Transcutaneous electrical nerve stimulation and solifenacin succinate versus solifenacin succinate alone for treatment of overactive bladder syndrome: A double-blind randomized controlled study.

OBJECTIVE: We evaluated a combination of transcutaneous electrical nerve stimulation (TENS) and solifenacin succinate versus solifenacin alone in the treatment of overactive bladder (OAB). METHODS: Ninety-seven female outpatients with OAB were screened for this double-blind randomized controlled study. Eighty-six patients who met our inclusion criteria were divided randomly into two groups. In group A (43 patients), patients received oral solifenacin and "fake" TENS on the foot; in group B (43 patients), patients received oral solifenacin and effective TENS on the foot. Improvements in OAB symptoms were assessed by Overactive Bladder Symptom Score (OABSS), Overactive Bladder Questionnaire (OAB-q), voiding diaries and urodynamic tests. 70 of 86 patients (36 in group A, 34 in group B) completed the 2 months of treatment and 3 months of follow-up. RESULTS: Statistically, the maximum bladder volume and OAB symptoms of both groups improved significantly after treatment. The improvement in group B was significantly better than that in group A, as indicated by the maximum bladder volume, OAB-q score and voiding diary. Some mild adverse effects were observed, including dry mouth, stomach upset, constipation, muscle pain and local paresthesia. CONCLUSION: The combination of TENS and solifenacin was more effective in improving OAB symptoms than solifenacin alone.

Therapeutic effects of Choreito, a traditional Japanese (Kampo) medicine, on detrusor overactivity induced by acetic acid in rats.

Choreito (CRT), a traditional Japanese (Kampo) medicine, is widely used for the treatment of overactive bladder (OAB) and other lower urinary tract symptoms in Japan. This study aimed to identify the effects and therapeutic mechanism of CRT on the improvement of detrusor overactivity (DO) using an experimental rat model. Forty-five female Sprague-Dawley rats were equally divided into three groups: intravesical saline instillation with normal food (normal group), intravesical acetic acid (AA) instillation with normal food (AA group), and intravesical AA instillation with CRT (AA with CRT group). To induce a decrease in bladder capacity, instillation of 0.2% AA was used based on prior studies. Cystometric investigation was employed to clarify the effects of AA and CRT. Microcirculation was performed using a laser blood flowmeter, and the localization of hypoxia-inducible factor 1α (HIF1α) was assessed by immunohistochemistry. The bladder capacities of the normal, AA, and AA with CRT groups were 1.2 ± 0.3 mL, 0.4 ± 0.1 mL, and 0.8 ± 0.1 mL, respectively. CRT significantly attenuated AA irritation of the urinary bladder and exerted protective effects on basal pressure, micturition pressure, micturition interval, and micturition volume. Furthermore, CRT could prevent the excess blood flow and edematous change under the urothelium induced by intravesical AA instillation. No obvious changes in immunohistochemical HIF1α staining were observed among the groups. CRT attenuated DO induced by intravesical AA instillation in a rat experimental model. CRT might impart therapeutic effects on OAB via the mitigation of urothelial damage and regulation of excess blood flow.

Ba-Wei-Die-Huang-Wan (Hachimi-jio-gan) can ameliorate ketamine-induced cystitis by modulating neuroreceptors, inflammatory mediators, and fibrogenesis in a rat model.

