【作者】 周喜燕；

【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】 背景中风病被称为“人类健康的头号杀手”,具有高患病率、高病死率、高致残率和高复发率的特点,是一种严重危害人类健康的全球性问题。脑血管病是我国人口死亡的第二位原因,其中1／3的患者死亡,另1／3的患者终身残疾,给社会和家庭都增加了不少的负担。治疗和防治中风病,首要的问题是对中风病发病危险因素的研究,通过控制这些危险因素来防治中风病。糖尿病是中风病的重要危险因素之一,也是动脉粥样硬化性脑血管疾病的独立危险因素之一。因此从治疗危险因素的角度对中风病进行治疗,并探讨其可能的作用机理,是降低致残率和死亡率,提高患者生活质量和防止复发的重要途径之一。中医药在治疗中风病方面有独到的优势,面对多因素所致的中风危急重症病人,临床上采取以辨证论治为核心的综合治疗方案,发挥综合效能,才能取得最好的疗效。本课题所用中医综合治疗方案包括中风协定方(益脑康胶囊),华佗再造丸和灯盏细辛注射液。目的本研究旨在采用多种统计方法,对“十五”数据库进行回顾性分析,探讨中医综合治疗方案对急性缺血中风合并糖尿病阴类证患者在神经功能缺损程度、残障程度、日常生活能力、中医症征积分等方面的治疗作用；并通过动物实验,来探讨益脑康胶囊治疗急性缺血中风的疗效,从胰岛素抵抗角度来探讨益脑康胶囊治疗急性缺血中风的可能作用机制。方法本研究临床部分依托国家“十五”攻关项目“急性缺血中风辨证规范和疗效评价的示范研究”数据库,利用SPSS 13.0统计分析软件进行回顾性分析。观察在中医综合方案治疗组中,合并糖尿病和不合并糖尿病的急性缺血中风患者其中医症征积分、神经功能缺损水平、残障水平、生活自理能力等方面的改善情况；观察有糖尿病病史的急性缺血中风患者在经中医综合治疗方案或西医基础治疗后,其中医症征积分、神经功能缺损水平、残障水平、生活自理能力等的改善情况,来探讨中医综合治疗方案对急性缺血中风合并糖尿病阴类证患者的治疗效果。本研究实验部分将115只大鼠随机分为正常组、动脉粥样硬化组、复合模型组、益脑康预防组、益脑康治疗组、立普妥治疗组。采用高脂膳食喂养法复制动脉粥样硬化大鼠模型,在此基础上复制缺血再灌注大鼠模型,从行为学、生化指标、病理等方面对模型进行评价；干预上分别给予预先灌服益脑康胶囊(预用益脑康组)和正常治疗时点的益脑康胶囊、立普妥胶囊。本文分别从行为学(ZeaLonga评分法评价神经行为学的改变)、生化指标(血糖、胰岛素、脂联素、游离脂肪酸,并计算胰岛素抵抗指数)、免疫组化(颈动脉脂联素表达水平的异常)、脑组织病理、大鼠脑含水量等方面来评价益脑康胶囊的治疗作用。观察益脑康胶囊对上述各项指标的作用。从胰岛素抵抗角度来探讨益脑康胶囊治疗急性缺血中风大鼠的可能作用机制。结果临床部分：中医综合治疗组中合并糖尿病和不合并糖尿病的急性缺血中风患者经治疗后,两组患者在神经功能缺损程度、残障水平、日常生活能力、中医症征积分(严重程度、对生活的影响)方面差异均无统计学意义(P>0.05)。合并糖尿病的急性缺血中风患者分别经中医综合治疗方案和西医基础治疗后,结果：神经功能缺损程度,与基线NIHSS总分相比较,两组在第21天的评分降幅有显著性差异,具有统计学意义(P<0.05)；残障水平,两组21天GOS比较差异有统计学意义(P<0.05)；日常生活能力,在第21天,随访的60天和90天,BI指数均无显著性差异(P>0.05)；中医症征积分中对生活的影响方面,在21天、90天比较差异有统计学意义(P<0.05)。由以上可以看出中医综合治疗方案可以改善患者神经功能缺损；减轻21天的残障水平；可以减轻治疗后21天和90天的中医症征；提高患者90天随访的生活能力；随着随访时间的延长,中医综合治疗方案有提高患者生存质量的趋势。可见此中医综合治疗方案治疗急性缺血血中风合并糖尿病阴类证患者确有疗效,值得进一步探讨。实验部分：本研究采用高脂饲料喂养诱发高血脂、胰岛素抵抗大鼠,在此基础上复制急性缺血再灌注大鼠模型,灌服益脑康胶囊治疗7天后,治疗前后对比,益脑康胶囊可降低模型鼠的血糖、胰岛素、胰岛素抵抗指数,立普妥可降低模型鼠的胰岛素水平,二者对脂联素水平影响不大,立普妥可降低模型鼠游离脂肪酸水平,预用益脑康胶囊可有效降低模型鼠游离脂肪酸水平。治疗后三个干预组组间比较,益脑康降血糖效果优于立普妥,三组在降低胰岛素水平、胰岛素抵抗指数、脂联素方面差异无显著性,在降低游离脂肪酸方面,预用益脑康组优于益脑康组,与立普妥组比较差异无显著性。模型鼠颈动脉脂联素免疫组化显示,治疗前复合模型组血管壁脂联素的阳性表达强度(2+)弱于正常组(3+),经药物干预后,各干预组血管壁脂联素的阳性表达强度均明显增强,其中预用益脑康组血管壁脂联素的阳性表达强度(4+)高于益脑康组和立普妥组(3+)。说明益脑康胶囊和立普妥在改善模型鼠胰岛素抵抗状态的同时,增加了血管壁脂联素的表达。且预用益脑康组增强明显,说明预防用药效果显著。脑组织病理检测显示：治疗结束后,复合模型组脑组织水肿加重,炎症明显。干预各组跟同期复合模型组相比,皮质层神经元修复明显,炎症消失,水肿减轻,其中预用益脑康组比益脑康组神经元修复和水肿减轻明显,提示预防用药治疗急性缺血中风效果显著。脑组织含水量,预用益脑康组、益脑康组、立普妥组均较复合模型组下降,但三组之间比较无统计学意义。结论临床部分：中医综合治疗方案可以改善急性缺血中风合并糖尿病阴类证患者的神经功能缺损程度,减轻残障水平；可以降低治疗后的中医症征积分；提高患者生活能力；随着随访时间的延长,中医综合治疗方案有提高患者生存质量的趋势。实验部分：益脑康胶囊能降低急性缺血中风大鼠游离脂肪酸水平,且预用益脑康效果显著；降低胰岛素抵抗指数；提高模型鼠颈动脉脂联素的阳性表达,预防用益脑康效果优于短时间用药；改善大鼠脑组织水肿,修复受损脑组织皮质神经元,减轻血管周围水肿。实验结果表明益脑康胶囊可能是通过改善急性缺血中风大鼠的胰岛素抵抗来发挥其治疗作用的,且预防用药效果优于短时用药。更多还原

【Abstract】 BackgroundStroke is known as "the first killer of human health", with high prevalence, high mortality, high morbidity and high recurrence rate. It is a serious public health problem of global issues. Cerebrovascular disease is the second cause of death in China, of which 1/3 of the patients died, the other 1/3 of patients had permanent disabilities, increasing burden considerably to social and family.Studing on stroke disease risk factors for treatment and prevention of stroke is the first question, by controlling these risk factors to prevent stroke. Diabetes is a major risk factor for stroke and one of the independent risk factor for atherosclerotic cerebrovascular disease. So treating cerebral infarction from the risk factors, and exploring its possible mechanism which is an important way to reduce the morbidity and mortality, improve quality of life and to prevent recurrence. Chinese medicine have unique advantages in the treatment of stroke. A comprehensive treatment program can obtain the best results, when we face the storke patients of many critical clinical syndrome. The comprehensive treatment based on traditional Chinese medicine consists of including yinaokao capsule, Huatuozaizao pill and Fleabane injection.PurposeThis study was designed to retrospectiviy