Antimuscarinics suppress adenosine triphosphate and prostaglandin E2 release from urothelium with potential improvement in detrusor overactivity in rats with cerebral infarction.

PURPOSE: Antimuscarinics improve detrusor overactivity. We evaluated the effects and action mechanisms of imidafenacin (Kyorin Pharmaceutical, Tokyo, Japan), a novel therapeutic agent for overactive bladder with antimuscarinic activity, on mediator release from urothelium and detrusor overactivity induced by cerebral infarction. MATERIALS AND METHODS: Bladder hydrodistention was achieved by intravesical infusion of Krebs solution. Bladder adenosine triphosphate and prostaglandin E(2) were measured in the presence and absence of anticholinergics using luciferin-luciferase assay and enzyme-linked immunoassay, respectively. Cerebral infarction was induced in rats by occluding the left middle cerebral artery. The effects of intravenous imidafenacin on bladder function were examined using cystometry in rats with cerebral infarction and in those pretreated with resiniferatoxin. RESULTS: Increased intravesical adenosine triphosphate and prostaglandin E(2) were shown by induced distention of isolated rat bladders. Imidafenacin and darifenacin (Kemprotec, Middlesbrough, United Kingdom) significantly suppressed the increases in adenosine triphosphate and prostaglandin E(2). Decreased bladder capacity was observed in rats with cerebral infarction. Detrusor overactivity was suppressed with a minimum intravenous dose of 0.001 mg/kg imidafenacin. The effects of imidafenacin were not noted in rats pretreated with resiniferatoxin. CONCLUSIONS: Results support the hypothesis or suggest that imidafenacin improves cerebral infarction induced detrusor overactivity by suppressing peripheral C-fibers. This effect is thought to be associated with suppression of the release of adenosine triphosphate and prostaglandin E(2) from the urothelium.

Effect of corticotropin-releasing factor receptor antagonist on psychologically suppressed masculine sexual behavior in rats.

INTRODUCTION: Corticotropin-releasing factor (CRF) coordinates various responses of the body to stress, and CRF receptors are important targets of treatment for stress-related disorders. AIM: To investigate the effect of a nonselective CRF receptor antagonist, astressin, on suppression of masculine sexual behavior by psychological stress in rats. METHODS: First, we investigated the influence of psychological stress, induced 2 hours per day for three consecutive days, on sexual behavior. Then, rats were divided into 4 groups: a control group, an astressin administration group (A), a psychological stress loading group (PS), and a psychological stress loading and astressin administration group (PS + A). The rats were exposed to sham or psychological stress for three consecutive days. After the last stress loading, the rats were injected with vehicle or astressin, and their sexual behavior was observed. We also measured serum levels of adrenocorticotropic hormone (ACTH). MAIN OUTCOME MEASURE: The effects of astressin on sexual behavior and serum levels of ACTH in rats affected by psychological stress were determined. RESULTS: Sexual behavior was reduced after psychological stress loading. The PS rats had significantly longer mount, intromission, and ejaculation latencies and lower ejaculation frequency than did the control, A, and PS + A rats. The intromission latency and ejaculation frequency in the PS + A rats did not achieve the level observed in the controls. There was no significant difference in these parameters between the control and A rats. Serum ACTH levels were significantly lower in PS + A rats than in PS rats. CONCLUSIONS: Psychologically suppressed masculine sexual behavior could be partially recovered with astressin administration in rats. These data provide a rationale for the further study of CRF receptor antagonists as novel agents for treating psychological sexual disorders.

[Combination chemotherapy of paclitaxel, carboplatin and gemcitabine in patients who have received prior cisplatin-based chemotherapy].

