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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. [ABSTRACT FROM AUTHOR]

The 'Japanese Clinical Guideline for Female Lower Urinary Tract Symptoms,' published in Japan in November 2013, contains two algorithms (a primary and a specialized treatment algorithm) that are novel worldwide as they cover female lower urinary tract symptoms other than urinary incontinence. For primary treatment, necessary types of evaluation include querying the patient regarding symptoms and medical history, examining physical findings, and performing urinalysis. The types of evaluations that should be performed for select cases include evaluation with symptom/quality of life ( QOL) questionnaires, urination records, residual urine measurement, urine cytology, urine culture, serum creatinine measurement, and ultrasonography. If the main symptoms are voiding/post-voiding, specialized treatment should be considered because multiple conditions may be involved. When storage difficulties are the main symptoms, the patient should be assessed using the primary algorithm. When conditions such as overactive bladder or stress incontinence are diagnosed and treatment is administered, but sufficient improvement is not achieved, the specialized algorithm should be considered. In case of specialized treatment, physiological re-evaluation, urinary tract/pelvic imaging evaluation, and urodynamic testing are conducted for conditions such as refractory overactive bladder and stress incontinence. There are two causes of voiding/post-voiding symptoms: lower urinary tract obstruction and detrusor underactivity. Lower urinary tract obstruction caused by pelvic organ prolapse may be improved by surgery. [ABSTRACT FROM AUTHOR]

Objective: The aim of the present study was to assess the effects of onabotulinumtoxinA injection for refractory non-neurogenic overactive bladder (OAB) for 12 months. Methods: For patients with persistent urgency urinary incontinence (UUI) more than once a week despite taking anti-cholinergic agents or incapability to continue the agents because of adverse effects, 100 units of onabotulinumtoxinA was injected at 30 sites in the sub-epithelial bladder wall. Efficacy was assessed every month up to 12 months after injection, using a three-day frequency-volume chart (FVC) and postvoid residual urine (PVR), three questionnaires, and a simple score of Global Response Assessment (GRA). Failure was defined as when GRA was negative and additional treatment was administered. Results: Nine men and eight women aged 67 ± 12 years were included. On FVC, frequencies of urgency, UUI and daytime urination significantly decreased up to the 11th month. PVR significantly increased at the first and second months but no patient required catheterization. The total scores of Overactive Bladder Symptom Score and International Consultation on Incontinence Questionnaire Short Form were significantly decreased for 10 and eight months, respectively. The score of GRA was significantly improved for eight months. The median time to failure was 11.0 months. Conclusion: This study suggests that onabotulinumtoxinA submucosal injection is promising for refractory non-neurogenic OAB. It is anticipated that the treatment is effective for eight to nine months and approximately 40% of the patients do not require anticholinergics at the 12th month postoperatively. [ABSTRACT FROM AUTHOR]

Objectives: To estimate the surgical and quality‐of‐life outcomes of artificial urinary sphincter implantation in patients with diabetes mellitus (DM). Subanalyses were performed using the same population as that in our previous multicenter, prospective, observational study. Methods: A total of 135 male patients who underwent primary artificial urinary sphincter implantation were divided into two groups: those with and without DM. The revision‐free rates, that is, the percentage of patients who did not require revision surgery, were compared between patients with and without DM. The number of urinary pads required per day, International Consultation on Incontinence Questionnaire‐Short Form, and King's Health Questionnaire were used to compare the continence status and quality of life (QOL) between the two groups preoperatively and at 1, 3, and 12 months after surgery. Results: Revision‐free rates were significantly lower in the DM group (83.9%, 77.4%, and 67.8% at 1, 2, and 3 years after implantation, respectively) than in the non‐DM group (95.5%, 92.5%, and 85.5% at 1, 2, and 3 years after implantation, respectively). Both continence status and QOL, assessed by questionnaires, markedly improved after surgery in patients with and without DM. Conclusions: Despite differences in the durability of the artificial urinary sphincters, patients with DM can obtain as much benefit from artificial urinary sphincter implantation regarding continence and quality‐of‐life improvement as patients without DM. Therefore, DM was not considered a comorbidity that contraindicated artificial urinary sphincter implantation. Additional large‐scale studies are required to verify our findings. [ABSTRACT FROM AUTHOR]

Objectives: Although the artificial urinary sphincter (AUS) is one of the most effective surgical treatments for severe urinary incontinence, little is known about its use in Japan. A nationwide survey was done to determine contemporary trends in AUS use and its long-term durability. Methods: Data on AUS units sold in Japan were provided directly by Takai Hospital Supply Co., Ltd., Tokyo, Japan, and a survey form was sent to all 44 institutes where AUS implantation had been carried out. The survey included various demographic and preoperative variables, surgical variables, and postoperative outcomes. Results: Between 1994 and 2007, a total of 100 AUS devices had been provided in Japan. Of the 44 institutes, 24 responded to the survey, and a total of 64 patients were enrolled in the study. Post-urological surgery incontinence accounted for 81.3% of the indications. During the mean follow-up of 50 months, mechanical failure occurred in four (6.2%), and the device was removed in 13 (20.3%) due to infection (14.0%), erosion (4.7%), or urination difficulty (1.5%). Of the 58 patients evaluated, 91.4% reported social continence. Five- and 10-year failure-free rates were 74.8% and 70.1%, respectively. On multivariate analysis, operative time was an independent predictor of treatment failure ( P = 0.0334). Conclusions: Considering recent trends in prostate surgery, the AUS may be significantly underused in Japan. Although excellent long-term durability has been achieved, a learning effect appears to be evident. The Japanese urological community needs to provide appropriate patients with this treatment option. [ABSTRACT FROM AUTHOR]

