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Purpose: This large dose-ranging study explored the benefits of different combinations of mirabegron and solifenacin on health-related quality of life (HRQoL), based on patient-reported outcomes (PROs), and patients ('responders') achieving clinically meaningful improvements in efficacy and HRQoL. Methods: SYMPHONY (NCT01340027) was a Phase II, placebo- and monotherapy-controlled, dose-ranging, 12-week trial. Adult patients with overactive bladder (OAB) for ≥3 months were randomized to 1 of 12 groups: 6 combination (solifenacin 2.5/5/10 mg + mirabegron 25/50 mg), 5 monotherapy (solifenacin 2.5/5/10 mg, or mirabegron 25/50 mg), or placebo. Change from baseline to end of treatment was assessed, versus placebo and solifenacin 5 mg in: PROs (OAB-q [Symptom Bother/total HRQoL] and Patient Perception of Bladder Condition score), and responders achieving minimally important differences (MIDs) in PROs and predetermined clinically meaningful improvements in efficacy (e.g. <8 micturitions/24 h). Changes in PROs and responders were analysed using an ANCOVA model and logistic regression, respectively. Results: The Full Analysis Set included 1278 patients. Combination therapy of solifenacin 5/10 mg + mirabegron 25/50 mg significantly improved PROs versus solifenacin 5 mg and placebo, and significantly more responders achieved MIDs in PROs and efficacy. Micturition frequency normalization was approximately twofold greater with 10 + 25 mg (OR 2.06 [95 % CI 1.11, 3.84; p = 0.023]) and 5 + 50 mg (OR 1.91 [95 % CI 1.14, 3.21; p = 0.015]) versus solifenacin 5 mg. Conclusion: Combining mirabegron 25/50 mg and solifenacin 5/10 mg improves objective and subjective efficacy outcomes compared with placebo or solifenacin 5 mg. [ABSTRACT FROM AUTHOR]

Aims The purpose of this study was to assess the safety, tolerability and impact on overactive bladder ( OAB) symptoms of a novel combination of tolterodine immediate-release ( IR) 2 mg and delayed-release pilocarpine 9 mg in patients with OAB. Methods Eligible patients with OAB were randomised to each of three treatments [tolterodine/pilocarpine (2/9 mg), tolterodine IR 2 mg or placebo] twice daily for 4 weeks in a double-blind, crossover fashion. At the end of the 12-week, double-blind treatment period, patients could enter an open-label extension during which they were re-randomised to either tolterodine/pilocarpine (3/13.5 mg) twice daily or tolterodine extended-release 4 mg once daily for 12 weeks. Results A total of 138 patients were randomised to double-blind medication. Both tolterodine/pilocarpine (2/9) and tolterodine IR 2 mg significantly reduced incontinence episodes and daily micturitions (p < 0.001 vs. placebo), with similar reductions in symptoms observed between active treatment groups. Tolterodine/pilocarpine (2/9) was associated with consistently lower Visual Analogue Scale ( VAS) scores for all dry mouth parameters compared with tolterodine alone. Salivary flow over a 3 h period remained fairly constant after tolterodine/pilocarpine (2/9) administration, similar to placebo, but decreased markedly after administration of tolterodine alone. In the extension study, patients receiving tolterodine/pilocarpine (3/13.5) reported comparable dry mouth VAS scores to tolterodine extended-release alone without additional side effects or loss of efficacy. The combination was well tolerated, and the adverse effects observed were consistent with the known safety profiles of tolterodine and pilocarpine. Conclusions A combination of tolterodine/pilocarpine (2/9) effectively reduced the incidence of dry mouth compared with tolterodine IR alone while maintaining treatment efficacy in OAB. [ABSTRACT FROM AUTHOR]

Lower urinary tract symptoms are common in women. They may be more broadly classified into storage and voiding disorders. Recent literature has focussed on the management of voiding dysfunction and the spectrum of symptoms presented by women with such disorders. Symptoms of voiding dysfunction and storage symptoms may coexist, making diagnosis and management even more challenging. The purpose of this paper is to review the literature regarding the definition and management of voiding dysfunction with and without associated storage symptoms. [ABSTRACT FROM AUTHOR]

