【作者】 王丽颖；

【导师】 王永炎； 王忠；

【作者基本信息】 中国中医科学院 ， 中医内科学， 2011， 博士

【摘要】 证候具有“内实外虚”的特征。所谓“实”,是指最能反映该病机的权重最大的关键内容,是群体在某一特定病变过程中所具有的共性规律,是干预的依据。“虚”则指具体某一患者所表现出的一系列个性化症状信息,它涵盖了所有能够表达个性化的内容,对干预原则和方法具有一定的影响作用。因此,药物干预证候的症状靶位不同,对证候的疗效判定也具有不同的意义。尼莫地平法是临床研究中评价证候疗效的常用方法。采用这种方法评价两种药物治疗冠心病心绞痛血瘀证的证候疗效,治疗前后两种药物的证候改善率均为50%,认为两种药物的证候疗效是相等的,但如果一种药物改善的主要是“胸痛”,另一种药物改善的主要是“脉细涩”。根据证候“内实外虚”理论,第一种药物治疗冠心病心绞痛血瘀证的效果要明显优于第二种药物。因此,本研究提出评价证候疗效,首先要进行证候的解构,明确证候的“内实”,分析证候“内实”的动态变化趋势。证候是随着时空的变迁而演化的过程流,随着时间的推移和状态的变化,证候有可能发生轻重程度的变化以及由此及彼的改变。证候的“内实外虚”也不是固定不变的,也具有随着时间的变化而不断变化的趋势。分析证候整体、证候“内实”以及单一症状的动态变化趋势,有利于探索证候变化的拐点,评价证候疗效,分析药物干预的症状靶位。因此,本研究在理解王永炎院士证候“内实外虚”理论的基础上,以心血康胶囊治疗冠心病心绞痛血瘀证的随机、双盲、多中心临床试验为研究模型,重视证候的整体性、结构性、动态性和非线性特征,为探索中医证候疗效评价方法进行了初步的尝试。1、研究目的：通过对证候的药效学解构,分析证候整体及其结构的动态变化趋势,探索随着时间的变化药物对证候和证候“内实”动态变化的影响,为进一步探索证候状态变化的拐点、评价中医证候临床疗效提供方法学方面的支撑。2、研究方法：本研究以心血康胶囊治疗冠心病心绞痛血瘀证的随机、双盲、多中心临床试验的数据作为研究对象,采用潜在类别模型对冠心病心绞痛血瘀证进行解构,分析冠心病心绞痛血瘀证的潜在类别及其“内实”部分。根据数据类型,针对有序分类变量,采用可以处理非正态、非独立数据的分析重复测量资料的常用方法——广义估计方程对不同药物干预下冠心病心绞痛血瘀证潜在类别的变化和构成冠心病心绞痛血瘀证的单一症状的变化进行分析;针对证候、证候“内实”等多维数据的变化,采用相似度分析方法,通过相似度的变化探索不同药物干预下的证候和证候“内实”动态变化趋势,在此基础上,以非线性混合效应模型拟合相似度随着时间变化的过程。3、研究结果3.1基线分析通过对入组时冠心病心绞痛轻重程度、血瘀证的轻重程度、理化检查指标等的基线水平比较分析,发现治疗组和对照组两组之间具有可比性。3.2一般统计分析分别采用t检验和单变量重复测量资料方差分析探索不同时间点和不同药物干预下中医证候的变化情况,t检验结果发现除第2周外,其余时间点的中医证候总分与基线的差异有统计学意义,3个月随访中医证候总分在两组间的差异是有统计学意义的。单变量重复测量资料方差分析结果发现：治疗后2周至随访3个月各时点,证候证候总分与基线的差异有统计学意义,治疗后4周、6周、8周及3个月随访的中医证候积分与基线的差异在A、B’两组之间有统计学意义。采用t检验和单变量重复测量资料方差分析不同时间点和不同药物干预下中医证候的变化情况,发现两种统计分析方法得到的结果存在一定的差异,后者是分析重复测量资料常用的方法之一,得到的结果比较可靠。3.3冠心病心绞痛血瘀证的解构采用潜在类别模型对冠心病心绞痛血瘀证进行解构,分析冠心病心绞痛血瘀证证候的潜在分类以及证候的“内实”部分。结果发现：冠心病心绞痛血瘀证的潜在分类包括两类,一类为轻证,一类为重证,其中轻证的概率是0.6320,重证的概率是0.3680。胸痛、胸闷、唇色紫暗、舌质紫暗是冠心病心绞痛血瘀证的“内实”部分。3.4证候的动态变化与证候状态变化的拐点采用夹角余弦法、Dice系数法、Jaccard系数法分别计算不同时间点不同组别的冠心病心绞痛血瘀证相似度值,以相似度值代替证候积分分析证候的动态变化,以非线性混合效应模型,探索证候动态变化趋势,分析证候状态变化的拐点。结果发现：不同方法计算的证候相似度值总体变化趋势基本一致,即随着治疗时间的延长,A、B两组证候相似度值均逐渐下降；证候的变化受到心绞痛积分、证候“内实”、试验中心的影响,说明地域不同,A、B两种药物对“血瘀证”的疗效存在一定的差异。心绞痛程度越重,药物对“血瘀证”的疗效越差；A、B两组证候变化存在差异,A药物治疗冠心病心绞痛血瘀证的疗效略优于B药物；以相似度值等于0.8作为界点,计算相此时药物使用时间,结果显示群体临床试验过程中,A药使用7.28周,B药使用10.72周时,入组时的冠心病心绞痛血瘀证状态发生变化。3.5证候潜在类别的动态变化通过潜在类别分析和广义估计方程分析,探索证候潜在类别的变化,结果显示：第2、4、6、8周和3个月随访的潜在类别与基线相比,均有统计学意义,并且相邻两个时间点潜在类别的差异也具有统计学意义。同时,在第4周时,时间与组别存在交互作用。说明A、B两种药物均可以缓解冠心病心绞痛血瘀证,并且随着治疗时间的延长,冠心病心绞痛血瘀证缓解越明显。A、B两组相比,在治疗后的第4周时潜在类别的变化有统计学差异。3.6证候“内实”的动态变化采用夹角余弦法、Dice系数法、Jaccard系数法分别计算不同时间点不同组别的冠心病心绞痛血瘀证“内实”相似度值,以相似度值代替证候积分分析证候“内实”的动态变化,以非线性混合效应模型,探索证候“内实”动态变化趋势。结果发现：随着治疗时间的延长,A、B两组证候“内实”的相似度值均逐渐下降,说明A、B两种药物都可以干预证候的“内实”部分。A药物干预下证候“内实”相似度的变化受到试验中心的影响,与心绞痛积分无关,说明无论心绞痛程度轻重,A药物均能较好的改善血瘀证的“内实”部分,并且在不同的研究中心,药物对“证候”内实部分的影响不同,说明地域不同,A药物对“血瘀证”内实的疗效存在一定的差异。B药物干预下证候“内实”相似度的变化受到心绞痛积分和试验中心的影响,说明地域不同,B药物对“血瘀证”内实的疗效存在一定的差异。同时,心绞痛程度越重,B药物对“血瘀证”内实的疗效越差。A、B两组证候“内实”的变化存在差异,A药物干预冠心病心绞痛血瘀证“内实”的疗效略优于B药物。3.7单一症状的动态变化分别采用秩和检验和广义估计方程对冠心病心绞痛血瘀证单一症状分析,秩和检验结果发现：除2周、4周B组的脉细涩外,其他时间点各项中医症状评分与其自身前后的差异有统计学意义。4周、6周、8周时舌质紫暗、脉细涩在两组间的差异有统计学意义,随访3个月时胸痛、舌质紫暗与脉细涩在两组间的差别有统计学意义。广义估计方程分析显示：6个单一症状在治疗后2周、4周、6周、8周、随访3个月与基线相比以及相邻2个时间点相比,症状积分变化有统计学意义,说明A药和B药都具有改善冠心病心绞痛血瘀证相关症状的作用,并且治疗时间越长,药物的疗效越好。同时发现,第20周胸痛的变化、2周、4周、8周及3个月随访心悸的变化、4周起舌质紫暗的变化在两组之间存在差异。采用秩和检验和广义估计方程分析不同时间点和不同药物干预下中医症状的变化情况,发现两种统计分析方法得到的结果存在一定的差异。后者是分析重复测量资料常用的方法之一,得到的结果比较可靠。4、结论4.1症状、证候潜在类别、证候的“内实”以及证候整体都具有时空演变的特征。证候疗效可通过分析证候“内实”的动态变化、证候整体的动态变化和单一症状的动态变化进行评价。4.2采用潜在类别模型等方法分析不同症状对证候的贡献度,可以用来探索证候的“内实”,潜在类别模型是诠释证候“内实外虚”特征的方法之一4.3研究资料属于重复测量数据时,要充分考虑不同观测时间之间的相关性,注重采用适合于重复测量数据的统计方法进行分析。4.4采用相似度分析结合非线性混合效应模型可有效地分析证候的高维性和非线性特征,探索证候状态变化的拐点。4.5本研究揭示了证候具有结构性和临界性的特征,为辨证论治疗效评价方法学提供了部分的理论依据和技术支撑。本研究首次提出对证候进行解构,指出证候“内实”的变化是证候疗效评价的主要指标,并采用潜在类别模型探索证候的“内实外虚”,利用相似度分析和非线性混合效应模型探索药物干预下证候的动态变化趋势及证候状态变化的拐点。课题采用相似度分析和NONMEM分析证候的动态变化趋势,是符合证候特征的研究方法,但由于证候的复杂性,我们的研究还需深入,开展进一步的研究。证候“外虚”的变化与证候疗效评价的关系,并未探讨,是本课题下一步主要研究的方向。更多还原

