Clinical Outcomes of Patients with High-risk Metastatic Hormone-naïve Prostate Cancer: A 3-year Interim Analysis of the Observational J-ROCK Study.

BACKGROUND: Androgen deprivation therapy (ADT), administered alone, as combined androgen blockade (CAB) or as ADT plus androgen receptor signalling inhibitors (ARSIs) or ADT plus docetaxel, is the standard treatment for metastatic hormone-naïve prostate cancer (mHNPC) in Japanese real-world practice. OBJECTIVE: To investigate treatment patterns and clinical outcomes in LATITUDE criteria high-risk mHNPC. DESIGN, SETTING, AND PARTICIPANTS: The longitudinal, multicentre, J-ROCK registry study enrolled patients initiating ADT in Japan after May 2019, and categorised them as cohort 1 (ADT or CAB) or cohort 2 (ADT plus ARSIs or docetaxel). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Prostate-specific antigen (PSA) response, progression-free survival (PFS), time to castrate-resistant prostate cancer (CRPC), overall survival (OS), and safety were evaluated. PFS, time to CRPC, and OS were estimated via the Kaplan-Meier method and between-cohort comparisons via multivariate Cox regression models. RESULTS AND LIMITATIONS: In total, 974 patients were included (cohort 1: 38.1%, cohort 2: 61.9%). CAB was preferred (67.4%) to ADT alone in cohort 1, and abiraterone acetate plus prednisolone was used most frequently in cohort 2 (59.4%). The proportion of patients with ≥50%/≥90% PSA decline or who achieved PSA ≤0.2/≤0.1 ng/ml tended to be higher in cohort 2. PFS (adjusted hazard ratio 0.42; 95% confidence interval [CI] 0.31-0.55), time to CRPC (0.28; 95% CI 0.23-0.36), and OS (0.54; 95% CI 0.35-0.82) were longer in cohort 2. In cohorts 1 and 2, adverse drug reactions of special interest (ADRSIs) occurred in 1.3% and 15.1%, and fatal adverse events occurred in 1.9% and 1.7%, respectively. Limitations included nonrandomised design, varying time since marketing authorisation for ARSIs, and limited safety assessments. CONCLUSIONS: ADT plus ARSIs or docetaxel was used more frequently to treat high-risk mHNPC than standard ADT/CAB and was associated with more favourable clinical outcomes. Although ADRSIs were reported more in cohort 2, the safety profile was considered tolerable. PATIENT SUMMARY: Although many treatment options are available for high-risk metastatic prostate cancer, there are limited reports on real-world clinical experience with different therapies outside of the clinical trial setting. In this study, we compared clinical and safety outcomes with different treatment regimens, using a large series of patients with high-risk metastatic hormone-naïve prostate cancer across Japan. We found that androgen deprivation therapy in combination with newer androgen receptor signalling inhibitors resulted in improved response compared with androgen deprivation therapy alone or in combination with a first-generation antiandrogen.

Treatment strategies and outcomes in a long-term registry study of patients with high-risk metastatic hormone-naïve prostate cancer in Japan: An interim analysis of the J-ROCK study.

OBJECTIVE: The prognosis of high-risk metastatic hormone-naïve prostate cancer is poor, and real-world evidence of therapeutic options and sequences is lacking. The J-ROCK study aimed to evaluate the outcomes in a real-world setting in Japan. METHODS: Patients with high-risk metastatic hormone-naïve prostate cancer diagnosed after May 2019 were eligible. Based on their treatment within 3 months after diagnosis, patients were allocated to either cohort 1 (androgen deprivation therapy alone or combined androgen blockade with bicalutamide) or cohort 2 (androgen deprivation therapy with abiraterone acetate+prednisolone, docetaxel, enzalutamide, or apalutamide). RESULTS: In this first interim analysis (cut-off January 2021), 410 patients were enrolled, including 163 patients in cohort 1 and 247 in cohort 2. The median follow-up period was 7.6 (range 0.1-20.5) months. A higher proportion of patients in cohort 2 (42.5%) achieved nadir prostate-specific antigen levels ≤0.2 ng/ml within a year, compared with cohort 1 (22.1%). Prostate-specific antigen-progression-free survival was also more favorable in cohort 2 (adjusted hazard ratio 0.629 [95% confidence interval 0.345-1.147]). CONCLUSIONS: The higher proportion of cohort 2 suggest a paradigm shift has occurred in the real-world treatment of high-risk metastatic hormone-naïve prostate cancer in Japan. Some factors including prostate-specific antigen may affect treatment selection but need further observation. Most patients in cohort 2 received abiraterone acetate+prednisolone. The proportion of patients in cohort 1 receiving combined androgen blockade was lower than previously reported in Japan. This analysis suggest that more intensive therapy tends to prolong prostate-specific antigen-progression-free survival in patients with high-risk metastatic hormone-naïve prostate cancer.

