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Urolithiasis is one of the most prevalent benign urological disorders globally with a high incidence rate. Male Sprague-Dawley rats were chemically induced to have urolithiasis and treated with triptonide and the standard antiurolithic drug cystone. Kidney weight was measured to detect calculi formation, and urinary parameters such as pH, 24-h urine volume, and protein content were measured to analyze the urolithiasis induction in rats. The inorganic ions, organic solutes, antioxidant levels, and inflammatory cytokines were measured in the experimental rats. Triptonide treatment significantly modulated the urinary pH, decreased the protein concentration, and increased the urinary outflow in urolithiasis induced rats. It also significantly decreased the urinary excretion of calcium and phosphorous and increased the excretion of magnesium, potassium, sodium, creatinine, and uric acid. SOD, CAT, and GPx levels were increased in triptonide-treated rats, and it significantly reduced the MDA levels. Triptonide treatment also decreased the levels of inflammatory cytokines and prevented the renal tissue from inflammation. To conclude, our results prove that triptonide significantly prevents calculi formation and protects renal tissue from urolithiasis-induced damage in rats. Further studies may prove triptonide a potent alternative to currently available antiurolithic drugs.

Benign prostatic hyperplasia (BPH) may decrease patient quality of life and often leads to acute urinary retention and surgical intervention. While effective treatments are available, many BPH patients do not respond or develop resistance to treatment. To understand molecular determinants of clinical symptom persistence after initiating BPH treatment, we investigated gene expression profiles before and after treatments in the prostate transitional zone of 108 participants in the Medical Therapy of Prostatic Symptoms (MTOPS) Trial. Unsupervised clustering revealed molecular subgroups characterized by expression changes in a large set of genes associated with resistance to finasteride, a 5α-reductase inhibitor. Pathway analyses within this gene cluster found finasteride administration induced changes in fatty acid metabolism, amino acid metabolism, immune response, steroid hormone metabolism, and kinase activity within the transitional zone. We found that patients without this transcriptional response were highly likely to develop clinical progression, which is expected in 13.2% of finasteride-treated patients. Importantly, a patient's transcriptional response to finasteride was associated with their pre-treatment kinase expression. Further, we identified novel expression signatures of finasteride resistance among the transcriptionally responded patients. These patients showed different gene expression profiles at baseline and increased prostate transitional zone volume compared to the patients who responded to the treatment. Our work suggests molecular mechanisms of clinical resistance to finasteride treatment that could be potentially helpful for personalized BPH treatment as well as new drug development to increase patient drug response., (© 2024. The Author(s).)

Introduction: Overactive bladder syndrome is a common chronic condition with a significant impact on quality of life and economic burden. Persistence with pharmacologic therapy has been limited by efficacy and side effects. A greater understanding of the pathophysiology of overactive bladder has led to the initial evaluation of several drugs affecting ion channels, the autonomic nervous system, and enzymes which may provide useful alternatives for the management of overactive bladder., Areas Covered: A comprehensive review was performed using PubMed and Cochrane databases as well as reviewing clinical trials in the United States. The current standard of care for overactive bladder will be discussed, but this paper focuses on investigational drugs currently in preclinical studies and phase I and II clinical trials., Expert Opinion: Current therapies for overactive bladder have limitations in efficacy and side effects. A greater understanding of the pathophysiology of overactive bladder has identified the role(s) of other pathways in the overactive bladder syndrome. Targeting alternative pathways including ion channels and enzymes may provide alternative therapies of overactive bladder and a more tailored approach to the management of overactive bladder.

The study aims to elucidate the impact of mirabegron versus solifenacin on autonomic function and peripheral arterial conditions in women with overactive bladder syndrome (OAB). All consecutive women with OAB were randomized to receive 12 weeks of mirabegron 25 mg or solifenacin 5 mg once per day. Heart rate variability, cardio-ankle vascular index, ankle-brachial pressure index, blood pressure, and heart rate were compared between the two groups. There were 87 women (mirabegron, n = 43; and solifenacin, n = 44) who completed 12-week treatment and underwent heart rate variability examination. Systolic blood pressure (median: - 4.5 to - 5.5 mmHg) and diastolic blood pressure (median: - 0.5 to - 3.5 mmHg) decreased after solifenacin treatment, and heart rate (median: + 2 bpm) increased after mirabegron treatment, despite of no between-group difference. In addition, posttreatment heart rate variability, cardio-ankle vascular index, and ankle-brachial pressure index did not differ compared with baseline; and there were no between-group differences. In conclusion, solifenacin might decrease blood pressure, and mirabegron might increase heart rate. Nonetheless, there were no significant impacts of 12-week mirabegron versus solifenacin treatment on autonomic function and arterial stiffness., (© 2022. The Author(s).)

The release of ATP from the epithelium of the urinary bladder (urothelium) in response to mechanical/chemical stimuli contributes to the visceral sensation in the micturition reflex. The nitric oxide (NO)-mediated induction of cyclic guanosine monophosphate (cGMP) has been detected in urothelial cells and may inhibit the micturition reflex. However, the function of the NO-cGMP pathway in the regulation of urothelial ATP release remains poorly understood in contrast to its effects on smooth muscles or primary afferent nerves. Therefore, we investigated the relevance of the NO-cGMP pathway to ATP release on the mucosal side in the present study. The administration of l-arginine (NO precursor) or NOC 12 (NO donor) significantly reduced ATP release to the mucosal side at a physiologically normal urine storage pressure (5 cmH 2 O). L-NAME (NO synthase inhibitor) significantly increased the distention-induced release of ATP. The phosphodiesterase-5 inhibitor, sildenafil, which increases cGMP levels, inhibited distention-induced ATP release. Furthermore, sildenafil significantly reduced ATP release in response to the administration of lipopolysaccharide. These results suggest that the NO-cGMP pathway inhibited urothelial ATP release during the storage phase under both physiological and pathological conditions., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

The International Prostate Symptom Score (IPSS), the quality of life (QoL) score, and the benign prostatic hyperplasia impact index (BII) are three different scales commonly used to assess the severity of lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH-LUTS). Based on a phase II clinical trial including 403 patients with moderate to severe BPH-LUTS, the objectives of this study were to (i) develop traditional pharmacometric and bounded integer (BI) models for the IPSS, QoL score, and BII endpoints, respectively; (ii) compare the power and type I error in detecting drug effects of BI modeling with traditional methods through simulation; and (iii) obtain quantitative translation between scores on the three abovementioned scales using a BI modeling framework. All developed models described the data adequately. Pharmacometric modeling using a continuous variable (CV) approach was overall found to be the most robust in terms of type I error and power to detect a drug effect. In most cases, BI modeling showed similar performance to the CV approach, yet severely inflated type I error was generally observed when inter-individual variability (IIV) was incorporated in the BI variance function (g()). BI modeling without IIV in g() showed greater type I error control compared to the ordered categorical approach. Lastly, a multiple-scale BI model was developed and estimated the relationship between scores on the three BPH-LUTS scales with overall low uncertainty. The current study yields greater understanding of the operating characteristics of the novel BI modeling approach and highlights areas potentially requiring further improvement.

Aims: This study aimed to investigate the efficacy and safety of mirabegron for Parkinsonism patients with overactive bladder (OAB) symptoms in a randomized, placebo-controlled, multicenter study., Materials and Methods: Inclusion criteria are Parkinsonism with OAB symptoms for 4 weeks or more, OAB symptom score (OABSS) questionnaire scores greater than 2, and OABSS urgency question scores greater than 1. After a 2-week wash-out period, the patients were randomized into placebo and mirabegron groups at visit 2. Visit 3 was performed after 4 weeks of medication. Mirabegron was prescribed to the two groups for the rest of the study period at visit 4., Result: The mean age was 68.1 ± 8.1 years and 72 males and 64 females were included. A total of 136 patients were screened, 117 patients were randomized, and 25 patients dropped out. The OABSS scores were significantly different between the two groups at Weeks 4 and 8. The OABSS scores became the same in the two groups at Week 12 (visit 5). The postvoid residual urine volume showed a mild increase to 64 ml in the mirabegron group compared to the placebo group at visit 4. Adverse events occurred in 27 patients (23.1%). The degree was mild in 26 cases (78.8%), moderate in five (15.2%), and severe in two (6.1%). Only 13 cases (39.4%) showed medication-related adverse events. Acute urinary retention occurred in a single case. The treatment satisfaction questionnaires showed no significant differences between the two groups., Conclusion: Mirabegron was effective in treating OAB symptoms in patients with Parkinsonism with acceptable adverse events., (© 2020 Wiley Periodicals LLC.)

