The importance of neural factors in the presentation and treatment of prostatic obstruction.

Symptomatic bladder outlet obstruction due to prostatic enlargement is a common problem in urological practice. Hyperactive detrusor function, "detrusor instability", occurs in up to 80% of patients presenting with prostatic obstruction and in most cases it resolves post-operatively when the obstruction has been relieved. This dysfunction is generally regarded as a modern concept but, in 1786, John Hunter recognised the complex nature of prostatic obstruction and reported: “The disease of the bladder arising from obstruction alone, is increased irritability, and its consequences, by which the bladder becomes quick in its action and thick and strong in its coats." Animal models have confirmed the relationship between obstruction and instability. Several hypotheses have been proposed to explain this link and include; (1) post-junctional hypersensitivity possibly related to denervation, (2) altered adrenoceptor function, (3) afferent nerve dysfunction, (4) an imbalance of peptide neuro-transmitters, and (5) a primary or acquired myogenic deficit. The principal motor control of the intraprostatic musculature is mediated by the sympathetic nervous system; however, the mechanism of action and specific localisation of prostatic adrenoceptors and the importance of non-adrenergic neurotransmission in man is poorly understood. A study of patients with symptomatic prostatic obstruction was undertaken to investigate the influence of neural pathways in determining the pathogenesis and clinical presentation of prostatic and detrusor dysfunction. Sixty-two patients were investigated using modern urodynamic techniques and sub-divided into three groups; control, stable obstructed and unstable obstructed. Biopsies of prostate, bladder neck and bladder muscle were taken at the time of surgery, and pharmacological, autoradiographic and histochemical studies performed. The prostate, bladder and bladder neck were found to be innervated by a complex network of noradrenaline-, acetylcholine-, neuropeptide-, and amine-containing nerves. Separate quantitative analyses of these neurons were carried out and corrections applied to compensate for muscle hypertrophy and hyperplasia. The histological findings were complemented wherever possible by biochemical assay of neuro transmitters. There was a significant reduction in the acetylcholinesterase positive innervation of the obstructed bladder compared with control, which was most marked in tissue from patients with detrusor instability. A similar reduction in the non-adrenergic, non-cholinergic sensorimotor neurotransmitters was evident. Biochemical changes within the detrusor included an increase in noradrenaline content and a decrease in the putative sensory neurotransmitter substance P. Detrusor muscle strips from obstructed patients showed increased contraction in response to acetylcholine, suggesting that denervation hypersensitivity might contribute to the pathogenesis of post-obstructive detrusor instability. Normal detrusor muscle relaxed in response to noradrenaline. In contrast, detrusor muscle from unstable obstructed patients contracted; a response most marked in detrusor muscle from patients who had presented in acute retention. In vitro prostatic muscle-strip experiments confirmed that contraction of prostatic muscle is produced by adrenoceptor stimulation. Radioligand binding assays endorsed the results of these experiments by demonstrating a clear excess of α1 receptors over α2 receptors in histologically normal and adenomatous prostate. Auto-radiography showed the precise localization of the two types of adrenoceptor and confirmed the predominance of α1 receptors within prostatic musculature. The complexity and potential importance of the autonomic nervous system in the pathogenesis and symptomatic expression of prostate-mediated bladder outflow obstruction, is demonstrated by this work. Marked changes in the innervation of both the prostate and bladder accompany obstructive benign enlargement of the prostate. The characterisation and localisation of the prostatic adrenoceptor is of considerable relevance since it validates the therapeutic use of selective prostatic α1 blockade in the clinical management of obstructed patients. Preliminary immunohistochemical studies of bladder, bladder neck and prostate are presented, which provide an histological basis for further functional investigative studies

Tissue engineering in urethral reconstruction

Tissue engineering is an exciting and rapidly evolving technology. In this review, we discuss the recent progress made in the field of urethral reconstruction and consider the clinical implications and further advancement of these endeavours

Synthetic Materials Used in the Surgical Treatment of Pelvic Organ Prolapse: Problems of Currently Used Material and Designing the Ideal Material

