Statin administration ameliorates ischemia-induced overactive bladder with improvement of blood flow and anti-inflammatory effects in rats.

AIMS: Statins are widely used to treat dyslipidemia and have been shown to reduce the risk of ischemic heart disease and cerebrovascular disease. The effects of statins on ischemia-induced overactive bladder (OAB) and the associated mechanisms were investigated in a rat model of chronic pelvic ischemia. METHODS: A pelvic ischemia model was created by iliac arterial injury (AI) and a high-fat diet using male Sprague-Dawley rats. Rats were assigned to 3 groups: control group, AI group, and AI + statin group. The control group underwent sham operation and was fed a normal diet. The AI group underwent AI surgery and was fed a high-cholesterol diet. The AI + statin group was administered a statin for 4 weeks. Cystometry was performed for 8 weeks after surgery. Blood flow was evaluated by laser meter. Thickness of the iliac arteries was measured, and microvascular density in the lamina propria was evaluated by immunostaining for CD31. Expressions of inflammatory cytokines in the bladder were measured by real-time PCR. RESULTS: Cystometry showed a significantly shorter voiding interval and lower bladder capacity in the AI group than in the control group. The AI + statin group showed improvement of these findings. The AI group showed decreased bladder blood flow, increased iliac arterial wall thickening, and decreased microvascular density compared to the control group. Statin administration improved blood flow. Iliac arterial wall thickening was suppressed, and microvascular density was increased by statin administration, though not significantly. Real-time PCR showed significantly higher expressions of inflammatory cytokines (IL-6, IL-8, and TNF-α) in the AI group than in the control group, and IL-6 and IL-8 expressions were lower in the AI + statin group than in the AI group. CONCLUSIONS: The present results suggest that statins are effective in OAB caused by arteriosclerosis and ischemia. The mechanism of their effects involves improved bladder blood flow and decreased bladder inflammation.

Ectopic endometriosis in the pelvic cavity evokes bladder hypersensitivity via transient receptor potential ankyrin 1 hyperexpression in rats.

INTRODUCTION AND HYPOTHESIS: In women with chronic pelvic pain (CPP), interstitial cystitis/bladder pain syndrome (IC/BPS) and endometriosis frequently coexist. The mechanism of these diseases coexisting is explained by cross-sensitization between endometriosis and IC/BPS. The overlapped symptoms may be related to cross-sensitization with transient receptor potential vanilloid 1 (TRPV1) and/or transient receptor potential ankyrin 1 (TRPA1) hyperexpression. This study was aimed at exploring whether bladder hypersensitivity is evoked in the surgically induced ectopic endometriosis rat and whether TRPV1 and/or TRPA1 play a vital role. METHODS: A total of 63 Sprague-Dawley female rats were divided into two groups, 39 for physiological examination and 24 for molecular analysis. Surgical induction of ectopic endometriosis (ENDO, n=27), surgical sham treatment (n=18), and treatment for endometriosis by GnRH analog (ENDO-G) (n=18) were performed. Bladder function was investigated by cystometry (for TRPV1 in the sham [n=6] and ENDO [n=9] groups and for TRPA1 in the sham [n=6], ENDO [n=9], and ENDO+G [n=9] groups), and TRPV1 and TRPA1 mRNA expressions were measured using real-time qPCR in the bladder and dorsal root ganglia (DRGs). RESULTS: On cystometry, the relative intercontraction interval (ICI) after/before resiniferatoxin (RTx; TRPV1 activator) infusion to the bladder showed no significant difference between the two groups, whereas relative ICI after/before allyl isothiocyanate (AITC; TRPA1 activator) infusion was significantly lower in the ENDO group than in the sham group. TRPA1 mRNA expression in the bladder and L5 DRG was considerably higher in the ENDO group than in the sham group on real-time qPCR. TRPA1 mRNA hyperexpression and bladder hypersensitivity after AITC infusion were reduced in the ENDO-G group. CONCLUSIONS: Bladder cross-sensitization in ENDO rats occurs in association with hyperexpression of TRPA1 at both the DRG and the bladder mucosa. This can be understood by the "cross-sensitization of endometriosis to bladder" theory explaining overlapping symptoms among BPS/IC and ectopic endometriosis.

Low-energy shock wave therapy ameliorates ischemic-induced overactive bladder in a rat model.

This study was to evaluate whether Low-energy shock wave therapy (LESW) improves ischemic-induced overactive bladder in rats and investigate its therapeutic mechanisms. Sixteen-week-old male Sprague-Dawley rats were divided into three groups: arterial injury (AI), AI with LESW (AI-SW), and control groups. LESW was irradiated in AI-SW during 20-23 weeks of age. At 24 weeks of age, conscious cystometry was performed (each n = 8). The voiding interval was shortened in AI (mean ± SEM: 5.1 ± 0.8 min) than in control (17.3 ± 3.0 min), whereas significant improvements were observed in AI-SW (14.9 ± 3.3 min). The bladder blood flow was significantly increased in AI-SW than in AI. Microarray analysis revealed higher gene expression of soluble guanylate cyclase (sGC) α1 and ß1 in the bladder of AI-SW compared to AI. Protein expression of sGCα1 and sGCß1 was higher in AI-SW and control groups than in AI. Cyclic guanosine monophosphate (cGMP) was elevated in AI-SW. As an early genetic response, vascular endothelial growth factor and CD31 were highly expressed 24 h after the first LESW. Suburothelial thinning observed in AI was restored in AI-SW. Activation of sGC-cGMP may play a therapeutic role of LESW in the functional recovery of the bladder.

Factors associated with non-response to naldemedine for opioid-induced constipation in cancer patients: A subgroup analysis.

