Update from TASCI, a Nationwide, Randomized, Sham-controlled, Double-blind Clinical Trial on Transcutaneous Tibial Nerve Stimulation in Patients with Acute Spinal Cord Injury to Prevent Neurogenic Detrusor Overactivity.

Transcutaneous tibial nerve stimulation has the potential to revolutionize the management of lower urinary tract dysfunction in patients with acute spinal cord injury. TASCI is a nationwide randomized, sham-controlled, double-blind clinical trial for which the preparatory phase has been successfully completed.

A medical device containing purified bovine colostrum (Monurelle Biogel) in the treatment of vulvovaginal atrophy in postmenopausal women: Retrospective analysis of urinary symptoms, sexual function, and quality of life.

OBJECTIVE: This study assessed the effectiveness and safety of a medical device containing purified bovine colostrum (Monurelle Biogel; Zambon, Bresso, Italy) in improving vulvovaginal atrophy (VVA), sexual function, urinary symptoms, and quality of life (QoL) in postmenopausal women. METHODS: In all, 172 postmenopausal women with VVA were included in the study. All women were treated with vaginal Monurelle Biogel daily for 12 weeks. Patients underwent clinical examinations, completed a 3-day voiding diary, and had VVA graded using the Vaginal Health Index (VHI) at baseline and 12 weeks. Patients also completed the Female Sexual Function Index (FSFI), overactive bladder questionnaire (OAB-Q), and the Urogenital Distress Inventory (UDI-6), among others. RESULTS: After 12 weeks, there were significant increases in mean (± SD) VHI (12.53 ± 3.67 vs. 19.31 ± 3.49; P < .0001), the number of patients engaging in regular sexual activity 102 (59.3%) vs. 144 (83.7%), and in the total FSFI score (21.64 ± 2.99 vs. 28.16 ± 1.93; P < .0001) compared with baseline. In addition, there were significant reductions in the mean number of 24-hour voids (9.57 ± 2.12 vs. 7.13 ± 1.22; P < .0001), urgent micturition episodes per 24 hours (1.75 ± 0.76 vs. 1.14 ± 0.87; P = .001), nocturia episodes (1.58 ± 0.85 vs. 0.97 ± 1.18; P = .0002), and urinary incontinence episodes per 24 hours (0.74 ± 0.59 vs. 0.28 ± 0.52; P = .003). Finally, after 12 weeks treatment, there were significant differences in UDI-6 (7.85 ± 0.81 vs. 5.56 ± 1.40), OAB-Q symptom (53.60 ± 12.57 vs. 22.08 ± 9.63), and OAB-Q health-related QoL (21.75 ± 8.51 vs. 69.34 ± 14.59) scores compared with baseline (P < .0001 for all). The Patient Impression of Global Improvement scale revealed global improvement in 143 women (83.14%). CONCLUSIONS: Monurelle Biogel is an effective treatment for VVA in postmenopausal women, improving sexual life, urinary symptoms, and QoL.

Sex difference in the contribution of GABAB receptors to tibial neuromodulation of bladder overactivity in cats.

This study investigated the role of γ-aminobutyric acid subtype B (GABAB) receptors in tibial and pudendal neuromodulation of bladder overactivity induced by intravesical administration of dilute (0.5%) acetic acid (AA) in α-chloralose-anesthetized cats. To inhibit bladder overactivity, tibial or pudendal nerve stimulation (TNS or PNS) was applied at 5 Hz and two or four times threshold (T) intensity for inducing toe or anal sphincter twitch. TNS at 2T or 4T intensity significantly (P < 0.05) increased the bladder capacity to 173.8 ± 16.2 or 198.5 ± 24.1%, respectively, of control capacity. Meanwhile, PNS at 2T or 4T intensity significantly (P < 0.05) increased the bladder capacity to 217 ± 18.8 and 221.3 ± 22.3% of control capacity, respectively. CGP52432 (a GABAB receptor antagonist) at intravenous dosages of 0.1-1 mg/kg completely removed the TNS inhibition in female cats but had no effect in male cats. CGP52432 administered intravenously also had no effect on control bladder capacity or the pudendal inhibition of bladder overactivity. These results reveal a sex difference in the role of GABAB receptors in tibial neuromodulation of bladder overactivity in cats and that GABAB receptors are not involved in either pudendal neuromodulation or irritation-induced bladder overactivity.