Background: Muscarinic receptors in the brain play an important role in cognitive function, especially memory, and there is growing awareness that specific antimuscarinic drugs for overactive bladder (OAB) may have adverse central nervous system (CNS) effects. Selection of an antimuscarinic OAB drug with reduced potential for CNS effects could be especially beneficial in the elderly people, in whom even the modest cognitive impairment may negatively affect independence. Purpose: The purpose of the study is to determine if trospium chloride is assay detectable in the CNS of older adults with OAB and to assess whether deterioration of memory occurs in these individuals. Methods: Twelve cognitively intact older adults (≥65–75 years old) with OAB were given extended-release trospium chloride 60 mg once daily over a 10-day period to achieve plasma steady-state levels. Standardised memory testing (Hopkins Verbal Learning Test-Revised and Brief Visuospatial Memory Test-Revised) was performed predose and postdose. Cerebrospinal spinal fluid (CSF) and plasma samples were drawn on day 10 and assayed for trospium chloride. Predose (day 0) and postdose (day 10) results on the memory tests were compared using a reliable change index to assess a meaningful change in learning or memory. Results: Trospium chloride levels in all the CSF samples ( n = 72) of all participants were assay undetectable (<40 pg/ml) on day 10 at steady-state peak plasma concentration concurrent with measureable peak plasma values ( Cmax = 925 pg/ml). Repeat memory testing revealed no significant net drug effect on learning or recall. Conclusions: This is the first study to investigate for the presence of an OAB antimuscarinic in the human brain, performed by assaying for concentrations of trospium chloride and correlating with simultaneous clinical cognitive safety measures. The results of both pharmacological and neuropsychological testing support the hypothesis of a lack of detectable CNS penetration for the quaternary amine trospium chloride. [ABSTRACT FROM AUTHOR]

We propose a simple and practical approach to the identification, evaluation and treatment of lower urinary tract symptoms (LUTS) resulting from an enlarging and obstructive prostate. The proposed Simplified Treatment for Enlarged Prostate (STEP) plan is a logical guide to patient management by the primary care provider (PCP). Symptoms of enlarged prostate (EP) are common and may frequently progress into a condition with profound adverse effects on quality of life. Despite the high prevalence, EP is underdiagnosed and undertreated. This situation may result from patient- and provider-related issues. Assessment of symptoms of EP should be initiated with a discussion of LUTS. Evaluation includes a focused history, physical examination and selected laboratory tests. Certain factors put the symptomatic patient at risk for disease progression; however, not all factors can be readily evaluated in the PCP setting. The serum prostate-specific antigen (PSA) level acts both as an indicator of prostatic size and a screening tool for prostatic cancer, and thereby provides an important tool for PCPs. The STEP plan is a logical guide to patient management. Step 1, watchful waiting, is appropriate in patients with symptoms that are not bothersome. If symptoms cause bother, the initiation of an alpha-blocker (AB) in step 2, provides relatively rapid symptom improvement. Patients with bothersome symptoms and a PSA ≥ 1.5 ng/ml are at risk for progression and consideration should be given to combination treatment with an AB and a 5α-reductase inhibitor (step 3). Patients with refractory symptoms should be referred to a urologist (step 4). Identification, evaluation and management of EP are within the domain of the primary care setting. The STEP approach provides a simple and practical framework for PCPs to manage most men with symptoms of EP. [ABSTRACT FROM AUTHOR]

Aim: To consider the currently available knowledge and understanding of the symptom of urgency. Materials & Methods: Each faculty member reviewed the literature base of a different aspect of urgency and along with their personal clinical experience provided a base of evidence for discussion. Results: This overview summarises relevant published literature and the current clinical experience of the authors. Discussion: Whilst the mechanisms producing the sensation of urgency are still not fully understood and we are working within a definition that may complicate measurement and treatment, our pressing need is to effectively manage our patients for whom the practical nature of urgency can be all too apparent. Conclusion: Health care professionals have an important role to play today in helping to alleviate the widespread problem of urgency and its consequences. [ABSTRACT FROM AUTHOR]