【Abstract】 Syndrome has the characteristics of "internal stability and external flexibility". The "internal stability" means the key syndrome that reflects pathogenesis and the common character in the group, which is the basis of intervention. The "external flexibility" means the individual syndrome, which can affects the principle and method of intervention. Therefore, if the syndrome target is different, the significance to evaluate efficacy is different. Nimodipine is the common method to evaluate the syndrome efficacy, which doesn’t conform to the characteristics of "internal stability and external flexibility". So the study proposed that deconstruction to syndrome and analysis to "internal stability" dynamic changes is the key part to evaluate syndrome efficacy.Syndrome is the dynamic process which varies with time, and so are the"internal stability" and "external flexibility" parts of Syndrome. The recognization of the dynamic change trend of syndrome especially "internal stability" and "external flexibility" part of Syndrome is the important foundation for the application into the clinical practice and enhancement of the treatment effect of TCM, and the critical process to evaluate the efficacy of the syndrome. Based on the theory of "internal stability and external flexibility" proposed by Pro. Wang Yongyan, a randomized, double-blind, multi-center trial of Xinxuekang Capsule for blood stasis syndrome of angina pectoris of coronary heart disease was conducted to find an approach to evaluating the effect in TCM syndrome.Object:To discuss the effect of the drug for Syndrome and the "internal stability" part of Syndrome under the change of time by clinical annotation to "internal stability and external flexibility" of Syndrome and its dynamic change, which would provide new method to evaluate the efficacy of the syndrome.Method:Based on the randomized, blind, multi-center clinical trial data of Xinxuekang capsule for the treatment of blood stasis syndrome in angina pectoris of coronary heart disease (CHD-AP-BSS),the study determined the latent class and the"internal stability" part of CHD-AP-BSS according to the latent class modeling (LCM). According to the class of the data, the study analyzed the change of latent class and single symptom of CHD-AP-BSS by Generalized Estimating Equations (GEE).And then the study discussed the dynamic change trends of syndrome and "internal stability" part of syndrome by similarity analysis under the different interventions based on the dynamic changes of dimensional data such as syndrome and "internal stability" part of syndrome. At last, the study applied NONMEM into the analysis of the changes in similarities with time.Results:1. According to the comparisons of the baseline in A and B2 groups, there were not any significant differences in CHD-AP, BSS and other test results between the two groups.2. By t-test analysis, the study found that the changes of the syndrome score between 4w,6w,8w or 3m after treating and baseline were significant, respectively. The changes of the syndrome score between A and B group at the 3 m after treating were significant, respectively.By single factor analysis of variance of repetitive measurement, the study found that syndrome score decreased by time. The changes of the syndrome score between 2w,4w,6w,8w or 3m after treating and baseline were significant, respectively. The