Corticospinal interface to restore voluntary control of joint torque in a paralyzed forearm following spinal cord injury in non-human primates.

The corticospinal tract plays a major role in the control of voluntary limb movements, and its damage impedes voluntary limb control. We investigated the feasibility of closed-loop brain-controlled subdural spinal stimulation through a corticospinal interface for the modulation of wrist torque in the paralyzed forearm of monkeys with spinal cord injury at C4/C5. Subdural spinal stimulation of the preserved cervical enlargement activated multiple muscles on the paralyzed forearm and wrist torque in the range from flexion to ulnar-flexion. The magnitude of the evoked torque could be modulated by changing current intensity. We then employed the corticospinal interface designed to detect the firing rate of an arbitrarily selected "linked neuron" in the forearm territory of the primary motor cortex (M1) and convert it in real time to activity-contingent electrical stimulation of a spinal site caudal to the lesion. Linked neurons showed task-related activity that modulated the magnitude of the evoked torque and the activation of multiple muscles depending on the required torque. Unlinked neurons, which were independent of spinal stimulation and located in the vicinity of the linked neurons, exhibited task-related or -unrelated activity. Thus, monkeys were able to modulate the wrist torque of the paralyzed forearm by modulating the firing rate of M1 neurons including unlinked and linked neurons via the corticospinal interface. These results suggest that the corticospinal interface can replace the function of the corticospinal tract after spinal cord injury.

Efficacy of TAC-302 for patients with detrusor underactivity and overactive bladder: a randomized, double-blind, placebo-controlled phase 2 study.

PURPOSE: This multicenter, randomized, double-blind, placebo-controlled phase 2 study evaluated the efficacy and safety of TAC-302, a novel drug that restores neurite outgrowth, in patients with detrusor underactivity (DU) and overactive bladder (OAB). METHODS: After 2-4 weeks of observation, patients were randomized 2:1 to receive oral TAC-302 200 mg or placebo twice daily for 12 weeks. The primary endpoint was detrusor contraction strength, estimated by bladder contractility index (BCI) for males and projected isovolumetric pressure 1 (PIP1) for females. Secondary endpoints included changes in bladder voiding efficiency (BVE) and safety. RESULTS: Seventy-six patients were included (TAC-302, n = 52; placebo, n = 24). The mean (standard deviation [SD]) BCI for males was 64.6 (16.6) at baseline and 75.2 (21.1) at week 12 (p < 0.001) with TAC-302 (n = 27), and 61.3 (16.6) and 60.5 (16.7) (p = 0.82) with placebo (n = 11). The respective mean (SD) PIP1 for females was 18.8 (6.6) and 29.4 (9.4) (p < 0.001) with TAC-302 (n = 15), and 20.6 (7.5) and 25.5 (9.6) (p = 0.14) with placebo (n = 7). TAC-302 significantly increased BCI in males and BVE in both sexes. TAC-302 efficacy on OAB was not clearly shown. The incidences of adverse events (AEs), serious AEs, and AEs leading to dose interruption were similar between groups; no adverse drug reactions occurred. CONCLUSION: Considering the significant effects on BCI in males and BVE in both sexes, TAC-302 may benefit patients with DU. REGISTRATION: ClinicalTrials.gov Identifier NCT03175029 registered 6/5/2017.

Primary Ewing's sarcoma/primitive neuroectodermal tumor of the kidney and its clinical features.

Introduction: Ewing sarcoma family tumor is a malignant tumor that is primarily of bone origin; it rarely occurs in the kidney. Case presentation: A 22-year-old woman presented with hematuria. Computed tomography revealed a 6 × 6-cm mass in the lower pole of the right kidney with invasion into the right renal vein. A right laparoscopic radical nephrectomy was performed. The tumor was completely encapsulated. Based on the small-round-cell histology, diffusely CD99-positive tumor cells, and EWS (ex7)-FLi1 (ex6) fusion gene break point transcript, we diagnosed Ewing sarcoma/primitive neuroectodermal tumor of the kidney. After surgery, eight cycles of adjuvant chemotherapy including vincristine, doxorubicin (Adriamycin®), cyclophosphamide, ifosfamide, and etoposide were given. No evidence of recurrence has been observed 13 months from diagnosis. Conclusion: This was a rare Ewing sarcoma family tumor in the kidney of a young female with no remarkable family medical history.

