Evaluation Of The Effectiveness And Safety Of Yunnan Baiyao Capsule And Discussion On The Related Mechanism Based On Network Pharmacology

ObjectiveTo evaluate the efficacy and safety of Yunnan Baiyao capsule,provide a scientific basis for the rational clinical use of Yunnan Baiyao capsule,ensure the safety and effectiveness of patients’ clinical medication,and provide a reference for the establishment of clinical safety evaluation mode and method of traditional Chinese medicine in line with Chinese national conditions;To explore the action mechanism of Yunnan Baiyao capsule in the treatment of traumatic injuries through the network pharmacology method by taking “Panax notoginseng-Aconitum kusnezoffii” as an example,in order to provide the basis for the research of pharmacological experiment and clinical application.Methods1.Analysis of curative effect hemorrhagic diseases and swelling All the articals involving clinical randomized controlled trials of Yunnan Baiyao capsule in several major databases,including Chinese journal full-text Database,Wanfang Academic journal full-text Database,Weipu journal full-text Database,PubMed database,were searched.The retrieval period was from the establishment of each database to February 2019.All the clinical randomized controlled trials involving Yunnan Baiyao capsule in the treatment of hemorrhagic diseases and all the clinical randomized controlled trials involving Yunnan Baiyao capsule in the treatment of swelling were included.Taking the clinical efficacy and adverse reactions as outcome indicators,the collected literatures were screened according to the inclusion and exclusion criteria,and the relevant data included in the literature were sorted out and evaluated.Meta analysis of Yunnan Baiyao capsule in the treatment of hemorrhagic diseases and swelling was carried out by using Review Manager 5.3 software.2.Analysis of adverse drug reactions Chinese journal full-text Database,Wanfang Academic journal full-text Database,Weipu journal full-text Database,PubMed database,were searched from the establishment of each database to February 2019.All research types related to Yunnan Baiyao capsule were included.Statistical literature information was recorded and processed by Microsoft Excel software.According to the extracted data,the adverse drug reactions of Yunnan Baiyao capsule were analyzed.3.Monitoring and analysis of adverse drug reactions 46 of second and third level hospitals in Northeast and southwest China were selected as the centralized monitoring points.The patients received Yunnan Baiyao capsule treatment in each monitoring point during the monitoring period were taken as the research objects,and the patients with adverse drug reactions were taken as the “case”,and the patients without adverse drug reactions as the “control”.The basic information and the medication situation of the patients in detail was recorded,during the treatment period,including family history,allergy history,combined medication situation,and all the discomfort symptoms during the treatment period;14th day after treatment,the occurrence of adverse drug reactions were followed up.Any adverse events in the study must be recorded in the safety monitoring case report form in detail.SPSS 18.0 software was used to analyze the data.4.Analysis of corresponding targets of radix notoginseng(RN)and Radix Aconitum Kusnezoffii(RAK)in treatment of injury based on network pharmacology TCMSP was used to search the active components and corresponding targets of RN and RAK.The effective compounds were screened out with the oral utilization of OB≥30% and drug like DL≥0.18 and screened through literature retrieval.The target names of RN and RAK collected were standardized by UniProt.Through the GeneCards database,the disease targets related to the injury were selected,and the common targets of the injury related diseases and the effective compounds of RN and RAK were obtained by VENNY 2.1 software.The target map of RN-RAK-components-diseases was made by using the software of Cytoscape 3.7.0.Through the STRING database,the human targets with confidence higher than 0.4 were selected,and the protein interaction network(PPI)was drawn by using the software of Cytoscape 3.7.0 to obtain the interaction relationship between the targets of RN and RAK.The core genes were selected by calculating the connectivity value of each target through the plug-in Network Analyzer of the software of Cytoscape 3.7.0.The core modules of the PPI network for the effective component targets were screened out by the plug-in MCODE.Through R 3.6.1 software,GO enrichment analysis