基于药代学与药效学关联的丹参红花多组分（丹红注射液为例）抗脑缺血作用机制研究

The Chinese herbal medicine formula is a concrete embodiment and commonly used method for traditional Chinese medicine syndrome differentiation and treatment. The therapeutic effects of traditional Chinese medicine have been gradually acknowledged in the field of medical science both at home and abroad. But it is not very clear that the Chinese herbal medicine formula how to play a role, How multi-components interact with each other, etc. The compound effect may be the result of the interactive integration and multidirectional adjustment integration of the multi-components in the body.. On the basis of the previous researches, based on the associated theory and method of pharmacokinetics and pharmacodynamics, use the methods of Pharmacology, pharmacology, analytical chemistry, mathematics and so on, to focuse on the metabolism of the components of salvia miltiorrhiza and safflower in the body, and the correlation of the metabolites and pharmacodynamics (PD) of anti-cerebral ischemia. With the multi-components compatibility of salvia miltiorrhiza and safflower for tools, from the levels of animals, cells, and so on, copy brain ischemic injury animal model, changes of components metabolism of the dialysate in blood, urine, brain, liver and kidney tissue will be tested by LC-MS etc. And simultaneous determination of pharmacodynamic indexes (Neurological function, atlas of PET, Glu etc.) by PET, microdialysis etc. Combining with the cellular pharmacology determine bioactive metabolites, the correlation of pharmacokinetics and pharmacodynamics are analyzed with mathematical methods.. Highlight the characteristics of the interaction and association and the integration of the effects in pharmacology and pharmacodynamics of salvia miltiorrhiza and safflower components, and explain the pharmacokinetics of salvia miltiorrhiza and safflower, the material basis of pharmacodynamics and the theory of prescription compatibility, which providing ideas and methods for the study of the Chinese herbal medicine formula in pharmacokinetics, and so on.

中药复方是中医辨证论治的具体体现和常用方法，中药疗效逐渐被国内外同行认可，但中药复方如何发挥作用、多组分如何相互作用等问题目前尚不十分清楚。复方疗效的发挥可能是多组分在体内多向动态调节整合作用的结果。. 在以往基础上，基于药代学与药效学关联理论与方法，采用药理学、药代学、分析化学、数学等方法，重点研究丹红多组分体内代谢过程、代谢产物与抗脑缺血药效学（PD）相关性。拟以丹参红花多组分配伍方为工具药，从动物、细胞等水平切入，复制脑缺血损伤动物模型，LC-MS等测定血、尿及脑、肝肾组织透析液中组分代谢变化，PET、微透析等同步测定药效学指标(神经功能、PET图谱、Glu等)；数理方法将药代与药效数据关联，结合细胞药理确定代谢产物的生物活性。. 突出丹红组分在药代学与药效学上相互作用及关联、整合发挥效应的特色，阐述丹红药代、药效物质基础、方剂配伍理论，为中药复方药代等研究提供思路与方法。

本项目总的研究期限为四年，现已按原项目研究计划圆满完成了全部研究任务。采用基于LS-SVM模型、低共熔溶剂等对丹参、红花中主要有效成分进行了提取工艺优化。完成丹参与红花主要有效成分正交配伍后对大鼠脑缺血再灌注损伤的保护作用，并筛选出配伍组合中的较优组合。进一步丹参与红花主要有效成分配伍组的药效学追踪并建立PK-PD数学模型。同时对丹参、红花经典组方的丹红注射液为例，深入研究了基于PERK/eIF2a/CHOP通路探讨丹红注射液体内体外细胞凋亡的保护作用及作用机制。丹红注射液对PC-12神经元细胞OGD/R损伤后自噬、线粒体自噬的影响。丹红注射液对大鼠神经元细胞线粒体自噬的影响及其作用机制。基于缺血半暗带细胞能量代谢的丹红注射液抗脑缺血损伤的作用机制研究。丹参红花药对主要成分的绿色提取和代谢行为研究丹红注射液及其活性成分保护血管内皮细胞作用机制。本项目突出丹参红花组分在药代学与药效学上相互作用及关联、整合发挥效应的特色，阐述丹红药代、药效物质基础、方剂配伍理论，为中药复方药代等研究提供思路与方法。本项目获得的实验结果能更好的指导临床应用。. 现已按原研究计划，在研究周期内完成了上述全部研究任务，开展了基于药代学与药效学关联的丹参红花多组分（丹红注射液为例）抗脑缺血作用机制研究，取得了较好的研究成果。现已将相关研究成果整理撰写发表相关科研论文，正式发表论文31篇，其中SCI收录22篇；国家发明专利2项；获省部级奖励2项；培养研究生10名。