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Objective To describe the surgical approach and outcomes in the treatment of adult patients with complications of childhood hypospadias surgery, as such patients present a significant reconstructive challenge due to the combination of anatomical and cosmetic deformity, which often results in major functional and psychosexual sequelae. Patients and methods We analysed prospectively collected data on 79 adults with complications of childhood hypospadias surgery, who were operated on between 2004 and 2016. Of the 79 patients, 48 underwent a two-stage urethroplasty using a buccal mucosa graft, and 31 underwent a one-stage distal urethroplasty. Results Patients were followed up using flexible cystoscopy (every 6-9 months). The mean (range) follow-up was 48 (12-96) months. Of the 48 patients who underwent a two-stage repair, eight (16%) needed a revision of the first-stage graft. In total, nine of the 48 patients (16%) developed fistula requiring closure after the second stage; all but one was closed successfully on the first attempt, whilst one required two attempts before closure. Only two of the 48 patients that underwent a two-stage procedure required a re-do urethroplasty within 3 years. Of the 31 patients who underwent a one-stage repair, six (19%) needed fistula closure, all of which were successful. No patient required a further urethroplasty during follow-up. Conclusions Despite the significant surgical challenges found in this patient group, excellent long-term functional outcomes can be achieved. As expected there is a need for additional intervention, either for revision of the first stage or to close fistulae and less commonly for further reconstruction for stricture recurrence.

Objectives To compare the efficacy of onabotulinumtoxinA, mirabegron, and anticholinergics in adults with idiopathic overactive bladder (OAB) using network meta-analysis (NMA). Subjects and Methods Information sources were searched for randomized blinded controlled trials, of at least 2 weeks duration, comparing any dose of onabotulinumtoxinA, eligible oral/transdermal anticholinergics, or mirabegron, with each other or placebo, in adults with OAB. Bayesian random-effects models were used to synthesize the results at week 12: NMA for responder analyses and network meta-regression (NMR) for change from baseline analyses. The NMR was used to adjust for differences in baseline severity between studies. Sensitivity analysis, excluding studies considered to be at a high risk of methodological bias, was conducted. Results 56 randomized trials were included in the networks. For each outcome, results are reported for all licensed treatment doses. For each NMR, results are based on patients with an average number of episodes of the outcome at baseline. After 12 weeks, all treatments are more efficacious than placebo. Patients who received onabotulinumtoxinA (100U) had, on average, the greatest reductions in urinary incontinence episodes (UIE), urgency, and micturition frequency, and the highest odds of achieving decreases of 100% and ≥50% in the daily number of UIE. When comparing onabotulinumtoxinA with other pharmacotherapies, mean differences favoured onabotulinumtoxinA 100U over all comparators for UIE and urgency (credible intervals excluded zero) and all but two of the comparators for micturition frequency. OnabotulinumtoxinA 100U was also associated with higher odds of achieving a 100% and ≥50% decrease in daily UIE than most other licensed treatments in the network. The exclusion of studies with a high risk of bias had little impact on the conclusions. Conclusion The results indicate that, after 12 weeks, onabotulinumtoxinA 100U provides greater relief of OAB symptoms compared with most other licensed doses of other pharmacotherapies in the network. This article is protected by copyright. All rights reserved.

Objective To evaluate efficacy and safety of silodosin in a pooled analysis of individual patient data from three registrational randomised controlled trials (RCTs) comparing silodosin and placebo in patients with lower urinary tract symptoms (LUTS). Patients and Methods A pooled analysis of 1494 patients from three 12-week, multicentre, double-blind, placebo-controlled phase III RCTs was performed. Efficacy and safety data were assessed across patients with different baseline characteristics. Results Silodosin was significantly more effective than placebo in improving all International Prostate Symptom Score (IPSS)-related parameters, and maximum urinary flow rate (Qmax) regardless of patients age (P < 0.041). Comparing the efficacy of silodosin in the different age groups, there were no differences for all the IPSS-related parameters, whereas Qmax improvement was slightly higher in patients aged

Objective To compare the long-term outcomes of a tension-free vaginal tape (TVT; Gynecare™, Somerville, NJ, USA), autologous fascial sling (AFS) and xenograft sling (porcine dermis, Pelvicol™; Bard, Murray Hill, NJ, USA) in the management of female stress urinary incontinence (SUI). Patients and Methods A multicentre randomised controlled trial carried out in four UK centres from 2001 to 2006 involving 201 women requiring primary surgery for SUI. The women were randomly assigned to receive TVT, AFS or Pelvicol. The primary outcome was surgical success defined as ‘women reporting being completely ‘dry’ or ‘improved’ at the time of follow-up’. The secondary outcomes included ‘completely dry’ rates, changes in the Bristol Female Lower Urinary Tract Symptoms (BFLUTS) and EuroQoL EQ-5D questionnaire scores. Results In all, 162 (80.6%) women were available for follow-up with a median (range) duration of 10 (6.6–12.6) years. ‘Success’ rates for TVT, AFS and Pelvicol were 73%, 75.4% and 58%, respectively. Comparing the 1- and 10-year ‘success’ rates, there was deterioration from 93% to 73% (P < 0.05) in the TVT arm and 90% to 75.4% (P < 0.05) in the AFS arm; ‘dry’ rates were 31.7%, 50.8% and 15.7%, respectively. Overall, the ‘dry’ rates favoured AFS when compared with Pelvicol (P < 0.001) and TVT (P = 0.036). The re-operation rate for persistent SUI was 3.2% (two patients) in the TVT arm, 13.1% (five) in the Pelvicol arm, while none of the patients in the AFS arm required further intervention. Conclusions Our study indicates there is not enough evidence to suggest a difference in long-term success rates between AFS and TVT. However, there is some evidence that ‘dry’ rates for AFS may be more durable than TVT.

Objective To validate the Bladder Control Self-Assessment Questionnaire (B-SAQ), a short screener to assess lower urinary tract symptoms (LUTS) and overactive bladder (OAB) in men. Patients and Methods This was a prospective, single-centre study including 211 patients in a urology outpatient setting. All patients completed the B-SAQ and Kings Health Questionnaire (KHQ) before consultation, and the consulting urologist made an independent assessment of LUTS and the need for treatment. The psychometric properties of the B-SAQ were analysed. Results A total of 98% of respondents completed all items correctly in

The term lower urinary tract symptoms (LUTS) encompasses a range of urinary symptoms, including storage symptoms (e.g. overactive bladder [OAB]) as well as voiding and post-micturition symptoms. Although treatment of male LUTS tends to focus on voiding symptoms, patients typically find storage symptoms the most bothersome. The core storage symptom is urgency, which drives the other main storage symptoms of increased daytime frequency, nocturia and incontinence. Although several validated questionnaires have been widely used to study urgency, few measure the two important storage parameters, urgency and frequency, in a single assessment. The total urgency and frequency score (TUFS) is a new validated tool that captures both variables and is derived from the Patient Perception of Intensity of Urgency Scale, which has been validated in patients with OAB and LUTS. The TUFS was first validated in OAB in the phase IIa BLOSSOM study, which was designed to assess the efficacy and safety of mirabegron, a β3 -adrenoceptor agonist, in 260 patients. The responsiveness of the TUFS to treatment has been confirmed in a further three large-scale randomized controlled trials of solifenacin in patients with OAB or LUTS. Changes in TUFS from baseline to end of treatment were consistent with changes in micturition diary variables in all four studies. Furthermore, the TUFS was significantly correlated with several health-related quality-of-life variables in the phase III NEPTUNE study. Thus, the TUFS appears to be useful for assessing improvements in major storage symptoms (urgency and frequency) in clinical trials.

