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Importance: A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M1/M4 preferring muscarinic receptor agonist with no direct D2 dopamine receptor blocking activity. KarXT combines xanomeline with the peripheral muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation. In prior trials, xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia., Objective: To evaluate the efficacy and safety of xanomeline-trospium vs placebo in adults with schizophrenia., Design, Setting, and Participants: EMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine. Data were analyzed from February to June 2023., Interventions: Participants were randomized 1:1 to receive xanomeline-trospium chloride (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks., Main Outcomes and Measures: The prespecified primary end point was change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures were change from baseline to week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also evaluated., Results: A total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group). At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , -20.6; placebo, -12.2; least squares mean difference, -8.4; 95% CI, -12.4 to -4.3; P < .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between the xanomeline-trospium (8 participants [6.4%]) and placebo (7 participants [5.5%]) groups. The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]). Measures of extrapyramidal symptoms, weight gain, and somnolence were similar between treatment groups., Conclusions and Relevance: Xanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the previously reported and consistent results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity., Trial Registration: ClinicalTrials.gov Identifier: NCT04738123.

Standard schizophrenia treatment involves antipsychotic medications that target D2 dopamine receptors. However, these drugs have limitations in addressing all symptoms and can lead to adverse effects such as motor impairments, metabolic effects, sedation, sexual dysfunction, cognitive impairment, and tardive dyskinesia. Recently, KarXT has emerged as a novel drug for schizophrenia. KarXT combines xanomeline, a muscarinic receptor M1 and M4 agonist, with trospium, a nonselective antimuscarinic agent. Of note, xanomeline can readily cross blood-brain barrier (BBB) and, thus, enter into the brain, thereby stimulating muscarinic receptors (M1 and M4). By doing so, xanomeline has been shown to target negative symptoms and potentially improve positive symptoms. Trospium, on the other hand, is not able to cross BBB, thereby not affecting M1 and M4 receptors; instead, it acts as an antimuscarinic agent and, hence, diminishes peripheral activity of muscarinic receptors to minimize side effects probably stemming from xanomeline in other organs. Accordingly, ongoing clinical trials investigating KarXT's efficacy in schizophrenia have demonstrated positive outcomes, including significant improvements in the Positive and Negative Syndrome Scale (PANSS) total score and cognitive function compared with placebo. These findings emphasize the potential of KarXT as a promising treatment for schizophrenia, providing symptom relief while minimizing side effects associated with xanomeline monotherapy. Despite such promising evidence, further research is needed to confirm the efficacy, safety, and tolerability of KarXT in managing schizophrenia. This review article explores the current findings and potential mechanisms of KarXT in the treatment of schizophrenia., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aim: To evaluate the efficiency of long-term use of trospium chloride (Spazmex) for the treatment of patients with neurogenic overactive bladder due to Parkinson's disease (PD) and to determine the influence of therapy on the cognitive status of patients., Materials and Methods: 60 patients with PD and neurogenic overactive bladder with stages 2.5, 3 and 4 according to Hoehn-Yahr scale were included in the main group. The mean age was 58.2+/-5.7 years. All patients were prescribed trospium chloride at entry into the study, with doses titrated gradually according to clinical efficacy (30 to 90 mg). The comparison group included 15 patients with PD and neurogenic overactive bladder at stages 2,5 and 3, who received tibial neuromodulation according to the standard technique with skin electrodes. The mean age of patients was 56.4+/-4.6 years. At baseline, both groups were comparable in terms of gender, age and cognitive status (p=0.801). All patients received treatment for 52 weeks. The efficiency of therapy was assessed according to bladder diaries, while safety outcomes included postvoid residual, side effects, cognitive status according to the MoCA scale and quality of life according to the SF-Qualiveen questionnaire., Results: clinical efficacy and satisfaction were achieved in all patients who completed the study (47 patients in the main group and 15 patients in the comparison group). Good clinical efficacy was demonstrated in both groups, since there was a decrease in the number of urinations, episodes of urgency and urinary incontinence. In addition, there was an improvement in the quality of life according to the SF-Qualiveen scale. The cognitive status during the entire follow-up period remained without significant changes in both groups., Conclusion: Trospium chloride is an effective drug in patients with PD. It does not affect cognitive functions during long-term use. Trospium chloride should be considered as first-line drug in those with urologic manifestations of PD.

Introduction: Unmet expectations are a major cause of perceived treatment failure and discontinuation of treatment. To enable evidence-based counselling of patients on realistic expectations, we determined the chance of patients with overactive bladder becoming free of a given symptom upon treatment with a muscarinic antagonist in a non-interventional setting., Methods: Two non-interventional studies included 1335 and 745 patients, respectively, who received 30 or 45 mg q.d. propiverine ER for 12 weeks. They were monitored for becoming free of urgency, urinary incontinence, frequency, or nocturia. Analyses were also performed in subgroups defined by basal symptom severity, age, and gender. Categorical data are shown as a percentage of the respective population. Continuous data are expressed as means or as median depending on whether the variability was considered to exhibit a normal distribution., Results: The probability of becoming symptom-free was largest for incontinence and frequency (about 50%), but lesser for urgency (about 20%) and nocturia (about 10%). Greater basal severity of a symptom reduced the chance to become free of that symptom upon treatment, but the chance to become free of incontinence and frequency was still considerable. Age and gender had only minor if any effects on the chance of becoming symptom-free. These findings are in line with those of a limited number of randomized controlled trials., Conclusion: These data provide an evidence base for the counselling of patients with overactive bladder on realistic expectations of treatment outcomes. We propose that realistic expectations can lead to greater long-term adherence., (© 2022. The Author(s).)

Background: The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown., Methods: In this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline-trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression-Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2., Results: A total of 182 patients were enrolled, with 90 assigned to receive xanomeline-trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline-trospium group and 96.6 in the placebo group. The change from baseline to week 5 was -17.4 points with xanomeline-trospium and -5.9 points with placebo (least-squares mean difference, -11.6 points; 95% confidence interval, -16.1 to -7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline-trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline-trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups., Conclusions: In a 5-week trial, xanomeline-trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline-trospium in patients with schizophrenia. (Funded by Karuna Therapeutics and the Wellcome Trust; ClinicalTrials.gov number, NCT03697252.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: Catheter-related bladder discomfort (CRBD) is a frequent complaint after awakening from anesthesia in patients receiving perioperative bladder catheterization. Overactive bladder (OAB) and CRBD show similar symptoms; thus, drugs used for the management of OAB influence symptoms of CRBD. Trospium chloride has been found effective in managing resistant cases of OAB. We evaluated the efficacy of oral trospium on CRBD in the postoperative period., Methods: Sixty-four male and female adult patients, with planned spinal surgery and requiring urinary bladder catheterization, were randomly divided into two groups of 32 each. Group T patients received 60 mg extended-release oral trospium (extended-release) 1 h before induction of anesthesia and Group C patients received a similar-looking placebo. The anesthetic technique was identical in both groups. The CRBD score was evaluated in the postoperative ward using a 4-point scale (1 = no discomfort, 2 = mild, 3 = moderate, 4 = severe). Readings were recorded on arrival (0 h), and 1 h, 2 h, and 6 h postoperatively. All patients received fentanyl for postoperative pain relief., Results: The incidence of CRBD was significantly higher in group C than in group T at 0 h (66% vs 22%, P=0.001) and 1 h postoperatively (72% vs 28%, P=0.001). The incidence of moderate to severe CRBD was higher in group C at postoperative 2 h (82% vs 14%, P=0.004). There was no significant difference in postoperative fentanyl requirements., Conclusions: Pretreatment with 60 mg ER trospium reduced the incidence and severity of CRBD in the early postoperative period.

Aim: To carry out a network meta-analysis of randomised controlled trials (RCTs) of anticholinergic drug treatment for people with overactive bladders., Methods: Comprehensive searches for relevant RCTs were carried out starting with RCTs included in previous systematic reviews with the last search in February 2017. Searches included terms for the anticholinergic drugs tolterodine, oxybutynin, trospium, propiverine, solifenacin, darifenacin, imidafenacin, and fesoterodine. Data was extracted from the systematic reviews or reports of studies for cure or improvement, voids per 24 hr, leakage episodes per 24 hr and dry mouth. Data was analysed using frequentist network meta-analysis., Results: 128 studies were found. There was no clearly best treatment for cure or improvement. The differences between treatments for voids and leakages were small and unlikely to be of clinical importance. Transdermally delivered oxybutynin was clearly the best treatment for dry mouth but was still worse than placebo., Conclusions: All the anticholinergic drugs were better than placebo but apart from dry mouth were similar in effect. Transdermal oxybutynin caused less dry mouth than the other treatments, so may be worth considering as the first treatment., (© 2018 Wiley Periodicals, Inc.)