Preventive Effect of Hydrogen Water on the Development of Detrusor Overactivity in a Rat Model of Bladder Outlet Obstruction.

PURPOSE: Bladder ischemia and oxidative stress contribute to the pathogenesis of bladder dysfunction caused by bladder outlet obstruction. H2 reportedly acts as an effective antioxidant. We investigated whether oral ingestion of H2 water would have a beneficial effect on bladder function in a rat model of bladder outlet obstruction. MATERIALS AND METHODS: H2 water was made by dissolving H2 gas in ordinary drinking water using a hydrogen water producing apparatus. The bladder outlet obstruction model was surgically induced in male rats. Rats with obstruction were fed H2 water or ordinary drinking water. On week 4 postoperatively cystometry was performed. Oxidative stress markers and the bladder nerve growth factor level were determined. Bladder tissues were processed for pharmacological studies and histological analysis. RESULTS: The micturition interval and micturition volume significantly decreased in obstructed rats given ordinary drinking water. These decreases were significantly suppressed by oral ingestion of H2 water. Increased post-void residual volume in obstructed rats was significantly reduced by H2 water. Obstruction led to a significant increase in bladder weight, oxidative stress markers and nerve growth factor. H2 water significantly suppressed these increases without affecting bladder weight. There was no significant difference in histological findings between rats with bladder obstruction given H2 water and ordinary drinking water. Decreased responses of detrusor muscle strips from obstructed bladders to KCl, carbachol and electrical field stimulation were reversed by H2 water ingestion. CONCLUSIONS: Results suggest that H2 water could ameliorate bladder dysfunction secondary to bladder outlet obstruction by attenuating oxidative stress.

Soluble guanylyl cyclase (sGC) degradation and impairment of nitric oxide-mediated responses in urethra from obese mice: reversal by the sGC activator BAY 60-2770.

Obesity has emerged as a major contributing risk factor for overactive bladder (OAB), but no study examined urethral smooth muscle (USM) dysfunction as a predisposing factor to obesity-induced OAB. This study investigated the USM relaxant machinery in obese mice and whether soluble guanylyl cyclase (sGC) activation with BAY 60-2770 [acid 4-({(4-carboxybutyl) [2-(5-fluoro-2-{[4-(trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] amino} methyl) benzoic] rescues the urethral reactivity through improvement of sGC-cGMP (cyclic guanosine monophosphate) signaling. Male C57BL/6 mice were fed for 12 weeks with a high-fat diet to induce obesity. Separate groups of animals were treated with BAY 60-2770 (1 mg/kg per day for 2 weeks). Functional assays and measurements of cGMP, reactive-oxygen species (ROS), and sGC protein expression in USM were determined. USM relaxations induced by NO (acidified sodium nitrite), NO donors (S-nitrosoglutathione and glyceryl trinitrate), and BAY 41-2272 [5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine] (sGC stimulator) were markedly reduced in obese compared with lean mice. In contrast, USM relaxations induced by BAY 60-2770 (sGC activator) were 43% greater in obese mice (P < 0.05), which was accompanied by increases in cGMP levels. Oxidation of sGC with ODQ [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one] (10 µM) potentiated BAY 60-2770-induced USM responses in the lean group. Long-term oral BAY 60-2770 administration fully prevented the impairment of USM relaxations in obese mice. Reactive-oxygen species (ROS) production was enhanced, but protein expression of ß1 second guanylate cyclase subunit was reduced in USM from obese mice, both of which were restored by BAY 60-2770 treatment. In conclusion, impaired USM relaxation in obese mice is associated with ROS generation and down-regulation of sGC-cGMP signaling. Prevention of sGC degradation by BAY 60-2770 ameliorates the impairment of urethral relaxations in obese mice.