Synthetic materials have long been used to provide structural support when surgically repairing pelvic organ prolapse (POP). The most widely used synthetic material is a mesh made of polypropylene (PPL). The use of mesh is intended to improve cure rates and prevent recurrences after POP surgery – however as more mesh materials have been implanted, it has become apparent that serious complications can occur in up to 30% of women, particularly when the mesh is implanted transvaginally. Over the years many different mesh kits have been marketed and used in the treatment of POP however polypropylene mesh was never designed or tested for use in pelvic floor. Instead it was approved for clinical use based on its biocompatibility and success in abdominal hernia repairs. It is now known that PPL meshes are neither compliant with the mechanical forces in the pelvic floor nor do they integrate well into paravaginal tissues. Better materials developed specifically for use in pelvic floor are urgently needed. The aim of this chapter is to define the requirements of an ideal mesh in terms of its material properties and to summarize the ongoing research on developing the next generation pelvic floor repair materials

α_1L-adrenoceptors mediate contraction of human erectile tissue

α1-adrenoceptor antagonists can impact upon sexual function and have potential in the treatment of erectile dysfunction. Human erectile tissue contains predominantly α1A-adrenoceptors, and here we examined whether contractions of this tissue are mediated by the functional phenotype, the α1L-adrenoceptor. Functional experiments using subtype selective agonists and antagonists, along with radioligand ([3H]tamsulosin) binding assays, were used to determine the α1-adrenoceptor population. A61603, a α1A-adrenoceptor agonist, was a full agonist with a potency 21-fold greater than that of noradrenaline. The α1A- and α1D-adrenoceptor antagonist tamsulosin antagonized noradrenaline responses with high affinity (pKD = 9.7 ± 0.3), whilst BMY7378 (100 nM) (α1D-adrenoceptor antagonist) failed to antagonize responses. In contrast, relatively low affinity estimates were obtained for both prazosin (pKD = 8.2 ± 0.1) and RS17053 (pKD = 6.9 ± 0.2), antagonists which discriminate between the α1A- and α1L-adrenoceptors. [3H]Tamsulosin bound with high affinity to the receptors of human erectile tissue (pKD = 10.3 ± 0.1) with a receptor density of 28.1 ± 1.4 fmol mg−1 protein. Prazosin displacement of [3H]tamsulosin binding revealed a single homogenous population of binding sites with a relatively low affinity for prazosin (pKi = 8.9). Taken together these data confirm that the receptor mediating contraction in human erectile tissue has the pharmacological properties of the α1L-adrenoceptor. Keywords: Erectile tissue, α1-adrenoceptor subtypes, α1L-adrenoceptor, Tamsulosin, Prazosi

Cardiovascular Safety of β3-adrenoceptor Agonists for the Treatment of Patients with Overactive Bladder Syndrome

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Cardiovascular safety in refractory incontinent patients with overactive bladder receiving add-on mirabegron therapy to solifenacin (BESIDE)

© 2017 John Wiley & Sons Ltd.Summary : Aims/objectives: : In the BESIDE study, combination therapy (antimuscarinic [solifenacin] and β3-adrenoceptor agonist [mirabegron]) improved efficacy over solifenacin monotherapy without exacerbating anticholinergic side effects in overactive bladder (OAB) patients; however, a potential synergistic effect on the cardiovascular (CV) system requires investigation. Methods: OAB patients remaining incontinent despite daily solifenacin 5 mg during 4-week single-blind run-in, were randomised 1:1:1 to double-blind daily combination (solifenacin 5 mg/mirabegron 25 mg, increasing to 50 mg after week 4), solifenacin 5 or 10 mg for 12 weeks. CV safety assessments included frequency of CV-related treatment-emergent adverse events (TEAEs), change from baseline in vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate) and electrocardiogram (ECG) parameters. Results: The frequency of hypertension, tachycardia and ECG QT prolongation, respectively, was low and comparable across combination (1.1%, 0.3%, 0.1%), solifenacin 5 mg (0.7%, 0.1%, 0.1%), and solifenacin 10 mg groups (0.8%, 0%, 0.1%). Adjusted mean (SE) change from baseline to end of treatment (EoT) in SBP, DBP, and pulse rate with combination (0.07 mm Hg [0.38], -0.35 mm Hg [0.26], 0.47 bpm [0.28]), solifenacin 5 mg (-0.93 mm Hg [0.38], -0.45 mm Hg [0.26], 0.43 bpm [0.28]) and solifenacin 10 mg (-1.28 mm Hg [0.38], -0.48 mm Hg [0.26], 0.27 bpm [0.28]) was generally comparable, with the exception of a mean treatment difference of ~1 mm Hg in SBP between combination and solifenacin monotherapy; SBP was unchanged with combination and decreased with solifenacin monotherapy. Mean changes from baseline to EoT in ECG parameters were generally similar across treatment groups, except for QT interval corrected using Fridericia's formula, which was higher with solifenacin 10 mg (3.30 mseconds) vs. combination (0.49 mseconds) and solifenacin 5 mg (0.77 mseconds). Conclusion: The comparable frequency of CV-related TEAEs, changes in vital signs and ECG parameters indicates no synergistic effect on CV safety outcomes when mirabegron and solifenacin are combined

