蒙定水教授益气升阳活血法治疗CHD的临床观察与作用机理探讨

发布时间：2018-06-10 20:42

本文选题：蒙定水 + 冠心病　；参考：《广州中医药大学》2016年博士论文

【摘要】：目的：笔者非常有幸成为第五批全国名老中医药专家学术经验继承人,师承名老中医蒙定水教授。并荣幸的成为广州中医药大学周福生教授的弟子。在周教授的精心指导下,作者主要从蒙定水教授学术师承溯源着手,以冠心病为主攻方向,较系统地挖掘整理蒙教授关于冠心病病因病机“五脏关联辨证观”,“无虚不发病”、“无瘀不发病”,与“益气升阳活血治法”新观点,以及辨治冠心病的组方规律与用药特点等学术思想与临证经验。受蒙教授的学术思想影响和熏陶,笔者近年来主要致力于冠心病“益气升阳活血法”的临床疗效与作用机理研究,并将其运用于治疗冠心病的临床实践中。同时分别从文献整理、临床疗效评价及作用机理等三个方面来深入研究探讨,以期进一步丰富和发展冠心病的中医病因病机及辨证论治的理论内涵。冠状动脉粥样硬化性心脏病简称冠心病(CHD),是指因冠状动脉粥样硬化(AS)而致冠脉血管狭窄或闭塞,进而导致心肌缺血、缺氧引起的心脏病。本病是一种由遗传因素和环境因素共同作用引起的复杂疾病,目前已经成为全球范围内死亡和致残的首要病因。关于其发病机制目前普遍认为与血管内皮功能紊乱,血小板活化、炎症反应、斑块破裂、血栓形成以及血清脂质代谢异常密切相关。现代医学治疗主要有药物治疗和血运重建(包括PCI和CABG术),虽然取得了长足进展。但介入治疗目前仍存在许多无法克服的问题,如介入术后再狭窄的问题,冠脉微血管病变和多支弥漫性病变无法植入支架等问题,仍有不少患者不能达到完全血运重建而影响预后。中医药治疗冠心病主要针对多部位、多靶点和双向调节等方面起作用,临床疗效显著,具有现代医学不可比拟的优势,目前已经受到国内外医学者普遍关注和重视。本课题是在前期临床研究工作的基础上,采用随机、盲法、安慰剂对照的研究方法,以期证明益气升阳活血中药加味丹葛止痛方治疗冠心病稳定型心绞痛是否具有绝对的有效性和安全性。通过人工实验动物造模成功后,并观察加味丹葛止痛方对气虚血瘀证急性心肌梗死大鼠模型血浆ET、NO的影响,以及对心肌梗死边缘区缺血心肌微血管新生的影响,从较深层次研究探讨中医药治疗冠心病的作用机理,为益气升阳活血中药加味丹葛止痛方治疗冠心病的现代病理生理机制提供可靠的理论依据。同时该研究亦能进一步为中医益气升阳活血法治疗冠心病提供更有力的实验证据。方法：本课题分为临床研究和实验研究两大部分。1临床研究方法：将符合纳入标准的冠心病稳定型心绞痛气虚血瘀证患者64例,按照1：1的比例随机分为两组即治疗组和对照组,每组各32例,治疗组予以加味丹葛止痛方颗粒口服,对照组予以安慰剂口服,采用随机、盲法、安慰剂对照的临床研究,并追踪随访,主要从临床心绞痛症状、中医证候积分、西雅图量表评分、心绞痛发作次数与持续时间、硝酸甘油服用量与服药后心绞痛缓解的时间以及对患者血脂水平、血清Hs-CRP和血液流变学等多项指标评价中药加味丹葛止痛方的临床疗效。观察疗程为4周,随访周期6个月。2实验研究方法：参照文献法先复制实验大鼠气虚血瘀证模型,复制成功后再采用结扎模型大鼠冠状动脉左前降支复制急性心肌梗死模型,然后将复制成功的气虚血瘀证AMI模型大鼠(除去死亡外)40只随机分为4组,即假手术组、模型组、加味丹葛止痛方(简称治疗组)和芪参益气滴丸组(简称对照组)。治疗组给予常规治疗剂量的加味丹葛止痛方药液灌胃,对照组予以常规治疗剂量的芪参益气滴丸药液灌胃,假手术组和模型组给予等体积溶液生理盐水灌胃,给药时间为2周,每日1次。用药期间密切大鼠一般情况,用药结束后观察大鼠治疗前后血浆NO、ET水平,采用HE染色观察气虚血瘀证AMI模型大鼠心肌组织病理形态改变,采用免疫组化法观察气虚血瘀证AMI模型大鼠心肌梗死边缘区缺血心肌微血管新生情况。结果：1临床研究结果1.1对冠心病稳定型心绞痛的胸闷、胸痛,心悸气短、神疲乏力等症状的改善更加明显：经过4周的治疗,通过西雅图心绞痛量表评分及中医证候积分比较,两组患者的各个症状都有明显改善,与对照组比较,治疗组的各个症状的改善程度较对照组改善更为明显。1.2心绞痛发作的频率、持续时间及硝酸甘油服用量与服药后心绞痛缓解的时间均明显减少：通过对患者进行4周的治疗观察,发现两组患者心绞痛发作的频率、持续时间及硝酸甘油服用量与服药后心绞痛的缓解时间均有明显减少。与对照组比较,结果显示治疗组上述指标减少更明显。1.3对患者实验室指标的改善更明显：经过4周1疗程的治疗观察,发现两组患者血清血脂中TC、TG、LDL-C均明显降低,HDL-C明显升高,以及Hs-CRP均明显降低,血液流变学各项指标均较治疗前有明显改善。与对照组比较,治疗组上述各项指标改善更明显。1.4治疗药物安全、且无明显毒副作用：经过4周一疗程的治疗观察,发现两组患者均未发生不良事件和不良反应,实验室的各项安全指标检查均为正常,表明中药加味丹葛止痛方颗粒治疗冠心病稳定型心绞痛气虚血瘀证安全有效。2实验研究结果：经过1疗程的治疗后,治疗组与对照组两组大鼠血浆ET水平均明显降低,血浆NO水平明显升高,与模型组比较,差异有统计学意义(PO.01)。且加味丹葛止痛方组前两项指标改善更明显,但与对照组比较,差异无显著性(P0.05)。除假手术组外,造模各组大鼠心肌梗死边缘区心肌内皮细胞CD34表达明显增强,MVC显著增加,提示急性心肌缺血后血管新生过程已经启动。加味丹葛止痛方组和芪参益气滴丸组大鼠急性心肌梗死边缘区缺血心肌微血管新生明显增加,缺血心肌内皮细胞数／微血管数(MVC)和微血管面积(MVD)明显增多,与模型组比较,差异有统计学意义(P0.05)。与芪参益气滴丸组比较,加味丹葛止痛方组心肌梗死大鼠缺血心肌内皮细胞数(MVC)和MVD明显增加,但差异无统计学意义(P0.05)。结论：1中药加味丹葛止痛方治疗冠心病稳定型心绞痛气虚血瘀证临床疗效显著,可以明显减轻患者心绞痛的症状,降低心绞痛的中医证候积分,减少心绞痛发作的次数及持续时间,减少硝酸甘油服用量与服药后心绞痛缓解时间,并能降低患者血脂水平、降低血清Hs-CRP和改善血液流变学指标,且药物安全无毒副作用。2中药加味丹葛止痛方治疗实验急性心肌梗死模型大鼠,能显著提高其血浆N0水平,降低其血浆ET水平；并能促进急性心肌梗死边缘区缺血心肌微血管新生,增加缺血心肌内皮细胞数／微血管数(MVC)和微血管面积(MVD)。表明加味丹葛止痛方对急性心肌梗死缺血心肌具有较好的保护作用。综合上述结果,考虑中药加味丹葛止痛方可能通过促进冠心病患者急性心肌梗死血缺血边缘区微血管新生,从而促进冠状动脉侧枝循环的建立；纠正NO/ET比例的失衡而对缺血心肌组织起保护作用,进而改善冠心病患者的临床症状,减少心绞痛发作次数及持续时间等。也更深层次证实益气升阳活血法指导下创建的加味丹葛止痛方对气虚血瘀证冠心病患者临床疗效显著,为益气升阳活血法治疗冠心病气虚血瘀证提供了更有力的证据。
[Abstract]:Objective: the author is very fortunate to be the fifth batch of the successor to the academic experience of Chinese traditional Chinese medicine experts, Professor Meng Ding Shui, a professor of the famous old Chinese medicine, and a disciple of Professor Zhou Fusheng of Guangzhou University of Chinese Medicine. Under the careful guidance of Professor Zhou, the author mainly starts from the academic division of Professor Meng Ding Shui and mainly focuses on the attack of coronary heart disease. To systematically excavate the academic thoughts and experience of Professor Meng's academic thought on the syndrome differentiation of the