimuscarinics. In the three pooled 12-week studies, significant differences were not seen for urgency and incontinence versus placebo, although mirabegron 50 mg did demonstrate significant improvements versus placebo for frequency.