基于丹酚酸A多靶点心血管保护作用机制的间接药动学-药效学模型的研究

Salvianolic acid A (SalA) is one of the major active water-soluble compounds extracted from Danshen which can be used to promote blood flow and to resolve blood stasis. SalA exerts its cardioprotective effects by integrated multitarget beneficial effects which is the common characteristics of traditional Chinese medicines (TCM). In fact, TCM usually exert therapeutical effect by multitarget. However, the present researches on TCM are mainly concentrated on single mechanism, which can't reflect the integrated therapeutic effects of TCM. Therefore, it is hard to exactly describe the integrated beneficial effects of TCM, which is a tough issue in the investigation of pharmacokinetics and pharmacology of TCM. In this project, multiple targets for cardioprotective effects of SalA will be screened to find the substitution of its cardioprotective effects. The cardioprotective effects mechanism of selected biomarkers of SalA will be further studied to develop mechanism based indirect PK/PD model. According to this PK/PD model, the relationship between SalA and its targets will be described and the interaction among the selected targets will be further investigated. The purpose of this project is to develop an indirect multitarget PK/PD model based on the cardioprotective mechanism of SalA. We hope to make a breakthrough in the research of PK/PD model of TCM and to provide a novel idea and method for the study of TCM.

丹酚酸A是临床常用活血化瘀药丹参的一个主要活性水溶性成分之一，通过对损伤心血管系统的多个靶标进行调节而发挥心血管保护作用，这也是大多数中药作用的一个共同特点- - 通过多靶点对机体进行整体干预，进而发挥疗效。现有的中药研究主要是针对某一靶标而进行的，忽略了中药作用的整体性，因而没有反映出其通过多个作用靶标共同作用而发挥整体药效的特征，这也是中药药动学和中药药理学所面临的一个共同难题。本课题通过对丹酚酸A心血管保护作用靶标的筛选，选择多个与其心血管保护作用相关的靶标作为药效评价的替代指标，借助于基于机制的间接PK/PD模型对其作用机制进行初步探讨。这一方面可以揭示丹酚酸A和各个靶标之间的内在联系；另一方面可以揭示各靶标之间的内在联系及其所对应的通路在心血管疾病中所发挥的作用。力争在中药的PK/PD模型研究中有所突破，为中药PK/PD研究提供一个新思路与新方法。

具有多靶点作用特征中药的PK-PD研究是一个难点。丹酚酸A是通过多靶点对机体进行整体干预，进而发挥心血管保护作用，本课题以丹酚酸A（Sal A）作为研究对象，考察其对心血管的多靶点保护作用，旨在建立合适的PK-PD模型用于中药的PK-PD研究。在此研究中，我们首先考察了Sal A心血管保护作用的不同机制，发现其可以通过调节心血管疾病危险因子不对称二甲基精氨酸（ADMA）的代谢，抑制尿酸的生成以及调节高半胱氨酸（Hcy）的代谢对心血管系统产生保护作用。在此基础上我们建立了Sal A的多靶点PK-PD模型考察其对高血压大鼠心血管系统的保护作用。为了更为全面准确地评价多靶点药物的PK-PD，我们从疾病的角度出发，考察反映疾病发生发展相关的多条生理病理通路，选择代表性的生物标记物建立多靶点的PK-PD模型，用于丹酚酸A的多靶点心血管保护作用的PK-PD研究。这一方法更为全面准确地反映多靶点药物对疾病的整体影响，为中药的PK-PD研究提供了一种新的思路和新方法。.经过4年的不懈努力，目前累计在国内外核心期刊发表论文11篇，其中SCI收录7篇，累计影响因子达23.9。本项目执行期间共培养博士生5名，硕士生12名。项目基本达到预期的研究目标。