Background: Benign prostatic hyperplasia (BPH) is a common condition in ageing men that may cause lower urinary tract symptoms (LUTS). Treatment aims are to relieve symptoms and prevent disease-related complications. Naftopidil is an alpha-blocker (AB) that has a high affinity for the A1d receptor that may have advantages in treating LUTS in this setting. This is an update of a Cochrane Review first published in 2009. Since that time, several large randomised controlled trials (RCTs) have been reported, making this update relevant., Objectives: To evaluate the effects of naftopidil for the treatment of LUTS associated with BPH., Search Methods: We performed a comprehensive search using multiple databases (the Cochrane Library, MEDLINE, Embase, Scopus, LILAC, and Web of Science), trials registries, other sources of grey literature, and conference proceedings with no restrictions on the language of publication or publication status up to 31 May 2018 SELECTION CRITERIA: We included all parallel RCTs. We also included cross-over design trials., Data Collection and Analysis: Two review authors independently classified and abstracted data from the included studies. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. Primary outcomes were urological symptom scores, quality of life (QoL) and treatment withdrawals for any reason; secondary outcomes were treatment withdrawals due to adverse events, acute urinary retention, surgical intervention for BPH, and cardiovascular and sexual adverse events. We considered outcomes measured up to 12 months after randomisation as short term, and later than 12 months as long term. We rated the certainty of the evidence according to the GRADE approach., Main Results: We included 22 RCTs with 2223 randomised participants across four comparisons for short-term follow-up. This abstract focuses on only two of four comparisons for which we found data since two comparators (i.e. propiverine and Eviprostat (phytotherapy)) are rarely used. One study comparing naftopidil to placebo did not report any relevant outcomes and was therefore excluded. There were no trials that compared to combination therapy with naftopidil or any 5-alpha reductase inhibitors (5-ARIs) to combination therapy with other ABs and any 5-ARIs.All included studies were conducted in Asian countries. Study duration ranged from four to 12 weeks. Mean age was 67.8 years, prostate volume was 35.4 mL, and International Prostate Symptom Score was 18.3. We were unable to perform any of the preplanned subgroup analyses based on age and baseline symptom score.Naftopidil versus tamsulosinBased on 12 studies with 965 randomised participants, naftopidil may have resulted in little or no difference in urological symptom score (mean difference (MD) 0.47, 95% confidence interval (CI) -0.09 to 1.04 measured on a scale from 0 to 35 with higher score representing increased symptoms), QoL (MD 0.11, 95% CI -0.09 to 0.30; measured on a scale from 0 to 6 with higher scores representing worse QoL), and treatment withdrawals for any reason (risk ratio (RR) 0.92, 95% CI 0.64 to 1.34; corresponding to 7 fewer per 1000 participants, 95% CI 32 fewer to 31 more). Naftopidil may have resulted in little to no difference in sexual adverse events (RR 0.54, 95% CI 0.24 to 1.22); this would result in 26 fewer sexual adverse events per 1000 participants (95% CI 43 fewer to 13 more). We rated the certainty of evidence as moderate for urological symptom score and low for the other outcomes.Naftopidil versus silodosinBased on five studies with 652 randomised participants, naftopidil may have resulted in little or no difference in the urological symptom scores (MD 1.04, 95% CI -0.78 to 2.85), QoL (MD 0.21, 95% CI -0.23 to 0.66), and treatment withdrawals for any reason (RR 0.80, 95% CI 0.52 to 1.23; corresponding to 26 fewer per 1000 participants, 95% CI 62 fewer to 32 more). We rated the certainty of evidence as low for all these outcomes. Naftopidil likely reduced sexual adverse events (RR 0.15, 95% CI 0.06 to 0.42; corresponding to 126 fewer sexual adverse events per 1000 participants, 95% CI 139 fewer to 86 fewer). We rated the certainty of evidence as moderate for sexual adverse events., Authors' Conclusions: Naftopidil appears to have similar effects in the urological symptom scores and QoL compared to tamsulosin and silodosin. Naftopidil has similar sexual adverse events compared to tamsulosin but has fewer compared to silodosin.

Background: Elderly people are representative for the patients most likely to be treated with anticholinergics for overactive bladder (OAB). They often receive further drugs with anticholinergic properties for concomitant conditions. This increases the risk for side effects, including central nervous system disorders. Data on comorbidities and baseline anticholinergic burden of OAB patients seen in urological practice is scarce. Therefore, we included an epidemiological survey on these issues in our study which assessed the effectiveness and tolerability of trospium chloride (TC) in established dosages under routine conditions., Methods: Outpatients (≥ 65 years of age), for whom treatment with TC was indicated, were eligible to participate in this non-interventional, prospective study performed in 162 urological practices in Germany. Epidemiological questions were evaluated by the Anticholinergic Burden (ACB) scale and the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) at baseline. Efficacy was assessed by changes in symptom-related variables of OAB after treatment. Dosage regimen, duration of treatment, adverse events, withdrawals, and ease of subdivision of the prescribed SNAP-TAB tablet were documented. Patients and physicians rated efficacy and tolerability of treatment. Statistics were descriptive., Results: Four hundred fourty-five out of 986 (47.54%) patients in the epidemiological population had a baseline ACB scale score > 0, 100 (24.72%) of whom a score ≥ 3. The median CIRS-G comorbidity index score for all patients was 5. 78.55% (608/774) of patients in the efficacy population received a daily dose of 45 mg TC. 60.03% (365/608) of them took this dose by dividing the SNAP-TAB tablet in three equal parts. Before-after-comparisons of the core symptoms of OAB showed clear improvements. An influence of the dosage scheme (1 × 45 mg TC/d vs 3 × 15 mg TC/d) on clinical outcome could not be observed. Most urologists and patients rated TC treatment as effective and well tolerated. 44 (4.37%) out of 1007 patients in the safety collective ended their treatment prematurely, while 75 patients (7.45%) experienced adverse events., Conclusions: Anticholinergic burden and comorbidities in elderly OAB patients are frequent. The acceptance of the SNAP-TAB tablet, which facilitates flexible dosing with TC, was high, which is supportive in ensuring adherence in therapy., Trial Registration: This non-interventional study was registered on October 29, 2014 with the number DRKS00007109 at the German Register of Clinical Studies (DRKS).

The objective of the study was immunohistochemical evaluation of distribution of various NO synthase fractions in the structural elements of the bladder wall under stress urinary incontinence and its overactivity prior and post Mirabegron, Spasmex, Quercetin therapies and their combinations with Testosterone and Estradiol. Using the immunohistochemical method, we studied the expression of the main fractions of NO synthase in experimental models of hyperactive bladder (OAB) and stress urinary incontinence (SUI). We found that OAB and SUI were characterized by emergence of expression of the inducible fraction (iNOS) predominantly in the interstitial cells of the muscular layer of the bladder and reduced expression of endothelial (eNOS) and neuronal (nNOs) NO synthase fractions. In contrast to Spasmex, Mirabegron and Quercetin in combination with Testosterone and Estradiol contributed to stabilization of eNOS and nNOs expression already at early observation phases, and reduced the level of iNOS expression with its further disappearance in the later observation period.

Objectives: To show the efficacy of propiverine hydrochloride in the management of symptoms of stress urinary incontinence in female patients with mixed-type urinary incontinence., Methods: The study was carried out as a multicenter single-arm clinical trial at 64 institutions in Japan. The participants were female patients aged ≥20 years with mixed-type urinary incontinence. The frequency of stress urinary incontinence and urgency urinary incontinence was evaluated at baseline and 4, 8 and 12 weeks after treatment with propiverine hydrochloride. Subjective symptoms were evaluated using the Overactive Bladder Symptom Score and the International Consultation on Incontinence Questionnaire-Short Form. Functional urethral length and maximum urethral closing pressure were also measured at baseline and 12 weeks after treatment at the institutions where the urethral pressure profile was taken., Results: In total, 49 mixed-type urinary incontinence patients were enrolled in the present study. The number of cases of urgency urinary incontinence was reduced time-dependently, which showed statistically significant differences between baseline and 4, 8 and 12 weeks after treatment. A similar statistically different reduction was also observed for stress urinary incontinence. The mean reduction rates of urgency urinary incontinence and stress urinary incontinence at 12 weeks after treatment were 63.9% and 44.3%, respectively. The total scores of International Consultation on Incontinence Questionnaire-Short Form and Overactive Bladder Symptom Score were gradually reduced, and the differences were statistically significant. Functional urethral length and maximum urethral closing pressure at 12 weeks after treatment did not show any statistical differences compared with those at baseline., Conclusions: Propiverine hydrochloride can be an effective therapeutic option for stress urinary incontinence in patients with mixed-type urinary incontinence., (© 2018 The Japanese Urological Association.)