The soluble guanylyl cyclase activator BAY 60-2770 ameliorates overactive bladder in obese mice.

PURPOSE: Activators of soluble guanylyl cyclase are of potential interest as treatment for cardiovascular diseases but to our knowledge they have never been proposed to treat overactive bladder. We evaluated the effects of the soluble guanylyl cyclase activator BAY 60-2270 on voiding dysfunction and detrusor overactivity in a mouse model of obesity associated overactive bladder. MATERIALS AND METHODS: C57BL/6 male mice fed for 10 weeks with standard chow or a high fat diet were treated with 1 mg/kg BAY 60-2770 per day for 2 weeks via gavage. Cystometric evaluations were done and responses to contractile agents in isolated bladders were determined. RESULTS: Obese mice showed an irregular micturition pattern characterized by significant increases in voiding and nonvoiding contractions, which were normalized by BAY 60-2770. Carbachol, KCl and CaCl2 produced concentration dependent contractions in isolated bladder strips, which were markedly greater in obese than in lean mice. BAY 60-2770 normalized bladder contractions in the obese group. A 78% increase in reactive oxygen species generation in the bladder tissue of obese mice was observed, which was unaffected by BAY 60-2770. Treatment with BAY 60-2770 generated a tenfold increase in cyclic guanosine monophosphate in the bladders of obese mice without affecting the nucleotide level in the lean group. Protein expression of the soluble guanylyl cyclase α1 and ß1 subunits was decreased 40% in the bladder tissue of obese mice but restored by BAY 60-2770. CONCLUSIONS: Two-week BAY 60-2770 therapy increased cyclic guanosine monophosphate and rescued expression of the soluble guanylyl cyclase α1 and ß1 subunits in bladder tissue, resulting in great amelioration of bladder dysfunction.

A galenical produced from Ba-Wei-Die-Huang-Wan (THC-002) provides resistance to the cold stress-induced detrusor overactivity in conscious rats.

AIMS: We determined if THC-002, a galenical produced from Ba-Wei-Die-Huang-Wan, could increase skin temperature and inhibit detrusor overactivity induced by sudden whole body cooling. Further, we determined if THC-002 could decrease expression of transient receptor potential melastatin 8 (TRPM8) channels associated with the cold responses. METHODS: Hind leg skin temperature of female 10-week-old Sprague-Dawley rats was measured by thermal imaging. Experimental rats (n = 12) were given oral 100 mg/kg THC-002 daily for one week, and controls (n = 12) were similarly treated with THC-002-free solution. Afterwards, thermal imaging and cystometric investigations of the freely moving conscious rats were performed at room temperature (RT, 27 ± 2°C) for 20 min. The rats were then transferred to a low temperature (LT, 4 ± 2°C) environment during which thermal imaging and cystometric measurements were taken at 5, 10, 20, 30, and 40 min. Afterward, the skin tissues were harvested to estimate expression levels of TRPM8 channels by immunohistochemistry and real-time reverse-transcription polymerase chain reaction. RESULTS: The RT skin temperature of THC-002-treated rats was significantly higher than controls. During the first 20 min under LT, the control rats exhibited cold stress-induced detrusor overactivity such as decreased voiding interval and bladder capacity. THC-002 partially inhibited the detrusor overactivity patterns. During the second 20 min, skin temperature was relatively stable, and the detrusor overactivity of both groups slowly disappeared. THC-002 significantly reduced expression of TRPM8 channel protein and mRNA. CONCLUSIONS: THC-002 inhibited cold stress-induced detrusor overactivity resulting from decreasing skin temperature. Therefore, THC-002 might provide resistance to cold stress-exacerbated lower urinary tract symptoms.

