Efficacy and safety of intravesical instillation of KRP-116D (50% dimethyl sulfoxide solution) for interstitial cystitis/bladder pain syndrome in Japanese patients: A multicenter, randomized, double-blind, placebo-controlled, clinical study.

OBJECTIVE: To evaluate the efficacy and safety of intravesical KRP-116D, 50% dimethyl sulfoxide solution compared with placebo, in interstitial cystitis/bladder pain syndrome patients. METHODS: Japanese interstitial cystitis/bladder pain syndrome patients with an O'Leary-Sant Interstitial Cystitis Symptom Index score of ≥9, who exhibited the bladder-centric phenotype of interstitial cystitis/bladder pain syndrome diagnosed by cystoscopy and bladder-derived pain, were enrolled. Patients were allocated to receive either KRP-116D (n = 49) or placebo (n = 47). The study drug was intravesically administered every 2 weeks for 12 weeks. RESULTS: For the primary endpoint, the change in the mean O'Leary-Sant Interstitial Cystitis Symptom Index score from baseline to week 12 was -5.2 in the KRP-116D group and -3.4 in the placebo group. The estimated difference between the KRP-116D and placebo groups was -1.8 (95% confidence interval -3.3, -0.3; P = 0.0188). Statistically significant improvements for KRP-116D were also observed in the secondary endpoints including O'Leary-Sant Interstitial Cystitis Problem Index score, micturition episodes/24 h, voided volume/micturition, maximum voided volume/micturition, numerical rating scale score for bladder pain, and global response assessment score. The adverse drug reactions were mild to moderate, and manageable. CONCLUSIONS: This first randomized, double-blind, placebo-controlled trial shows that KRP-116D improves symptoms, voiding parameters, and global response assessment, compared with placebo, and has a well-tolerated safety profile in interstitial cystitis/bladder pain syndrome patients with the bladder-centric phenotype.

Chemotherapy-Induced IL8 Upregulates MDR1/ABCB1 in Tumor Blood Vessels and Results in Unfavorable Outcome.

Tumor endothelial cells (TEC) lining tumor blood vessels actively contribute to tumor progression and metastasis. In addition to tumor cells, TEC may develop drug resistance during cancer treatment, allowing the tumor cells to survive chemotherapy and metastasize. We previously reported that TECs resist paclitaxel treatment via upregulation of ABCB1. However, whether TEC phenotypes are altered by anticancer drugs remains to be clarified. Here, we show that ABCB1 expression increases after chemotherapy in urothelial carcinoma cases. The ratio of ABCB1-positive TEC before and after first-line chemotherapy in urothelial carcinoma tissues (n = 66) was analyzed by ABCB1 and CD31 immunostaining. In 42 cases (64%), this ratio increased after first-line chemotherapy. Chemotherapy elevated ABCB1 expression in endothelial cells by increasing tumor IL8 secretion. In clinical cases, ABCB1 expression in TEC correlated with IL8 expression in tumor cells after first-line chemotherapy, leading to poor prognosis. In vivo, the ABCB1 inhibitor combined with paclitaxel reduced tumor growth and metastasis compared with paclitaxel alone. Chemotherapy is suggested to cause inflammatory changes in tumors, inducing ABCB1 expression in TEC and conferring drug resistance. Overall, these findings indicate that TEC can survive during chemotherapy and provide a gateway for cancer metastasis. Targeting ABCB1 in TEC represents a novel strategy to overcome cancer drug resistance. SIGNIFICANCE: These findings show that inhibition of ABCB1 in tumor endothelial cells may improve clinical outcome, where ABCB1 expression contributes to drug resistance and metastasis following first-line chemotherapy.

Evaluation of prostaglandin E2 and E-series prostaglandin receptor in patients with interstitial cystitis.

