Proof of concept trial of tanezumab for the treatment of symptoms associated with interstitial cystitis.

PURPOSE: In this randomized, double-blind, placebo controlled phase 2 study we investigated tanezumab, a humanized monoclonal antibody that specifically inhibits nerve growth factor as a treatment for interstitial cystitis pain. MATERIALS AND METHODS: Patients with interstitial cystitis received a single intravenous dose of 200 µg/kg tanezumab or placebo. Patients recorded daily pain scores (on an 11-point numerical rating scale) 7 days before attending study visits and completed a urinary symptom diary for 3 of those days. Patients also completed the Interstitial Cystitis Symptom Index questionnaire and a global response assessment. The primary end point was change in average daily numerical rating scale pain score from baseline to week 6. Secondary end points included global response assessment, Interstitial Cystitis Symptom Index score, micturition and urgency episode frequency per 24 hours, and mean voided volume per micturition. The incidence of adverse events was also assessed. RESULTS: A total of 34 patients received tanezumab and 30 received placebo. At week 6 tanezumab produced a significant reduction from baseline in average daily pain score vs placebo (treatment difference [LS mean, 90% CI] was -1.4 [-2.2, -0.5]). A significantly higher proportion of patients on tanezumab responded as improved in the global response assessment and tanezumab also significantly reduced urgency episode frequency vs placebo. Tanezumab had no significant effect on Interstitial Cystitis Symptom Index score, micturition frequency or mean voided volume per micturition. The most common adverse events were headache (tanezumab 20.6%, placebo 16.7%) and paresthesia (tanezumab 17.6%, placebo 3.3%). CONCLUSIONS: Tanezumab has shown preliminary efficacy in the treatment of pain associated with interstitial cystitis.

Melatonin pharmacotherapy for nocturia in men with benign prostatic enlargement.

PURPOSE: Nocturia is a common condition often attributed in aging men to benign prostatic enlargement. Older adults are prone to nocturnal sleep disturbance, of which disturbed circadian rhythm may be a component since it improves with nighttime administration of melatonin. This study was designed to investigate melatonin as a potential treatment for nocturia associated with bladder outflow obstruction in older men. MATERIALS AND METHODS: A total of 20 men with urodynamically confirmed bladder outflow obstruction and nocturia were entered into a randomized, double blind, placebo controlled crossover study assessing the effect of 2 mg controlled release melatonin at night on nocturia. Symptoms were assessed at baseline and after each 4-week treatment period using a frequency volume chart, the International Prostate Symptom Score and symptom problem index. Maximum urinary flow rate and post-void residual urine volume were also assessed. RESULTS: Baseline frequency of nocturia was 3.1 episodes per night. There were 7 men (35%) with detrusor overactivity and 10 (50%) had nocturnal polyuria. Melatonin and placebo caused a decrease in nocturia of 0.32 and 0.05 episodes per night (p = 0.07) and a decrease in the nocturia bother score of 0.51 and 0.05, respectively (p = 0.008). Nocturia responder rates (a reduction from baseline of at least -0.5 episodes per night) differed between the active medication and placebo groups (p = 0.04). Daytime urinary frequency, International Prostate Symptom Score, relative nocturnal urine volume, maximum urinary flow rate and post-void residual were unaffected by melatonin treatment. CONCLUSIONS: Melatonin treatment is associated with a significant nocturia response rate, improvement in nocturia related bother and a good adverse effect profile. However, it is uncertain whether the observed changes in this study are clinically significant.

Model of peripheral autonomous modules and a myovesical plexus in normal and overactive bladder function.

Normal bladder function is controlled by the central nervous system (CNS) and any peripheral contribution to bladder control is believed to be small. Nevertheless, anatomically and functionally, such a contribution might exist. Taking account of this evidence, we propose that the detrusor muscle is arranged into modules, which are circumscribed areas of muscle active during the filling phase of the micturition cycle. These modules might be controlled by a peripheral myovesical plexus, consisting of intramural ganglia and interstitial cells. Detrusor overactivity is the occurrence of abnormal increases in pressure during bladder filling, which the patient cannot inhibit. This disorder is thought to be a consequence of abnormal expression of the micturition reflex or changes in the properties of the smooth muscle. We propose that detrusor overactivity results from exaggerated symptomatic expression of peripheral autonomous activity, resulting from a shift in the balance of excitation and inhibition in smooth muscle modules. These structures responsible for origin and spread of peripheral autonomous activity could be targeted to help develop new therapeutic strategies.