The objective of this study was to evaluate the efficacy and toxicity of combination chemotherapy with paclitaxel, carboplatin and gemcitabine in patients with advanced urothelial carcinoma, who have received prior cisplatin-based chemotherapy. Eligible patients had pathologically proven measurable metastatic urothelial carcinoma. Between April 2005 and May 2009, 8 patients with a mean age of 7 0 years were treated every 3 weeks with paclitaxel (200 mg/m² on day 1), carboplatin (AUC= 5/body on day 1) and gemcitabine (800 mg/m² on day 1 and 8). A total of 4 0 (median 4) cycles were administered. None of the 8 patients achieved a complete response(CR), but 3 patients (37. 5%) achieved a partial response (PR) and 3 were stable with the disease(SD). The median overall survival time and the median progression-free survival time were 8. 0 and 4. 5 months, respectively. Grade 4 hematological toxicities included neutropenia in 6 cycles (15. 0%), thrombocytopenia in 8 cycles (20. 0%) and anemia in 11 cycles (27. 5%). Three of the 8 patients had febrile neutropenic episodes, and no toxic death was observed. Our results suggest that the combination chemotherapy of paclitaxel, carboplatin and gemcitabine was effective, and an acceptable treatment for patients with advanced urothelial carcinoma who have received prior cisplatin-based chemotherapy.

Selective α1A-blocker improves bladder storage function in rats via suppression of C-fiber afferent activity.

PURPOSE: In the present study, we used animal models to investigate whether the selective α(1A)-blocker silodosin exerts inhibitory effects on detrusor overactivity by modulating C-fiber afferent activity. METHODS: To desensitize C-fiber afferents, 0.3 mg/kg of resiniferatoxin (RTX) was subcutaneously injected into some female Sprague-Dawley rats 2 days before creation of each model. (1) Left middle cerebral artery occlusion was performed to create a cerebral infarction (CI) model (CI rats). The effects of intravenous (i.v.) and intrathecal (i.t.) administrations of silodosin on cystometrography parameters were evaluated in conscious rats. (2) Rhythmic bladder pressure was recorded in rats under urethane anesthesia. Prostaglandin (PG) E(2) (0.4 mg/mL) was continuously administered intraurethrally, and the effects of intra-arterial (i.a.) silodosin on the micturition reflex (MR) were investigated. RESULTS: (1) Silodosin (i.v.) dose-dependently increased bladder capacity (BC) in CI rats without decreasing bladder contraction pressure, but had no effects on BC in RTX-CI rats. Silodosin (i.t.) markedly increased BC in CI rats, but not in RTX-CI rats. (2) After intraurethral administration of PGE(2), the bladder contraction interval (BCI) was markedly reduced in non-RTX rats, but unchanged in RTX rats. Silodosin (i.a.) significantly prolonged BCI in non-RTX rats receiving intraurethral PGE(2). CONCLUSIONS: These results suggest that the α(1A)-AR subtype activates C-fiber afferents, and that consequently α(1A)-blockade can improve bladder storage function.

[Nodular fasciitis arose in the pelvis : a case report].

A 58-year-old woman presented to our emergency room with cystitis-like symptoms and macroscopic hematuria. Her symptoms were improved by the administration of an antibiotic, but transabdominal ultrasonography revealed a mass in her pelvis. The pelvic magnetic resonance imaging (MRI) depicted a solid tumor in the retropubic space. The patient requested hasty surgical excision of the tumor, rather than the conservative treatment after the diagnosis by cytology and biopsy. The postoperative histopathological examination revealed nodular fasciitis. She has been followed up for 8 months without any evidence of local recurrence. Nodular fasciitis is a mesenchymal lesion of proliferated fibroblast and commonly occurs in the subcutaneous tissue of the extremities. Frequently, it resembles a sarcoma, but it is said to be a benign disorder. In the urological domain, 14 intravesical cases have been reported. To our knowledge, this is the first case of the nodular fasciitis arising in the pelvis. We report this case and discuss the literature.

11C-Acetate PET imaging for renal cell carcinoma.

PURPOSE: In this study, we investigated the effectiveness of positron emission tomography (PET) with (11)C-acetate (AC) for evaluation of renal cell carcinoma. METHODS: Enrolled in the study were 20 patients with suspected renal tumour, one of whom had three renal lesions. In all, 22 renal lesions were evaluated. Following administration of 350 MBq (10 mCi) of AC, whole-body PET images were obtained. Based on these PET findings, kidney lesions were scored as positive or negative. The PET results were correlated with the CT findings and histological diagnosis after surgery. RESULTS: In 18 patients, 20 tumours were diagnosed as renal cell carcinoma. Lesions in the remaining two patients were diagnosed as complicated cyst without malignant tissue. Of the 20 renal cell carcinomas. 14 (70%) showed positive AC PET findings; 6 were negative. The two patients with complicated cyst had negative AC PET findings. Of the 20 renal cell carcinomas, 19 were clear-cell carcinoma and 1 was a papillary cell carcinoma. This papillary cell carcinoma showed high AC uptake. CONCLUSION: AC demonstrates marked uptake in renal cell carcinoma. These preliminary data show that AC is a possible PET tracer for detection of renal cancer.