changes of the syndrome score between A and B group at the 4w,6w,8w or 3m after treating were significant, respectively.The results of t-test analysis and single factor analysis of variance of repetitive measurement is different. The latter is the common method to analyze the repetitive measurement data, which the results is dependable.3. Based on the results of LCM to CHD-AP-BSS, the study found that the patients can be classified to "the mild" and "the serious". The symptoms like chest pain, chest distress, dark purple lip, dark tongue were relatively more stable than other symptoms in CHD-AP-BSS, which is the "internal stability" part of CHD-AP-BSS.4. Based on the results of similarity analyses to CHD-AP-BSS at different times and in different groups by Cosine method, Dice method and Jaccard method, the study found that the total change trend of the similarity values was similar by different methods, although the details of similarity values were different in different methods, which shows that the similarity values were decreased gradually in both A and B groups with the time of treatment. It suggested that both A and B group can improve the blood stasis syndrome.Analyzing syndrome changing trend with time by nonlinear mixed effected model, the research found that similarity of syndrome changed with time in both A and B groups. The change of the similarity was influenced by angina pectoris scores, "internal stability" part of syndrome, et al. At the same time, the factor "group" was related to the change of syndrome, which suggested that the change of syndrome between A group and B group was different significantly.Take the similarity values equal to 0.8 as the boundary point, the study found that at that time, A is used 7.28w and B is used 10.72w, which is considered to the change of CHD-AP-BSS.5. By LCM and GEE, the research found that the latent class in 2w,4w,6w,8w and 3m was significantly different compared with the baseline, respectively. At the 4w, the factor "time" and "group" existed interaction. The results illustrated that CHD-AP-BSS alleviates gradually. The change of latent class in 4w after treatment between A group and B group is different significantly.6. Based on the results of the similarity values of "internal stability" part of CHD-AP-BSS at different time and in different groups by Cosine method, Dice method and Jaccard method, the research found that although the similarity values were different by different methods, its total change trend was similar in each method. It suggested that the similarity values were decreased gradually in both A and B groups with the time of treatment, which illustrated that both A and B group can improve the "internal stability" part of CHD-AP-BSS.According to the analysis of the correlation between the change of "internal stability" part of CHD-AP-BSS and time by NONMEM, the results showed that similarity of "internal stability" part of syndrome changed with time. The factor "test centre" was an influence factor for the similarity change of "internal stability" part in both A and B group. The factor "angina pectoris scores" affected the similarity change of "internal stability" part of CHD-AP-BSS only in B group. The difference of similarity change of "internal stability" part of CHD-AP-BSS between group A and group B was significant.7. According to the analysis of the single symptoms of CHD-AP-BSS by rank test, the study found that the changes of symptom scores of chest pain, chest distress, palpitation, dark purple