five zang organs, "no deficiency and no disease", "no blood stasis and no disease", the new viewpoint of "promoting Qi Yang and activating blood circulation method", as well as the prescription and drug characteristics of coronary heart disease, and other academic thoughts and clinical experience. In recent years, the author is mainly devoted to the study of the clinical effect and mechanism of "Yiqi Yang activating blood activating method", and it is used in the clinical practice of treating coronary heart disease. At the same time, it is studied in three aspects, including literature sorting, clinical efficacy evaluation and mechanism of action, in order to further enrich and develop coronary heart disease. Coronary atherosclerotic heart disease (CHD) refers to coronary artery stenosis or occlusion caused by coronary atherosclerosis (AS), which leads to myocardial ischemia and hypoxia induced heart disease. This disease is caused by a combination of genetic factors and environmental factors. Miscellaneous diseases have now become the leading cause of death and disability worldwide. Its pathogenesis is generally believed to be closely related to vascular endothelial dysfunction, platelet activation, inflammatory reaction, plaque rupture, thrombosis and serum lipid metabolism. Modern medical treatment mainly includes drug treatment and blood transport reconstruction. Although great progress has been made in PCI and CABG, there are still many problems that can not be overcome, such as the problems of restenosis after interventional procedure, coronary microvascular lesions and multiple diffuse lesions that can not be implanted into the stent. Many patients still can not achieve complete revascularization and affect the prognosis. Chinese medicine for the treatment of coronary heart disease is the main problem. In view of the role of multi site, multi target and two-way regulation, the clinical curative effect is remarkable, and it has an incomparable advantage in modern medicine. At present, it has been paid much attention to and paid attention to by the medical researchers both at home and abroad. This topic is based on the earlier clinical research work, using random, blind, placebo control research methods, with a view to prove the benefit. The effect and safety of Qi Yang Huoxue Chinese medicine plus Zhisan Zhitong prescription in the treatment of coronary stable angina pectoris. After the success of artificial animal models, the effects of gisan Ge Zhitong Recipe on the plasma ET, NO in the rat model of acute myocardial infarction with Qi deficiency and blood stasis syndrome, and the ischemic myocardium in the marginal zone of myocardial infarction were observed. The effect of microvascular neovascularization, the mechanism of traditional Chinese medicine treatment of coronary heart disease was studied from a deeper level, and a reliable theoretical basis was provided for the modern pathophysiological mechanism of coronary heart disease treated with Yiqi Shengyang Huoxue traditional Chinese medicine and Gudan Zhitong prescription. Experimental evidence of force. Methods: the subject was divided into two.1 clinical research methods: clinical research and experimental research: 64 patients with coronary heart disease stable angina pectoris Qi deficiency and blood stasis syndrome were divided into two groups according to the proportion of 1:1, the treatment group and the control group, each group was divided into 32 cases, and the treatment group was given the decoction of Gudan Ge Zhitong. Orally, the control group was given