【作者】 陈杰；

【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】 动脉粥样硬化和缺血中风存在炎症反应、基质金属蛋白酶活性的改变。吸烟是脑血管病的危险因素,文献表明：吸烟通过炎症反应、促血栓作用、及改变基质金属蛋白酶活性等途径,导致动脉粥样硬化发生、发展及心脑血管事件的发生。因此,吸烟与中风预后有一定的相关性。十五课题表明,中医综合治疗方案切中中风病情、疗效确切,文章临床试验将研究此方案对缺血中风吸烟患者疗效评价指标的影响；益脑康胶囊是此法下产生的治疗缺血中风的有效方药,文章动物实验将探讨益脑康胶囊对动脉粥样硬化性缺血中风大鼠炎症反应机制的影响。临床试验目的中医综合疗法对吸烟的缺血中风患者疗效指标的影响方法病例来源于国家科技十五攻关项目的受试患者,以其中的吸烟患者和不吸烟患者为研究对象,探讨中医综合方案(A方案)和单纯西医治疗方案(B方案)对上述两种人群缺血中风疗效评价指标：脑卒中3个层次评定量表(残损水平：NIH量表、残疾水平：BI量表、残障水平：MRS量表)和生活质量量表(SS-QOL量表)与相应时点中医证候要素评价量表(SS-TCM量表)变化的影响。结果1、对于缺血中风吸烟患者：A、B方案对患者第7天、14天及21天NIH量表的影响均无统计学差异,P值分别为(0.623、0.314、0.199)。A、B方案对患者第21天、60天及90天BI量表、MRS量表的影响均无统计学差异,P值分别为(0.415、0.650、0.190)、(0.092、0.128、0.157)。A、B方案对患者第14天、21天、60天及90天SS-QOL量表的影响均无统计学差异,P值分别为(0.587、0.639、0.783、0.437)。A、B方案对患者第7天、14天、21天、60天及90天SSTCM积分对生活影响评分的影响均无统计学差异,P值分别为(0.268、0.595、0.902、0.378、0.176)。2、对于缺血中风不吸烟患者：A、B方案对患者第7天、14天及21天NIH量表的影响均无统计学差异,P值分别为(0.933、0.315、0.109)。A、B方案对患者第21天、60天及90天BI量表的影响均无统计学差异,P值分别为(0.915、0.505、0.091)。A、B方案对患者第21天、60天MRS量表的影响均无统计学差异,P值分别为(0.433、0.285),对第90天MRS量表的影响有统计学意义,P值为0.033。A、B方案对患者第14天、21天、60天及90天SS-QOL量表的影响均无统计学差异,P值分别为(0.914、0.648、0.388、0.283)。A、B方案对患者第7天、14天、21天、60天SSTCM积分对生活影响评分的影响均无统计学差异,P值分别为(0.693、0.061、0.106、0.060),对第90天SSTCM积分对生活影响评分的影响均有统计学差异,P值为0.005。结论1、对于缺血中风吸烟患者,在现有的观察期限内,中医综合方案和单纯西医方案对患者疗效评价指标的影响相当,但是随着时间的延长,相比较单纯西医方案,中医综合方案有提高患者疗效愈加明显的趋势。2、对于缺血中风不吸烟患者,在现有的观察期限内,中医综合方案改善患者第90天残障能力(MRS量表评分)、第90天SSTCM积分对生活影响评分的能力优于单纯西医方案,对其它疗效评价指标的影响相当,但是随着时间的延长,相比较单纯西医方案,中医综合方案有提高患者疗效愈加明显的趋势。3、从研究人群的一般特征及指标选取及评价时间点来看,相比较单纯西医方案,中医综合方案的优势在于：对具有伴发心脏病、糖尿病等慢性基础病、年龄相对较大、不吸患者有较好疗效,并且此疗效在一些随访时间较长的量表中显示更加明显。动物实验目的探讨益脑康胶囊对动脉粥样硬化性急性缺血中风大鼠脑组织MMP-9、TIMP-1活性、ICAM-1表达；血液ICAM-1含量的影响。方法115只大鼠随机分为正常组、动脉粥样硬化组(AS组)、急性中风组、预防用药组、益脑康组、立普妥组。建立动脉粥样硬化叠加急性缺血中风大鼠复合模型,采取预防性用药与治疗性用药相结合的方式灌胃治疗,预防用药组灌胃治疗贯穿整个造模前后,益脑康组和立普妥组在中风模型成功后灌胃治疗1周。通过观察用药后大鼠实验室检测项目(脑组织MMP-9、TIMP-1活性的测定、脑组织及主动脉ICAM-1的表达、血液ICAM-1含量的测定、脑组织含水量测定等)的变化,探讨益脑康胶囊对上述检测项目的影响。结果1、与正常组比较,动脉粥样硬化组大鼠血液中ICAM-1含量显著升高(P<0.01),主动脉ICAM-1的表达增强。2、与动脉粥样硬化组比较,中风模型成功时,大鼠血液中ICAM-1含量显著升高(P<0.01),脑组织ICAM-1的表达增强。3、与中风模型成功时比较,中风后1周,中风模型组大鼠血液中ICAM-1含量显著升高(P<0.01),脑组织ICAM-1的表达增强。治疗1周后,与中风组相比,预防组、益脑康组、立普妥组大鼠血液中ICAM-1的含量均显著降低(P<0.01),脑组织ICAM-1的表达减弱；预防组、益脑康组、立普妥组组间比较,大鼠血液中ICAM-1的含量无差异(P>0.05)。而与中风模型成功时比较,预防组、益脑康组、立普妥组大鼠血液中ICAM-1的含量无差异(P>0.05)。4、各组大鼠脑组织MMP-9活性的比较：中风治疗1周后,与正常组比较,中风组、预防组、益脑康组、立普妥组大鼠脑组织MMP-9的活性均显著升高(P<0.01)；与中风组比较,预防组、益脑康组、立普妥组大鼠脑组织MMP-9的活性均显著降低(P<0.01)；预防组、益脑康组、立普妥组组间比较,大鼠脑组织MMP-9的活性无差异(P>0.05)。5、各组大鼠脑组织TIMP-1活性的比较：中风治疗1周后,与正常组比较,预防组、益脑康组、立普妥组大鼠脑组织TIMP-1的活性均显著升高(P<0.01),中风组大鼠脑组织TIMP-1的活性无差异(P>0.05)；与中风组比较,预防组、益脑康组、立普妥组大鼠脑组织TIMP-1的活性均显著升高(P<0.01)；预防组、益脑康组、立普妥组组间比较,大鼠脑组织TIMP-1的活性无差异(P>0.05)。6、中风治疗1周后,与中风组比较,预防组、益脑康组、立普妥组脑组织含水量明显下降(P<0.01)；预防组、益脑康组、立普妥组组间比较,脑组织含水量差异无统计学意义。结论1、动脉粥样硬化和缺血中风存在炎症反应。2、益脑康胶囊能够有效降低动脉粥样硬化性缺血中风大鼠血液ICAM-1的含量。3、益脑康胶囊具有降低动脉粥样硬化性缺血中风大鼠脑组织MMP-9活性、升高脑组织TIMP-1活性的作用。4、益脑康胶囊具有降低动脉粥样硬化性缺血中风大鼠脑组织含水量的作用。5、益脑康胶囊抑制动脉粥样硬化性缺血中风大鼠炎症反应、减轻脑水肿的可能机制是：降低血液中ICAM-1含量以及降低脑组织MMP-9活性、升高TIMP-1的活性。更多还原

