【作者】 余锋；

【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】 背景毒壅血瘀为急性冠脉综合征的基本病机所在,根据导师多年临床经验及复习近年来多项临床研究显示,解毒活血法可不同程度地减轻机体的炎症反应,调节脂质代谢,提高机体抗缺氧能力和抗细胞凋亡的作用,减轻心肌细胞凋亡,提高患者生存质量。目的评价解毒活血法治疗急性冠脉综合征1个月后临床疗效和安全性,旨在初步观察解毒活血法干预急性冠脉综合征患者的临床疗效及作用机制,并对中医药的疗效作出客观评价；实验方面,采用大鼠垂体后叶素造模心肌缺血动物模型,以解毒活血法进行干预,并设立对照组,进一步明确解毒活血法在急性冠脉综合征中的治疗作用,从而为临床的治疗效果提供更有力的实验证据。方法对符合本研究纳入条件的80例急性冠脉综合征患者随机分为治疗组和对照组,对照组予以西医规范化治疗,治疗组在西医规范化处理基础上加用解毒活血汤进行干预。在严格按照临床研究设计的基础上,对纳入两组患者进行组间比较及治疗前后比较,通过分析治疗前后疗效指标、中医证候疗效指标、主要疗效指标、实验室炎症指标及肝肾功能等情况的变化,进行治疗前后的比较,安全性指标及不良反应、实验室检查和心电图等。进而分析治疗前后实验室指标及血清IL-1、TNF-a、SCD40L及MMP-9等相关资料的变化关系,通过统计学分析、探讨解毒活血法对急性冠脉综合征患者作用的机制所在。动物实验方法：以大鼠垂体后叶素造模心肌缺血为动物模型,以心酶、心电图及炎症介质标志物IL-1、TNF-a作为观察指标,观察解毒活血汤高、中、低剂量组(32g、16g、8g/kg)的治疗效果,采用ELISA法测定IL一1β、TNF-α的含量。结果1、临床研究(1)两组患者治疗后心绞痛疗效分析：治疗4周后,治疗组患者中显效24例,改善13例,无效3例；对照组治疗4周后显效17例,改善15例,无效8例,总有效率比较治疗组总有效率为92%,对照组为80%,两组相比有显著统计学意义见(P<0.05)。(2)两组患者治疗前后心绞痛发作情况对比：治疗组在治疗前心绞痛发作频率为(12.60±2.17)次／周,心绞痛发作持续时间(9.50±1.72)分／次,对照组心绞痛发作频率为(13.90±2.60)次／周,心绞痛发作持续时间(9.10±2.13)分／次,两组相比无显著差异(P>0.05),具有可比性。治疗4周后,治疗组发作频率(4.00±1.41)次／周,持续时间(3.90±1.29)分／次,对照组为(5.70±1.42)次／周,持续时间(5.20±1.32)分／次,两组心绞痛发作频率以及持续时间较治疗前均有显著降低,但治疗组降低更明显,组间比较有统计学意义(P<0.05)。(3)两组患者接受治疗期间心血管事件发生次数比较：接受治疗干预期间,治疗组的心血管事件事件发生次数比对照组的发生次数明显要少,但主要是一般心血管事件事件的差异,而严重心血管事件(不包括终末事件如患者死亡)两组发生次数无明显差异。(4)两组患者治疗前后中医临床症状积分比较：治疗前在症状积分方面,治疗组与对照组比较差异无统计学意义(P>0.05)；治疗后症状积分差值,治疗组高于对照组组,差异有显著性统计学意义(P<0.01)；治疗前后症状积分比较,二组治疗后均较治疗前降低,差异有显著性统计学意义(P<0.01)。(5)两组患者APACHEⅡ评分比较：入院时治疗组APACHE II评分平均为(15.10±3.47)分,对照组APACHEⅡ评分平均为(14..50±3.95)分,两组评分无显著差异(P>005)。纳入本研究的两组患者在疗程2周时各项主要疗效指标治疗组与对照组比较无显著性异(P>0 05),但和入院时评分比较有显著性差异(P<0 05)；在治疗4周时,两组评分都呈下降趋势,但治疗组组下降更明显,治疗组与对照组比较有显著差异(P<0.05)。(6)两组硝酸甘油停减情况：治疗后对照组与治疗组相比无明显统计学意义(P>005)。2、实验室指标分析：(1)两组患者治疗前后心电图变化：治疗组干预四周后显效13例,改善16例,无效11例,对照组显效14例,有效18例,无效8例,两组比较无显著性统计学差异(P>0.05)。(2)两组治疗前后血脂变化比较：完成本研究的两组患者治疗后血脂较治疗前均有明显改善,具体表现在TC、TG、LDL-C降低,HDL-C升高,但治疗组和对照组相比,治疗组血脂改善幅度更加明显,组间比较有统计学意义(P<0.05)。(3)两组治疗前后超敏CRP (hs-CRP)变化：治疗前两组hs-CRP(单位：mg／1)T值：0.207,P值=0.838>0.05,两组比较无统计学意义,具有可比性。治疗后两组hs-CRP值较治疗前均有明显降低,但治疗组降低更加明显,组间比较有有统计学意义(P<0.05)。(4)治疗前后白细胞计数比较：治疗前两组WBC计数比较无统计学意义,具有可比性。治疗后两组WBC均有明显降低,但治疗组下降更明显,组间比较具有统计学意义(P<0.05)。两组治疗前后差值比较无统计学意义(P>0.05)。(5)两组治疗前后纤维蛋白原(FIB)变化情况：两组治疗后FIB均较治疗前有明显降低,差异有统计学意义(P<0.05),但组间比较无明显统计学意义(P>0.05)(6)两组治疗前后IL-1,TNF-a、SCD40L及MMP-9的变化：经统计分析,两组患者治疗前血中IL-1、TNF-a、SCD40L及MMP-9各项指标比较,差异无显著性意义(P>0.05)；治疗后组间比较治疗组各项指标均低于对照组(P<0.05)。其中治疗4周后,对照组血清MMP-9较治疗前略有下降,但均无显著性差异,治疗组MMP-9水平不但较治疗前有显著下降(P<0.01),两且较对照组亦有显著下降(P<0.01),说明治疗组在改善患者炎症指标方面优于对照组。3.安全性评价：治疗前后,对接受本研究的80例患者行血、尿、大便常规及肝、肾功能等检查,其中对照组治疗后4周有1例患者出现ALT轻度升高,经予以护肝药口服,1月后复查肝功正常,1例患者出现轻度血色素下降,未予特殊处理；治疗组5例出现恶心、纳差等胃肠道不适症状未予特殊处理。实验中未发现其他患者肝肾功能异常等情况。4、实验研究：大鼠垂体后叶素造模心肌缺血模型结果提示在心电图变化情况比较上,解毒活血汤高剂量组可改善垂体后叶素引起的心肌缺血,与模型组相比差异有显著性(P<0.05),低剂量显示改善倾向,但无统计学差异；各组大鼠实验室检测指标变化情况上,模型组心酶指标明显高于空白对照组,而解毒活血汤低、中及高剂量组可以显著改善心肌酶CK、LDH,在高剂量组尤其明显,有显著统计学意义(P<0.01)；血清lL-1β、TNF-α检测结果,模型组血清1L-1β、TNF-α明显高于空白对照组,而解毒活血汤低、中及高剂量组可以显著降低该两项指标,在高剂量组此种作用尤其明显,有显著统计学意义(P<0.01)。结论(1)应用解毒活血法治疗ACS在改善患者临床症状及症候分级量化上均有一定作用,能很好的控制病情,疗效优于单纯西药治疗组；(2)解毒活血法在改善ACS患者的实验室指标方面与对照组相比均有显著性差异,提示可能通过调节血脂和降低血清炎症因子水平、改善内皮功能等途径起到抗炎和抗动脉粥样硬化的作用；(3)动物垂体后叶素心肌缺血模型显示解毒活血法能明显改善心肌缺血,降低血清IL—1、TNF—α等促炎因子水平,在高剂量组这种作用尤为明显,为解毒活血法取得的临床疗效提供了充分的实验依据支持。更多还原