Objectives To identify candidate materials which have sufficient potential to be taken forward for an in vivo tissue-engineering approach to restoring the tissue structure of the pelvic floor in women with stress urinary incontinence (SUI) or pelvic organ prolapse (POP). Materials and Methods Oral mucosal fibroblasts were seeded onto seven different scaffold materials, AlloDerm ( LifeCell Corp., Branchburg, NJ, USA), cadaveric dermis, porcine dermis, polypropylene, sheep forestomach, porcine small intestinal submucosa (SIS) and thermoannealed poly(L) lactic acid (PLA) under both free and restrained conditions. The scaffolds were assessed for: cell attachment using AlamarBlue and 4,6-diamidino-2phenylindole (DAPI); contraction using serial photographs; and extracellular matrix production using Sirius red staining, immunostaining and scanning electron microscopy. Finally the biomechanical properties of all the scaffolds were assessed. Results Of the seven, there were two biodegradable scaffolds, synthetic PLA and natural SIS, which supported good cell attachment and proliferation. Immunostaining confirmed the presence of collagen I, III and elastin which was highest in SIS and PLA. The mechanical properties of PLA were closest to native tissue with an ultimate tensile strength of 0.72 ± 0.18 MPa, ultimate tensile strain 0.53 ± 0.16 and Young's modulus 4.5 ± 2.9 MPa. Scaffold restraint did not have a significant impact on the above properties in the best scaffolds. Conclusion These data support both PLA and SIS as good candidate materials for use in making a tissue-engineered repair material for SUI or POP.

What's known on the subject? and What does the study add? Urethral amyloidosis is rare and urethrotomy has been proposed as a suitable treatment option. By reviewing the literature and comparing our own experiences, we have shown urethroplasty to have good medium term outcomes in patients with urethral amyloidosis, whereas urethrotomy may lead to recurrence. OBJECTIVE • Urethral amyloidosis (UA) is a rare condition which may be encountered by an urological surgeon. We reviewed the literature regarding the presentation, investigation and management of UA. PATIENTS AND METHODS • A systematic review of the English literature on PubMed was conducted and we indentified 39 articles which reported 45 patients. We included our experience with four patients from our tertiary centre. RESULTS • The majority of patients reported symptoms consistent with a urethral structure. Most patients were treated with urethrotomy, only two patients have been reported to have had a urethroplasty in the literature. Medium and long term outcome data is lacking for urethrotomy and urethroplasty. We found recurrence in our patients after urethromoty and incomplete resection of UA. We describe short (6 month) and medium term (18 month) outcomes in two patients who underwent augmentation urethroplasty. CONCLUSION • Although urethrotomy and dilatation have been proposed in the past, we found these may still lead to disease progression and therefore urethroplasty may be the most appropriate long term management option.

Objective • To examine the prevalence and burden of overactive bladder (OAB) with bother in the UK and Sweden compared to OAB without bother and no/minimal OAB/lower urinary tract (LUTS) symptoms, respectively. Patients and methods • A cross-sectional population-representative survey was conducted via the Internet in the UK, Sweden and USA. • Participants rated the frequency and bother of OAB and LUTS. Patient outcomes included the Overactive Bladder Questionnaire Short Form, Patient Perception of Bladder Condition, Short Form-12, Hospital Anxiety and Depression Scale-Anxiety and Hospital Anxiety and Depression Scale-Depression, as well as questions about treatment seeking and work productivity. • OAB was defined as urgency at least sometimes or the presence of urinary urgency incontinence. Three subgroups were compared: no/minimal symptoms, OAB without bother and OAB with bother. • Analyses were conducted by gender and country using general linear and logistic regression models to examine bothersome OAB and treatment seeking. Results • Survey response was 59.2%; 10,000 people (4724 men and 5276 women) participated. • The prevalence of OAB with bother at least 'somewhat' was 10.9% and 14.6% for men in the UK and Sweden, and 22.5% and 33.7% for women in the UK and Sweden, respectively. • Men and women with bothersome OAB were significantly more likely to seek treatment, report the lowest levels of health-related quality of life and work productivity and the highest levels of anxiety and depression compared to those with no/minimal symptoms and OAB without bother. • Greater symptom severity of urgency, urgency urinary incontinence, frequency, nocturia, and increasing levels of anxiety were strongly predictive of OAB bother in both men and women. • Predictors of treatment seeking included frequency, bother as a result of urgency, and lower levels of depressive symptoms in men, and frequency, nocturia and urgency in women. Conclusions • OAB is common in the UK and Sweden, and women are more likely to be affected then men. • The impact of OAB is evident across generic and condition-specific domains of health-related quality of life.

What’s known on the subject? and What does the study add? The use of tissue engineered buccal mucosa in substitution urethroplasty removes some of the potential drawbacks of harvesting buccal mucosa however it introduces the risk of using donor tissue (allodermis) in its creation. Biocompatible biodegradable non-woven fabrics created by electrospinning can be used as entirely synthetic matrices for seeding with autologous cells, creating tissues for implantation. This would both remove the donor tissue disease transmission risk and reduce the potential risks of harvesting buccal mucosa. While removing the risks of donor tissue, we showed that we can indeed make a replacement tissue which has similar biomechanical properties to buccal mucosa. We also found that each processing step in the creation of such a tissue is critical, for example the initial sterilisation can have a profound effect on the tissue created. OBJECTIVE To develop a synthetic biodegradable alternative to using human allodermis for the production of tissue-engineered buccal mucosa for substitution urethroplasty, looking specifically at issues of sterilization and cell-seeding protocols and, comparing the results to native buccal mucosa. MATERIAL AND METHODS Three methods of sterilization, peracetic acid (PAA), γ-irradiation and ethanol, were evaluated for their effects on a biodegradable electrospun scaffold of polylactide-co-glycolide (PLGA, 85 : 15), to identify a sterilization method with minimal adverse effects on the scaffolds. Two protocols for seeding oral cells on the scaffold were compared, co-culture of fibroblasts and keratinocytes on the scaffolds for 14 days, and seeding fibroblasts for 5 days then adding keratinocytes for a further 10 days. Cell viability and proliferation on the scaffolds, scaffold contraction and mechanical properties of the scaffolds with and without cells were examined. RESULTS γ-irradiation and PAA sterilized scaffolds remained sterile for >3 months when incubated in antibiotic-free culture medium, while ethanol sterilized and unsterilized samples became infected within 2–14 days. All scaffolds showed extensive contraction (up to 50% over 14 days) irrespective of the method of sterilization or the presence of cells. All methods of sterilization, particularly ethanol, reduced the tensile strength of the scaffolds. The addition of cells tended to further reduce mechanical properties but increased elasticity. The cell-seeding protocol of adding fibroblasts for 5 days followed by keratinocytes for 10 days was the most promising, achieving a mean (sem) ultimate tensile stress of 1.20 (0.24) × 105 N/m2 compared to 3.77 (1.05) × 105 N/m2 for native buccal mucosa, and a Young’s modulus of 2.40 (0.25) MPa, compared to 0.73 (0.09) MPa for the native buccal mucosa. CONCLUSION This study adds to our understanding of how sterilization and cell seeding affect the physical properties of scaffolds. Both PAA and γ-irradiation appear to be suitable methods for sterilizing PLGA scaffolds, although both reduce the tensile properties of the scaffolds. Cells grow well on the sterilized scaffolds, and with our current protocol produce constructs which have ≈30% of the mechanical strength and elasticity of the native buccal mucosa. We conclude that sterilized PLGA 85 : 15 is a promising material for producing tissue-engineered buccal mucosa.