AIM: We investigated the effects of Ba-Wei-Die-Huang-Wan (BWDHW) on ketamine-induced cystitis (KIC) in a rat model. METHODS: Female Sprague-Dawley rats were distributed into three groups: control (saline), ketamine (25 mg/kg/day for 28 days), or ketamine (25 mg/kg/day for 28 days) plus BWDHW (90 mg/kg/day, started from day 14). Functional magnetic resonance imaging (fMRI), metabolic cage study, and cystometry were evaluated. Bladder histology was evaluated. Western blots of the bladder proteins were carried out. RESULTS: Compared with controls, ketamine-treated rats showed stronger fMRI intensity in the periaqueductal gray area and bladder overactivity in the bladder functional study, but the ketamine/BWDHW-treated rats did not. Furthermore, ketamine breached the uroplakin III membrane at the apical surface of the urothelium, enhanced substance P spread over the urothelium, induced suburothelial hemorrhage and monocyte/macrophage infiltration, and caused interstitial fibrosis deposition. By contrast, the BWDHW-treated rats exhibited less substance P spread, lower suburothelial monocyte/macrophage infiltration, and lower interstitial fibrosis deposition. The ketamine group showed significant overexpression of neuroreceptors in the bladder mucosa (the transient receptor potential vanilloid 1 and M2 - and M3 -muscarinic receptors) and detrusor (M2 - and M3 -muscarinic receptors); inflammatory mediators in the detrusor (interleukin-1ß [IL-1ß], IL-6, tumor necrosis factor-α, nuclear factor-κB, cyclooxygenase-2, and intercellular adhesion molecule-1); and fibrogenesis molecules in the detrusor (transforming growth factor-ß1, collagen I, collagen III, and fibronectin). However, no significant changes were noted between the ketamine/BWDHW and control groups. CONCLUSION: BWDHW could exert therapeutic effects by inhibiting the upregulation of neuroreceptors, modulating inflammatory mediators, suppressing fibrogenesis, and ameliorating bladder overactivity in rats with KIC.

Isosamidin, an extract of Peucedanum japonicum, inhibits phenylephrine-mediated contractions of the human prostate in vitro.

Isosamidin is a pharmacologically active compound extracted from Peucedanum japonicum which is used as a health food in East Asia. Our preliminary animal data suggested that isosamidin may have sufficient potency to treat patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia or overactive bladder. However, the efficacy of isosamidin in humans is unknown. Here, we examined whether isosamidin inhibits agonist-stimulated contractions in isolated human bladder and prostate tissue strips in vitro. Human bladder and prostate strips obtained from 9 to 10 male patients, respectively, were suspended in organ baths. After administration of isosamidin (10, 30, and 100 µM), concentration-response curves to agonists (acetylcholine or phenylephrine) were constructed by cumulatively increasing agonist concentration. Isosamidin inhibited phenylephrine-stimulated contractions of isolated human prostate tissue strips in a concentration-dependent manner, with significant differences observed between control and 100 µM isosamidin. In contrast, isosamidin had no effect on acetylcholine-stimulated contractions of isolated human bladder tissue strips. Isosamidin may have pharmacological potency in the treatment of male patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Clinical studies are needed to confirm the efficacy and safety of isosamidin in humans.

Perilla extract improves frequent urination in spontaneously hypertensive rats with enhancement of the urothelial presence and anti-inflammatory effects.

OBJECTIVE: To investigate the effects of perilla extract on urinary symptoms in spontaneously hypertensive rats as a model of spontaneous overactive bladder. METHODS: Spontaneously hypertensive rats were randomly divided into two groups and fed either a control diet or a perilla extract-containing diet. Cystometry, gene expression and histological analyses were carried out to evaluate the effects of perilla extract after 2-week feeding of either the control or the perilla extract diet. The expression of inflammation-related genes in the human urothelial cell line HT-1376 and the normal human bladder epithelial cell was measured after the treatment with perillaldehyde, the main component of perilla extract, or perillic acid, the final metabolite of perillaldehyde. RESULTS: A significant 27% increase in the micturition interval and decreased expression of nerve growth factor, tumor necrosis factor-α, interleukin-1ß and transient receptor potential V1 were observed in the perilla group compared with the control group. The level of uroplakin 3A was 40% higher in the perilla group than in the control group. The urothelium in the control group was thin or defective, but it was almost completely intact in the perilla group. Perillaldehyde and perillic acid suppressed the induction of nerve growth factor and tumor necrosis factor-α by interleukin-1ß in HT-1376 and normal human bladder epithelial cells. CONCLUSIONS: The present findings suggest that perilla extract improves frequent urination, and this improvement seems to be mediated, at least in part, by enhancement of the urothelial presence and by the anti-inflammatory effects of perilla.

