【作者】 付先军；

【导师】 管华诗；

【作者基本信息】 中国海洋大学 ， 药物化学， 2009， 博士

【摘要】 21世纪是海洋的世纪,新的海洋药用资源大大增加,丰富了海洋中药的资源种类。如何加快研发速度,将海洋新的药用资源尽快应用到临床是现阶段海洋中药研究面临的重大问题。目前海洋中药的研究多集中在单味药的化学成分以及粗提物的分离提取和药效研究等层次,不能解决海洋中药研发中面临的应用问题。本论文根据海洋中药几千年的发展规律,在继承前人用药经验和对海洋中药认识的基础上,结合现代新的科学技术,在中医药理论的指导下,借鉴陆地中药的发展轨迹,采用多学科相互融合、渗透,选择归肺经中药及肺系方剂的研究作为突破口,在前人研究成果的基础上,以大样本量的中药化学与生物药效信息为基础,通过文献检索收集了数百种归肺经中药及肺系方剂化学成分、临床功效、药理作用等方面的信息资料数十万条,创造性的引进数据挖掘及化学信息技术,结合化学成分分析、药理研究及临床研究等实验方法,解析并验证中药归经作用与方剂配伍规律,进行了以下的研究:1.通过文献检索,对归肺经中药化学成分、临床功效及药理作用信息的分析与知识挖掘,总结归肺经中药在化学成分构成、临床功效及药理作用方面的分布规律;结果发现:(1)化学成分类别方面,归肺经中药归经作用的主要药效成分可能与萜类化合物、生物碱类化合物及甾体类化合物相关,还可能与Fe等微量元素有关;(2)临床功效方面,止咳、利咽、润肺功效与归肺经作用的关联程度最高,其次是平喘、祛痰;(3)药理作用方面,抗菌、抗炎、抗肿瘤等药理作用在归肺经中药中最常见,而镇咳、祛痰、平喘作用与归肺经作用的关联程度较高。通过实验研究,对典型归肺经中药桔梗进行了成分分析及其药理研究,采用电感耦合等离子质谱法分析归肺经中药无机元素,验证了数据挖掘结果。将这些规律应用于海洋植物中药归肺经作用的预测和评价,准确率较高。2.通过文献检索,采用频数分析及关联规则的挖掘技术,对肺系方剂中药组成及其配伍规律,以及组成中药化学成分类别构成规律进行分析,探讨肺系方剂化学成分类别的构成情况及可能的配伍关系,尤其是君臣佐使药化学成分构成特征。结果发现:(1)从用药情况看,肺系方剂所用中药大部分归肺经,不归肺经的中药多与归肺经中药配伍;麻黄、甘草、杏仁、五味子是肺系方剂中应用最多的药物;(2)从方剂组成中药化学成分类别看,肺系方剂主要药效成分可能与萜类、生物碱及甾体成分有关,而君药成分可能与生物碱、黄酮成分有关,臣药及佐药成分与萜类及甾体类成分有关,使药成分多与萜类、生物碱及甾体有关,其中君药、臣药成分在肺系方剂组方中具有重要意义。3.对比归肺经中药及肺系方剂主要化学成分构成,萜类、生物碱、甾体类成分可能是归肺经中药及肺系方剂的主要药效成分;结合君臣佐使药的化学成分构成特点及肺系方剂组成中药的归经构成情况,肺系方剂组方设计应该考虑以下几个方面:一、优先考虑归肺经中药,在应用不归肺经中药时要配伍归肺经中药;二、组方时应考虑含萜类、甾体及生物碱类化合物的中药;治疗肺咳病及咳嗽症状时可以考虑含萜类化合物的中药,治疗气喘症状时可以考虑含生物碱类化合物的中药;三、在确定组方中药或化学成分配伍关系时,君药多考虑含生物碱、黄酮类化合物的中药;臣药、佐药可以考虑含萜类及甾体类化合物中药;使药可以考虑含萜类、甾体类及黄酮类化合物的中药。为进一步验证这一思路的可靠性,从海洋藻类植物中药肺系方剂中筛选了高频四味药团昆布、海藻、干姜、细辛的配伍,符合肺系方剂的组方设计思路和中医组方配伍原则;临床研究结果发现,辅用昆海姜辛汤可以提高临床总疗效,具有较好的临床安全性。以上的研究结果提示,在中医药理论指导下进行的海洋中药研发可以增加研发的针对性,尤其是归经理论的研究应用可以更好的确定海洋中药药效靶向系统,而复方配伍组合可以提高其药效,缩短其研发周期,使海洋新的药用资源可以更快、更加安全有效的进入临床应用;为海洋中药的研发与应用提供科学依据与理论指导,让海洋中药为人类的健康做出更大的贡献。另一方面,随着中药现代药理学研究及成分研究数据资料的大量积累,数据挖掘技术和化学信息技术是利用现代科学技术发展祖国传统医药的又一新思路,数据挖掘技术和化学信息技术在中医药研究中的应用将有越来越广阔的前景。更多还原