[The pathophysiology underlying overactive bladder syndrome possibly due to benign prostatic hyperplasia].

The pathophysiology in the development of overactive bladder syndrome (OAB) possibly due to benign prostatic hyperplasia (BPH) has not fully been understood. The clinical study in male outpatients aged over 50 years with lower urinary tract symptoms showed that the frequency of urgency was significantly associated with aging, bladder outlet obstruction (BOO) and benign prostatic enlargement (BPE). From the results of the experiments we did using rats, the mechanisms underlying the development of OAB were suggested as follows. The functional impairment of acetylcholine neuron in the central nervous system is induced by aging and decreases the bladder capacity. Non-voiding contractions of the bladder may have some bearing on OAB associated with BOO. The C-fiber in the urethra may be involved in the generation of the detrusor overactivity associated with BPE. These results showed that the pathophysiology of OAB related to BPH is quite complex, suggesting that a multidisciplinary approach is necessary for the treatment.

Effects of antimuscarinics on voiding function after cerebral infarction in a rat model of overactive bladder.

Muscarinic receptor antagonists are used clinically for their therapeutic peripheral effects on bladder function. However, these agents may also act on central muscarinic receptors, especially in individuals with compromised blood-brain barrier function. We compared the effects of atropine and tolterodine, agents that do and do not readily cross the blood-brain barrier, respectively, administered peripherally (intravenous [i.v.]) and centrally (intracerebroventricular [i.c.v.]) on cystometrography in conscious rats after cerebral infarction induced by middle cerebral artery occlusion or sham surgery. We hypothesized that tolterodine would produce greater improvement in bladder capacity and less impairment in bladder contractility and that the effects of both agents would be greater in rats with cerebral infarction and sham-operated rats after peripheral administration, but that tolterodine and atropine would exert similar effects after central administration. Bladder capacity was markedly reduced following cerebral infarction. Low-dose i.v. tolterodine (or=20 nmol/kg) significantly increased bladder capacity but also significantly increased residual volume and decreased bladder contraction pressure. Tolterodine was significantly more efficacious than atropine in increasing bladder capacity, whereas atropine produced significantly greater increases in residual volume and reductions in bladder contraction pressure; these treatment group differences were also observed in sham-operated animals. Tolterodine and atropine administered i.c.v. significantly increased bladder capacity following cerebral infarction or sham surgery; however, this was accompanied by significantly increased residual volume and decreased bladder contraction time. The decrease in bladder contraction time was significantly smaller after tolterodine vs atropine. Peripherally acting muscarinic receptor antagonists may be preferable to centrally acting agents for minimizing adverse events, such as incomplete bladder emptying, even in individuals with compromised blood-brain barrier function.

Prognostic value of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography imaging for patients with prostate cancer.

PURPOSE: The purpose of this study was to investigate the prognostic value of measuring glucose metabolism of primary prostate cancer lesions, using 2-Deoxy-2-[F-18]Fluoro-D-Glucose positron emission tomography (FDG-PET). PROCEDURES: Forty-two patients with prostate cancer were investigated with FDG-PET, and standardized uptake value (SUV) of the prostate was calculated. After PET study, radical prostatectomy was performed in 17 patients (RPT group), and endocrine therapy in 25 patients (ET group). Relapse-free survival curves were created by the Kaplan-Meier method. RESULTS: In the RPT group, the patients with high SUV had a poorer prognosis compared to those with low SUV (P = 0.033). In the ET group, the patients with high SUV were likely to have a poorer prognosis with low significance at a level of P = 0.087. CONCLUSIONS: FDG-PET appeared to have a defined prognostic value for patients with prostate cancer undergoing radical prostatectomy, and more patients need to be studied for patients undergoing endocrine therapy.