【Abstract】 There is inflammatory response and changes of matrix metalloproteinase activity in atherosclerosis and ischemic stroke. Smoking is a risk factor of cerebrovascular disease, literature shows that smoking leads to atherosclerotic and cardiovascular and cerebrovascular diseases through inflammatory response, effect of promoting thrombosis, changes of matrix metalloproteinase activity and so on. Thus, there is some correlation between smoking and the prognosis of stroke. The fifteenth project-research shows that integrated TCM therapy hit the stroke disease and do good effect. The clinical trail of paper will study the influence of the integrated TCM therapy on outcome assessments indexes. Yi Naokang capsule is an effective effective prescriptions in the treatment of ischemic stroke resulting from above-mentioned therapeutic theory. The animal experiment of paper will investigate the influence of Yi Naokang capsual on inflammatory reaction about rats with atherosclerotic ischemic stroke.The clinical trailObjectiveThe influence of the integrated TCM therapy on outcome assessments indexes about smoking patients with ischemic stroke.MethodThe cases were from patients in fifteenth project-research, selecting the smoking and non-smoking patients to investigate the influence of integrated TCM therapy(A plan) and simple western medicine program(B plan) on outcome assessments indexes for ischemic stroke, Namely three measuring scale levels about the disease(NIH, BI, MRS, SS-QOLand SS-TCM). Result1. For smoking patients with ischemic stroke:There is no statistical difference about score NIH in patients treated with A and B plan respectively on 7,14 and 21 days after entering the group. The statistical P are(0.623,0.314,0.199).There is no statistical difference about score BI and MRS in patients treated with A and B plan respectively on 21,60 and 90 days after entering the group. The statistical P are(0.092,0.128,0.157). There is no statistical difference about score SS-QOL in patients treated with A and B plan respectively on 14,21,60 and 90 days after entering the group. The statistical P are(0.587,0.639,0.783,0.437). There is no statistical difference about score SS-QOL in patients treated with A and B plan respectively on 14,21,60 and 90 days after entering the group. The statistical P are (0.587,0.639,0.783,0.437). There is no statistical difference about score of SSTCM affecting life in patients treated with A and B plan respectively on 7,14,21,60 and 90 days after entering the group. The statistical P are (0.268,0.595,0.902,0.378,0.176).2. For non-smoking patients with ischemic stroke:There is no statistical difference about score NIH in patients treated with A and B plan respectively on 7,14 and 21 days after entering the group. The statistical P are(0.933,0.315,0.109). There is no statistical difference about score BI in patients treated with A and B plan respectively on 21,60 and 90 days after entering the group. The statistical P are(0.915,0.505,0.091). There is no statistical difference about score MRS in patients treated with A and B plan respectively on 21 and 60 days after entering the group. The statistical P are(0.433,0.285). But there is statistical difference on the 90th day (P=0.033). There is no statistical difference about score SS-QOL in patients treated