【作者】 秦秀德；

【导师】 黄燕；

【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：中风(stroke)是指一切在供应脑组织血液的血管壁病变或血流障碍的基础上发生的缺血或出血及其引起的短暂或持久、局部或弥漫的脑损害。中风病具有高发病率高致残率、高致死率、高复发率,低治愈率等特点。我国每年有195万新发生的卒中病人,每年有156万人死于脑卒中,生存的脑卒中病人达500万-700万人。对于发展中的中国,这无疑是个沉重的社会及家庭负担。因此对中风病防治的研究一直是医疗领域研究的热点和重点。脑血管疾病和心脏病排在人类致死病因的前三位,并且心脏病是中风的一个危险因素,二者在病理生理机制方面也有诸多的共同之处。探讨二者的关系一直是临床及基础研究的热门课题。中医药对疾病的治疗具有多靶点,多方位的特点。脑脉1号是广东省中医院刘茂才教授治疗中风病多年的经验方,其针对中风阴类证的病机气虚血瘀,痰瘀阻络而设,具有益气活血、化痰通络的作用,已被开发为广东省中医院院内制剂并广泛应用于临床,并且临床疗效显著,深得患者的好评,深入了解其治疗中风的作用机理意义重大。目的：本课题临床研究部分是在国家科技部十五攻关课题“急性缺血中风辨证规范与疗效评价的示范研究”(任务书编号：2004BA721A02)数据库的基础上进行。拟一方面从中医综合方案与基础治疗方案治疗前后中风后患者神经功能缺损、残障和生存质量、中医症征相关积分等多角度评价中医综合方案对心脏病基础急性缺血性中风患者疗效情况,另一方面从前后时点各种积分的对比评价中医综合方案治疗对心脏病基础的急性缺血中风患者的疗效。动物实验部分拟就益脑康对动脉粥样硬化及动脉粥样硬化基础上的急性缺血性中风SD大鼠的血脂、ox-LDL、ICAM-1、VEGF等指标进行研究,以期部分阐述其作用机制。方法：本研究临床部分利用SPSS13.0统计分析软件对十五攻关课题“急性缺血中风辨证规范与疗效评价的示范研究”数据库中采用中医综合治疗方案和西医基础治疗方案的具有心脏病基础的急性缺血性中风阴类证患者的心脏病罹患情况进行描述性统计,对其BI评分、GCS评分、NIHSS评分及中医方面的相关评分情况进行统计学分析,并对心脏病基础的急性缺血性中风阴类证患者中采用中医综合治疗方案的各时点的各种评分进行前后配对对比分析。动物实验部分选取体重180g±20g SD雄性大鼠115只,采用随机数字表将115只大鼠随机分为A组(正常组)15只；B～E组(模型组)100只。其中C组为动脉粥样硬化组、D组为复合模型组、B组为益脑康预防组、E组为益脑康治疗组、F组为立普妥治疗组)。B、C、D、E、F组共100只大鼠,在第8天开始一次性VD3腹腔注射后开始给养高脂饲料复制AS模型,第65天,除C组外均采用ET-1 MCA附近注射法复制AIS模型。观察造模后大鼠的一般状态,第74天,每组大鼠随机抽取10只采血采用酶联免疫吸附试验(ELISA法)测定血脂及ox-LDL、ICAM、VEGF浓度,每组2只采集脑组织HE染色观察脑组织病理改变情况。结果：临床研究：①明确有心脏疾病的病人达到了106例,占所有病例的19.73%,其中有明确的冠心病心绞痛及心肌梗塞病史的病人共计60例,占诊断明确的心脏病病人的56.60%,占纳入的缺血性中风阴类证病人的11.55%；②A、B两组心脏病基础的急性缺血性中风阴类证患者不同时点的NIHSS、BI、SS-QOL、中医症征积分症状严重程度评分、中医症征积分对生活影响评分、中医症征积分总分评分比较均无显著性差异(P>0.05)；③中医综合治疗方案对有无心脏病基础的两组各时点NIHSS评分组间比较,基线时两组间比较有统计学差异(P<0.05),7天、14天、21天时比较差异无统计学意义(P>0.05)。两组各时点BI评分组间比较在21天时差异无统计学意义(P>0.05),在60天、90天比较时差异有统计学意义(P<0.05)。两组各时点SS-QOL评分组间比较,在14天、21天比较两组差异均无统计学意义(P>0.05),但在60天、90天比较有显著性差异(P<0.05)。两组各时点中医症征积分症状严重程度评分组间比较,在0天、7天时差异无统计学意义(P>0.05),14天、21天、60天、90天时两组间比较差异均有统计学意义(P<0.05)；两组各时点中医症征积分对生活影响评分组间比较,在0天时差异无统计学意义(P>0.05),在7天、14天、21天、60天及90天时差异有统计学意义(P<0.05)；两组各时点中医症征积分总分评分组间比较,在0天、7天两组间比较差异无统计学意义(P>0.05),在14天、21天、60天、90天时差异有统计学意义(P<0.05)。④A组心脏病基础的急性缺血性中风阴类证患者NIHSS、BI、SS-QOL、中医症征积分症状严重程度评分、中医症征积分对生活影响评分、中医症征积分总分评分前后时点配对比较,差异均有统计学意义(P<0.05)。实验研究：①预用益脑康组的血脂指标TCHO, TG、LDL、HDL、ApoA与动脉粥样硬化组相比均具有显著的统计学差异。预用益脑康组的ox-LDL、ICAM、VEGF水平与动脉粥样硬化组相比差异均具有统计学意义。且在降低TG、HDL上预用益脑康组及益脑康组与动脉粥样硬化组相比有统计学意义,而立普妥组未得出与前述两组相似的统计学意义。中药组与立普妥组相比在改善血脂相关指标方面没有得出统计学方面的差异,但预用中药组及益脑康组在降低TCHO、TG、LDL-C方面显示出与立普妥组在数值方面的优势。②预用益脑康组、益脑康组及立普妥组在降低TCHO、LDL-C及升高ApoA方面与动脉粥样硬化组及AIS组相比在统计学方面均有显著的差异；预用中药组及益脑康组在降低TCHO、TG、LDL-C方面显示出与立普妥组在数值方面的优势。预用益脑康组、益脑康组和立普妥组的ox-LDL水平与AS组及AS基础AIS组相比差异均具有显著的统计学意义(P<0.05)；预用益脑康组与动脉粥样硬化组的ICAM相比差异具有显著的统计学意义(P<0.05),预用益脑康组、益脑康组及立普妥组的ICAM水平与AIS组相比差异具有显著的统计学意义(P<0.05)；预用益脑康组、益脑康组和立普妥组的VEGF水平与动脉粥样硬化组和AIS组相比差异均具有显著的统计学意义(P<0.05)。临床研究：①本课题的卒中患者中具有较高的冠心病患病率；②中医综合防治方案在改善缺血性中风阴类证患者的神经功能缺损、生活能力、残障、生存质量、中医症征积分等方面并未显示出与西医基础治疗方案的统计学差异；③心脏病基础的缺血性中风患者的临床症状在发病后的不同时点均重于无心脏病基础的患者；中医综合治疗方案对无心脏病基础的缺血性中风阴类证患者在前两周就可以得到较好的评分结果,但对心脏病基础的患者大多在两周后评分改善才趋于加快。