PURPOSE: We evaluated PGE2 and EP receptor in patients with interstitial cystitis. MATERIALS AND METHODS: Enrolled in the study were 20 female patients with interstitial cystitis (11 with and 9 without Hunner lesions), 9 female controls with another urological disease who needed a cystoscopic procedure and 10 normal volunteers. In all participants we determined O'Leary-Sant symptom and problem scores, and obtained voluntary urine specimens for PGE2 analysis. Using anesthesia the bladder was distended by saline in stepwise fashion from 100 ml to maximum capacity in patients with interstitial cystitis. Each time the infused saline was retrieved for PGE2 analysis. We also measured PGE2 and the expression of EP receptor mRNA in bladder biopsy tissue in patients with interstitial cystitis. RESULTS: Symptom and problem indexes in patients with interstitial cystitis and Hunner lesions were significantly higher than in patients with interstitial cystitis without Hunner lesions. Urinary PGE2 in patients with interstitial cystitis and Hunner lesions was significantly higher than in patients with interstitial cystitis without lesions, controls and normal volunteers. PGE2 in retrieved saline in patients with interstitial cystitis and Hunner lesions increased depending on infusion volume but not in patients with interstitial cystitis without lesions. PGE2 content in bladder biopsy tissue was significantly higher in patients with interstitial cystitis and Hunner lesions than in controls. In patients with interstitial cystitis and Hunner lesions the expression of EP1 and EP2 mRNA was significantly higher than in controls. CONCLUSIONS: Our study showed increased PGE2 production and mRNA expression of EP1 and EP2 receptors in the bladder in patients with interstitial cystitis and Hunner lesions. Further studies are warranted to explore the pathophysiological and therapeutic implications.

Botulinum toxin A submucosal injection for refractory non-neurogenic overactive bladder: early outcomes.

The objective of the present study was to assess the short-term effects of botulinum toxin A (BTX-A) injection for refractory non-neurogenic overactive bladder (OAB) in the setting of a prospective multicenter clinical trial. Refractory OAB was defined as persistent urgency urinary incontinence (UUI) ≥ once a week despite taking anticholinergic agents, or the incapability to continue the agents because of the adverse effects. A total of 100 U of BTX-A were reconstituted in 15 mL of normal saline and an aliquot of 0.5 mL was injected at 30 submucosal sites of the bladder wall. Nine men and eight women aged 67 ± 12 years were included. Subjective daytime frequency, urgency and UUI significantly decreased after treatment. On a 3-day frequency-volume chart, the daytime and night-time frequency of UUI significantly decreased from 5.5 and 0.5 pre-injection to 2.0 and 0.3 postinjection, respectively. Daytime urinary incontinence completely disappeared in six subjects. A urodynamic study showed the disappearance of detrusor overactivity in eight patients and a decrease in five patients. Maximum bladder capacity significantly increased from 179.9 to 267.3 mL. Difficulty on micturition or feeling of incomplete emptying was reported by 23.5% and 43.8% of patients at weeks 2 and 4, respectively. Postvoid residual urine increased to >100 mL in seven patients and >200 mL in one patient after injection; however, none of the patients required clean intermittent catheterization. These findings suggest promising efficacy of BTX-A in Japanese OAB patients.

[Overactive bladder syndrome. How to manage it].

Overactive bladder syndrome (OAB) is a chronic and distressing condition characterized by urinary urgency and increased frequency of micturition with or without urge incontinence. Such symptoms can exert a negative impact on many aspects of quality of life, including social function and interaction, physical activity and psychological well-being. In a survey of some 4500 people aged more than 40 years old in Japan, the prevalence of OAB was 12.4%. Even though OAB is prevalent and troublesome, many patients with OAB never seek medical help for their symptoms because of embarrassment and misconception about bladder control problems. Thus, it is important to broaden the actual knowledge about OAB among community-based people. We hope that this citizen joint symposium would help the participants to understand the useful information about OAB.

The long-term voiding function and sexual function after pelvic nerve-sparing radical surgery for rectal cancer.