analysis of the database by using a variety of statistical methods. Discussing the therapeutic effect of the comprehensive treatment based on traditional Chinese medicine for acute ischemic stroke patients with diabetes mellitus for neurologic impairment, disability, activities of daily living, traditional Chinese Medicine Syndrome and Symptoms. We copy the rat model of acute ischemic stroke based on atherosclerosis through animal experiments, and assess it from the behavioral, biochemical, immunohistochemistry and pathology; Mainly abserving the effect of Yinaokang capsule on blood biochemical parameters about insulin resistance and adiponectin levels, expression of adiponectin in vascular wall and pathological changes in brain tissue. We try to explain the possible action mechanism about Yinaokao capsule treating acute ischemic stroke from the insulin resistance.MethodClinical research:We analyzed retrospectively the database by the statistical analysis software SPSS13.0. Observing the effect of acute ischemic stroke patients with diabetes and without diabetic in the group of treated by the comprehensive treatment based on TCM. The effect consists of the level of neurological impairment, disability level, ADL, BI, their stroke symptom of TCM. Observing the effect of the acute ischemic stroke patients with or without a history of diabetes treated by the compretensive treatment based on TCM or Western medicine treatment. We discuss the effect of the compretensive treatment based on TCM for acute ischemic stroke with diabetes for their stroke symptom of TCM, the level of neurological impairment, disability level, BI, ADL.Animal experiment,115 rats were randomly divided into normalcontrol group, atherosclerotic group, compound model group, the Yinaokang capsule prevention group, Yinaokang capsule treatment group, Atorvastatin Calcium capsule treatment group., We replicate the rat models of atherosclerosis by feeding them high fat diet, then copy the ischemia model based on atherosclerosis rate models. Evaluating the model from the behavioral, biochemical, pathological and other aspects. We give Yinaokang Capsule to the the Yinaokang capsule prevention group in advance, and Yinaokang Capsule, Atorvastatin Calcium capsule to the other groups in normal treatment time. We evaluate the effect of the Yinaokang Capsule treatment from the behavior (Zea Longa neurological evaluation score), biochemical (glucose, insulin, adiponectin, free fatty acids, and calculated insulin resistance index), immunohistochemistry (adiponectin expression level in carotid artery expression), brain pathology, brain water content and so on. We try to explain the possible action mechanism about Yinaokao capsule treating acute ischemic stroke from the insulin resistance.ResultClinical part:For the comprehensive treatment based on TCM group with diabetes and non-diabetic patients of acute ischemic stroke after treatment, Results:There is no significantly difference in neurologic impairment, disability level, activities of daily living, Stroke symptom score of TCM between the two groups patients(P>0.05). After treated by the comprehensive treatment based on TCM or western medicine treatment for the acute ischemic stroke patients with diabetes. We can obtain that there are significant differences in decline, with statistically significant (P<0.05), compared with the baseline NIHSS score in the first 21 days for the degree of neurological impairment scores. There is significant difference between the GOS score (p<0.05) for disability levels between two groups in 21 days; BI index is not significant difference (P>0.05) on the first 21 days, following 60 days and 90 days;Stroke syndrome of TCM about life in 21 days,90 days has the statistically significant difference (P<0.05).It is seen that the comprehensive treatment