Perioperative outcomes in patients undergoing robot-assisted partial nephrectomy: Comparative assessments between complex and non-complex renal tumors.

INTRODUCTION: The aim of this study was to investigate the effects of renal tumor complexity on perioperative outcomes in patients receiving robot-assisted partial nephrectomy (RAPN). METHODS: This study included 153 consecutive patients with cT1 renal masses undergoing RAPN and analyzed their perioperative outcomes, particularly tumor complexity. In this series, cT1b, completely endophytic, hilar, and cystic tumors were considered complex tumors. Patients with tumors that met at least one of the complex criterion were placed in the complex tumor group; patients with tumors that did not meet any of the complex criteria were placed in the non-complex tumor group. RESULTS: Of the 153 patients, 54 (35.3%) had complex tumors; specifically, 18 (11.8%) had cT1b tumors, 15 (9.8%) had completely endophytic tumors, 28 (18.3%) had hilar tumors, and 8 (5.2%) had cystic tumors. The non-complex group included 99 patients (64.7%). The complex tumor group had significantly longer warm ischemia and console times than the non-complex tumor group, but there was no significant difference between them in the achievement of the trifecta. Both warm ischemia and console times were significantly correlated with the number of complex factors. Multivariate analyses of complex factors demonstrated that completely endophytic and cT1b tumors were independently associated with warm ischemia time and console time, respectively. CONCLUSIONS: For patients with complex tumors, RAPN may be a feasible procedure with acceptable perioperative outcomes. However, special attention should be paid to long warm ischemia and console times, particularly in those with completely endophytic and/or cT1b tumors.

[Evaluation of CT-Guided Percutaneous Needle Biopsy for Diagnosis of Renal Tumor].

We performed computed tomographic (CT)-guided percutaneous needle biopsy for renal tumors that were difficult to diagnose or were inoperable malignant renal tumors. Nineteen patients who underwent CT-guided percutaneous needle biopsy between November 2007 and March 2015 at Hamamatsu University Hospital were included in this study. The median tumor diameter was 78 mm (40-140 mm). Seventeen patients were diagnosed pathologically by biopsy, but 2 patients could not be diagnosed despite the existence of adequate sample volume. One patient had an adverse complication ; fever (CTCAE ver 4.0 grade 1). The median duration of follow-up was 21 months (0-111 months), no one had tumor seeding along a needle tract. CT-guided percutaneous needle biopsy of renal tumors is helpful for pathological diagnosis and further treatment planning. However, there are still some limitations to obtain an accurate diagnosis.

Systematic regional lymph node dissection for upper tract urothelial carcinoma improves patient survival.

OBJECTIVE: Unlike for bladder cancer, the impact of regional lymph node dissection for upper tract urothelial carcinoma is unclear. We explored whether patient survival was influenced by systematic regional lymph node dissection, using resection templates according to the main tumor location, during radical nephroureterectomy for upper tract urothelial carcinoma. METHODS: The systematic regional lymph node dissection group was defined as cases in which the dissection of nodes and surrounding tissues followed the established template, and the non-systematic regional lymph node dissection group as cases undergoing limited or no lymph node dissection. We performed radical nephroureterectomy on 98 consecutive patients with various stages of upper tract urothelial carcinoma from May 1994 to September 2014 at our institution. Of these, 77 patients with cTanyN0M0 of upper tract urothelial carcinoma undergoing radical nephroureterectomy were grouped into systematic regional lymph node dissection or non-systematic regional lymph node dissection cohorts according to the extent of dissection, and their outcomes compared. RESULTS: Forty-four patients were categorized as systematic regional lymph node dissection and 33 as non-systematic regional lymph node dissection, including 17 with more limited nodal dissection and 16 with no nodal dissection. Five-year recurrence-free survival and cancer-specific survival were significantly higher in the systematic regional lymph node dissection (93% and 94%, respectively) than in the non-systematic regional lymph node dissection group (75% and 77% recurrence-free survival and cancer-specific survival, respectively). Further, 5-year recurrence-free survival and cancer-specific survival of muscle-invasive upper tract urothelial carcinoma (pT2-4) were significantly higher in the systematic regional lymph node dissection (87% and 91%, respectively) than in the non-systematic regional lymph node dissection group (59% and 62%, respectively) (P = 0.0237 and P = 0.0224). Neither recurrence-free survival nor cancer-specific survival was significantly prolonged by systematic dissection in patients with pTis-1 histology. CONCLUSIONS: Systematic regional lymph node dissection during radical nephroureterectomy for cTanyN0M0 upper tract urothelial carcinoma patients has a significantly beneficial impact on survival compared with patients undergoing more limited dissection, especially in the cases involving muscle invasion.