To evaluate the long-term safety, tolerability and efficacy of extended-release (ER) tolterodine in Japanese patients completing 12-week treatment in a randomized, double-blind trial comparing tolterodine ER 4 mg once daily, oxybutynin 3 mg three times daily or placebo in patients with overactive bladder. Of 293 Japanese patients completing the 12-week study, 188 continued in the open-label trial and received tolterodine ER 4 mg once daily for 12 months, irrespective of previous treatment. The primary objective was to assess the safety of tolterodine ER for up to 52 weeks of treatment and at post-treatment follow-up. Secondary endpoints included changes in micturition diary variables, patient perception of bladder condition and urgency and treatment benefit. Overall, 77% of patients completed 12 months of open-label treatment. Tolterodine ER was well tolerated and the most common adverse event was dry mouth (33.5%). In general, there was no increase in adverse event frequency with long-term treatment compared with short-term treatment. The efficacy of tolterodine ER was maintained over the 12-month period. The complete analysis showed a median reduction in incontinence episodes/week (−92.9%; mean reduction,−77.2%), a mean reduction in micturitions/24 h (−21.3%) and a mean increase in volume voided per micturition (19.6%). Of patients completing the 12-month study, 78.6% reported improvement in patient perception of bladder condition, 52.4% reported improvement in perception of urgency and 89.7% reported treatment benefit. Favorable safety, tolerability and efficacy of once-daily tolterodine ER was maintained over 12 months in a Japanese overactive bladder patient population. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: We developed a simple self-checkable screening tool for chronic prostatitis (S-CP) and internally validated it to encourage men (in the general population) with possible chronic prostatitis to consult urologists. Methods: The expert panel proposed the S-CP, which comprises three domains: Area of pain or discomfort (6 components), accompanying Symptom (6 components), and Trigger for symptom flares (4 components). We employed logistic regression to predict chronic prostatitis prevalence with the S-CP. We evaluated the predictive performance using data from a representative national survey of Japanese men aged 20 to 84. We calculated the optimism-adjusted area under the curve using bootstrapping. We assessed sensitivity/specificity, likelihood ratio, and predictive value for each cutoff of the S-CP. Results: Data were collected for 5,010 men—71 (1.4%) had a chronic prostatitis diagnosis. The apparent and adjusted area under the curve for the S-CP was 0.765 [95% confidence interval (CI) 0.702, 0.829] and 0.761 (0.696, 0.819), respectively. When the cutoff was two of the three domains being positive, sensitivity and specificity were 62.0% (95% CI 49.7, 73.2) and 85.4% (95% CI 84.4, 86.4), respectively. The positive/negative likelihood ratios were 4.2 (95% CI 3.5, 5.2) and 0.45 (95% CI 0.33, 0.60), respectively. The positive/negative predictive values were 5.7 (95% CI 4.2, 7.6) and 99.4 (95% CI 99.1, 99.6), respectively. Conclusion: The reasonable predictive performance of the S-CP indicated that patients (in the general population) with chronic prostatitis were screened as a first step. Further research would develop another tool for diagnostic support in actual clinical settings. [ABSTRACT FROM AUTHOR]

This Asia‐Pacific (AP) AMS 800™ artificial urinary sphincter (AUS) consensus statement aims to provide a set of practical recommendations to assist surgeons with the AMS 800 device surgery. The AP consensus committee consisted of key opinion leaders with extensive experience with AMS 800 surgery across several AP countries. The panel reviewed and discussed relevant findings with emphasis on locoregional and specific clinical challenges relevant to the AP region. Recommendations were made in key areas namely (1) patient selection and informed consent process; (2) preoperative assessment; (3) dealing with co‐existing urological disorders; (4) surgical principles and intraoperative troubleshooting; (5) postoperative care; (6) special populations; and (7) cost analysis and comparative review. The AMS 800 device should be offered to males with moderate to severe stress urinary incontinence (SUI). Full informed consent should be undertaken, and emphasis is placed on surgical contraindications and high‐risk candidates. The presence of a surgical mentor or referral to experts is recommended in complex AUS candidates. Preoperative cystoscopy with or without multichannel urodynamic study is necessary and patients with pre‐existing urological disorders should be treated adequately and clinically stable before surgery. Adherence to strict patient selection and safe surgical principles are critical to ensure excellent clinical outcomes and minimize complications. Given that InhibiZone‐coated device is not available in many AP countries, the use of prophylactic antibiotics pre‐and post‐operatively are recommended. The AMS 800 device should be prepared according to the manufacturer's guidelines and remains a cost‐effective treatment for male SUI. The AMS 800 device remains the surgical benchmark for male SUI but is associated with certain mechanical limitations and a unique set of complications. [ABSTRACT FROM AUTHOR]

Presents a summary of the Urodynamic Workshops in Interstitial Cystitis in Kyoto, Japan. Difference between oversensitive bladder and overactive bladder; Case for urodynamics in all cases.