Phosphodiesterase 5 inhibitor suppresses prostate weight increase in type 2 diabetic rats.

AIMS: Hyperinsulinemia is an important causative factor of prostate enlargement in type 2 diabetes (T2D), however, clinically prostate weight increases during hypoinsulinemic condition. To investigate the pathogenesis of prostate enlargement and effects of phosphodiesterase 5 inhibitor (PDE5i), male Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats were used as T2D and control, respectively. MATERIALS AND METHODS: OLETF and LETO rats were treated with oral tadalafil (100 µg/kg/day) or vehicle for 12 wks from at the age of 36 wks. KEY FINDINGS: Prostate weight of OLETF rats was significantly higher than that of LETO at 36 wks, and increased at 48 wks. In OLETF rats, prostate blood flow was significantly lower at 48 wks versus 36 wks. Twelve-week-tadalafil treatment increased prostate blood flow and suppressed prostate weight increase in both strains. This change was inversely correlated with changes in prostate expressions of hypoxia-inducible factor-1 alpha (HIF-1α) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Increases with age were observed in mRNA and/or protein levels of cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha (TNF-α) and cell growth factors insulin-like growth factor-1 (IGF-1), basic fibroblast growth factor (bFGF), and transforming growth factor-beta (TGF-ß); especially IL-6, TNF-α, IGF-1, bFGF and TGF-ß increased with T2D. Tadalafil suppressed these cytokines and growth factors. SIGNIFICANCE: These data suggest chronic ischemia caused by T2D leads to oxidative stress, resulting in prostate enlargement through upregulation of several cytokines and growth factors. Treatment with PDE5i improves prostate ischemia and might prevent enlargement via suppression of cytokines and growth factors in T2D.

Gastrointestinal AA amyloidosis secondary to chronic pyelonephritis presenting with refractory diarrhea and severe hypoalbuminemia.

Secondary amyloidosis is a rare complication of chronic inflammatory diseases, such as collagen diseases, and is often difficult to treat. In addition, the gastrointestinal tract is frequently involved in amyloid deposition that often results in various disorders and symptoms. A 70-year-old woman was admitted to our hospital with refractory diarrhea and hypoalbuminemia. Abdominal computed tomography demonstrated extensive edematous wall thickening of the small intestine and colon. Video capsule endoscopy revealed multiple ulcerations with a white mossy appearance of the ileum. Double-balloon endoscopy showed severe circumferential ulcers in the entire ileum. Histological examination of ileum biopsy samples revealed severe amyloid deposition in the lamina propria and perivascular areas of the submucosa. The patient was diagnosed with gastrointestinal AA amyloidosis. The cause of AA amyloid deposition was presumed to be chronic pyelonephritis due to ureteral stones that had been left untreated for 35 years. After treatment with ureteral drainage and antibiotics, the patient's symptoms and serological abnormalities improved dramatically. Here, we describe a case of severe gastrointestinal AA amyloidosis secondary to chronic pyelonephritis. Clinicians should thoroughly investigate the entire gastrointestinal tract in patients with refractory diarrhea and severe hypoalbuminemia considering the possibility of gastrointestinal amyloidosis.

Efficacy and safety of onabotulinumtoxinA in patients with overactive bladder: subgroup analyses by sex and by serum prostate-specific antigen levels in men from a randomized controlled trial.