with A and B plan respectively on 14,21,60 and 90 days after entering the group. The statistical P are(0.914,0.648,0.388,0.283). There is no statistical difference about score of SSTCM affecting life in patients treated with A and B plan respectively on 7,14,21 and 60 days after entering the group. The statistical P are(0.693,0.061,0.106,0.060).But there is statistical difference on the 90th day(P=0.005).Conclusion1.For smoking patients with ischemic stroke:In the current observation period, the integrated TCM therapy and simple western medicine program have equivalent effects on outcome assessments indexes for patients. But with the time longer, compared with simple western medicine program, the integrated TCM therapy has the increasingly significant trend of improving the efficacy.2. For non-smoking patients with ischemic stroke:In the current observation period, for improving the 90th score MRS and score of SSTCM affecting life, the integrated TCM therapy make better than simple western medicine program. But there are no differences of other outcome assessments indexes between A and B plans. With the time longer, compared with simple western medicine program, the integrated TCM therapy still has the increasingly significant trend of improving the efficacy.3. According to the general characteristics of patients and the selection and time of evaluation about outcome assessments indexes, compared with simple western medicine program, the advantages of the integrated TCM therapy are that there is better efficacy for non-smoking ischemic stroke patients with heart disease, diabetes and other chronic underlying diseases, relatively older.The clinical effect shows more apparent in some scales with longer follow-up time.ObjectiveTo investigate the influence of Yi Naokang capsule on content of MMP-9, TIMP-1 and expression of ICAM-1 in brain tissue and the level of serum ICAM-1 about rats with atherosclerotic ischemic stroke.Method115 rats were divided into 6 groups randomly:normal group, arterioscl-erosis group, ischemic stroke group, preventive medication group, Yi Nao kang group and Lipitor group. Duplicating atherosclerotic ischemic stroke model, and the rats were administered by intragastric injection using preventive and therapeutic usage. Preventive medication group was irrigated the stomach once a day before and after modeling, Yi Naokang group and Lipitor group were irrigated the stomach once a day for seven days. At the last day of irrigating the stomach, observing the changes of experiment items(the activity of MMP-9 , TIMP-1 and the expression of ICAM-1 in brain tissue,the content of serum ICAM-1, and brain watercontent), investigating the influence of Yi Naokang capsule on forging index. Result1.Cmpared with normal group, the content of serum ICAM-1 was improved significantly(P<0.01)in arteriosclerosis group and the expression of ICAM-1 in aorta was more obviously.2. Compared with arteriosclerosis group,the content of serum ICAM-1 was improved significantly(P<0.01)in ischemic stroke group and the exp-ression of ICAM-1 in brain tissue was more obviously.3.The content of