BACKGROUND: The aim of the present study is to symptomatically analyze the extent to which pelvic nerve-sparing radical surgery for rectal cancer impacts on long-term voiding and male sexual function. METHODS: A self-administered questionnaire was mailed to 68 patients who underwent pelvic nerve-sparing radical surgery for invasive rectal cancer with 52 responses (28 men and 24 women; 27 complete and 25 incomplete preservation; response rate 76.5%). Each patient was asked to record if there had been any changes in lower urinary tract symptoms after surgery. Sexual function was also investigated in men. RESULTS: Of the 52 patients, 48 (92%) maintained voluntary voiding without catheterization in the long term. Clean intermittent self-catheterization was performed in only four patients with incomplete preservation because of persistent voiding dysfunction. Subjectively, approximately 60% of the patients remained unchanged in lower urinary tract symptoms after surgery. The satisfaction rate regarding the current voiding status was significantly higher in women than in men (83% versus 61%, P = 0.0294), but was not significantly different between those with complete (76%) and incomplete preservation (64%). Despite the acceptable urinary status, 88% of men had some deterioration in the erectile function, regardless of the types of surgical procedures. Overall, 64% of men were unsatisfied with the current sexual function. CONCLUSIONS: Pelvic nerve-sparing radical surgery for rectal cancer preserved the long-term voiding function in the majority of patients. In completely preserved patients and in women, symptomatic outcomes were more satisfactory. Postoperative erectile dysfunction was found to be a serious problem, even in complete nerve-sparing procedure.

Urodynamic effects of alpha1-blocker tamsulosin on voiding dysfunction in patients with neurogenic bladder.

BACKGROUND: The therapeutic role of alpha-blockers in the treatment of voiding disorders due to benign prostatic hyperplasia has been extensively examined. To investigate a possible effect of alpha1-blocker on urodynamic voiding parameters in patients with neurogenic bladder, we conducted a clinical trial using tamsulosin. METHODS: Twenty-four patients (14 men and 10 women) ranging from 24 to 82 years of age (mean age 61 years) with neurogenic bladder were analyzed. Urodynamic studies were performed before and after treatment with 0.4 mg tamsulosin daily for 4 weeks. RESULTS: On uroflowmetry, the average flow rate (from 4.6 +/- 3.3 to 6.7 +/- 3.0 mL/s, P = 0.04), maximum flow rate (from 9.4 +/- 6.8 to 14.1 +/- 7.0 mL/s, P = 0.016) and residual urine rate (from 46 +/- 29 to 32 +/- 21%, P = 0.02) improved significantly. In patients with detrusor contraction during voiding, detrusor opening pressure and detrusor pressure at maximum flow decreased significantly from 69.0 +/- 36.2 to 49.2 +/- 26.4 cmH2O (P = 0.046) and from 66.7 +/- 34.6 to 53.6 +/- 26.5 cmH2O (P = 0.007), respectively. On the other hand, in patients with detrusor areflexia, vesical opening pressure (from 78.2 +/- 23.4 to 61.6 +/- 25.2 cmH2O), or vesical pressure at maximum flow (from 68.6 +/- 23.2 to 62.9 +/- 25.2 cmH2O) did not change significantly after treatment. CONCLUSION: Tamsulosin reduces functional urethral resistance during voiding and improves flow rate in patients with neurogenic bladder. It has more beneficial urodynamic effects in patients with detrusor contraction during voiding than in patients with detrusor areflexia.

Effects of chronic blockade of N-methyl-D-aspartate receptors by MK-801 on neuroplasticity of the micturition reflex pathway after partial urethral obstruction in the rat.

PURPOSE: To determine the role of N-methyl-D-aspartate (NMDA) glutamatergic receptors in the development of functional bladder changes after partial urethral obstruction we investigated the effects of repeat injection of MK-801, a noncompetitive NMDA receptor antagonist, on the micturition reflex in conscious obstructed rats. MATERIALS AND METHODS: In 9 female Wistar rats 1.0 mg/kg MK-801 was injected intramuscularly once weekly just prior to the creation of partial urethral obstruction until 5 weeks after obstruction. Five to 7 days after the last injection of MK-801 conscious filling cystometry was performed and compared with that in 9 obstructed rats treated with vehicle (saline). Conscious filling cystometry was also compared in 9 and 7 sham operated rats treated with repeat injection of MK-801 and vehicle, respectively. RESULTS: Partial urethral obstruction caused a significant increase in bladder weight. However, chronic MK-801 treatment did not affect bladder weight in obstructed or sham operated rats. In the obstructed/MK-801 vs the obstructed/vehicle group chronic treatment with MK-801 significantly increased bladder capacity (2.29 +/- 0.12 vs 1.73 +/- 0.16 ml, p <0.01) and voided volume (2.00 +/- 0.10 vs 1.56 +/- 0.17 ml, p <0.05) without changes in voiding efficiency (87.5% +/- 1.6% vs 87.8% +/- 1.7%) or micturition pressure (55.8 +/- 2.3 vs 56.4 +/- 3.0 cm water). Interestingly neither the frequency nor amplitude of premicturition contractions during filling was different in the groups. In sham operated rats chronic MK-801 treatment did not change bladder capacity, voided volume, voiding efficiency or micturition pressure significantly. CONCLUSIONS: The results in the current study suggest that bladder outlet obstruction causes NMDA receptor mediated alterations in bladder afferent pathways in the rat.