PURPOSE: We aimed to assess onabotulinumtoxinA treatment outcomes by sex in patients with overactive bladder (OAB) and then explore the impact of serum prostate-specific antigen (PSA) levels in men. METHODS: Patients inadequately managed with OAB medications were randomized to receive single-dose onabotulinumtoxinA (100 U) or placebo intravesical injection in a phase III trial in Japan. We performed subgroup analyses by sex and post-hoc subgroup analyses using male PSA categories. RESULTS: In women (n = 186), onabotulinumtoxinA demonstrated statistically significant and clinically relevant improvements in all urinary symptoms at Week 12. In men with lower PSA (< 1.5 ng/mL, n = 40), onabotulinumtoxinA also showed numerically greater reductions in urinary symptom frequency than placebo; the between-group differences (onabotulinumtoxinA minus placebo) in change from baseline in the average daily number at Week 12 for urinary incontinence (UI), urgency UI, micturition, urgency, and nocturia were - 1.43, - 1.79, - 2.81, - 2.45, and - 0.32 episodes, respectively. In men with higher PSA (≥ 1.5 ng/mL, n = 22), onabotulinumtoxinA did not reduce urinary symptom frequency. Some patients treated with onabotulinumtoxinA showed elevated post-void residual urine volume at Week 2 (≥ 200 mL): 4 of 91 women, none of the men with lower PSA and 3 of 11 men with higher PSA. CONCLUSIONS: OnabotulinumtoxinA was efficacious and well tolerated in women and in men with lower PSA levels. Given our post-hoc subgroup analyses which suggested that onabotulinumtoxinA treatment is a good treatment option for OAB males with lower PSA levels, future studies having prostate volume data with larger sample size are warranted to verify our findings. CLINICALTRIALS. GOV IDENTIFIER: NCT02820844 (first posted July 1, 2016). https://clinicaltrials.gov/ct2/show/NCT02820844 .

Botulinum toxin injections for Japanese patients with urinary incontinence caused by neurogenic detrusor overactivity: Clinical evaluation of onabotulinumtoxinA in a randomized, placebo-controlled, double-blind trial with an open-label extension.

OBJECTIVE: To assess the efficacy and safety of botulinum toxin treatment (onabotulinumtoxinA 200 units) for Japanese patients with neurogenic detrusor overactivity caused by spinal cord injury or multiple sclerosis. METHODS: Patients with urinary incontinence refractory to pharmacological treatment were enrolled and randomized in a phase III trial. A single dose of onabotulinumtoxinA (n = 11) or placebo (n = 10) was given in the double-blind phase, and repeat injections of onabotulinumtoxinA were given in the subsequent open-label phase. Outcomes included urinary incontinence episodes, urodynamics, patient-reported outcomes and adverse events. RESULTS: The onabotulinumtoxinA group showed a numerically greater reduction in the number of urinary incontinence episodes per day than the placebo group, with the difference between the groups at week 6 of -3.02 (95% confidence interval -5.85 to -0.19). The onabotulinumtoxinA group also showed greater improvements in urodynamic assessments. Adverse events related to onabotulinumtoxinA injections were hematuria, urinary retention, urinary bladder hemorrhage, autonomic dysreflexia and epididymitis. Most events were deemed mild or moderate. CONCLUSIONS: Intradetrusor injections of onabotulinumtoxinA are efficacious and tolerable for Japanese patients with neurogenic detrusor overactivity-related symptoms that are difficult to manage with anticholinergics and/or ß3 -adrenergic receptor agonists.

Cardiovascular safety of vibegron, a new ß3-adrenoceptor agonist, in older patients with overactive bladder: Post-hoc analysis of a randomized, placebo-controlled, double-blind comparative phase 3 study.

AIMS: To examine the safety and efficacy of vibegron, a new ß3-adrenoceptor agonist, in patients aged ≥65 years, with a focus on the effects on cardiovascular system and overactive bladder (OAB) symptoms. METHODS: A post-hoc subgroup analysis was performed of a randomized, placebo-controlled, double-blind comparative phase 3 study of vibegron, including those assigned to receive either vibegron 50 mg (V50), vibegron 100 mg (V100), or placebo for 12 weeks. Subjects were stratified into two subgroups based on age: a <65-year subgroup and a ≥65-year subgroup. Safety (changes in systolic and diastolic blood pressure, pulse rate, and residual urine volume) and efficacy (changes in the numbers of micturitions, urgency episodes, urgency urinary incontinence [UUI] episodes, and the voided volume/micturition) were assessed in the subgroups treated with vibegron vs. placebo. RESULTS: There were no significant differences in the cardiovascular outcomes (blood pressure and pulse rate), nor in the changes in residual urine volume, between the V50/100 and placebo groups in the <65-year or ≥65-year subgroup after 12-week treatment. Adverse events were slightly increased in the ≥65-year subgroup. In the efficacy analysis, V50/100 demonstrated similar efficacy in the <65-year and ≥65-year subgroups; an increasing trend in the voided volume/micturition was observed in subjects aged ≥65 years compared to subjects aged <65 years. CONCLUSIONS: Vibegron was suggested to be similarly effective in patients ≥65 and <65 years and to have minimal influence on cardiovascular parameters.