Aim: To report the prospective multicentered study of the tension-free vaginal tape (TVT) procedure for stress urinary incontinence. Methods: One hundred and fifty-one women with stress urinary incontinence were operated on by the TVT procedure and were followed up at 3, 12, and 24 months after surgery. Patients’ age and body mass index (BMI) averaged 57 years and 23.9, respectively. Forty-nine women were classified as type I, 46 women type II and 56 women type III (McGuire’s classification). Local anesthesia was used in the operations on 137 women (91%) and epidural or general anesthesia was used in 14 (9%). Surgical outcomes were analyzed with Kaplan-Meier survival curves. Results: The subjective and objective cumulative cure rates 24 months later were 92% and 77%, respectively ( P > 0.05). The TVT operation for women with type III (62%) resulted in a significantly lower cure rate compared to those with type I or with type II (83%) ( P < 0.001). Post-operatively a urethral catheter was indwelt one day in 77 women (51%), two days in 14 (9%) and 3–7 days in 60 (40%). Surgical complications were encountered in 43 women (28%). The most frequent was bladder perforation in 24 women followed by postoperative difficulty in urination and de novo urgency. Conclusions: The TVT surgery was promising for the treatment of stress incontinence because of minimal surgical invasiveness and satisfactory surgical results. Women with type III incontinence resulted in fewer satisfactory outcomes than those with type I or II incontinence. [ABSTRACT FROM AUTHOR]

Diagnostic methods for CP have not been established.4 Thus, we proposed "The Project to Develop a Novel Diagnostic Tool for Chronic Prostatitis" to enable the easy diagnosis of CP by patients and medical professionals who are not urologists. Crowdfunding may also be effective for raising nonmedical professionals' awareness regarding CP. Abbreviation & Acronym CP chronic prostatitis Obtaining research grants is a critical global issue for researchers.1 In Japan, research grants are typically provided using public funds, such as the JSPS KAKENHI Grant, or given by public interest foundations. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Objective: To determine the burden of male stress urinary incontinence (SUI) in Japan and to identify candidates for artificial urinary sphincter (AUS) implantation. Methods: In 2008, a survey form was sent to all 1202 training hospitals certified by the Japanese Urological Association. The survey included questions about the number of patients with moderate to severe SUI who could be candidates for AUS implantation, the etiology, and incidence of SUI in 2007. Results: Overall, 682 (56.7%) responded to the survey. The total number of patients was 1276. The most common reported etiology for SUI was post-radical prostatectomy (59.1%), followed by neurogenic bladder (23.0%), surgery for benign prostatic hyperplasia (10.3%), neobladder reconstruction (2.8%), urethral injury (2.4%), and others (2.4%). There were 203 new cases in 2007. Adjusted by the response rate, the prevalence and annual incidence were estimated to be 2235 and 358 cases, respectively. Conclusions: This survey confirms that a significant number of men suffer from moderate to severe SUI, with the majority of cases being post-prostatectomy incontinence. The Japanese urological community needs to provide appropriate treatment for these patients. [ABSTRACT FROM AUTHOR]

Anorexia is a serious problem in patients with gastric cancer who have undergone gastrectomy. Ghrelin, an orexigenic hormone primarily secreted from the stomach, has been proposed to prevent anorexia. Significant reduction in plasma ghrelin levels after gastrectomy may contribute to lack of appetite and weight loss. In this study, we investigated the effects of Z-505, a ghrelin receptor agonist, on anorexia after total gastrectomy (TG) in a rat model. Male Sprague–Dawley rats were used to establish a TG model, and then sham-operated (control) and TG rats were randomly assigned to four subgroups receiving administration of Z-505 (100 mg/kg, p.o., once daily) or vehicle for 14 d from day 14 to day 27 after TG. The food intake, body weight, and fat weight were evaluated during the test period. Moreover, the neuronal activity in the hypothalamus was evaluated on day 21 to investigate the mechanism of action of Z-505. In TG rats, Z-505 significantly improved the decrease in cumulative food intake induced by the surgery over 14 d (TG + vehicle; 213.8 ± 15.3 g, n = 12 versus TG + Z-505; 258.2 ± 13.1 g, n = 14, P < 0.05). Z-505 also significantly increased fat weight and had a milder effect on body weight over 14 d. In addition, Z-505 significantly increased the number of c-Fos-positive cells in the hypothalamic arcuate nucleus (TG + vehicle; 17.8 ± 2.0, n = 12 versus TG + Z-505; 72.2 ± 11.8, n = 12, P < 0.001). Z-505 may be a useful therapeutic treatment for anorexia after TG. [ABSTRACT FROM AUTHOR]

Despite its therapeutic advantages, chemotherapy with anti-cancer drugs can cause adverse effects, including anorexia and weight loss. Although most patients with cancer suffer from anorexia during chemotherapy, resulting in the need to suspend or cease treatment and thereby worsening prognosis, treatment options for anorexia remain limited. Ghrelin is an orexigenic hormone that has been proposed to prevent anorexia. To investigate the potential of ghrelin receptor agonists, synthetic small-molecule compounds, as preventive therapies for chemotherapy-induced anorexia, we studied the effects of Z-505 hydrochloride (Z-505), a new oral growth hormone secretagogue receptor 1a (GHSR1a) agonist, in cisplatin- and 5-fluorouracil (5-FU)-induced anorexia animal models. The agonistic activity of Z-505 was examined using calcium flux assays in Chinese hamster ovary (CHO-K1) cells stably expressing rat or mouse GHSR1a. Z-505 showed agonistic activity for rat GHSR1a and mouse GHSR1a, with a half maximal effective concentration (EC 50 ) of 2.08 nM and 5.46 nM, respectively. In a cisplatin-induced anorexia rat model, administration of Z-505 (30, 100 or 300 mg/kg, p.o., once daily) significantly improved the cisplatin-induced reduction in food intake and body weight. In addition, treatment with Z-505 (100 or 300 mg/kg, p.o., once daily) prevented the 5-FU-induced decrease in food intake and body weight in the 5-FU-induced mouse model. Our results demonstrate that Z-505 ameliorates cisplatin- and 5-FU-induced anorexia through the activation of the ghrelin receptor, GHSR1a, suggesting its usefulness in the preventive treatment of anorexia during chemotherapy. [ABSTRACT FROM AUTHOR]

