吴焕林治疗冠心病经验数据挖掘及优选方抗血小板机制研究

发布时间：2018-05-11 10:35

本文选题：冠心病 + 五脏相关　；参考：《广州中医药大学》2016年博士论文

【摘要】：目的：梳理吴焕林教授对国医大师邓铁涛五脏相关学说治疗冠心病的继承和发展；运用数据挖掘的方法,分析吴焕林教授在五脏相关理论指导下治疗冠心病的临床用药规律；将临床用药规律挖掘结果与学术理论互证,确定实验药物,对药物的抗血小板聚集、抗动脉血栓形成的作用及机理进行探讨,为临床用药经验提供依据。方法：学术思想研究主要通过文献分析及跟诊师承的方法,梳理五脏相关治疗冠心病的源流与发展。运用数据挖掘技术对临床用药规律分析研究根据纳入、排除标准,对吴焕林教授医案进行采集、标准化和结构化,形成规范可用的数据库；运用中医传承辅助平台软件对医案用药进行四气统计、五味统计、归经统计、基于关联规则的药物模式分析及规则分析、基于改进的互信息法的药物的关联度分析、基于复杂系统熵聚类的药物提取组合分析、基于无监督熵层次聚类的新方组合分析。实验研究将66只SPF级SD大鼠随机分为6组,分别是空白组、高剂量组、中剂量组、低剂量组、阳性对照组,每组12只,模型组为6只,干预7天。将模型组全组、半数的高、中、低剂量组、半数的阳性对照组给予三氯化铁外敷法颈动脉血栓造模,半数的空白组给予假手术对照,监测颈动脉血流、石蜡病理切片及HE染色,分析实验药物体内抗动脉血栓的疗效；其余的动物给药干预7天后,腹主动脉取血,通过血小板聚集率检测、血小板cAMP的ELISA检测、PI3K-Akt及PKC-Erk通路蛋白western blot检测,分析实验药物抗血小板的机制。结果：五脏相关学说是在五行学说的基础上发展而来,指以五脏为中心的五个系统内部、五个系统之间、五个系统与机体、与自然界、与社会相互影响与制约。在传承和发展的基础上,五脏相关治疗冠心病的临证思想可分为三个阶段：心肝相关阶段,心脾相关阶段、心肺肾相关阶段,注重每一阶段的主要受病脏腑和临床特征。在每个不同的阶段,有着不同的病机、不同的治则治法和方药。用药规律研究：共纳入了1044条方,191味药物。使用频率大于100次的药物有41味；药物归经依次主要为脾、胃、肺、肝、心、肾；药物四气归类依次为：温、平、凉、寒、热；药物五味归类依次为：甘、苦、辛、淡、咸、酸。基于关联规则的用药模式分析,将支持度设为550,得到药物模式45个,涉及7味药；将支持度设为500,涉及8味药；将支持度设为450,涉及9味药。药物的规则分析,支持度为550,置信度为0.90的药物规则101个；置信度大于0.98的药物规则38个。基于改进的互信息法的药物的关联度分析,将相关度设为8,惩罚度设为2,得到关联系数大于0.03的药对24个。基于复杂系统熵聚类的药物提取组合分析,得到3-4味药物的核心组合20个；通过无监督的熵层次聚类算法,得到潜在的新方组合10个。Omin颈动脉基础血流,各个组间没有差异(P0.05),15min颈动脉血流监测表明,实验药物高剂量组增加造模后颈动脉的血流量(P0.05)；25min颈动脉血流监测表明,实验药物中、高剂量组增加造模后颈动脉的血流量(P0.01)。石蜡切片及HE染色结果表明,实验药物呈剂量依赖性的减少造模后颈动脉内的血栓量。实验药物中、高剂量组降低血小板聚集率(P0.05,P0.01)。进一步研究发现,与ADP组比较,高剂量组小板内cAMP的含量升高(P0.01)。蛋白免疫印迹结果分析表明,实验药物高剂量组可降低血小板内PI3Kp110β的表达量(P0.05)。高剂量组使得血小板内p-Akt/t- Akt表达量降低(P0.01)。与ADP组相比,实验药物的低、中、高剂量组皆不能改变血小板内p-pkc的表达量(P0.05)。实验药物的高剂量组可以降低血小板内p-erk/t- erk的表达量(P0.05)。结论：五脏相关学说源于五行学说,基于五行学说的局限性及临床实践的需求,五脏相关学说孕育而生,吴焕林教授对五脏相关治疗冠心病在原来基础上进行了细化和发展,渐渐成为较成熟的理论。用药规律挖掘：在心脾阶段病例占较大比例的前提下,药物以益气健脾、化痰湿、活血类药物为主,药物归经以脾、胃、肺、肝、心、肾为主；四气以温、平为主;五味以甘、苦、辛为主。挖掘出了主要药物模式、药物规则、关联药对、药物提取组合、潜在的新方等,采用人机对话的形式,得出用药规律,可以较好的指导临床。实验研究：实验药物具有抗SD大鼠颈动脉血栓形成的作用；抑制血小板激活,降低血小板聚集率,其机制可能是上调cAMP表达水平,抑制了PI3K-Akt-erk信号通路的激活。
[Abstract]:Objective: to sort out professor Wu Huanlin's inheritance and development of the Deng Tietao five Zang related theory in the treatment of coronary heart disease, and the method of data mining to analyze the clinical medication rule of Professor Wu Huanlin in the treatment of coronary heart disease under the guidance of the related theory of five zang organs. The effect and mechanism of antiplatelet aggregation and anti arterial thrombosis are discussed, and the basis for clinical use of drugs is provided. Methods: the study of academic thought mainly through the literature analysis and the method of following up with the doctor, combing the origin and development of coronary heart disease related to the five zang organs related treatment. The application of data mining technology to the clinical drug use law analysis According to the inclusion and exclusion criteria, the medical cases of Professor Wu Huanlin were collected, standardized and structured to form a standardized database, and the traditional Chinese Medicine Inheritance auxiliary platform software was used to make four statistics, five statistics, statistics, drug model analysis based on association rules and rules analysis based on association rules, based on improved mutual information. Analysis of the degree of association of the drugs, based on the combination analysis of drug extraction with complex system entropy clustering, based on the combination analysis of the unsupervised entropy hierarchical clustering. 66 SPF grade SD rats were randomly divided into 6 groups, which were blank group, high dose group, middle dose group, low dose group, positive control group, 12 rats in each group, 6 rats in model group and 7 intervention. 7 The whole group of the model group, half of the high, middle and low dose group, half of the positive control group were given the carotid artery thrombosis with iron trichloride external application, half of the blank groups were given the sham operation control, the blood flow of the carotid artery, the pathological section of paraffin and HE staining, the effect of the anti arterial thrombosis in the experimental drugs were analyzed; the rest of the animals were given 7 intervention. After the abdominal aorta, the blood was taken from the abdominal aorta, the platelet aggregation rate was detected, the ELISA detection of platelet cAMP, the PI3K-Akt and the PKC-Erk pathway protein Western blot were detected, and the mechanism of antiplatelet antiplatelet agents was analyzed. Results: the five organs related theory developed