The Exploration And Verification Of The "target Association Method" In The Clinical Safety Evaluation Of The Combined Use Of Chinese And Western Medicine

With the increasing recognition of traditional Chinese medicine in the world,herb-drug combination is becoming more and more common.But the risk is unknown.However,the existing research methods for the safety evaluation are relatively independent of feature and target mechanism,which fails to form a link to indicate the risk of combination.If from the drug-clinical characteristics,the drug attribution is not clear for many interference factors.If only from the drug-mechanism,the data from the laboratory is difficult to assist clinical decision-making directly.How to integrate resources,establishing a clinical safety evaluation method of herb-drug combination,which can be related to clinical characteristics and target mechanism,to prompt the research of clinical risk and follow-up mechanism is an urgent research.Objective:Based on the analysis of the safety information report and characteristics of the herb-drug combination,this paper explores the methodology of the safety evaluation from the perspective of clinical characteristics.This paper attempts to put forward the "feature-target correlation method" to indicate the risk of herb-drug combination and explore the mechanism of adverse reactions(ADRs).From the common Chinese-Western medicine injection combination,the feasibility of the method will be preliminarily verified in safety evaluation of Xiyanping(XYP)-Ribavirin(RB)combination.Methods:1.Safety information report of herb-drug combination evaluationThe manuals of exclusive varieties Chinese medicine injections(including all manufacturers)and involved in the Catalogue of National Basic Medical Insurance,Work Injury Insurance and Maternity Insurance-Chinese patent medicines(2019)were searched.The safety information was analyzed according to the requirements of the relevant regulations and the guiding principles for prescription drugs of traditional Chinese medicine and natural drugs issued by National Medical Products Administration.2.Exploration and establishment of "feature-target correlation method"To explain the design of safety evaluation method of herb-drug combination.From the perspective of the correlation between clinical characteristics and internal mechanism,a"feature-target correlation method" was established to evaluate the clinical safety of herb-drug combination,indicating the risk of drug use.The paper introduced its constituent elements,application characteristics and implementation basis.3.An example of "feature-target correlation method " application3.1 Factors and Variable Importance in Projection(VIP)on the severity of adverse reactions(ADRs)of XYP-others drug combinationFrom January 2004 to December 2017,all ADRs of XYP were involved in the China National Adverse Drug Reaction Spontaneous reporting system.Data were analyzed with respect to age,gender,ethnicity,previous ADRs,family history of ADRs,dosage specification,medication frequency specification,body weight,route of administration,herb-drug interactions by univariate analysis,multivariate analysis and propensity score matching.The contribution intensity and direction of factors having significant influence on the severity were analyzed by VIP.3.2 Constructing a multielement evidence body for Safety InformationMultielement evidence body for safety information of XYP combination was used to analyze the clinical characteristics,distribution,correlation strength from the four major parts,the case reports of ADRs,randomized controlled trial studies,spontaneous reporting of system safety data,and large sample centralized monitoring trials by BCPNN method,meta-analysis and traditional frequency method.3.3 Feature-target analysis on rash caused by XYP-RB combinationMain components of XYP,RB and rash as key words,the drug targets,disease targets and literature databases were searched systematically.XYP-RB combination acting on rash targets which were obtained,was represented by Venn diagram.Using DAVID,KEGG database and Cytoscape 3.7.2 software,the four parts of GO analysis and KEGG pathway were carried out to predict the mechanism of rash initiation,which were XYP-RB and rash target intersection,XYP and rash target intersection,RB and rash target intersection,XYP-RB target intersection.It compared the biological function and pathway distribution,and analyze the possible mechanism of combined use in regulating skin rash.3.4 Experimental and mechanism studies on XYP-drug combination's anaphylactoid reaction(rash)ICR mice were injected with 250 mg/kg and 500 mg/kg doses of XYP,two doses of combined drugs,and cross doses of XYP combined with drugs.The blue staining area of mouse auricle was scored with 0.8%Evans blue solution as indicator after 30 minutes and blood were collected from eyeballs and ears.And the amount of Evans blue exudation from ear tissue was measured quantitatively,48 hours later.The expression levels of IL-1?,IL-2,IL-4,L-5,IL-6,CXCL1,IFN-?,TNF-? in serum of mice were detected by Luminex multi factor assay.RT-PCR was used to detect the mRNA expression of Caspase 8 and Fas in the ear.It explored the mechanism of anaphylactoid reaction induced by XYP-RB combination.Results:1.Safety information report evaluation about herb-drug combination692 instructions were collected.Among the 21 injection instructions,95.2%had no relevant information on drug