说明由于心脏病的影响,有心脏病基础的患者需要干预较长的时间才能达到与无心脏病基础的病人一致的效果；④通过BI评分、GCS评分、NIHSS评分及中医症征积分等各方面积分的自身前后时点配对比较表明中医综合治疗方案对心脏病基础的急性缺血性中风阴类证患者具有良好的治疗效果。实验研究：①益脑康可以通过降低TCHO、TG、LDL水平而调高具有保护性及对抗动脉粥样硬化作用的HDL、ApoA改善脂质代谢,并通过降低ox-LDL、ICAM、VEGF水平从而部分程度上阻止动脉粥样硬化的发展。②益脑康能显著降低AS基础的AIS大鼠的ox-LDL、VEGF、ICAM水平,推断益脑康对缺血性中风的治疗效果可能与调节血脂代谢及对动脉粥样硬化形成发展过程中的ox-VEGF、ICAM的抑制有关。更多还原

【Abstract】 Background:Stroke refers to brain ischemic or hemorrhage based on blood vessel wall lesion or blood flow disorders,which cause temporary or persistent、local or diffused brain damage. It is a kind of disease of high incidence、high morbidity、high mortality、high recurrence rate and low cured rate. China has 1.95 million of new stroke patients each year, and 1.56 million people died of stroke,5-7 million people survive of cerebral apoplexy. To a developing country, it is undoubtedly a heavy burden to the society and patients’family. Therefore the research of stroke prevention and therapy is always a hotspot in the medical field. Cerebrovascular disease and heart disease are ranked in the first three main causes of death, and heart disease is a risk factor for stroke. Cerebrovascular disease and cardiovascular disease have many common in the pathophysiological mechanisms. Exploring their clinical and basic relationship has been the hot topic all the while. TCM is a kind of medicine of curing disease from more capable of targets and aspects. YiNaokang is an experienced formula of Guangdong hospital of TCM’s famous professor LiuMaocai for curing stroke,it has a function of supplementing qi and activating blood circulation eliminating phlegm and freeing channel and has been exploited to be the hospital’s preparations and been widely used in clinical and clinical curative effect is distinct, consequently it is of great significance to further study its mechanism of curing stroke.Objective:This dissertation is made up of two parts, the first part was clinical research and the second was animal experiment. The clinical research part is based on the Ministry of Science and Technology’s 10th five year science research project "Demonstration Research of Acute Ischemic Stroke’s Syndrome Differentiation and Therapeutic Effect Evaluation" (NO.2004BA721A02)’s database. Its main purpose is to evaluate the TCM comprehensive plan’s therapeutic effect on these acute ischemic stroke patients who once have heart disease through statistic their NIHSS、BI、SS-QOL score and SSTCM related scores and compared them with Western Medicine’s foundational scheme. Animal experiments is designed to study how the YiNaokang affect the atherosclerosis SD mices’and AS based acute ischemic stroke SD mices’blood cholesterol、ox-LDL、ICAM-l、VEGF、etc, so as to explain its