Efficacy of holmium laser enucleation of the prostate (HoLEP) in men with bladder outlet obstruction (BOO) and non-neurogenic bladder dysfunction.

We aimed to compare the short-term outcomes of men who had urodynamic evidence of detrusor underactivity (DU) or detrusor overactivity (DO) of a non-neurogenic etiology as well as bladder outlet obstruction (BOO) and who underwent Holmium Laser Enucleation of the prostate (HoLEP). A database of 322 patients who underwent HoLEP between 2010 and 2014 was analyzed. Patients were classified into three groups according to the results of a preoperative urodynamic study. Preoperative parameters such as International Prostate Symptom Score (IPSS), Quality of Life (QoL) index, IPSS grade, uroflowmetry were compared with postoperative parameters measured at 6 months. There were 138 patients with BOO-only and 89 patients with BOO and detrusor dysfunction including 56 with DO and 33 with DU. The degree of improvement in IPSS-total (BOO: 10.7, DO: 8.3, DU: 7.0; p = 0.023) was greater in the BOO-only group than in the DU group. There were more patients whose IPSS grade improved in the BOO-only group (71%) than in the detrusor dysfunction group (DO: 53.6% and DU: 45.5%). Postoperative IPSS-voiding (4.5 vs 7.0), and Qmax (18 vs 13.7) in the BOO-only group were significantly better than those in the DU group. Additionally, postoperative IPSS-storage (4.7 vs 6.7), and IPSS-total (9.1 vs 12.3) in the BOO-only group were significantly better than in the DO group (all p < 0.05). In conclusion, early surgical management for men with severe LUTS and associated BPH before secondary degeneration occurs may be beneficial for preserving detrusor function and yield better treatment outcomes.

Pathophysiology of idiopathic overactive bladder and the success of treatment: a systematic review from ICI-RS 2013.

AIMS: To investigate the frequency of phenotype profiling of patients with idiopathic overactive bladder (OAB) syndrome, and to determine the effectiveness of treatment among individuals with different pathophysiologic profiles. METHODS: The electronic databases MEDLINE, EMBASE, Cochrane CENTRAL, Cochrane Database of Systematic Reviews, and CINAHL were searched from January 1, 1980 to August 12, 2013 for interventional randomized controlled treatment trials (RCTs) of idiopathic OAB. Phenotying for pathophysiologies originating in the urothelial/mucosal layer of the bladder, the detrusor muscle cell layer, and the central nervous system were sought. Articles that analyzed urgency outcomes based on pathophysiologic profiling were selected. Due to the heterogeneity of the included interventions and outcome assessment measures, meta-analysis was not appropriate and a qualitative synthesis was undertaken. RESULTS: Of 239 original RCTs of idiopathic OAB, 48 (20%) profiled participants on underlying pathophysiology. Less than half of these (n = 20) reported treatment efficacy for urgency symptoms by pathophysiological sub-type. One examined the effect of botulinum A toxin on interstitial cell protein expression. Four compared treatment efficacy in OAB patients with and without involuntary detrusor contractions. Fifteen compared the effect of treatment on urgency reduction in patients with detrusor overactivity. There were no consistent trends in treatment efficacy according to pathophysiologic sub-type. No studies examined urothelial dysfunction or abnormal central processing of bladder afferent signaling in response to treatment. CONCLUSIONS: In order to advance the field of idiopathic OAB, more trials are needed that profile and test urgency outcomes in participants according to suspected underlying pathophysiology. Neurourol. Urodynam. 33:611-617, 2014. © 2014 Wiley Periodicals, Inc.

[Features of neurohumoral regulation in children with combined dysfunction of the pelvic organs].

