【作者】 宋竖旗；

【导师】 张亚强；

【作者基本信息】 中国中医科学院 ， 中医外科学， 2008， 博士

【摘要】 慢性前列腺炎(Chronic Prostatitis,CP)是中青年男性的常见病、多发病,该病症状复杂,病程较长,且容易复发,严重影响患者的身心健康。如何提高临床疗效,改善患者临床症状,是目前该研究领域中最迫切的课题。导师张亚强教授是中西医结合泌尿外科专家刘猷枋教授的学术继承人,他在充分继承刘猷枋教授学术经验的基础上,在运用活血化瘀法治疗慢性前列腺炎方面有其独到之处。本论文在对中医治疗慢性前列腺炎历代文献整理基础上,对导师治疗慢性前列腺炎的临床经验,用现代科学手段进行了深入挖掘。同时,以自身免疫性前列腺炎大鼠模型为载体,采用酶联接免疫吸附测定法(ELISA)、实时荧光定量PCR(RT-PCR)等技术,从整体——细胞因子——基因等层次,深入探讨了活血化瘀法及组方丹蒲胶囊治疗慢性前列腺炎的分子机制,从一个侧面揭示了中医药治疗慢性前列腺炎的理论依据和导师临床治验的科学内涵。一、理论研究1.历代医家著述对后世慢性前列腺炎的治疗具有指导意义通过整理祖国医学历代文献对慢性前列腺炎的认识,可以总结出中医对该病的认识可分为四个时期:①秦汉时期为萌芽期,对前列腺炎形成了初步的认识;②隋唐时期是发展期,在原有认识基础上又有了一定的发展,该时期医家对淋证病因病机、治法、方药有了更深一步的描述,尤其是淋证分类出现了七淋、五淋的见解,为以后的发展奠定了坚实的基础;③宋金元时期是充实期,这一时期百家争鸣,产生了很多学术流派,派生出许多学术观点,对“淋、浊、小便不利”的见解更深刻、特点更鲜明;④明清时期是成熟期,是这一疾病的集大成期。明清医家在充分继承前贤学术思想的同时,又结合自己的临床体验,不断地推陈出新,使对“淋”、“浊”、“小便不利”等的认识更加成熟,更加趋于完善。如何充分挖掘祖国医学文献这一宝库,并以此为切入点,探讨现代中医对慢性前列腺炎辨证论治规律并指导临床,将对当代慢性前列腺炎的中医治疗学的发展产生深远的意义。2.导师治疗慢性前列腺炎的学术经验导师在充分继承了刘猷枋教授学术思想的基础上,根据“血瘀贯穿疾病发展始终”的病机特点,临床治疗:①将活血化瘀法作为治疗该病的根本方法,在活血基础上,根据疾病的寒热虚实辨证论治,兼湿热者,佐以清热利湿;兼肾虚者,辅以补肾中药;②根据病程、病情程度论治,轻证多以湿热、血瘀者为多,治以清热利湿、活血止痛;重证或顽固证病程日久,多虚多瘀,在活血益气的基础上,重用三棱、莪术、王不留行、穿山甲等破血化瘀药,同时佐以虫类物如水蛭、地龙等;③注重心理疏导,强调饮食调摄。大量的临床实践表明,长期坚持活血化瘀法中医药治疗能改善患者临床症状(尤其对疼痛的缓解尤为突出),提高患者的生活质量。二、临床研究1.借助数据挖掘方法,总结导师治疗慢性前列腺炎的学术经验利用数据挖掘生物信息学技术,以导师临床诊疗典型病例为研究对象,以保留导师辨证论治特色的结构化的临床数据为基础,以方药为线索,利用频数分析,从多个角度进行分析对比、综合归纳,初步研究名老中医的方——证关系、证——药、症——药关系等,提取导师辨证特点和遣方用药规律等知识,总结导师继承名老专家刘猷枋教授学术思想基础上运用活血化瘀法辨治慢性前列腺炎的学术经验及其理论内涵。根据90例病历资料分析,展现该病常见临床症状:会阴部不适、尿频、尿不尽、尿后滴白、舌暗红等症状;总结出导师对慢性前列腺炎辨证分为气滞血瘀型、湿热蕴结型、肾虚型3个基本证型,其中,临床两证、三证兼见时有发生。总结出导师治疗慢性前列腺炎常用治法6种、常用药物25味、常用基础方7个、常用的25对药对。在导师常用45味中药功能分类的基础上,归纳出导师在治疗CP的药物使用频次上,活血化瘀药居首位,清热利湿药、补肾药次之,同时采用理气、解表、温里、泻下药等从多方面多层次治疗,说明导师在辨证论治基础上处方,主次分明,脉络清晰。2丹蒲胶囊治疗慢性前列腺炎的临床研究目的及方法:采用随机对照的方法对丹蒲胶囊治疗慢性前列腺炎进行再评价。结论:①丹蒲胶囊治疗慢性前列腺炎的总有效率为83.3%,对照药前列泰片为56.4%,治疗组优于对照组(P＜0.05)。②丹蒲胶囊能明显降低前列腺液白细胞数(EPS-WBC),增加前列腺液卵磷脂小体密度(EPS-CORP)。治疗后两组EPS-WBC均减少,经统计学处理,两组差异有显著性意义,治疗组优于对照组(P＜0.05);治疗后两组EPS-CORP密度较治疗前均可见增加,经统计学处理,两组差异有显著性意义,治疗组优于对照组(P＜0.05)。③丹蒲胶囊能明显改善少腹疼痛、小便频急、尿后余沥不尽、尿道灼热、会阴疼痛、腰骶部疼痛、睾丸疼痛、阴囊潮湿、尿后滴白等单项症状,降低NIH-CPSI评分、NIH-疼痛评分,提高患者生活质量。其中,在降低EPS-WBC、提高EPS-CORP密度,缓解前列腺炎患者少腹疼痛、小便频急、尿后余沥不尽、尿道灼热等症状,以及降低NIH-CPSI评分、NIH-疼痛评分方面,优于对照组(P＜0.05)。进一步证实了丹蒲胶囊能改善能通过改善慢性前列腺炎患者临床症状(尤其对疼痛症状的缓解)、降低NIH-CPSI评分,而达到其治疗作用,研究展示了中医药治疗慢性前列腺炎的优势。三、实验研究本课题实验研究以自身免疫性前列腺炎大鼠模型为载体,采用ELISA、RT-PCR等技术,从整体——细胞因子——基因等层次,深入探讨了活血化瘀法及组方丹蒲胶囊治疗慢性前列腺炎的分子机制,从一个侧面揭示了中医药治疗慢性前列腺炎的理论依据和导师临床治验的科学内涵。1.优选出建立自身免疫性前列腺炎大鼠模型方法——加强免疫法,为研究丹蒲胶囊治疗慢性前列腺炎的分子机制奠定了坚实的实验基础。2.应用加强免疫法建立实验性自身免疫性前列腺炎大鼠模型,光镜和电镜下观察丹蒲胶囊对模型组织形态学及超微结构的变化。结果表明:模型组光镜表现:前列腺腺体遭到破坏,间质及腺体充满大量弥散的淋巴细胞、单核细胞;电镜表现:腺体破坏,粗面内质网扩张明显,线粒体扩张或呈空泡化,核膜皱缩,细胞器扩张,染色质周边凝聚。模型组病理改变符合前列腺慢性炎症表现。丹蒲胶囊能明显减轻或消除模型大鼠的前列腺组织炎症,其中,大剂量组最优。为丹蒲胶囊的临床疗效提供了病理组织学依据。3.丹蒲胶囊对复杂的细胞因子网络有免疫调控作用,对IL-1β、IL-2、IL-8均有抑制作用,对高水平的IL-10有降低效应,同时能抑制NF-κB的表达而发挥治疗作用。4.丹蒲胶囊对自身免疫性前列腺炎模型大鼠前列腺组织NGF有抑制作用,对前列腺组织及血清中的PGE2水平有降低效应,通过这种抑制作用而发挥该药的镇痛效应。5.自身免疫性前列腺炎大鼠模型出现NF-κB、NGF基因mRNA的高表达,丹蒲胶囊通过抑制NF-κB、NGF基因mRNA的表达发挥治疗效应。研究从基因水平阐释了中药丹蒲胶囊对慢性前列腺炎治疗作用的分子机制。四、本研究的特色及创新之处1.