Aims: To compare efficacy and tolerability of solifenacin 5 mg/day versus other oral antimuscarinic agents for the treatment of overactive bladder (OAB)., Methods: Literature searches of MEDLINE, Embase, and the Cochrane Library were undertaken to identify randomized controlled trials in OAB (2000-2015) for antimuscarinic agents. A network meta-analysis (NMA) was performed to estimate efficacy and tolerability outcomes for solifenacin 5 mg/day relative to other antimuscarinics., Results: The NMA included 53 eligible trials (published, n = 48; unpublished on search date, n = 5). Solifenacin 5 mg/day was significantly more effective than tolterodine 4 mg/day for reducing incontinence and urgency urinary incontinence (UUI) episodes, but significantly less effective than solifenacin 10 mg/day for micturition; no other statistically significant differences were noted for efficacy. Solifenacin 5 mg/day had a statistically significant lower risk of dry mouth compared with darifenacin 15 mg/day, fesoterodine 8 mg/day, oxybutynin extended-release 10 mg/day, oxybutynin immediate-release (IR) 9-15 mg/day, tolterodine IR 4 mg/day, propiverine 20 mg/day, and solifenacin 10 mg/day. There were no significant differences between solifenacin 5 mg/day and other antimuscarinics for risk of blurred vision, or for 11 of 17 active comparators for risk of constipation., Conclusions: This NMA suggests that the efficacy of solifenacin 5 mg/day is at least similar to other common antimuscarinics across the spectrum of OAB symptoms analyzed, and is more effective than tolterodine 4 mg/day in reducing incontinence and UUI episodes. Solifenacin 5 mg/day has a lower risk of dry mouth compared with several agents., (© 2017 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc.)

Aim: To evaluate the effect of adding low dose trospium chloride with transcutaneous posterior tibial nerve stimulation (TPTNS) in the treatment of overactive bladder (OAB) in females after failure of behavioral therapy., Methods: We randomized 30 women with OAB, in two groups: G I received 30 min TPTNS, three times a week; GII received TPTNS plus 20 mg trospium chloride daily. OAB Symptom Score questionnaire (OABSS), Incontinence Impact Questionnaire-short form 7 (IIQ-7), 3 day voiding diary and urodynamics at weeks 0 and 8 were evaluated., Results: The groups were similar before treatment. Eight weeks after treatment, the mean OABSS decreased significantly to 8.53 ± 1.30 for group II vs 10.0 ± 2.0 for GI (P < 0.024). The mean IIQ-7 score decreased significantly to 51.86 ± 17.26 in group I vs 31.99 ± 9.26 in group II (P < 0.001). Before treatment, 11 (73.3%) and 4 (26.7%) patients in each group had moderate and poor quality of life (QoL), respectively. After treatment, 6 (40%) and 14 (93.3%) had good QoL, 7 (46.7%) and 1 (6.7%) had moderate QoL in GI and GII, respectively. Two (13.3%) patients in GI had poor QoL. The mean frequency was reduced to 8.60 ± 0.83 vs 10.60 ± 2.32 for GII and GI respectively (P = 0.006). The cystometric capacity increased from 263.40 ± 50.45 to 377.80 ± 112.92 mL (P = 0.001) for GII vs 250.13 ± 56.24 to 296.40 ± 99.0 mL (P = 0.026) for GI., Conclusion: TPTNS combined with low dose trospium chloride proved to be more effective than TPTNS alone in the treatment of OAB in females., (© 2017 Wiley Periodicals, Inc.)

Surgery is often necessary after failure of conservative therapy for urinary incontinence. Guidelines recommend urodynamic studies before surgery. A distinction is made between non-invasive (uroflowmetry) and invasive methods (cystometry and pressure-flow study, if necessary as combined videourodynamics, as well as urethral pressure profile). All examinations serve to objectify and quantify the symptoms, to correctly assign symptoms to the pathophysiology and anatomy as well as to identify risk factors, which often have a significant influence on the success of surgical therapy. Given appropriate experience, complications and often significant sequelae of bladder dysfunction affecting the patient's quality of life and life expectancy can be recognized. Urodynamic studies are performed to help narrow down potential diagnoses, to develop therapeutic strategies, and to obtain prognostic parameters. The following article is intended to provide some support.

Purpose: To investigate the effect of trospium chloride, which has an anticholinergic effect, used in overactive bladder (OAB) treatment on the intraocular pressure (IOP) and tear secretion after 12 weeks of treatment., Materials and Methods: This prospective study was performed at a single center between October 2014 and January 2016. A detailed history was obtained from the female OAB patients at the eye outpatient department. After checking the exclusion criteria, oral trospium chloride 30 mg bd was started. The patients were followed-up in terms of drug effectiveness and ophthalmic and other side effects at the 4th and 12th weeks. All procedures were repeated at both of these time-points., Results: The mean age of the patients was 48.98 ± 11.98 years (range 19-75). The data of 80 OAB patients were evaluated in the study. Trospium chloride did not cause any significant change in the OAB patients regarding their 4th week and 12th week IOP measurements (p = 0.251, p = 0.340, respectively). It was found to decrease tear secretion significantly at both time-points (p = 0.020, p = 0.001, respectively). Trospium chloride treatment of one patient (1.25%) was discontinued due to dry eye., Conclusions: Trospium chloride decreases the symptoms in female OAB patients. Trospium chloride can be safely used in female OAB patients with normal IOP and no comorbidity as regards IOP changes as it did not cause a significant change in IOP in these patients. Pre-treatment and post-treatment dry eye symptoms of OAB patients about to start using trospium chloride should be queried beforehand as it can cause a statistically significant decrease in tear secretion. We concluded that it would be appropriate to refer the patients to an ophthalmologist before starting the drug if relevant symptoms are present.

Objective: To compare the efficacy of combination therapy with an alpha-blocker and an anticholinergic to monotherapy with an alpha blocker on lower urinary tract symptoms (LUTS) following brachytherapy in prostate cancer patients., Material and Methods: A total of 124 patients that had been clinically diagnosed with localized prostate cancer and underwent prostate brachytherapy were enrolled in the present study. Patients were randomized and allocated to two groups, including 60 to the combination group (tamsulosin 0.2 mg/day and trospium chloride 20 mg twice daily) and 64 to the monotherapy group (tamsulosin 0.2 mg/day). Treatment began 1 day after brachytherapy and continued for 6 months. LUTS were compared between the two groups using the total International Prostate Symptom Score (IPSS), storage and voiding IPSS subscores, quality of life (QoL) scores, maximum flow rate (Qmax), and postvoid residual (PVR) urine volume at 1, 3, 6, and 12 months after implantation., Results: In all, 111 patients were ultimately analyzed in the study. Compared with pretreatment scores, a significant increase in total IPSS was found at 1, 3, and 6 months in both groups, but no statistically significant differences were observed between the two groups. The combination therapy group showed a greater decrease in the IPSS storage score compared with the monotherapy group at 1, 3, and 6 months (p = 0.031, 0.030 and 0.042, respectively). Patients receiving tamsulosin plus trospium chloride also showed significant improvements in QoL at 1 and 3 months compared with tamsulosin alone (P = 0.039, P = 0.047). Between the two groups, there was no significant difference in IPSS voiding score, Qmax, and PVR from baseline to each point of the study period., Conclusions: Combination therapy with tamsulosin and trospium chloride helped to improve IPSS storage symptoms and Qol scores in prostate brachytherapy patients with LUTS compared with tamsulosin monotherapy.

Purpose: We aimed to compare the safety and efficacy of solifenacin versus trospium chloride and compare each drug versus placebo regarding the relief of stent-related symptoms following uncomplicated ureteroscopic lithotripsy (URSL)., Methods: In a prospective, randomized, double-blind study, 210 eligible patients who underwent URSL with double-J stent insertion were recruited and randomly assigned to either the first group, receiving solifenacin (10 mg), second group, receiving trospium chloride (60 mg), or the third group, receiving placebo (one tablet). All patients were kept on study medication once daily during the entire 2-week postoperative period. All subjects were asked to complete a brief-form questionnaire to assess the lower urinary symptoms, stent-related body pain and hematuria, preoperatively and 2 weeks postoperatively., Results: There were no statistically significant differences among the study groups in terms of mean age, gender, anthropometric measurements, stone and stent criteria. The overall symptom score, urgency, urge incontinence, flank pain, urethral pain and gross hematuria scores were significantly lower in solifenacin group compared to trospium chloride and placebo groups (p < 0.001). Concerning frequency and nocturia, there was no significant difference in mean scores across all groups. Drug-related side effects, particularly constipation, were higher in trospium group than in solifenacin one., Conclusions: Solifenacin treatment showed significant improvement in almost all domains of stent-related symptoms than trospium. In terms of safety and tolerance, both drugs were comparable. Future studies should be designed to address the impact of combined drugs and lower doses in the management of DJ stent-related symptoms.