Cancer cachexia is a progressive wasting syndrome characterized by anorexia and weight loss, specifically muscle wasting and fat depletion. There is no therapeutic agent for treatment of this syndrome. We investigated the anti-cachexia effects of Z-505 hydrochloride (Z-505), a new oral growth hormone secretagogue receptor 1a (GHSR1a) agonist, using a mouse model of cancer cachexia. We performed a calcium flux assay in Chinese hamster ovary (CHO-K1) cells stably expressing human GHSR1a to quantify the agonistic activity of Z-505. In Colon 26 tumor-bearing mice, Z-505 (300 mg/kg, p.o., twice daily) was administered for 7 days to assess its anti-cachexia effects. Body weight and food intake were monitored during the period, and the skeletal muscle and epididymal fat weights were measured. Serum levels of insulin, insulin-like growth factor 1 (IGF-1), interleukin-6 (IL-6), and corticosterone were measured to confirm the mechanism of the anti-cachexia action of Z-505. Z-505 showed strong agonistic activity similar to that of human ghrelin, with a half maximal effective concentration (EC 50 ) value of 0.45 nM. Z-505 treatment significantly increased food intake and inhibited the progression of weight loss. Z-505 also significantly attenuated muscle wasting and fat loss, and increased circulating levels of anabolic factors such as insulin and IGF-1, but not catabolic factors such as IL-6 and corticosterone. These findings suggest that Z-505 might be effective in the treatment of cachexia via the increased anabolic hormone levels stimulated by the activation of the ghrelin receptor, GHSR1a. [ABSTRACT FROM AUTHOR]

Macrophages are a major component of the innate immune system, and the cytokines they secrete are involved in antitumor responses. Z-100 is obtained from hot-water extract of human-type Mycobacterium tuberculosis strain Aoyama B and activates the innate immune response. However, while Z-100 is known to modulate macrophage activity, the mechanism behind this modulation is not fully understood. We evaluated the effects of Z-100 on the murine macrophage cell line RAW264.7. Tumor necrosis factor-alpha (TNF-α) production from RAW264.7 cells was strongly induced by Z-100 and interferon-gamma (IFN-γ) stimulation but only weakly induced by Z-100 alone. Quantitative gene expression analysis showed that nucleotide-binding oligomerization domain containing 2 (Nod2) expression was up-regulated by IFN-γ treatment in RAW264.7 cells while Z-100-induced TNF-α production was attenuated by Nod2 gene silencing. Further, componential analysis demonstrated that muramic acid and amino acids distinctive of muramyl dipeptide (MDP) were contained within Z-100 and Z-100Fr I, the low-molecular-weight fraction containing components <3 kDa in size. In addition, Z-100Fr I enhanced TNF-α production in RAW264.7 cells and promoted NOD2-dependent nuclear factor-kappa B (NF-κB) activation in murine NOD2-expressing SEAP reporter HEK293 (HEK-Blue-mNOD2) cells. Taken together, these results suggest that Z-100 contains MDP-like molecules and augments NF-κB signaling via the direct activation of Nod2 in macrophages, which might be one mechanism driving the innate immune responses induced by Z-100 in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

The novel gastroprokinetic agent acotiamide improves gastric motility by inhibiting acetylcholinesterase activity in stomach; however, the mechanism of distribution of acotiamide from blood to stomach has not been clarified. Here, the tissue distribution of acotiamide was investigated in rats. The tissue-to-plasma concentration ratio ( Kp,app, in vivo) for stomach decreased from 4.1 to 2.4 mL/g of tissue at steady state with increasing plasma concentrations, whereas the Kp,app, in vivo for skeletal muscle was much lower and constant, regardless of the concentration of acotiamide in plasma. In vitro binding to stomach tissue protein exhibited a linear profile, with a predicted Kp,app, in vitro of 2.2 from free fractions under linear conditions. Therefore, protein binding to stomach tissue might only play a limited role in the stomach distribution of acotiamide. The influx permeability ( f u,b × PSinf,app) in the stomach exhibited dose-dependent saturation at the lowest range of examined blood unbound concentrations of acotiamide, whereas that in skeletal muscle exhibited only minimal dose dependence. In addition, the unbound concentration ratio of stomach to plasma (2.8) at steady state was markedly higher than unity. Taken together, these results suggest that carrier-mediated concentrative uptake processes play an important role in the distribution of acotiamide to the stomach but not skeletal muscle. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4965-4973, 2011 [ABSTRACT FROM AUTHOR]

