Effects of α1-adrenergic receptor antagonists on the development and progression of urothelial cancer

We recently demonstrated that silodosin, a selective α₁-blocker often prescribed for the symptomatic treatment of benign prostatic hyperplasia (BPH), could inactivate a c-fos proto-oncogene regulator ELK1 in bladder cancer cells possessing a functional androgen receptor (AR). However, the clinical impact of α₁-blockers on the development and progression of bladder cancer remained poorly understood. In the present study, we investigated if α₁-blockers clinically used, including silodosin, tamsulosin, and naftopidil, could prevent the neoplastic/malignant transformation and cell growth, using non-neoplastic urothelial SVHUC sublines with carcinogen/MCA challenge and bladder cancer lines, respectively. Bladder cancers in men treated with silodosin, tamsulosin, or naftopidil for their BPH were then compared. Silodosin at 1-10 µM significantly inhibited the neoplastic transformation of MCA-SVHUC-AR cells, but not that of AR-negative MCA-SVHUC-control cells. In MCA-SVHUC-AR, silodosin significantly reduced the expression levels of oncogenes (c-fos/NF-κB1) and induced those of tumor suppressors (p27/PTEN). However, tamsulosin (up to 1 µM) or naftopidil (up to 10 µM) failed to significantly inhibit the neoplastic transformation of AR-positive or AR-negative urothelial cells. Similarly, cell proliferation/migration of AR-positive bladder cancer lines was considerably inhibited only by silodosin. Meanwhile, the incidence of bladder cancer in patients with silodosin [49/540 (9.1%)] was marginally lower, compared to those with tamsulosin [64/523 (12.2%); P=0.094] or tamsulosin or naftopidil [64+28/523+236 (12.1%); P=0.082]. There were no significant differences in tumor grade/stage among the 3 cohorts. Outcome analysis revealed lower risks for disease progression of non-muscle-invasive bladder tumors in the silodosin group than in the naftopidil group (P=0.011) or tamsulosin+naftopidil groups (P=0.035). Similarly, silodosin patients with muscle-invasive tumor had lower risks for disease progression, compared with tamsulosin (P=0.006) or tamsulosin+naftopidil (P=0.028) patients. Multivariate analysis further showed that silodosin treatment in those with non-muscle-invasive tumor was associated with improved progression-free survival, compared with naftopidil (hazard ratio=0.086; 95% confidence interval=0.008-0.905; P=0.041) or tamsulosin/naftopidil (hazard ratio=0.128; 95% confidence interval=0.016-1.036; P=0.054) treatment. Our in vitro studies thus indicate that both urothelial tumorigenesis and tumor growth are inhibited by silodosin, but not by tamsulosin or naftopidil. Clinical data further suggest that even pharmacological doses (e.g. 0.1 µM) of silodosin contribute to preventing bladder cancer progression.     

Efficacy and safety of solifenacin plus tamsulosin oral controlled absorption system in men with lower urinary tract symptoms: a meta-analysis

We performed a meta-analysis to compare treatment with a combination of solifenacin plus tamsulosin oral controlled absorption system (TOCAS) with placebo or TOCAS monotherapy. The aim of the meta-analysis was to clarify the efficacy and safety of the combination treatments method for lower urinary tract symptoms (LUTS). We searched for trials of men with LUTS that were randomized to combination treatment compared with TOCAS monotherapy or placebo. We pooled data from three placebo-controlled trials meeting inclusion criteria. Primary outcomes of interest included changes in International Prostate Symptom Score (IPSS) and urinary frequency. We also assessed postvoid residual, maximum urinary flow rate, incidence of urinary retention (UR), adverse events. Data were pooled using random or fixed effect models for continuous outcomes and the Mantel–Haenszel method to generate risk ratio. Reductions in IPSS storage subscore and total urgency and frequency score (TUFS) were observed with solifenacin 6 mg plus TOCAS compared with placebo (P < 0.0001 and P < 0.0001, respectively). Reductions in IPSS storage subscore and TUFS were observed with solifenacin 9 mg plus TOCAS compared with placebo (P = 0.003 and P = 0.0006, respectively). Reductions in TUFS was observed with solifenacin 6 mg plus TOCAS compared with TOCAS (P = 0.01). Both combination treatments were well tolerated, with low incidence of UR. Solifenacin 6 mg plus TOCAS significantly improved total IPSS, storage and voiding symptoms compared with placebo. Solifenacin 6 mg plus TOCAS also improved storage symptoms compared with TOCAS alone. There was no additional benefit of solifenacin 9 mg compared with 6 mg when used in combination with TOCAS.     