Aims: Neuromodulation (nerve stimulation) can produce analgesia. One form, bilateral pudendal nerve stimulation (bPNS), suppresses responses to urinary bladder distension (UBD) in hypersensitive rats. Drugs can modify this effect (eg, benzodiazepines, but not opioids, suppress bPNS effects). Prior to a clinical trial of bPNS effects on bladder pain, we felt it was prudent to survey the effects of medications commonly used in patients with bladder disorders., Methods: Bladder hypersensitivity was produced by neonatal bladder inflammation in rat pups coupled with a second inflammatory insult as an adult. Antimuscarinic (oxybutynin), β 3 -adrenoceptor agonist (mirabegron, CL316243), α 1 -adrenoceptor antagonist (tamsulosin), antidepressant (amitriptyline), muscle relaxing (baclofen), and sedative (propofol) agents were administered and effects of bPNS on responses to UBD assessed. bPNS consisted of bilateral biphasic electrical stimulation of the mixed motor/sensory component of the pudendal nerves. Visceromotor responses (VMRs; abdominal muscle contractile responses) were used as nociceptive endpoints., Results: Many of these drugs directly inhibited the VMRs to UBD, but only mirabegron, at the doses employed, significantly reduced inhibitory effects of bPNS. In the presence of the other drugs, bPNS continued to produce statistically significant inhibition of VMRs to UBD., Conclusions: This study suggests that concurrent therapy with drugs used to treat bladder disorders could affect assessment of the effects of bPNS on bladder hypersensitivity. This study gives guidance to clinical trials using bPNS for the treatment of painful bladder syndromes and suggests potential clinical use of some of these medications in the treatment of these same disorders., (© 2020 Wiley Periodicals, Inc.)

Aims: There have been few reports on whether long-term oral phosphodiesterase 5 inhibitor administration can ameliorate bladder changes due to bladder outlet obstruction (BOO). Therefore, we clarified the chronological changes of the bladder using male BOO rats and evaluated the effects of tadalafil on these changes., Methods: Eight-week-old male Sprague-Dawley rats were used. BOO was created by placing a polyethylene catheter around the urethra. Then, the rats were orally treated with a vehicle, or tadalafil 2 or 10 mg/kg until each evaluation period. Cystometric measurements were performed and the degree of fibrosis in the smooth muscle layer was evaluated at 2, 4, and 16 weeks., Results: In BOO rats, a significant increase in the number of non-voiding contractions (NVCs) and a shortened intercontraction interval (ICI) were observed in the earlier phase (2 and 4 weeks) compared to Sham rats. In the chronic phase (16 weeks), markedly increased residual urine volume and an extended ICI were observed accompanied by enhanced smooth muscle fibrosis. These results indicated that the bladder in BOO rats represented the overactive phenotype in the earlier phase and changed into the underactive phenotype in the chronic phase. Even in Sham rats, an increased number of NVCs and enhanced fibrosis were observed with time. Tadalafil administration significantly prevented these bladder changes in both BOO and Sham rats., Conclusions: Long-term oral administration of tadalafil can prevent functional and histological changes in the BOO rat bladder. This agent is also effective for the bladder functional change even in non-obstructed rats., (© 2020 Wiley Periodicals LLC.)

Benign prostatic hyperplasia (BPH), a nonmalignant enlargement of the prostate, is among the most common diseases affecting aging men, but the underlying molecular features remain poorly understood, and therapeutic options are limited. Here we employ a comprehensive molecular investigation of BPH, including genomic, transcriptomic and epigenetic profiling. We find no evidence of neoplastic features in BPH: no evidence of driver genomic alterations, including low coding mutation rates, mutational signatures consistent with aging tissues, minimal copy number alterations, and no genomic rearrangements. At the epigenetic level, global hypermethylation is the dominant process. Integrating transcriptional and methylation signatures identifies two BPH subgroups with distinct clinical features and signaling pathways, validated in two independent cohorts. Finally, mTOR inhibitors emerge as a potential subtype-specific therapeutic option, and men exposed to mTOR inhibitors show a significant decrease in prostate size. We conclude that BPH consists of distinct molecular subgroups, with potential for subtype-specific precision therapy.

Introduction: Interstitial cystitis (IC), as a common disease in urology, is prolonged and repeated. IC has caused great harm to the patient's physical and psychological. Traditional Chinese medicine (TCM) is characterized by overall concepts and dialectical treatment. It provides clinicians with safer and more reliable alternatives in terms of clinical prescriptions and prepared medicines, and also improves the quality of life of patients with IC. Therefore, in this study, we will use the research method of randomized controlled trials to explore the effects of TCM combined with western medicine on renal function and urine metabolism on middle-aged women with IC., Methods/design: Use randomized controlled trials. According to the proposed diagnostic, inclusion, and exclusion criteria. Sixty patients with interstitial bladder inflammation that met the criteria were randomized into a treatment group and a control group of 30 cases each. The intervention group was treated with integrated traditional Chinese and western medicine. The control group was given conventional Western medicine treatment. The course of treatment is 8 weeks. Interstitial bladder inflammation symptoms score (ICS worker), problem score (worker CPI), pelvic pain and urinary urgency symptoms, and urodynamics were used as the evaluation criteria., Discussion: This trial may provide evidence regarding the clinical effectiveness, safety, and cost-effectiveness of TCM for patients with IC., Trial Registration: ClinicalTrials.gov, ChiCTR2000029971, Registered on 17 February 2020.

Importance: Placebo responses in the treatment of erectile dysfunction (ED) are poorly described in the literature to date., Objective: To quantify the association of placebo with ED outcomes among men enrolled in placebo-controlled, phosphodiesterase 5 inhibitor (PDE5I) trials., Data Sources: For this systematic review and meta-analysis, a database search was conducted to identify double-blind, placebo-controlled studies using PDE5Is for the treatment of ED published from January 1, 1998, to December 31, 2018, within MEDLINE, Embase, Cochrane Library, and Web of Science. Only articles published in the English language were included., Study Selection: Double-blind, placebo-controlled randomized clinical trials of PDE5Is for ED were included. Studies were excluded if they did not provide distribution measures for statistical analysis. Study selection review assessments were conducted by 2 independent investigators. A total of 2215 studies were identified from the database search, and after review, 63 studies that included 12 564 men were analyzed., Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed in abstracting data and assessing validity. Data were extracted from published reports by 2 independent reviewers. Quality assessment was performed using the Jadad scale. Data were pooled using a random-effects model., Main Outcomes and Measures: The main outcome was improvement in the erectile function domain of the International Index of Erectile Function questionnaire in the placebo arm of the included studies. Effect size was reported as bias-corrected standardized mean difference (Hedges g). The hypothesis was formulated before data extraction., Results: A total of 63 studies that included 12 564 men (mean [SD] age, 55 [7] years; age range, 36-68 years) were included. Erectile function was significantly improved among participants in the placebo arm, with a small to moderate effect size (Hedges g [SE], 0.35 [0.03]; P < .001). Placebo effect size was larger among participants with ED associated with posttraumatic stress disorder (Hedges g [SE], 0.78 [0.32]; P = .02) compared with the overall analysis. No significant difference was found between placebo and PDE5Is for ED after prostate surgery or radiotherapy (Hedges g [SE], 0.30 [0.17]; P = .08)., Conclusions and Relevance: In this study, placebo was associated with improvement of ED, especially among men with ED-related posttraumatic stress disorder. No difference was found between placebo and PDE5I among men treated for ED after prostate surgery.

The effects of solifenacin and mirabegron on vesical and urethral function were compared in rats with or without spinal cord injury (SCI). Isovolumetric cystometry and urethral pressure recording were initially performed in intact rats. Then, the bladder neck was ligated under urethane anesthesia, after which a catheter was inserted through the bladder dome for isovolumetric cystometry and another catheter was inserted into the urethra to measure urethral pressure. Solifenacin (0.03-3 mg/kg) or mirabegron (0.03-3 mg/kg) was injected intravenously, and bladder and urethral activity were recorded. To create rats with SCI, the spinal cord was transected at the lower thoracic level under isoflurane anesthesia. After 2 weeks, a catheter was inserted through the bladder dome for single cystometry and bladder activity was recorded without anesthesia following intravenous injection of solifenacin or mirabegron. Isovolumetric cystometry revealed a larger decrease in maximum bladder contraction pressure after injection of solifenacin, whereas prolongation of the interval between bladder contractions was greater with mirabegron. In SCI rats, single cystometry showed that solifenacin and mirabegron both increased bladder volume at the first non-voiding bladder contraction and decreased the maximum bladder contraction pressure. Mirabegron also increased the voided volume and decreased the percentage residual volume without altering bladder capacity. Solifenacin and mirabegron both inhibited bladder contractility, and mirabegron possibly also induced urethral relaxation. Mirabegron may be suitable for patients with overactive bladder and residual urine., (© 2019 John Wiley & Sons Australia, Ltd.)