Abstract: Aims: As activation and overexpression of the cholecystokinin-2 (CCK-2)/gastrin receptor can lead to carcinogenesis, it has been explored as a therapeutic target in pancreatic cancer. We demonstrated that Z-360, a CCK-2/gastrin receptor antagonist, combined with gemcitabine prolonged survival and reduced gemcitabine-induced vascular endothelial growth factor (VEGF) expression in a pancreatic carcinoma orthotopic xenograft mouse. In this study, we investigated the role of the CCK-2/gastrin signaling pathway on gemcitabine-induced VEGF expression in PANC-1 human pancreatic carcinoma cells. Main methods: In PANC-1 cells treated with Z-360, anti-gastrin IgG or kinase inhibitors, the gene expression levels were analyzed by quantitative real-time RT-PCR, and the protein levels of Akt and phosphorylated Akt (p-Akt) in cellular extracts were measured by ELISA. Key findings: Gemcitabine-induced expression of VEGF and hypoxia-inducible factor-1 alpha (HIF-1 alpha) were suppressed by the treatment with an anti-gastrin antibody. In addition, VEGF and HIF-1 alpha gene expression was inhibited by treatment with an inhibitor of phosphatidylinositol 3-kinase (PI3K), which is involved in the downstream signaling pathway of the CCK-2/gastrin receptor, and was also suppressed by treatment with Z-360. Moreover, although Akt phosphorylation was increased by treatment with gemcitabine, this elevation was partially, but significantly, inhibited by an exposure of Z-360. Significance: Gemcitabine might induce gene expression of VEGF via the PI3K/Akt signaling pathway in the downstream of the CCK-2/gastrin receptor. The suppression of the CCK-2/gastrin signaling pathway by treatment with Z-360 could be a useful approach for potentiating prolonged survival of pancreatic cancer patients receiving gemcitabine therapy. [Copyright &y& Elsevier]

Abstract: In clinical trials, acotiamide hydrochloride (acotiamide: Z-338) has been reported to be useful in the treatment of functional dyspepsia. Here, we investigated the effects of acotiamide on gastric contraction and emptying activities in rats in comparison with itopride hydrochloride (itopride) and mosapride citrate (mosapride). We also examined in vitro the compound''s inhibitory effect on acetylcholinesterase (AChE) activity derived from rat stomach. In in vivo studies, acotiamide (30 and 100mg/kg s.c.) and itopride (100mg/kg s.c.) markedly enhanced normal gastric antral motility in rats. In gastric motility dysfunction models, acotiamide (100mg/kg s.c.) and itopride (100mg/kg s.c.) improved both gastric antral hypomotility and the delayed gastric emptying induced by clonidine, an α2-adrenoceptor agonist. In contrast, mosapride (10mg/kg s.c.) had no effect on these models. Like the AChE inhibitors itopride (30mg/kg s.c.) and neostigmine (10μg/kg s.c.), acotiamide (10mg/kg s.c.) also clearly enhanced gastric body contractions induced by electrical stimulation of the vagus, which were abolished by atropine and hexamethonium, whereas mosapride (3 and 10mg/kg s.c.) did not. In in vitro studies, acotiamide concentration-dependently inhibited rat stomach-derived AChE activity (IC50 =2.3μmol/l). In addition, stomach tissue concentrations of acotiamide after administration at 10mg/kg s.c. were sufficient to produce inhibition of AChE activity in rat stomach. These results suggest that acotiamide stimulates gastric motility and improves gastric motility dysfunction in rats by inhibiting AChE activity, and may suggest a role for acotiamide in improving gastric motility dysfunction in patients with functional dyspepsia. [Copyright &y& Elsevier]

OBJECTIVES: • To assess the effect of a 1-D/A adrenoceptor antagonist naftopidil on patients with neurogenic lower urinary tract dysfunction (NLUTD) and voiding difficulty. • To explore the effectiveness of naftopidil in these patients by using urodynamic variables, including pressure flow study (PFS), and to find good and simple parameters (International Prostate Symptom Score (IPSS), Post-void residual urine (PVR), and uroflowmetry (UFM) parameters) as substitution of PFS for predicting the effect of naftopidil. PATIENTS AND METHODS: • The main inclusion and exclusion criteria were, IPSS ⩾8, voiding symptoms with IPSS ⩾5, IPSS-quality of life (QOL) ⩾2, PVR ⩾50 mL, and without prostatic enlargement ⩾20 mL. • After initial assessment, patients were stepwisely administered for 12 weeks with the following: placebo for 2 weeks, naftopidil 25 mg/day for 2 weeks, naftopidil 50 mg/day for 2 weeks, and naftopidil 75 mg/day for 6 weeks. At the end of both placebo and 6 weeks' naftopidil 75 mg/day, their IPSS, UFM, PVR, and PFS were assessed. • A total of 82 Japanese patients (men 40, women 42) with lower urinary tract symptoms complicated by NLUTD, with a mean age of 63.9 years, were included from private or institutional clinics. • The lesions were spinal cord 42, and peripheral nervous system 40. The spinal cord lesions were all lumbar spine (injury or lumbar canal stenosis). RESULTS: • In all patients, pressure at maximum urinary flow rate (Pdet Qmax ) in PFS significantly decreased ( P < 0.05), and maximum urinary flow rate in UFM significantly increased ( P < 0.01). Analysis of data for men and for women also showed a significant decrease in PVR, %PVR, and total IPSS score. • The degree of improvement of voided volume, PVR (%), and IPSS in patients with PVR < 300 mL was significantly greater than those in patients with PVR ⩾300 mL. • The degree of improvement of Pdet Qmax in PFS, and IPSS in patients with bladder contractility was significantly greater than that in patients without bladder contractility. CONCLUSIONS: • a 1-D/A adrenoceptor antagonist naftopidil has a significant effect on both symptoms and urodynamic variables of patients of both genders with NLUTD in Japan. • PVR < 300 mL and bladder contractility are predictive factors for the efficacy of naftopidil on patients with NLUTD. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify the urodynamic features of women with stress urinary incontinence (SUI) or with high-stage (stage 3 or greater) cystocele (HSC) as compared with symptom-free women. Fifty-six neurologically intact women with SUI and 47 women with HSC but without SUI were prospectively evaluated. All patients underwent full urodynamics, in addition to basic clinical evaluations. The urodynamic parameters of SUI and HSC were compared to the ones obtained from 78 urologically symptom-free normal women over the same period. Patients with HSC, after correction of cystocele using a temporary vaginal pessary, had consistently lower maximum urinary flow rate with a lower detrusor pressure during micturition than the controls or those with SUI. On the other hand, patients with SUI had an equivalent to higher maximum urinary flow rate, normal detrusor contraction strength with a lower detrusor pressure during micturition than the controls. Both maximum Watts factor and bladder contractility index were significantly lower in the whole HSC cohort in comparison to the controls and patients with SUI. The urodynamic characteristics observed among the three groups were all maintained even after adjusting for age. Women with SUI demonstrate voiding with low-pressure, normal contraction strength with an equivalent to high urinary flow rate. Women with HSC demonstrate voiding with low pressures with weak contraction strengths and low urinary flow rates, suggesting a higher prevalence of detrusor underactivity. Chronically decreased or increased urethral resistance might alter voiding dynamics and performance. [ABSTRACT FROM AUTHOR]

