三角函数结合法对经方三黄泻心汤药效物质基础PK-PD 临床运用“清热解毒法”的新阐释

"Clean heat and removal toxin" theory is one of the common clinical therapies for traditional Chinese Medication. Sanhuang Xiexin decoction (SXD) is the classic heat-clearing and antidote. However, there is no clear research method based on the pharmacokinetics- pharmacodynamics (PK-PD) of detoxification of traditional Chinese medicine. SXD, an effective decotion which drug substance, components obsorpiton into blood, are clear. It is mainly belonging to berberine alkaloids, anthraquinones and scutellariae flavonoids permeated into the systemic circulation to play a pharmacodynamic effect. Therefore, SXD is deemed as the research object; enzymes, cells and pathological state of experimental animals are selected as PK-PD correlation model based on the blood steady-state plasma concentration of active components. Pharmacologica indexes such as body temperature, ATP, inflammasome for the pharmacological indicators are selected for PD investigation. PK-PD model are constrcucted to integrate the efficacy of substance and efficacy-related "detoxification". The PK-PD research method are established based on Chinese medicine characteristics theory of the holistic view of TCM and syndrome bsed on differentiation, which could provide a new method to guide the clinical study on PK-PD of traditional Chinese medicine "clean heat and removal toxin". And constantly Triangular Function Method theory will be improvedaccording to the new method of bioinformatics in this research area。

“清热解毒”法为中医临床常用疗法，三黄泻心汤为经典的清热解毒剂，然而基于中药清热解毒的药代动力学-药效学（PK-PD）目前尚无明确研究方法。三黄泻心汤药效物质基础明确，入血成分清楚，主要以黄连生物碱，大黄蒽醌和黄芩黄酮进入体循环发挥药效。因此我们以三黄泻心汤为研究对象，先采用酶、细胞、病理状态下实验动物进行PK- PD相关性模型，以入血稳态血药浓度活性组分群进行研究，以体温、ATP、炎症小体为药理指标；介入三角函数方程，以期获得能够整合药效物质与疗效相关性的“清热解毒法”的PK-PD 模型。据此建立符合中医特色理论整体观的复方中药PK-PD研究方法，为指导临床“清热解毒”中药PK-PD研究提供新方法;并根据生物信息学新方法不断完善该理论。

“清热解毒”法为中医临床常用疗法，三黄泻心汤为经典的清热解毒剂，然而基于中药清热解毒的药代动力学-药效学目前尚无明确研究方法。本研究以黄连生物碱、大黄蒽醌和黄芩黄酮为活性成分的大黄黄连泻心汤为研究对象，建立泻心汤中主要活性物质的生物样品的LC/MS/MS分析方法；采用湿热证模型结合腹腔注射脂多糖建立的炎症发热动物模型；并对泻心汤的主要活性物质的PK相互作用机制和PK行为进行研究，建立黄连组、黄芩组和泻心汤组单次或连续给药后稳态的PK模型；对发热动物模型及给药组动物的体温、血浆炎症小体和炎症因子进行测定和PD研究；本研究发现：黄连生物碱类成分均有多峰现象，这与其低细胞渗透性，胆汁外排和肝肠循环有关；经配伍给药后，小檗碱、巴马汀、药根碱和黄连碱的峰浓度和暴露量均明显增加，小檗碱的AUC增加2.5-2.7倍，这与配伍对吸收转运体和代谢酶的相互作用有关；连续7天给药（早晚各1次）后的稳态与单次给药比较，各成分的峰浓度和AUC也明显增加，达峰时间有所推迟。其中AUC增加约2-5倍，在LPS病理模型中，其峰浓度和AUC增加明显，说明黄连在疾病状态下更易吸收和蓄积。因此临床中应重视黄连的使用剂量和持续使用时间。经配伍后连续给药，黄芩苷的达峰时间会提前1-2h；病理模型下，其峰浓度和AUC均有一定程度的增加，证实本品在病理状态下易吸收和蓄积；比较单次和稳态给药及LPS病理状态下大黄蒽醌类成分，大黄酸的峰浓度和AUC略有增加，但达峰时间和半衰期变化不明显，但病理状态下大黄素和芦荟大黄素的半衰期明显缩短；三种成分均显示在病理状态更易吸收和蓄积，从体内吸收代谢角度证实此类苦寒药物在临床使用时均需注意中病即止，应重视苦寒药物的使用剂量和持续使用时间。本研究建立了符合中药复方特点的PK-PD研究方法， 为临床合理使用苦寒类药物提供可行的用药依据。