Study Type – Therapy (RCT) Level of Evidence 1b OBJECTIVE To determine whether the efficacy and safety of a combination of tolterodine extended-release (ER) plus α-blocker treatment varies with high or low levels of serum prostate-specific antigen (PSA) in men who have persistent overactive bladder (OAB) symptoms after any α-blocker monotherapy. PATIENTS AND METHODS Men aged ≥40 years were eligible if they reported ≥8 micturitions/24 h, including ≥1 urgency episode/24 h with or without urgency urinary incontinence (UUI), and at least some moderate bladder-related problems at baseline despite receiving treatment with an α-blocker for ≥1 month. Exclusion criteria included a postvoid residual urine volume (PVR) of ≥200 mL and history of acute urinary retention requiring catheterization. Subjects were randomly assigned to tolterodine-ER 4 mg or placebo for 12 weeks; all subjects continued their α-blocker treatment throughout the study. Subjects completed 5-day bladder diaries at baseline and week 12, in which they recorded all micturitions and rated the sensation associated with each micturition using the 5-point Urinary Sensation Scale (USS). For this post hoc analysis, efficacy, safety, and tolerability data were stratified by the study median PSA concentration at baseline (1.41 ng/mL). RESULTS In the tolterodine-ER +α-blocker and placebo +α-blocker groups, 160 and 159 men, respectively, had PSA levels of

OBJECTIVE To estimate and compare the prevalence and associated bother of lower urinary tract symptoms (LUTS) in the general populations of the USA, UK and Sweden using current International Continence Society (ICS) definitions, as no previous population-based studies evaluating the prevalence of LUTS in the USA, using the 2002 ICS definitions, have been conducted. SUBJECTS AND METHODS This cross-sectional, population-representative survey was conducted via the Internet in the USA, the UK and Sweden. Members of Internet-based panels were randomly selected to receive an e-mailed invitation to participate. If interested, respondents selected a link to an informed consent page, followed by the survey. Participants were asked to rate how often they experienced individual LUTS during the previous 4 weeks, on a five-point Likert scale, and, if experienced, how much the symptom bothered them. Descriptive statistics were used to summarize and present the data. RESULTS Responses rates for the USA, the UK and Sweden were 59.6%, 60.6% and 52.3%, respectively, with a final sample of 30 000 (USA 20 000; UK 7500; Sweden 2500). The mean age (range) of the participants was 56.6 (40–99) years; the mean percentages for race were 82.9% white, 6.7% black, 6.0% Hispanic and 4.4% Asian/other. The prevalence of LUTS was defined by two symptom frequency thresholds, i.e. at least ‘sometimes’ and at least ‘often’ for all LUTS except incontinence, where frequency thresholds were at least ‘a few times per month’ and at least ‘a few times per week’. The prevalence of at least one LUTS at least ‘sometimes’ was 72.3% for men and 76.3% for women, and 47.9% and 52.5% for at least ‘often’ for men and women, respectively. For most LUTS, at least half of the participants were bothered ‘somewhat’ or more using a frequency threshold of at least ‘sometimes’. For a threshold of at least ‘often’, ‘somewhat’ or more bother was reported by ≥70% of participants except for terminal dribble in men and split stream in women. CONCLUSION In this large population study of three countries, LUTS are highly prevalent among men and women aged >40 years. In general, LUTS experienced ‘often’ or more are bothersome to most people.

OBJECTIVE To determine whether urological symptom clusters, as identified in previous studies, were associated with health-related quality-of-life (HRQoL) and use of healthcare. SUBJECTS AND METHODS The Boston Area Community Health Survey is a population-based epidemiological study of 2301 male and 3201 female residents of Boston, MA, USA, aged 30-79 years. Baseline data collected from 2002 to 2005 were used in this analysis. Data on 14 urological symptoms were used for the cluster analysis, and five derived symptom clusters among men and four among women were used in multivariate linear regression models (adjusted for age group, race/ethnicity, and comorbidity) to determine their association with physical (PCS-12) and mental health component scores (MCS-12) calculated from the Medical Outcomes Study 12-item Short Form Survey. RESULTS For both men and women, being in the most symptomatic cluster was associated with decrements in the PCS-12 score (men, cluster 5, -10.42; women, cluster 4, -9.80; both P < 0.001) and the MCS-12 score (men, cluster 5, -9.35; women, cluster 4, -6.24; both P < 0.001) compared with the asymptomatic groups. Both men and women in these most symptomatic clusters appeared to have adequate access to healthcare. CONCLUSION For men and women, those with the most urological symptoms reported poorer HRQoL in two domains after adjusting for age and comorbidity, and despite adequate access to care.

OBJECTIVE To compare, in a post hoc analysis of a phase III trial, the maximum recommended doses of fesoterodine (8 mg) and tolterodine (4 mg) for improving overactive bladder (OAB) symptoms and health-related quality of life (HRQoL), as fesoterodine effectively reduces OAB symptoms vs placebo. PATIENTS AND METHODS Eligible patients with frequency (≥eight voids/24 h) and either urgency (≥six episodes over 3 days) or urgency urinary incontinence (UUI; ≥three episodes over 3 days) were randomized to placebo, fesoterodine 4 or 8 mg, or tolterodine extended-release (ER) 4 mg for 12 weeks; fesoterodine 4 mg data were published elsewhere. Patients completed a 3-day bladder diary in which they recorded the time of each void, voided volume (VV), and the severity of urgency. A post hoc inferential analysis was conducted on the primary endpoint (voids/24 h), the two co-primary endpoints (UUI episodes/24 h and treatment response), several secondary endpoints (severe urgency plus UUI per 24 h, mean VV (MVV)/void, and continent days/week), HRQoL, using the King’s Health Questionnaire (KHQ) and the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), and self-reported bladder-related problems. A subanalysis also assessed all endpoints for patients who were incontinent at baseline. Tolerability and safety were assessed by evaluating adverse events, residual urine volume, laboratory variables and treatment withdrawals. RESULTS By week 12, patients with OAB in both active-treatment groups showed significant improvements in most bladder diary variables and treatment response rates compared with placebo. Fesoterodine 8 mg was statistically significantly better than tolterodine ER 4 mg for improving UUI episodes, severe urgency plus UUI, mean VV, and number of continent days/week. In addition, the fesoterodine and tolterodine ER groups showed significantly greater improvements in HRQoL than the placebo group, with positive changes in most domains of the KHQ and an improvement in ICIQ-SF score. The fesoterodine 8-mg group had statistically significant improvements over placebo in eight of nine KHQ domains. A major improvement in the severity of bladder-related problems was reported by 39% of the fesoterodine 8 mg and 34% of the tolterodine ER groups vs 25% of those on placebo (P ≤ 0.01). Results for the subgroup of incontinent patients at baseline were similar to the overall results. Adverse events reported most commonly with active treatment included dry mouth, constipation, dry eye, dry throat, and nausea. CONCLUSIONS Both fesoterodine and tolterodine ER significantly improved OAB symptoms and HRQoL, with statistically significant advantages for fesoterodine 8 mg compared with tolterodine ER on several important endpoints.

Contains fulltext : 52392.pdf (Publisher’s version ) (Closed access) The overactive bladder symptom complex (OAB) is the commonest cause of urinary incontinence in older people, and is usually due to underlying detrusor overactivity, and as such is a treatable condition. Older people are a heterogeneous group, which includes fit community-dwelling individuals and those with significant medical comorbidity; thus the requirements of care for this group are many and varied. The International Continence Society definition of the frail elderly, those aged >65 years with continence problems, who by virtue of comorbidity are house-bound or living in an institution, is clearly not applicable to all. However, many conditions begin to appear in later life and practitioners need to be aware of the need to manage these, and their treatment, when dealing with older people. Studies of medication for OAB have included the elderly and there is evidence of an equivalent benefit in younger people. The impact of treatment on the cognitively impaired and those receiving acetylcholinesterase inhibitors is discussed.

The tamsulosin oral-controlled absorption system (OCAS®) is a new tablet formulation of the α1-adrenoceptor (α1-AR) antagonist tamsulosin, which is used for treating lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). The tablet uses the OCAS technology, which was specifically designed to give a more continuous 24-h release of tamsulosin, resulting in a more consistent and continuous 24-h plasma concentration, a lower maximum plasma concentration (Cmax) and an independence of pharmacokinetics (PKs) on food intake. It was expected that the improved PK profile would translate into a better control of day- and night-time symptoms of BPH and a lower risk of adverse events. Phase I PK studies showed that tamsulosin OCAS indeed has a flattened PK profile with a lower Cmax and a more stable and consistent 24-h concentration of tamsulosin, independent of food intake, compared to conventional tamsulosin. A study combining γ-scintigraphy and PK analysis of blood samples confirmed that the improved PK profile of tamsulosin OCAS is attributed to the tablet being consistently and continuously released throughout the entire gastrointestinal tract, including the colon.

