【摘要】：清開靈注射劑目前有清開靈注射液和注射用清開靈(凍干)兩個品種,均主要由膽酸、豬去氧膽酸、水牛角、黃芩苷、梔子、金銀花、板藍根、珍珠母組成,功效為清熱解毒、化痰通絡、醒神開竅,具有抗菌、抗病毒、解熱、抗炎、免疫調節(jié)、保肝及改善腦循環(huán)、保護腦細胞功能等多種藥理作用。清開靈注射劑臨床應用廣泛,尤其在腦血管疾病、上呼吸道感染、肝炎、高熱等方面具有良好的療效。清開靈注射劑的藥效物質基礎、作用機制及臨床評價研究一直是學術界的研究熱點。本研究基于網絡藥理學的研究方法,利用"藥物-成分-靶標-疾病"多層次生物網絡,結合基因功能注釋和KEGG通路,開展清開靈注射劑的作用機制研究;基于Meta分析和系統(tǒng)評價的循證醫(yī)學手段,科學地評估各項臨床隨機對照試驗的方法學質量和相關數據,為清開靈注射劑治療特定疾病提供更加可靠的證據,以供臨床參考。研究目的1探討清開靈注射劑的藥理作用機制,從微觀角度揭示清開靈注射劑藥理作用特點。2系統(tǒng)評價清開靈注射劑治療急性上呼吸道感染、肺炎、流行性腮腺炎的臨床療效及安全性。研究方法(一)網絡藥理學利用公共數據庫(如TCMSP、PubChemCompound和TCMID)收集清開靈注射劑的成分及其分子信息,結合藥物分子的ADME性質參數及文獻研究,預測和篩選活性分子,并獲取其靶標、基因及疾病信息,利用Microsoft Access 2010構建數據庫;提取數據,利用Cytoscape 3.4.0軟件構建"藥物-成分-靶標-疾病"網絡圖,進行網絡拓撲學分析,確定網絡關鍵節(jié)點或關鍵模塊,再通過GO功能富集分析和KEGG通路富集分析,分析其基因集合的主要功能,多層次、多角度探討清開靈注射劑的作用機制。(二)Meta 分析通過全面檢索國內外文獻數據庫,包括中國知網、萬方、維普、SinMed、PubMed、Springer、Web of Science、Cochrane Central Register of Controlled Trials 等,收集清開靈注射劑治療特定疾病的臨床隨機對照試驗(RCTs),納入符合標準的RCTs,并對其進行質量評價和資料提取;對同質性較好的研究進行Meta分析,以森林圖呈現(xiàn)結果;異質性較大時可采用Meta回歸、亞組分析、敏感性分析探討異質性來源,采用敏感性分析檢驗結果的穩(wěn)定性,以漏斗圖檢測發(fā)表偏倚。研究結果(一)基于網絡藥理學的作用機制研究1數據庫構建:所構建的"清開靈注射劑網絡藥理學基礎信息數據庫"包含清開靈注射劑的8個藥物所涉及的116個成分,1 271個靶標,929種疾病,以及3 786條成分、靶標、疾病對應關系。2清開靈注射劑作用機制的拆方分析研究:(1)"膽酸-豬去氧膽酸"作用機制研究:主要成分膽酸、豬去氧膽酸均具有較好的類藥性;該藥對的"藥物-成分-靶標-疾病"網絡涉及6個靶標和8種疾病,以鹽皮質激素受體(MR)和肝X受體(LXRα、LXRβ)為關鍵靶標,主要涉及腦損傷、動脈粥樣硬化、血脂異常等疾病;GO富集主要在甘油三酯的合成、膽固醇的儲存及流出調控等生物學過程方面,KEGG通路主要富集在胰島素抵抗通路等。(2)"水牛角-珍珠母"作用機制研究:共篩選出6個成分,其總體類藥性較好;該藥對的"藥物-成分-靶標-疾病"網絡涉及765個靶標和595種疾病,以前列腺素內過氧化物合酶2(COX-2)和過氧化物酶體增殖物激活受體γ(PPARγ)為關鍵靶標,以精神分裂癥、阿爾茨海默癥和炎癥為度值最高的疾病;GO富集主要在小分子代謝、細胞代謝等生物學過程方面,KEGG通路主要富集在多種氨基酸代謝通路中。(3)"黃芩苷-梔子"作用機制研究:共篩選出20個成分,其總體類藥性較好;該藥對的"藥物-成分-靶標-疾病"網絡涉及198個靶標和369種疾病,以COX-2、PPARy和5-脂氧合酶(5-LOX)等為關鍵靶標,疾病主要涉及腫瘤、糖尿病、心血管疾病等;GO富集主要在化學刺激響應、細胞增殖調控、細胞凋亡及細胞程序性死亡調控等生物學過程方面,KEGG通路主要富集在多種癌癥通路和乙型肝炎通路等。(4)"金銀花-板藍根"作用機制研究:共篩選出92個成分,其總體類藥性較好;該藥對的"藥物-成分-靶標-疾病"網絡涉及665個靶標和609種疾病,以COX-2、熱休克蛋白90α(HSP86)、前列腺素內過氧化物合酶1(COX-1)和PPARγ等為關鍵靶標,疾病主要涉及腫瘤、心血管疾病、糖尿病、阿爾茨海默癥、炎癥等;GO富集主要在細胞表面受體相關信號通路、化學刺激響應等生物學過程方面,KEGG通路主要富集在cAMP信號通路、鈣離子信號通路、多種癌癥通路及乙型肝炎通路等。3清開靈注射劑作用機制的整體研究:共篩選出116個成分,其總體類藥性較好;清開靈注射劑的"藥物-成分-靶標-疾病"網絡涉及1 271個靶標和929種疾病,以COX-2、HSP86、COX-1靶標度值最高,主要涉及腫瘤、心血管疾病、糖尿病、阿爾茨海默癥、精神分裂癥、炎癥等疾病;GO富集主要在化學刺激響應、信號傳遞、代謝過程等生物學過程方面,KEGG通路主要富集在cAMP信號通路、cGMP-PKG信號通路、多種氨基酸代謝通路、癌癥通路和乙型肝炎通路等;模塊分析所得6個模塊對應基因的GO富集主要在心率調控、心肌收縮調控等生物學過程中,KEGG通路主要富集在心肌細胞腎上腺素信號通路和cGMP-PKG信號通路等;具有血腦屏障通透性的29個成分對應基因的GO富集主要在膽固醇代謝過程、膽固醇體內平衡等生物學過程中,KEGG通路主要富集在PPAR信號通路、多種氨基酸的合成通路及尼古丁成癮通路等。(二)基于Meta分析的臨床評價研究1清開靈注射劑治療急性上呼吸道感染:納入42項研究,累計患者5 905例;在單用或聯(lián)合西醫(yī)對癥治療基礎上,清開靈注射劑在提高急性上呼吸道感染的臨床療效總有效率方面優(yōu)于利巴韋林注射劑(RR=1.19,95%CI:1.16～1.22,P0.000 01)等;12項研究累計報告試驗組42例藥品不良反應/不良事件(ADRs/ADEs),11項研究累計報告對照組34例ADRs/ADEs。2清開靈注射劑治療肺炎:納入17項研究,累計患者1 702例;在應用抗生素和對癥治療基礎上,聯(lián)用清開靈注射劑可提高治療肺炎的臨床療效總有效率(RP= 1.23,95%CI:1.14～1.33,P0.000 01)等;4 項研究累計報告試驗組 27 例 ADRs/ADEs,對照組64例ADRs/ADEs。3清開靈注射劑治療流行性腮腺炎:納入7項研究,累計患者580例;清開靈注射劑聯(lián)合對癥治療在縮短流行性腮腺炎的退熱時間方面優(yōu)于利巴韋林注射劑聯(lián)合對癥治療或僅對癥治療(MD =-1.16,95%CI:-1.36～-0.96,P0.000 01)等;3項研究未發(fā)生ADRs/ADEs,4項研究未報告ADRs/ADEs。