on the basis of the five line theory, which refers to the five internal organs and five systems with the five viscera as the center. Between the five systems and the body, and the nature, and society mutual influence and restriction. On the basis of inheritance and development, the five organs related to the treatment of coronary heart disease can be divided into three stages: the related stage of the heart and the liver, the related stage of the heart and the spleen, the related stage of the heart and the lung and the kidney, and pay attention to the main viscera and clinical features of each stage. At the same stage, there were different pathogenesis, different treatment rules and prescriptions. Study on the rule of drug use: a total of 1044 prescriptions and 191 flavors were included. The drugs used in more than 100 times were 41 flavors; the drugs were mainly divided into spleen, stomach, lung, liver, heart and kidney in turn: warm, flat, cold, cold, and heat, and the five flavors of drugs were classified in turn. Gump, bitterness, symplectic, light, salty, acid. Based on the association rules of the drug model analysis, the support was set to 550, the drug model was set to 45, involving 7 flavors; the support was set to 500, and the support was set to 450, involving 9 drugs. The drug rule analysis, the support degree of 550, the confidence degree 0.90 of the drug rules 101; confidence greater than 0.9. 8 drug rule 38. Based on the correlation analysis of improved mutual information method, the correlation degree is set to 8, the penalty degree is set to 2, and the correlation coefficient is more than 0.03 to 24. The combination analysis of drug extraction based on the entropy clustering of complex system is obtained, and 20 core combinations of the 3-4 flavors are obtained. Through the unsupervised entropy hierarchical clustering algorithm, the results are obtained. The potential new side combined 10.Omin carotid artery base blood flow, and there was no difference between each group (P0.05). 15min carotid artery blood flow monitoring showed that the high dose group increased the blood flow of the carotid artery (P0.05) in the high dose group, and the 25min carotid artery blood flow monitoring showed that the high dose group increased the blood flow of the carotid artery (P0.01) in the high dose group (P0.01) and paraffin wax. The results of slicing and HE staining showed that the experimental drug was dose-dependent to reduce the volume of thrombus in the carotid artery. In the experimental drug, the high dose group reduced the platelet aggregation rate (P0.05, P0.01). Further studies found that the content of cAMP in the high dose group was higher than that in the ADP group (P0.01). The results of protein immunoblotting showed that the experiment was carried out. The high dose group could reduce the expression of PI3Kp110 beta in the platelet (P0.05). The high dose group reduced the expression of p-Akt/t- Akt in the platelets (P0.01). Compared with the ADP group, the low, middle and high dose groups of the experimental drugs could not change the p-pkc expression in the platelets (P0.05). The high dose group of the experimental drugs could reduce the p-erk/t- ER in the platelets. K expression (P0.05). Conclusion: the theory of five zang organs related to the theory of five elements, based on the limitations of the five line theory and the needs of clinical practice, the five Zang related theories gestation and birth, Professor Wu Huanlin on the five Zang related treatment of coronary heart disease on the basis of the original refinement and development, gradually become a more mature theory. On the premise of a large proportion of the spleen stage cases, the drug is based on Invigorating Qi to invigorate the spleen, eliminating phlegm dampness and activating blood type drugs. The drugs are mainly treated with spleen, stomach, lung, liver, heart and kidney; the four gases are mainly warm and flat; five flavors are Gump, bitter and symplectic. In the form of machine dialogue, the rule of drug use can be obtained to guide the clinical. Experimental study: experimental drugs have the effect of anti SD rat carotid thrombosis, inhibit platelet activation, reduce platelet aggregation rate, its mechanism may be up regulation of cAMP expression and inhibit the activation of PI3K-Akt-erk signaling pathway.

【学位授予单位】：广州中医药大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R249;R259

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