α 1 -Adrenoceptor (AR) antagonists are widely used for the relief of urinary retention secondary to benign prostatic hyperplasia (BPH). While the five Food and Drug Administration-approved α 1 -AR antagonists (terazosin, doxazosin, alfuzosin, tamsulosin, and silodosin) share similar efficacy, they differ in tolerability, with reports of ejaculatory dysfunction. The aim of the present work was to revisit their α 1 -AR subtype selectivity as well as of LDT5 (1-(2-methoxyphenyl)-4-[2-(3,4-dimethoxyphenyl) ethyl]piperazine monohydrochloride), a compound previously described as a multitarget antagonist of α 1A -/ α 1D -AR and 5-HT 1A receptors, and to estimate their affinity for D 2 , D 3 , and 5-HT 1A receptors, which are putatively involved in ejaculatory dysfunction. Competition binding assays were performed with native (D 2 , 5-HT 1A ) or transfected (human α 1A -, α 1B -, α 1Dt -AR, and D 3 ) receptors for determination of the drug's affinities. Tamsulosin and silodosin have the highest affinities for α 1A -AR, but only silodosin is clearly a selective α 1A -AR antagonist, with K i ratios of 25.3 and 50.2 for the α 1D - and α 1B -AR, respectively. Tamsulosin, silodosin, and LDT5 (but not terazosin, doxazosin, and alfuzosin) have high affinity for the 5-HT 1A receptor ( K i around 5-10 nM), behaving as antagonists. We conclude that the uroselectivity of tamsulosin is not explained by its too-low selectivity for the α 1A - versus α 1B -AR, and that its affinity for D 2 and D 3 receptors is probably too low for explaining the ejaculatory dysfunction reported for this drug. Present data also support the design of "better-than-LDT5" new multitarget lead compounds with pharmacokinetic selectivity based on poor brain penetration and that could prevent hyperplastic cell proliferation and BPH progression. SIGNIFICANCE STATEMENT: The present work revisits the uroselectivity of the five Food and Drug Administration-approved α 1 adrenoceptor antagonists for the treatment of benign prostatic hyperplasia (BPH). Contrary to what has been claimed by some, our results indicate that the uroselectivity of tamsulosin is probably not fully explained by its too-weak selectivity for the α 1A versus α 1B adrenoceptors. We also show that tamsulosin affinity for D 3 and 5-HT 1A receptors is probably too low for explaining the ejaculatory dysfunction reported for this drug. Based on our lead compound LDT5, present data support the search for a multitarget antagonist of α 1A -α 1D and 5-HT 1A receptors with poor brain penetration as an alternative for BPH treatment., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Aim: Renal fibrosis plays a pivotal role in the development and progression of chronic kidney disease, which affects 10% of the adult population. Previously, it has been demonstrated that the cyclooxygenase-2 (COX-2)/prostaglandin (PG) system influences the progression of renal injury. Here, we evaluated the impact of butaprost, a selective EP 2 receptor agonist, on renal fibrosis in several models of kidney injury, including human tissue slices., Methods: We studied the anti-fibrotic efficacy of butaprost using Madin-Darby Canine Kidney (MDCK) cells, mice that underwent unilateral ureteral obstruction and human precision-cut kidney slices. Fibrogenesis was evaluated on a gene and protein level by qPCR and Western blotting., Results: Butaprost (50 μM) reduced TGF-β-induced fibronectin (FN) expression, Smad2 phosphorylation and epithelial-mesenchymal transition in MDCK cells. In addition, treatment with 4 mg/kg/day butaprost attenuated the development of fibrosis in mice that underwent unilateral ureteral obstruction surgery, as illustrated by a reduction in the gene and protein expression of α-smooth muscle actin, FN and collagen 1A1. More importantly, a similar anti-fibrotic effect of butaprost was observed in human precision-cut kidney slices exposed to TGF-β. The mechanism of action of butaprost appeared to be a direct effect on TGF-β/Smad signalling, which was independent of the cAMP/PKA pathway., Conclusion: In conclusion, this study demonstrates that stimulation of the EP 2 receptor effectively mitigates renal fibrogenesis in various fibrosis models. These findings warrant further research into the clinical application of butaprost, or other EP 2 agonists, for the inhibition of renal fibrosis., (© 2019 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiology Society.)

Purpose of Review: Update on recent regenerative medicine approaches to the treatment of stress urinary incontinence (SUI) caused by intrinsic sphincter deficiency (ISD)., Recent Findings: In the treatment of female SUI/ISD, results using different types of cellular therapy have been disappointing, and new approaches are desirable. To advance our regenerative medicine approaches to SUI/ISD, it is critical to utilize animal models that best parallel the pathophysiology of this disease in women. Many current animal models mimic acute SUI/ISD. However, SUI/ISD in women is usually a chronic condition resulting from previous muscle and nerve sphincter damage during parturition or muscle loss during aging. Similar to women, a nonhuman primate (NHP) model of chronic SUI/ISD has demonstrated only modest response to cell therapy. However, treatment with stromal cell-derived factor 1 (SDF1), also known as C-X-C motif chemokine 12 (CXCL12) restored continence in this model., Summary: As a potential therapeutic approach, the use of a well characterized chemokine, such as CXCL12, may by-pass the lengthy and expensive process of cell isolation, expansion, and injection. Recent findings in this new NHP model of chronic SUI/ISD may open up the field for noncell-based treatments.

Mirabegron (Myrbetriq) is a β3-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 β3-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., Competing Interests: The authors declare no conflict of interest.

Objectives: To examine the effects of tadalafil on bladder function and object recognition ability in rats with alterations in urinary frequency and locomotor activity as a result of pelvic venous congestion., Methods: A total of 48 female rats were divided into three groups (sham, pelvic venous congestion and pelvic venous congestion/tadalafil groups). In the pelvic venous congestion and pelvic venous congestion/tadalafil groups, the bilateral common iliac veins and uterine veins were ligated under anesthesia. Rats in the pelvic venous congestion/tadalafil group received a diet containing tadalafil, and the other rats were fed a normal diet. After 4 weeks, rats underwent analysis of voiding behavior, locomotor activity, a novel object recognition test, continuous cystometry, measurement of plasma monoamines, and measurement of plasma and urinary nitric oxide metabolites. Expression of nitric oxide synthase messenger ribonucleic acid in the bladder wall was also assessed, along with histological examination of the bladder., Results: Rats with pelvic venous congestion showed a higher urinary frequency, lower locomotor activity, and lower plasma and urinary nitric oxide levels than sham rats. The bladder wall endothelial nitric oxide synthase messenger ribonucleic acid level was low and object recognition was impaired. Pelvic venous congestion/tadalafil rats showed improvement in locomotor activity, bladder function and object recognition compared with pelvic venous congestion rats, as well as elevation of plasma and urinary nitric oxide, plasma monoamines, and bladder neuronal nitric oxide synthase messenger ribonucleic acid expression. Bladder wall vascularity was greater in pelvic venous congestion/tadalafil rats compared with sham rats., Conclusions: In rats with pelvic venous congestion, tadalafil might improve bladder function and the general condition by increasing blood flow to the bladder and brain, and by increasing dopamine levels., (© 2019 The Japanese Urological Association.)

Aims: In two open-label trials, imipramine alleviated symptoms in patients with stress urinary incontinence and is therefore used off-label for this indication. However, it has never been confirmed that imipramine increases urethral pressure in a placebo-controlled setting. The purpose of this study was to investigate whether imipramine increases the opening urethral pressure compared to placebo in healthy women using urethral pressure reflectometry., Methods: A randomized, double-blind, placebo-controlled, crossover study in 16 healthy women. Opening urethral pressure was measured predose and 1 hour after a single dose of 50 mg imipramine or placebo. The washout period was minimum of 1 week. The study was approved by the local ethics committee, conducted according to the Good Clinical Practice guidelines, and registered on ClinicalTrials.gov and EudraCT before recruitment of subjects. Funding was provided by the clinical department., Results: There were no dropouts and no serious adverse events. There were 13 adverse drug reactions related to imipramine in seven subjects, one adverse event related to placebo, and two adverse events related to the measurements with urethral pressure reflectometry. Imipramine compared to placebo increased opening urethral pressure in the resting condition with 6.5 cmH 2 O (95% confidence interval [CI]: -0.5, 13.5), P = 0.07, and in the squeeze condition with 7.9 cmH 2 O (95% CI: -0.3, 16.1), P = 0.06., Conclusions: In conclusion, the increase in opening urethral pressure after imipramine treatment compared to placebo was neither statistically significant nor clinically relevant, and we do therefore not recommend the off-label use of imipramine for the treatment of stress urinary incontinence., (© 2019 Wiley Periodicals, Inc.)