坦索罗辛联合索利那新治疗BPH伴膀胱过度活动症的临床观察

目的:探讨坦索罗辛联合索利那新治疗BPH伴膀胱过度活动症(OAB)患者的临床疗效及安全性。方法:2009年12月～2011年6月期间收集BPH伴有OAB患者262例,随机分成试验组(134例)和对照组(128例)。试验组患者口服坦索罗辛0.2mg,每天一次,同时口服索利那新5mg,每天一次;对照组患者仅口服坦索罗辛,用量用法同实验组。两组患者均药物治疗4周。观察两组患者治疗前后主观指标IPSS评分、OABSS评分及QOL评分和客观指标最大尿流率(Qmax)、24h排尿次数、尿急次数、急迫性尿失禁次数、夜尿次数、每次排尿量的变化,评估治疗后BPH患者OAB症状的改善情况及其安全性。结果:两组患者主观指标和客观指标治疗前后组内对比,差异均有统计学意义(P<0.05)。试验组治疗前后的主观指标和客观指标变化值与对照组相比,除Qmax和每次排尿量外,差异均有统计学意义(P<0.05)。两组患者的Qmax和每次排尿量治疗前后的变化值相比,差异均无统计学意义(P>0.05)。试验组和对照组不良事件总发生率较低,分别为4.58%和2.47%,无严重不良事件发生。结论:坦索罗辛联合索利那新治疗BPH伴有OAB患者的疗效,较单用坦索罗辛的疗效显著,且安全性好。     

Effects of alpha1‐adrenoceptor antagonist (tamsulosin) on incident of ejaculation and semen quality in the goat

Male temporary contraception is occasionally required in some animals. Alpha1‐adrenoceptor antagonist (tamsulosin) can cause ejaculation disorder. Two sets of Latin square were applied to six male goats to received either normal saline, dimethylsulphoxide or tamsulosin (179.8 nmol kg^?1) at 1‐week interval. Semen collection and libido scoring were undertaken at 3, 6 and 24 h post‐injection. For ejaculated semen, its quality was evaluated. Physiological measurements including body temperature, respiration and heart rates were measured before injection and at 30 min before semen collection. The results showed that libido score and physiological changes were not affected by treatments and time periods. Anejaculation was observed in 11 (91.7%), 5 (41.7%) and 1 (8.3%) males at 3, 6 and 24 h post‐tamsulosin injection respectively. The incidence returned to normal when compared with control groups at 24 h. The percentages of motile and live spermatozoa at 6 h post‐tamsulosin injection were significantly lower (P < 0.05) than that of normal saline group. At 24 h post‐injection, there were no significant differences of all semen parameters among treatments. This study demonstrated that tamsulosin had temporary effects on ejaculation and semen quality without reducing sex desire and physiological functions in male goats.     

盐酸坦索罗辛联合吲哚美辛栓治疗输尿管下段结石的初步研究

目的评价盐酸坦索罗辛与吲哚美辛栓联合治疗输尿管下段结石的临床疗效。方法 89例确诊为单纯输尿管下段结石(结石均小于8mm)的患者,随机分为三组:试验组,口服盐酸坦索罗辛(0.4mg/d)和吲哚美辛栓0.1g塞肛,1次/d;对照组1,口服中药排石颗粒4g/次,2次/d;对照组2,口服盐酸坦索罗辛0.4mg,1次/d;观察结石排出率、排出时间、肾绞痛发生率、药物不良反应发生率、干预治疗率等。结果试验组结石排出率为90.63%(29/32),对照组1和对照组2结石排除率分别为42.31%(11/26)和70.97%(22/31),试验组与对照组1比较,试验组与对照组2比较,两个对照组比较,差异均有统计学意义(χ2分别=4.76、3.94、15.65;P均<0.05)。试验组的结石排出时间为(8.73±2.15)d,对照组1和对照组2结石排出时间分别为(12.31±1.52)d和(9.52±1.61)d,试验组与对照组1比较,试验组与对照组2比较,两个对照组比较,差异均有统计学意义(t分别=6.77、-1.70、-7.35;P均<0.05)。试验组、对照组1、照组2的肾绞痛发生率分别为31.25%(10/32)、63.28%(17/26)、45.16%(14/31),试验组和对照组2以及对照组1和对照组2比较,差异均无统计学意义(χ2分别为1.29、2.33,P均>0.05);试验组和对照组1比较,差异有统计学意义(χ2=8.24,P<0.05)。三组患者均未发生严重的药物不良反应(χ2分别=0.33、0.23、0.35,P均>0.05)。结论联合应用盐酸坦索罗辛和吲哚美辛栓治疗输尿管下段结石安全、副作用小,能明显提高排石率,缩短排石时间,并能减少镇痛药物的应用。     