a placebo orally, using a randomized, blind, placebo controlled clinical study and followed up, mainly from clinical angina symptoms, TCM syndrome scores, Seattle scale score, the frequency and duration of angina pectoris, the time of the dosage of nitroglycerin and the remission of angina pectoris after the medication and the blood lipid of the patients. Levels, serum Hs-CRP and hemorheology and other indexes were used to evaluate the clinical effect of Chinese herbal medicine plus Gudan Ge Zhitong prescription. The treatment course was 4 weeks, and the follow-up period was 6 months.2 experimental research method: the experimental model of qi deficiency and blood stasis syndrome was replicated by the reference method, and the acute coronary artery left anterior descending branch of the model rats was replicated after the replication of the model. The model of myocardial infarction was then divided into 4 groups randomly: AMI model rats (excluding death) of qi deficiency and blood stasis syndrome, which were divided into 4 groups randomly, namely, sham operation group, model group, Gutan Kishi Fang (treatment group) and Qi Shen Yiqi dropping pill group (abbreviated as control group). The treatment group was given gutta gutta Zhitong prescription in the treatment group, and the control group was given to the control group. The conventional treatment dose of Qi Shen Yiqi dropping pill was given to the stomach. The sham operation group and the model group were given the same volume of saline solution for 2 weeks, 1 times a day. During the medication, the blood plasma NO and ET were observed before and after the treatment, and the AMI model rats of qi deficiency and blood stasis syndrome were observed by HE staining. Pathological changes of myocardial tissue and immunohistochemical method were used to observe the microvasculature of ischemic myocardium in the marginal zone of AMI model rats with Qi deficiency and blood stasis syndrome. Results 1 clinical results 1.1 improved the symptoms such as chest tightness, chest pain, palpitation, palpitation, fatigue and other symptoms of coronary heart disease stable angina pectoris. After 4 weeks of treatment, By comparing the score of Seattle angina scale and TCM syndrome score, the symptoms of the two groups were obviously improved. Compared with the control group, the improvement of each symptom in the treatment group was more obvious than that of the control group. The duration of the treatment and the time of the use of nitroglycerin and the time of relieving the angina pectoris after the treatment were more obvious than that of the control group. By 4 weeks of treatment, the frequency of angina pectoris in the two groups, duration of nitroglycerin and the time of remission of angina pectoris were significantly reduced in the two groups. The results showed that the reduction of the above indexes in the treatment group was more obvious in the improvement of the laboratory index of.1.3. More obvious: after 4 weeks of 1 courses of treatment observation, it was found that TC, TG, LDL-C in serum lipids of the two groups were significantly decreased, HDL-C was significantly increased, and Hs-CRP was significantly reduced. All indexes of blood rheology were significantly improved compared with those before treatment. Compared with the control group, the indexes of the treatment group improved more obviously with the safety of.1.4 treatment, and no Obvious toxic and side effects: after 4 Monday courses of treatment observation, the two groups of patients were found to have no adverse