lip, tongue and pulse manifestations in 2w,4w,6w,8w and 3m were significantly different significantly compared with the baseline except pulse manifestations in 2w,4w in B group. The differences of chest pain in 20w, palpitation in 2w,4w,8w and 20w, tongue picture from 4w to 20w between group A and group B were significant.According to the analysis of the single symptoms of CHD-AP-BSS by GEE, the research found that the changes of symptom scores of chest pain, chest distress, palpitation, dark purple lip, tongue and pulse manifestations in 2w,4w,6w,8w and 3m were significantly different significantly compared with the baseline, and the differences between the symptoms scores at the two adjacent time points were also different significantly. It indicated that both drug A and B could improve the symptoms of CHD-AP-BSS and the longer the patients were treated, the better the efficacy would be got. The differences of chest pain in 20w, palpitation from 2w to 20w, tongue picture from 4w to 20w between group A and group B were significant.The results of rank test analysis and single factor analysis of variance of repetitive measurement is different. The latter is the common method to analyze the repetitive measurement data, which the results is dependable. Conclusion1. Symptoms contributing to the syndrome, the latent class and the "internal stability" part of the syndrome and the syndrome itself are in constant change with space and time. The effect in TCM syndrome can be evaluated by analyzing the change of contributing symptoms, the "internal stability" part of the syndrome and the syndrome itself。2. LCM can analyze the contribution of symptom to syndrome, which can find out the "internal stability" part of the syndrome. LCM is one of the effective methods to annotate, the "internal stability" part of the syndrome.3. The data type should be considered carefully during analysis. When the data belongs to repeated measurement data, the relationship between data in different observation point must be considered. The analysis method should be fit for repeated measurement data.4. The integration method of similarity analysis and NONMEM can better display the high dimensionality and nonlinear character of syndrome and find out the inflection point of syndrome change.5. The study suggested that syndrome has the character of constitutive property and criticality, which provides part theoretical foundation and technical support for efficacy evaluation of treatment based on syndrome differentiation.The study proposed that the analysis to the dynamic change of "internal stability and external flexibility" of syndrome was the entry point to evaluate the effect in TCM syndrome for the first time. Determine the "internal stability and external flexibility" of syndrome by LCM. Determine the dynamic change trend and the knee point of the change in syndrome by similarity analysis and NONMEM. The approach of analysis to dynamic change trend by similarity analysis and NONMEM is suitable for syndrome study, which is one of the entry points to evaluate the effect in TCM syndrome. But due to the complicated property of the syndrome, the further study is needed in the future.2. The study suggested that the change of "internal stability" part of syndrome was the main indicator to evaluate the effect in TCM syndrome. However, the relationship between the change in "external flexibility" part of syndrome and the effect of syndrome isn’t discussed in this study, which is the direction to further study.更多还原