interaction labeling,and 4.8%did not make any labeling.Only 5.2%of the non-injection instructions indicated drug interactions in details.71.3%of the instructions did not give any indication of toxic drugs and 96.3%of the instructions did not indicate the incompatibility.64.6%of the instructions in the labeling of ADRs were not clear,and the incidences of ADRs was not standardized(20.0%).A total of 138 traditional Chinese medicine injections'instructions(52 kinds)were involved.81.9%of the instructions have no interaction information,0.7%of the instructions are not clear,only 17.4%of the instructions have related description.There were not any tips of "Eighteen Incompatible Medicaments" and "Nineteen Medicaments of Mutual Restraint" on 75.0%of the instructions.18.1%of the instructions did not clearly mark the ADRs and the description of the incidences of ADRs(20.2%)was not standardized.The existing Chinese patent medicine instructions are insufficient for clinical medication guidance and the combination information is mostly missing.The safety evaluation of herb-drug combination is fragmented as a whole,due to the lack of corresponding evaluation methods.Due to the lack of connection between clinical features and target mechanism,the safety research of Integrated Chinese and Western medicine is fragmented.2.Exploration and establishment on "feature-target correlation method""Feature-target correlation method " refers to the safety evaluation method which can be used to indicate the risk by linking the clinical features with the action targets in the safety evaluation process of herb-drug combination.The components include risk identification,feature extraction,target connection and experimental verification.It is characterized by the systematic analysis of multi-source clinical data,from the perspective of action target,the clinical characteristics and internal mechanism are related to evaluate the clinical safety of herb-drug combination.3."Feature-target correlation method" applicationThe study included 26317 cases.Age and RB combination were factors for severity of ADRs.The severity of ADRs with XYP alone tended to be slight.Age and combination were included in VIP analysis,aged 0-6 patients tended to have mild ADRs,and patients over 40 tended to have severe ADRs.XYP-RB combination is a risk factor for the severity of ADRs and tends to aggravate ADRs.There was no case related to XYP-RB combination ADRs in the case reports and the hospital centralized monitoring study.The quality of randomized controlled trials was low and there was risk of bias.In children with rotavirus enteritis,upper respiratory tract infection and upper respiratory tract infection,combination did not affect the incidence of RB's ADRs.In children with hand foot mouth disease and viral pneumonia,XYP-RB combination reduced the incidence of ADRs.The most common primary disease of ADRs was hand foot mouth disease in children.ADRs was the highest proportion on 10-15 mg/kg RB and 5-10 mg/kg XYP once a day,56.9%combination group's ADRs were found in the skin reactions.The skin reactions were strongly associated with XYP-RB combination(E(ICij)=0.70).59.1%of ADRs appeared in the first combination,showed rash(82.5%)and pruritus(17.5%).Rash is the most frequent clinical feature.There were 21 targets about XYP-RB combination on rash.Metabolism in each target spectrum was the highest and may be the key biological process of XYP-RB combination(58.33%?31.33%?58.82%?60.00%).XYP and RB specifically regulate skin rash and increase signal transduction,protein metabolism and other functions.The higher proportion of target groups was found in inflammation(over 23.07%)and apoptosis(over 53.33%).Single drug can also specifically activate HIF-1 signaling pathway,microRNAs in cancer and other pathways.The combination may play a role in superimposing or regulating the pathway spectrum of more extensive skin rash targets.In the anaphylactoid reaction experiments,the vascular exudation of XYP and RB injection alone were relatively slight and the combination groups were significantly increased,but no significant change in ear weight were observed.IL-1? and IL-2 were lower than the detection limit.The expression of IL-6 in other groups were higher than that in the control group(P<0.05).There was no difference between administration alone and combination group.Compared with the control group,the mRNA of Fas in 250 mg/kg XYP+150 mg/kg RB group increased significantly(P<0.05)and no significant difference between the single group and the combination group.the mRNA of caspase 8 in 250 mg/kg XYP+150 mg/kg group only showed a growing trend.Combination can cause anaphylactoid reaction characterized by IL-6 and Fas targets,increasing vascular exudation to cause rash reactions,corresponding to the clinical features.Conclusions:Based on the analysis of the safety information report of herb-drug combination,the "feature-target correlation method " was proposed to evaluate the safety of herb-drug combination from the perspective of feature-target correlation.It was applied to the clinical safety evaluation of XYP-RB combination.It was found that the combination may induce anaphylactoid reaction by regulating IL-6 and Fas related inflammation and apoptosis pathways,vascular permeability changing.It is consistent with the clinical features of rash,which can indicate the XYP-RB combination risk.The feasibility of this method is preliminarily demonstrated.