events and adverse reactions, and all the laboratory safety indexes were all normal. The results showed that the traditional Chinese medicine plus zhitadong Zhitong granule in the treatment of coronary heart disease stable angina pectoris Qi deficiency and blood stasis syndrome.2 experimental results: after 1 courses of treatment After treatment, the plasma ET level of the two groups in the treatment group and the control group were significantly reduced, the plasma NO level was significantly increased, and the difference was statistically significant (PO.01) compared with the model group. And the first two indexes of the group were more obvious, but compared with the control group, the difference was not significant (P0.05). Except for the sham operation group, the model rats were made in each group. The expression of CD34 in myocardial endothelial cells in the marginal zone of myocardial infarction was obviously enhanced and MVC increased significantly, suggesting that the angiogenesis process had started after acute myocardial ischemia. The microvasculature of ischemic myocardium in the marginal zone of acute myocardial infarction in the group of gisorudan Ge Zhitong and Qi Shen Yiqi dropping pills group increased significantly, and the number of endothelial cells / microvessels in the ischemic myocardium was the number of microvessels. (MVC) and microvascular area (MVD) significantly increased, compared with the model group, the difference was statistically significant (P0.05). Compared with the Qisheng Yiqi dropping pill group, the number of ischemic myocardium (MVC) and MVD in the rats with myocardial infarction increased significantly, but the difference was not significant (P0.05). Conclusion: 1 Chinese medicine plus gisan Ge Zhitong prescription treatment crown The clinical curative effect of qi deficiency and blood stasis syndrome of angina pectoris stable angina is significant. It can obviously reduce the symptoms of angina pectoris, reduce the score of TCM syndrome, reduce the frequency and duration of angina pectoris, reduce the dosage of nitroglycerin and the time of relieving angina pectoris, and reduce the level of blood lipid, reduce the Hs-CRP and the serum level of the patients. The improvement of blood rheology index, drug safety and non-toxic side effect.2 Chinese herbal medicine plus Zhisan Zhitong prescription can significantly improve the level of plasma N0 and reduce the level of plasma ET, and can promote the microvascular neovascularization of the ischemic myocardium in the marginal area of acute myocardial infarction and increase the number of ischemic myocardial endothelial cells / Microblood. The number of tubes (MVC) and microvascular area (MVD) showed that gisan Ge Zhitong prescription had a good protective effect on the ischemic myocardium of acute myocardial infarction. To correct the imbalance of NO/ET ratio and to protect the ischemic myocardium, to improve the clinical symptoms of the patients with coronary heart disease, to reduce the frequency and duration of angina pectoris, and to further prove the clinical effect of gisan Ge Zhitong, which was created under the guidance of the method of solid gas promotion and blood activating, on the patients with Qi deficiency and blood stasis syndrome. It provides more convincing evidence for the treatment of qi deficiency and blood stasis syndrome of coronary heart disease by supplementing qi, Promoting Yang and activating blood circulation.
【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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