坦索罗辛与硝苯地平辅助治疗急诊肾绞痛患者86例的临床疗效比较

目的分析比较坦索罗辛与硝苯地平口服辅助治疗肾绞痛的临床疗效及耐受性。方法86例输尿管结石致肾绞痛患者随机分为两组,A组常规止痛治疗加用坦索罗辛口服0．4mg1）L／d;B组常规止痛治疗加用硝苯地平10mg3坎／d。所有患者被要求饮水2L／d,疗程为4周或至结石排出。观察患者疼痛缓解情况（视觉模拟量表）、结石排出率、生活质量评分以及药物不良反应发生率并作统计分析。结果A组患者疼痛缓解情况（视觉模拟量表）、结石排出率、生活质量评分均优于B组患者（P〈0．05）,两组药物不良反应发生率无差别。结论口服坦索罗辛辅助治疗肾绞痛总体效果优于口服硝苯地平,可以减轻患者的绞痛程度、减少止痛药的用量和辅助排石,且临床耐受性好。     

Beneficial Effect of Increasing the Dose of Tamsulosin to 0.4 mg in Japanese Patients with Benign Prostatic Hyperplasia

Objective: Tamsulosin is often administered at a dose of 0.2 mg in Japan, Korea, and elsewhere in Asia, while a dose of 0.4 mg is more common in the West. In order to determine the higher dose might also be appropriate in the North-East Asian setting, we studied whether the effect of increasing the dose to 0.4 mg in Japanese patients who had dysuria associated with benign prostatic hyperplasia.Patients and Methods: Twenty-two cases with a voiding volume ≥ 100 ml assessed by uroflowmetry out of 31 patients with benign prostatic hyperplasia and an IPSS (International Prostate Symptom Score) ≥ 8 whose symptoms were controlled with 0.2 mg of tamsulosin were entered into this study. We evaluated IPSS and QOL (quality of life) score, urinary flow parameters and residual urine volume before and 4 weeks after increasing the dose of tamsulosin.Results: Statistical analyses performed using the Wilcoxon test showed no significant alteration in IPSS total score or QOL score with the increased dose, but Qmax (maximum urinary flow rate) improved from 10.1 ± 5.5 ml/s to 12.1 ± 6.5 ml/s (p = 0.013), and residual urine volume improved from 37.6 ± 26.4 ml to 22.2 ± 24.3 ml (p = 0.012). Two of the 31 patients complained of new symptoms; 1 complained of breast pain and the other complained of dizziness.Conclusions: From the lack of side effects of more than moderate grade in the present study, increasing the dose of tamsulosin might be recommended before switching patients to other drugs.     

磁疗椅对慢性盆腔疼痛综合征的治疗作用

目的：观察磁疗椅对慢性盆腔疼痛综合征（CPPS）的疗效。方法：2005年6月～2007年4月,我院收治ⅢB型CPPS患者40例,随机分为两组,一组单用α-受体阻滞剂坦索罗辛（O．2mg／d）（单用组）治疗;另一组并用坦索罗辛（0．2mg／d）和磁疗椅（并用组）治疗,磁疗椅每周2次,每次约30min,4周为1个疗程;治疗前后作前列腺炎症状评分（NIH—CPSI）。结果：所有患者均按要求完成治疗。与单用组比较,并用组NIH—CPSI、疼痛评分、排尿评分、严重程度和生活质量评分均有显著下降（P〈0．05）。结论：磁疗椅对CPPS有显著疗效,且操作简单,患者无明显不适,依从性好,值得在临床上推广运用。     

Synergistic Effect by Co‐Administration of Tamsulosin and Solifenacin on Bladder Activity in Rats

Objectives: We examined the effects of alpha1‐adrenoceptor antagonist (tamsulosin hydrochloride) and antimuscarinic agent (solifenacin succinate) alone or in combination on the urinary adenosine triphosphate (ATP) level and cystometric parameters before and after bladder stimulation. Methods: Female rats were administered tamsulosin hydrochloride (0.5 or 3 µg/kg/h) and/or solifenacin succinate (20 or 100 µg/kg/h) via a subcutaneously implanted osmotic minipump. Rats receiving distilled water were used as control. After 2 weeks, continuous cystometry with physiological saline or 0.1% acetic acid solution was performed. Urinary ATP level was also measured before and after stimulation by 0.1% acetic acid solution. Results: During cystometry with bladder stimulation, the interval between voiding became shorter and the maximum voiding pressure (MVP) became higher in the control group. In the high‐dose tamsulosin and solifenacin groups, the inhibition of urinary frequency was observed. The MVP also became higher in the high‐dose tamsulosin group, but such a change was not seen in the high‐dose solifenacin group. In case of low‐dose administration, either agent alone did not inhibit the increase of urinary frequency and MVP due to bladder stimulation. However, co‐administration of these ineffective low doses of tamsulosin and solifenacin resulted in the inhibition of urinary frequency. The high‐dose or low‐dose solifenacin group and the co‐administration group showed similar inhibition of the increase of urinary ATP after bladder stimulation. Conclusion: Tamsulosin may have a different effect on the bladder and/or the neuronal pathways that is unrelated to ATP, so the combination of tamsulosin and solifenacin may synergistically inhibit urinary frequency after bladder stimulation.