Aim: To consider the currently available knowledge and understanding of the symptom of urgency. Materials & Methods: Each faculty member reviewed the literature base of a different aspect of urgency and along with their personal clinical experience provided a base of evidence for discussion. Results: This overview summarises relevant published literature and the current clinical experience of the authors. Discussion: Whilst the mechanisms producing the sensation of urgency are still not fully understood and we are working within a definition that may complicate measurement and treatment, our pressing need is to effectively manage our patients for whom the practical nature of urgency can be all too apparent. Conclusion: Health care professionals have an important role to play today in helping to alleviate the widespread problem of urgency and its consequences. [ABSTRACT FROM AUTHOR]

Background: Trospium chloride is an antimuscarinic agent with a hydrophilic polar quaternary amine structure that is minimally metabolised by hepatic cytochrome P450 and is actively excreted in the urine, each of which confers a potential benefit with regard to efficacy and tolerability. Purpose: We analysed pooled data from two identically designed phase III trials of a once-daily, extended-release (XR) formulation of trospium chloride (trospium XR 60-mg capsules) in subjects with overactive bladder syndrome (OAB). Methods: Adults with OAB of ≥ 6 months’ duration with urinary urgency, frequency and ≥ 1 urge urinary incontinence (UUI) episode/day were enrolled in these multicentre, parallel-group, double-blind trials. Participants were randomised (1 : 1) to receive trospium XR 60 mg or placebo for 12 weeks. Primary efficacy variables were changes in urinary frequency and the number of UUI episodes/day. Adverse events (AEs) were recorded throughout. Results: In total, 1165 subjects were randomised (trospium XR, 578; placebo, 587). At baseline, subjects averaged 12.8 toilet voids/day and 4.1 UUI episodes/day. Compared with placebo, subjects treated with trospium XR had significantly greater reductions from baseline in the mean number of toilet voids/day (−1.9 vs. −2.7; p < 0.001) and UUI episodes/day (−1.8 vs. −2.4; p < 0.001) at week 12. The most frequent AEs considered possibly related to study treatment were dry mouth (trospium XR, 10.7%; placebo, 3.7%) and constipation (trospium XR, 8.5%; placebo, 1.5%). Notably, rates of central nervous system (CNS) AEs were lower with trospium XR vs. placebo (dizziness: 0.2% vs. 1.0%; headache: 1.4% vs. 2.4%). Conclusions: Treatment with trospium XR resulted in statistically significant improvements in both of the dual primary and all of the secondary outcome variables. Trospium XR demonstrated favourable rates of AEs, particularly CNS AEs (numerically lower than with placebo) and dry mouth (lower than previously reported with trospium immediate-release, although not compared in a head-to-head study). [ABSTRACT FROM AUTHOR]

Objective: It has been assumed that a patient’s underlying baseline overactive bladder (OAB) incontinence severity is predictive of the resulting efficacy of pharmacological treatment. The objective of this study was to stratify and analyse the effects of baseline incontinence disease severity on the treatment outcome of the percentage of patients continent (PPC) during treatment with once-daily trospium chloride 60 mg extended release (XR). Methods: A post hoc analysis was conducted on pooled data from two 12-week, randomised, double-blind phase III studies in the USA in which 1165 patients with baseline urgency, and an average of ≥ 1 urge urinary incontinence (UUI) episode/day and ≥ 10 toilet voids/day on a 3-day bladder diary, received once-daily trospium chloride 60 mg XR ( n = 578) or placebo ( n = 587). Patients were stratified by the mean number of UUIs/day (1.0, > 1.0–2.0, > 2.0–5.0 or > 5.0) at baseline. The efficacy parameter that was analysed was complete continence (defined as no UUIs on a 3-day bladder diary collected at week 12 of treatment). Results: Baseline UUI levels were inversely correlated with the week 12 PPC (p < 0.0001). Post-treatment PPCs were higher with trospium chloride XR vs. placebo at all degrees of severity. Complete continence was achieved in 75% of trospium chloride XR recipients with 1.0 UUI/day at baseline and 48% of those with > 1.0–2.0 UUIs/day at baseline. Conclusions: These findings support the assumption that baseline incontinence severity affects the likelihood of achieving continence from OAB therapy, and that patients with less severe OAB (e.g. 1 UUI/day) can expect higher ‘dry rates’ following treatment (e.g. up to 75%) than those with more severe OAB. This information can provide a useful tool for the physician and patient in establishing expectations during therapy. [ABSTRACT FROM AUTHOR]

