【作者】 黄汉超；

【导师】 陈镜合；

【作者基本信息】 广州中医药大学 ， 中医内科学， 2010， 博士

【摘要】 【背景】急性冠状动脉综合症(简称ACS)包括ST段抬高与非ST段抬高的急性心肌梗死与不稳定型心绞痛三大类病变。现时研究表明,从不稳定型心绞痛到非Q波心肌梗死,再到急性心肌梗死之间没有明确的界限,它们的病理学和病理生理基础有相似的地方,都是在冠状动脉内不稳定斑块破裂的基础上继发血栓形成的结果。ACS具有进展急骤,预后不良的特点,是心血管疾病的急危重症之一,其发病率有逐年增高的趋势,严重威胁人民健康,已成为心血管领域的研究热点之一。ACS属祖国医学“胸痹心痛病”“真心痛”范畴。张仲景在《金匮要略》中提出“阳微阴弦”是该病的发病机理,并载有用乌头赤石脂丸治疗治疗阴寒痼结、阳气衰微的胸痹心痛病的记载。近年来的证型研究表明,阳虚、寒凝是冠心病不稳定型心绞痛、急性心肌梗死的主要证型之一。小样本研究提示乌头赤石脂汤治疗不稳定型心绞痛安全有效。【目的】通过设立中西医结合治疗组及单纯西医治疗组并对比其疗效,评价乌头赤石脂汤对ACS的临床疗效、安全性,并通过随机、前瞻性动物实验研究其可能的作用机制,为今后更深一步的研究打下基础。【方法】临床研究采用随机、单盲研究方法。自2008年9月至2010年3月期间,从广州中医药大学第一附属医院急诊、心内科以及广东省第二中医院急诊、心内科的收取符合标准的住院病人77例,随机分为治疗组及对照组,两组均使用常规西医治疗,治疗组在此基础上服用乌头赤石脂汤,对照组服用中药安慰剂(甘草、谷芽、麦芽),均为每天两次,每次200ml,直至住院结束。观察住院期间患者中、西医症候以及生命体征静息心电图、三大常规、肝肾功能、凝血功能、C反应蛋白、白介素-6、纤维蛋白原等指标的变化以及记录服药后的不良反应、住院期间有无恶性心脑血管事件的发生。垂体后叶素造模是近年来研究比较充分的造模方法。本研究将在此基础上进行改进。通过比较不同途径注射垂体后叶素所引起的心肌缺血效应特点,明确最佳的给药方式；并通过比较注射不同剂量的垂体后叶素(Pit)的心肌缺血效应、不良事件发生率等以摸索出最佳造模剂量；同时通过心电监测,明确静注垂体后叶素后所造成的心肌缺血持续时间特点,进而把握给药时机。随机对照试验中于成功造模后,予十二指肠穿刺给药,观察给药前后前后大鼠心电图、血清肌钙蛋白(cTNI)、羟自由基、超氧化物歧化酶(SOD)水平的变化从而评估可能的作用途径。【结果】统计发现本研究使用的中医症候积分量表和患者病情轻重程度有良好的相关性,中医症候积分越高的患者,病情越重；疗效方面,治疗组在心绞痛症状改善上显效22例,有效14例,无效4例,总有效率90%,对照组显效16例,有效19例,无效2例,总有效率94.59%,差异无统计学意义；中医症候改善上,治疗组为27.38%,对照组15.16%,治疗组之间比较差异具有显著性,治疗组对于心气不足、心阳不振症候的改善优于对照组(P<0.05),对于心血瘀阻证、痰浊闭塞证,治疗组改善程度有优于对照组的趋势,尚未具统计学意义,其余证型改善不大,但均无恶化情况；实验室指标变化方面,两组相比较差异无显著性(P>0.05)。不良事件比较,两组患者服药后出现呕吐的共有4人,多为急性心肌梗死的患者,治疗组仅有2人不能耐受乌头赤石脂汤者,口干、头胀等不良反应的发生率与对照组相比差异无显著性。两组病人在住院观察期间均无出现心绞痛加重、恶性心律失常、新发心衰、心源性猝死等情况,治疗组患者行PCI术或溶栓后凝血时间未有显著延长。动物预实验提示股静脉注射垂体后叶素较之腹腔注射、尾静脉注射等可能为比较理想的造模途径。心肌缺血效应、稳定性与剂量呈正相关,但随着Pit用量的增加,实验过程之中大鼠出现恶性心律失常、血尿、猝死等不良事件的机率也随之增加,同时心肌损伤的程度也有所增加。垂体后叶素造模不出现心肌梗死病理学改变。动物随机对照试验提示治疗组较空白对照组的心电图具有一定的改善,可使下移的ST段有一定的回复,实验室指标方面SOD、羟自由基等指标于用药后无明显改善。实验期间无一大鼠于用药后出现心率加快、室性心动过速、猝死等不良事件。【结论】1、中医症候积分量表和病情有良好的相关性,积分高的患者多有阳虚、痰浊闭塞、心血瘀阻互相夹杂等的情况,符合中医“阳微阴弦”的理论。该表不仅可用于患者病情的评估,同时更可全面客观化描述和评价中医药的疗效,较之单纯用胸痛症候改善、硝酸甘油用量变化、静息心电图变化等传统指标更能反映中医的整体、客观疗效。2、乌头赤石脂汤治疗ACS安全有效,治疗组患者中医症候总体改善情况比对照组有显著性差异,其中对于证属“心阳不振”、“心气亏虚”型的ACS患者中医症候改善最为明显。用药后无一患者出现心肌缺血加重、生命体征改变、肝肾功能损伤等的情况。3、动物随机实验方面提示乌头赤石脂汤对急性期心肌缺血的改善具有一定的疗效,但不甚显著,并且对SOD、羟自由基等指标无改善作用,考虑其可能的机制为直接扩张痉挛的冠脉而起作用。今后尚需进行深入的研究。实验期间无一大鼠于用药后出现心率加快、恶性心律失常、血尿等情况,cTNI亦无增高的趋势,提示该药是安全有效的。4、本研究用静脉滴注垂体后叶素的方法进行造模研究,初步表明该法较以往的造模方法可造出更稳定的心肌缺血模型,但实验中的垂体后叶素剂量较大,部分大鼠有血尿的出现,考虑大剂量垂体后叶素不仅造成冠脉痉挛,尚可收缩肾动脉、肠系膜动脉、颈动脉等全身其他重要脏器的供血动脉,而且对心脏的损伤也比较大,因此该模型和临床实际的病例相比较,尚有一定的差异,难以完全客观评估药物疗效。因此个人认为垂体后叶素造模并非最佳的心肌缺血造模药物。5、本研究提示乌头赤石脂汤在急性期改善胸痛症状方面较之单纯西医治疗不具有优势,而在整体症候的改善上有优势,提示ACS急症期使用中药的价值可能不在于改善缺血症状上,而在于提高整体疗效上。而且中医症候积分的改善尚未达到显效的标准,估计与观察时间较短有关,故今后有关的中医药干预心肌缺血的研究不应着眼于急症期,而应延长观察期,方可体现中医药治疗心血管急危重症的价值和定位所在。另外用生存质量描述中医疗效可能是一个比较合理的角度,更能反映中医的治疗价值所在。更多还原

【Abstract】 【Background】Acute Coronary Syndrome (ACS) covers the spectrum of clinical conditions ranging from unstable angina (shortened as UA) to non-ST-segment elevation myocardial infarction (shortened as NSTEMI) and ST-segment elevation myocardial infarction (shortened as STEMI) Present studies show that it is difficult to separate the three precisely because they have no clear boundary, and their basic pathology and path physiology are almost the same, which takes place due to the unstable coronary plaque rupture and then cause thrombosis, which will stop the blood supply to the heart or even sudden death.ACS is a disease with poor prognosis, its incidence has now increased year by year, which will do great harm to people’s health, now it has become a focus in the research field of cardiovascular.The clinical manifestation of ACS is similar to a Traditional Chinese Medicine (shortened as TCM) disease named "chest pain" and "true heart pain. Zhang Zhongjing in his famous medical works " Synopsis of Prescriptions of Golden Cabinet" mentioned that "insufficiency of yang" maybe the most important pathogenic mechanism of it and used "Wutou Chishizhi Tang" to treat patients diagnosed as "purplish clots caused by insufficiency of yang syndrome"In recent years, evidence-based studies have shown that insufficiency of yang, cold coagulation may be the main TCM syndrome type of unstable angina, acute myocardial infarction. Small sample studies show that-Wutou Chishizhi Tang safe and effective treatment of unstable angina pectoris.