An international group of authors present a pooled analysis of data from their phase III multicentre double-blind clinical trials in patients with overactive bladder, which evaluated the efficacy, tolerability and safety of darifenacin. They found the drug, a muscarinic M3 selective receptor antagonist, to be effective in the treatment of this condition, with excellent tolerability and safety. A paper from Denmark compares the efficacy and safety of alfuzosin and tamsulosin in a large randomized, double-blind, placebo-controlled, multicentre study. There were similar improvements in urinary symptoms and maximum urinary flow with the two drugs compared to placebo, but the incidence of sexual function adverse events was higher with tamsulosin than placebo. OBJECTIVE To evaluate the efficacy, tolerability and safety of darifenacin, a muscarinic M3 selective receptor antagonist (M3 SRA), from an analysis of pooled data from three phase III, multicentre, double-blind clinical trials in patients with overactive bladder (OAB). PATIENTS AND METHODS After a 4-week washout/run-in period, 1059 adults (85% women) with symptoms of OAB (frequency and urgency with urge incontinence) for ≥ 6 months were randomized to once-daily oral treatment with darifenacin (7.5 mg, 337; or 15 mg, 334) or matching placebo (388) for 12 weeks. Efficacy was evaluated using electronic patient diaries that recorded incontinence episodes (including those resulting in a change of clothing or pads), frequency and severity of urgency, voiding frequency, and bladder capacity (volume voided). Safety was evaluated by analysis of adverse events (AEs), withdrawal rates and laboratory tests. RESULTS Relative to baseline, 12 weeks of treatment with darifenacin resulted in a significant reduction in the median (% change, interquartile range) number of incontinence episodes per week; 7.5 mg (−8.8, −68.4%, −15.1 to −4.4); 15 mg; (−10.6, −76.8%, −17.3 to −5.8: both P

OBJECTIVE To review the concept of urinary urgency and its practical measurement in clinical trials, and advance the hypothesis that while urge is experienced by normal people, urgency is always pathological. METHODS According to the International Continence Society (ICS) definition, urgency is the primary symptom of the overactive bladder (OAB) syndrome, but in clinical trials there are inconsistencies in both the definition and assessment of urgency. We searched the PubMed and BIOSIS databases for publications and abstracts related to the clinical assessment of urgency in patients with OAB. RESULTS The differentiation of urgency from the normal physiological desire to void is discussed. In clinical studies of OAB, urgency has been measured both qualitatively and quantitatively. Existing qualitative assessment scales for urgency are deficient in accuracy, validation or both, and are largely inconsistent with the currently accepted ICS definition of urgency. The quantitative assessment of urgency by diary entry has been validated and may be the most accurate, reproducible and clinically meaningful method available for measuring this variable. CONCLUSION Based on the existing ICS definition of urgency as ‘a compelling desire to pass urine that is difficult to defer’, the concept of qualitative assessment of urgency may be flawed.

OBJECTIVE To assess the effect of solifenacin succinate treatment on quality of life (QoL) measured in clinical trials in patients with overactive bladder (OAB). PATIENTS AND METHODS QoL data using the King's Health Questionnaire (KHQ) were analysed from two phase-3, 12-week studies (1984 patients) and a long-term extension of these studies (1637 patients) where patients received solifenacin for up to an additional 40 weeks (i.e. a 52-week exposure to solifenacin). The 12-week studies were multinational, multicentre, randomized, double-blind, and placebo-controlled. The 10 domains from the KHQ evaluated were general health perception, incontinence impact, role limitations, physical limitations, social limitations, personal relationships, emotions, sleep/energy, severity measures, and symptom severity. Changes from baseline to endpoint in QoL variables were assessed by analysis of variance, and from pooled outcomes of the 12-week studies by analysis of covariance. Descriptive statistics were used to evaluate data in the extension study. RESULTS In the two 12-week studies (1033 and 857 patients), those receiving once-daily solifenacin had statistically significantly better QoL than those on placebo. Changes in the KHQ were statistically significantly (P

Less than 10 years ago surgery and watchful-waiting were the only widely accepted management options for lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) and benign prostatic obstruction (BPO). There has been an enormous decline in the popularity of surgery and it is now apparent that medication is the most frequently used treatment for BPH/LUTS; this has arguably therefore been the most major change in urological clinical practice in the last decade. Currently alpha(1)-adrenoceptor antagonists are the commonest medical therapy, and are thought to act by relaxing prostatic smooth muscle, the neural or so-called 'dynamic' component of BPO. 5alpha-reductase inhibitors (finasteride, dutasteride) are another option for BPH/LUTS, which reduce prostatic mass and therefore the mechanical or 'static' component of BPO. In the last 10 years there have been four direct comparative studies between alpha(1)-adrenoceptor antagonists and finasteride, including their combination, the results of which, and their implications for therapy, are discussed. Another group of agents are the phytotherapeutic extracts, which act via various mechanisms, many as yet poorly defined. This review critically assesses existing publications relating to the medical management of BPH/LUTS.

To compare the serotonin (5-HT)4-receptor-mediated effects of 5-HT on the potentiation of cholinergic responses to electrical-field stimulation (EFS) in isolated strips of detrusor muscle from patients with normal or neurogenic overactive bladders.Strips of detrusor muscle were field-stimulated (10 Hz, 0.01 ms duration, 60 V for 5 s) at 100-s intervals until consistent responses were obtained. In the presence of methiothepin, ketanserin and ondansetron (all 1 mumol/L) to block 5-HT1, 5-HT2 and 5-HT3 receptors, respectively, the cumulative administration of 5-HT or the selective 5-HT4 agonist cisapride, produced concentration-dependent enhancement of responses to EFS in both types of tissue.The maximum potentiation induced by 5-HT in neurogenic overactive detrusor muscle was reduced (P0.05) by about half compared to normal detrusor muscle, but EC50 values obtained in normal and overactive tissue were not significantly different. Cisapride was less potent than 5-HT and acted as a partial agonist relative to 5-HT. The selective 5-HT4 receptor antagonist RS-100235 was a potent antagonist of the 5-HT-induced potentiation of responses to EFS. At 3 nmol/L RS-100235 antagonized the effects of 5-HT in both groups of tissues without affecting the maximum responses. The affinity estimates (apparent pKB values of 9.2-9.5) for this antagonist were similar in normal and overactive detrusor muscle.These results indicate that 5-HT4 receptor-mediated potentiation of field-stimulated responses is lower in the neurogenic overactive detrusor muscle than in normal tissue. 5-HT4 receptor antagonist affinity is unchanged in the neurogenic overactive bladder.

Early results using two new agents to treat urinary incontinence are published. The use of Ro 115–1240 in women with stress urinary incontinence is presented, with encouraging results. This will lead to further studies in more patients. Solifenacin was evaluated in a dose-finding study and the results presented here; the results of the phase III study appear next month. OBJECTIVES To evaluate the dose-response relationship and safety/tolerability of solifenacin succinate (YM905) in the treatment of overactive bladder (OAB), and to compare its efficacy and safety/tolerability with tolterodine 2 mg twice daily. PATIENTS AND METHODS This multicentre study included a 2-week single-blind placebo run-in, a 4-week double-blind placebo-controlled active treatment phase, and a 2-week follow-up. Men and women with an OAB and urodynamic evidence of detrusor overactivity were randomized to placebo or solifenacin 2.5, 5, 10 or 20 mg once daily, or tolterodine 2 mg twice daily. RESULTS Of 265 patients enrolled, 225 were randomized and 192 completed the study. Solifenacin 5, 10 and 20 mg produced statistically significant (P