Comparison of mirabegron and imidafenacin for efficacy and safety in Japanese female patients with overactive bladder: A randomized controlled trial (COMFORT study).

OBJECTIVES: To evaluate the efficacy and safety of mirabegron compared with imidafenacin for the treatment of female patients with overactive bladder. METHODS: Patients (n = 89) were randomized to receive 0.1 mg imidafenacin twice daily (n = 47) or 50 mg mirabegron once daily (n = 42) for 12 weeks. The primary efficacy end-point was change in total Overactive Bladder Symptom Score. Secondary efficacy end-points included change in Overactive Bladder Symptom Score, 3-day micturition diary, International Prostate Symptom Score and Overactive Bladder Questionnaire. Safety assessments included adverse events, vital signs, post-void residual volume and patient-reported incidence, and severity of distinctive symptoms related to adverse events. RESULTS: The mirabegron group showed a significantly reduced mean total Overactive Bladder Symptom Score from baseline, but no significant differences were noted in change of total Overactive Bladder Symptom Score compared with the imidafenacin group. Significant improvements in secondary efficacy end-points were observed regarding the mean number of micturitions/24 h, mean number of urgency episodes/24 h, mean number of incontinence episodes/24 h, mean volume voided/micturition, total International Prostate Symptom Score and quality of life in both groups, with no significant differences between the groups. The overall incidence of adverse events and the incidence of dry mouth were significantly higher in the imidafenacin group than in the mirabegron group. Patient-reported incidence and the severity of dry mouth were significantly exacerbated in the imidafenacin group. CONCLUSIONS: Treatment with 50 mg mirabegron once daily effectively relieves overactive bladder symptoms in women with fewer adverse events than treatment with antimuscarinics.

The expression of ß3-adrenoceptors and their function in the human prostate.

BACKGROUND: Little is known about ß3-adrenoceptor (AR) expression and function in human prostate. We examined the expression and distribution of ß-AR subtypes in normal prostate and benign prostatic hyperplasia (BPH) tissues, and investigated which selective ß-AR subtype agonist was most involved in the relaxation of isolated human prostate strips. METHODS: Messenger RNA (mRNA) expression for ß1-, ß2-, and ß3 -ARs was investigated using reverse transcriptase-polymerase chain reactions (RT-PCR). Quantitative analysis of mRNA expression of ß-AR subtypes between normal prostate and BPH tissues was performed using quantitative RT-PCR (qPCR). Distributions were examined by immunohistochemistry (IHC). Strips of human normal prostate or BPH were suspended in organ baths and exposed to isoproterenol, dobutamine, procaterol, and TRK-380 to investigate their relaxant effects on KCl-induced contractions, and their inhibitory effects on electrical field stimulation (EFS)-induced contractions. RESULTS: We confirmed the presence of mRNA for ß1-, ß2-, and ß3-ARs both in normal prostate and in BPH tissues. For ß3-AR, mRNA expression in BPH tissues was significantly higher than in normal prostate tissues, but there was no significant difference in ß1- and ß2-AR expression between normal and BPH tissues. IHC revealed differences in staining intensity between smooth muscle cells and glandular cells, with different proportions for different ß-AR subtypes. Staining of ß3-AR was particularly intense in smooth muscle cells as opposed to glandular cells. Isoproterenol and TRK-380 significantly decreased the tone of KCl-induced contractions of the normal prostate strips. The rank order of relaxant effects was isoproterenol > TRK-380 > procaterol > dobutamine. All selective ß-AR agonists significantly decreased the amplitude of EFS-induced contractions of the normal prostate strips. The rank order of inhibitory effects was isoproterenol > dobutamine >TRK-380 > procaterol. In BPH strips, all selective ß-AR agonists showed no significant relaxant or inhibitory effects on KCl- or EFS-induced contractions. CONCLUSIONS: ß3 -AR is abundant in human prostate smooth muscle, whose relaxation is mediated by ß1- and ß3-AR stimulation. ß3-AR agonists may have clinical use in the treatment of male non-BPH patients or neurogenic bladder patients with voiding dysfunction.