Impact of self-decision to stop cancer treatment on advanced genitourinary cancer patients.

ABSTRACT: Decision-making to stop cancer treatment in patients with advanced cancer is stressful, and it significantly influences subsequent end-of-life palliative treatment. However, little is known about the extent to which the patient's self-decisions influenced the prognostic period. This study focused on the patient's self-decision and investigated the impact of the self-decision to stop cancer treatment on their post-cancer treatment survival period and place of death.We retrospectively analyzed 167 cases of advanced genitourinary cancer patients (kidney cancer: 42; bladder cancer: 68; prostate cancer: 57) treated at the University of Fukui Hospital (UFH), who later died because of cancer. Of these, 100 patients decided to stop cancer treatment by themselves (self-decision group), while the families of the remaining 67 patients (family's decision group) decided to stop treatment on their behalf because the patient's decision-making ability was already impaired. Differences in the post-cancer-treatment survival period and place of death between the 2 groups were examined. The association between place of death and survival period was also analyzed.The median survival period after terminating cancer treatment was approximately 6 times longer in the self-decision group (145.5 days in self-decision group vs 23.0 days in family's decision group, P < .001). Proportions for places of death were as follows: among the self-decision group, 42.0% of patients died at UFH, 45.0% at other medical institutions, and 13.0% at home; among the family's decision group, 62.7% died at UFH, 32.8% at other medical institutions, and 4.5% at home. The proportion of patients who died at UFH was significantly higher among the family's decision group (P = .011). The median survival period was significantly shorter for patients who died at UFH (UFH: 30.0 days; other institutions/home: 161.0 days; P < .001).Significantly longer post-cancer-treatment survival period and higher home death rate were observed among patients whose cancer treatment was terminated based on their self-decision. Our results provide clinical evidence, especially in terms of prognostic period and place of death that support the importance of discussing bad news, such as stopping cancer treatment with patients.

Urinary reabsorption in the rat kidney by anticholinergics.

Anticholinergics, therapeutic agents for overactive bladder, are clinically suggested to reduce urine output. We investigated whether this effect is due to bladder or kidney urine reabsorption. Various solutions were injected into the bladder of urethane-anesthetized SD rats. The absorption rate for 2 h was examined following the intravenous administration of the anticholinergics imidafenacin (IM), atropine (AT), and tolterodine (TO). The bilateral ureter was then canulated and saline was administered to obtain a diuretic state. Anticholinergics or 1-deamino-[8-D-arginine]-vasopressin (dDAVP) were intravenously administered. After the IM and dDAVP administrations, the rat kidneys were immunostained with AQP2 antibody, and intracellular cAMP was measured. The absorption rate was ~ 10% of the saline injected into the bladder and constant even when anticholinergics were administered. The renal urine among peaked 2 h after the saline administration. Each of the anticholinergics significantly suppressed the urine production in a dose-dependent manner, as did dDAVP. IM and dDAVP increased the intracellular cAMP levels and caused the AQP2 molecule to localize to the collecting duct cells' luminal side. The urinary reabsorption mechanism through the bladder epithelium was not activated by anticholinergic administration. Thus, anticholinergics suppress urine production via an increase in urine reabsorption in the kidneys' collecting duct cells via AQP2.

Adrenal pheochromocytoma treated by combination of adrenal arterial embolization and radiofrequency ablation.

Combined therapy with adrenal arterial embolization and RF ablation may represent a useful therapeutic option with curative properties in select patients with pheochromocytoma.

Expression of functional E-selectin ligands on the plasma membrane of carcinoma cells correlates with poor prognosis in clear cell renal cell carcinoma.