【Objective】This thesis aims to lay the foundation for further research through the establishment of Integrated Traditional and Western treatment group and western medicine group, the comparison of their efficacies, the evaluation of ACS Wutou Chishizhi Tang on the clinical efficacy and safety, and the randomized, prospective animal study on its possible mechanism.[Methods] The author used a randomized, single blind methods in clinical research. From September,2008 to March,2010, the author collected 77 patients who met the diagnosis criterion of AMI and UA/NSTEMI from the First Affiliated hospital of Guangzhou TCM University and the second TCM hospital of Guangdong Province. We randomly divided them into the treatment group and the control group. Both groups used the modern standard western medicine, yet the treatment group used Wutou Chishizhi Tang, and the control group used a TCM placebo decoction (made of licorice, millet sprout, malt). Both groups took medicine twice a day and 200ml each time till the end of hospitalization. While in hospital, symptoms including physical feeling, adverse reactions after taking the drugs, cardiovascular events would be recorded. Vital signs, electrocardiogram, blood and urine and stool regular Test as well as liver and kidney function would be checked twice, the effect index such as blood coagulation, C-reactive Protein, interleukin-6, Fibrinogen would also be checked.In the preliminary animal experiment, the experimenter used different dose of vasopressin (Pit) in Animal experiments as to find out the most suitable dose by comparing the effect of myocardial ischemia time, heart rate through ECG monitoring as well as all adverse events. In the randomized controlled trials, after myocardial ischemia animal models were produced, the experimenter would give Wutou Chishizhi Tang through the duodenum puncture, and would check the serum troponin (cTNI), hydroxyl radical, superoxide dismutase (SOD) levels changes in order to assess the possible pathways.[Results] The statistics shows that TCM symptom scores have a good correlation with that of severity of ACS, i.e. patients who have higher symptom scores are in a more serious condition. In terms of healing effect, in the treatment group, there are 22 cases of remarkable change on angina symptoms 14 effective cases,4 noneffective cases, and the total efficiency rate is 90%. In comparison, in the control group, there are 16 cases of remarkable change,19 effective cases and 2 noneffective cases, and the total efficiency rate is 94.59%, and there is no significant difference. In terms of the improvement of TCM symptom, statistics in the treatment group is 27.38%, and 15.16% in the control group. The difference is of statistically significant, especially for the qi-deficiency of heart, yang deficiency symptoms (P<0.05). And for blood stasis, phlegm obstruction, both group shows no significant difference though there is a trend of better improvement in the treatment group than in the control group, and no patient in both groups got worse. Laboratory indicators shows no significant difference between two groups(P> 0.05). When Comparing the adverse events, the author found four patients in two groups had experienced vomiting after taking TCM decoction, mostly were caused bt acute myocardial infarction. There are only only two people in the treatment group who cannot tolerate Wutou Chishizhi Tang, There are no significant difference in terms of thirsty, headache or other adverse events rate between the two groups. Patients of both groups had not experienced angina, arrhythmia, new heart failure, sudden cardiac death, and so on during hospitalization observation. The