Authors from Sheffield and the USA investigated the role of neurokinin receptors in mediating contraction of detrusor muscle strips from human and pig. They found that NK-2 receptors subtypes mediate neurokinin A-induced contraction of the detrusor muscle, and that the NK-3 receptor appears not to have such a role. Another study, from a variety of European and American centres, determined the expression and plasma membrane location of isoforms of Na,K-ATPase in the rat ventral prostate; they were localised in the lateral and basolateral plasma membrane domain prostatic epithelial cells, and the authors draw conclusions about the significance of these findings. Finally authors from Yale University investigated the effects of castration on the expressions of endothelins, endothelin receptors and converting enzyme-1 in the rat seminal vesicle. Their findings led them to suggest that testosterone has a regulatory role in the expression of the endothelin receptor system in the rat seminal vesicle. OBJECTIVE To investigate the role of neurokinin (NK)-2 and -3 receptors in mediating the contraction of detrusor muscle strips from human and pig, to determine whether the pig is a good model for the study of tachykinin receptors in the human bladder, as the biological actions of tachykinins, e.g. substance P and NKA are mediated via three distinct receptor subtypes, NK-1, -2 and -3. MATERIALS AND METHODS Strips of detrusor muscle were obtained from the bladder dome and neck of female pigs and from patients undergoing cystectomy. Cumulative concentration-response curves to NKA were obtained in the absence and presence of either the NK-2 receptor-selective antagonist SR48968 or the NK-3 receptor-selective antagonist SB223412. RESULTS NKA produced concentration-dependent contractions in the human and pig detrusor muscle; the curves were shifted to the right by SR48968, with high affinity (pKB 8.9, 8.3 and 8.0 in the human, pig dome and pig neck, respectively), whereas SB223412 had a minimal effect (pKB 5.8, 5.8 and 6.3, respectively). CONCLUSION These data confirm that the NK-2 receptor subtype mediates NKA-induced contraction of the human and pig detrusor muscle. The NK-3 receptor appears to have no role in detrusor contraction of either species. The results also provide evidence that the NK-2 receptor in human and pig are the same, and the latter may be an appropriate species to study tachykinin-induced contractions in human bladder.

OBJECTIVE To evaluate the effect of magnetic stimulation of the pelvic floor (MSPF) on involuntary detrusor activity observed during natural filling, and on the overactive bladder symptom complex. PATIENTS AND METHODS Eighteen women with detrusor overactivity on conventional cystometry underwent ambulatory urodynamic monitoring over two filling cycles. Fluid intake was standardized, provocative manoeuvres applied at regular intervals and symptoms documented contemporaneously. During the second filling cycle MSPF was delivered whenever the detrusor pressure increased by> 5 cmH2O. The women were subsequently treated with MSPF for 6 weeks; their lower urinary tract symptoms were assessed before and after treatment. RESULTS Comparing the second (stimulated) cycle with the first (unstimulated) cycle, cystometric capacity was higher (373 vs 224 mL, P

Objective To assess the superiority of fesoterodine 8 mg vs 4 mg for improvement in urgency urinary incontinence (UUI) episodes and other diary variables, diary-dry rate (proportion of patients with >0 UUI episodes on baseline diary and 0 UUI episodes on post-baseline diary), and improvements in measures of symptom bother, health-related quality of life (HRQL), and other patient-reported outcomes (PROs). Patients and Methods This was a 12-week, randomised, double-blind, placebo-controlled, multinational trial of men and women aged ≥18 years with overactive bladder (OAB) symptoms including UUI (ClinicalTrials.gov ID NCT01302067). Patients were randomised (2:2:1) to receive fesoterodine 8 mg, fesoterodine 4 mg, or placebo once daily; those randomised to fesoterodine 8 mg started with fesoterodine 4 mg once daily for 1 week, then 8 mg once daily for the remaining 11 weeks. Patients completed bladder diaries at baseline and weeks 4 and 12 and the Patient Perception of Bladder Condition (PPBC), Urgency Perception Scale (UPS), and Overactive Bladder Questionnaire (OAB-q) at baseline and week 12. The primary endpoint was change from baseline to week 12 in UUI episodes per 24 h. Results At week 12, patients receiving fesoterodine 8 mg (779 patients) had significantly greater reductions from baseline in UUI episodes, micturitions, and urgency episodes than patients receiving fesoterodine 4 mg (790) or placebo (386); diary-dry rate was significantly higher in the fesoterodine 8-mg group vs the fesoterodine 4-mg and placebo groups (all P < 0.05). At week 12, patients receiving fesoterodine 8 mg also had significantly greater improvements in scores on the PPBC, UPS, and all OAB-q scales and domains than patients receiving fesoterodine 4 mg or placebo (all P < 0.01). Patients receiving fesoterodine 4 mg had significantly greater improvements in UUI episodes, urgency episodes, and micturitions; significantly higher diary-dry rates; and significantly greater improvement in PPBC scores and OAB-q scores than patients receiving placebo (all P < 0.05). Dry mouth was the most commonly reported adverse event (AE) in the fesoterodine groups (placebo group, 3.4%; fesoterodine 4-mg group, 12.9%; fesoterodine 8-mg group, 26.1%); most cases were mild or moderate in all treatment groups. Rates of serious AEs and discontinuations due to AEs were low in all groups. Conclusions In a 12-week, prospectively designed, superiority trial, fesoterodine 8 mg showed statistically significantly superior efficacy vs fesoterodine 4 mg and placebo, as measured by reductions in UUI episodes and other diary variables, diary-dry dry rate, and improvements in measures of symptom bother, HRQL, and other PROs; clear evidence of dose-dependent efficacy is unique to fesoterodine among antimuscarinics and other oral agents for the treatment of OAB. Fesoterodine 4 mg was significantly more effective than placebo on all outcomes except for improvements in UPS scores. These data support the benefit of having two doses of fesoterodine in clinical practice, with the recommended starting dose of 4 mg for all patients and the fesoterodine 8-mg dose available for patients who require a higher dose to achieve optimal symptom relief.

To compare the long-term outcomes of a tension-free vaginal tape (TVT; Gynecare™, Somerville, NJ, USA), autologous fascial sling (AFS) and xenograft sling (porcine dermis, Pelvicol™; Bard, Murray Hill, NJ, USA) in the management of female stress urinary incontinence (SUI).A multicentre randomised controlled trial carried out in four UK centres from 2001 to 2006 involving 201 women requiring primary surgery for SUI. The women were randomly assigned to receive TVT, AFS or Pelvicol. The primary outcome was surgical success defined as 'women reporting being completely 'dry' or 'improved' at the time of follow-up'. The secondary outcomes included 'completely dry' rates, changes in the Bristol Female Lower Urinary Tract Symptoms (BFLUTS) and EuroQoL EQ-5D questionnaire scores.In all, 162 (80.6%) women were available for follow-up with a median (range) duration of 10 (6.6-12.6) years. 'Success' rates for TVT, AFS and Pelvicol were 73%, 75.4% and 58%, respectively. Comparing the 1- and 10-year 'success' rates, there was deterioration from 93% to 73% (P0.05) in the TVT arm and 90% to 75.4% (P0.05) in the AFS arm; 'dry' rates were 31.7%, 50.8% and 15.7%, respectively. Overall, the 'dry' rates favoured AFS when compared with Pelvicol (P0.001) and TVT (P = 0.036). The re-operation rate for persistent SUI was 3.2% (two patients) in the TVT arm, 13.1% (five) in the Pelvicol arm, while none of the patients in the AFS arm required further intervention.Our study indicates there is not enough evidence to suggest a difference in long-term success rates between AFS and TVT. However, there is some evidence that 'dry' rates for AFS may be more durable than TVT.

