The use of 5-alpha reductase inhibitors in the treatment of benign prostatic hyperplasia

Benign prostatic hyperplasia(BPH)is characterized by an enlarged prostate,lower urinary tract symptoms(LUTS),and a decreased urinary flow rate.Common in older men,BPH is a progressive disease that can eventually lead to complications including acute urinary retention(AUR)and the need for BPH-related surgery.Both normal and abnormal prostate growth is driven by the androgen dihydrotestosterone(DHT),which is formed from testosterone under the influence of 5-alpha reductase.Thus,5-alpha reductase inhibitors(5-ARIs)effectively reduce the serum and intraprostatic concentration of DHT,causing an involution of prostate tissue.Two 5-ARIs are currently available for the treatment of BPHdfinasteride and dutasteride.Both have been demonstrated to decrease prostate volume,improve LUTS and urinary flow rates,which ultimately reduces the risk of AUR and BPH-related surgery.Therefore,either alone or in combination with other BPH medications,5-ARIs are a mainstay of BPH management.

Differential expression of 5-alpha reductase sozymes in the prostate and its clinical implications

The development of human benign or malignant prostatic diseases is closely associated with androgens, primarily testosterone （T） and dihydrotestosterone （DHT）. T is converted to DHT by 5-alpha reductase （5-AR） isozymes. Differential expression of 5-AR isozymes is observed in both human benign and malignant prostatic tissues. 5-AR inhibitors （5-ARI） are commonly used for the treatment of benign prostatic hyperplasia （BPH） and were once promoted as chemopreventive agents for prostate cancer （PCa）. This review discusses the role of the differential expression of 5-AR in the normal development of the human prostate and in the pathogenesis and progression of BPH and PCa.

Medical therapy for clinical benign prostatic hyperplasia:α1 Antagonists,5α reductase inhibitors and their combination

Medical therapy for clinical benign prostatic hyperplasia(BPH)has advanced significantly in the last 2 decades.Many new a1 antagonists and 5a reductase inhibitors(5ARi)are now commercially available.The practicing urologist must decide on the most appropriate medication for his patients,taking into consideration various factors like efficacy,dosing regime,adverse effects,cost,patient’s socioeconomic background,expectations,drug availability and his own clinical experience.The use of combination therapy added further to the complexity in clinical judgment when prescribing.We highlight some of the key points in prescribing a1 antagonists,5ARi and their combination,based on our viewpoints and experience as urologists in an Asian clinical setting.

Pre-Androgen Ablation Prostate Cancer Patients Who Bleed Do Well with 5 Alpha Reductase Inhibitors

Background: Patients with gross haematuria are sometimes found to have prostate cancer after clinical evaluation. The treatment of such haematuria could be very challenging. Use of a 5 alpha reductase inhibitor like dutasteride has been found helpful in bleeding prostate cancer patients if they have not undergone hormonal manipulation before they developed haematuria. Patients and Method: 26 patients with gross haematuria of prostatic origin who had histologic confirmation of adenocarcinoma of the prostate but who have not had chemical or surgical castration were randomized to receive daily dutasteride in addition to vigorous saline irrigation and antibiotics on one arm and vigorous saline irrigation and antibiotics only as control on the other arm. The time taken before haematuria resolved and the amount of irrigation fluid used were noted. Statistical analysis was done using SPSS. Student’s t-test and Kaplan Meier survival analysis were used to test various variables at 0.5 significant levels. Results: Of the 26 patients 12(46.2%) received 0.5 mg oral dutasteride in addition to saline irrigation while 14 (53.8%) received saline irrigation only. Haematuria stopped in all of 12 (100%) patients on dutasteride arm but on 12 (85.7%) of the 14 patients on the control arm. It took significantly shorter time and lesser volume of irrigation fluid before haematuria resolved in those treated with dutasteride than in those on the control arm. Conclusion: Dutasteride is effective in the control of acute haematuria in pre-androgen ablation prostate cancer patients.