Alpha 1-adrenoceptor blocker may improve not only voiding but also storage lower urinary tract symptoms caused by (125) I brachytherapy for prostate cancer.

Purpose. To assess changes in lower urinary tract symptoms (LUTS) within 1 year after brachytherapy in patients receiving alpha 1-adrenoceptor antagonists. Methods. We retrospectively evaluated 116 patients who underwent (125)I prostate brachytherapy in our institute. Seventy-one patients were treated with a combination of external beam radiation therapy and brachytherapy. Alpha 1-adrenoceptor antagonists were prescribed to all patients after brachytherapy. International Prostate Symptom Score (IPSS) forms and postvoid residual urine volume were recorded at all follow-up visits. Results. Forty-nine patients were given tamsulosin hydrochloride, 32 were given silodosin hydrochloride, and 35 were given naftopidil for up to 6 months after seed implantation. Patients given tamsulosin or naftopidil tended to show a higher peak IPSS and slower recovery to baseline values than those given silodosin. The patients given naftopidil showed an insufficient recovery in storage symptoms in naftopidil group in comparison with tamsulosin group at 3 months and with silodosin group at 6 and 9 months. Conclusions. In the management of LUT after brachytherapy, silodosin may provide a more favorable improvement. Silodosin and tamsulosin may have an advantage in improving not only voiding but also storage lower urinary tract symptoms after brachytherapy.

Diagnosis of complex renal cystic masses and solid renal lesions using PET imaging: comparison of 11C-acetate and 18F-FDG PET imaging.

PURPOSE: The study aims to assess the usefulness of PET with C-acetate and F-FDG to differentiate renal cell carcinoma (RCC) from complicated renal cysts. METHODS: Thirty-one patients were enrolled, 14 patients with complicated renal cysts (12 with Bosniak III and 2 with Bosniak IV) and 17 patients with 19 solid renal tumors. The patients underwent both C-acetate PET and FDG PET. Nephrectomy or partial nephrectomy was performed after the PET scans. RESULTS: In 29 patients, 32 renal lesions were diagnosed as RCC. Twenty-three of the 32 RCCs (72%) had positive C-acetate PET findings, whereas only 7 FDG PET studies were positive (22%). Considering the relationship between tumor size measured by macroscopic appearance of resected tumors and PET results, 22 of 25 (88%) tumors more than 1.5 cm showed positive C-acetate PET findings. In 12 patients with Bosniak III renal cysts, 10 renal lesions were diagnosed as RCC. In this subgroup, 5 of the 10 RCCs (50%) had positive C-acetate PET findings, whereas 2 RCCs (20%) had positive FDG PET findings. None of the cases with benign findings had positive C-acetate PET or FDG PET scans. CONCLUSIONS: C-acetate PET demonstrates a pronounced increase in tracer uptake in RCC, especially in renal tumors more than 1.5 cm, and displays a higher sensitivity than FDG PET. These preliminary data show that C-acetate may be a useful PET tracer to exclude RCC in complex renal cysts.

Surgical treatment of adrenal gland metastasis originating from small cell carcinoma of the urinary bladder.

We report a rare case of a solitary adrenal metastasis from small cell carcinoma of the urinary bladder that was successfully treated with surgical resection. A 71-year-old man was suffering from bladder tamponade for hematuria. Computed tomography (CT) revealed a bladder tumor at the left wall. The patients underwent radical cystectomy. Histopathological results were obtained in small cell carcinoma of the bladder with muscle invasion. Thus, he received two courses of adjuvant etoposide and cisplatin chemotherapy, followed by the regimen for small cell lung cancer. Seven months after surgery, follow-up CT showed a gradually enlarged mass enhanced heterogeneously in the right adrenal gland. There was a solitary adrenal metastasis without any other metastasis; therefore, we performed right laparoscopic adrenalectomy. The patient has remained uneventful for four years after the adrenal gland surgery. For patients who have a solitary adrenal metastasis, adrenalectomy may provide a survival benefit.