[Strangulation of the Penis by Four Metallic Washers].

We report here a case of strangulation of the penis. A 69-year-old male visited our hospital suffering from a swollen penis and dysuria after installation of four metallic washers to the penis. He had mischievously put them on his penis four days before and subsequently was unable to remove them. We found erosion on the surface of the penis, reduction in blood flow by ultrasonography, and high C-reactive protein levels. Because we could not remove washers by blood removal from glans penis or ring cutter, we performed percutaneous cystostomy and then cut the washers with an electric grinder under general anesthesia. The operation took 2 hours and 25 minutes. The postoperative course was uneventful. Neither disturbance of blood flow nor urethral stricture was found. He completely recovered without erectile dysfunction or difficult urination 7 months after the operation. Management of this rare condition is discussed.

[FIRST CASES OF ANTEROPOSTERIOR DISSECTION TUEB (TRANSURETHRAL ENUCLEATION WITH BIPOLAR)].

PURPOSE: We examined the efficacy of anteroposterior dissection transurethral enucleation with bipolar (TUEB) for benign prostate hyperplasia (BPH). PATIENTS AND METHODS: We performed anteroposterior dissection TUEB on 21 patients with BPH between October 2012 and June 2013. In anteroposterior dissection TUEB, the lateral lobes are anteroposteriorly dissected from the 12 o'clock position to the 6 o'clock position after enucleation of the middle lobe. Mean age was 73 years, mean estimated prostate volume was 62.8 ml, mean estimated transition zone volume was 44.5 ml, mean International Prostate Symptom Score (IPSS) score was 15.5, mean quality of life (QOL) score was 4.1, peak flow rate (Qmax) was 8.6 ml/s, and mean residual urine volume was 42.4 ml. RESULTS: The mean operation time was 69 min, the mean weight of removed prostate tissue was 27.3 g, and the mean decrease in hemoglobin level was 1.8 g/dl. Three months after surgery, mean IPSS score was 5.9, mean QOL score was 1.9, mean Qmax was 28 ml/s, and mean residual urine volume was 1.0 ml, values which were significantly improved over pre-surgery data. No complications such as perforation or bladder injury occurred during surgery, but 1 case (4.7%) of stress urinary incontinence and 1 case (4.7%) of urethral stricture were reported after surgery. Of note, urethral stricture was determined using a flexible cytoscope at 1 week, 1 month, and 3 months post-surgery. CONCLUSION: Anteroposterior dissection TUEB can be conducted safely and may be useful in reducing frequency of urethral stricture post-surgery.

Expression and functional role of ß3 -adrenoceptors in the human ureter.

OBJECTIVES: To investigate the presence of ß-adrenoceptor subtypes in the human ureter, and to examine whether ß(3) -adrenoceptors modulate relaxation of the human ureter. METHODS: Expression of messenger ribonucleic acid of ß-adrenoceptors in the human ureter was determined by reverse transcription polymerase chain reaction, and distribution of ß-adrenoceptors was examined by immunohistochemistry. In functional studies, the relaxant effects of isoproterenol, procaterol, TRK-380, salbutamol and BRL 37344 on KCl-induced contraction of the human ureter were evaluated, and the inhibitory effects of isoproterenol, procaterol and TRK-380 on electrical field stimulation-induced contractions were determined. RESULTS: Expression of ß(1) -, ß(2) - and ß(3) -adrenoceptor messenger ribonucleic acid in the human ureter was confirmed by reverse transcription polymerase chain reaction. Positive staining for ß(1) -, ß(2) - and ß(3) -adrenoceptor was identified not only in smooth muscle, but also in the urothelium of the human ureter. All ß-adrenoceptor agonists decreased the tone of KCl-induced contractions of the human ureter with a rank order of relaxant effects of isoproterenol > procaterol > TRK-380 > salbutamol > BRL 37344. Furthermore, isoproterenol, procaterol and TRK-380 significantly decreased the amplitude of electrical field stimulation-induced contractions with a rank order of inhibitory effects of isoproterenol > procaterol > TRK-380. CONCLUSIONS: Human ureteral relaxation is mediated by both ß(2) - and ß(3) -adrenoceptor stimulation. ß(3) -Adrenoceptor agonists have the potential to relax the human ureter, and their clinical application in the treatment of ureteral stones is expected.