Expression of 5α-Reductase Type 2 Gene in Human Testis, Epididymis and Vas Deferens

Objectives To study the expression pattern of 5α-reductase type 2 gene in human male reproductive organsMethods The expression level of 5α-reductase type 2 gene inhuman testis, epididymis and vas deferens tissues was determined by in situ hybridization using Digoxin labeled 5α-reductase type 2 cRNA probe.Results The brown granules of hybridizing signals distributed in the cytoplasm of Sertoli and Leydig cells of the testis, the principle cells of epididymis and the epithelial cells of vas deferens, but there was no positive signal in the nuclei of above-mentioned cells. No positive signal was observed in germ cells, basement of the testis, interstium of epididymis and basement, as well as smooth muscle of vas deferens. Conclusion This study confirmed that the 5α-reductase type 2 gene expressed in Sertoli , Leydig cells of the testis, and the principle cells of epididymis. The expression pattern of the gene in these cells in human was similar to that of rat and monkey. The presence of 5α-reductase type 2 gene in epithelial cells of the vas deferens suggested it might possess an important physiological role in human reproduction.

5α-reductase type 2 gene expression in human testis, epididymis and vas deferens

To study the expression pattern of 5α-reductase type 2 gene in human male reproductive organs. Methods: The expression level of 5ct-reductase type 2 gene in human testis, epididymis and vas deferens tissues was determined by in situ hybridization using a digoxin-labeled 5α-reductase type 2 cRNA probe. Results: The brown granules of hybridizing signals distributed in the cytoplasm of the Sertoli and Leydig cells of the testis, the principle cells of epididymis and the epithelial cells of vas deferens, but there was no positive signal in the nuclei of these cells. No positive signal was observed in the germ cells, basement of the testis, interstium of the epididymis and basement and the smooth muscle cells of vas deferens. Conclusion: This study confirmed that the 5a-reductase type 2 gene expressed in the Sertoli and Leydig cells of the testis and the principle cells of the epididymis. The expression pattem of the gene in these cells in the human was similar to that in the rat and monkey. The presence of 5α-reductase type 2 gene in the epithelial cells of the vas deferens suggests that it may play a physiological role in human reproduction. [Reprod Contracep (in English) 2002; 13: 67]

酶标仪法5α-还原酶抑制剂体外筛选模型的建立

目的:建立酶标仪法5α-还原酶抑制剂体外筛选模型。方法:取6只雌性SD大鼠肝脏制备5α-还原酶,检测酶活性后,利用96孔板、酶标仪及酶标仪法分析软件建立5α-还原酶抑制剂体外筛选模型,并通过已知5α-还原酶抑制剂爱普列特及非那甾胺验证模型的可靠性。实验分别设置0、30、60 nmol/L爱普列特组及0、30、60 nmol/L非那甾胺组,96孔板依次加入终浓度0～40μmol/L系列睾酮溶液、22μmol/L的NADPH、终浓度0～60 nmol/L爱普列特或0～60 nmol/L非那甾胺及20μl 5α-还原酶,Tris-HCl缓冲液将每孔溶液体积调至200μl。将96孔板放置于酶标仪中,分别测定0、10 min的A340 nm,并对读取数据进行分析。结果:5α-还原酶的Km值为3.794μmol/L,Vmax为0.271μmol/(L.min);爱普列特的酶抑制常数(Ki)为148.2 nmol/L,半数抑制浓度(IC50)为31.5 nmol/L,曲线图分析为反竞争性抑制剂;非那甾胺的Ki为158.8 nmol/L,IC50为13.6 nmol/L,曲线图分析为竞争性抑制剂;二者结果均同文献报道相同。结论:建立的体外快速筛选模型能够有效地筛选5α-还原酶抑制剂。