OBJECTIVES: Given the relatively high frequency of metastatic recurrence of clear cell renal cell carcinoma (ccRCC), reliable prognostic markers of ccRCC, particularly those associated with metastasis, are needed. Here, in search of those factors, we assessed the contribution of sialyl Lewis x (sLex) and sialyl Lewis a (sLea), as well as functional E-selectin ligand carbohydrates expressed on carcinoma cells, to metastasis and consequent poor prognosis in ccRCC. MATERIALS AND METHODS: Patients who underwent surgical resection (curative nephrectomy) for RCC, and whose post-operative pathological diagnosis was ccRCC (n = 117) were enrolled in this study. Expression of sLex/sLea carbohydrate antigens in ccRCC was evaluated by immunohistochemistry with an anti-sLex/sLea monoclonal antibody HECA-452. To evaluate membrane expression of sLex/sLea carbohydrate antigens quantitatively, we employed a histological scoring system used to evaluate membrane expression of human epidermal growth factor receptor 2 (HER2) in breast cancer. We also conducted an E-selectin•IgM chimera in situ binding assay to assess expression of functional E-selectin ligand carbohydrates in ccRCC. We then carried out statistical analysis to determine whether membrane expression of HECA-452-reactive sLex/sLea glycans as well as of E-selectin•IgM-binding functional E-selectin ligand carbohydrates correlates with progression-free, overall, or cancer-specific survival. RESULTS: Based on HECA-452 immunochemistry, 106 of 117 ccRCC specimens expressed detectable levels of sLex/sLea glycans, primarily on the plasma membrane, and of those, 31 that showed robust membrane expression were judged as HECA-452-positive. Membrane expression of HECA-452-positive sLex/sLea glycans correlated with shortened progression-free and overall survival. Moreover, in in situ analysis, these HECA-452-positive ccRCC tissues were decorated with E-selectin•IgM chimeric proteins, calcium-dependently. Comparable analysis in normal kidney showed both HECA-452 positivity and chimera binding almost exclusively in epithelial cells that constitute proximal tubules. Membrane expression of functional E-selectin ligand carbohydrates, as detected by the E-selectin•IgM chimera, correlated more significantly with poor prognosis of patients, namely, shortened progression-free, overall and cancer-specific survival, than did HECA-452 positivity. CONCLUSIONS: Expression of E-selectin•IgM-binding functional E-selectin ligand carbohydrates can serve as a reliable and potentially superior prognostic biomarker of patients with ccRCC.

Clinical Guidelines for Female Lower Urinary Tract Symptoms (second edition).

The present article is an abridged English translation of the Japanese Clinical Guidelines for Female Lower Urinary Tract Symptoms (second edition), published in September 2019. These guidelines consist of a total of 212 pages and are unique worldwide in that they cover female lower urinary tract symptoms other than urinary incontinence. They contain two algorithms for "primary treatment" and "specialized treatment," respectively. These guidelines, consisting of six chapters, address a total of 26 clinical questions including: (i) treatment algorithms; (ii) what are female lower urinary tract symptoms?; (iii) epidemiology and quality of life; (iv) pathology and illness; (v) diagnosis; and (vi) treatment. When the patient's symptoms mainly involve voiding and post-micturition symptoms, specialized treatment should be considered. In the event of voiding symptoms concurrent with storage symptoms, residual urine should be measured; if the residual urine volume is <100 mL, then diagnosis and treatment for storage symptoms is prioritized, and if the volume is ≥100 mL, then specialized treatment should be considered. When storage symptoms are the primary condition, then the patient is subject to the primary treatment algorithm. Specialized treatment for refractory overactive bladder includes botulinum toxin injection and sacral nerve stimulation. For stress urinary incontinence, surgical treatment is indicated, such as urethral slings. The two causes of voiding symptoms and post-micturition symptoms are lower urinary tract obstruction and detrusor underactivity (underactive bladder). Mechanical lower urinary tract obstruction, such as pelvic organ prolapse, is expected to improve with surgery.

Impact of Medical Castration on Malignant Arrhythmias in Patients With Prostate Cancer.