Objective: We previously found that mirabegron exerts a relaxant effect in the presence of the β 3 -adrenoceptor antagonist SR58894A during carbachol-induced contraction in human and pig detrusor. The aim of this study was to explore the possible mechanism underlying the relaxant effects of mirabegron using detrusor smooth muscle., Methods: Human tissue was obtained from urinary bladders of patients undergoing radical cystectomy at Kyushu University and Harasanshin Hospital. Pig tissue was obtained from an abattoir. Tension force (organ bath experiments) was measured in intact or permeabilised (α-toxin or β-escin) detrusor smooth muscle strips. The contribution of cAMP-dependent signaling and the inhibition of Ca 2+ sensitization to the relaxant effects of mirabegron were characterized using 1 μM SR58894A, 100 μM SQ22536 (an adenylyl cyclase inhibitor), 10 μM H-89 (a protein kinase [PK] A inhibitor), 10 μM Y-27632 (a selective Rho kinase inhibitor), and 10 μM GF-109203X (a selective PKC inhibitor)., Results: 30 μM Mirabegron impaired carbachol (0.03-1 μM)-induced contraction in human detrusor smooth muscle. SR58894A only partially attenuated the relaxant effects of mirabegron in human and pig detrusor strips precontracted with 1 μM carbachol. In α-toxin-permeabilized detrusor strips, tension force at 1 μM [Ca 2+ ] i was decreased by mirabegron in a concentration-dependent manner. The relaxant effect of mirabegron was only slightly attenuated by H-89 and not significantly affected by SQ22536. Y-27632 potentiated the relaxation response to mirabegron, but attenuated responses to cAMP; GF-109203X had little effect. Mirabegron but not cAMP had a notable relaxant effect in the pig detrusor smooth muscle permeabilized with β-escin., Conclusions: Mirabegron-induced relaxation of pig and human detrusor smooth muscle occurs via both a β 3 -adrenoceptor/cAMP-dependent and -independent pathway., (© 2019 John Wiley & Sons Australia, Ltd.)

Although there is a clear need for improving men's health, treatment with suitable natural substances has not yet been well established. Previously, it was reported that MR-10, a novel complex of Korean dandelion and rooibos found by screening many natural products, improved sperm generation and activity. Here, the ability of MR-10 to increase testosterone levels and enhance men's health was tested. Treatment with MR-10 (400 mg/day) for a month significantly increased levels of free testosterone, total testosterone, and the testosterone precursor dehydroepiandrosterone by 22%, 14%, and 32%, respectively, in clinical studies. Also, men's health in terms of mental, physical, and sexual aspects, as determined by using the clinical questionnaires Androgen Deficiency of Aging Men and Aging Males' Symptoms, was improved. Furthermore, the safety of MR-10 was determined by testing levels of prostate-specific antigen, glutamic oxaloacetic transaminase, and glutamic pyruvate transaminase; and the lack of changes due to MR-10 treatment supports the safety of MR-10. In conclusion, this study suggests that MR-10 is a safe and effective natural product improving men's sexual health.

Male infertility is due to genetics, hormonal or environmental causes, or is idiopathic. Azoospermia is linked to local testicular microenvironment deregulation, with inflammatory cells present in the 15% of testicular biopsies of infertile patients. As widely reported, spermatogenesis and steroidogenesis are controlled by local immunoregulatory agents produced by immune and nonimmune cells. Moreover IL-6R, TNFR1, Fas and IL-1R are expressed on germ cells, indicating a direct action of pro-inflammatory agents on these cells. Beyond the known function of cytokines and nitric oxide on testicular function at the stable levels present in the normal testis, this review focalises on the effect of pro-inflammatory factors on germ cell survival and death when inflammatory conditions are established in the testis. As no cure for male infertility has been found up to the present, intracytoplasmic sperm injection is the therapeutic option for azoospermic patients who wish to achieve genetic parenthood. Therapies with antioxidant and anti-inflammatory agents in experimental models of testicular damage have been successful. However, clinical implementation is uncertain in cases with a prolonged inflammatory state of the testis. Therapies offering multiple approaches to treat infertility by restoring the spermatogonial stem cell niche and protecting germ cells from apoptosis should be considered., (© 2018 Blackwell Verlag GmbH.)

Purpose: To histopathologically and biochemically evaluate the hypothesis that tadalafil increases the uptake of a second medication into the prostate tissue by increasing the blood supply in the prostate., Methods: Forty 12-week-old Sprague Dawley male rats were equally divided into 5 groups and were administered drugs orally as follows: Group 1 - no drugs, Group 2 - 10 days of finasteride, Group 3 - 10 days of finasteride + tadalafil, Group 4 - 30 days of finasteride, and Group 5 - 30 days of finasteride + tadalafil. At the end of 10 days of drug administration in Group1, 2, and 3, and at the end of 30 days of drug administration in Group 4 and 5,blood samples were collected from rats and analyzed for serum androgen levels. In addition, prostate tissues were removed for histological examination., Results: The mean DHT level as well as the minimum and maximum epithelial thicknesses in Group 3 were lower than those in Group 2. However, there was no statistical significant difference (P = 0.989, P = 0.176, and P = 0.070, respectively). The mean DHT level as well as the minimum and maximum epithelial thicknesses in Group 5 were lower than those in Group 4. However, there was no statistical significant difference (P = 0.984, P = 0.147, and P= 0.478, respectively). The mean minimum and maximum epithelial thicknesses in Group 3 and Group 4 were not statistically different (P = 0.488 and P = 0.996, respectively)., Conclusion: The similarity of the mean minimum and maximum epithelial thickness in Group 3 and Group 4 may be indicate that the combination therapy provides an early histological effect. However, the fact that there was no statistical significant difference between Group 2 and Group 3, and between Group 4 and Group 5, in terms of the mean DHT level and minimum-maximum epithelial thicknesses suggests that longer term studies with more rats are necessary to test the validity of our hypothesis.

Varicocele is one of the common correctable causes of male infertility. Recent studies have demonstrated varicocelectomy in males with abnormal semen parameters was associated with better fertility outcome, but the effect of adjuvant drug therapy after varicocelectomy on fertility outcome in patients with varicocele-associated infertility remains undefined. Hence, the present meta-analysis was performed to assess the efficacy of adjuvant drug therapy after varicocelectomy. The protocol was registered with PROSPERO (No. CRD42018093749). Ten randomised controlled trails containing 533 patients with adjuvant drug therapy after varicocelectomy and 368 patients with no medical treatment after varicocelectomy were included. Our analysis revealed that the improvement in pregnancy rate after adjuvant drug therapy was insignificant. (OR = 1.70, 95%CI = 0.99-2.91), but resulted in significant improvements in sperm concentration (MD = 13.71, 95%CI = 5.80-21.63) and motility (MD = 4.77, 95%CI = 3.98-5.56) at 3 months, sperm DNA integrity (SMD = 3.13, 95%CI = 1.50-4.75) and serum FSH level (MD = -1.02, 95%CI = -1.79 to -0.24). Therefore, compared to no medical treatment, the adjuvant drug therapy, especially the use of antioxidants seems to be associated with better fertility outcome. However, more evidences with high-quality studies are necessary to conform its benefits., (© 2018 Blackwell Verlag GmbH.)