【Abstract】 backgroundThe basic pathogenesis of Acute Coronary Syndrome (ACS) was pyretic toxicity and blood stasis.according to the Professor chenjinghe’s theory of acute coronary syndrome, who is famous in the first hospital affiliated to Guangzhou university of Chinese Medicine, as well as a number of clinical studies has shown in recent years. The detoxicating and promoting blood circulation therapy plays an important role in the the treatment of ACS by alleviating the body’s inflammatory response in a certain degree, regulating lipid metabolism, enhancing the body resistance to hypoxia and anti apoptosis,r educing cardiomyocyte apoptosis, so as to improve the quality of life in the patients with ACS.ObjectiveTo objectively assess the clinical efficacy and safety of the detoxicating and promoting blood circulation therapy after 1 month treatmen and it’s mechanism, thereby make an objective evaluation for the efficacy of Chinese medicine;as far as the experiment was concerned, the ecectrocardiograph(ECG) was observed in myocardial ischemia rats induced by pituitrin(Pit) through lingual vein, the contents of CK, LDH, IL-1β、TNF-αin serum was assayed respectively,in myocardial ischemia mice which pituitrin was peritoneal injected. the control group was established, for the purpose of definiting this method’s effect (the detoxicating and promoting blood circulation therapy) in the treatment of ACS, so as to provide powerful experimental evidence for the clinical treatment. Method:80 cases with Acute coronary syndrome were collected and randomly divided into treatment and control groups, the control group was treated with Standard treatment method of Western medicine, while the treatment group was treated with standard Western medicine methos and the detoxicating and promoting blood circulation decoction. Therapeutic effect was evaluated according to the standard by Assessment on electrocardiograph(ECG), nitroglycerin consumption, symptom effect of Chinese Medicine, laboratory indicators of inflammation, Liver and kidney function before and after 4 weeks treatment between the two groups, analyze the correlative laboratory parameters such as the IL-1、TNF-a、SCD40L, MMP-9 in serum through statistical analysis so as to explore the mechanism, The side effect, The incidence rate of main cardiovascular lesion in the patients during treatment were recorded as well.the animal experiment research:the ecectrocardiograph(ECG) was observed inmyocardial ischemia rats induced by pituitrin(Pit) through lingual vein and intervened by the detoxicating and promoting blood circulation in high, medium and low dose (32g、16g、8g/kg) the contents of CK, LDH, IL-1β、TNF-αin serum was assayed respectively, in myocardial ischemia mice which pituitrin was peritoneal injected. subjects. sCD40L and TNF-a levels were measured by Enzyme-linked immunosorbent assay.Result(1)clinical therapeutic efect analysis of angina pectoris after treatment in the two groups:24 cases markedly effective, improved in 13 cases,3 cases invalid after four weeks intervention in the treatment group, the total effective percentage was 92%. while the cases was 17,15,8 rspectively in the control group, and the total effective percentage was 80%, there was distinct significance