Background Medical castration, gonadotropin-releasing hormone agonists, and antiandrogens have been widely applied as a treatment for prostate cancer. Sex steroid hormones influence cardiac ion channels. However, few studies have examined the proarrhythmic properties of medical castration. Methods and Results This study included 149 patients who underwent medical castration using gonadotropin-releasing hormones with/without antiandrogen for prostate cancer. The changes in the ECG findings during the therapy and associations of the electrocardiographic findings with malignant arrhythmias were studied. The QT and corrected QT (QTc) intervals prolonged during the therapy compared with baseline (QT, 394±32 to 406±39 ms [P<0.001]; QTc, 416±27 to 439±31 ms [P<0.001]). The QTc interval was prolonged in 119 (79.9%) patients during the therapy compared with baseline. In 2 (1.3%) patients who had no structural heart disease, torsade de pointes (TdP) and ventricular fibrillation (VF) occurred ≥6 months after starting the therapy. In patients with TdP/VF, the increase in the QTc interval from the pretreatment value was >80 ms. However, in patients without TdP/VF, the prevalence of an increase in the QTc interval from the pretreatment value of >50 ms was 11%, and an increase in the QTc interval from the pretreatment value >80 ms was found in only 4 (3%) patients. Conclusions Medical castration prolongs the QT/QTc intervals in most patients with prostate cancer, and it could cause TdP/VFs even in patients with no risk of QT prolongation before the therapy. An increase in the QTc interval from the pretreatment value >50 ms might become a predictor of TdP/VF. Much attention should be paid to the QTc interval throughout all periods of medical castration to prevent malignant arrhythmias.

Efficacy and safety of the noradrenaline reuptake inhibitor, TAS-303, in women with stress urinary incontinence: Results of a double-blind, randomized, placebo-controlled, early phase II trial.

OBJECTIVE: To carry out an exploratory assessment of the efficacy and safety of TAS-303, a noradrenaline reuptake inhibitor, in women with stress urinary incontinence. METHODS: In a double-blind, placebo-controlled, early phase II study, women with stress urinary incontinence and stress urinary incontinence-predominant mixed urinary incontinence were randomized to a placebo or TAS-303 (3 or 6 mg) once daily for 8 weeks. The main efficacy end-points were mean percentage change in incontinence episode frequency per 24 h from baseline to week 8 (the primary end-point) and week 4. RESULTS: At week 8, the mean percentage change in incontinence episode frequency per 24 h was -34.73% in the TAS-303 3 mg group, -35.41% in the TAS-303 6 mg group and -28.07% in the placebo group (differences vs placebo, not significant). In patients with stress urinary incontinence, or incontinence episode frequency less than two episodes per 24 h at baseline, TAS-303 significantly reduced incontinence episode frequency versus placebo after 4 weeks; some secondary end-points also showed a tendency to improve in the same subgroups. No serious adverse events (e.g. central nervous system or cardiovascular effects) were observed; TAS-303 was well tolerated and had a favorable safety profile. CONCLUSION: These findings suggest that TAS-303 is effective for improving stress urinary incontinence symptoms in some subgroups of patients with stress urinary incontinence. Therefore, further research is warranted.

Duration of smoking cessation is negatively associated with the magnitude of chronic prostatic inflammation and storage dysfunction in patients with benign prostatic hyperplasia.

OBJECTIVES: To evaluate the impact of smoking and the benefit of smoking cessation on lower urinary tract function and prostatic inflammation in patients with benign prostatic hyperplasia. METHODS: The medical records of 118 benign prostatic hyperplasia patients who underwent transurethral prostatic surgery between 2006 and 2016 were analyzed. Their smoking history was confirmed. The relationship between smoking and main clinical parameters, International Prostate Symptom Scores, uroflowmetry, pressure flow study, magnitude of prostatic inflammation and the level of serum C-reactive protein was investigated. Furthermore, the relationships between smoking cessation and these clinical parameters were assessed. RESULTS: The International Prostate Symptom Scores for straining among the non-smokers were significantly lower than those of the smokers (1.71 vs 2.60, P = 0.029). In the pressure flow study, there were negative correlations between the duration of smoking and strong desire to void (correlation coefficient -0.314, P = 0.013), urgency (correlation coefficient -0.349, P = 0.008) and bladder volume at initial detrusor overactivity (correlation coefficient -0.417, P = 0.021). The duration of smoking cessation was negatively correlated with the magnitude of chronic prostatic inflammation (correlation coefficient -0.253, P = 0.027). In the pressure flow study, the duration of smoking cessation was positively correlated with urgency (correlation coefficient 0.286, P = 0.030) and maximum cystometric capacity (correlation coefficient 0.241, P = 0.050). CONCLUSIONS: Smoking could be a risk factor for the exacerbation of storage dysfunction in benign prostatic hyperplasia patients. Smoking cessation is effective in improving chronic prostatic inflammation and storage dysfunction.