Erectile dysfunction (ED) associated with type 2 diabetes is a severe problem that requires effective treatment. Pancreatic kininogenase (PK) has the potential to improve the erectile function of ED patients. This study aims to investigate the effect of PK on erectile function in streptozotocin-induced type 2 diabetic ED rats. To achieve this goal, we divided male Sprague-Dawley rats into five groups. One group was not treated, and the other four groups were treated with saline, sildenafil, PK or sildenafil, and PK, respectively, for 4 weeks after the induction of type 2 diabetic ED. Then, intracavernous pressure under cavernous nerve stimulation was measured, and penile tissue was collected for further study. Endothelial nitric oxide synthase levels, smooth muscle content, endothelium content, cyclic guanosine monophosphate (cGMP) levels in the corpus cavernosum, and neuronal nitric oxide synthase levels in the dorsal penile nerve were measured. Improved erectile function and endothelium and smooth muscle content in the corpus cavernosum were observed in diabetic ED rats. When treating diabetic ED rats with PK and sildenafil at the same time, a better therapeutic effect was achieved. These data demonstrate that intraperitoneal injection of PK can improve erectile function in a rat model of type 2 diabetic ED. With further research on specific mechanisms of erectile function improvement, PK may become a novel treatment for diabetic ED., Competing Interests: All authors declared no competing interests

Cholesterol rich membrane invaginations, caveolae, have important roles in various cellular activities, one of them being signal transduction. This signaling pathway seems to be affected during various bladder disorders and the current study aimed to elucidate the plausible involvement of caveolae mediated signal transduction during cyclophosphamide induced cystitis. Furthermore, the urothelial cholinergic part of ATP-evoked contractions and its possible link to caveolae were investigated. Cholinergic, as well as purinergic, contractile responses in rat urinary bladders were examined using a classic organ bath set-up with full-thickness strip preparations or a whole bladder model that enabled luminal administration of substances. Furthermore, sub groups with and without urothelium were examined. The expression of caveolin-1 was also tested using western blot and immunofluorescence. Caveolae cholesterol depletion by methyl-β-cyclodextrin entailed a significant decrease of ATP-evoked bladder contractility. Interestingly, after muscarinic blockade the ATP induced contractions were significantly reduced in the same manner. Furthermore, this atropine-sensitive part of ATP-evoked responses was absent in denuded as well as inflamed bladders. A tendency towards a reduced expression of caveolin-1 was observed in rats with experimental cystitis. The cholinergic part of ATP-induced contractile responses seemed to be affected by urothelium denudation as well as caveolae depletion. Removing one of these structures nullifies the effect of the other, suggesting an important interaction between the urothelium and the caveolar structures. These effects are absent in inflamed animals and might be one pathophysiological aspect behind BPS/IC., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: The impact of mirabegron on clinical outcome and urodynamic parameters may be important for clinical practice. Thus, the aim of this study was to compare the clinical outcomes and urodynamic effects of mirabegron (Betmiga 50 mg) versus tolterodine (Detrusitol ER 4 mg) treatment for women with overactive bladder syndrome (OAB)., Methods: Women with OAB were randomized to receive 12 weeks of mirabegron 50 mg, tolterodine extended-release 4 mg or placebo treatment. The clinical outcomes and urodynamic effects were compared between the subgroups., Results: Thirty-three women completed 12 weeks of mirabegron (n = 12), tolterodine (n = 12) or placebo (n = 9) treatment. A significant increase in the volumes at strong desire to void and a decrease in the daytime frequency episodes were identified in the mirabegron and tolterodine groups (all P < 0.05). Nonetheless, a decrease in the total voided volume was identified following mirabegron treatment but not tolterodine (P = 0.02)., Conclusions: Mirabegron and tolterodine exhibit similar changes in the urodynamics and bladder diary parameters. However, mirabegron may decrease the total voided volume. These findings may serve as an initial guide or assist in consultations regarding the treatment of OAB patients with mirabegron., (© 2017 John Wiley & Sons Australia, Ltd.)

Background: Improvement of bladder emptying by modulating afferent nerve activity is an attractive therapeutic strategy for detrusor underactivity. Transient receptor potential vanilloid 4 (TRPV4) is a sensory ion channel in urothelial cells that contribute to the detection of bladder filling., Objective: To investigate the potential benefit of intravesical TRPV4 agonists in a pelvic nerve injury rat model for detrusor underactivity., Design, Setting, and Participants: Female wild-type and Trpv4 knockout rats underwent sham surgery or bilateral pelvic nerve injury (bPNI). Four weeks later, rats underwent cystometry with infusion of the TRPV4 agonist GSK1016790A. Bladders were harvested for in vitro pharmacological studies, quantitative reverse polymerase chain reaction and immunohistochemistry., Outcome Measurements and Statistical Analysis: Data are expressed as median ± interquartile range. Statistical comparisons were made using the Mann-Witney U test and Wilcoxon signed rank test as appropriate., Results and Limitations: Rats with bPNI showed a phenotype characteristic of detrusor underactivity with lower-amplitude voiding contractions, decreased voiding frequency, and increased postvoid residual. Intravesical application of GSK1016790A increased voiding frequency and reduced postvoid residual in wild-type, but not Trpv4 -/- , rats. In isolated bladder strips, GSK1016790A did not induce relevant contractions, indicating that the observed improvements in bladder function are the result of increased afferent signalling through TRPV4 activation, rather than a local effect on the detrusor. The altered urinary phenotype of Trpv4 -/- mice was not apparent in the Trpv4 -/- rat model, suggesting species-related functional variations. Our results are limited to the preclinical setting in rodents., Conclusions: Intravesical activation of TRPV4 improves bladder dysfunction after bPNI by increasing afferent signalling., Patient Summary: We demonstrate that the sensory protein transient receptor potential vanilloid 4 (TRPV4) can be targeted to improve bladder function in animals that have iatrogenic injury to the nerves innervating the bladder. Further research is required to determine whether these results can be translated to patients with an underactive bladder., (Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.)

Fesoterodine (as one of three drugs: dutasteride, finasteride and fesoterodine) was classified B (beneficial) by LUTS-FORTA 2014, indicating that it is a medicinal product with proven or obvious efficacy in the elderly, with limited side effects and/or safety concerns. A systematic literature review was undertaken in January 2018 using the PubMed and Google Scholar databases with the following individual and combined keywords: "fesoterodine", "pharmacology", "overactive bladder" and "antimuscarinics". The aim of the review was to determine which of fesoterodine's pharmacological properties explains its clinical benefits in general patient populations with OAB and the elderly in particular. The articles in the results were then selected by publication language (English and French only), methodology (off-topic studies, reported cases and literature reviews were excluded), relevance to the subject matter and publication date prior to 31 January 2018. A total of 205 articles was initially obtained, with 115 read and 45 selected. It appears that the association of four pharmacological properties specific to fesoterodine can explain that this drug has a good balance between efficacy and tolerability. These properties are namely the drug's high and nearly equal affinity for both the M2 and M3 muscarinic receptors, poor penetration of the blood-brain barrier, lack of hepatic first-pass activation -fesoterodine being rapidly and extensively converted to its active metabolite, 5-hydroxymethyl tolterodine, by ubiquitous esterases-, and its extended-release formulation. Fesoterodine's pharmacological profile is optimal for the treatment of overactive bladder. It is now recognized as one of the leading first-line treatment for this indication., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aims: We investigated the effects of silodosin, an α1A-adrenoceptor (AR) antagonist, on bladder function, especially on non-voiding contractions (NVCs), in a male rat model of bladder outlet obstruction (BOO) by evaluating cystometry (CMG) findings and bladder mechanosensitive single-unit afferent activities (SAAs), related with microcontractions, which may be similar with NVCs and to be of myogenic origin, in the rat model., Methods: BOO was created by partial ligation of the posterior urethra. At 4 days after surgery for BOO, an osmotic pump filled with silodosin (0.12 mg/kg/day) or its vehicle was subcutaneously implanted. At 10 days after surgery, CMG and SAAs measurements were taken under conscious and urethane-anesthetized conditions, respectively. The SAAs of Aδ- and C-fibers, which were identified by electrical stimulation of the pelvic nerve and by bladder distention, and intravesical pressure were recorded during constant bladder-filling with saline. Microcontractions were divided into three phases: "ascending," "descending," and "stationary.", Results: The silodosin-treated group showed a smaller number of NVCs in CMG measurements and lower SAAs of both Aδ- and C-fibers than the vehicle-treated group during bladder-filling. Moreover, in the vehicle-treated groups, the SAAs of both fibers for the ascending phase of microcontractions were significantly higher than those for the other two phases. On the contrary, no significant change was found between any of these three phases in the silodosin-treated group., Conclusion: The present results suggest that silodosin inhibits the SAAs of mechanosensitive Aδ- and C-fibers at least partly due to suppressing myogenic bladder contractions in male BOO rats., (© 2018 Wiley Periodicals, Inc.)