During examination of 165 children aged 5 to 15 years (primarily identified during planned monitoring in Petrozavodsk children's institutions) with dysfunctional urination and encopresis without organic lesion of the central nervous system, autonomic dysfunction syndrome (ADS) was revealed. According to the results of urological examination, which was supplemented with the registration of spontaneous voiding rate and counting the radial pulse, overactive bladder syndrome and insufficient relaxation of the pelvic floor muscles during urination and defecation were detected; relationship between the number of heart rate (as a marker of sympathetic nervous system activity) and the effective volume was identified. It was revealed that the children with ADS in the presence of tachycardia show intermittent decrease of effective amounts of urination, and have residual urine. The standard course of treatment using colon hydrotherapy and biofeedback to activate cystic and obturator reflex caused a positive but short-term therapeutic effect; clinically and statistically significant increase in the effective volume of the bladder was not achieved, despite the reduction in residual urine volume. During the course of treatment using methods of biofeedback, bladder volume remained almost unchanged and tachycardia persisted, indicating the continued oppression of the sympathetic activity. The course of treatment using nootropic drug picamilon and alpha-adrenoblocker doxazosin with peripheral actions allowed to restore the reservoir and evacuation functions of the bladder, to achieve a regular bowel movement without encopresis. It was revealed that the combined dysfunction of pelvic organs occur in children with high activity of the sympathetic division of the ANS, which has a direct impact on the accumulation phase of voiding cycle and relaxation of the pelvic floor muscles.

Efficacy of sacral neuromodulation on urological diseases: a multicentric research project.

INTRODUCTION AND AIM OF THE STUDY: Sacral neuromodulation has been used as a safe, effective treatment option for patients with lower urinary tract dysfunction (LUTD). Several clinical studies demonstrated its positive effects on refractory urge incontinence, non-osbstructive urinary retention, urgency frequency syndrome, as well as on other non- urological disorders, such as fecal incontinence and chronic constipation. The aim of this research project was to evaluate the efficacy and safety of sacral neuromodulation on the management of LUTD refractory to the standardized first line treatment options. MATERIALS AND METHODS: We retrospectively collected and evaluated data from patients undergoing sacral neuromodulations between September 2001 and November 2010 in 4 Urological Centres of North-East Italy. The patients were affected by Overactive Bladder Syndrome (OAB), Urinary Retention (UR), Fecal Incontinence (FI), Constipation (CO), Chronic Pelvic Pain (CPP). All the patients were evaluated with voiding diaries, before and after implantation.Patients included in the present evaluation were followed up in a network of 4 Italian urological centres, which participate to in the Italian Clinical Service project - a national urological database and medical care project aiming at describing and improving the use of implantable urological devices in the Italian clinical practice. Continuous normally distributed variables were reported as the mean value ± standard deviation (SD). Continuous non-normally distributed variables were presented as the median values and an interquartile range (IQR). The t-test and Wilcoxon test were used to compare continuous variables, as appropriate. A two-sided p <0.05 was considered statistically significant. RESULTS: Overall, 157 patients underwent implantation of sacral neuromodulator during the period under review. Eighty-three out of 157 (53%) patients complained of OAB; 52 (33%) of UR; 5 (3%) of faecal incontinence; 4 (2%) of chronic constipation; 12 (8%) of CPP. The median follow- up was 11 months (IQR 1 - 91 months). In patients treated for OAB, we documented a statistically significant reduction in the mean number of: incontinence episodes/die, pads/die, daily micturitions, nocturnal micturitions and global micturitions. In patients treated for UR, we observed a statistically significant reduction in the mean post- voiding residual volume and in the number of self catheterization. Interpretation of results: It is difficult to translate into quantifiable data the subjective perception of improvement of the symptoms expressed by the patients, as they are frequently subjective perceptions, not always numeric data. This subjective perception makes it difficult to the clinician to evaluate the real outcomes of this procedure, and makes it difficult to achieve a complete follow-up. CONCLUSIONS: This multicenter research project confirmed the midterm safety and effectiveness of sacral neuromodulation in the treatment of refractory overactive bladder syndrome and urinary retention, showing high cure rates and low complication rates.

Instillation of liposomes vs dimethyl sulphoxide or pentosan polysulphate for reducing bladder hyperactivity.

