基于中药功效矢量阈值的山楂质量控制方法研究

Most of Chinese Herbal Medicine (CHM) possess various efficacies characteristics in clinic. Since ancient times, dosage of CHM is the key of Traditional Chinese Medicine treatment. In other words, with the change of dosage, the efficacy of CHM is changed in the aspect of action strength, even action direction. So, In this study, we use of reference of the concept of "vector" in mechanics analysis, to endow the efficacy of CHM with double attribute of action strength and action direction, namely the efficacy vector of CHM. According to rules of vector operation, the efficacy vector of CHM is equal to the efficacy vector projection of all chemical substances from the CHM, under the threshold of dosage of the efficacy vector of CHM. Hereby, with fruit of Crataegi Fructus as example, from "Xiao Shi Jian Wei" and "Xing Qi San Yu" of the efficacy of fruit of Hawthorn, we adopt the Gastrointestinal Function experiment and Myocardial Ischemia experiment, respectively, in order to determine the threshold of dosage of the above two efficacy vector of Crataegi Fructus. Under the above two threshold of dosage, we get effective components by screening experiments, respectively, and establish quantity relative ratio relationship between effective components. According to the main effective component, we establish composition-activity relationship between chemical composition and efficacy , and quantity relative ratio relationship between effective constituents, respectively. Thus, the quality evaluation system of Crataegi Fructus with various efficacies characteristics of CHM is established, in order to provides a reference for promoting the quality standard of CHM .

大多数中药在临床上具有多种功效的特点。自古就有"中医不传之秘在于量上"之说，即同一中药随着临床用药剂量的改变，其功效不仅是在强弱上发生改变，而且作用方向也会发生一定的改变。本研究借鉴力学"矢量"概念，对中药功效赋予方向和强度的双重属性，即中药功效矢量。根据矢量运算规则，在某一剂量阈值内，中药某一功效矢量为该中药内各化学物质组分的功效矢量在此功效矢量方向上的投影加和。据此，本研究以山楂为例，从"消食健胃"与"行气散瘀"两功效作用入手，分别采用胃肠功能药效实验和心肌缺血药效实验，确定山楂在上述两种功效方向上的剂量阈值,以此为基础，筛选出相应的功效组分，建立功效组分之间的量比关系，并确定主要功效组分及其含量范围。利用人工神经网络技术对主要功效组分化学信息与药效信息进行相关性分析，建立主要功效组分"组效关系"，进而确定主要有效成分之间量比关系及其含量范围，建立符合中药多功效特点的山楂质量控制方法。

本研究以山楂为模式药物，采用胃肠运动、高血脂及心肌缺血再灌注损伤药效模型，确定山楂在上述药效作用方向上的剂量阈值分别为0.8 g、3~12 g以及12~48g 生药量（以人体重为60 kg计算）。再利用上述各药效模型，以山楂原药材为药效参照，从不同化学组分（Ⅰ、Ⅱ、Ⅲ、Ⅳ）中，分别筛选得到具有促进小肠运动的组分Ⅲ、降血脂作用组分Ⅲ及保护心肌细胞损伤的组分Ⅳ，同时，确定上述有效组分中总黄酮和总有机酸的量比关系。在此基础上，利用QTOF-MS技术，对上述两组分进行定性分析，分别发现组分Ⅲ主要含有11个成分（B型原花青素二聚体、原花青素C1、B型原花青素二聚体、芦丁、金丝桃苷、异槲皮苷、B型原花青素二聚体、表儿茶素、槲皮素、5-O-咖啡奎尼丁酯）和组分Ⅳ主要含有15个成分（琥珀酸、龙胆酸、香草酸、新绿原酸、绿原酸、隐绿原酸、儿茶素、表儿茶素、咖啡酸、异咖啡酸、丁香酸、白矢车菊素、金丝桃苷、异槲皮苷、槲皮素）。利用BP人工神经网络技术和偏最小二乘法，将上述两个组分的化学信息分别与相应药效信息进行相关性分析，分别建立主要功效组分的“组效关系”，经综合分析，最终，确定山楂在不同药效下质控指标成分及量比关系。本项目研究从中药功效矢量阈值思路出发，为建立符合中药多成分，多功效特点的中药质量控制方法和提升我国《中国药典》（2015版）中药质量标准研究提供了参考。