Assessment of Therapeutic Effect of Sunitinib by (11)C-Acetate PET Compared with FDG PET Imaging in a Patient with Metastatic Renal Cell Carcinoma.

Although sunitinib shows a high response rate in patients with untreated metastatic renal cell carcinoma (mRCC), quite a few patients show no therapeutic effect. Therefore, it is crucial to distinguish the patients who respond to sunitinib from those who do not as early as possible after the administration of the therapy. We herein report a case of mRCC in which (11)C-acetate (AC) positron emission tomography (PET) showed an early therapeutic effect of sunitinib treatment 4 weeks after its administration.

Urethral Sensations are Related to the Development of Detrusor Overactivity.

Urgency is the core symptom of the overactive bladder symptom complex, but the underlying mechanisms are not fully understood. Clinical findings have led to the assumption that bladder outlet obstruction (BOO) caused by benign prostatic enlargement (BPE) induces storage symptoms and detrusor overactivity. Presumably, BOO by BPE accounts for urgency; however, urgency is not always caused by BOO. Sensory nerves in the wall of the urethra fire in response to urethral fluid flow, and this activity initiates bladder contractions in the quiescent bladder and augments ongoing contractions in the active bladder. In humans, prostatic urethral anesthesia results in significant increases in bladder capacity among BPH patients without neurological diseases, therefore sensory stimuli from an anatomically altered prostatic urethra has the possibility to induce urgency and detrusor overactivity. Studies in animals demonstrate the basis for an excitatory urethra to bladder reflex. Urethral stimulation by prostaglandin E2 induces an excitatory effect on micturition reflex by activation of C-fiber afferent nerves. α1A -adrenoceptor blocker has an inhibitory effect on the micturition reflex, suggesting excitatory urethra to bladder reflex is mediated by α1A -adrenoceptor. Even if there is no obstruction, increase in urethral sensory due to BPE may induce the development of the detrusor overactivity.

Association between lower urinary tract symptoms and serum levels of sex hormones in men.

OBJECTIVES: Despite the well-known association between lower urinary tract symptoms (LUTS) and male sexual dysfunction, few data are available that describe the relationship between LUTS and sex hormones. The aim of this study was to investigate a possible association between the severity of LUTS and the serum levels of sex hormones in men. METHODS: A total of 182 randomly selected men attending our general urology clinic were recruited. All participants completed the International Prostate Symptom Score (IPSS), and their sera were evaluated for serum levels of prostate-specific antigen, total and free testosterone, dehydroepiandrosterone sulfate (DHEA-S), luteinizing hormone, follicle-stimulating hormone, prolactin, and estradiol. Storage symptoms were evaluated by the sum of IPSS questions 2, 4, and 7. Voiding symptoms were evaluated by the sum of IPSS questions 3, 5, and 6. The relationship between the IPSSs and serum hormone levels was determined. RESULTS: On univariate analysis, the total IPSS was significantly associated with age, DHEA-S, and free testosterone. Storage symptoms were significantly associated with age, DHEA-S, free testosterone, and prostate-specific antigen. Voiding symptoms were significantly associated with age and DHEA-S. On multivariate linear regression analysis, only age was significantly associated with LUTS. However, within the subgroup of men 65-82 years old, DHEA-S was significantly associated with the total IPSS and storage symptoms. CONCLUSIONS: In our study, the severity of LUTS was not associated with serum levels of sex hormones in men. However, in older men, storage symptoms could be affected by the serum DHEA-S level.

Ultrasound-estimated bladder weight predicts risk of surgery for benign prostatic hyperplasia in men using alpha-adrenoceptor blocker for LUTS.

