| The combination of the modern disease diagnosis and the traditional syndrome differentiation is currently the major diagnostic method in the clinics of traditional Chinese medicine(TCM). In contrast to modern medicine, TCM has its unique theoretical system and TCM doctors have accumulated invaluable and rich experiences in the diagnosis and treatment of diseases in the thousands of years’ practice, which were recorded in the ancient Chinese medical literatures(ATCMLs). Because of the significant differences between TCM and modern medicine in the theoretical and terminological systems, it is difficult to learn from the recorded ancient TCM therapies when the diseases are identified according to the modern medical system. In order to solve this problem, this dissertation aims to use viral hepatitis as an example to build up the strategy to mine the diagnosis and treatment experiences of diseases from ATCMLs, and therefore, provide a platform for the development of new drugs from ancient TCM literatures.1. Aims, methods and scope of the studyThe aim of this study is to set up the strategy of data mining of knowledge of diseases from ATCML, and dig out the diagnosis and treatment experiences of viral hepatitis-related diseases recorded in ATCMLs to provide useful information to screen therapies of viral hepatitis from TCM. The scope of ATCMLs in this study focuses on the literatures of jaundice published in Ming and Qing dynasty, which was collected by taking the methods within philology and history. This study built up the database by the selected literatures according to the correlation between viral hepatitis and the related diseases in ATCMLs by symptomatology. The analysis of the database by the statistical methods like frequency analysis, correlation analysis, and cluster analysis reveals the diagnosis and treatment experiences of viral hepatitis-related diseases in Ming and Qing dynasty. Furthermore, the systematic analysis of anti-hepatitis B virus(HBV) activity of individual TCMs as well as the meta analysis of the contemporary clinical studies on hepatitis B provide pharmacological and clinical materials for backward reasoning of the mined knowledge of viral hepatitis-related diseases from ATCML.2. Results(1) This study established the correlation of viral hepatitis and the related diseases recorded in ATCMLs based on the statistics of the16symptoms from the research of epidemiology and symptomatology of viral hepatitis, which included jaundice, fatigue, loss of appetite, dark-colored urine, fever, nausea, vomiting, abdominal pain, abdominal distension, liver pain, chest congestion, constipation, loose stool, fainting, mental confusion, and sexual dysfunction. The inclusion and exclusion criteria of the ATCMLs on jaundice published in Ming and Qing dynasty for the database construction were set up on the basis of correlated symptoms.(2) The database of viral hepatitis-related medical records in Ming and Qing dynasty was built up based on the symptoms-directed inclusion and exclusion criteria. This database included211medical records, which recorded180Chinese medicinals totally and about11Chinese medicinals in average for each record. The frequency analysis by SPSS20.0showed that the most frequently used medicinals were poria cocos and capillary wormwood herb, the most frequently appeared properties were warmness and coldness, the most frequently appeared favor was bitterness, sweetness and pungency, and the most frequently appeared effects were hot-clearing and dampness-draining. The correlation analysis of highly frequently used medicinals(>20) showed that there were100kinds of significantly correlated medicinal combinations whose major effects were dampness-draining and hot-clearing, while the correlation analysis of lowly frequently used medicinal(>5,<20) showed that there were159kinds of significantly correlated medicinal combinations whose major effects were tonifying and replenishing. The cluster analysis showed that the82medicinals whose frequencies were above5could be clustered into two categories:the first category included dampness-draining and hot-clearing medicinals, and the other included tonifying and replenishing medicinals. In addition, the medicinal could be further clustered into three formula, which were Yinchen wuling powder, Mahuang lianqiao chixiaodou decoction, and Zhuye shigao decoction. The mechanisms of the viral hepatitis-related diseases in the database could be classified as jaundice with dampness-heat, jaundice with cold-dampness, jaundice with blood stasis, and jaundice with exterior attack, and almost70%of the literatures in the database recorded the mechanism which was jaundice with dampness-heat. The most frequently recorded symptoms were jaundice, abdominal distension and dark-colored urine. The correlation analysis showed that the significantly correlated symptom combinations were fever and loose stool, nausea and vomiting, fatigue and sexual dysfunction, dark-colored urine and constipation. The cluster analysis showed that the symptom "fatigue" was clustered with tonifying and replenishing medicinals, and the most clustered and correlated was ginsheng; the symptoms "dark-colored urine" and "constipation" were clustered with hot-clearing medicinal, and the most clustered and correlated were rheum palmatum, amur cork-tree bark, and cape jasmine fruit; the symptom "abdominal distension" was clustered with qi-regulating and digestant medicinals, and the most clustered and correlated were magnolia officinalis and betelnut peel; the symptom "liver pain" was clustered with phlegem resolving medicinal, and the most clustered and correlated were rhizoma pinelliae and inula japonica thumb; the symptom "sexual dysfunction" was clustered with kidney-tonifying medicinal, and the most clustered and correlated medicinal were eucommia bark and semen cuscutae. The mechanisms "jaundice with dampness-heat" and "jaundice