临床研究在临床应用丹蒲胶囊有效的基础上,利用数据挖掘生物信息学技术,以导师临床诊疗典型病例为研究对象,以保留导师辨证论治特色的结构化临床数据为导向,以方药为线索,利用频数分析,从多个角度进行分析对比、综合归纳,初步研究名老中医的方——证关系、证——药、症——药关系等,提取导师辨证特点和遣方用药规律等知识,总结导师在继承名老专家刘猷枋教授学术思想基础上,运用活血化瘀法辨治慢性前列腺炎的学术经验及理论内涵,为深层次继承挖掘名老专家学术经验提供了新思路。未见同类研究报道。2.实验研究2.1优选出成功建立实验性自身免疫性前列腺炎大鼠模型的加强免疫法,为进一步探索前列腺炎的自身免疫学说奠定了实验基础,是本研究的特色之一。2.2以动物前列腺组织及血清为观察对象,以IL-1β、IL-8、IL-10、IL-2、NF-κB、NGF、PGE2等细胞因子为观测指标,研究了丹蒲胶囊这些因子的调节作用,从一个侧面揭示了丹蒲胶囊免疫调节及镇痛作用的分子机制,为活血化瘀法治疗慢性前列腺炎提供了新的实验依据。在前列腺炎疗效机制的系统研究上未见同类报道。3.理论创新本课题针对“前列腺炎与细胞因子”的研究热点,首次提出“活血化瘀法及组方丹蒲胶囊可能通过调控NF-κB、NGF的基因mRNA表达而发挥治疗效应”的假说,应用RT-PCR的方法证实丹蒲胶囊对模型大鼠NF-κB、NGF的基因mRNA的表达有抑制效应,验证了假说。研究揭示了活血化瘀法治疗慢性前列腺炎分子基础的科学内涵,为中医药防治慢性前列腺炎的研究提供了新思路。更多还原

【Abstract】 Chronic Prostatitis(CP) is a common disease in young and middle aged men.It has impact on physical and mental health with the characteristics of symptom complex,longer course,and easy recurrence.How to improve clinical symptoms and increase the clinical efficacy is the most critical topic in the field of CP currently.Advisor Professor Zhang Ya-qiang is the academic inheritor of Professor Liu You-fang who is the founder of urology combined traditional Chinese and western medicine in China.On the basis of inheriting academic experience of Professor Liu You-fang,Advisor Professor Zhang often obtain a unique efficacy especially in the treatment of chronic prostatitis by applying the method of promoting blood circulation and removing blood stasis.According to collecting a great deal of the ancient TCM literature on CP,advisor’s clinical experience of treating CP is mined thoroughly by means of modern scientific method.Meanwhile,the experimental autoimmune prostatitis(EAP) animal model was adopted.And the modern techniques of Enzyme-Linked Immunosorbent Assay (ELISA),Real-Time polymerase chain reaction(RT-PCR) were applied to detect test targets.The molecular mechanisms on DanPu capsule in the therapy of CP were explored at different levels from the whole-cytokine-gene.And the scientific content of the theory of TCM treating CP and the clinical experience of the tutor were revealed from one aspect.PartⅠ:Theoretical studies1.The ancient literature of TCM having significant meaning in the therapy of Chronic ProstatitisOn the basis of combing a great deal of the ancient TCM literature about CP,the idea of TCM on such disease was divided into four periods:①It was the sprouting period that during the Qin & Han Dynasties. ②It was the development period in the Sui and Tang Dynasties.③It was the substantial period that from the Song Dynasty to Yuan Dynasty.④It was mature period during the Ming and Qing Dynasties.2.Academic experience on advisor of treating CPAccording to the pathogenesis characteristic of "the syndrome of Blood Stasis is crossing the course of CP",on the basis of inheriting the academic thoughts of Pro LIU You-fang,the clinical experiences of my tutor are as follows:①To advocate major therapeutic method of promoting blood circulation and removing blood stasis in the therapy of chronic prostatitis.