基于痰证理论的中药经典方剂“栝蒌薤白半夏汤”治疗胸痹心痛的体内药效物质研究

Chest stuffiness and pains and coronary heart disease have become the most-watched public health problem due to the high incidence and mortality in 21st century. Meanwhile, there are limitations by modern medical treatments, while traditional Chinese medicine have a long history for the treatment of chest stuffiness and pains. Gualou-Xiebai-Banxia decoction, a famous Traditional Chinese Medicine prescription (TCMP) from Synopsis of Golden Chamber (Jin-Kui-Yao-Lve) written by Doctor Zhang Zhongjing in Han Dynasty, was widely used for chest stuffiness and pains based on the theory of “eliminating stagnation to activate yang and treatment of phlegm turbidity”. However, the pharmacodynamic materials and action mechanism of Gualou-Xiebai-Banxia decoction still remain unclear. In previous study, we had finished the studies on the isolation and identification of chemical compounds in herbal medicines Allii Macrostemonis Bulbus and Fructus Trichosanthis, chemical and metabolic profiling of Allii Macrostemonis Bulbus. On the basis of these results above, the aim of this project is to perform the characterization of chemical constituents and in vivo xenobiotics and the metabolism and pharmacokinetics of multiple in vivo absorbed components using a “representative structure based homologous xenobiotics identification” (RSBHXI) strategy by UPLC/Q-TOF-MS. Furthermore, to finish the activities evaluation and mechanism investigation of Gualou-Xiebai-Banxia decoction and its main in vivo absorbed absorbed components in its related in vivo and in vitro models which could well matched with its clinical indications atherosclerosis based on phlegm syndrome theory of traditional Chinese medicine. Moreover, to carry out the target prediction and validation of main in vivo absorbed absorbed components by Reverse virtual screening technology. Taken altogether, these work would partly reveal the in vivo effective materials and action mechanism of Gualou-Xiebai-Banxia decoction for the treatment of chest stuffiness and pains from the point of "disease symptoms-efficacy-in vivo components-action target". And also, it would provide important experimental basis for its clinical application by synergistic effect of complex system, and provide a useful example for the discovery of effective components in TCMP by the combination of chemistry and biology.

胸痹心痛或冠心病因高发生率和死亡率成为21世纪最受关注的公众健康问题，现代医药手段存在局限。中医药治疗胸痹心痛已上千年，出自《金贵要略》的中药经典方剂栝蒌薤白半夏汤是其中备受推崇的“宣痹通阳、痰浊论治”的主方，但药效物质及作用机制不清。在对薤白、栝蒌和类似经方化学分离、薤白成分检识与体内代谢等基础上，拟基于代表性结构的同源外源物检识策略下的液-质联用法开展该复方入方成分和大鼠体内外源物、多成分体内代谢及动力学研究；基于痰证，采用与冠心病临床适应症动脉粥样硬化匹配的体内外模型进行复方及体内主要吸收成分的活性评价与机制探讨，并应用计算机反向虚拟筛选技术进行与冠心病相关靶点的预测及验证，以期从“病症-药效-体内成分-作用靶点”关联角度揭示该复方治疗胸痹心痛的体内药效物质与作用机理、初步表征复杂体系下的协同作用提供一定实验依据，并为化学-生物学相结合的传统中药经典方剂的药效物质发现提供有益借鉴。

本项目瞄准发病率高且社会公众危害严重而现代医疗存在局限的胸痹心痛症（即冠心病），选择《金匮要略》中最能展示中医“宣痹通阳、痰浊论治”治疗胸痹心痛特色的临床有效中药经典方剂栝蒌薤白半夏汤，围绕为何有效及如何有效的科学内涵开展研究。首先以代表性结构同源外源物检识策略下的液-质联用法对栝蒌薤白半夏汤整体化学轮廓及代表结构的主含成分进行了定性与定量描绘，通过对大鼠体内外源物检识结合代表单体体内代谢途径描绘了该经方多成分体内代谢特征，对吸收入血和小肠内容物中主要成分分别开展血浆药动学研究和经时变化考察、表征了该经方多成分体内药动学特征和揭示了其体内高暴露量成分；同时采用与该经方临床适应症密切关联的ApoE-/-小鼠动脉粥样硬化模型及ox-LDL诱导的巨噬细胞泡沫化模型对该经方及体内高暴露成分进行了抗动脉粥样硬化活性评价与机制探讨，并随行分析血浆样本发现了与经方药效相关的内源性成分；进而以经方主含成分和体内高暴露量成分为候选药效成分，利用网络药理学手段构建起“经方候选药效成分-冠心病靶点-经方药效相关的内源性成分”关联网络以确定该经方潜在药效成分，结合分子对接和体外生物活性评价揭示了经方中2个药效成分以及可能作用机制。同步地，设置缺半夏组平行进行上述各步对比考察，通过药味缺失对该经方的化学成分、体内代谢及动力学特征的影响描绘了半夏对该经方药味组方的协同贡献并给予了药效验证、表征了多组方药味多药效成分间相互作用。上述研究可以为从“病症-药效-体内成分-作用靶点”关联角度部分揭示中药经方栝蒌薤白半夏汤治疗胸痹心痛体内药效物质与作用机理、初步表征复杂体系下药味间协同作用提供重要实验依据，为化学-生物学相结合发现中药经典方剂药效物质提供有益借鉴，亦有利于该经方标准制剂的进一步研发、推进传统中药经典方剂现代制剂研究提供参考。目前已发表SCI研究论文7篇、培养博士研究生1名、硕士研究生4名。