Correcting imbalance of sex hormones by a phosphodiesterase 5 inhibitor improves copulatory dysfunction in male rats with type 2 diabetes.

INTRODUCTION: Sexual dysfunction is a common complication in men with type 2 diabetes and is often refractory to treatment. This study investigated the long-term influence of the phosphodiesterase 5 inhibitor (PDE5I) tadalafil on the level of sex hormones and sexual function in male Otsuka Long-Evans Tokushima Fatty (OLETF) rats as an animal model of spontaneous type 2 diabetes. RESEARCH DESIGN AND METHODS: We treated 36-week-old male OLETF and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats with oral tadalafil (100 µg/kg/day) for 12 weeks; sham groups received vehicle for 12 weeks. Before and after tadalafil treatment, serum levels of total and free testosterone, estradiol, luteinizing hormone (LH), follicle-stimulating hormone and proinflammatory cytokines were compared among four treatment groups. Copulatory function was examined by matching each rat to an estrous female. After completion of the experiment, total fat mass in the abdomen was measured. RESULTS: Testosterone levels were significantly lower in OLETF versus LETO rats at 36 weeks. After 12 weeks of tadalafil treatment, levels of testosterone were significantly increased both in OLETF-tadalafil and LETO-tadalafil groups versus vehicle groups. Tadalafil decreased estradiol levels both in OLETF and LETO rats. Furthermore, tadalafil increased serum LH levels with a reduction of proinflammatory cytokines. Total fat mass was significantly lower in the OLETF-tadalafil group versus the OLETF-vehicle group. A significant suppression of copulatory behavior, that is, elongation of intromission latency was found in OLETF rats. However, tadalafil treatment for 12 weeks shortened the intromission latency. CONCLUSION: Our results indicate that tadalafil treatment might improve copulatory disorder in the type 2 diabetic model via improvement of an imbalance in sex hormones and an increase in LH levels.

OnabotulinumtoxinA (botulinum toxin type A) for the treatment of Japanese patients with overactive bladder and urinary incontinence: Results of single-dose treatment from a phase III, randomized, double-blind, placebo-controlled trial (interim analysis).

OBJECTIVE: To evaluate the efficacy and safety of onabotulinumtoxinA (botulinum toxin type A) 100 U in patients with overactive bladder and urinary incontinence. METHODS: This was a phase III, randomized, double-blind, placebo-controlled trial in Japanese patients who were inadequately managed with overactive bladder medications (anticholinergics and/or ß3 -adrenergic receptor agonists). Eligible patients were randomized 1:1 to receive a single dose of either onabotulinumtoxinA or placebo into the detrusor muscle (n = 124 each). The primary end-point was the change in the number of daily urinary incontinence episodes at week 12 from baseline. Secondary end-points included volume voided per micturition, other symptomatic measures (urinary urgency incontinence, micturition, urgency and nocturia) and patient-reported outcomes. RESULTS: In the onabotulinumtoxinA group, there was a significantly greater decrease from baseline in the mean number of daily urinary incontinence episodes compared with the placebo group (2.16; P < 0.001), and significantly greater improvement for all secondary end-points (P < 0.05). Urinary tract infection, dysuria, urinary retention and post-void residual urine volume increased represented adverse events occurring at a higher rate in the onabotulinumtoxinA group. The majority of these were mild or moderate in severity. CONCLUSIONS: Statistically significant and clinically relevant improvements in symptoms and patient-reported outcomes, and tolerability were seen in patients with overactive bladder and urinary incontinence who had been inadequately managed with overactive bladder medications after using onabotulinumtoxinA.