Expression of ß-Adrenoceptor Subtypes in Urothelium, Interstitial Cells and Detrusor of the Human Urinary Bladder.

OBJECTIVE: We examined whether interstitial cells (ICs) of the human urinary bladder expressed ß-adrenoceptor (AR) subtypes, and semiquantitatively compared the staining intensity among urothelium, ICs and detrusor muscles. METHODS: Paraffin sections of the human urinary bladder were obtained from histologically normal areas of formalin-fixed specimens removed for bladder carcinoma. Double-labeling immunohistochemical methods using antibodies against each ß-AR subtype and vimentin were performed to identify ICs of the human urinary bladder. The staining intensity of ß-ARs was semiquantitatively compared among urothelium, ICs and detrusor muscles. Further, gender-related difference or age-related correlation in the staining intensity of ß-ARs was compared in the same cell types. RESULTS: The expression of ß1 -, ß2 -, and ß3 -AR was observed in vimentin-positive ICs localized in suburothelium, between detrusor muscle bundles, and within these bundles of the human urinary bladder. The rank order of the staining intensity was urothelium > ICs = detrusor muscles in ß1 -AR, urothelium > ICs > detrusor muscles in ß2 -AR, whereas its order was ICs = detrusor muscles > urothelium in ß3 -AR. Except for urothelial ß1 -AR, there was no gender-related difference in the signal intensity of ß-ARs in the urothelium, ICs or detrusor muscles. Age negatively correlated with the signal intensity of all ß-AR subtypes. CONCLUSION: ß-ARs were expressed in vimentin-positive ICs of the human urinary bladder. As for ß2 - and ß3 -AR, there was no gender-related difference or age-related correlation in urothelium, ICs and detrusor muscles. In the human urinary bladder, ß-ARs expressed in ICs may play a role in bladder physiology.

Pharmacological effect of TRK-380, a novel selective human ß3-adrenoceptor agonist, on mammalian detrusor strips.

OBJECTIVE: To clarify the potential of TRK-380 as a drug for overactive bladder in humans by evaluating the agonistic activities for human ß-adrenergic receptors (ß-ARs) and the relaxing effects on isolated detrusor strips. METHODS: The agonistic activities for human ß-ARs were evaluated in SK-N-MC cells (for human ß(3)-ARs) and Chinese hamster ovary cells expressing human ß(1)- or human ß(2)-ARs using the cyclic adenosine monophosphate accumulation assay. The relaxing effects on the resting tension in isolated detrusor strips from humans, monkeys, dogs, and rats and on carbachol- or KCl-induced contractions in human detrusor strips were evaluated. RESULTS: In the cyclic adenosine monophosphate accumulation assay, the agonistic activity of TRK-380 for human ß(3)-ARs was potent and equivalent to that of the potent nonselective ß-AR agonist isoproterenol and superior to that of selective ß(3)-AR agonists, such as BRL-37344 and CL316,243. TRK-380 showed no agonistic activity for human ß(1)-ARs and a weak agonistic effect on human ß(2)-ARs. In isolated detrusor strips, the concentration-dependent relaxing effects of TRK-380 on the resting tension were equivalent to those of isoproterenol in humans, monkeys, and dogs but weaker than the effects in rats. The selective ß(3)-AR antagonist SR59230A shifted the concentration-response curve in a concentration-dependent manner to TRK-380 for the resting tension of human detrusor strips to the right. TRK-380 had a concentration-dependent relaxing effect on the contractile responses to carbachol and KCl in human detrusor strips. CONCLUSION: TRK-380 was a potent and selective human ß(3)-AR agonist, and the isolated human detrusor relaxation was mainly mediated by activation of the ß(3)-AR. Consequently, TRK-380 might be a promising compound for the treatment of overactive bladder.