Purpose of Review: Lower urinary tract symptoms (LUTS) result from age-related changes in detrusor function and prostatic growth that are driven by alterations in the ratio of circulating androgens and estrogens. Alpha-adrenergic receptor blockers are commonly used to treat LUTS because they influence urethral tone and intra-urethral pressure. Molecular cloning studies have identified three α 1 -adrenergic receptor subtypes (α 1A , α 1B , and α 1D ). The α 1A subtype is predominant in the human prostate but is also present in many parts of the brain that direct cognitive function. Tamsulosin is the most widely used α 1 -adrenergic receptor antagonist with 12.6 million prescriptions filled in 2010 alone. When compared to the other common types of α 1 -adrenergic receptor antagonists (i.e., terazosin, doxazosin, and alfuzosin), tamsulosin is 10- to 38-fold more selective for the α 1A versus the α 1B subtype., Recent Findings: Duan et al. have recently shown that men taking tamsulosin have a higher risk of developing dementia when compared to men taking other α-adrenergic antagonists or no α-adrenergic antagonists at all (HR 1.17; 95% CI 1.14-1.21). Based upon this retrospective analysis, we believe that tamsulosin, because of its unique affinity for α 1A -adrenergic receptors, may increase the risk of developing dementia when used for an extended period of time. If these findings are confirmed, they carry significant public health implications for an aging society.

Background: Αim of the study was to determine the effect of mirabegron, used for overactive bladder (OAB) treatment, on female sexual function., Methods: Eighty five sexually active women suffering from overactive bladder were prospectively enrolled in this study. Females were divided into two groups. In Group A (control), 48 patients received no treatment and in Group B, 37 patients received mirabegron 50 mg/daily for 3 months. Patients were evaluated with FSFI-Gr at the beginning of the study and again after a period of 3 months., Results: In Group B, there was a significant increase post-treatment compared to baseline (p < 0.001) in total FSFI (20.3 (3.8) to 26.6 (4.2)) and all domains (desire: 3.0 (1.2) to 4.8 (1.2)), arousal: 3.0 (0.8) to 4.8 (0.9), lubrication: 3.9 (1.1) to 4.8 (1.2), orgasm: 3.6 (0.8) to 4.8 (1.0), satisfaction: 3.2 (0.4) to 4.0 (0.8) and pain: 3.2 (0.8) to 4.4 (1.2)). In Group A, there were no statistically significant changes in pre- and post-observation values., Conclusions: This study is one of the few demonstrating that management of OAB with mirabegron improves female sexual function., Trial Registration: TRN ISRCTN17199301 , 20/10/2017, retrospectively registered.

Aim: The aim of this study was to compare the efficacy and tolerability of solifenacin and mirabegron in patients with overactive bladder (OAB) syndrome., Methods: We carried out a retrospective analysis in 342 women affected by OAB syndrome; 168 were treated with solifenacin 5 mg/daily and 174 with mirabegron 50 mg/daily. A clinical evaluation, 3-day voiding diary, and urodynamic testing was performed. Patients completed the Overactive Bladder Questionnaire - Short Form, the King's Health Questionnaire, and the Patient Global Impression of Improvement questionnaire. The adverse effects were evaluated. The two groups were compared at baseline and at 12 weeks., Results: After 12 weeks, a significant reduction in the mean number/24 h of voids and urgent micturition episodes/24 h was observed in both groups. Detrusor overactivity decreased from 58.3% to 13.1% in the solifenacin group and from 58% to 11% in the mirabegron group. Twenty (12%) and 18 (10.7%) patients taking solifenacin reported constipation and dry mouth, respectively, versus four (2.3%) and five (2.9%) patients taking mirabegron, respectively, but there was no difference between the groups in the change in vital signs. The Overactive Bladder Questionnaire - Short Form and King's Health Questionnaire scores did not demonstrate significant differences and the abandonment rates in the solifenacin and mirabegron groups were 25.5% and 20%, respectively., Conclusion: Solifenacin and mirabegron showed the same efficacy in the treatment of OAB but solifenacin had more adverse effects., (© 2017 Japan Society of Obstetrics and Gynecology.)

Existing drugs that have been used in clinical practice for other purposes can prove useful for reutilization, since much of the safety profile and pharmacokinetics have been completed. Therefore, the drugs can enter clinical practice for a variety of causes with less regulatory burden. Metformin may prove to be such a drug; it may have a role in other diseases, besides the management of diabetes. In this perspective, we provide our findings and understanding of metformin as an alternative way to treat urological abnormal proliferation. We propose the potential mechanisms into two hallmarks: direct antiproliferative function via insulin-like growth factor (IGF) signaling pathway and epigenetic modulating via adjusting DNA methylation. These specific hallmarks may ultimately contribute to a better understanding of metformin in treating prostatic diseases.

Background: Storage lower urinary tract symptoms (LUTS) including overactive bladder (OAB) and urinary incontinence (UI) affect millions of people worldwide, significantly impacting quality of life. Plant based medicines have been documented both empirically and in emerging scientific research to have varying benefits in reducing bladder symptoms. We assessed the efficacy of Urox®, a proprietary combination of phytomedicine extracts including, Cratevox™ (Crataeva nurvala) stem bark, Equisetem arvense stem and Lindera aggregata root, in reducing symptoms of OAB and UI., Methods: Efficacy of the herbal combination on a variety of bladder symptoms compared to an identical placebo, were documented in a randomised, double-blind, placebo controlled trial conducted at two primary care centres. Data were collected at baseline, 2, 4 and 8 weeks, with the primary outcome being self-reported urinary frequency. Statistical analysis included mixed effects ordered logistic regression with post hoc Holm's test to account for repeated measures, and included an intention-to-treat analysis., Results: One hundred and fifty participants (59% female, aged; mean ± SD; 63.5 ± 13.1 years) took part in the study. At week 8, urinary day frequency was significantly lower (OR 0.01; 95%CI 0.01 to 0.02; p < 0.001) in response to treatment (mean ± SD; 7.69 ± 2.15/day) compared to placebo (10.95 ± 2.47/day). Similarly, episodes of nocturia were significantly fewer (OR 0.03; 95%CI 0.02 to 0.05) after 8 weeks of treatment (2.16 ± 1.49/night) versus placebo (3.14 ± 1.36/night). Symptoms of urgency (OR 0.02; 95%CI 0.01 to 0.03), and total incontinence (OR 0.03; 95% CI 0.01 to 0.06) were also lower (all p < 0.01) in the treatment group. Significant improvements in quality of life were reported after treatment in comparison to placebo. No significant side effects were observed resulting in withdrawal from treatment., Conclusions: The outcome of this study demonstrated both statistical significance and clinical relevance in reducing symptoms of OAB, urinary frequency and/or urgency and incontinence. The demonstrated viability of the herbal combination to serve as an effective treatment, with minimal side-effects, warrants further longer term research and consideration by clinicians., Trial Registration: NCT02396160 (registered on 17 March 2015 - before any statistical analyses commenced).

Overactive bladder (OAB) is defined as urgency, with or without urge incontinence, usually with frequency and nocturia. Antimuscarinic drugs are often prescribed as a standard care; however, the treatment discontinuation due to the adverse events including dry mouth and constipation has been an issue. Taking these situations into account, we considered that a novel OAB drug having a different mechanism from antimuscarinics fills the unmet medical need. It has been known that, during bladder filling, activation of sympathetic nerves results in bladder smooth muscle relaxation via the β-adrenergic receptor (AR) stimulation. In 1999, three Japanese groups independently provided evidence for the existence of β 3 -AR in human bladder smooth muscles and some of these groups showed that β 3 -AR activation is mainly involved in the relaxation induced by β adrenergic stimulation. Therefore, we conducted pharmacological research focusing on β 3 -AR as a novel target molecule for the treatment of OAB. A selective β 3 -AR agonist mirabegron showed the relaxant effect in rat bladder smooth muscle and decreased resting intravesical pressure in anesthetized rats. Mirabegron also improved storage function in a rat detrusor overactivity model. Furthermore, in vitro isometric contraction study using human bladder tissues was conducted to predict the clinical efficacy and mirabegron showed the relaxant effect in human bladder smooth muscle. In clinical studies with OAB patients, mirabegron demonstrated promising efficacy and tolerability. These pharmacological evidences contributed to the approval of mirabegron as a first-in-class drug for OAB treatment in Japan ahead of other countries.