and KEGG pathway enrichment analysis were carried out,the results of P<0.05 were retained,and relevant graphs were drawn.Through the difference analysis database GEO,chip data was analysis by GEO2 R tool,and the gene expression differences between injured and uninjured people were compared,GraphPad Prism 8 software was used for drawing.Results1.The meta analysis of Yunnan Baiyao capsule in the treatment of hemorrhagic diseases was finally included in 20 studies.There were 6 studies on the treatment of hemoptysis,including 412 patients,207 in the treatment group and 205 in the control group,the total clinical effective rate[OR=6.64,95%CI(3.61,12.22),P<0.00001].There were 3 studies on the treatment of upper gastrointestinal ulcer hemorrhage,including a total of 264 patients,154 in the treatment group and 110 in the control group,the total clinical effective rate[OR=4.92,95%CI(2.49,9.70),P<0.00001].There were 3 studies on the treatment of gingival bleeding,with a total of 286 patients included,143 in the treatment group and 143 in the control group,the total clinical effective rate[OR=6.34,95%CI(2.70,14.88),P<0.00001].There were 3 studies on the treatment of bleeding after lipu operation,including 600 patients,300 in the treatment group and 300 in the control group,bleeding time [OR=4.09,95%CI(2.75,6.09),P<0.00001],blood loss[OR=3.43,95%CI(2.01,5.86),P<0.00001].There were 13 studies on adverse drug reactions,including 1231 cases,646 cases in the treatment group and 585 cases in the control group,[OR=0.2,95%CI(0.06,0.63),P=0.006];Meta analysis of Yunnan Baiyao capsule in the treatment of swelling was finally included in 7 studies,including 682 patients,346 in the treatment group and 336 in the control group.The total clinical effective rate [OR=3.45,95%CI(1.95,6.10),P<0.0001];serum C-reactive protein [OR=-7.29,95%CI(-7.74,-6.84),P<0.00001];the effective rate [OR=2.67,95%CI(1.65,4.31),P<0.0001].2.16 studies were included,including 11 randomized controlled trials,1 non randomized controlled trial and 4 case reports.The total number of adverse drug reactions was 102.The main adverse drug reactions were gastrointestinal reactions,such as nausea and vomiting,with the proportion of 86.36%.3.Among the 2925 patients who used Yunnan Baiyao capsule in Northeast China,85 cases had adverse events,18 of them were judged as adverse drug reactions,the incidence of adverse drug reactions was 0.62%;among the 4987 patients who used Yunnan Baiyao capsule in Southwest China,194 cases had adverse events,16 of them were judged as adverse drug reactions,the incidence of adverse drug reactions was 0.32%.4.23 effective chemical components were screened out,and 85 common targets of RN-RAK-injury related diseases were selected.The core genes screened in PPI network mainly involve IL6,CASP3,EGFR,VEGFA,MYC,ESR1,CCND1,AR,ERBB2,FOS,etc.There are 106 biological process items indicated by GO enrichment.The GO biological process of PPI core module mainly involves ubiquitin protein ligase binding,protein heterodimer activity,nuclear receptor activity,transcription factor activity,direct ligand regulated sequence specific DNA binding,DNA binding transcriptional activator activity,RNA polymerase II specificity,etc.The concentration of KEGG indicated that there were 44 signaling pathways.The KEGG pathway of PPI core module mainly involved MAPK signaling pathway,EGFR tyrosine kinase inhibitor resistance,ERBB signaling pathway,HIF-1 signaling pathway,Platinum drug resistance,Endocrine resistance,etc.Conclusions1.Yunnan Baiyao capsule has significant curative effect and good safety in the treatment of hemorrhagic diseases,but the conclusion needs more comprehensive high-quality research to further verify;Yunnan Baiyao capsule has obvious detumescence effect,but the safety is not mentioned,and the number of included literature is small,still needs to be included in more high-quality research for further analysis.2.Published research data show that the adverse drug reactions of Yunnan Baiyao capsule are mainly mild and moderate,accounting for 96.55%,and the overall safety is acceptable.3.The incidence of adverse drug reactions of Yunnan Baiyao capsule in Northeast China is slightly higher than that in Southwest China,but all of them belong to the rare level.It can be seen that the safety of Yunnan Baiyao capsule in different areas is good,which is worthy of clinical application and promotion.4.RN-RAK has the characteristics of multi-component and multi-target.The core target and pathway of RN-RAK mainly involve anti-inflammatory,promoting angiogenesis,regulating bone metabolism and so on.