[A case of proliferative cystitis forming ureterovesical junction obstruction].

We report a case of proliferative cystitis forming ureterovesical junction obstruction. A 28-year-old man presented with a complaint of gross hematuria. Abdominal ultrasonography revealed left hydronephrosis and bladder tumor. Drip infusion pyelography (DIP) demonstrated left ureterovesical junction obstruction and cystoscopic findings appeared papillary sessile tumor around the bladder neck, trigone, and bilateral ureteral orifice. Transurethral resection of the bladder tumor (TURBT) was performed. The pathological diagnosis of the tumor was proliferative cystitis and confirmed that left ureterovesical junction obstruction was derived from proliferative cystitis. The tumor was not responsive to medical treatment. After the 4th TURBT, the tumor was completely resected, and left hydronephrosis and ureterovesical junction obstruction were improved. One year after the last operation, there is no evidence of recurrence of the tumor. Tumor formation arising from proliferative cystitis is relatively rare. Pathogenesis and management of this rare condition are discussed.

Expression and functional role of beta-adrenoceptors in the human urinary bladder urothelium.

We investigated the presence of beta-adrenoceptor subtypes in human urinary bladder urothelium and examined whether beta-adrenoceptors in the urothelium modulate the relaxation responses of isolated human detrusor strips to a beta-adrenoceptor agonist. Expression of beta1-, beta2-, and beta3-adrenoceptor mRNA in urothelium and detrusor smooth muscle was determined by reverse transcription-polymerase chain reaction, and the distribution of beta1-, beta2-, and beta3-adrenoceptors in human urinary bladder urothelium were examined by immunohistochemistry. Paired human longitudinal detrusor strips with and without an intact urothelium were suspended in organ baths to construct concentration-response curves to isoproterenol. The possible involvement of urothelium-derived nitric oxide (NO) in this response was examined in additional experiments with urothelium-intact strips in the presence of NG-nitro-L-arginine methylester (L-NAME). Results confirmed the expression of beta1-, beta2-, and beta3-adrenoceptors in the human urinary bladder urothelium. Further, the presence of the urothelium caused a parallel rightward shift of the concentration-response curve to isoproterenol with a significant reduction in potency (pEC50). L-NAME failed to exert any significant effect on the relaxation response to isoproterenol in the urothelium-intact strips. These results confirm the presence of beta1-, beta2-, and beta3-adrenoceptors in human urinary bladder urothelium. Further, they suggest that urothelial beta-adrenoceptors induce the release of a urothelium-derived factor which inhibits the beta-adrenoceptor agonist-induced relaxation of the human detrusor smooth muscle and that this inhibitory mechanism might not involve NO.

Effects of a novel beta(3)-adrenoceptor agonist, AJ-9677, on relaxation of the detrusor muscle: an in vitro study.

OBJECTIVES: To examine the relaxant effects of AJ-9677, a novel beta(3)-adrenoceptor agonist, on the isolated rat, monkey and human detrusor muscle. METHODS: The isolated detrusor strips of rats, monkeys and humans were mounted in organ baths containing Krebs solution. By the cumulative addition of beta-adrenoceptor agonists (isoproterenol, AJ-9677, CL 316,243 and salbutamol in rats; isoproterenol, AJ-9677 and CL 316,243 in monkeys and humans), concentration-relaxation curves were obtained. The maximal relaxation responses and pEC(50) values were calculated. In rats, concentration-relaxation curves to isoproterenol and AJ-9677 were obtained in the presence and absence of propranolol or SR 59230A. RESULTS: Isoproterenol, AJ-9677, CL 316,243 and salbutamol induced concentration-dependent relaxation in rats. The rank order of their relaxing potency in the rat detrusor muscle was AJ-9677 > isoproterenol > CL 316,243 > salbutamol. Isoproterenol and AJ-9677 also produced a concentration-dependent relaxation with high potency in monkeys and humans, whilst CL 316,243 had low relaxing potency. According to the antagonist studies in rats, propranolol and SR 59230A caused a rightward shift of the concentration-relaxation curves to isoproterenol or AJ-9677, respectively. CONCLUSIONS: AJ-9677 has a high relaxant potency on the rat, monkey and human detrusor smooth muscle, and it may have the potential to treat overactive bladder.