treatment group were treated with surgery or PCI after thrombolysis did not affect the clotting time.Animal experiments suggest that the administration of vasopressin via vein is better than intraperitoneal injection, and intravenous injection may be an ideal modeling approach. Effect of myocardial ischemia, stability is positively correlated with dose, however, the greater dose we used, the more possibility of causing adverse events as malignant arrhythmias, hematuria, sudden death myocardial injury and so on. Vasopressin could not change myocardial infarctionAnimals randomized controlled trial suggested that the treatment group improved a little better than the control group by ECG assessment, which recover the ST segment depression. laboratory indicators such as SOD, hydroxyl radical show no significant improvement after treatment. During the experiment no rats had the manifestations of heart-beating rate rising, ventricular tachycardia, sudden death and other adverse events.[Conclusion] 1. There is a high correlation between symptom scores and disease scale in that the higher the scores, the more serious a patient will be. And patients with yang deficiency are usually with the symptom of phlegm obstruction, blood stasis, which is in accordance with the TCM theory "Weak pulse at yang and wiry pulse at yin ". The table can be used not only to evaluate patients with ACS disease, but also to describe and evaluate the efficacy of TCM in a more comprehensive and objective manner. Therefore, it can reflect the comprehensiveness and objectivity of TCM by comparison to that of the change of chest pain, the amount of nitroglycerin, ECG.2, Wutou Chishizhi Tang is safe and effective for ACS patients. Patients treated with TCM improve better than that in the control group, especially for "yang deficiency" and "heart qi deficiency" type.No patient got worse after treatment3. Animals experiments suggest a mild and non-significant effect of acute Wutou Chishi Zhi Tang on myocardial ischemia, and no improvement for the SOD, and other indicators of hydroxyl radical. So the author considers the possible mechanism may be the expansion of coronary spasm, but further studies would be needed in the future so as to find out the mechanism. During the experiment, rats show no arrhythmia, hematuria and so on, and no increasing trend of cTNI, which suggests that the drug is safe.4、This study used intravenous infusion of vasopressin in ischemic modeling, which have shown better effect than previously method used, but some rats came to hematuria due to larger dose of pituitary. The reason we think is that high-dose vasopressin may act not only on coronary but also on other vital artery such as the renal artery, mesenteric artery, the carotid artery and so on, so many important organs will be damaged during the injection, which may difficultly evaluate drug efficacy. I personally believe that vasopressin may not be the best medicine for making drug-producing- myocardial- ischemia model.5. The present research shows that Wutou Chishizhi Tang does not have the advantage in the improvement of chest pain in comparison to western medicine, but does have the advantage in overall syndromes. So while in acute period of ACS, useing TCM drugs may not improve the ischemic symptoms, but may have an improvement in terms of overall syndromes. The reasons that symptom scores improved in the standards have not yet reached the estimated standard may be due to the insufficient time for observation. Thus for the future TCM-related intervention researches, we should focus no more on myocardial ischemia change in the acute phase, but should extend the observation time, through which we may finally reflect the real value and assessment for TCM drugs used in CAD. Furthermore, describing TCM effect by means of life quality description maybe more appropriate, and thus can embody the remedial values of TCM.更多还原