The term lower urinary tract symptoms (LUTS) encompasses a range of urinary symptoms, including storage symptoms (e.g. overactive bladder [OAB]) as well as voiding and post-micturition symptoms. Although treatment of male LUTS tends to focus on voiding symptoms, patients typically find storage symptoms the most bothersome. The core storage symptom is urgency, which drives the other main storage symptoms of increased daytime frequency, nocturia and incontinence. Although several validated questionnaires have been widely used to study urgency, few measure the two important storage parameters, urgency and frequency, in a single assessment. The total urgency and frequency score (TUFS) is a new validated tool that captures both variables and is derived from the Patient Perception of Intensity of Urgency Scale, which has been validated in patients with OAB and LUTS. The TUFS was first validated in OAB in the phase IIa BLOSSOM study, which was designed to assess the efficacy and safety of mirabegron, a β3 -adrenoceptor agonist, in 260 patients. The responsiveness of the TUFS to treatment has been confirmed in a further three large-scale randomized controlled trials of solifenacin in patients with OAB or LUTS. Changes in TUFS from baseline to end of treatment were consistent with changes in micturition diary variables in all four studies. Furthermore, the TUFS was significantly correlated with several health-related quality-of-life variables in the phase III NEPTUNE study. Thus, the TUFS appears to be useful for assessing improvements in major storage symptoms (urgency and frequency) in clinical trials.

Objective To evaluate the efficacy and safety of silodosin in a pooled analysis based on individual patients data from three randomised controlled trials (RCTs) comparing silodosin and placebo. Patients and methods A pooled analysis of 1494 patients from three 12-week, similarly designed, parallel-group, multicentre, randomised, double-blind, placebo-controlled phase III RCTs (SI04009, SI04010, KMD3213-IT-CL 0215) was performed. Differences from placebo for the mean change from baseline to the end of treatment for the International Prostate Symptom Score (IPSS) and uroflowmetry data were tested using an analysis of covariance model. Results At study end, in the intention-to-treat population, silodosin was significantly more effective than placebo in improving IPSS total score (adjusted means differences [AMD] 2.7; P < 0.001). Silodosin was significantly more effective than placebo in improving storage, voiding, and quality-of-life-item subscores (all P < 0.001). Similarly, silodosin was more effective than placebo in improving maximum urinary flow rate (Qmax; AMD 0.8; P = 0.002). The most frequently reported adverse event (AE) was ejaculatory dysfunction, reported in 186 (22%) patients in the silodosin group and six (0.9%) in the placebo group (odds ratio 28.14; P < 0.001). Dizziness and orthostatic hypotension rates were similar in silodosin and placebo groups. Conclusions Silodosin is an effective treatment for male lower urinary tract symptoms suggestive of benign prostatic hyperplasia. The drug is able to improve total IPSS, all IPSS-related parameters, and Qmax at uroflowmetry. Ejaculatory dysfunction is the main treatment-related AE, whereas prevalence of cardiovascular AEs was similar to placebo.

Objective To examine the potencies of the potassium-channel openers (KCOs) levcromakalim and YM934 as relaxing agents on human detrusor and human mesenteric artery smooth muscle, and to determine their bladder-vascular selectivity in vitro. Materials and methods Strips of human detrusor muscle and mesenteric artery (with the endothelium removed) were set up in physiological salt solution and the tension developed by the tissues recorded. Tissues were precontracted with a concentration of carbachol (detrusor) or phenylephrine (artery) which caused 80% of maximal contraction, and relaxation responses to levcromakalim and YM934 were then obtained. Results Both KCOs caused relaxation of the bladder detrusor muscle and the mesenteric artery. Maximal responses, when plotted as a percentage of the precontraction, were greater for both KCOs in the bladder muscle than the artery, but the differences were small and not statistically significant. The sensitivity (drug potency) of the detrusor muscle to the KCOs was more than twice that of the artery but this selectivity was only statistically significant for YM934. Conclusions Only minor bladder-vascular selectivity for levcromakalim and YM934 could be detected in vitro. This suggests that neither drug would be tolerated clinically, although the results suggest that further development of bladder-selective KCO agents appears feasible.

Objective To compare detrusor function and outlet behaviour on ambulatory urodynamic monitoring (AUM) with conventional cystometrography in symptomatic men with borderline evidence of bladder outlet obstruction (BOO), as determined by conventional cystometrography, and to assess the usefulness of AUM in reclassifying this population of patients into obstructed and unobstructed groups. Patients and methods Sixty-nine consecutive men (mean age 59.6 years) with lower urinary tract symptoms (mean International Prostate Symptom Score 19.1) and borderline BOO on a medium-fill conventional urodynamic study (CUS) were examined prospectively with AUM. Detrusor contractility, obstruction grade, maximal voiding detrusor pressure (pdetmax), detrusor pressure at peak flow (pdet Qmax) and peak flow rate (Qmax ) determined by both methods were compared. The incidence of detrusor instability (DI) detected by both modalities was also evaluated. Results There was considerable disagreement between the investigations during the voiding phase. Detrusor contractility was higher on AUM than on CUS (P=0.003) and obstruction grade was significantly lower on AUM (P=0.018). There was no difference in pdetmax nor pdet Qmax . The mean (95% confidence interval) Qmax was higher on AUM, at 12.9 (1.3) mL/s, than on CUS, at 8.9 (0.8) mL/s. On the Abrams-Griffiths nomogram the most significant changes were six men (10%) from equivocal to obstructed, seven (11%) from equivocal to unobstructed and two (3%) from obstructed to unobstructed on CUS and on AUM, respectively. Thus, in 24% of patients there was a potentially clinically significant change resulting from the information generated by AUM. DI was identified on CUS in 26 (41%) men and on AUM in 25 (40%); 35 men (56%) had evidence of DI on either AUM or CUS. Conclusion The significant disagreement between the findings on CUS and AUM suggests that the conditions under which pressure-flow investigations are carried out significantly affect findings in borderline cases. The reclassification of patients by AUM into obstructed and unobstructed groups occurs in 24% and may be clinically relevant. AUM appears to be complementary to CUS in the assessment of men who are borderline for obstruction on conventional testing, but the clinical implications of this have yet to be determined.

Objective To evaluate the responsiveness of the ICSmale questionnaire to the outcome of treatments for lower urinary tract symptoms (LUTS). Patients and methods Consecutive men aged >45 years attending 23 urology centres in 12 countries, with symptoms suggestive of bladder outlet obstruction secondary to benign prostatic hyperplasia (BPH), were recruited to Phase I of the International Continence Society (ICS)-‘BPH’ study. In Phase II of the ICS-‘BPH’ study, 355 men in 15 centres in nine countries were followed up, having proceeded to treatment according to clinical practice. All men completed the ICS-‘BPH’ study questionnaire at baseline and follow-up, including the ICSmale which concerns LUTS and related problems. Results Patients included in Phase II were similar to those in Phase I according to age and levels of baseline symptoms. Patients received a range of treatments: 32% TURP, 29% drug therapies, 20% watchful waiting, 9% minimally invasive therapies and 10%‘others’ (including open prostatectomy). For patients who underwent TURP, most LUTS, including voiding and filling symptoms, were highly statistically significantly better at follow-up than at baseline (P

Objective To investigate the presence of functional neuropeptide Y (NPY) receptors in human bladder and prostate (both richly endowed with NPY-containing nerve fibers) using peptide YY (PYY) as the agonist. Materials and methods Binding studies were conducted using [125I]PYY as the radioligand. Organ-bath studies were performed on isolated tissue strips for direct (postjunctional) contractile effects and for (prejunctional) inhibition of field stimulation effects. Any possible degradation of PYY was determined using high-performance liquid chromatography (HPLC). Results In the radioligand binding studies no quantifiable specific [125I]PYY binding was detected in human bladder or prostate, while specific high-affinity binding was readily seen in rat cerebral cortex. In organ-bath experiments, PYY (up to 1 µmol/L) caused no contraction of human prostate or bladder, whereas noradrenaline and carbachol, respectively, were effective; the potency or efficacy of noradrenaline and carbachol were not altered by PYY. Field stimulation-induced contraction was not affected by PYY in either human bladder or prostate, but was readily inhibited in rat vas deferens. HPLC detected no relevant PYY degradation by human bladder or prostate homogenates. Conclusion Human bladder and prostate express only very few if any functional NPY receptors.