mechanism.Method:This study’s clinical part based on the Ministry of Science and Technology’s 10th five year science research project "Demonstration Research of Acute Ischemic Stroke’s Syndrome Differentiation and Therapeutic Effect Evaluation" (NO.2004BA721A02)’s database, firstly analysis and describe the patients who has heart disease, then statistic their BI、NIHSS、SS-QOL score and SSTCM related scores to compare the therapeutic effect of TCM comprehensive treatment and western medicine’s basic treatment, at the same time, pair the back and forth time of the different kinds of scores of TCM comprehensive treatment group’s so as to evaluate the TCM comprehensive treatment’s effect on them.Animal experiments part:select male SD rats weighted 180g±20g, using random number way to divide them into A group (normal) 15;B-E group (model) 100, among them group C is atherosclerosis group、D is composite group、B is Yi Naokang foregoing group、E is YiNaokang group、F is lipitor group. At the 8th day the 100 rats of groupB、C、D、E、F would be given intraperitoneal injection of VD3 one-time and then begain to supply with high fat feed to copy AS model, at the 65th day, inject ET-1 near the MCA area except group C to copy AIS model. Observe the general condition of them, at the 74th,10 rats would be picked out randomly to draw blood so as to test (ELISA way) blood lipids and LDL、ox-LDL、ICAM、VEGF concentration, pick out 2 randomly from each group to observe the brain pathological change.Result:Clinical research:①Of all patients,106 patients have heart disease, occupied 19.73%,60 have coronary heart disease or angina or miocardial infarction, occupied 56.60% of all the patients with heart disease,11.55% of all the 537 patients;②NIHSS、BI、SS-QOL、TCM related scores of AIS patients with heart disease between A, B groups have no significant statistical difference (P>0.05);③Treated with TCM comprehensive method, between the AIS patients with and without heart disease, the NIHSS scores have significant statistical difference(P<0.05) at the baseline, have no significant statistical difference on the day 7th、14th、21th; the BI scores have significant statistical difference (P<0.05) on the day 60th、90th, have no significant statistical difference on the 21th day (P>0.05);SS-QOL score have no significant statistical difference on the 14th、21th day (P>0.05), have significant statistical difference(P<0.05) on the day 60th、90th; SSTCM-Severity score have no significant statistical difference on the 0th、7th day (P>0.05), have significant statistical difference(P<0.05) on the day 14th、21th、60th、90th; SSTCM-Influence on day-life have no significant statistical difference on the 0th day (P>0.05), have significant statistical difference on the day7th、14th、21th、60th、90th (P<0.05); SSTCM-Total Score have no significant statistical difference on the 0th、7th day (P>0.05), have significant statistical difference on the day 14th,21th、60th、90th(P<0.05).