between the two group (P<0.05)(2)Angina onset conparison before and after treatment between the two groups:the frequency and duration of angina attacks in the treated group before intervention was (12.60±2.17) times/week, (9.50±1.72) minutes /time,while it was (13.90±2.60) times/week, (9.10±2.13) minutes/time respectively in the control group, there was no significant difference between the two group (P>0.05). the frequency and duration of angina attacks in the treatment group after intervention was (4.00±1.41) times/week, (3.90±1.29) minutes/time, while in the control group it was (5.70±1.42) times/week, (5.20 ±1.32) minutes/time, There was obvious improvement in the two group, but the decrease margin in the treated group was more significant than that of the controlled group(p<0.05).(3)The incidence rate of main cardiovascular events:compared with the control group, the times of cardiac incidents of the treated group was much less, but the difference comes from the times of common cardiac incidents, in terms of the times of serious cardiac incidents, there was no significant difference between the two group.(4)The syndromes score of TCM:after being treated,the scores of clinical symptoms of the patients in two groups were reduced much and the clinical symptoms of two groups were improved effectively, when compared with the controlled group, the reduction of the scores of clinical symptoms in the treated group was more significant(P<0.01).(5)the acute physiological and chronic healthy evaluationⅡ(APACHEⅡ) scores between the two group:the APACHEⅡscore was (15.10±3.47) in the treatment group, and it was (14..50±3.95) in the control group, there was no significant difference between the two group before intervention and after 2 weeks treatment, but the significance was obvious when compared with admission.- There was apparent improvement in the two group after 4 weeks treatment, but the improvement in the treated group was more significant than that of the controlled group(p<0.05).(6)Nitroglgcerin withdrawal in the two group:there was no statistical significance between them after treatment (P>0.05)2. laboratory test analysis(1)The electrocardiograph(ECG) changes after treatment:13 cases markedly effective, improved in 16 cases,11 cases invalid after four weeks intervention in the treatment group, while The cases was 14,18,8 rspectively in the control group. there wase no obvious significance between the two group (P>0.05).(2)The lipid level before and after the treatment:after the treatment, the lipid level of each group was both improved than that of the before, Such as the total cholesterol, total triglyceride, low density lipoprotein declined and high density lipoprotein rised. however, the improvement extent of the lipid level in the treated group was more significant than that of the controlled group(p<0.05).(3)The level of hypersensitive C-reactive protein(hs-CRP):after the treaatment, the level of hs-CRP of each group was both lower than that of the before(p<0.01), but the decrease margin of the hs-CRP level in the treated group was more significant than that of the controlled group, (p<0.05).