Aims: Overactive bladder (OAB) is common in men and may exist concomitantly with benign prostatic hyperplasia (BPH) and obstruction. We present a subanalysis of results from men with OAB in a 6-month, open-label study of treatment with the oxybutynin transdermal system (OXY-TDS). Broad entry criteria were incorporated to yield a clinically representative population.Methods: All participants received OXY-TDS 3.9 mg/day. Effectiveness was assessed by changes in scores on validated questionnaires, which included the single-item Patient Perception of Bladder Condition (PPBC), the King's Health Questionnaire (KHQ) and the Beck Depression Inventory-II (BDI-II).Results: The proportion of men (n=369; mean age=69.6 years) who reported that their bladder condition caused moderate, severe or many severe problems (PPBC>or=4) improved from 77.3% at baseline to 38.1-53.6% in subsequent months. Mean KHQ scores decreased significantly (p12 (associated with a diagnosis of depression) decreased from 23.9% to 17.9% (p=0.0055). Men with a history of 'prostate problems' or use of 'BPH medication' (32.2%) had KHQ domain changes that were similar (p>or=0.1016) to those of other men. Most men (76.2%) reported no treatment-related adverse events; two men (0.5%) experienced symptoms of mild urinary retention, but neither required catheterisation.Conclusions: Oxybutynin transdermal system treatment of men with OAB was effective and well tolerated, regardless of history of prostate condition. [ABSTRACT FROM AUTHOR]

Aims: Overactive bladder (OAB) is common in men and may exist concomitantly with benign prostatic hyperplasia (BPH) and obstruction. We present a subanalysis of results from men with OAB in a 6-month, open-label study of treatment with the oxybutynin transdermal system (OXY-TDS). Broad entry criteria were incorporated to yield a clinically representative population. Methods: All participants received OXY-TDS 3.9 mg/day. Effectiveness was assessed by changes in scores on validated questionnaires, which included the single-item Patient Perception of Bladder Condition (PPBC), the King's Health Questionnaire (KHQ) and the Beck Depression Inventory-II (BDI-II). Results: The proportion of men ( n = 369; mean age = 69.6 years) who reported that their bladder condition caused moderate, severe or many severe problems (PPBC ≥ 4) improved from 77.3% at baseline to 38.1–53.6% in subsequent months. Mean KHQ scores decreased significantly (p ≤ 0.0196) from baseline to study end in eight of 10 domains, indicating improved health-related quality of life. The proportion of men with BDI-II score > 12 (associated with a diagnosis of depression) decreased from 23.9% to 17.9% (p = 0.0055). Men with a history of ‘prostate problems’ or use of ‘BPH medication’ (32.2%) had KHQ domain changes that were similar (p ≥ 0.1016) to those of other men. Most men (76.2%) reported no treatment-related adverse events; two men (0.5%) experienced symptoms of mild urinary retention, but neither required catheterisation. Conclusions: Oxybutynin transdermal system treatment of men with OAB was effective and well tolerated, regardless of history of prostate condition. [ABSTRACT FROM AUTHOR]

Aims: Lower urinary tract symptoms (LUTS) are common in both men and women, and are among the most prevalent patient complaints heard by primary care physicians (PCPs). This article aims to provide PCPs with a logical algorithm for the assessment and initiation of treatment for LUTS in the male patient. Results: Management of LUTS involves a focused history and physical, as well as the assessment of bother. In patients for whom treatment is warranted, a series of decisions regarding therapy should be considered. Male patients commonly suffer from storage and/or voiding symptoms. Treatment of male LUTS is commonly begun with agents that are aimed at remedying the outlet symptoms of benign prostatic hyperplasia (BPH). When this intervention is ineffective or when refractory symptoms persist, consideration should be given to treating the storage symptoms characteristic of overactive bladder (OAB). Discussion: This article is intended to provide the PCP with a logical guide to the treatment of male LUTS. Benign prostatic hyperplasia and OAB predominate among the causes of these symptoms, and the PCP should be comfortable treating each. Recent data detailing the safety of the use of these treatments in the male patient are reviewed and incorporated into the algorithm. Conclusion: Primary care physicians are in a unique position to successfully identify and treat male patients with LUTS. With this paper, they now have a tool to approach treatment logically and practically. [ABSTRACT FROM AUTHOR]