serum ICAM-1 was improved significantly(P<0.01)and the expression of ICAM-1 in brain tissue was obviously one week after ischemic stroke. One week at the end of treatment, compared with ischemic stroke group , the content of serum ICAM-1 was decreased significantly (P<0.01) in preventive medication group,Yi Naokang group and Lipitor group, and the expression of ICAM-1 in brain tissue was decline, but there is no statistical difference in the content of serum ICAM-lamong preven- tive medication group,Yi Naokang group and Lipitorgroup(P>0.05). Compared with ischemic stroke group one week before treatment, there is no statis- tical difference in the content of serum ICAM-lamong ischemic stroke group, preventive medication group, Yi Naokang group and Lipitor group (P>0.05).4. The comparison of the activity of MMP-9 in brain tissue for each gr-oup:One week after treatment of stroke, compared with normal group, the act-ivity of MMP-9 in brain tissue was improved significantly(P<0.01)in pre-ventive medication group,Yi Naokang group and Lipitor group.At the end of treatment, compared with ischemic stroke group, the activity of MMP-9 in brain tissue decreased obviously(P<0.01)in preventive medication group, Yi Naokang group and Lipitor group,but there is no statistical difference(P>0.05)among preventive medication group, Yi Naokang group and Lipitor group.5. The comparison of the activity of TIMP-1 in brain tissue for each group: One week after treatment of stroke, compared with normal group, the activity of TIMP-1 in brain tissue was improved significantly(P<0.01)in preventive medication group, Yi Naokang group and Lipitor group, but there is no statis-tical difference(P>0.05)in ischemic stroke group.At the end of treatment, compared with ischemic stroke group, the activity of TIMP-1 in brain tissue increased obviously(P<0.01)in preventive medication group, Yi Naokang group and Lipitor group, but there is no statistical difference(P>0.05)among pre-ventive medication group, Yi Naokang group and Lipitor group. 6. One week after treatment of stroke, compared with ischemic stroke group, the brain water content decreased obviously (P<0.01)in preventive medication group, Yi Nao kang group and Lipitor group,but there is no statis-tical difference(P>0.05)among preventive medication group, Yi Naokang group and Lipitor group.Conclusion1. Inflammatory responce exists between artherosclerosis and ischemic stroke.2. Yi Nao kang capsule can reduce the content of serum ICAM-1 and Expression of ICAM-1 in brain tissue in rats with atherosclerotic ischemic stroke effectively.3. Yi Nao kang capsule can reduce the activity of MMP-9 but enhance the activity of TIMP-1 in brain tissue in rats with atherosclerotic ischemic stroke effectively.4. Yi Nao kang capsule can reduce brain water content in rats with Atherosclerotic ischemic stroke.5.The possible mechanism of depressing inflammatory responce and cerebral edema by Yi Naokang capsule was that it can reduce the content of serum ICAM-1, the expression of ICAM-1 in brain tissue,the activity of MMP-9 in brain tissue and improve the activity of TIMP-1.更多还原