Effects of a selective metabotropic glutamate receptor agonist on the micturition reflex pathway in urethane-anesthetized rats.

AIMS: To determine a possible role of metabotropic glutamate receptors in the spinobulbospinal micturition reflex pathway in the rat. MATERIALS AND METHODS: A selective metabotropic glutamate receptor agonist, trans-(+/-)-1-amino1,3-cyclopentanedicarboxylic acid (trans-ACPD) was administered to the lumbosacral spinal cord via an intrathecal catheter in urethane anesthetized rats. Amplitude of reflex bladder contractions evoked by bladder distension under isovolumetric condition as well as amplitude of bladder contractions elicited by electrical stimulation of the pontine micturition center (PMC) were examined before and after administration of trans-ACPD. The effect of trans-ACPD on the urethral activity during isovolumetric bladder contractions was also examined by monitoring urethral perfusion pressure and electromyography of the external urethral sphincter (EUS-EMG). RESULTS: Trans-ACPD (3-10 microg) completely inhibited reflex bladder contractions evoked by bladder distension and the duration of inhibition was dose dependent (3 microg: 11.4 +/- 2.8 min, 5 microg: 13.2 +/- 1.3 min, 10 microg: 36.2 +/- 2.4 min). The mean amplitude of bladder contractions evoked by electrical stimulation of the PMC was reduced to 12.6 +/- 2.3% of control by 10 microg of trans-ACPD. In addition, bursting activity of EUS-EMG and corresponding high frequency oscillations of urethral pressure during isovolumetric bladder contractions were completely abolished by 10 microg of trans-ACPD. CONCLUSIONS: These results indicate that intrathecal administration of a selective metabotropic glutamate receptor agonist to the lumbosacral spinal cord has an inhibitory effect on the spinobulbospinal micturition reflex pathway in urethane-anesthetized rats. This pharmacological action is attributed at least to the inhibitory effect on the descending pathway from the PMC to the lumbosacral spinal cord.

Laparoscopic antegrade continence enema procedure for fecal incontinence in a patient with spina bifida.

We report a laparoscopic procedure for antegrade continence enema (LACE) that was performed successfully in 39-year-old man patient with spina bifida suffering from severe fecal incontinence. The patient had been receiving regular follow-up at our clinic. He desired the antegrade continence enema procedure to improve his intractable fecal incontinence with a less invasive procedure. Following the placement of the first port at the umbilicus using an open access technique, two additional ports were introduced at the upper and lower abdomen in the midline. The appendix was laparoscopically mobilized to the right lower abdomen and brought out through another port. Next, an in situ appendicocutaneostomy was created. The patient began oral intake the day after surgery. Initial irrigation was performed on the second postoperative day. Convalescence was quick and there were no postoperative complications. Although a minor skin incision was required afterward for superficial stoma stenosis, the patient has been in a satisfactory condition with regular enemas. Laparoscopic appendicocutaneostomy can be a reasonable surgical alternative for antegrade continence stoma procedure. LACE has a clear advantage over conventional open procedures in view of its less invasive nature and better cosmetic results.

Transient neonatal expression of NR2B/2D subunit mRNAs of the N-methyl-D-aspartate receptor in the parasympathetic preganglionic neurons in the rat spinal cord.