Objectives To assess the efficacy and safety of trospium chloride (TCl, 20 mg twice daily) in the treatment of detrusor instability, compared with placebo. Patients and methods In all, 208 patients were allocated at random to either TCl or placebo in a double-blind clinical study; the patients were treated for 3 weeks. Urodynamic values were measured at the beginning and end of the treatment period. Adverse events were recorded on patient diary cards. A confirmatory adaptive procedure with one planned interim analysis was used to evaluate efficacy. Results Trospium chloride produced significant improvements in maximum cystometric bladder capacity (median treatment effect 22.0 mL, mean 37.3 mL, one-sided P = 0.0054) and urinary volume at first unstable contraction (median treatment effect 45.0 mL, mean 63.6 mL, one-sided P = 0.0015). The patients’ assessment of efficacy showed significantly greater clinical improvement in the TCl group than in the placebo group (two-sided P = 0.0047). Furthermore, TCl was well tolerated, with similar frequencies of adverse events reported in both groups (68% in the TCl and 62% in the placebo group). Conclusion Trospium chloride (20 mg twice daily) is an effective and safe option for the treatment of detrusor instability.

Objective To evaluate the anatomical location, histological appearances and mechanism of action of sili-cone polymer (Macroplastique®) after transurethral implantation. Materials and methods An in vivo pig model was developed to investigate the organization of Macroplastique 6 weeks after injection. The results were compared with the immediate appearance of injected Macroplastique in a surgical training device (using isolated pig urethrae) and with the histological appearances of Macroplastique in an explanted human specimen. Results Macroplastique was subserosal in all specimens; it provoked a marked foreign-body inflammatory reaction, producing firm nodules 6 weeks after implantation. The histological appearances in the in vivo pig model and the human specimen were indistinguishable. Conclusions These findings indicate that the mechanism of action of Macroplastique is to augment pressure transmission to the proximal urethra by producing focal but firm expansion of periurethral tissues.

Objective To determine whether detrusor muscle from the pig can be used as a model to study presynaptic 5-hydroxytryptamine (HT)4-receptor-mediated effects on the electrical field stimulated (EFS) cholinergic responses previously identified in the human bladder. Materials and methods Strips of detrusor muscle were mounted in physiological Krebs' solution under 1 g tension and field stimulated (25 Hz, 0.01 ms duration, 60 V for 5 s) at 100-s intervals and allowed to equilibrate. Concentration-response curves to 5-HT (1 nmol/L to 300 µmol/L) were constructed in the presence and absence of the 5-HT4-selective antagonists RS-100235 and GR-113808 (both at 0.3, 1 and 3 nmol/L). All experiments were conducted in the presence of methiothepin and ondansetron (both 1 µmol/L) to block 5-HT1, -HT2 and -HT3 receptors. Results 5-HT potentiated the cholinergic responses to EFS in pig bladder strips in a concentration-dependent manner, with a maximum mean ( sem) potentiation of 48.3 (7.7)% of the resting tension (n = 25). BothRS-100235 and GR-113808 antagonized the effect of 5-HT with high affinity, yielding apparent pKB values which were consistent with the responses being mediated via the 5-HT4 receptor subtype. Conclusion These data indicate that 5-HT can potentiate EFS responses in isolated pig bladder strips and that the 5-HT4 receptor subtype mediates this response. Therefore, the pig may be used as an effective model to study presynaptic 5-HT4 receptors previously reported in the human bladder.

A wealth of clinical evidence supports the view that muscarinic receptor antagonists are effective in the treatment of overactive bladder. However, treatment-limiting adverse effects such as dry mouth, constipation, and blurred vision have restricted the usefulness of previously available agents, such as oxybutynin. A real need therefore existed for effective and well-tolerated agents for the long-term management of the troublesome symptoms of overactive bladder. This review outlines the various approaches that have been used in attempts to overcome the tolerability problems of oxybutynin. It also describes how advances in our understanding of muscarinic receptors and bladder function has led to the potential development of either tissue- or subtype-selective antimuscarinic agents with improved tolerability. Drugs that have been developed in this way include tolterodine and darifenacin, each of which shows some bladder selectivity in animal models. Unlike darifenacin, however, the bladder selectivity of tolterodine has been confirmed by numerous clinical studies. Tolterodine’s improved tolerability compared with oxybutynin, along with its equivalent therapeutic efficacy at recommended dosages, permits patients to experience the beneficial effects of long-term treatment. Tolterodine therefore represents a real alternative for the long-term management of overactive bladder. The results of ongoing clinical studies with darifenacin are awaited before it can be concluded that selective antagonism of M3 receptors leads to improved tolerability over existing agents in the treatment of overactive bladder. Similarly, the potential improvements in tolerability associated with different dosage formulations of oxybutynin, and the clinical utility of S-oxybutynin, are yet to be conclusively demonstrated. UROLOGY 55 (Suppl 5A): 33‐46, 2000. © 2000, Elsevier Science Inc.

Objective: To investigate the direct effect of onabotulinumtoxinA (OnaBotA) on bladder afferent nerve activity and release of ATP and acetylcholine (ACh) from the urothelium. Materials and Methods: Bladder afferent nerve activity was recorded using an in vitro mouse preparation enabling simultaneous recordings of afferent nerve firing and intravesical pressure during bladder distension. Intraluminal and extraluminal ATP, ACh, and nitric oxide (NO) release were measured using the luciferin–luciferase and Amplex® Red assays (Molecular Probes, Carlsbad, CA, USA), and fluorometric assay kit, respectively. OnaBotA (2U), was applied intraluminally, during bladder distension, and its effect was monitored for 2 h after application. Whole-nerve activity was analysed to classify the single afferent units responding to physiological (low-threshold [LT] afferent 15 mmHg) distension pressures. Results: Bladder distension evoked reproducible pressure-dependent increases in afferent nerve firing. After exposure to OnaBotA, both LT and HT afferent units were significantly attenuated. OnaBotA also significantly inhibited ATP release from the urothelium and increased NO release. Conclusion: These data indicate that OnaBotA attenuates the bladder afferent nerves involved in micturition and bladder sensation, suggesting that OnaBotA may exert its clinical effects on urinary urgency and the other symptoms of overactive bladder syndrome through its marked effect on afferent nerves.

To identify candidate materials which have sufficient potential to be taken forward for an in vivo tissue-engineering approach to restoring the tissue structure of the pelvic floor in women with stress urinary incontinence (SUI) or pelvic organ prolapse (POP).Oral mucosal fibroblasts were seeded onto seven different scaffold materials, AlloDerm ( LifeCell Corp., Branchburg, NJ, USA), cadaveric dermis, porcine dermis, polypropylene, sheep forestomach, porcine small intestinal submucosa (SIS) and thermoannealed poly(L) lactic acid (PLA) under both free and restrained conditions. The scaffolds were assessed for: cell attachment using AlamarBlue and 4,6-diamidino-2-phenylindole (DAPI); contraction using serial photographs; and extracellular matrix production using Sirius red staining, immunostaining and scanning electron microscopy. Finally the biomechanical properties of all the scaffolds were assessed.Of the seven, there were two biodegradable scaffolds, synthetic PLA and natural SIS, which supported good cell attachment and proliferation. Immunostaining confirmed the presence of collagen I, III and elastin which was highest in SIS and PLA. The mechanical properties of PLA were closest to native tissue with an ultimate tensile strength of 0.72 ± 0.18 MPa, ultimate tensile strain 0.53 ± 0.16 and Young's modulus 4.5 ± 2.9 MPa. Scaffold restraint did not have a significant impact on the above properties in the best scaffolds.These data support both PLA and SIS as good candidate materials for use in making a tissue-engineered repair material for SUI or POP.