(4)The level of leukocytes after treatment:there were no significance between the two group before treatment(P>0.05), while the difference were obvious after treatment between the two group(P<0.05) although the WBC count obviously declined in the control group. The difference value before and after treatment showed no statistically significant difference.(5)The level of fibrinogen(FIB):there were obvious decline after treatment in the two group(P<0.05), while difference between two group showed no significant difference (P>0.05)(6)Changes and relations betwvee IL-1, TNF-a、SCD40L and MMP-9 in patients of ACS after 4 weeks treatment:there was no statistical significance(P>0.05) between the two group before treatment, while the Serum IL-1, TNF-a、SCD40L and MMP-9 level was obviously lower in the treatment group than in control group after treatment((P<0.05). there was no significant difference in the level of MMP-9 before and after treatment in the control group, however the level of MMP-9 was obviously declined in the treatment group after treatment, and the difference was also visible between the two group. so the treatment group was superior to the control group in respect of inflammatory indicators improvement.3. Observation of adverse reactions:1 patient had slightly elevated ALT and one case with slight low hemoglobin were observed in the control group after 4 weeks treatment,and the former’s liver function got right 1 month later after took hepatinica orally,no special treatment measures was adopted for the latter.5 cases with nausea, poor appetite in the treatment group, other patients had no adverse reactions after treatment.4. experimental study:the ecectrocardiograph(ECG) changes in myocardial ischemia rats induced by pituitrin(Pit) through lingual vein and intervened by the detoxicating and promoting blood circulation in high, medium and low dose shows high-dose group could improve pituitrin-induced myocardial ischemia much better than the model group (P<0.05), Low dose group showed improvement, but without significant difference.in terms of the changes in laboratory parameters, the cardiac enzyme, IL-1β、TNF-αwas much higher in the model group than the blank control group, and the low, middle and high dose group could improve cardiac enzyme and IL-1β、TNF-αin serum significantly, this change was particularly evident in the high dose group (P<0.01).Conclusion(1) The detoxicating and promoting blood circulation therapy had much better curative effect than the simple western medicine group for the ACS paients, particularly for the improvement in clinical symptoms. This therapy was safe and reliable, with no obvious toxicity;(2) For the treated group,there was an obvious improvement in their laboratory parameters than the control group;(3) the myocardial ischemia rats model induced by pituitrin(Pit) through lingual vein shows the detoxicating and promoting blood circulation therapy had a marked improvement in myocardial ischemia, reduction of serum IL-1, TNF-αpro-inflammatory cytokines, The clinical efficacy of Chinese medicine in curing ACS had to be further support by high-quality experimental trials. The suppression on the inflaumatory reaction of ACS may be one mechanism of TCM in treating patients with ACS.更多还原