Physiological studies have shown that lower urinary tract function is regulated through glutamate receptors at the levels of spinal and supraspinal cord. Of the receptor family, N-methyl-D-aspartate (NMDA) receptors mediate activity-dependent changes of synaptic efficacy, underlying synaptic plasticity and synapse development. To know the ontogenic changes of NMDA receptor expression in the visceromotor system innervating pelvic organs, including the bladder, we employed double labeling technique of retrograde neuronal tracing and in situ hybridization for detecting NMDA subunit mRNAs in preganglionic neurons (PGNs) of the lumbosacral cord. Rats at postnatal day 7 (P7), 14 (P14), 21 (P21), and adult were used. In situ hybridization was conducted using 35S-labeled antisense oligonucleotides specific to mRNAs for NMDA receptor subunits. Hybridizing signals in PGNs were detected by a dark-field microscope equipped fluorescence detector. PGNs showed strong signals for NR1 subunit mRNA at each developmental stage examined. Moderate signals for the NR2B and NR2D subunit mRNAs were found in PGNs at P7. However, their expression levels decreased thereafter, reaching the minimal level in adults. No significant signals for NR2A and NR2C subunit mRNAs were detected at any stages. This temporal pattern of expression suggests a possible involvement of NMDA receptors in the development of micturitional neural circuit through activity-dependent mechanisms.

Diameter of the external urethral sphincter as a predictor of detrusor-sphincter incoordination in children: comparative study of voiding cystourethrography.

PURPOSE: Voiding cystourethrography is a diagnostic procedure widely used to evaluate lower urinary tract abnormalities in children. In children with and without suspected voiding dysfunction we measured the internal diameter of the external urethral sphincter on voiding cystourethrography to evaluate its diagnostic accuracy as a predictor of detrusor-sphincter incoordination. MATERIALS AND METHODS: In part 1 of the study 59 boys and 37 girls with normal voiding function underwent voiding cystourethrography. In each child 1 to 6 voiding cystourethrograms (mean 2.1) were performed as a part of urological evaluation. Thus, a total of 200 voiding cystourethrograms were obtained. Underlying urological disease was primary vesicoureteral reflux in 57 cases, congenital hydronephrosis in 9, urinary tract infection in 6, ureteral anomalies in 11 and other in 13. To determine external urethral sphincter inner diameter on a given voiding cystourethrogram the sphincter was measured on consecutive images and the widest diameter was chosen. In part 2 of the study 43 children with suspected voiding dysfunction underwent voiding cystourethrography and external urethral sphincter electromyography. Electromyography results were comparatively analyzed with external urethral sphincter data. RESULTS: In part 1 an age dependent increase in external urethral sphincter inner diameter was noted in children with normal voiding function. External urethral sphincter inner diameter in mm. was determined by the formula, 0.166 x age in years + 4.31 in boys (p = 0.0001, r = 0.374) and 0.222 x age in years + 2.73 in girls (p <0.0001, r = 0.595). Overall the incidence of an external urethral sphincter inner diameter of less than 3 mm. was only 4% (8 of 200 patients). In part 2 external urethral sphincter electromyography documented detrusor-sphincter incoordination in 15 children (35%). When we defined an external urethral sphincter inner diameter of less than 3 mm. as a cutoff value for predicting detrusor-sphincter incoordination, the sensitivity, specificity, positive and negative predictive values were 93%, 89%, 82% and 96%, respectively. CONCLUSIONS: External urethral sphincter inner diameter has satisfactory sensitivity and specificity as a predictor of detrusor-sphincter incoordination in children. Thus, simple measurement of the inner diameter of the external urethral sphincter on voiding cystourethrography should be recommended in children with suspected voiding dysfunction before performing rather invasive urodynamic studies.

Ureteral stricture developing after partial nephrectomy with a microwave tissue coagulator: case report.

A 32-year-old man with a 1.7-cm tumor in the left kidney underwent laparoscopy-assisted partial nephrectomy. Although his postoperative course was uneventful, a 6-month postoperative CT scan showed hydronephrosis secondary to a severe stricture at the ureteropelvic junction. Heat injury to the urinary tract was strongly suspected. The use of microwave tissue coagulator for the tumor close to the renal sinus and excessive coagulation should be avoided to prevent heat-related complications.

Detrusor instability with equivocal obstruction: A predictor of unfavorable symptomatic outcomes after transurethral prostatectomy.