Radiotelemetered cystometry in pigs: validation and comparison of natural filling versus diuresis cystometry.

PURPOSE: Cystometry has previously been performed in awake animals using vesical and abdominal catheters, and artificial bladder filling. Conventional urodynamic recordings may be obtained in this manner, albeit under nonphysiological and potentially stressful conditions. Therefore, we developed a technique to perform continuous, ambulatory cystometric monitoring in pigs. MATERIALS AND METHODS: A dual pressure radiotelemetry device was surgically implanted in 22 large white pigs. Vesical and abdominal pressures were recorded and validated, subtracted detrusor pressures were derived and natural fill and diuresis cystometry was compared. RESULTS: Continuous recordings were obtained for 1 to 24 hours, and the devices remained in the animals for up to 3 months. There were few complications and incrustation of the intravesical catheter tip occurred but it did not appear to affect recorded pressures. The pressure data were validated by comparison with filling pressures during bladder distention and simultaneous conventional cystometry at the end of the experimental period. Comparison of natural filling and diuresis cystometrograms showed that natural bladder filling results in higher maximum detrusor pressure during voiding (38.1 versus 33.9 cm. H2O, p <0.05), higher detrusor pressure after contractions (42.6 versus 32.2 cm. H2O, p <0.05) and more frequent detection of unstable contractions in pigs with detrusor instability secondary to experimental manipulation of the lower urinary tract (77.8% versus 45.0%, p <0.05). CONCLUSIONS: This technique allows continuous cystometric monitoring in less stressed animals under more physiological conditions for relatively long periods and, thus, allows prolonged assessment of bladder function in pigs in response to pathological and pharmacological manipulations. Nonphysiological rates of bladder filling have been shown to result in detrusor inhibition, which emphasizes the importance of ambulatory cystometry when describing bladder function.

Structural and functional denervation of human detrusor after spinal cord injury.

The bladder receives an extensive nerve supply that is predominantly cholinergic, but several putative transmitters are present, some of which are colocalized. Previous studies have shown increased levels of sensory nerves, reduced inhibitory transmitters, and structural and functional changes in the excitatory input in unstable bladder conditions. The present study compared the end-organ nerve supply to the bladder in spinal cord injury (SCI) with uninjured controls. Acetylcholinesterase histochemistry and double-label immunofluorescence were used to investigate neurotransmitter content, with confocal laser scanning microscopy to assess colocalization. Organ bath studies provided functional correlates for the structural changes in the excitatory innervation. Control samples had dense innervation of the detrusor containing a diverse range of transmitters. Hyperreflexic SCI samples showed patchy denervation, and areflexic SCI samples were diffusely denervated. Vasoactive intestinal polypeptide-, neuropeptide Y-, neuronal nitric oxide synthase-, and galanin-immunoreactive nerve fibers were reduced from frequent or moderately frequent to infrequent or very infrequent in SCI. Calcitonin gene-related peptide-immunoreactive fibers were infrequent in controls and SCI samples. Patterns of colocalization were unchanged, but significantly fewer fibers expressed more than one transmitter. The subepithelial plexus was markedly reduced and several of the smaller coarse nerve trunks showed no immunoreactivity to the transmitters assessed. There was no reduction in sensitivity to electrical field stimulation of intrinsic nerves in SCI, but the maximum force generated by each milligram of bladder tissue and the peak force as a proportion of the maximum carbachol contraction were significantly reduced and the responses were protracted. There was no significant functional atropine-resistant neuromuscular transmission in controls or SCI. The reported findings have clinical implications in the management of chronic SCI and development of new treatments.

The contribution of cholinergic detrusor excitation in a pig model of bladder hypocompliance.

OBJECTIVE: To investigate the role of cholinergic excitation in mediating changes in detrusor compliance (manifested on conventional cystometry as an incremental rise in detrusor pressure as bladder volume increases) under conditions of propofol-sedation in the pig. Materials and methods Consecutive cystometrograms (CMGs) were obtained from eight female Large White pigs at a bladder filling rate of 50 mL/min. The first CMG was obtained while the pig was awake and unsedated. Two subsequent CMGs were obtained after light to moderate sedation with propofol (2-8 mg/kg/h) before and after the administration of intravenous atropine (0.02 mg/kg). RESULTS: All bladders were highly compliant over the volumes instilled (before sedation) with a maximum pressure during the filling phase of 0.9 cmH2O and a compliance of 943 mL/cmH2O. After sedation with propofol, the maximum pressure during the filling phase increased to 14 cmH2O with a compliance of 69 mL/cmH2O. Atropine antagonized this change in compliance; after sedation and atropine, the maximum pressure during the filling phase decreased to 4 cmH2O (P < 0.05) and the compliance increased to 337 mL/cmH2O (P < 0.05). CONCLUSION: The decrease in compliance seen in the pig bladder after sedation with propofol is mediated via muscarinic excitation. This probably occurs as a result of low-level tonic release of acetylcholine by the efferent parasympathetic nerves. The existence of such efferent excitatory activity during the storage phase in the overactive human bladder might explain the efficacy of bladder-selective muscarinic antagonists in a proportion of patients with detrusor hyper-reflexia and instability.