单用α肾上腺受体阻滞剂与联合5α-还原酶抑制剂治疗良性前列腺增生疗效的Meta分析

目的:比较单用α肾上腺受体阻滞剂与α肾上腺受体阻滞剂联合5α-还原酶抑制剂治疗良性前列腺增生(BPH)的疗效。方法:检索中/英文公开发表的随机对照试验(RCT)。计算机检索Pub Med、EMbase、the Cochrane Central Register of Controlled Trials(CENTRAL)、CNKI、CBM、VIP、万方数据库。检索时间为建库至2015年6月30日。同时,手检纳入文献的参考文献。按纳入排除标准进行RCT的筛选、资料提取和质量评价后,采用Rev Man 5.2软件进行Meta分析。结果:共纳入4个研究,403例患者。Meta分析结果显示:有效性方面,两组在降低IPSS评分[SMD=0.89,95%CI(-0.66,2.45)P=0.26]、提高最大尿流率[SMD=-3.67,95%CI(-8.88,1.54)P=0.17]、减少残余尿量[SMD=0.62,95%CI(-0.97,2.22)P=0.17]上无明显统计学差异;与单用药物相比,联合用药在减少前列腺体积上[SMD=6.94,95%CI(2.06,11.81)P=0.005]效果更好,两组在出现不良反应(头晕[SMD=0.57,95%CI(0.16,1.98)P=0.38]、性功能减退[SMD=0.57,95%CI(0.16,1.98)P=0.38])上无明显统计学差异。结论:单用α肾上腺受体阻滞剂与α肾上腺受体阻滞剂联合5α-还原酶抑制剂相比,两者疗效相似,对于前列腺体积不大的患者,单用α肾上腺受体阻滞剂即可达到很好的疗效,避免了不必要的经济负担;对于前列腺体积较大的患者,则推荐联合用药。对于前列腺具体多大的体积才是单用α肾上腺受体阻滞剂与联合5α-还原酶抑制剂治疗的分界阈值,则需要更多高质量、大样本的RCT进一步论证。

5α还原酶抑制剂与前列腺癌预防

5α还原酶抑制剂通过抑制5α还原酶降低双氢睾酮水平。应用5α还原酶抑制剂进行的前列腺癌预防研究显示,5α还原酶抑制剂可以降低前列腺癌发病率,但同时也出现高级别前列腺癌病例增加的现象,引起广泛关注。有研究和分析显示,5α还原酶抑制剂使前列腺体积缩小,同时也缩小Gleason评分为3分患者的前列腺癌体积,使得再次穿刺更容易发现Gleason评分为4分以上的前列腺癌。另外5α还原酶抑制剂显著提高前列腺穿刺诊断前列腺癌和高级别前列腺癌敏感度。笔者认为5α还原酶抑制剂不但不增加高级别前列腺癌的发生率,反而会帮助我们更早发现高级别前列腺癌。

5α-还原酶抑制剂治疗前列腺增生体积≥30 mL患者临床疗效观察

目的研究5α还原酶抑制剂对前列腺体积≥30 mL前列腺增生患者的治疗效果。方法将我院泌尿外科2016年1月—2017年1月住院、门诊200例前列腺体积≥30 mL前列腺增生患者随机分为2组,对照组:盐酸坦洛新缓释胶囊0.2 mg口服,每天1次;治疗组:非那雄胺5 mg口服qd,盐酸坦洛新缓释胶囊0.2 mg口服,每天1次。2组用药6个月后,根据最大尿流率(mL/s)、前列腺体积(mL)、残余尿量(mL)、I-PSS评分评定疗效。结果治疗组和对照组患者最大尿流率均较治疗前提高,前列腺体积、残余尿、I-PSS评分均较治疗前降低,且治疗组的改善幅度优于对照组,差异有统计学意义(P<0.05)。结论 5α还原酶抑制剂对前列腺体积≥30mL前列腺增生患者的治疗有明显效果。

裂木质素类化合物与5α-还原酶的构效关系研究

5-α还原酶(5-αreductase,5-AR)是治疗良性前列腺增生的关键酶。前期研究发现裂木质素类化合物有抑制5-AR的作用,为了深化对荨麻属裂木质素类植物的研究,并探索裂木质素类抑制剂对5-AR的抑制作用及二者构效关系,采用同源模建的方法构建5-AR的三维空间结构模型,并利用Ramachandran plot、verify3D和ERRAT程序对模型进行评价,同时通过分子力学等方法对最优模型进行优化。利用分子对接的方法将5-α还原酶抑制剂(5α-reductase inhibitors,5-ARI)对接到12个活性位点,其中5个位点与配体对接成功,并预测了41种裂木质素化合物的ADMET性质。本文研究结果对裂木质素类化合物的药物设计具有一定的理论指导作用,并且为良性前列腺增生的治疗研究提供新思路。