研究結論1清開靈注射劑各藥對的網絡關鍵節(jié)點分析、基因GO功能注釋和KEGG通路富集分析的結果各有側重,反映了清開靈注射劑各藥對之間功效的差異及各藥對之間作用機制方面的相互配合,體現(xiàn)了中醫(yī)配伍用藥和復方用藥的意義。2清開靈注射劑可能由多個成分通過作用于LXR、COX-2、HSP86和PPARγ等關鍵靶標,調控膽固醇代謝與其體內平衡、氨基酸代謝、細胞增殖及細胞凋亡等多個生物學過程,參與多個信號通路、代謝通路和癌癥等疾病通路,在腫瘤、心血管疾病、糖尿病、阿爾茨海默癥、精神分裂癥及炎癥等疾病中發(fā)揮作用。3清開靈注射劑臨床主要用于腦血管疾病,用于心血管疾病治療的報道較少,但本研究發(fā)現(xiàn)其多個作用靶標、相關通路與心肌梗死、缺血性心臟病等心血管疾病密切相關,值得進一步深入研究。4清開靈注射劑各藥對及其整體處方的"藥物-成分-靶標-疾病"網絡均具有部分無標度和小世界特性,模塊屬性很低,適宜采用識別關鍵節(jié)點的方法進行網絡分析,模塊分析的方法根據具體情況可以選用。5在臨床應用方面,相較于僅采用西醫(yī)常規(guī)治療或對癥治療,聯(lián)合清開靈注射劑可以提高急性上呼吸道感染、肺炎和流行性腮腺炎的治療效果。但是本研究通過納入文獻的分析,在清開靈注射劑的安全性方面尚無法給出確切結論。
[Abstract]:Qingkailing injection has two varieties of Qingkailing injection and injection Qingkailing (freeze-dried), which are mainly composed of cholic acid, porcine deoxycholic acid, water ox horn, baicalin, gardenia, honeysuckle, Radix Isatidis root, pearl mother. The effect is clearing heat and detoxifying, removing phlegm and dredging collaterals, opening the orifices, antivirus, antipyretic, anti-inflammatory, immune regulation, liver preservation and improvement. Qingkailing injection has a wide range of clinical applications, especially in cerebrovascular disease, upper respiratory tract infection, hepatitis, high fever and so on. The pharmacological basis, mechanism and clinical evaluation of Qingkailing injection have always been a hot topic in the academic field. In the study of network pharmacology, the mechanism of the action mechanism of Qingkailing injection was studied by using the multilevel biological network of "drug component - target disease", combined with gene functional annotation and KEGG pathway, and based on the evidence-based medical methods of Meta analysis and systematic evaluation, the methodological quality and phase of various clinical randomized controlled trials were evaluated scientifically. To provide more reliable evidence for the treatment of specific diseases by Qingkailing injection for clinical reference. Objective 1 to explore the pharmacological mechanism of Qingkailing injection and to reveal the pharmacological and functional characteristics of Qingkailing injection from the microcosmic point of view.2 system evaluation of Qingkailing injection for the treatment of acute upper respiratory infection, pneumonia, and epidemic parotid gland. The clinical efficacy and safety of inflammation. (I) network pharmacology uses public databases (such as TCMSP, PubChemCompound and TCMID) to collect the components and molecular information of Qingkailing injection, combined with the ADME properties and literature research of drug molecules, to predict and screen the active molecules, and to obtain their targets, gene and disease information, and use M Icrosoft Access 2010 constructs the database, extracts the data, uses the Cytoscape 3.4.0 software to construct the "drug component target disease" network map, carries out network topology analysis, determines the network key nodes or key modules, and then analyzes the main functions of the gene