②To treat CP based on different course and state of patients.③At the same time,to emphasize the importance of adjusting the food,drink and the mental state.PartⅡ:Clinical studies1.The clinical study about medication and syndrome on advisor in thetreatment of Chronic ProstatitisTo make use of the bioinformation data mining(DM),and to take advisor’s prescription and medicine as the clues,90 pieces of the primitive prescriptions were carried out to analyze from multi-angles.Regularities were summarized as follow:①Chronic Prostatitis was divided into three basic syndromes by Syndrome differentiation and treatment.②6 elementary methods,25 common Chinese herbs,6 elementary prescriptions and 25 couple of herbs were summarized respectively.③According to functional classification of herbs,it was the first place that a kind of drug for removing blood stasis.It was the second place that a kind of the drug for eliminating dampness and heat and a kind of the drug for nourishing the kidney.2.the clinical research on DanPu capsule in the therapy of CPPurpose and method:To reevaluate the clinical efficacy of DanPu capsule treating CP by means of randomized controlled trial(RCT).Conclusions:①The total effective rate of DanPu capsule and the control drug were 83.3%and 56.4%respectively.The effect in DanPu capsule group is better than that of the control group(P＜0.05). ②DanPu capsule can reduce the white blood count in expressed prostatic secretion(EPS) and increase the lecithin corpuscle count of EPS,which is superior to the control group.③DanPu capsule can improve clinical symptoms such as pain in the lower abdomen,frequent urination,burning urethra,perineal pain,lumbosacral pain, testicular pain,scrotum humidity and so on.Besides,It can also lower NIH-CPSI (National Institutes of Health Chronic Prostatitis Symptom index),NIH-pain-score and elevate the quality of life.PartⅢexperimental researchThe modern techniques of ELISA and RT-PCR were applied to detect the lab indexes.From the different layers of the whole-cytokine-gene,to explore extremely the molecular mechanisms of DanPu capsule in the therapy of CP.From one aspect,the scientific content of was brought to light,which were the theories of TCM and the clinical experience of the advisor.1.Selecting the stable method of establishing experimental autoimmune prostatitis(EAP) animal model—booster immunization.2.Under light microscope and electron microscope,it is found that DanPu capsule can lessen and eliminate the prostatic inflammation of EAP rat model.3.DanPu capsule has the inhibitory action on IL-1β,IL-2,IL-8 levels in the prostatic tissue and serum of rats.Meanwhile,it has the descending effect on IL-10 and NF-κB(Nuclear Factor-κB) as well.4.DanPu capsule has the depressant effect on NGF,PGE2 levels in the prostatic tissue & serum of rats.5.DanPu capsule has the inhibitory action on the expression NF-κB-mRNA、NGF-mRNA in the prostatic tissue & serum of rats.更多还原