BACKGROUND: Opioid-induced constipation (OIC) is one of the most common adverse events of opioid therapy and can severely reduce quality of life (QOL). Naldemedine is the orally available peripheral-acting µ-opioid receptor antagonist approved for OIC treatment. However in daily clinical practice, some cancer patients show insufficient control of OIC even while receiving naldemedine. OBJECTIVE: To identify factors associated with non-response to naldemedine in cancer patients. METHODS: This study retrospectively analyzed 127 cancer patients prescribed naldemedine at Seirei Hamamatsu General Hospital in Japan between November 2016 and June 2021. For the regression analysis of factors associated with OIC, variables were extracted manually from electronic medical records. Naldemedine had been prescribed by the attending physician after the presence of OIC had been defined with reference to Rome IV diagnostic criteria. Naldemedine was evaluated as "effective" in cases where the number of defecations increased at least once in the first 3 days after starting naldemedine. Multivariate logistic regression analysis was performed to identify factors associated with non-response to naldemedine. The data used were from the group of patients who received naldemedine in our previous study. RESULTS: Factors significantly associated with non-response to naldemedine included chemotherapy with taxanes within 1 month of evaluation of naldemedine effect (odds ratio [OR] = 0.063; 95% confidence interval [CI] = 0.007-0.568), and addition of or switching to naldemedine due to insufficient efficacy of prior laxatives (OR = 0.352, 95% CI = 0.129-0.966). CONCLUSION: The identification of factors associated with non-response to naldemedine prescribed for OIC may help improve QOL among cancer patients.

Risk factors for opioid-induced constipation in cancer patients: a single-institution, retrospective analysis.

PURPOSE: To identify risk factors for opioid-induced constipation (OIC). METHODS: This study retrospectively analyzed 175 advanced cancer patients who were receiving pain treatment with opioids and were newly prescribed laxatives for OIC at Seirei Hamamatsu General Hospital between November 2016 and June 2021. For the regression analysis of factors associated with OIC, variables were extracted manually from clinical records. The effect of newly prescribed laxatives for OIC was evaluated as "effective" in cases where the number of spontaneous bowel movements increased at least once in the first 3 days. The OIC was defined based on Rome IV diagnostic criteria. Multivariate logistic regression analysis was performed to identify risk factors for OIC. Optimal cutoff thresholds were determined using receiver operating characteristic analysis. Values of P < 0.05 (two-tailed) were considered significant. RESULTS: Significant factors identified included body mass index (BMI) (odds ratio [OR] = 0.141, 95% confidence interval [CI] = 0.027-0.733; P = 0.020), chemotherapy with taxane within 1 month of evaluation of laxative effect (OR = 0.255, 95% CI = 0.068-0.958; P = 0.043), use of naldemedine (OR = 2.791, 95% CI = 1.220-6.385; P = 0.015), and addition or switching due to insufficient prior laxatives (OR = 0.339, 95% CI = 0.143-0.800; P = 0.014). CONCLUSION: High BMI, chemotherapy including a taxane within 1 month of evaluation of laxative effect, no use of naldemedine, and addition or switching due to insufficient prior laxatives were identified as risk factors for OIC in advanced cancer patients with cancer pain.

Effects of Chemotherapy-Induced Neutropenia on Overall Survival in Patients With Unresectable or Metastatic Urothelial Carcinoma to Gemcitabine Plus Cisplatin Combination Chemotherapy.

BACKGROUND: Chemotherapy-induced neutropenia (CIN) is an important dose-limiting toxicity of chemotherapy. However, evidence suggests that the occurrence of CIN may be predictive of treatment outcome. Indeed, studies have revealed that the onset of CIN is associated with a good chemotherapeutic response. OBJECTIVE: The purpose of this study was to investigate the association between the onset of CIN and overall survival in patients with unresectable or metastatic urothelial carcinoma (UC) who received a combination regimen of gemcitabine and cisplatin (GC). METHODS: Medical records from 56 patients with unresectable or metastatic UC who were treated with a combination GC regimen between December 2005 and May 2016 were retrospectively analyzed to investigate the association between CIN development and survival. RESULTS: The median duration of survival was 521 days (95% CI = 147-193 days) for patients with severe CIN and 287 days for patients without CIN. Additional multivariate analysis revealed that both the presence of severe CIN (hazard ratio [HR] = 0.399; 95% CI = 0.180-0.880, P = 0.023) and baseline hemoglobin (HR = 2.167; 95% CI = 1.170-4.014, P = 0.014) represented independent prognostic factors for the survival of patients with unresectable or metastatic UC receiving GC treatment. Conclusion and Relevance: CIN onset was associated with longer survival in patients receiving GC therapy for unresectable or metastatic UC, suggesting that neutropenia monitoring during GC chemotherapy may be predictive of treatment efficacy.

Updated recommendation on molecular-targeted therapy for metastatic renal cell cancer.

Molecular-targeted therapy was recommended for the systemic therapy of renal cell cancer (RCC) in the RCC guidelines, but these guidelines do not address the order of administration of the multiple presently available agents. There are several aspects that remain unknown regarding the optimal administration order and combination of molecular-targeted drugs. Until the optimal treatment sequence is determined by clinical trials, treatment individualization is required for each patient based on patient and disease characteristics. We herein investigate 12 cases of RCC patients who received axitinib. Axitinib was used as the first-line drug in 4 cases, second-line in 5 cases, third-line in 1 case and as a fourth-line drug in 2 cases. Partial response (PR) was observed in 4 cases (30%) and stable disease in 4 cases (30%) during axitinib treatment, with an overall response rate of 60%. The duration of PR ranged from 6 to 19 months. Based on our cases, axitinib exhibited reasonable therapeutic efficacy as first- as well as second-line treatment. However, more cases are required to draw firm conclusions.