【Abstract】 The 21st century is to be‘a marine century’. With the new resources of marine drug increased greatly, the varieties of Traditional Marine Chinese Medicine (TMCM) augment. How to accelerate the study of TMCM and apply them on clinic became the focal point. Most of previous studies concentrated on the extraction of chemical composition from the marine material rather than on the application of new resource on clinic. Based on the analysis of the origin and development of TMCM, a new idea and method of studying TMCM was put forward: under the guide of the theory of Traditional Chinese Medicine (TCM), assigning the new resource of the marine drug the meridian tropism nature according to Meridian Tropism Theory (MTT) and composing prescriptions, which is possible to accelerate the study and application on clinic. However, the problem is that previous study achievement of MTT and prescriptions couldn’t be applied in the study of TMCM directly.To solve this problem, thousands of information data on clinic effects, pharmacologic action and chemical composition of hundreds of Lung Meridian Tropism Chinese Medicine (LMTCM) and Lung System Prescriptions (LSP) were collected based on predecessors’study achievements. The data mining and chemical information techno1ogy were innovatively introduced into this research. The main ideas of this paper are listed below:1. The distribution law of clinic effects, pharmacologic action and chemical composition of LMTCM were studied by mining the data of clinic effects, pharmacologic action and chemical composition, including mineral element of hundreds of LMTCM and nor-LMTCM. To prove the laws, mineral element of 14 LMTCMs were analyzed by the Inductively Coupled Plasma Mass Spectrograph (ICP-MS) method, the analysis of relationship of pharmacologic action and chemical composition, including amino acids, mineral element and terpene saponin of a typical LMTCM-platycodon radix and its lung meridian tropism effects were studied. The results showed that, the clinic effects of stop coughing, relieving sore-throat and moistening lung, the pharmacologic action of preventing cough, eliminating phlegm and antiasthmatic, chemical composition of steroid compounds have close relationship with the LMTCM. The contents of mineral elements, like Fe, in LMTCMs were higher than that of nor-LMTCM. The result of analysis of mineral element of 14 LMTCMs by ICP-MS method also showed the content of Fe have something to do with lung meridian tropism effects. The result of the study of platycodon radix approved the laws too. These laws were used to predict if the marine medicines have the lung meridian tropism effects.2. The Compatibility laws of Medicines and their chemical composition in LSP were studied by mining the data of the constituent herbs and their chemical composition. The results showed that the most constituent medicines of lung system prescriptions have lung meridian tropism. Radix glycyrrhizae, herba ephedrae, semen armeniacae amarum, fructus schisandrae Chinese and their compatibility are common in lung system prescriptions. Terpene, alkaloid, steroid, and flavanoid compounds and their compatibility are common in lung system prescriptions.3. The marine phycophyta medicines of LSP were studied by the same method. And the clinic effects of typical marine phycophyta medicines prescription of lung system-Kunhaijiangxin tang were studied by clinic research. In marine phycophyta medicines lung system prescriptions, thallus laminariae, sargassum, rhizome zingiberis, herba asari and their compatibility are common. The result of clinic research implied that typical The marine phycophyta medicines of LSP-Kunhaijiangxin prescription can improve the curative effect in acute episode of chronic bronchitis.In conclusion, assigning the new resource of the marine drug the meridian tropism nature according to MTT may discover their act target effects, composing prescriptions can improve their clinic effects, and it is possible that the theory of TCM can be used to help accelerate the process of drug development from preclinical study to clinical application. With the increasing of accumulation of the data of pharmacology study and composition study, the data mining and Chemical Information technology will be applied in the study of TCM extensively.更多还原