based on TCM can improve neurologic impairment; to reduce the level of 21-day disability; to reduce the 90-day ADL after treatment;to reduce the 21-day and 90-day SSTCM; to improve the living capacity of patients up to 90 days; There is the trend of improving the quality of life of patients treated by the comprehensive treatment based on TCM. It is worth further research to the comprehensive treatment based on TCM.Experimental part:We feed the rats high fat diet to induce hyperlipidemia-insulin resistant rats, based on which reproducing the acute ischemia-reperfusion rat models in this study, which according to the pathogenesis of human ischemic stroke. Yinaokang capsule can reduces the blood glucose level, insulin level, insulin resistance index of the rat models compared before and after treatment; Atorvastatin Calcium capsule can reduce the insulin levels of the rat model, both medicines have little effect on the level of adiponectin. Atorvastatin Calcium capsule can reduce the level of free fatty acid of the rat model;the Yinaokang capsule prerusing can reduce the level of free fatty acids in rats. Three treatment groups are compared with eath other. The effect of Yinaokang capsule is better than Atorvastatin Calcium capsule for reducing the level of blood glucose. There is no significant difference between the three groups eath other in reducing insulin levels, insulin resistance index, adiponectin. The preusing Yinaokang effect of the reduction of free fatty acids better than the Atorvastatin Calcium capsule. no significant differences.Adiponectin Immunohistochemistry of the rats’carotid artery showes that positive adiponectin expression (2+) in the rats’vascular wall of compound model group weaker than the normal group (3+) before treatment. The positive expression of adiponectin is significantly increased strength than before in all of intervention groups after drug intervention. Expression of adiponectin in strength (4+) of the perusing Yinaokng group more strong than the other groups (3+) among them. We can see that Yinaokang capsule and Atorvastatin Calcium capsule can increase the expression of adiponectin in vascular wall, while improving insulin resistance of the rat model, And the expression of adiponectin of preusing Yinaokang group is enhanced more significantly than the other two groups.Pathological examination of brain tissue showed:the brain tissue of composite model group has serious edema and inflammation after treatment. There are significant cortical neurons repaired, inflammation disappeared, edema alleviated for intervention groups which compared with composite model in the same time. The effect is more better of perusing Yinaokang group than Yinaokang group, which suggests that preventive treatment of acute ischemic stroke effect is remarkable.Brain water content of the three intervention groups is decreased than of composite model group. But there is no statistical significance among the three groups.ConclusionClinical part:The comprehensive treatment of TCM can improve neurologic impairment degree, reduce disability levels, improve life ability, reduce SSTCM of the acute ischemic stroke with diabetic patients; The comprehensive treatment of TCM can improve the quality of life of patients with the trend.Experimental part:Yinaokang capsule can reduce the free fatty acid levels of ischemic stroke rats, and pre-using Yinaokang group’effect more better; Yinaokang capsule can significantly reduce the insulin resistance index, improve the adiponectin expression of the rats’carotid, improve the brain issue edema, repair the damaged cortical neurons of brain, and reduce the perivascular edema. The experiment results show that the treatment effect of Yinaokang by improving insulin resistance state, and prevention of drug better than the short-term medication.更多还原