围手术期应用5α-还原酶抑制剂在经尿道双极等离子电切术治疗较大体积良性前列腺增生中的优势探讨

目的探讨围手术期常规应用5α-还原酶抑制剂(5ARI)在经尿道双极等离子电切术(TUPKP)治疗较大体积良性前列腺增生(BPH)患者的术中术后优势。方法选取2014年10月至2019年8月铜陵市人民医院治疗的192例较大体积BPH患者的临床资料进行回顾性分析。按围手术期是否应用5ARI分为联合用药组(n=107)和单纯电切组(n=85)。比较两组患者术中手术时间、失血量、出血强度、前列腺切除组织量、前列腺腺体与尿道下黏膜微血管密度(MVD)变化,术后尿色转清时间、冲洗液体量、国际前列腺症状评分(IPSS)、生活质量评分(QOL)、最大尿流率(Qmax)变化以及继发性出血并发症发生情况。结果联合用药组患者的手术时间、失血量、出血强度、前列腺腺体、尿道下黏膜MVD均小于单纯电切组患者,差异具有统计学意义(P<0.05);但两组患者前列腺组织切除量、IPSS、QOL、Qmax比较,差异无统计学意义(P>0.05);联合用药组患者术后尿色转清时间、冲洗液体量、继发性出血发生率明显小于单纯电切组患者,差异具有统计学意义(P<0.05)。结论围手术期应用5ARI在TUPKP治疗较大体积BPH中,能明显减少术中术后出血风险,具有安全可靠、效率高、恢复快等优势,适合在广大基层医院应用推广。

5α-还原酶抑制剂非那甾胺的合成

以甾烯酮酸为起始原料 ,经酰胺化、氧化开环、环合、氢化、脱氢合成了非那甾胺 .优化了氢化反应及氢化产物分离条件 ,控制 5 β异构体杂质含量低于 2 % ,经脱氢、纯化 ,得到符合药用要求的非那甾胺 ,适合工业化生产 .

新的前列腺癌治疗剂17-( 5′-异噁唑基 )雄甾-4,16-二烯-3-酮合成方法的改进(英文)

17 (5′ 异唑基 )雄甾 4 ,16 二烯 3 酮 (4,L 39)是最有希望的P4 5 0 17α和 5α 还原酶的双重抑制剂 ,对前列腺癌及前列腺肥大具有潜在的治疗作用。对其合成路线进行改进 ,收率极大提高。首先 ,Claisen缩合物 2用羟胺在乙醇中环和得到纯 5′ 异唑 3a ,用Swern氧化反应直接氧化 3a ,然后在在酸中异构化后得到L 39(4)。或者 ,化合物 2在无水甲酸中与羟胺环和得到 3 甲酯物 (6 ) ,后者以改良奥氏氧化法直接氧化生成 4 烯 3 酮物 (4)。

5α-还原酶抑制剂联合α受体阻滞剂治疗前列腺增生的临床疗效

目的探讨5α-还原酶抑制剂(非那雄胺)联合α受体阻滞剂(特拉唑嗪)治疗前列腺增生(BPH)的临床疗效。方法选取2012年1月—2014年6月达州市达川区南城社区卫生服务中心收治的BPH患者124例,随机分为观察组与对照组,各62例。观察组给予非那雄胺联合特拉唑嗪治疗,对照组给予特拉唑嗪治疗,比较两组的国际前列腺症状评分表(IPSS)评分、最大尿流率(Qmax)、前列腺体积、残余尿量。结果治疗前,两组患者IPSS评分、Qmax、前列腺体积、残余尿量比较,差异无统计学意义(P>0.05);治疗6个月后观察组IPSS评分低于对照组,Qmax高于对照组,前列腺体积小于对照组,残余尿量少于对照组,差异有统计学意义(P<0.05)。结论非那雄胺联合特拉唑嗪治疗BPH的疗效显著,可缩小前列腺体积,减少残余尿量,改善患者的排尿功能及相关临床症状。