OBJECTIVES: Although invasive and expensive, the pressure-flow study is known as the reference standard for the diagnosis of bladder outlet obstruction. We investigated the usefulness of ultrasound-estimated bladder weight (UEBW) as a predictor of the need for surgery for benign prostatic hyperplasia (BPH). METHODS: A total of 97 consecutive male patients >50 years old with lower urinary tract symptoms (LUTS) were prospectively enrolled in this study. The surgery rate was correlated with the UEBW, the results of uroflowmetry, the postvoid residual urine volume, prostate volume, and International Prostate Symptom Score. RESULTS: Surgery for BPH was performed in 37 of the 97 patients studied. The surgery rate was associated with a high UEBW (>or=35 g), severe LUTS (International Prostate Symptom Score of >or=20), a voided volume of <100 mL at free uroflowmetry, and poor uroflow (maximal flow rate of <10 mL/s). Multivariate analysis revealed that severe LUTS and a high UEBW were the risk factors for surgery for BPH. CONCLUSIONS: The results of our study have shown that the UEBW can be regarded as a useful parameter to identify patients with LUTS who are at risk of needing surgery for BPH.

Long-lasting breaches in the bladder epithelium lead to storage dysfunction with increase in bladder PGE2 levels in the rat.

Increase in bladder mucosal permeability can be reproduced by intravesical administration of protamine sulfate (PS); however, the influence of PS once administered into the bladder disappears within several days. We developed a chronic animal model of urothelial injury using PS. Insertion of a polyethylene catheter through the bladder dome was performed in female Wistar rats. The other end of the catheter was connected to an osmotic pump for continuous delivery of PS or vehicle for 2 wk. Urinary frequency (UF) and voided volume (VV) were measured in the metabolic cage. The fifth group of rats received a high dose of PS (10 mg/ml) for 2 wk and were followed for a further 2 wk without PS. The sixth group received a high dose of PS for 2 wk and loxoprofen (0.1 mg.kg(-1).day(-1)) for 4 wk. UF was increased, and VV was reduced in rats treated with a high dose of PS but not changed in rats treated with a vehicle or a low dose of PS (1 mg/ml). UF was further increased in the fifth group, while unchanged in the sixth group. Histological sections in rats treated with a high dose of PS demonstrated a loss of the upper layer of urothelial cells and an increased number of mast cells. PGE2 level in the bladder was significantly elevated in the fifth group. These results indicate that chronic urotherial injury leads to an increase in UF and a decrease in VV. Increased PGE2 level in the bladder is likely to be associated with long-lasting storage dysfunction.

Antimuscarinic drug inhibits detrusor overactivity induced by topical application of prostaglandin E2 to the urethra with a decrease in urethral pressure.

PURPOSE: Antimuscarinic drugs increase bladder capacity without prominent side effects such as urinary retention even when administered to patients with mild to moderate bladder outlet obstruction. Some mechanisms might exist in the urethra to compensate for the emptying function of the detrusor after the administration of antimuscarinic drugs. We investigated the influence of the antimuscarinic drug propiverine (Taiho Pharmaceutical, Tokyo, Japan) on urethral function. MATERIALS AND METHODS: Urethral pressure and rhythmic bladder pressure were simultaneously monitored in urethane anesthetized female Sprague-Dawley rats. Prostaglandin E(2) was continuously administered intravesically or intraurethrally to induce detrusor overactivity. To eliminate the influence of bladder activity and monitor urethral baseline pressure isovolumetric pressure of the urethra was then recorded after cystectomy and ligation of the external urethral meatus. Furthermore, in vitro contractile responses of the urethral circular smooth muscle to field stimulation were examined in the presence of propiverine, tamsulosin (Taiho Pharmaceutical), verapamil, omega-conotoxin and atropine (Sigma). RESULTS: Intravesical or intraurethral administration of prostaglandin E(2) significantly decreased the bladder contraction interval by 10.7% and 36.0%, respectively. Intra-arterial administration of 2 x 10(2) nM/kg propiverine significantly increased the bladder contraction interval in rats receiving intraurethral prostaglandin E(2) by 81.8% but it had no marked effect on rats receiving intravesical prostaglandin E(2). Significant decreases in urethral baseline pressure were found after propiverine administration. Field stimulation induced contraction was inhibited by propiverine and verapamil but not by tamsulosin, omega-conotoxin or atropine. CONCLUSIONS: These results suggest that the inhibitory effects of propiverine are more prominent in rats with detrusor overactivity induced by intraurethral prostaglandin E(2) than by intravesical prostaglandin E(2). Propiverine may compensate for detrusor function by decreasing urethral resistance in the voiding phase.