OBJECTIVE: To investigate the efficacy of intravesical liposomes against dimethyl sulphoxide (DMSO), and pentosan polysulphate (PPS) in reducing chemically induced bladder hyperactivity in rats. MATERIALS AND METHODS: Bladder reflex activity of female Sprague-Dawley rats was evaluated by continuous cystometry under urethane anaesthesia (1.0 g/kg). After obtaining a control cystometrogram (CMG) with normal saline (0.04 mL/min) for 2 h, bladder hyperactivity was then induced by 1 h infusion of protamine sulphate (10 mg/mL) followed by a 1-h infusion of KCl (500 mm). Six rats each were then infused with KCl-based preparations containing either 50% DMSO, PPS (6 mg/mL), or liposomes (2 mg/mL) for 2 h. The variables measured included the intercontraction interval (ICI), pressure threshold (PT) and baseline pressure (BP). RESULTS: Sequential infusion of protamine sulphate/KCl induced hyperactive bladder with no significant difference in ICI, PT or BP among groups before initiating treatment. ICI was significantly increased after infusion of PPS (58.1% increase) and liposomes (156.8% increase) but there was no increase with DMSO. PT was not significantly affected by liposome infusion but slightly increased with PPS (12.4% increase). There was a large and significant increase in PT and BP with DMSO (116.5% increase) and BP largely remained unchanged after instillation with liposomes or PPS. CONCLUSIONS: Intravesical liposomes and PPS have a beneficial effect in a bladder hyperactivity rat model, while acute instillation of DMSO does not. Intravesical liposomes were effective in doubling the ICI compared with PPS, and might be a new treatment option for bladder hyperactivity.

Protective action of intravesical oxybutynin on bladder ultrastructure in rabbits with detrusor overactivity.

To evaluate the protective effect of intravesical oxybutynin on the ultrastructure of rabbits with detrusor overactivity (DO). Seventeen North Folk male rabbits were distributed into three groups: GI (n = 5) used as control, GII (n = 5), and GIII (n = 5) with DO. One animal from GII and one from GIII were excluded because they did not develop DO. In GIII, the animals were treated with daily intravesical application of 0.5 mg/Kg of oxybutynin for 30 days. Bladder weight was significantly higher in animals from GII and GIII as compared to GI. After 30 days, cystometric study revealed that vesical capacity was significantly decreased in GII and GIII. Detrusor pressure was significantly higher in GII. Electron microscopy showed increase of intercellular space, cell junctions and caveolae areas asymmetries, mitochondria and cellular degeneration in GII, while in GIII, these alterations have improved after a 30-day treatment. Animals treated with intravesical oxybutynin presented ultrastructural aspect similar to normal.

Effect of eviprostat on bladder overactivity in an experimental cystitis rat model.

OBJECTIVE: The purpose of this study was to investigate the effects of eviprostat, a phytotherapeutic drug, on bladder overactivity and inflammation in a cyclophosphamide (CYP)-induced cystitis rat model. METHODS: Female Sprague-Dawley rats received a single intraperitoneal injection of CYP (200 mg/kg) or saline. After the CYP injection, eviprostat (9, 18 or 54 mg/kg per day) or a vehicle was orally given twice each day. Four days after the CYP injection, bladder function was evaluated by cystometrograms under urethane anesthesia. In a separate group, bladder inflammation was compared between the eviprostat- or vehicle-treated animals. Furthermore, the effects of eviprostat on carbachol-induced muscle contraction were evaluated by an in vitro experiment. RESULTS: The intercontraction interval (ICI) significantly decreased in the CYP-injected rats in comparison to the saline-injected rats. In the CYP-injected group, 18 and 54 mg/kg per day of eviprostat treatment significantly increased the ICI, but did not change the maximum voiding pressure in comparison to the vehicle treatment. In the saline-injected group, no significant changes of any parameters in the cystometrograms were observed between the eviprostat- and vehicle-treated groups. CYP-induced bladder inflammation tended to be lower in the eviprostat-treated group in comparison to the vehicle-treated group. An in vitro experiment revealed that eviprostat failed to inhibit carbachol-induced muscle contraction. CONCLUSION: The oral administration of eviprostat suppressed CYP-induced bladder overactivity. The effects of eviprostat on the micturition reflex may be irrespective of antimuscarinic action. The present findings raise the possibility that eviprostat could be an effective treatment for bladder overactivity associated with inflammation.