Aim: Transobturator tape (TOT) kits approved as medical instruments are still not available in Japan. This study aimed to: (1) assess the outcomes of TOT using Monarc (American Medical Systems; AMS Inc, Minnetonka, MN, USA) in women with stress urinary incontinence (SUI); (2) evaluate possible different surgical outcomes in women with urethral hypermobility (UH) and/or intrinsic urethral deficiency (ISD); and (3) evaluate the possibility of improvement of preoperative urgency and urge urinary incontinence after TOT in mixed urinary incontinence (MUI). Methods: Data from 140 women with SUI in a prospective multicenter study were examined at 3-6 months follow-up. Results: 82.1% of the patients were cured and 10.7% showed improvement. The surgical outcome was significantly better in UH than in UH combined with ISD or ISD. In 44 MUI patients, 79.6% were cured and 15.9% showed improvement. Urgency improved in about 75% of patients after TOT. Conclusion: TOT is effective for both SUI and MUI, with urgency improving. [ABSTRACT FROM AUTHOR]

Background: Z-360 is an orally active cholecystokinin-2 (CCK2)/gastrin receptor antagonist currently under development as a therapeutic drug for pancreatic cancer. It was previously reported that Z-360 treatment in combination with gemcitabine prolonged the survival period in a lethal pancreatic cancer xenograft model in mice. In a phase Ib/IIa clinical study, Z-360 treatment displayed a trend of reduced pain in patients with advanced pancreatic cancer in combination with gemcitabine including analgesics such as opioids. Here, we investigated the mechanism of analgesic action of Z-360 in a severe cancer-induced pain model in mice, which is considered to be opioid-resistant, by examining ephrin B1 gene expression, N-methyl-D-aspartate receptor NR2B subunit phosphorylation, and interleukin-1β (IL-1β) production. Results: In a mouse model of cancer-induced pain, ephrin B1 gene expression in dorsal root ganglia (DRGs) and the phosphorylation of NR2B in the spinal cord were induced. Z-360 treatment inhibited both ephrin B1 gene expression and the phosphorylation of NR2B. In addition, IL-1β production increased in the cancer-inoculated hind paw of mice, but could be suppressed by treatment with Z-360. Moreover, we observed that the CCK1 receptor antagonist devazepide similarly suppressed up-regulation of ephrin B1 gene expression and IL-1β production, and that the intraperitoneal injection of sulfated CCK-8 induced the production of IL-1β in the cancer-inoculated region. Conclusions: We have identified a novel pain cascade, in which IL-1β production in cancer-inoculated regions induces ephrin B1 gene expression in DRGs and then ephrin B1 enhances the tyrosine phosphorylation of NR2B via Eph B receptor in the spinal cord. Notably, Z-360 relieves cancer-induced pain by preventing this pain cascade through the suppression of IL-1β production, likely via the blockade of CCK1 receptor. The pre-clinical results presented here support the analgesic action of Z-360 in pancreatic cancer patients with severe, opioid-resistant pain. Pre-clinical and clinical results have demonstrated that Z-360 combined with gemcitabine represents a promising pancreatic cancer therapy approach with characteristic analgesic effects in addition to the prolongation of survival. [ABSTRACT FROM AUTHOR]

