Systematic Evaluation Of Zaoren Anshen Capsule In The Treatment Of Insomnia And Its Network Pharmacological Analysis

Objective1 To systematically evaluate the efficacy and safety of Zaoren Anshen Capsule in the treatment of insomnia,and to provide evidence-based medicine reference for its rational clinical practice.2 To explore the molecular mechanism of synergistic effect of Zaoren Anshen Capsule in the treatment of insomnia,and revealing the pharmacological action characteristics of Zaoren Anshen Capsule from the microscopic view.Methods1 Meta-analysis Retrieved from Chinese and English databases(Pub Med,EBSCO,the Cochrane Library,CNKI,VIP and Wanfang Data),randomized controlled trials(RCTs)about therapeutic efficacy of Zaoren Anshen Capsule in the treatment of insomnia were collected.The time limit of the retrieval was from the construction to the March 2021.The study quality was evaluated according to the inclusion criteria,data were extracted and meta analyzed by Rev Man 5.3 software.2 Network pharmacology According to the comprehensive evaluation of content and activity,the anti-insomnia chemical constituents of Zaoren Anshen Capsule were screened by literature analysis.The anti-insomnia targets of Zaoren Anshen Capsule were obtained from Swiss Target Prediction,Drugbank,Pub Med and Gen CLip 3 databases,and then the network of chemical constituents of Zaoren Anshen Capsule-anti-insomnia was constructed by Cytoscape 3.6.1 software.The protein-protein interaction network and MCODE analysis of targets of Zaoren Anshen Capsule were performed by using STRING and MCODE plugin,and the anti-insomnia key targets of Zaoren Anshen Capsule were further obtained according to the topological parameter analysis.The GO biological process enrichment of anti-insomnia targets of Zaoren Anshen capsule was carried out by using Clue GO plugin.Finally,KEGG pathway enrichment of key targets of Zaoren Anshen capsule was conducted through DAVID 6.8 database.Results1 Clinical evaluation studies based on Meta analysis A total of 12 RCTs involving 1127 patients were included in this study.Clinical efficacy [RR=1.04,95%CI(0.99,1.10),P=0.11],and PSQI [MD=-0.40,95%CI(-1.94,1.14),P=0.61] showed that the efficacy of Zaoren Anshen Capsule in the treatment of insomnia was similar to benzodiazepine receptor agonists,and there was no statistical significance between the two.However,the incidence of adverse reactions in patients was far lower than the benzodiazepine receptor agonists.Dizziness and headache [RR=0.07,95%CI(0.02,0.18),P < 0.00001],lethargy [RR= 0.13,95%CI(0.05,0.31),P < 0.00001],hangover [RR= 0.14,95%CI(0.03,0.62),P=0.009],fatigue[RR =0.46,95%CI(0.31,0.68),P=0.0001].2 The mechanism research based on network pharmacology20 kinds of anti-insomnia chemical constituents of Zaoren Anshen Capsule,including Jujuboside A,Spinosin,Schisandrol A,TanshinoneⅠ,Tanshinonel IIA,Salvianolic acid B,etc,involved 120 anti-insomnia targets,among which 31 targets involved neurotransmitter receptors or transport proteins,including serotonin receptors,gamma-aminobutyric acid receptors,acetylcholine receptors,dopamine receptors,glutamate receptors,histamine receptors,opioid receptors,orexin receptor,melatonin receptor,neuropeptide receptor,and neurotransmitter transport proteins.These anti-insomnia chemical constituents of Zaoren Anshen Capsule could act on 26 anti-insomnia key targets such as HTR1 A,HTR2A,HTR2 C,DRD2,PTGS2,TNF,MAPK1,MAPK3,CNR1,and MAOA,participate in biological processes such as neurotransmitter receptor activity,regulation of circadian sleep/wake cycle,regulation of phosphatidylinositol biosynthetic process phosphatidylinositol biosynthetic,calcium-mediated signaling using extracellular calcium source,and regulation of chronic inflammatory response,regulate serotonergic synapse,neuroactive ligand-receptor interaction,retrograde endocannabinoid signaling,cocaine addiction,amphetamine addiction,MAPK,PI3K-Akt,TNF and other signaling pathways.Conclusions1 Zaoren Anshen Capsule is effective in the treatment of insomnia with less and light adverse reaction.Due to the limitations of the number and quality of studies included,the conclusion still needs to be verified by more randomized controlled trials with more centers and higher quality.2 Zaoren Anshen Capsule can treat insomnia by regulating neurotransmitters,protein phosphorylation,central analgesia,anti-inflammatory,improving anxiety and depression.