Aims: We evaluated long-term efficacy and safety of a combination therapy (CT) with an anticholinergic agent and an α1-blocker for patients with benign prostatic enlargement (BPE) complaining of voiding and overactive bladder (OAB) symptoms, in comparison with those of α1-blocker monotherapy (MT), by conducting a urodynamic study (UDS)., Methods: This was a randomized prospective study involving 120 outpatients with untreated BPE associated with urinary urgency at least once per week and OABSS of ≥3. The patients were randomly assigned to receive MT with silodosin at 8 mg/day or CT with silodosin at 8 mg/day and propiverine at 20 mg/day. Changes in parameters from baseline to 12 weeks and 1 year after administration were assessed based on IPSS, IPSS-QOL, OABSS, and voiding and storage functions as measured by UDS., Results: In efficacy analysis, 53 patients with MT and 51 with CT were included. Although mean IPSS and OABSS significantly improved in both groups, the CT group showed statistically significant improvement in OABSS (-3.4 in CT, -2.4 in MT, P = 0.04), IPSS-QOL (-1.9, -1.2, P = 0.01), and OAB-urgency score (-1.8, -1.2, P < 0.01) at the long-term evaluation. In storage function, both groups showed significant improvements, but the CT group demonstrated a greater improvement in terms of disappearance rate of detrusor overactivity (54.5% in CT, 34.2% in MT, P = 0.07) and bladder capacity (+61 mL, +33 mL, P = 0.02)., Conclusions: Long-term combination treatment with silodosin and propiverine was effective and safe for BPE patients with voiding and OAB symptoms. Neurourol. Urodynam. 36:748-754, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Purpose: Study of validity of the Medication Adherence Self-Report Inventory (MASRI) for use in clinical practice to treat patients with benign prostatic obstruction (BPO) accompanied with overactive bladder (OAB) symptoms., Methods: During 12 weeks of the randomized study, 452 patients with BPO and OAB symptoms (mean age of 61.3 (12.7)) were studied for adherence to the treatment with Tamsulosin, Solifenacin and Trospium using the MASRI. External monitoring instruments included the Brief Medication Questionnaire (BMQ) and the visual remaining pill count. The state of the prostate gland and the lower urinary tract was monitored using questionnaires I-PSS, OAB Awareness Tool, uroflowmetry and voiding diaries., Result: Correlation between the percentage of men non-adherent to treatment (MASRI) and the percentage of patients having a belief barrier on the screen of the BMQ was r = 0.89, p ≤0.05, r = 0.92, p ≤0.01, r = 0.85, p ≤0.05, a number of missed doses on the Regimen Screen of the BMQ was r = 0.79; p ≤0.05; r = 0.81; p ≤0.05; r = 0.75, p ≤0.05, a number of non-adherent patients according to the BMQ was r = 0.83 (p ≤0.05), r = 0.88 (p ≤0.05), r = 0.79, p ≤0.05, the results of the pill count were r = 0.65-0.76; p ≤0.05-0.01. These data confirm high validity of the MASRI., Conclusion: The MASRI is a valid tool for rapid assessment of adherence to treatment of patients with BPO and OAB receiving Tamsulosin and antimuscarinic drugs and may be recommended for use in clinical practice.

Patients with spinal cord injury (SCI) usually develop lower urinary tract dysfunctions, including detrusor overactivity which is also known to be a risk factor for upper urinary tract dysfunction. Antimuscarinic agents, such as propiverine, have been used clinically for the treatment of detrusor overactivity. Also, propiverine has been known to possess antagonistic activity against L-type Ca 2+ channels and transient receptor potential vanilloid subtype 1 (TRPV1), in addition to activity against muscarinic receptors. These mechanisms of action may contribute to improving detrusor overactivity in SCI. We therefore investigated the effects of antagonists of these mechanisms on non-voiding contraction (NVC) in SCI rats that are similar to clinical cases of detrusor overactivity, and considered whether these action mechanisms contribute to the incidence of NVC in SCI. Cystometry was performed in rats 4 weeks after spinal transection. Urinary functions were evaluated before and after intravenous administration of propiverine and specific antagonists for muscarinic receptors (atropine), L-type Ca 2+ channels (verapamil), and TRPV1 (capsazepine). Propiverine markedly decreased the amplitude pressure of NVC in SCI rats, which was partially inhibited by atropine. Verapamil also suppressed the amplitude pressure of NVC to the same degree as propiverine. NVC disappeared almost completely after C-fiber desensitization, although capsazepine exerted no evident effects. These findings suggest that muscarinic receptors, L-type Ca 2+ channels, and C-fiber afferent nerves contribute to the incidence of detrusor overactivity in SCI, and a drug that has multiple antagonistic effects, such as propiverine, is very effective for the treatment of lower urinary tract dysfunctions in SCI., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: Evaluation of the efficacy and safety of different doses of trospium chloride in patients with idiopathic overactive bladder., Materials and Methods: Large-scale observational program "Resource" included 669 patients with idiopathic OAB - 359 women and 310 men. At the first visit, all patients were assigned to use of trospium chloride at a standard dose of 45 mg per day. The results of treatment were evaluated during follow-up visits at 3, 6, 9 and 12 weeks. Depending on the results of examination, the dose was reduced in the presence of adverse events and increased in case of insufficient treatment effects., Results: After 12 weeks, 102 patients have been receiving the drug at a dose of 30 mg/day, 241 - at a dose of 45 mg/day, 257 - at a dose of 60 mg/day, and 22 - at a dose of 75 mg/day., Conclusions: Individual approach to the selection of doses of trospium chloride in patients with idiopathic OAB can be quite effective and safe measure to achieve optimal clinical outcome with a good safety profile.

Objectives: To study the effectiveness and safety of combined standard-dosed Solifenacin and Trospium for management of symptoms of overactive bladder (OAB) in elderly patients after the treatment with Tamsulosin., Patients and Methods: A total of 417 men over 50 years of age (average age 57.9 (8.3)) with diagnosed prostatic obstruction (score 8-19 according to I-PSS), who had not taken Tamsulosin before, were enrolled in the study. I-PSS questionnaire (from 8 to 19 - moderate) and Awareness Tool questionnaire for evaluating OAB symptoms (total score for OAB symptoms over 8) were used at the beginning and at the end of the observation. Also, urodynamic parameters were examined., Result: Percentage of patients with prevalent symptoms of obstruction of urethra decreases after the treatment with Tamsulosin and then rises again (36.2%), but absolute number of patients remains smaller than initial data. Percentage of patients with relative prevalence of symptoms of overactive bladder slightly increases against administration of Tamsulosin and reaches initial values at the time of administration of anti-muscarinic drugs with absolute decrease in number of such patients., Conclusion: Combination of Trospium and Solifenacin is an effective way to manage residual symptoms of hyperactive bladder during treatment of early obstruction of urinary bladder.

Purpose: We carried out a systematic review and meta-analysis to assess the efficacy and safety of imidafenacin for treating overactive bladder in adult., Methods: A literature review was performed to identify all published randomized placebo-controlled trials of imidafenacin for the treatment of OAB. The search included the following databases: MEDLINE, EMBASE. The reference lists of retrieved studies were also investigated., Results: Five publications involving a total of 1,428 patients were used in the analysis, which compared imidafenacin with propiverine and solifenacin. We found that imidafenacin was effective in treating OAB in our meta-analysis, which was similar to propiverine in its efficacy. The mean number of UI per week (the standardized mean difference (SMD) = 1.23, 95% CI -0.19 to 2.65, p = 0.09), the mean number of urgency episodes per day (SMD = 0.26, 95% CI -0.11 to 0.63, p = 0.17), the mean number of micturitions per day (SMD = 0.01, 95% CI -0.30 to 0.31, p = 0.96), and the mean urine volume (ml) per micturition (SMD = -13.04, 95% CI -20.45 to -5.62, p = 0.0006) indicated that imidafenacin was similar to propiverine in its efficacy. Mean OABSS (SMD = 0.48, 95% CI -0.08 to 1.03, p = 0.09) indicated that imidafenacin was also similar to solifenacin in its efficacy. Besides, imidafenacin was better tolerated than propiverine in the safety, indicated by dry mouth (OR 0.73, 95% CI 0.54-0.98, p = 0.04) and any adverse events (OR 0.63, 95% CI 0.46-0.88, p = 0.006). Moreover, imidafenacin was also better tolerated than solifenacin in the safety, indicated by constipation (OR 0.21, 95% CI 0.08-0.53, p = 0.001) and any adverse events (OR 0.33, 95% CI 0.15-0.71, p = 0.004)., Conclusions: This meta-analysis indicates that imidafenacin was similar to propiverine or solifenacin in its efficacy for OAB and was better tolerated than propiverine or solifenacin in the safety for OAB. We conclude that imidafenacin is preferable to propiverine or solifenacin from a perspective of safety.