Abstract: Aims: To clarify the mechanism underlying the effect of polaprezinc on hypogeusia, we investigated the uptake of polaprezinc by the tongue in rats. Main methods: Rats were fed a zinc-sufficient (Zn(+)) or zinc-deficient (Zn(−)) diet. After 4weeks on the Zn(−) diet, polaprezinc (1, 3, or 10mg/kg) or [65Zn] polaprezinc (10mg/kg) was administered orally once a day. The zinc concentration or the 65Zn radioactivity of the tongue was measured by inductively-coupled plasma mass spectrometry or gamma counting, respectively. In addition, the distribution of 65Zn in the tongue was analyzed by microautoradiography and the proliferative activity of taste bud cells was measured from the uptake of 5-bromo-2′-deoxyuridine. Key findings: The zinc concentration of the lingual epithelium, but not the whole tongue, was markedly decreased in Zn(−) rats compared with Zn(+) rats. After administration of polaprezinc to Zn(−) rats at doses of 1, 3, and 10mg/kg, the zinc concentration in the lingual epithelium increased significantly from 85±4 to 105±7 (p <0.05), 120±3 (p <0.001), and 124±3 (p <0.001) µg/g, respectively. After administration of [65Zn] polaprezinc, the 65Zn radioactivity of the tongue and serum were higher in Zn(−) rats than in Zn(+) rats. 65Zn was mainly detected in the epithelium on microautoradiograms of the tongue in Zn(−) rats. In addition, polaprezinc (3 and 10mg/kg) improved the reduced proliferation of taste bud cells due to zinc deficiency. Significance: Polaprezinc is distributed to the lingual epithelium and restores its zinc concentration in Zn(−) rats resulting in improvement of cellular functions, especially proliferation. [Copyright &y& Elsevier]

Objectives: To evaluate changes in prostate volume (PV) and its association with selected urological measures and risk of surgical intervention in Japanese men with benign prostatic hyperplasia (BPH). Methods: The medical records of all consecutive urologist-diagnosed BPH patients of ≥40 years old who attended any of four urology clinics in Japan during January 2004–June 2006 were reviewed. Both cross-sectional and longitudinal data were captured to analyze baseline correlations among urological measures, to evaluate the longitudinal changes in PV and selected urological measures, and to examine the predictors of surgical intervention. Results: The follow-up period was 2.8 years. Mean PV and mean prostate-specific antigen (PSA) of 1331 eligible patients were 34.0 mL and 4.0 ng/mL, respectively. Both measures increased directly with age. Baseline PV correlated with residual urine volume (r = 0.18, P < 0.05) and PSA (r = 0.41, P < 0.001). Among 319 patients who had more than one PV measurement, PV increased in 51% of patients, remained the same in 28% and decreased in 21%. Use of α-blockers at baseline and during follow up was not associated with PV change. Patients who had a PV ≥30 mL, a severe International Prostate Symptom Score and a PSA level ≥1.5 ng/mL at baseline, were more likely to have surgical intervention during the follow-up period. Conclusions: Predictors generated in this study may help to identify a subset of BPH patients at high risk of surgical intervention. [ABSTRACT FROM AUTHOR]

Interstitial cystitis (IC) is a disease of the urinary bladder with lower urinary tract symptoms such as urinary frequency, bladder hypersensitivity and/or bladder pain and resultant serious impairment of quality of life. In Japan, assuming that IC is very rare, research activity and medical care of IC have been sparse until 2001, when the Society of Interstitial Cystitis of Japan (SICJ) and a patient support group were founded. 1,2 Subsequently the International Consultation on Interstitial Cystitis Japan (ICICJ) was held in Kyoto in 2003. 3 On the other hand, the etiology of IC has not been well clarified, which complicates its diagnosis and treatment at clinical settings. We have thus developed the Japanese Clinical Guideline, 4 which is targeted at healthcare professionals including specialists in urology and women's health care who may engage in the diagnosis and treatment of IC. This article is the English translation of a shortened version of the Guideline for convenience of readers worldwide. [ABSTRACT FROM AUTHOR]

Gastrin is known to enhance the growth of pancreatic carcinoma via the cholecystokinin (CCK)-2/gastrin receptor. We investigated the anti-tumor effect of Z-360 (calcium bis [( R)-(−)-3-[3-{5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-2,3,4,5-tetrahydro-1 H-benzo[ b][1,4]diazepin-3-yl}ureido]benzoate]), a novel orally active CCK-2 receptor antagonist alone or combined with the chemotherapeutic agent, gemcitabine in human pancreatic adenocarcinoma cell lines. Z-360 potently inhibited specific binding of [3H]CCK-8 to the human CCK-2 receptor, with a K i value of 0.47 nmol/l, and showed antagonistic activity for this receptor. The anti-tumor effect of Z-360 alone or combined with gemcitabine was assessed using subcutaneous xenografts of MiaPaCa2 and PANC-1 and an orthotopic xenograft model (PANC-1). Oral administration of Z-360 significantly inhibited the growth of MiaPaCa2 (41.7% inhibition at 100 mg/kg, P < 0.01). Combined administration of Z-360 and gemcitabine significantly inhibited subcutaneous PANC-1 tumor growth compared with either agent alone (27.1% inhibition compared to effect with gemcitabine, P < 0.05), and significantly prolonged survival compared with the vehicle control (median survival of 49 days in vehicle compared to 57 days in the combination group, P < 0.05). In vitro studies showed that Z-360 significantly inhibited gastrin-induced proliferation of human CCK-2 receptor-expressing cells, and also significantly reduced gastrin-induced PKB/Akt phosphorylation to the level of untreated controls. In the present study, we have shown that Z-360 combined with gemcitabine can inhibit pancreatic tumor growth and prolong survival in a pancreatic carcinoma xenograft model, on a possible mode of action being the inhibition of gastrin-induced PKB/Akt phosphorylation through blockade of the CCK-2 receptor. Our results suggest that Z-360 may be a useful adjunct to gemcitabine for the treatment of pancreatic carcinoma and a therapeutic option for patients with advanced pancreatic cancer. [ABSTRACT FROM AUTHOR]