Basic mechanisms of urgency: roles and benefits of pharmacotherapy

Introduction Since urgency is key to the overactive bladder syndrome, we have reviewed the mechanisms underlying how bladder filling and urgency are sensed, what causes urgency and how this relates to medical therapy. Materials and methods Review of published literature. Results As urgency can only be assessed in cognitively intact humans, mechanistic studies of urgency often rely on proxy or surrogate parameters, such as detrusor overactivity, but these may not necessarily be reliable. There is an increasing evidence base to suggest that the sensation of ‘urgency’ differs from the normal physiological urge to void upon bladder filling. While the relative roles of alterations in afferent processes, central nervous processing, efferent mechanisms and in intrinsic bladder smooth muscle function remain unclear, and not necessarily mutually exclusive, several lines of evidence support an important role for the latter. Conclusions A better understanding of urgency and its causes may help to develop more effective treatments for voiding dysfunction

Persistence and Adherence with Mirabegron versus Antimuscarinic Agents in Patients with Overactive Bladder: A Retrospective Observational Study in UK Clinical Practice

Background: Persistence with antimuscarinic therapy in overactive bladder (OAB) is poor, but may be different for mirabegron, a β3-adrenoceptor agonist with a different adverse event profile. Objective: To compare persistence and adherence with mirabegron versus tolterodine extended release (ER) and other antimuscarinics in routine clinical practice over a 12-mo period. Design, setting, and participants: Retrospective, longitudinal, observational study of anonymised data from the UK Clinical Practice Research Datalink GOLD database. Eligibility: age ≥18 yr, ≥1 prescription for target OAB drug (between May 1, 2013 and June 29, 2014), and 12-mo continuous enrolment before and after the index prescription date. Interventions: Mirabegron, darifenacin, fesoterodine, flavoxate, oxybutynin ER or immediate-release (IR), propiverine, solifenacin, tolterodine ER or IR, and trospium chloride. Outcome measurements and statistical analysis: The primary endpoint was persistence (time to discontinuation). Secondary endpoints included 12-mo persistence rates and adherence (assessed using medication possession ratio, MPR). Cox proportional-hazards regression models and logistic regression models adjusted for potential confounding factors were used to compare cohorts. Analyses were repeated after 1:1 matching. Results and limitations: The study population included 21. 996 eligible patients. In the unmatched analysis, the median time-to-discontinuation was significantly longer for mirabegron (169 d, interquartile range [IQR] 41-not reached) compared to tolterodine ER (56 d, IQR 28-254; adjusted hazard ratio [HR] 1.55, 95% confidence interval 1.41-1.71; p <. 0.0001) and other antimuscarinics (range 30-78 d; adjusted HR range 1.24-2.26, p <. 0.0001 for all comparisons). The 12-mo persistence rates and MPR were also significantly greater with mirabegron than with all the antimuscarinics. Limitations include the retrospective design, use of prescription records to estimate outcomes, and inability to capture reasons for discontinuation. Conclusions: Persistence and adherence were statistically significantly greater with mirabegron than with tolterodine ER and other antimuscarinics prescribed for OAB in the UK. Patient summary: This study assessed persistence and adherence (or compliance) with medications prescribed for OAB in a large UK population. We found that patients prescribed mirabegron remained on treatment for longer and showed greater adherence than those prescribed traditional antimuscarinics. For chronic conditions such as overactive bladder, long-term adherence is important to maintain treatment benefit. Persistence with antimuscarinics is a recognised challenge. This analysis of a UK primary care database demonstrates that persistence and adherence are significantly greater with mirabegron versus antimuscarinics