α_(1A)-阻滞剂与5α-还原酶抑制剂治疗BPH疗效观察

目的探讨肾上腺能α_(1A)-受体阻滞剂与5α-还原酶抑制剂联用治疗良性前列腺增生症(benign prostatic hyperplasia,BPH)的疗效。方法选取我院2015年1月—2017年1月收治良性前列腺增生症患者为研究对象,对照组50例患者口服盐酸坦洛新缓释胶囊,观察组50例患者在对照组基础上口服爱普列特,对比两组患者治疗前后前列腺特异性抗原、膀胱残余尿量、前列腺体积、生活质量、前列腺症状以及不良反应发生率。结果治疗前两组患者前列腺特异性抗原、膀胱残余尿量、前列腺体积、QOL、IPSS评分对比差异无统计学意义(P>0.05);治疗后两组患者膀胱残余尿量、IPSS评分均明显下降,QOL显著升高,但两组间对比差异无统计学意义(P> 0.05);治疗后观察组患者前列腺体积明显小于对照组,差异具有统计学意义(P <0.05)。观察组患者不良反应发生率20.00%,稍高于对照组14.00%,但是对比差异无统计学意义(P> 0.05)。结论两种药物联合使用效果更好,能缩小前列腺体积,改善临床症状,达到标本兼治效果,且安全性高。

120W绿激光前列腺汽化术在不同BPH患者群体间的疗效及安全性分析

目的:对比研究120 W绿激光前列腺汽化术(PVP)在不同良性前列腺增生(BPH)患者群体中的疗效及安全性。方法:对2013年7月至2014年9月于我科诊断为BPH并行120 W PVP的患者,按前列腺体积(PV)(<80 ml和≥80 ml)、有无服用5-α还原酶抑制剂(5-ARIs)(持续时间>1个月)以及有无既往急性尿潴留史(AUR)进行分组对照研究,观察记录术前及围手术期情况,并于术后1、3个月随访。结果:共174例患者纳入研究,38例患者术中转为经尿道前列腺电切术(TURP),其余136例患者顺利完成手术并随访至术后3个月。患者年龄(69.4±7.7)岁,术前PV(67.9±29.8)ml,手术时间(49.4±16.3)min。术中无输血、电切综合征及前列腺包膜穿孔发生,术后2例患者发生尿道狭窄、2例患者出现膀胱颈口挛缩。各组患者的术后疗效指标均较术前显著提高,且各对照组间(大体积前列腺组与非大体积前列腺组、5-ARIs服用组与5-ARIs未服用组、AUR病史组与无AUR病史组)无统计学差异。结论:120 W PVP治疗BPH安全有效,且疗效不受PV、术前是否规律服用5-ARIs、既往有无AUR史影响,但术前留置导尿管可能增加手术难度及术中中转TURP的风险。

治疗良性前列腺增生的药物研究进展

良性前列腺增生是中老年男性常见的一种疾病,随着不可避免的人口老龄化,良性前列腺增生的发病率较以前相比有大幅度的提高,已成为全球中老年男性最常见的老年病之一。近几十年来,随着治疗良性前列腺增生的一些新药的引进,良性前列腺增生已经从一个急性手术形疾病转化为一个慢性疾病。目前临床上用于治疗良性前列腺增生的药物主要包括α1-ARs拮抗剂、5α-还原酶抑制剂、磷酸二酯酶5抑制剂和植物制剂,本文对近几十年来已上市的治疗良性前列腺增生的药物进展进行综述,希望能对良性前列腺增生药物治疗的研究提供参考和借鉴。

良性前列腺增生的药物治疗现状

良性前列腺增生（BPH）是中老年男性的常见病。目前，以5a-还原酶抑制剂及a-肾上腺素受体阻滞剂为主的药物治疗已经替代传统的经尿道前列腺切除术，成为多数BPH患者的治疗首选。本文就BPH的药物治疗现状作简要综述。

良性前列腺增生症的药物治疗与评价

目的:伴随老龄社会深化和人数增加,属于老年医学范畴的一组泌尿系统疾病(良性前列腺增生症、前列腺癌、前列腺炎、勃起功能障碍、早泄和膀胱过度活动症)的治疗正日益受到关注,用药情况呈明显上升趋势,本文对抗前列腺增生药的临床应用进行分析评价。方法:采用国内外文献分析方法。结果与结论:抗良性前列腺增生症药的合理和安全应用尤为重要。