Efficacy of vibegron, a novel ß3-adrenoreceptor agonist, on severe urgency urinary incontinence related to overactive bladder: post hoc analysis of a randomized, placebo-controlled, double-blind, comparative phase 3 study.

OBJECTIVE: To evaluate the efficacy of a novel and selective ß3-adrenoreceptor agonist vibegron on urgency urinary incontinence (UUI) in patients with overactive bladder (OAB). PATIENTS AND METHODS: A post hoc analysis was performed in patients with UUI (>0 episodes/day) who were assigned to receive vibegron or placebo in a vibegron phase 3 study. Patients were subclassified into mild/moderate (>0 to <3 UUI episodes/day) or severe UUI (≥3 UUI episodes/day) subgroup. Changes from baseline in number of UUI episodes/day, in number of urgency episodes/day, and in voided volume/micturition were compared between the groups. The percentage of patients who became UUI-free ('diary-dry' rate) and the response rate (percentage of patients with scores 1 [feeling much better] or 2 [feeling better] assessed by the Patient Global Impression scale [PGI]) were evaluated. RESULTS: Changes in numbers of UUI episodes at week 12 in the vibegron 50 mg, vibegron 100 mg and placebo groups, respectively, were -1.35, -1.47 and -1.08 in all patients, -1.04, -1.13 and -0.89 in the mild/moderate UUI subgroup, and -2.95, -3.28 and -2.10 in the severe UUI subgroup. The changes were significant in the vibegron 50 and 100 mg groups vs placebo regardless of symptom severity. Change in number of urgency episodes/day was significant in the vibegron 100 mg group vs placebo in all patients and in both severity subgroups. In the vibegron 50 mg group, a significant change vs placebo was observed in all patients and in the mild/moderate UUI subgroup. Change in voided volume/micturition was significantly greater in the vibegron 50 and 100 mg groups vs placebo in all patients, as well as in the both severity subgroups. Diary-dry rates in the vibegron 50 and 100 mg groups were significantly greater vs placebo in all patients and in the mild/moderate UUI subgroup. In the severe UUI subgroup, however, a significant difference was observed only in the vibegron 50 mg group. Response rates assessed by the PGI were significantly higher in the vibegron groups vs placebo in all patients and in the both severity subgroups. Vibegron administration, OAB duration ≤37 months, mean number of micturitions/day at baseline <12.0 and mean number of UUI episodes/day at baseline <3.0 were identified as factors significantly associated with normalization of UUI. CONCLUSIONS: Vibegron, a novel ß3-adrenoreceptor agonist, significantly reduced the number of UUI episodes/day and significantly increased the voided volume/micturition in patients with OAB including those with severe UUI, with the response rate exceeding 50%. These results suggest that vibegron can be an effective therapeutic option for OAB patients with UUI.

Low-dose Docetaxel Enhanced the Anticancer Effect of Temsirolimus by Overcoming Autophagy in Prostate Cancer Cells.

BACKGROUND/AIM: Chemotherapy with docetaxel (DTX) is used for castration-resistant prostate cancer (CRPC), but it is inadequate. MATERIALS AND METHODS: We evaluated the effect of the combination treatment DTX and the mTOR inhibitor temsirolimus (TEM) in the PC3 prostate cancer cell line, by focusing on the induction of autophagy and apoptosis. RESULTS: TEM induced autophagy but not apoptosis even at a high dose, whereas DTX induced apoptosis. The combination of low-dose DTX and TEM caused a 34% suppression in cell proliferation compared to monotherapy with a higher dose of DTX. The induction of apoptosis was increased by their combination. The combination with DTX overcame the induction of autophagy by TEM. The combination treatment suppressed tumor growth 72% less than the control group after 14 days of treatment in vivo. CONCLUSION: The combination of TEM and DTX induced apoptosis by overcoming autophagy and enhanced the anticancer effect compared to monotherapy.