基于疾病过程对证治疗的中药复方药物代谢动力学研究

The pharmacokinetics of traditional Chinese medicine is the key scientific issues in medicine scientific research based on symptomatic treatments of disease process. Multi-component and multi-target mechanism of Chinese herbal compound determines the pharmacokinetic parameters of multi-component properties of the herbal compound. The properties attribute can be adapted to the needs of the symptomatic treatments. The shenfu injection has been to have curative effects in clinical treatments. In the proposed study, early and medium-term cardiac shock rats will be used as animal model to explore the concentration-activity relationship of shenfu injection in. Firstly, we are going to analyze the affect of different and drugs by metabolic group's comprehensive characterization; secondly we are going to determine different dosed of drugs in the blood composition peak area change, build up quantity matrix (X) and then different doses of the drug metabolism group, volume change and the effect matrix (Y) will be assessed. Then the relationship between quantity matrix (X) and effect matrix (Y) will be analyzed by the partial least squares for the ingredient difference of shenfu injection on early, medium-term cardiac shock resistance. Moreover, the relationship between active compounds and their activity as well as the relationship of different activity compounds will be defined in this proposed study. After pharmacokinetic parameters and the effect compounds of shenfu injection by the metabolic pharmacological effects, we will discussed the rationality and scientific nature of drug metabolism parameters based on the symptomatic treatments from disease process. This study will provide a new research model for pharmacokinetic study of traditional Chinese medicine compounds.

基于疾病过程对证治疗中药复方药代动力学是中医药科学研究中的关键科学问题。中药复方多成分、多靶点的作用机制，决定了多种成分的药动学参数是中药复方的客观属性。该客观属性可适应对证治疗的需要。本课题以临床疗效确切的参附注射液为模式对象；以早、中期心源性休克大鼠为动物模型；探讨参附注射液在两种动物模型中的量效关系；以代谢组综合表征药物不同病证的效应并进行途径分析；测定不同剂量血液中药物成分峰面积变化，构建量矩阵（X）；同时测定不同剂量药物代谢组量的变化，构建效矩阵（Y）；以偏最小二乘法分析量矩阵（X）与效矩阵（Y）间的关系；明确参附注射液抗早、中期心源性休克的成分差异，明确效应成分与效应的关系，效应成分间的关系；以代谢组药理效应法的参附注射液的药动学参数与效应成分的药动学参数进行比较，探讨基于疾病过程对证治疗的药代参数的合理性与科学性。为中药复方药动学的研究提供一种新的研究模式。

中医临床辨证论治，辨病因、病位、病性、病势等，按“君、臣、佐、使”遣方施药。但并未说明给药方式，临床上有一日两次服，顿服，频服、中病即止，服药的方式是经验式，缺乏科学依据。因此，中药复方药代动力学如何为临床给药方案服务成为中医药领域关键科学问题。.本课题全面分析了参附汤中的红参、黑顺片的化学成分及血液移行成分，并建立了其成分数据库；建立了心源性休克早期（缺血缺氧期）、中期（淤血缺氧期）大鼠模型；建立了以代谢物组量化的整体效应评价方法，探讨参附注射液治疗心源性休克早期、中期的量效关系，同时探讨了生理指标的量效关系，阐明了以代谢物组为整体效应的中药复方量效关系的科学合理性。结果表明：参附注射液治疗心源性休克早期给药剂量以参附注射液说明书的推荐最小用量减半；治疗心源性休克中期给药剂量按 推荐用量的最大用量。.本课题通过参附注射液血浆药物成分分析，建立了药物成分矩阵X；通过代谢物组的量化建立了效应矩阵Y。以代谢物整体效应为Y变量，血浆成分为X变量，建立偏最小二乘法分析模型。结果表明：早期相关成分为：Melibiose、Picraconitine、ginsenosideRc、Hokbusine A（Pcoor>0.8，vip> 1）；中期相关成分：notoginsenoside Fe、notoginsenoside N 、ginsenoside R0、ginsenoside Rg5（Pcoor>0.9，vip> 1）。.通过结合量效关系、相关物质基础及成分药动学参数，提出了参附注射液临床治疗心源性休克早期、中期给药方案建议：①心源性休克早期（代偿期）血压略有下降，参附注射液各药味同等重要。由于乌头碱类成分半衰期短，其中苯甲酰新乌头碱半衰期t1/2=13.3min。建议临床宜小剂量静脉滴注。②心源性休克中期（失代期）血压下降，参附注射液红参起重要作用。由于人参皂苷类成分半衰期相对较长，且Rg类成分在中期起重要作用，其中人参皂苷Rg1半衰期t1/2=97.1min。建议临床宜大剂量静脉推注。