What's known on the subject? and What does the study add? Urethral amyloidosis is rare and urethrotomy has been proposed as a suitable treatment option. By reviewing the literature and comparing our own experiences, we have shown urethroplasty to have good medium term outcomes in patients with urethral amyloidosis, whereas urethrotomy may lead to recurrence.• Urethral amyloidosis (UA) is a rare condition which may be encountered by an urological surgeon. We reviewed the literature regarding the presentation, investigation and management of UA.• A systematic review of the English literature on PubMed was conducted and we identified 39 articles which reported 45 patients. We included our experience with four patients from our tertiary centre.• The majority of patients reported symptoms consistent with a urethral structure. Most patients were treated with urethrotomy, only two patients have been reported to have had a urethroplasty in the literature. Medium and long term outcome data is lacking for urethrotomy and urethroplasty. We found recurrence in our patients after urethromoty and incomplete resection of UA. We describe short (6 month) and medium term (18 month) outcomes in two patients who underwent augmentation urethroplasty.• Although urethrotomy and dilatation have been proposed in the past, we found these may still lead to disease progression and therefore urethroplasty may be the most appropriate long term management option.

To determine whether the efficacy and safety of a combination of tolterodine extended-release (ER) plus α-blocker treatment varies with high or low levels of serum prostate-specific antigen (PSA) in men who have persistent overactive bladder (OAB) symptoms after any α-blocker monotherapy.Men aged ≥ 40 years were eligible if they reported ≥ 8 micturitions/24 h, including ≥ 1 urgency episode/24 h with or without urgency urinary incontinence (UUI), and at least some moderate bladder-related problems at baseline despite receiving treatment with an α-blocker for ≥ 1 month. Exclusion criteria included a postvoid residual urine volume (PVR) of ≥ 200 mL and history of acute urinary retention requiring catheterization. Subjects were randomly assigned to tolterodine-ER 4 mg or placebo for 12 weeks; all subjects continued their α-blocker treatment throughout the study. Subjects completed 5-day bladder diaries at baseline and week 12, in which they recorded all micturitions and rated the sensation associated with each micturition using the 5-point Urinary Sensation Scale (USS). For this post hoc analysis, efficacy, safety, and tolerability data were stratified by the study median PSA concentration at baseline (1.41 ng/mL).In the tolterodine-ER +α-blocker and placebo +α-blocker groups, 160 and 159 men, respectively, had PSA levels of1.41 ng/mL, and 166 and 160 men, respectively, had PSA levels of ≥ 1.41 ng/mL. Men with higher PSA levels were slightly older and had higher PVR at baseline compared with men with lower PSA levels. At week 12, improvements in daytime micturitions, 24-h urgency episodes, and daytime urgency episodes were significantly greater with tolterodine-ER +α-blocker vs placebo +α-blocker both in men with PSA levels of ≥ 1.41 ng/mL and those with PSA levels of1.41 ng/mL (P0.05). Among men with PSA levels of1.41 ng/mL, improvements in 24-h micturitions and frequency-urgency sum (sum of USS ratings for all micturitions) were also significantly greater with tolterodine-ER +α-blocker vs placebo +α-blocker (P0.05). There were no significant treatment differences in change in UUI episodes in either PSA group (although only 19% of subjects reported UUI at baseline), nor in nocturnal micturitions or nocturnal urgency episodes. Among men with PSA levels of ≥ 1.41 ng/mL, there was a statistically significant increase in PVR (P = 0.036) and decrease in maximum urinary flow rate (Q(max); P = 0.038) with tolterodine-ER +α-blocker vs placebo +α-blocker; these changes were not considered clinically meaningful. There were no treatment differences for changes in PVR or Q(max) among men with PSA levels of1.41 ng/mL. One subject receiving tolterodine-ER +α-blocker (PSA concentration of ≥ 1.41 ng/mL) and two subjects receiving placebo +α-blocker (one each in the PSA concentration subgroups of ≥ 1.41 ng/mL and1.41 ng/mL) had acute urinary retention requiring catheterization.In a 12-week study, the addition of tolterodine-ER to α-blocker therapy improved key OAB symptoms and appeared to be well tolerated compared with placebo +α-blocker in men with persistent OAB symptoms, regardless of subjects' prostate size as judged by serum PSA concentration.

To develop a synthetic biodegradable alternative to using human allodermis for the production of tissue-engineered buccal mucosa for substitution urethroplasty, looking specifically at issues of sterilization and cell-seeding protocols and, comparing the results to native buccal mucosa.Three methods of sterilization, peracetic acid (PAA), γ-irradiation and ethanol, were evaluated for their effects on a biodegradable electrospun scaffold of polylactide-co-glycolide (PLGA, 85:15), to identify a sterilization method with minimal adverse effects on the scaffolds. Two protocols for seeding oral cells on the scaffold were compared, co-culture of fibroblasts and keratinocytes on the scaffolds for 14 days, and seeding fibroblasts for 5 days then adding keratinocytes for a further 10 days. Cell viability and proliferation on the scaffolds, scaffold contraction and mechanical properties of the scaffolds with and without cells were examined.γ-irradiation and PAA sterilized scaffolds remained sterile for3 months when incubated in antibiotic-free culture medium, while ethanol sterilized and unsterilized samples became infected within 2-14 days. All scaffolds showed extensive contraction (up to 50% over 14 days) irrespective of the method of sterilization or the presence of cells. All methods of sterilization, particularly ethanol, reduced the tensile strength of the scaffolds. The addition of cells tended to further reduce mechanical properties but increased elasticity. The cell-seeding protocol of adding fibroblasts for 5 days followed by keratinocytes for 10 days was the most promising, achieving a mean (sem) ultimate tensile stress of 1.20 (0.24) × 10⁵ N/m² compared to 3.77 (1.05) × 10⁵ N/m² for native buccal mucosa, and a Young's modulus of 2.40 (0.25) MPa, compared to 0.73 (0.09) MPa for the native buccal mucosa.This study adds to our understanding of how sterilization and cell seeding affect the physical properties of scaffolds. Both PAA and γ-irradiation appear to be suitable methods for sterilizing PLGA scaffolds, although both reduce the tensile properties of the scaffolds. Cells grow well on the sterilized scaffolds, and with our current protocol produce constructs which have ≈ 30% of the mechanical strength and elasticity of the native buccal mucosa. We conclude that sterilized PLGA 85:15 is a promising material for producing tissue-engineered buccal mucosa.

Several studies with modern antimuscarinics have used a flexible-dosing strategy. We reviewed data from several studies with solifenacin, darifenacin and oxybutynin extended-release that evaluated the impact of dose flexibility on clinical management. A strategy based on patient-requested dose increases was found to be consistently effective in improving the symptoms of overactive bladder. Patients requesting a dose increase often had more severe symptoms at baseline than those who did not request a dose increase, and these patients derived most benefit from the increased dose. Specialists and family doctors should encourage open discussion with their patients about requesting dose titration so as to meet patients' individual needs.

OBJECTIVE To explore the risk factors and comorbid conditions associated with subgroups of lower urinary tract symptoms (LUTS) in men and women aged ≥40 years in three countries, using data from the EpiLUTS study, as LUTS are common amongst men and women and increase in prevalence with age. SUBJECTS AND METHODS This cross-sectional, population-representative survey was conducted via the Internet in the USA, the UK and Sweden. Participants were asked to rate how often they experienced individual LUTS during the past 4 weeks on a 5-point Likert scale. Eight LUTS subgroups were created. Descriptive statistics and logistic regressions within each LUTS subgroup were used to assess the data. RESULTS The survey response rate was 59%. The final sample was 30 000 (men and women). The voiding + storage + postmicturition (VSPM) group reported the highest rates of comorbid conditions for both men and women, and the fewest were reported in the no/minimal LUTS and the postmicturition-only groups. Increasing age was associated with increasing LUTS in men, but not in women. Comorbid conditions significantly associated with the VSPM group were arthritis, asthma, chronic anxiety, depression, diabetes (men only), heart disease, irritable bowel syndrome, neurological conditions, recurrent urinary tract infection, and sleep disorders. Risk factors, such as body mass index, exercise level and smoking, played less of a role, except for childhood nocturnal enuresis, which was significantly associated with most LUTS subgroups. CONCLUSION In this large population study, many comorbid conditions and risk factors were significantly associated with LUTS among both men and women. Further longitudinal investigations of the associations noted here would help physicians to understand the pathophysiology of LUTS and comorbid conditions, and provide clinical guidelines for patient management of comorbid conditions sharing common pathophysiological pathways.