④The different kinds of scores of AIS patients with heart disease in the TCM comprehensive treatment group compared back and forth time all have significant statistical difference.Experiment research:①The YiNaokang foregoing group’s TCHO、TG、LDL、HDL、ApoA are significant statistically different compared with AS group. The YiNaokang foregoing group’s ox-LDL、ICAM、VEGF level are significant statistically different compared with AS group, and in lowering TG、HDL, YiNaokang foregoing group and YiNaokang group are significantly statistically different compared with AS group. Chinese traditional medicine showed numerical advantage over lipitor group in reducing TCHO and TG, LDL-C.②In reducing TCHO、TG、LDL-C and rising ApoA, the YiNaokang foregoing group、YiNaokang group and lipitor group have significant statistical difference compared with AS and AIS group. YiNaokang foregoing group、YiNaokang group showed numerical advantage over lipitor group in reducing TCHO、TG and LDL-C. YiNaokang foregoing group、YiNaokang group and lipitor group have statistical significant difference compared with AS group and AIS group in lowering ox-LDL. YiNaokang foregoing group、YiNaokang group and lipitor group have significant statistical difference compared with AIS group in lowering ICAM. YiNaokang foregoing group、YiNaokang group and lipitor group have significant statistical difference compared with AS group and AIS group in VEGF level.Conclusion:Clinical research:①Stroke patients with higher prevalence of coronary artery disease;②The TCM comprehensive treatment doesn’t show significant statistical difference compared with western medicine’s basic treatment on patients with and without heart disease;③The symptoms are obviously heavier on the AIS patients with heart disease than those without heart disease in different time; The TCM comprehensive treatment show good effect on AIS patients without heart disease in the first 2 weeks, but show effect on AIS patients with heart disease after the first 2 weeks.④The TCM comprehensive treatment show good effect on the AIS patients with heart disease through comparing the different kinds of scores of AIS patients with heart disease back and forth time.Experiment research:①YiNaokang could prevents atherosclerosis devel-opment through reducing TCHO、LDL、TG、ox-LDL、ICAM、VEGF and rising HDL、ApoA level.②YiNaokang can significantly decrease AIS SD rats’s ox-LDL, ICAM and VEGF level, so it is inferred that YiNaokang’s treatment effect on ischemic stroke is probably through regulating lipid metabolism and lowering ox-LDL、VEGF、ICAM in the process of atherosclerosis’formation and development.更多还原