collection by GO function enrichment analysis and KEGG pathway enrichment analysis, and the multilevel and multi angle analysis. The effect mechanism of Qingkailing injection was discussed. (two) Meta analysis through the comprehensive retrieval of domestic and foreign literature database, including China know net, Wanfang, VP, SinMed, PubMed, Springer, Web of Science, Cochrane Central Register of Controlled, collect the clinical randomized controlled trial of Qingkailing injection for the treatment of specific diseases. The quality evaluation and data extraction were included in the standard RCTs, and Meta analysis was carried out for better homogeneity research. The result of forest map was presented. Meta regression, subgroup analysis, sensitivity analysis were used to investigate the heterogeneity, and sensitivity analysis was used to test the stability of the results. 1 database construction based on network pharmacology: the construction of "Qingkailing injection network pharmacology basic information database" contains 116 components, 1271 targets, 929 diseases, 3786 components, target, and disease correspondence.2 Qingkailing for the 8 drugs of Qingkailing injection network pharmacology. Analysis and Study on the mechanism of the action of injections: (1) the mechanism of the action of cholic acid - porcine deoxycholic acid: the main component of cholic acid, porcine deoxycholic acid has a better class property; the drug - drug - ingredient - target - disease network involves 6 targets and 8 diseases, and the key target is the MR and the liver X receptor (LXR a, LXR beta). Mainly related to brain injury, atherosclerosis, dyslipidemia and other diseases, GO enrichment mainly in the synthesis of triglycerides, cholesterol storage and regulation of biological processes, the KEGG pathway is mainly enriched in the insulin resistance pathway. (2) the "water cow angle pearl mother" mechanism: a total of 6 components, its overall drug resistance Well, the drug's "drug - component - target - disease" network involves 765 targets and 595 diseases, with prostaglandin endogenous peroxidase 2 (COX-2) and peroxisome proliferator activated receptor gamma (PPAR gamma) as the key target, with schizophrenia, Alzheimer's disease and inflammation as the highest degree of disease; GO enrichment is mainly in small molecular generations. KEGG pathway is mainly enriched in a variety of amino acid metabolic pathways. (3) the mechanism of "baicalin - Gardenia" is studied: a total of 20 components are screened, and their overall drug resistance is better; the drug "drug component target disease" network involves 198 targets and 369 diseases, with COX-2, PPARy, and 5- lipoxygenase. 