Nicorandil ameliorates hypertension-related bladder dysfunction in the rat.

AIMS: There is increasing evidence that ischemia is one of the main etiology in overactive bladder (OAB), and that nicorandil prevents OAB. We investigated the effect of nicorandil on hypertension-related bladder dysfunction in spontaneously hypertensive rats (SHRs). METHODS: Twelve-week-old SHRs received six-weeks treatment with nicorandil (0, 3, or 10 mg/kg, i.p. every day). Wistar rats were used for normotensive controls. Six weeks after nicorandil treatment, the bladder blood flow was estimated by hydrogen clearance method, and the bladder functions were estimated by voiding behavior studies and functional studies. Tissue levels of nerve growth factor (NGF) were measured by ELISA method. Furthermore, the participation levels of K(ATP) channel pores were investigated by real-time PCR. RESULTS: SHRs showed significant increases in blood pressure, micturition frequency, tissue levels of NGF and expressions of both K(IR) 6.1 and K(IR) 6.2 mRNAs, and a significant decrease in the bladder blood flow. The carbachol-induced contractile responses were similar in all groups. Although both doses of nicorandil failed to decrease the blood pressure, nicorandil significantly decreased the micturition frequency, tissue levels of NGF and increased the bladder blood flow in a dose dependent manner. The expressions of K(IR) 6.1 and K(IR) 6.2 mRNAs were slightly up-regulated by the low dose of nicorandil, whereas the high dose of nicorandil significantly up-regulated those expressions compared to non-treated SHRs. CONCLUSIONS: These data indicate that nicorandil prevents hypertension-related bladder dysfunction in the SHR, which may be related to its effect on the increased blood flow in the bladder.

Dietary phytoestrogens maintain contractile responses to carbachol with age in the female rat isolated bladder.

AIMS: Development of urinary incontinence, for many women, occurs following menopause. Dietary phytoestrogens consumed over the long term may affect the contractile function and maintenance of the urinary bladder in post menopausal women. This study examined the muscarinic receptor mediated contractile responses in the rat isolated bladder in response to ovariectomy and long term dietary phytoestrogen consumption. MAIN METHODS: Ovariectomised or sham-operated female Wistar rats (8 weeks) were fed either normal rat chow (soy, phytoestrogens) or a non-soy (phytoestrogen free) diet. Bladders were dissected from rats at 12, 24 and 52 weeks of age and placed in 25 ml organ baths filled with McEwans solution. KEY FINDINGS: The contractile response to carbachol, in 12 week old female rats did not change as a result of dietary phytoestrogens or ovariectomy (P>0.05). At 24 weeks of age, detrusor muscle strip responses to carbachol from non-soy fed ovariectomised rats were attenuated (P<0.05). At 52 weeks, bladder detrusor strip responses to carbachol were reduced in all treatment groups with the exception of the soy-fed sham operated rats. SIGNIFICANCE: These results suggest an age-related reduction in the contractile response of the detrusor to the muscarinic receptor agonist carbachol, which may be prevented by long term dietary phytoestrogen intake.

Determining outcomes, adverse events, and predictors of success after sacral neuromodulation for lower urinary disorders in women.

INTRODUCTION AND HYPOTHESIS: The objective of this study was to determine the predictors of successful treatment of lower urinary tract disorders with sacral nerve stimulation (SNS) and the rate of adverse events and reoperations. METHODS: A retrospective case series of patients who underwent SNS at a single institution was analyzed. RESULTS: Seventy-six patients underwent stage I trial of SNS. Fifty-eight (76%) patients experienced improvement and underwent placement of an implantable pulse generator with a mean follow-up of 23.7 months (SD ± 22.3). Surgical revisions occurred in 14/58 (24%) patients and 15/58 (26%) patients had the device explanted after a mean of 2.8 years (SD ± 1.7). Patients with greater than ten incontinence episodes per day were more likely to have a successful stage I trial compared to those with less than five (OR = 10.3; 95% CI 2.1 to 50.60). CONCLUSIONS: Although SNS is a safe and effective therapy for lower urinary tract disorders, it is associated with a high reoperation rate.