Purpose: To determine changes in autonomic nervous system activity after treatment in men with lower urinary tract symptoms (LUTS), we evaluated changes in patients' symptoms, uroflowmetry, and heart rate variability (HRV) after treatment with alpha-blockers for 12 weeks., Materials and Methods: Ninety-five men who had LUTS (International Prostate Symptom Score [IPSS] ≥8) were included in this study. We divided them into two groups on the basis of a low frequency/high frequency (LF/HF) ratio of 1.6. After treatment with Xatral XL (Handok Inc., Korea) 10 mg for 3 months, we rechecked their IPSS, uroflowmetry, HRV and compared these with the baseline measurements., Results: Fifty-four men were assigned to the low LF/HF group (group A: LF/HF ≤1.6) and 41 men to the high LF/HF group (group B: LF/HF >1.6). At baseline and 12 weeks, none of the parameters differed significantly between the groups except for HF, which is one of the parameters of HRV. IPSS, the IPSS-voiding subscore, and the IPSS-storage subscore decreased and maximal uroflow increased significantly after 12 weeks of treatment. Whereas the baseline LF/HF ratio increased from 0.89±0.407 to 1.80±1.804 after treatment in group A, it decreased from 3.93±5.471 to 1.79±1.153 in group B., Conclusions: The efficacies of Xatral XL were clear in both groups. We found that the LF/HF ratio in the two groups merged to a value of approximately 1.79 after treatment. We suggest that this could be a clue to the importance of balance in autonomic nervous system activity in men with LUTS., Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose.

Objective: This technical update addendum reviews success rates and comparative evidence of the anticholinergic fesoterodine, as well as mechanism of action, safety profile, success rates, and comparative evidence of the β3 agonist mirabegron in the treatment of non-neurogenic overactive bladder syndrome (OAB). This adds to OAB pharmacotherapy recommendations initially published in 2012., Intended Users: Residents and other trainees, primary care practitioners, gynaecologists, urologists, urogynaecologists, and other health care providers who assess, counsel, and treat women with OAB., Target Population: Adult women with symptomatic OAB., Options: This addition relates to fesoterodine, mirabegron, and anticholinergic-β3 agonist combination pharmacotherapy., Outcomes: The outcomes of interest are clinical efficacy of fesoterodine compared with no treatment or other OAB therapies; mechanism of action and safety profile of mirabegron, clinical efficacy of mirabegron compared to no treatment or other OAB therapies; clinical efficacy of anticholinergic-β3 agonist combination pharmacotherapy for OAB., Evidence: PubMed, Medline, and the Cochrane Database were searched using the key words "fesoterodine" and "mirabegron." Results were restricted to English or French and human clinical and pharmacological research. Animal research and clinical studies including only male participants were excluded. Articles were included until the end of December 2016. Grey literature was not searched. Clinical practice guidelines, guidelines of specialty societies, and systematic reviews were included. RCTs and observational studies were included when evidence for the outcome of interest or in the target population was not available from systematic reviews. New studies not yet included in systematic reviews were also included. References of included articles were also searched to ensure comprehensive inclusion of relevant literature., Values: The content and recommendations were drafted and agreed upon by the principal author, as well as members of the Urogynaecology Committee. The Board of the SOGC approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology framework. The Summary of Findings is available upon request., Benefits, Harms, And/or Costs: It is expected that this technical update will benefit patients with OAB by providing physicians and other interested health care providers with additional options for and knowledge of safe and effective OAB pharmacotherapy. The benefits clearly outweigh the potential harms or costs of implementation of this technical update, although there are no direct harms or costs identified. UPDATES: "Evidence will be reviewed 5 years after publication to decide whether all or part of the document should be updated. However, if important new evidence is published prior to the 5-year cycle, the review process may be accelerated for a more rapid update of some recommendations.", Sponsors: Not applicable., (Copyright © 2017 Society of Obstetricians and Gynaecologists of Canada. Published by Elsevier Inc. All rights reserved.)

Urolithins (UROs) are metabolites derived from ellagic acid (EA) and ellagitannins (ETs) by gut microbiota after consumption of different ETs. The health effects attributed to UROs are numerous and diverse, ranging from antimalarial properties to anticancer activities and regulation of gene expression. The aim of this work was at assessing the effect of URO-A; -B; -C; -D on the oxidative status of colon epithelium using as a model colorectal adenocarcinoma cell line (Caco-2). No significant cytotoxic effects of UROs was noted, with the applied treatments. Supplementation of cell growth medium with a mixture of UROs decreased the level of intracellular reactive oxygen species both after short- and long-term exposure. UROs also affected the activity of antioxidative enzymes within the cell, especially catalase., Conclusions: At concentrations reached in the lumen of the gut, UROs can exert beneficial effects on the cells by decreasing oxidative stress thus preventing the damage caused by reactive oxygen species.

Objective: To examine the effect of an aqueous extract of Radix Paeoniae Alba (RPA) on the formation of calcium oxalate (CaOx) stones and the potential mechanism underlying the effect., Materials and Methods: An in vitro assay was used to determine whether the RPA extract prevents the formation of CaOx or promotes CaOx dissolution. We also investigated the efficacy of the extract in vivo as a preventive and therapeutic agent for experimentally induced CaOx nephrolithiasis in rats. Various biochemical, molecular, and histological parameters were assessed in kidney tissue and urine at the end of the in vivo experiment., Results: Significant dissolution of formed crystals (8.99 ± 1.43) and inhibition of crystal formation (2.55 ± 0.21) were observed in vitro after treatment with 64 mg/mL of the RPA extract compared with a control treatment (55.10 ± 4.98 and 54.57 ± 5.84, respectively) (p < .05). In preventive protocols, the RPA extract significantly reduced urinary and renal oxalate levels and increased urinary calcium and citrate levels compared to the control. In addition, the RPA preventive protocol significantly decreased osteopontin expression, renal crystallization, and pathological changes compared to the control. These changes were not observed in rats on the therapeutic protocol., Conclusions: RPA is a useful agent that prevents the formation of CaOx kidney stones.

Aim: We aimed to clarify the impact of night-time dosing with tolterodine extended release (ER) on nocturia., Methods: The bladder diaries, urodynamic studies, and medical records of female patients with overactive bladder syndrome who were diagnosed between January 2005 and December 2015, and treated with tolterodine ER 4 mg once per day (night-time or daytime dosing) for 12 weeks in the urogynecology outpatient clinics of two tertiary referral centers were reviewed retrospectively., Results: A total of 72 female patients were reviewed. Thirty-six patients were in the daytime dosing group, and the other 36 patients were in the night-time dosing group. In the daytime dosing group, a decrease in the volume of fluid intake was found at 06.00-12.00, 12.00-18.00, and 18.00-24.00 hours, and a decrease in total voided volume was found at 12.00-18.00, 18.00-24.00, and 24.00-06.00 hours with a between-group difference at 18.00-24.00 hours (coefficient = 542 mL, P = 0.01). In the night-time dosing group, an increase in voided volume per micturition was found at 06.00-12.00 and 24.00-06.00 hours with a between-group difference at 24.00-6.00 hours (coefficient = 92 mL, P = 0.003) compared with the daytime dosing group. Nonetheless, pre-treatment proportions of nocturnal polyuria did not differ from post-treatment proportions (night-time: 20% vs 20%, P = 1.00; daytime: 48% vs 42%, P = 0.48). Decreases in the number of voiding and urgency episodes at nearly all time periods and increases in the volumes at strong desire to void were also found in both groups., Conclusion: Night-time dosing of tolterodine ER may benefit female patients suffering from nocturia due to a greater voided volume per micturition at midnight., (© 2017 Japan Society of Obstetrics and Gynecology.)

Background: Overactive bladder syndrome (OAB) is a chronic and prevalent condition which has a negative impact on Quality of Life. The National Institute of Clinical Excellence issued two documents which give slightly varying algorithms of pharmacotherapy for OAB, offering mirabegron as a possible treatment in certain circumstances. In the absence of trials involving a direct comparison of therapies, an indirect comparison can provide useful information on the difference in treatment effects between competing interventions., Objective: To compare effectiveness of available medical therapies for OAB using Bucher indirect treatment comparison (ITC) model., Methods: A systematic literature search identified randomised controlled trials (RCT) assessing effectiveness of drugs for OAB versus placebo. Then indirect comparisons of the treatments effects were made, preserving the randomisation of the originally assigned patient groups, using Bucher method., Main Results: 25 RCTs met inclusion criteria. In keeping with ITC method validity, four assessments were undertaken of mirabegron against anticholinergics, which were number of incontinence episodes, micturition episodes, urgency episodes in 24 h and volume of micturition. This indirect treatment analysis suggests that mirabegron is as effective as anticholinergics in managing of OAB, except for solifenacin which appears to be superior., Conclusions: These findings suggest that work looking into treatment choice should be individualized to patient characteristics rather than fitting patients to a treatment. Further work is required to identify what patient characteristics may be crucial and indicate that studies exploring the most effective sequence of managing treatment naïve patients and those with refractory disease., (© 2017 Wiley Periodicals, Inc.)