Objectives: To investigate whether the anticholinergic agent, propiverine hydrochloride, is clinically effective for stress urinary incontinence., Methods: The participants were adult female patients with the chief complaint of stress incontinence. Propiverine (20 mg once daily) was given for 8 weeks. If the response was inadequate after 4 weeks of treatment, the dose was increased to 40 mg/day. Before and after 4 and 8 weeks of treatment, lower urinary tract symptoms were assessed. The urethral pressure and blood catecholamine levels were also measured., Results: A total of 37 patients (mean age 69 ± 11 years) were enrolled, including 15 patients with stress incontinence and 22 with mixed incontinence. The number of episodes of stress incontinence decreased significantly from 2.6 ± 2.3 times per day to 1.3 ± 2.2 times per day after 4 weeks, and 0.4 ± 0.6 times per day after 8 weeks. The daytime and night-time frequency of urination, and quality of life score showed significant improvement. The maximum urethral closing pressure and the functional urethral length increased significantly after treatment, but blood catecholamine levels, blood pressure and pulse rate at 8 weeks were not significantly different from those at baseline., Conclusions: Propiverine could be an effective drug for stress urinary incontinence by increasing urethral closing pressure without increasing blood catecholamine levels., (© 2014 The Japanese Urological Association.)

Objectives: To evaluate the efficacy of anticholinergic agents in the treatment of neurogenic overactive bladder (NOAB) and neurogenic detrusor overactivity (NDO) in spinal cord injury (SCI) patients on clean intermittent catheterisation (CIC)., Methods: Chronic suprasacral SCI patients on CIC presenting with at least one urinary leakage a day were included. Urodynamics and voiding diaries were performed at baseline and 1 month follow-up. In case of NDO at baseline, an anticholinergic drug was prescribed., Results: The 231 SCI patients presented with one to five urinary leakages per day (mean 2.1). Urodynamics showed NDO in all patients. A new anticholinergic treatment was started in all, either in monotherapy (134 patients) or in association with the existing anticholinergic drug (oxybutynin+trospium bitherapy, 97 patients). The mean maximum bladder capacity significantly increased from 225 to 441 ml, and the mean involuntary detrusor contractions (IDC) significantly decreased from 67 to 41 cm H2O. Only 75 SCI patients (32%) were fully continent. However, 25 out of these 75 patients showed persistent NDO, with amplitudes of IDC above 40 cm H2O in 12 patients. Incontinence was still found in 156 SCI patients (67%), with an average of 1,2 leakages a day. In 100 patients, amplitudes of IDC remained above 40 cm H2O. There was no statistical difference between patients on anticholinergic monotherapy or bitherapy at follow-up., Conclusion: Anticholinergic treatment is not always satisfactory in terms of control of NDO and rarely allows full continence. Urodynamic follow-up is mandatory in all patients, even in those showing clinical continence.

Idiopathic pulmonary fibrosis is thought to involve lung injury caused by reactive oxygen species (ROS), which in turn is followed by abnormal fibrosis. A transforming growth factor (TGF)-β1-induced increase in myofibroblast number plays an important role in this abnormal fibrosis. We recently found that mepenzolate bromide (mepenzolate), which has been used clinically to treat gastrointestinal disorders, has ROS-reducing properties. In the present study, we examined the effect of mepenzolate on bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. The severity of pulmonary fibrosis was assessed by histopathologic evaluation and determination of hydroxyproline levels. Lung mechanics (elastance) and respiratory function [forced vital capacity (FVC)] were assessed using a computer-controlled ventilator. Respiratory function was also evaluated by monitoring percutaneous arterial oxygen saturation (SpO2). Intratracheal administration of mepenzolate prior to bleomycin treatment reduced the extent of pulmonary fibrosis and changes in lung mechanics and led to a significant recovery of both FVC and SpO2 compared with control. Furthermore, mepenzolate produced a therapeutic effect even when it was administered after the development of fibrosis. Administration of mepenzolate also prevented bleomycin-induced pulmonary cell death and inflammatory responses and increased myofibroblast number. Mepenzolate also decreased NADPH oxidase activity and active TGF-β1 level or increased glutathione S-transferase (GST) activity in the presence of bleomycin treatment. These results show that the intratracheal administration of mepenzolate reduced bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. These effects may be due to this drug's inhibitory effect on NADPH oxidase and TGF-β1 activities and its stimulatory effect on GST., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)

Objective: To carry out a cost-utility analysis comparing initial treatment of patients with overactive bladder (OAB) with solifenacin 5 mg/day versus either trospium 20 mg twice a day or trospium 60 mg/day from the perspective of the German National Health Service., Methods: A decision analytic model with a 3 month cycle was developed to follow a cohort of OAB patients treated with either solifenacin or trospium during a 1 year period. Costs and utilities were accumulated as patients transitioned through the four cycles in the model. Some of the solifenacin patients were titrated from 5 mg to 10 mg/day at 3 months. Utility values were obtained from the published literature and pad use was based on a US resource utilization study. Adherence rates for individual treatments were derived from a United Kingdom general practitioner database review. The change in the mean number of urgency urinary incontinence episodes/day from after 12 weeks was the main outcome measure. Baseline effectiveness values for solifenacin and trospium were calculated using the Poisson distribution. Patients who failed second-line therapy were referred to a specialist visit. Results were expressed in terms of incremental cost-utility ratios., Results: Total annual costs for solifenacin, trospium 20 mg and trospium 60 mg were €970.01, €860.05 and €875.05 respectively. Drug use represented 43%, 28% and 29% of total costs and pad use varied between 45% and 57%. Differences between cumulative utilities were small but favored solifenacin (0.6857 vs. 0.6802 to 0.6800). The baseline incremental cost-effectiveness ratio ranged from €16,657 to €19,893 per QALY., Limitations: The difference in cumulative utility favoring solifenacin was small (0.0055-0.0057 QALYs). A small absolute change in the cumulative utilities can have a marked impact on the overall incremental cost-effectiveness ratios (ICERs) and care should be taken when interpreting the results., Conclusion: Solifenacin would appear to be cost-effective with an ICER of no more than €20,000/QALY. However, small differences in utility between the alternatives means that the results are sensitive to adjustments in the values of the assigned utilities, effectiveness and discontinuation rates.

Purpose: The efficacy and safety of treatment with alfuzosin 10 mg plus propiverine 10 or 20 mg in men with lower urinary tract symptoms (LUTS) and an overactive bladder were investigated., Materials and Methods: In this parallel-arm, prospective, multicentre, single-blind study, men who were ≥ 40 years old, had an International Prostate Symptom Score (IPSS) of ≥ 8, an Overactive Bladder Symptom Score (OABSS) of ≥ 3 and an OABSS urgency item score of ≥ 2 were randomised in a 1 : 1 :1 ratio to receive alfuzosin 10 mg alone (Group A) or with propiverine 10 mg (Group B) or 20 mg (Group C) for 8 weeks. Four and 8 weeks after commencing treatment, OABSS was measured along with IPSS, maximal urinary flow rate (Qmax ) and postvoid residual volume (PVR). Adverse events were recorded., Results: A total of 135 men, including 43 in Group A, 48 in Group B and 44 in Group C, completed the study. Relative to baseline, all groups demonstrated significant reductions in OABSS and the IPSS after eight treatment weeks (p < 0.005). The improvement of OABSS in Group C was significantly greater than Group A and B (Group A: 0.70 ± 1.94; Group B: 2.50 ± 2.98; Group C: 4.30 ± 3.40; p < 0.005). An observed improvement of Qmax and PVR in the three groups did not achieve statistical significance. Overall adverse event rates were higher in Group C but not significant compared with others., Conclusion: In patients with LUTS and overactive bladder, combined therapy with alfuzosin 10 mg plus propiverine 20 mg was significantly more effective than alfuzosin monotherapy and propiverine 10 mg combined therapy in terms of improving OABSS while not significantly affecting Qmax or PVR., (© 2014 John Wiley & Sons Ltd.)