AIMS: To elucidate whether preoperative urodynamic findings can predict outcomes of transurethral resection of the prostate (TUR-P). METHODS: Sixty-two patients with symptomatic benign prostatic hyperplasia were categorized in three different ways based on findings of preoperative pressure-flow study (PFS) and cystometry: urodynamic obstruction (determined by the Abrams-Griffiths nomogram), detrusor instability (DI), and combination of both. Outcomes of TUR-P regarding symptom, function, and quality of life (QOL) were analyzed by changes in the International Prostate Symptom Score (I-PSS), maximum flow rate in uroflowmetry, and QOL index before and after TUR-P, respectively. Overall outcome was defined as success when all of the three categories showed successful improvement. RESULTS: Neither urodynamic obstruction alone nor DI alone predicted outcomes of TUR-P. However, symptomatic and overall outcomes were significantly worse in patients who were not obstructed but had DI. Postoperative persistent DI was more frequently noted in patients without clear obstruction (60%) than in those with obstruction (27%). Patients with equivocal obstruction showed less satisfactory symptomatic outcomes of TUR-P when DI was accompanied. Persistent DI might be the principle cause of unfavorable outcomes. CONCLUSIONS: Preoperative evaluation of DI is of benefit because it enhances predictive value of the PFS.

NK(1) receptor and its interaction with NMDA receptor in spinal c-fos expression after lower urinary tract irritation.

The role of neurokinin 1 (NK(1)) receptor and possible interaction between NK(1) and N-methyl-D-aspartic acid (NMDA) glutamatergic receptors were investigated on spinal c-fos expression after lower urinary tract irritation with acetic acid infusion in rats. At both levels of the first (L(1)) and sixth lumbar (L(6)) spinal cord, where most of hypogastric nerve and pelvic nerve afferent terminals project, respectively, the selective NK(1) receptor antagonist CP-99,994 dose dependently reduced the total number of c-fos protein (Fos)-positive cells. However, CP-100,263, the enantiomer of CP-99,994 with a very low affinity for NK(1) receptor, did not have any effect on the total number of Fos-positive cells. Coadministration of a low dose (1 mg/kg) of CP-99,994 and NMDA receptor antagonist (MK-801), either of which alone did not affect c-fos expression, significantly inhibited c-fos expression at both levels of the spinal cord. Regarding regional differences, the number of Fos-positive cells decreased significantly at all regions of the L(6) level, but only at the dorsal horn of the L(1) level. These results indicate that NK(1) receptor is involved in spinal c-fos expression after lower urinary tract irritation and that NK(1) and NMDA receptors have a synergistic interaction in the spinal processing of nociceptive input from the lower urinary tract.

Questionnaire analysis on sex difference in lower urinary tract symptoms.

OBJECTIVES: To examine the sex difference in the prevalence and severity of lower urinary tract symptoms in Japanese men and women. METHODS: Of 970 individuals who attended the public lectures by urologists and a famous veterinarian that were organized as a public service of the 88th Annual Meeting of the Japanese Urological Association (June 2000, Sapporo, Japan), 677 (70%) completed the self-administered International Prostate Symptom Score (IPSS) questionnaire. The scores of 653 attendees aged 30 to 79 years (446 men, mean age 67.5 and 207 women, mean age 60.7) were the basis of this study. RESULTS: A significant age-related increase in IPSS and quality-of-life score was observed in both men and women. The ratio of moderate (IPSS 8 to 19) to severe (IPSS 20 or greater) symptoms in the 50s, 60s, and 70s was 52%, 72%, and 80% in men and 27%, 36%, and 55% in women, respectively. Additional analysis in each decade showed that at age 50 years and older the total score and voiding symptom score of IPSS, as well as the quality-of-life score, were significantly greater in men than in women. CONCLUSIONS: The total IPSS and quality-of-life score correlated highly with age in both sexes. At the age of 50 years and older, men had severer voiding symptoms than did women. Although the age-related changes in bladder function predispose both men and women equally to lower urinary tract symptoms, the higher incidence of bladder outlet obstruction in men having a prostate may have a significant influence on the higher voiding symptom score in men.