Objective: To explore the effects of Xialiqi Capsules(XLQ) on the expressions of the proliferating cell nuclear antigen (PCNA) and caspase-3 in the prostate tissue of the BPH rat model., Methods: Fifty male SD ratswereequally randomized into groups A (sham operation control), B (BPH model control), C (high-dose XLQ), D (low-dose XLQ), and E (finasteridecontrol) andthe BPH modelswere established by subcutaneous injection of testosterone propionate at 0.5 mg per kilogram of the body weight per day for 30 days after castration. After modeling, the animals in groups A and B were treated intragastricallywith normal saline, while those in C, D, and E with XLQ at 1.20 and 0.61 g per kilogram of the body weight per day or finasterideat 0.8 mg per kilogram of the body weight per day, respectively, all for 30 days. Then,the bilateral prostates were harvestedfrom the rats for calculation of the prostatic index (prostate wet weight/ body weight) and determination of the expressions of PCNA and caspase-3 in the prostate tissue by immunohistochemistry and immunofluorescence staining, respectively., Results: The prostate wet weight and prostate index were significantly increased in group B as compared with group A, (［1326±60］ vs［471±17］ g, P<0.01; ［2.89±0.18］ vs ［1.06±0.06］ mg/g, P<0.01), but decreased in groups C (［914±36］ g;［2.02±0.08］ mg/g), D (［1 099±46］g;［2.39±0.11］ mg/g), and E (［817±53］ g;［1.83±0.10］ mg/g)in comparison with B (P<0.01), with statistically significant differences among groups C, D, and E(P<0.01) and most significantly in E.The PCNA level in the prostate tissue wasremarkably higher in group B than in A, but lower in groups C, D and E than in B. The expression of caspase-3 was down-regulatedin group B as compared with A, but up-regulated in groups C, D and E in comparison with B, most significantly in E., Conclusions: Xialiqi Capsules can effectively reduce the prostate wet weight and prostatic index of in rats with BPH by inhibiting the level of PCNA and promoting the expression of caspase-3.

Aims: Our aim was to investigate the effects of doxazosin, sildenafil, and their combination on bladder tissue contractility and adrenergic receptor (AR) and inducible nitric oxide synthase (iNOS) expression utilizing a male rat model of partial urethral obstruction (PUO)., Methods: Thirty male Sprague Dawley rats were divided into five groups. Except the SHAM group, all animals in remaining four groups underwent surgery for PUO. No further treatment was given to the first group (NT group). Remaining three groups received 6 weeks of treatment with 20 mg/kg doxazosin (D group), 20 mg/kg sildenafil (S group), 20 mg/kg doxazosin, and 20 mg/kg sildenafil combination (DS group), respectively via oral gavage. Then, bladder strips were harvested from each animal for isometric tension studies and for real time polymerase chain reaction studies of both AR subtypes and iNOS mRNA., Results: Contractile responses to carbachol and electrical field stimulation at various concentrations/frequencies showed a significant increase after PUO. Any treatment helped to normalize these increased responses. Alpha 1a and 1d AR subtype expressions were found to be down- and up-regulated, respectively, in every group with PUO, compared to SHAM group. iNOS expression was similar in D and NT groups and significantly increased in S and DS groups., Conclusions: Contractile changes of rat bladder tissue due to PUO were prevented by sildenafil or doxazosin alone or in combination where combination treatment did not provide any additional advantage. Further studies are needed to clarify the role of phosphodiesterase inhibitors and combination treatment in the treatment of LUTS., (© 2016 Wiley Periodicals, Inc.)

Aim of the study is to investigate the relationship between non-contrast computed tomography (NCCT) findings and stone expulsion rate with medical expulsive therapy (MET) using silodosin for ureteral stones in male adults. Between January 2014 and June 2015, we retrospectively reviewed the patient charts with uncomplicated ureteral stones on NCCT images, who were treated with silodosin for MET. Stone diameter, volume and hounsfield units (HU) measured by NCCT and treatment findings were noted at the end of treatment. Patients were divided into three groups according to the localization as distal, mid and proximal ureteral stones. NCCT and treatment findings were compared between MET success and failure groups in different localizations. Stone expulsion rate was 81.3% for 134 distal, 45.5% for 22 mid and 27.7% for 47 proximal stones. Stone diameter, volume, and HU were significantly lower for success groups with distal and proximal stones (p < 0.05). In ROC analysis the cut-off values for stone volume and HU were detected as 48.7 mm 3 and 598 HU for success group with proximal stones. Stone expulsion rate was found to be 24 times more (OR = 24; p = 0.001) in patients with <598 HU and 14 times more (OR = 14; p = 0.002) in patients with <48.7 mm 3 proximal stones. Lower stone diameter, volume and HU were significant predictors of success with silodosin for MET for ureteral stones. Patients with <598 HU and/or <48.7 mm 3 proximal stones may be prescribed silodosin for MET., (Copyright © 2017. Published by Elsevier Taiwan.)

Objectives: To investigate single or combined effect of silodosin, an α1A-adrenoceptor antagonist, and imidafenacin, an antimuscarinic agent, on bladder function in a subacute bladder outlet obstruction (BOO) model of male rats., Methods: Partial BOO was created in male Wistar rats by ligating the urethra with a steel rod. On day 10 after surgery, when frequent voiding was most remarkable on voiding behavior measurement in a metabolic cage, cystometric investigations in a conscious restrained condition were conducted with cumulative intravenous administration of silodosin alone (0.1, 1, 10, and 100 µg/kg), imidafenacin alone (1, 3, and 10 µg/kg), or a combination of the two drugs., Results: When compared with the Sham rats, the BOO rats showed an increase in bladder capacity, residual volume, mean amplitude and the number of non-voiding contractions (NVCs), accompanied with an increase in bladder weight. In the BOO rats, silodosin alone at 100 µg/kg significantly decreased the number of NVCs, whereas imidafenacin alone at 3 and 10 µg/kg significantly decreased both the number and mean amplitude of NVCs. The combination administration with lower doses (silodosin at 10 µg/kg and imidafenacin at 1 µg/kg) significantly suppressed both the number and mean amplitude of NVCs., Conclusions: The present results indicate a suppressive effect of silodosin or imidafenacin alone and a synergic effect of the combination of these two drugs on NVCs in a subacute BOO model of male rats., (© 2015 Wiley Publishing Asia Pty Ltd.)

Aims: To investigate the effects of combined therapy with an anticholinergic agent and a β3-adrenoceptor agonist on bladder dysfunction and proliferation-related molecule expression in rats with spinal cord injury (SCI)., Methods: The spinal cord was transected at the level of T8-9 in female Sprague-Dawley rats, which were divided into four groups; A: Vehicle, B: 10 mg/kg/day of oxybutynin, C: 10 mg/kg/day of mirabegron, and D: combined administration of oxybutynin and mirabegron. Drugs were administered by oral gavage from 2 to 4 weeks after spinal cord transection. We evaluated urodynamic parameters and bladder tissue remodeling factors., Results: Non-voiding contractions (NVCs) during the storage phase of cystometrograms tended to be decreased in all three treated groups with a significant reduction in group D versus A. Bladder compliance was improved, and intercontraction intervals, voided volume and bladder capacity were increased in group D. In all three treated groups (B-D), the expression of HIF1-α and TGF-β1 was decreased compared to group A. The expression of collagen-III and bFGF was decreased in groups B and D. The total bladder elastin level was increased in group D., Conclusions: The combination therapy of an anticholinergic agent and a β3-adrenoceptor agonist elevated the bladder elastin level, reduced NVCs, and increased bladder compliance more effectively than the monotherapy in SCI rats. Thus, the combination therapy could be effective for the treatment of neurogenic bladder dysfunction including bladder remodeling. Neurourol. Urodynam. 36:1039-1045, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Aims: To review and assess the definitions of drug resistance and the evidence supporting treatment for drug resistant overactive bladder/detrusor overactivity (OAB/DO)., Methods: Evidence review of the extant literature and consensus of opinion was used to derive the summary recommendations., Results: Drug resistance or drug refractory status has been inconsistently defined and reported in current evident sources. Recent publications use some correlation of lack of efficacy and or experienced side effects to define drug resistance. Algorithms based upon these definitions largely relate to the appropriate use of neuromodulation or botulinum neurotoxin, based upon patient selection and patient choice. Current treatment pathways are hampered by inability to consistently profile patients to optimize management, particularly after failure of initial pragmatic treatment., Conclusions: Further research is recommended to better identify patient phenotype for purposes of directing optimized therapy for OAB/DO. Current treatment algorithms are influenced by extensive data generated from recent neuromodulation and botulinum neurotoxin trials., (© 2017 Wiley Periodicals, Inc.)