The objectives of the current study were to investigate the influence of denaverine hydrochloride and carbetocin on softening and dilatation of the birth canal, the need for assistance during parturition, calf mortality, retention of fetal membranes, endometritis, and subsequent fertility. Altogether 200 animals (100 cows and 100 heifers) of the Simmental breed were divided into 2 groups: treatment (n = 100) and control (n = 100). Animals in the treatment group received denaverine hydrochloride and carbetocin (a maximum of twice for each, depending on the progression of labor) during delivery over a maximum of 4 waiting periods (30 min each), whereas control animals experienced the same waiting periods but received no treatment. The treatment protocol had a positive influence on the ease of calving and postpartum reproductive health. The treatment increased the number of animals with the birth canal dilated by more than 25 cm, and halved the need for any assistance at parturition. In addition, treatment decreased the occurrence of difficult calving, the need for episiotomy, the appearance of birth canal lesions, and clinical endometritis. The treatment protocol had an effect throughout the entire puerperal period, as treated animals conceived with fewer artificial inseminations (1.3 vs. 1.6 artificial inseminations/pregnancy) and sooner (67 vs. 78 d open) compared with control animals. Denaverine hydrochloride and carbetocin administered in combination during parturition affected the progression and ease of calving, and thus the welfare of cows in labor and subsequently. However, further studies are needed to confirm the findings and to establish best practices., (Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the long term efficacy and safety of the use of propiverine and terazosine combination in patients with LUTS and DO by a placebo controlled study., Materials and Methods: One hundred patients were enrolled in the study. They were randomized into two groups (each group consisted of 50 patients). Terazosine and placebo were administered to the patients in Group 1 and terazosine plus propiverine HCL was administered to Group 2. The patients were evaluated by international prostate symptom score (IPSS), the first four questions of IPSS (IPSS4), the 8th question of IPSS (quality of life-QoL), overactive bladder symptom score questionnaire (OAB-q V8), PSA test, urodynamic studies, post voiding residue (PVR). All patients were followed for one year and were reassessed for comparison., Results: IPSS, IPSS4, OAB symptoms, QoL score, PVR, and Qmax scores of the groups did not differ. After one year treatment, there was significant improvement in IPSS, IPSS4, OAB symptoms, QoL and Qmax values in Group 2. No significant improvement was noted for the same parameters in Group 1., Conclusion: This is the first study to show long term safety and efficacy of anticholinergic therapy for patients with LUTS. In patients with OAB or DO, long term anticholinergic treatment may be regarded as a treatment option.

Objective: To examine the efficacy of trospium chloride and tolterodine on the renal parenchymal inflammatory process and upper urinary dilation in rats with chronic partial upper urinary tract obstruction., Materials and Methods: A total of 32 rats were divided into 4 groups: group 1, control; group 2, obstruction; group 3, obstruction plus tolterodine; and group 4, obstruction plus trospium chloride. In all groups, except for group 1, partial upper urinary tract obstruction was induced by embedding the upper quarter of the right ureter into the psoas muscle for 14 days. At the end of the experiment, the rats were killed. The catalase, malondialdehyde, and protein carbonyl levels were determined in renal tissue. Tubular dilation and parenchymal inflammation were evaluated using hematoxylin-eosin staining. Smooth muscle actin and cytoglobin were examined with immunohistochemical staining., Results: The obstruction group demonstrated severe pelvic dilation and parenchymal inflammation and increased smooth muscle actin staining in the wall of upper urinary tract (P <.05). The treatment of the rats with tolterodine and trospium chloride markedly attenuated the inflammatory alterations and reduced tubular dilation. This treatment also reduced elevated oxidative stress product levels and restored the depleted renal antioxidant enzyme., Conclusion: These findings imply that increased renal pelvic pressure can contribute to renal parenchymal injury in chronic pelvic upper urinary tract obstruction. Antimuscarinic medications such as tolterodine and trospium chloride exert renoprotective effects, probably by prevention of pelvic pressure increases., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Introduction and Hypothesis: Anticholinergics are used to treat overactive bladder. Anticholinergic agents such as propiverine hydrochloride reportedly increase plasma catecholamine levels in rats. It is also known that active urethral closure mechanisms prevents stress urinary incontinence (SUI), which is enhanced by central and peripheral noradrenergic system activation. Therefore, we examined the influence of propiverine hydrochloride on urethral anti-incontinence function in rats., Methods: Adult female rats were divided into propiverine and vehicle-treated groups. The propiverine group was given propiverine orally once a day for 2 weeks, after which urethral function and plasma concentrations of catecholamine (dopamine, norepinephrine, epinephrine) were tested., Results: Urethral baseline pressure measured by a microtransducer-tipped urethral catheter and leak-point pressure during passive intravesical pressure elevation were significantly increased in the propiverine group compared with the vehicle group. Plasma norepinephrine and epinephrine levels in the propiverine group were also significantly increased., Conclusions: Propiverine treatment that increases plasma catecholamine levels could contribute to improvement of SUI conditions by increasing urethral resistance.

Purpose: The aim of this study is to evaluate the efficacy and the tolerability of three classic antimuscarinic drugs used in the treatment of over active bladder syndrome using clinical data and quality of life tests, and to evaluate the parameters affecting the success of these drugs., Methods: A total of 90 patients with urge urinary incontinence were randomly allocated into three groups either to receive tolterodine (group A), trospium chloride (group B) or oxybutynin (group C). Urogenital distress inventory short form (UDI-6) and Incontinence impact questionnaire short form (IIQ-7) of the Turkish Urogynecology and Pelvic Reconstructive Surgery Association were performed to each patient before and after treatment to evaluate the effectiveness and tolerability of the antimuscarinic drugs. Adverse events were also recorded during treatment., Results: Improved urodynamic test values were recorded after 6 weeks of treatment in each group. Similarly, statistically significant differences were observed in UDI-6 and IIQ-7 test scores before and after treatment. Complete cure was achieved in 86 % of patients in group A; however, complete cure rates were 67 and 80 % in group B and C, respectively. Although, patients reported comparable tolerability against trospium chloride (77 %) and tolterodine (80 %), only 23 % of patients using oxybutynin considered the drug as tolerable. The most common side effect was dry mouth, followed by insomnia. Both dry mouth and insomnia was highest in group C (50 %). One patient (0.3 %) in group B and two patients (0.7 %) in group C reported that they did not want to continue to use the drug., Conclusion: Antimuscarinic medications are very successful in the treatment of urge urinary incontinence; however, the success of treatment is not only limited to clinical improvement. Patients do not regard a drug as successful unless it is tolerable, easy to adapt to the daily life and improve the quality of life even it has very successful clinical outcomes.

Background: Overactive bladder is a common disorder that affects approximately 34 million adults in the United States. Anticholinergic (antimuscarinic) agents are the most widely used pharmacological option for overactive bladder., Objective: This study set out to identify and characterize the influence of a number of intrinsic characteristics on the pharmacokinetics of the anticholinergic agent trospium chloride (Sanctura(®)) 60 mg extended release (XR), and to evaluate the correlation between trospium chloride exposure and key efficacy and safety outcomes in subjects and patients., Study Design: Pharmacokinetic data were obtained from three studies in which a total of 349 subjects received trospium chloride XR for up to 12 weeks. Plasma trospium chloride concentration data were pooled and a population pharmacokinetic model was derived using non-linear mixed-effects modelling. Demographic factors were assessed for influence on the model. The correlation between trospium chloride exposure and key efficacy variables was evaluated. Correlations between exposure and safety outcomes were also assessed., Intervention: Trospium chloride XR 60 mg once daily for 10 days in healthy volunteers or trospium chloride 60 mg XR once daily for either 2 weeks or 12 weeks in patients with overactive bladder., Results: The best population pharmacokinetic model was determined to be a two-compartment model with zero-order release into the depot compartment and first-order absorption. Body surface area (BSA) was the only covariate to significantly (P < 0.05) impact trospium chloride 60 mg XR pharmacokinetics. Significant relationships (P < 0.05) were observed between exposure [maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve from time zero to 24 h (AUC(24))] and efficacy outcomes in the <65-year age group for change in average number of voids/day, change in number of incontinence episodes, and change in urgency severity, and in the ≥65-year age group statistical significance (P < 0.05) was achieved for C(max), but not for AUC(24), for these same three efficacy measures. Statistically significant relationships (P < 0.004) were also observed between exposure and both dry mouth and constipation, with increased benefit and increased incidence of adverse events (AEs) associated with higher concentrations; the correlation coefficients were low against the aggregate of AEs of interest (0.19 for AUC(24) and 0.18 for C(max)), indicating only mild strength of association., Conclusion: This population pharmacokinetic analysis demonstrated that the only demographic characteristic associated with trospium chloride pharmacokinetics was BSA. Thus, treatment of most patients with overactive bladder with once-daily trospium chloride 60 mg XR should not require consideration of key intrinsic demographic parameters. Furthermore, while efficacy and tolerability outcomes were found to be correlated with trospium chloride exposure, the strength of the association was modest in this study.