Abstract: Although Knudson''s two-hit hypothesis with functional loss of a tumor suppressor gene has been widely accepted, accumulating evidence suggests that several genes are regulated by the quantity of their product in a dose-dependent manner (gene dosage effect). The study was designed to identify the influence of gene dosage effect of 8p22 on patient prognosis. With a median age of 71 years, 40 patients with prostate cancer (11 organ-confined, 13 capsular penetrating, and 16 nodal and/or distant metastatic) were followed for a median of 68.5 months. A fluorescence in situ hybridization (FISH) technique was applied using a region-specific cosmid probe combined with centromeric probe. Allelic losses of 8p22, 8p21.3, 8p21.1∼2, and 8p12 were found in 23, 22, 14, and 9 patients, respectively. A Cox proportional hazard model revealed that decreased fraction (i.e., the fraction of nuclei with a lesser number of cosmid signals than of centromeric probe signals) of 8p22 proved to be the sole independent prognostic factor predicting cancer-specific death, as well as disease progression—but allelic loss of 8p22 was not predictive. Cytogenetic estimation of 8p22 by FISH can yield quantitative evaluation of relevant gene dosage, which may become a useful biomolecular marker predicting poor patient prognosis. [Copyright &y& Elsevier]

The effect of polaprezinc, a chelate compound consisting of zinc ion and L-carnosine, on abnormalities of taste sensation induced by feeding a zinc-deficient diet to rats was examined by using the two-bottle preference test (quinine hydrochloride as a bitter taste and sodium chloride as a salty taste). Rats were fed either a zinc-deficient or a zinc-sufficient diet. The zinc-deficient diet increased the preference for both taste solutions, while polaprezinc (at doses of 3 and 10 mg/kg) restored the altered taste preferences. We also evaluated the proliferation of taste bud cells using 5-bromo-2'-deoxyuridine (BrdU). The BrdU incorporation into taste bud cells was significantly reduced in rats fed a zinc-deficient diet compared with rats fed a zinc-sufficient diet (from 50.8% to 45.0%, p<0.05) and this reduction was reversed by polaprezinc at doses of 1, 3, and 10 mg/kg, increasing to 50.2%, 53.5%, and 52.5%, respectively. These findings indicate that zinc deficiency induces the delayed of proliferation of taste bud cells, while polaprezinc improves cell proliferation. In conclusion, polaprezinc had a therapeutic effect in a rat model of abnormal taste sensation. Its mechanism of action was suggested to involve improvement of the decrease in taste bud cell proliferation caused by zinc deficiency. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To elucidate the predictive factors regarding the treatment outcomes after transurethral resection of the prostate for symptomatic benign prostatic enlargement with detrusor underactivity. Methods: A retrospective study was conducted in 190 patients with detrusor underactivity of 1397 men who had undergone transurethral resection of the prostate. All patients had completed the International Prostate Symptom Score and quality-of-life (QOL) questionnaires and had undergone a full urodynamic analysis before surgery. The outcomes were assessed at 3 and 12 months postoperatively using the International Prostate Symptom Score, QOL score, and peak urinary flow rate. The association between the baseline variables and improvement in the outcome variables was analyzed statistically. Results: Preoperative urodynamic abnormalities included bladder outlet obstruction in 58.9% and detrusor overactivity (DO) in 32.1%. Multivariate analysis suggested that the initial level of storage symptoms, as well as the QOL score, were predictive of an improvement in the QOL. Postoperative improvement in symptoms and QOL was consistently influenced by the presence of DO before surgery. The baseline degree of bladder outlet obstruction, as well as patient age, consistently influenced the improvement in the peak urinary flow rate. Conclusions: In selected patients with benign prostatic enlargement associated with detrusor underactivity, greater baseline storage symptom scores and the presence of DO were negative predictive factors for QOL improvement. Baseline DO was also predictive of poorer improvement in the subjective symptoms after transurethral resection of the prostate. A greater degree of baseline bladder outlet obstruction positively predicted for postoperative peak urinary flow rate improvement, and patient age predicted negatively for it. [Copyright &y& Elsevier]

Objectives: We investigated the characteristics of recent male and female patients diagnosed with interstitial cystitis (IC), then investigated which therapy was chosen by the attending urologist. Methods: Materials were 282 IC patients diagnosed and treated during the past 3 years (sampling from Japanese IC database). Gender, age, medical history and predominant symptoms were investigated. In addition, we investigated the interval before a diagnosis was established. In laboratory findings, we investigated voided volume, urinalysis findings and cystoscopic findings. Regarding therapy, we investigated which therapy was chosen as the first line. Results: The gender ratio was about 1.0:5.6 (male : female). Regarding age distribution, patients in their 60s were the most frequent (65 cases, 31.3%). The interval before diagnosis of IC was 36.5 months on average (1–360 months). Regarding medical history, intrapelvic surgery was the most common and repeated urinary tract infection was next. The most frequent symptom was urinary frequency (295 cases, 98.3%). Urinary urgency was noted in 186 cases (62%) and supra-pubic pain was noted in 125 cases (41.6%). The once voided volume was 104.3 mL on average (50–200 mL). The most common cystoscopic finding was glomerulation (158 cases). Ulcer was present in only 19 cases. The most widely carried out therapy was hydrodistension (208 cases, 67.9%). Oral suplatast tosilate (197 cases, 65.6%), antihistamine (77 cases, 25.6%) and intravesical dimethylsulfoxide (69 cases, 23%) followed. Conclusions: Regarding characteristics, the age distribution was older than other countries. The most frequent symptom was urinary frequency. Oral suplatast tosilate was one of the popular therapies in Japan. [ABSTRACT FROM AUTHOR]