Identification Study Of The Core Effector Response Substance In "Liang Guanxi" Drug Pair Of Danshen-jiangxiangin Vivo For Open Complex Giant System

Ischemic stroke is an interruption in the blood supply of the brain and the pathogenesis of this disease is quite complex.The traditional Chinese medicine(TCM)with the characteristics of multi-component and multi-target is widely applied to ischemic stroke.After the various components of TCM being absorbed into body,drug-body forms a "drug-body" open complex giant system(OCGS).The effective analysis of the massive data from "drug-body" OCGS to discover and select important components andelaborating their corresponding mechanism of action of these components in OCGS wereconsidered as a key basic theoretical problem.We choose the cause-effect relationship as a cut-in point to solve this problem.Firstly,we exactly defined the cause-effect relationship with the qualitative and quantitative describtionbased on the random dynamical system and ergodic theory.Then,we present corresponding statistic,confidence level and confidence interval of cause-effect relationshipsfor discrete time seriesUnder the guidance of above theories,we choose "liang relationship"drug pair of Danshen-Jiangxiang as an example to analysis the data from the microdialysis sample and plasma of rat model of middle cerebral artery occlusion after intravenous injection of Xiangdan Injection or Danshen Injection and to explain the detailed procedures to discover and select core effector response substances.As a result,we find danshensu isopropyl ester(IDHP)and rosmarinic acid as core effector response substances from microdialysis sample and danshensu,rosmarinic acid,salvianolic acid B,FES 18?NM 34 and FES 40 from plasma.Now we give a brief description of each chapter.1.Based on Xuesen Qian's theory of OCGS,Prigogine's dissipative theory,Haken'stheory of synergy,theory of TCM and systems biology,we establish the the dissipative-synergy theory of“drug-body"open complex giant system.The mechanism of effective components of drug in OCGS lies in the input of negative entropy.Dynamic fluctuation of all the substances in body,including TCM,endogenous substance and new metabolite,contribute to synergistic effect which makes the bodyaway from diseased state and then forms a new "drug-body"dissipative structure and finally achieves the purpose of health care.Thesubstances with high cause-effect relationship are considered as the key substance basis of"drug-body" dissipative structure generated under synergistic action.Therefore,we define these substancesaskey effector response substances.We choose the cause-effect relationship as a cut-in point to solve this problem.Firstly,we exactly defined the cause-effect relationship with the qualitative and quantitative describtion based on the random dynamical system and ergodic theory.Then,we present corresponding statistic,confidence level and confidence interval of cause-effect relationshipsfor discrete time series.Under the guidance of above theories;we focus on the time series from biological samples to search one-way and mutual cause-effect relationships.The substances with high mutual cause-effect relationships are called core effector response substances.Thus we can find the core effector response substances which serve as the key substance basis of "drug-body"dissipative structure generated under synergistic action.This research can provide a new strategy to develop new drug2.We selected the qualified medicinal materials of Radix Salviaemiltiorrhizae(Danshen)and Lignum Dalbergiaeodoriferae(Jiangxiang)according to Chinese Pharmacopoeia of(2015).And then we prepared Xiangdan injection and Danshen injection base on the "Pharmaceutical Standards of the Ministry of Health of the People's Republic of China".The results of the quality control study show that the content of protocatechuic aldehyde meets the Ministry of Health Drug Standards The results of clarity and hemolysis test are finewhich indicated that Xiangdan injection and Danshen injection satisfy management standard for clinical use of TCM injection3.From the point of view of pharmacokinetic study,we compare Xiangdan injection and Danshen injection.We observed clear growth of bioavailability of many components after intravenous administration of Xiangdan injection rather than Danshen injection.This is the possible mechanism of synergistic interaction between Danshen and Jiangxiang in complex prescription consisting of the two herbs Therefore,we will select effector response substance from Xiangdan injection4.We choose "liang relationship" drug pair of Danshen-Jiangxiang as an example to analysis the data from the microdialysis sample and plasma of rat models of middle cerebral artery occlusion after intravenous injection of Xiangdan Injection or Danshen Injection and to discover and select core effector response substances Finally,we find danshensu isopropyl ester(IDHP)and rosmarinic acid as core effector response substances from microdialysis sample and danshensu,rosmarinic acid,salvianolic acid B,FES 18?NM 34 and FES 40 from plasma.We use the above examples to explain the detailed procedures of cause-effect analysis of time series of equal and unequal time intervals.Our previous researches and other researches in literatures have verified the efficacyofanti-cerebral ischemia of known substances,which serves as a new strategy to realize the molecularization and digitalization of TCM,and is beneficial to develop original new drug.