基于毒效结合数学模式优化中药复方处方和工艺的方法学研究

As adverse effect of Chinese prepared midicine increasingly appeared, how to study the mechanism of creatation and optimizing its formula and technology scientific and reasonablely become a problem to urgently solve.At present,the method of disassembled formulas of toxicology,the optimization of formula and praeparatum technology to be short of combination of toxin and effect that lead to the result of adverse effect mechanism and optimization of formula and praeparatum technology were indefinitely. This topic firstly lead mathematics mode in toxic Optimization of complex prescription which combined with praeparatum technology to illuminate the mechanism of creatation of adverse effect of Chinese prepared midicine ,and found optimization of complex prescription mode with the combination of toxin and effect to reach the purpose of optimizating formula and technology scientificly at the same time. Zhixue capsule is a representative Chinese prepared midicine which composed by Kushen and Baixianpi that has mutual promotion between two drugs. Recently, much more adverse effect of hepatic lesion about Zhixue capsule were reported. We try to found the mode of optimizating formula and technology of Chinese prepared midicine which has adverse effect through this topic which based on mathematical optimization of complex prescription of Combination of toxin and effect.

随着近年来中药复方制剂不良反应日益增多，如何科学合理地进行中药复方制剂不良反应发生机理及其处方、工艺的优化研究，成为当前亟需解决的课题。目前研究中存在毒理学拆方研究方法欠科学以及处方、工艺优化研究较少考虑毒效平衡等问题，导致目前对多数中药复方制剂不良反应发生机理阐述不清，处方和工艺得不到科学合理的优化。本课题首次采用数学模式指导的毒理学拆方和工艺筛选相结合的方法，从处方和工艺两方面寻找中药复方制剂不良反应发生的机理；同时，首次采用毒效结合数学模式优化中药复方处方和工艺，以达到科学合理优化处方和工艺的目的。痔血胶囊处方仅以白鲜皮和苦参二味药相须为用，但近年来肝损害的不良反应报道较多，选择痔血胶囊研究具有代表性意义。通过本课题研究，试图建立一种针对出现不良反应中药复方制剂的毒效结合数学方法优化处方和工艺的研究模式。

随着近年来中药复方制剂不良反应日益增多，如何科学合理地进行中药复方制剂不良反应发生机理及其处方、工艺的优化研究，成为当前亟需解决的课题。本课题首次采用数学模式指导的毒理学拆方和工艺筛选相结合的方法，从处方和工艺两方面寻找中药复方制剂不良反应发生的机理；同时，首次采用毒效结合数学模式优化中药复方处方和工艺，以达到科学合理优化处方和工艺的目的。通过痔血胶囊不同工艺提取物对大鼠肝毒性的影响实验，我们发现痔血胶囊全方醇提物存在明确的肝脏毒性，组织病理学主要表现为肝小叶周边带肝细胞小泡型脂肪变性；并且其肝毒性与提取溶剂中乙醇含量正相关；此外根据大鼠肝脏小灶状炎细胞浸润评分，发现痔血胶囊的抗炎作用，水提组明显优于醇提组，说明痔血胶囊醇提物较水提物药效降低，说明制剂工艺是导致痔血胶囊出现肝毒性的主要原因。课题实验结果提示，工艺因素对中药复方制剂的安全性具有重要影响，今后新药研发，应关注现代工艺对中药安全性的影响，过分强调成分富集存在严重的安全隐患，工艺筛选应采用毒效结合的思路。处方优化方面，以对小鼠出凝血时间的影响为评价指标，进行痔血胶囊拆方药效学实验，得出痔血胶囊药效学最优方为白鲜皮5g、苦参3g。通过本课题研究，初步建立一种针对出现不良反应中药复方制剂的毒效结合数学方法优化处方和工艺的研究模式，为今后进行系统合理的中成药复方优化奠定了基础。