The aim of the study was to evaluate the efficacy, safety and effect on quality of life of the Reliance urinary control insert (Uromed Corp., Needham, MA) in women with genuine stress incontinence. Efficacy was evaluated at baseline and at the end of the 12-month study period by standardized pad-weight studies and by rating scales measuring acceptability, incontinence symptom improvement, ease of learning, comfort and time to habituation, recorded in diaries at monthly intervals in 63 women. The SF-36 Health Survey questionnaire was used to assess quality of life status at baseline without the device and after 12 months of device use. A significant decrease in urine loss at 12 months compared with baseline was shown by standardized pad-weight studies, with and without the device in situ. Urine loss was reduced by more than 80% in 91% of the 63 patients, and 79% were completely dry. Patient diaries showed significant improvement in control of leakage, comfort, and ease of device use during the study period. Short-term-36 Health Status data also indicated significant improvement in the physical functioning score at 12 months. Urinary tract infection and hematuria were the most common adverse effects. The Reliance urinary control insert is an efficacious and safe means of controlling genuine stress incontinence in women. The device was perceived as easy to use and comfortable for these 63 women, and resulted in improved quality of life. [ABSTRACT FROM AUTHOR]

Extended voiding cystometry was performed for 3-10 h at the natural filling rate of 20 patients with complete suprasacral spinal cord injury and detrusor hyperreflexia and vesicosphicter dyssynergia who had normal upper tracts. This technique provided documentation of the frequency, duration, and amplitude of and the change in the intercontraction pressure during multiple physiologic voiding cycles. The percentage of time occupied by contractile activity and that during which intravesical pressures were >40 cmHO were also calculated. The detrusor activity in this patient group has not previously been reported. Although our patients demonstrated frequent (2.1 contractions/h) high-amplitude (56.8 cmHO), long (4 min/contraction) contractions and spent substantial time (13.8% of the time monitored) in contractile activity that maintained intravesical pressures of >40 cmHO (8.4%), they showed no evidence of upper tract disease. The five patients who underwent outlet procedures because of clinically problematic autonomic dysreflexia demonstrated a statistically significant postoperative decrease in contraction amplitude ( P<0.01) and in time during which intravesical pressures were >40 cmHO ( P<0.05). Extended voided cystometry enabled the measurement of detrusor contractility patterns and resting intravesical pressures that resulted from physiologic filling rates over an extended period, therefore providing considerably more information about detrusor activity than do conventional cystometric techniques. [ABSTRACT FROM AUTHOR]

The anticholinergic and musculotropic relaxant properties of desmethylimipramine (DMI) on smooth muscle were investigated utilizing cholinergic radioligand receptor binding and in-vitro muscle bath techniques. Receptor binding studies revealed the direct antimuscarinic potency of DMI to be 1/480th that of atropine. Muscle bath studies characterized discrete antimuscarinic and musculotropic actions. An initial, competitive antimuscarinic action could be separated from a delayed onset, noncompetitive musculotropic action by altering the time between the addition of DMI and the addition of bethanechol to the smooth muscle bath. [ABSTRACT FROM AUTHOR]

- Experimental models to represent the surgical methods of bladder transection in humans were performed on dogs and rabbits. The effects on vesical neurophysiology were studied by cystometry with bethanechoI supersensitivity testing; by in vitropharmacoIogicaI responsiveness; by determination of autonomic receptor densities using radio-ligand binding and by autonomic neurohistochemical staining. Analysis revealed that transection with or without neurovascular preservation resulted in an alpha-adrenergic denervation and cholinergic decentralization. A comparison with the surgical models is presented and proposed mechanisms of action are discussed in relation to the experimental results. [ABSTRACT FROM AUTHOR]

Urinary control urethral insert devices have been introduced as a non-surgical remedy to treat female urinary incontinence. Several early clinical trials have demonstrated the degrees of safety and efficacy, and have defined the morbidity and complications of these urethral inserts. This is a descriptive review of urethral insert devices in clinical use or currently undergoing clinical investigation. [ABSTRACT FROM AUTHOR]