with deficiency" were significantly correlated with the symptom "dark-colored urine", and the symptoms "fatigue" as well as "dysfunctional sex" separately. The mechanism "jaundice with dampness-heat" was clustered with hot-clearing and dampness-resolving medicinals, and the most clustered and correlated were scutellaria baicalensis and coptis root; the mechanism "jaundice with cold-dampness" was clustered with interior-warming and yang-tonifying medicinal, and the most clustered and correlated were radix aconiti and cinnamomum cassia; the mechanism "jaundice with deficiency" was clustered with tonifying and replenishing medicinal, and the most clustered and correlated were astragalus and radix paeoniae alba; the mechanism "jaundice with blood stasis" was clustered with blood-activating and tonifying medicinal, and the most clustered and correlated were common ginger and aangclica root. The cluster and correlation analysis of the database strongly suggest that the medicinal used by TCM doctors in Ming and Qing dynasty in the treatment of viral hepatitis-related diseases was correlated with the mechanisms. Furthermore, certain symptoms were crucial for the mechanism identification and could determine the medicinal composition in the prescription.(3) The typical characteristics of viral hepatitis natural history included "jaundice". and "infection". Here, this dissertation set up the database of the ATCMLs which recorded viral hepatitis related diseases with infectious characteristic, and57medical records were found according to the inclusion criteria. The number of medicinal used was55with the total frequency306, and there were5-6medicinals for each record in average. For the medicinals used in viral hepatitis-related diseases with infection characteristic in Ming and Qing dynasty, the most frequently used medicinals were capillary wormwood herb, cape jasmine fruit, and rheum palmatum; the most frequently appeared properties were coldness and warmness; the most frequently appeared favor was bitterness, pungency and lightness; the most frequently appeared effects were hot-clearing and dampness-draining. The correlation and cluster analysis suggested the major formulae applied in the treatment were Yinchenhao decoction, Xiaochaihu decoction, and Yinchen wuling powder. Furthermore, rheum palmatum was found to be the most important medicinal in the treatment of viral hepatitis-related diseases with infection characteristic in Ming and Qing dynasty. (4) This dissertation systematically analyzed and ranked the anti-HBV effect of individual Chinese herbs based on the research of individual TCMs in vitro and in vivo, which were published from1995to2012. Among76Chinese herbs, this study found compounds or extracts isolated from18Chinese herbs showing strong inhibitory effect on HBV DNA, HBeAg or HBsAg release with low cytotoxicity in HBV cell models, and agents from12Chinese herbs showed strong anti-DHBV effect in DHBV-infected ducks. In addition, the compounds isolated from rheum palmatum and scutellaria baicalensis displayed strong anti-HBV activity both in cell and animal models. Interestingly, most of the Chinese herbs showing strong anti-HBV activity belonged to hot-clearing and stasis-resolving medicinals. The Chinese herbs which were rheum palmatum, scutellaria baicalensis and radix bupleuri showed strong anti-HBV effect in pre-clinical studies, and they were highly frequently used not only in the treatment of viral hepatitis-related diseases in Ming and Qing dynasty, but also in the treatment of hepatitis B in the modern era. The statistic analysis of the medicinal used in the meta analysis of TCM clinical studies in the treatment of hepatitis B suggested the frequency of hot-clearing medicinal usage was1.7times more than that of tonifying and replenishing medicinals, which were significantly clustered with the mechanism "jaundice with deficiency", but negatively correlated with the mechanism "jaundice with with dampness-heat" in the database of ATCMLs which recorded viral hepatitis-related diseases. In parallel, the tonifying and replenishing medicinal exhibited low anti-HBV activity in virto and in vivo. These results suggested that the tonifying and replenishing medicinal may exert anti-HBV activity indirectly.3. The constructive points in this dissertation include:(1) This study set up the strategy of data mining of knowledge of diseases from ancient Chinese medical literatures by using viral hepatitis as an example.(2) This study established the correlation of viral hepatitis and the related diseases recorded in ATCMLs based on the statistics of symptoms from the research of epidemiology and symptomatology of viral hepatitis, and mined the related diagnosis and treatment experiences from TCM doctors in Ming and Qing dynasty from database construction.(3) This study established the correlation of viral hepatitis and the related diseases recorded in ATCMLs with infection characteristic based on the research of natural history of viral hepatitis, and analyzed the related diagnosis and treatment experiences from TCM doctors in Ming and Qing dynasty from database construction.(4) This study analyzed the mined knowledge of viral hepatitis-related diseases from ATCMLs in Ming and Qing dynasty in the backward reasoning manner by applying the systematic analysis of anti-HBV activity of individual TCMs which were published from1995to2012and the the meta analysis of the contemporary clinical studies on hepatitis B.This dissertation built up the strategy to mine the knowledge of diseases from ATCMLs, and statistically analyzed the diagnosis and treatment experiences of viral hepatitis-related diseases from literatures in Ming and Qing dynasty by applying this method. In face of new diseases, this strategy will provide a platform to screen the TCM therapies by learning from ancient TCM literatures. |
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