Propiverine is a well established antimuscarinic agent with a mixed mode of action in the treatment of symptoms associated with overactive bladder (OAB). As well as blocking muscarinic receptors in the detrusor muscle, the drug also inhibits cellular calcium influx, thereby diminishing muscle spasm. In patients with symptoms of OAB resulting from idiopathic detrusor overactivity (IDO) or neurogenic detrusor overactivity (NDO), propiverine demonstrated dose-dependent efficacy and tolerability, with adverse events consistent with those associated with all antimuscarinic agents. In adults with IDO, propiverine demonstrated similar efficacy to that of other antimuscarinic agents (including solifenacin, tolterodine, oxybutynin and imidafenacin) and, in adults with NDO, propiverine and oxybutynin demonstrated similar efficacy. Propiverine was generally well tolerated in these patient populations, with a lower incidence of dry mouth than that associated with oxybutynin. In men with lower urinary tract symptoms (LUTS), and in whom the presence of benign prostatic enlargement (BPE) was implicated, propiverine administered as add-on therapy to an α(1)-adrenoceptor antagonist demonstrated similar or superior efficacy to that achieved with an α(1)-adrenoceptor antagonist alone, and combination therapy was particularly effective in patients with urinary storage symptoms. Combination therapy was generally well tolerated, but was associated with a higher incidence of adverse events than an α(1)-adrenoceptor antagonist alone. In children and adolescents with IDO/OAB or NDO, propiverine was generally more effective and better tolerated than oxybutynin. In conclusion, propiverine provides a valuable option for the treatment of adults and children with OAB associated with IDO or NDO, and in men with storage LUTS.

Introduction: Antimuscarinics (AMs) are the mainstay of pharmacological treatment of overactive bladder (OAB), a symptom complex defined by the presence of urinary urgency, usually associated with frequency and nocturia, with or without urgency urinary incontinence. The AMs used to treat OAB differ in their pharmacological profiles, which may affect their potential for causing adverse effects (AEs)., Areas Covered: The present article aims to review the literature about pharmacokinetics (PK) of the different AMs used in the treatment of OAB. Furthermore, the AEs related to the use of these drugs and their incidence are presented. This systematic review is based on material searched and obtained via Medline, Pubmed and EMBASE up to March 2012 using the search terms "adverse events, pharmacokinetics, tolerability" in combination with "darifenacin, fesoterodine, imidafenacin, oxybutynin, propiverine, solifenacin, tolterodine, and trospium.", Expert Opinion: Antimuscarinics are the first-line pharmacological treatment for OAB. Despite the development of new molecules that improve their efficacy/safety profile, there are some drugs that are pharmacokinetically more appropriate to be prescribed in specific populations such as patients with neurological disease or the elderly. Moreover, research should be encouraged in evaluating antimuscarinics in conjunction with other drugs such as estrogens or beta-agonists. The identification of prognostic criteria for pharmacological therapy would be helpful.

Objective: To evaluate prospectively the efficacy and tolerability of propiverine for long-term treatment of neurogenic detrusor overactivity (NDO) in children., Materials and Methods: 17 children and adolescents with NDO (10 female, 7 male; average age at last consultation 13.0 years) were evaluated during long-term treatment with propiverine (0.8 mg/kg body weight/day). Outcome measurements included urodynamic parameters, continence, hydronephrosis and tolerability of propiverine., Results: Average follow-up was 3.6 years (range 2.0-5.9). The average maximum detrusor pressure was 33.2 ± 4.8 cmH(2)O and bladder compliance was 20.0 ± 5.4 ml/cmH(2)O at the last follow-up visit. Maximum cystometric bladder capacity (MCBC) within the normal range was attained in 11 patients; it was still reduced (average of 61% of expected MCBC) in the remaining 6. Incontinence occurred on average once per day. Hydronephrosis was classified for each renal unit separately: grade 0 was measured in 26 and 22 cases, grade 1 or 2 in 6 and 8 cases, grade 3 or 4 in 2 and 4 cases pre and post treatment, respectively. In 6/17 patients adjuvant intravesical oxybutynin was applied, in 4 out of these 6 patients more invasive procedures, such as untethering, augmentation cystoplasty or botulinum toxin injections, were necessitated. Propiverine monotherapy was well tolerated in 11/17 patients. No serious adverse events were encountered during the study period., Conclusion: Long-term efficacy and tolerability of propiverine for NDO in children and adolescents is promising: clinically relevant improvements in key urodynamic outcomes were paralleled by improvements in incontinence score., (Copyright © 2011 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

It is not uncommon for patients with spinal cord injury to have both detrusor overactivity during the storage phase and detrusor underactivity during the voiding phase. However, there has been no information about the efficacy of combined treatment with cholinesterase inhibitors and anti-muscarinic agents for this condition. Therefore, the effect of co-administration of distigmine bromide (a cholinesterase inhibitor) and propiverine hydrochloride (an anti-muscarinic agent) on bladder activity was examined in rats with spinal cord injury. Rats were anesthetized with isoflurane and the lower thoracic spinal cord was transected. The bladder was emptied by abdominal compression twice a day for 14 days after surgery. A total of 4 weeks after surgery, the animals were anesthetized with urethane, and the effect of intravenous injection of distigmine (0.01-1 mg/kg) followed by propiverine (1 mg/kg) on continuous cystometry parameters was examined. After injection of distigmine (0.1 and 1 mg/kg), the maximum bladder contraction pressure was significantly increased, and the duration of bladder contraction and the interval between bladder contractions were significantly prolonged. The baseline bladder pressure was not changed by injection of distigmine. After the addition of propiverine, the interval between bladder contractions was significantly further prolonged without any change of the maximum contraction pressure, baseline pressure or duration of bladder contraction. The residual volume after voiding bladder contraction was less than 0.1 mL in all animals. In conclusion, co-administration of distigmine with propiverine might improve both bladder underactivity during the voiding phase and bladder overactivity during the storage phase., (© 2012 The Japanese Urological Association.)

Objectives: To provide an overview on the efficacy, tolerability, safety and health-related quality of life (HRQoL) of drugs with a mixed action used in the treatment of overactive bladder (OAB)., Evidence Acquisition: MEDLINE database and abstract books of the major conferences were searched for relevant publications from 1966 to 2011 and using the key words 'overactive bladder', 'detrusor overactivity', 'oxybutynin', 'propiverine', and 'flavoxate'. Two independent reviewers considered publications for inclusion and extracted relevant data, without performing a meta-analysis., Evidence Synthesis: Old and conflicting data do not support the use of flavoxate, while both propiverine and oxybutynin were found to be more effective than placebo in the treatment of OAB. Propiverine was at least as effective as oxybutynin but with a better tolerability profile even in the pediatric setting. Overall, no serious adverse event for any product was statistically significant compared to placebo. Improvements were seen in HRQoL with treatment by the oxybutynin transdermal delivery system and propiverine extended release., Conclusions: While there is no evidence to suggest the use of flavoxate in the treatment of OAB, both oxybutynin and propiverine appear efficacious and safe. Propiverine shows a better tolerability profile than oxybutynin. Both drugs improve HRQoL of patients affected by OAB. Profiles of each drug and dosage differ and should be considered in making treatment choices., (Copyright © 2012 S. Karger AG, Basel.)

Objective: To assess the responsiveness and minimal clinically important change (MCIC) in the Overactive Bladder Symptom Score (OABSS), a single score used to quantify overactive bladder symptoms., Methods: The data were derived from a clinical trial of propiverine in patients with overactive bladder. The analysis included participants who completed the OABSS, a bladder diary, and patient-reported outcome measures (urgency and incontinence impact) at baseline and 12 weeks. Responsiveness was assessed with effect sizes, correlations between the OABSS items and bladder diary variables, and comparisons between the score changes and symptom improvement. The MCIC was comprehensively estimated from the discriminating thresholds for minimal symptom improvement, and the receiver operating characteristics curve analyses were used to derive cutoff scores for symptom improvement., Results: A total of 282 participants were included in the present analysis. The effect sizes for the OABSS ranged from -0.369 to -1.485, and correlations between the changes in the OABSS items and the corresponding bladder diary variables were moderate to large. A linear tendency was found between the changes in the OABSS and symptom improvement. The mean change for urgency and incontinence impact was -2.59 and -2.49 for "no change" and -3.67 and -3.78 for "minor improvement," respectively. The optimal cutoff score ranged from -4 to -3. Integrating the MCIC analyses, -3 was estimated as the minimal threshold for a meaningful change., Conclusion: With good responsiveness, the OABSS is a useful tool for assessing the treatment of OAB symptoms. Furthermore, the results of our study suggest that the MCIC of the OABSS is -3., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aims: To evaluate the relationship between treatment-related changes in Overactive Bladder Symptom Scores (OABSS) and health-related quality of life (HRQOL) questionnaires., Methods: Ninety-five patients with OAB symptoms were enrolled. All patients completed the OABSS, International Prostate Symptom Score (IPSS)-Quality Of Life (QOL) index and King's Health Questionnaire (KHQ) at enrollment and then again 4, 8, and 12 weeks after treatment with propiverine hydrochloride 10 mg twice daily. We evaluated the relationship between treatment-related changes in the OABSS, IPSS-QOL, and KHQ., Results: Statistically significant improvements were observed in all 4 OABSS subscales and total OABSS from baseline to 4 weeks with further improvements occurring at 12 weeks (all P < 0.01). The OABSS after antimuscarinic treatment correlated positively with both the IPSS-QOL index and KHQ domain scores. There was a moderate but statistically significant correlation between the change in total OABSS and 2 OABSS subscales (urinary urgency and urge incontinence) and improvement in the IPSS-QOL index (P < 0.01). Treatment-related changes in total OABSS were significantly correlated with changes in six KHQ domains. Moderate but statistically significant correlations were observed between the change in total OABSS and impact on life, physical limitations, emotions, and severity measures (r > 0.30, P < 0.05). Small but statistically significant correlations were observed between the change in total OABSS and role limitations or social limitations (P < 0.05)., Conclusions: Improvement in the OABSS correlated with improvements in HRQOL after treatment. The OABSS is a useful tool to evaluate OAB symptom severity after medical treatment., (Copyright © 2011 Wiley-Liss, Inc.)