Studies of the pathophysiology of idiopathic detrusor instability: the physiological properties of the detrusor smooth muscle and its pattern of innervation.

PURPOSE: Idiopathic detrusor instability (IDI) is a common cause of lower urinary tract storage symptoms, such as urgency, frequency and urge incontinence. We have investigated the in vitro properties and pattern of innervation of the detrusor from patients with this condition. MATERIALS AND METHODS: Full thickness bladder specimens were obtained perioperatively from 14 patients with IDI and from 14 cadaveric controls undergoing transplant organ retrieval. Isolated detrusor smooth muscle strips were mounted in organ baths for isometric tension recording. Frequency-response curves to electrical field stimulation (EFS) (1 Hz to 50 Hz) and concentration response curves for carbachol (10(-7) M to 5 x 10(-4) M) and potassium (12 mM to 120 mM) were constructed. Acetylcholinesterase histochemistry and immunohistochemistry for both phosphorylated and non-phosphorylated neurofilaments was carried out on frozen sections of control and IDI bladders. RESULTS: IDI strips developed greater spontaneous tone (0.25 gm./mg. versus 0.12 gm./mg.; p <0.0001) and more spontaneous fused tetanic contractions (16.8% versus 6.8%; p <0.005) during an initial 90 minutes equilibration period. The IDI strips were less responsive than controls to nerve stimulation (max. response to EFS 0.79 gm./mg. versus 1.23 gm./mg.; p <0.0001) and were supersensitive to potassium (EC50 39.7 mM versus 45.7 mM; p = 0.003) but not to carbachol (EC50 7.3 x 10(-6) M versus 6.6 x 10(-6) M; p = 0.48). Morphometric studies revealed reduced staining of presumed cholinergic nerves, with 34.7% of IDI smooth muscle bundles appearing denervated compared with 1.5% of controls (p <0.0001). CONCLUSIONS: Our study supports the notion that there is a fundamental abnormality in IDI at the level of the bladder wall, with evidence of altered spontaneous contractile activity consistent with an increased electrical coupling of cells, a patchy denervation of the detrusor and a potassium supersensitivity.

Blood supply to the bladder during filling.

Amongst other features of bladder physiology, the mechanics of cyclic filling and emptying make the blood supply of the bladder unique with respect to other organs of the body. Blood vessels are required to lengthen and shorten, whilst maintaining sufficient perfusion of the smooth muscle. Interruption of the blood supply may result in ischaemia and, ultimately reperfusion, resulting in bladder pathologies. The blood flow is also likely to be affected by factors such as increased intra-abdominal pressure. In this article, several features of the blood supply to the bladder- and also the urethra--are discussed.

Prospective randomized controlled trial to compare skin staples and polypropylene for securing the mesh in inguinal hernia repair.

BACKGROUND: The Lichtenstein tension-free repair has become the standard method for repairing inguinal hernia in many surgical units. This study compared two methods of mesh fixation. METHODS: Fifty men undergoing unilateral primary Lichtenstein inguinal hernia repair under general anaesthesia were randomized into two groups. In the control group polypropylene mesh was secured with 2/0 polypropylene sutures and the skin closed with subcuticular 3/0 polydioxanone. In the study group polypropylene mesh was secured with skin staples and the skin was closed with staples from the same staple gun. Duration of the operation was recorded. Early follow-up was achieved by patient review at 6 weeks and postal questionnaire at 12 weeks. RESULTS: The operation was significantly shorter when staples were used (median 20 min 0 s versus 29 min 30 s, P < 0.001). There was no significant difference in the incidence of postoperative complications or pain score. The study group reported earlier return to normal activity (4 weeks 0 days versus 6 weeks 2 days, P < 0.01) although there was no difference in the time taken to return to work or driving. CONCLUSION: The use of skin staples to secure mesh in the Lichtenstein inguinal hernia repair significantly reduced the duration of the operation and was as effective as conventional mesh fixation with polypropylene in the short term.