An extract (THC-002) of Ba-Wei-Die-Huang-Wan inhibits expression of tachykinins, and P2X3 and TRPV1 receptors, and inhibits ATP-induced detrusor overactivity in spontaneously hypertensive rats.

AIMS: To investigate possible mechanisms of action of THC-002 (HARNCARE), a galenical produced from the traditional Chinese herbal mixture Ba-Wei-Die-Huang-Wan, which has been reported to improve lower urinary tract symptoms (LUTS) in patients. METHODS: Forty-five female SHRs were randomly separated into three groups. Two groups were given 20 ml physiological saline solution (PSS) per kg-body weight orally daily for 1 week. An hour after the administration of PSS, one of the groups received 20 mg THC-002 per kg body weight, and the other a similar volume of THC-002-free saline. The third group received no treatments. The bladders were analyzed by real time RT-PCR (n = 6) and immunohistochemistry (n = 3) for the expression of tachykinins and P2X3 and TRPV1 receptors. Cystometric investigation (n = 6) was conducted after intravesical instillation of saline followed by 5 mg/ml ATP solution. RESULTS: Treatment with PSS caused and upregulation of tachykinins and P2X3 and TRPV1 receptors, which was prevented in the group treated with THC-002. In the normal (non-treated) and non-THC-002-treated SHRs, instillation of the ATP solution decreased voiding interval, micturition volume, and bladder capacity compared to the instillation of saline. However, in the THC-002-treated SHRs, ATP instillation had no effect. CONCLUSIONS: In SHRs, THC-002 reduced the bladder expression of tachykinins and P2X3 and TRPV1 receptors, and inhibited ATP-induced detrusor overactivity. These effects may explain part of its beneficial effects on LUTS.

Overactive bladder syndrome in the older woman: conservative treatment.

Over active bladder syndrome (OAB) is the most common cause of urinary incontinence in the older population (Gadgil and Wagg, 2008). Many women do not seek medical help and advice as they consider it to be an inevitable part of ageing. It can have significant impact on sufferers' lives and can contribute to an increased risk of falls, reduced quality of life, social isolation and depression. It is also known to be hugely underreported as patients are often too embarrassed to discuss their symptoms with members of their family or health professionals. OAB syndrome can however, be treated effectively in primary care with conservative, nurse-led treatments. This article will discuss the causes, implications, assessment and conservative treatments available to women over 65 years old presenting with OAB syndrome in primary care.

[Treatment of overactive bladder in elderly and old people]. / Die Therapie der Blasenüberaktivität bei älteren und alten Menschen.

Overactive bladder syndrome is a widespread disorder that leads to considerable impairment of quality of life. Besides behavioural therapy (bladder training), methods used in physiotherapy, electrotherapy and instrumental biofeedback have also proved to be successful approaches to treatment. With their good clinical and urodynamic efficacy, substances with antimuscarinic action at M3 receptors in particular and possibly also at M2 receptors have proved successful as first-line agents for the treatment of overactive bladder (OAB). Despite the frequently high level of suffering and severe impairment of quality of life, however, compliance is poor. Muscarine receptors do have a significant effect on detrusor function, but numerous other mechanisms and receptor entities also play a role. Whether patient acceptance can be significantly increased by the development of selective M-receptor antagonists, improved bladder selectivity or formulating innovations remains to be proven by broad-based clinical testing and independent, comparative, scientific studies. At present, it is not possible to estimate with absolute certainty the risk of an anticholinergic-induced deterioration in cognitive abilities, in particular in elderly individuals. Initial data suggest that primarily M3-selective receptor blockage with darifenacin could be beneficial.