Background: Urinary incontinence (bedwetting, enuresis) is the commonest urinary symptom in children and adolescents and can lead to major distress for the affected children and their parents. Physiological and non-physiological types of urinary incontinence are sometimes hard to tell apart in this age group., Methods: This article is based on selected literature retrieved by a PubMed search and on an interdisciplinary expert consensus., Results and Conclusion: Nocturnal enuresis has a variety of causes. The main causative factors in monosymptomatic enuresis nocturna (MEN) are an impaired ability to wake up when the bladder is full, due to impaired or absent perception of fullness during sleep, and an imbalance between bladder capacity and nocturnal urine production. On the other hand, non-monosymptomatic enuresis nocturna (non-MEN) is usually traceable to bladder dysfunction, which is also the main cause of diurnal incontinence. A basic battery of non-invasive diagnostic tests usually suffices to determine which type of incontinence is present. Further and more specific testing is indicated if an organic cause is suspected or if the treatment fails. The mainstay of treatment is urotherapy (all non-surgical and non-pharmacological therapeutic modalities). Some patients, however, will need supportive medication in addition. Urinary incontinence has different causes in children and adults and must therefore be diagnosed and treated differently as well. All physicians who treat the affected children (not just pediatricians and family doctors, but also pediatric nephrologists, urologists, pediatric surgeons, and child psychiatrists) must be aware of the specific features of urinary incontinence in childhood.

Objectives: The aim of this study was to investigate the efficacy and safety of propiverine for overactive bladder (OAB) in Japanese patients., Methods: In this multicentre, randomized, double-blind study, patients ≥ 20 years old with symptoms of OAB for ≥ 12 weeks were allocated to either propiverine (20 mg once daily) or placebo for 12 weeks. Efficacy and quality of life were assessed using a 7-day bladder diary, the OAB symptom score, and King's Health Questionnaire. Safety was mainly assessed by adverse events and the QTc interval., Results: A total of 567 patients were allocated. Change in number of micturitions/24 h was significantly greater in the propiverine group than in the placebo group (-1.86 vs-1.36, P = 0.001). Compared to placebo, propiverine produced significant improvements in urgency, urgency incontinence, urine volume/micturition, and the OAB symptom score. Significant improvements in urgency, urgency incontinence, and micturition frequency were observed at the first 4 weeks of treatment. All nine domains of King's Health Questionnaire were improved more with propiverine than with placebo. Adverse effects with propiverine were mostly mild, and no patient developed QTc interval prolongation exceeding 500 ms., Conclusion: Propiverine is effective for Japanese OAB patients by improving their symptoms and quality of life with a predictable side-effect profile., (© 2011 The Japanese Urological Association.)

Purpose: Comparison of efficacy of propiverine extended release (ER) 30 mg o.d. in the treatment of male OAB administered as monotherapy (MT) or add-on to α-blockers (combination treatment, CT) in relation to maximum urinary flow (Q(max)) in a non-interventional study., Methods: Men ≥40 years with OAB symptoms, Q(max) ≥10 ml/s, prostate volume <40 ml, post-void residuals (PVR) <100 ml, and IPSS <20 were included. OAB symptoms, IPSS, and PVR were recorded before and after 12 weeks of treatment. Participants were stratified by Q(max) (group A ≥15 ml/s, group B <15 ml/s) and CT vs. MT. Safety parameters were monitored., Results: A total of 2,219 men participated and were involved in safety analysis; 1,849 men (mean age 66 years) fulfilled the inclusion criteria and were involved in efficacy analysis. In group A, 291 men received MT and 479 CT; in group B, 184 men received MT and 895 CT. OAB symptoms improved significantly in all groups throughout the study without differences between MT and CT. IPSS improvement in group B was less with MT than with CT (-3.9 vs. -5.2; P < 0.001), whereas IPSS improvement was similar in group A (-4.6 vs. -5.1). Mean PVR change was not clinically relevant, but two men (0.1%) experienced urinary retention., Conclusions: Under real-life conditions, treatment of OAB symptoms with propiverine ER is equally effective in men with MT or CT regardless of baseline Q(max). In men with reduced Q(max), IPSS improvement is significantly smaller with MT. The incidence of urinary retention during propiverine ER treatment is low.

Objective: To assess the cost-effectiveness of solifenacin vs other antimuscarinic strategies commonly used in UK clinical practice, based on the results of a recent published review., Methods: Overactive bladder (OAB) syndrome is characterized by symptoms of urgency, frequency, incontinence and nocturia. Pharmacological treatment comprises oral antimuscarinic agents, which are divided into older-generation treatments, including oxybutynin, and new-generation treatments, comprising solifenacin, tolterodine, darifenacin and fesoterodine. The latter have reduced central nervous system penetration and have better selectivity for the M3 subclass of acetylcholine receptors, resulting in improved tolerability. A recent systematic review and meta-analysis of the efficacy and safety of antimuscarinics provided an opportunity for an economic evaluation of these agents using a rigorous assessment of efficacy. A cost-utility analysis was undertaken using a 1-year decision-tree model. Treatment success was defined separately for urgency, frequency and incontinence, with efficacy data taken from the recent review. Treatment persistence rates were taken from the Information Management System database. Utility values for the calculation of quality-adjusted life-years (QALYs) were taken from published sources. The analysis included costs directly associated with treatment for OAB, i.e. antimuscarinic therapy, consultations with general practitioners, and outpatient contacts. Resource use was based on expert opinion. Costs were reported at 2007/2008 prices. Extensive deterministic and probabilistic analyses were conducted to test the robustness of the base-case results., Results: Solifenacin was associated with the highest QALY gains (per 1000 patients) for all three outcomes of interest, i.e. urgency (712.3), frequency (723.1) and incontinence (695.0). Solifenacin was dominant relative to fesoterodine, tolterodine extended-release (ER) and tolterodine immediate-release (IR), and cost-effective relative to propiverine ER for urgency, frequency and incontinence. Solifenacin was not found to be cost-effective relative to oxybutynin IR for the frequency and incontinence outcomes, with an incremental cost-effectiveness ratio of > pound30,000/QALY threshold., Conclusions: Solifenacin provided the greatest clinical benefit and associated QALYs for all three outcomes of interest across all therapies considered, and to be either dominant or cost-effective relative to all other new-generation agents, but not cost-effective relative to oxybutynin for frequency and incontinence.

Objectives: Adenosine triphosphate (ATP) is released from bladder urothelium in response to stretch and may act as a sensory neurotransmitter. ATP release from the bladder urothelium is augmented in many pathophysiologic conditions, resulting in bladder overactivity. Patients who have bladder overactivity are treated with antimuscarinics with symptom improvement. We investigated the effects of oxybutynin and propiverine on bladder overactivity induced by intravesical instillation of ATP., Material and Methods: Under urethane anesthesia, cystometry was performed in female Sprague-Dawley rats. After a 2-hour baseline period, protamine sulfate (10 mg/mL) was instilled for 1 hour, and then ATP (60 mM, pH 6.0) was instilled intravesically. Oxybutynin, propiverine, pyridoxal-(5) phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), atropine, 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP), and methoctramine were given intravenously when ATP-induced bladder overactivity was stable., Results: When protamine sulfate was infused intravesically, the intercontraction interval (ICI) did not decrease significantly, but intravesical instillation of ATP after protamine sulfate treatment decreased the ICI compared with baseline. Oxybutynin, propiverine, and PPADS given intravenously reversed the ATP-induced ICI reduction in a dose-dependent manner. In contrast, ATP-induced ICI reduction was not reversed by intravenous atropine, 4-DAMP, or methoctramine. Maximum voiding pressure did not change with ATP but decreased with antimuscarinics. Pressure threshold (PT) decreased with ATP and stayed reduced after dose of oxybutynin or propiverine., Conclusions: Bladder overactivity induced by intravesical instillation of ATP with protamine pretreatment was suppressed by oxybutynin, propiverine, and PPADS, and not by atropine, 4-DAMP, and methoctramine. Oxybutynin and propiverine suppress ATP-induced bladder overactivity other than through antimuscarinic mechanisms., (Copyright 2010 Elsevier Inc. All rights reserved.)