5-LOX) and so on as the key target, the disease mainly involves tumor, diabetes, cardiovascular disease and so on. The enrichment of GO is mainly in the biological process of chemical stimulation response, cell proliferation regulation, cell apoptosis and programmed cell death regulation. The KEGG pathway is mainly enriched in many kinds of cancer pathways and hepatitis B pathway. (4) "honeysuckle isatis root" effect Mechanism study: a total of 92 components were screened, and their overall drug class was better; the drug "drug component target disease" network involved 665 targets and 609 diseases, with COX-2, heat shock protein 90 alpha (HSP86), prostaglandin synthase 1 (COX-1) and PPAR gamma as the key targets, and the disease mainly involved tumor, cardiovascular disease, diabetes, Alzheimer's disease, inflammation and so on; GO enrichment mainly in the cell surface receptor related signaling pathway, chemical stimulation response and other biological processes, the KEGG pathway is mainly enriched in the cAMP signal pathway, calcium signal pathway, various cancer pathways and hepatitis B pathway and other.3 Qingkailing injection mechanism of the overall study: a total of 116 COX-2, HSP86, COX-1 target value is the highest, mainly involving tumor, cardiovascular disease, diabetes, Alzheimer's disease, Alzheimer's disease, semen schizophrenia, inflammation and other diseases; GO enrichment mainly in chemical stimulation response, letter KEGG pathway is mainly enriched in cAMP signaling pathway, cGMP-PKG signaling pathway, multiple amino acid pathway, cancer pathway and hepatitis B pathway, and the GO enrichment of the 6 module corresponding genes is mainly in biological processes such as heart rate regulation, myocardial contraction regulation and other biological processes, KEGG pathway. The epinephrine signaling pathway and cGMP-PKG signaling pathway are mainly enriched in the cardiac myocytes; the GO enrichment of the 29 components corresponding to the permeability of the blood brain barrier is mainly in the biological process of cholesterol metabolism and cholesterol balance, and the KEGG pathway is mainly enriched in the PPAR signaling pathway, the synthesis pathway of various amino acids and the NiO Ding Chengyin pathway, etc. (two) clinical evaluation based on Meta analysis 1 Qingkailing Injection in the treatment of acute upper respiratory tract infection: 42 studies and 5905 cumulative patients; on the basis of single use or combined treatment of Western medicine, the total effectiveness of Qingkailing Injection in improving the clinical efficacy of acute upper respiratory infection is superior to Leigh Bhave Lin. Injection (RR=1.19,95%CI:1.16 ~ 1.22, P0.000 01), 12 studies reported 42 cases of adverse drug reactions / adverse events (ADRs/ADEs) in the experimental group, and 11 studies reported 34 cases of ADRs/ADEs.2 Qingkailing injection for pneumonia in the control group: 17 studies were included in 1702 cases, combined with antibiotics and symptomatic treatment. Qingkailing injection could improve the total effective efficiency of the treatment of pneumonia (RP= 1.23,95%CI:1.14 ~ 1.33, P0.000 01), 4 studies reported 27 cases of ADRs/ADEs in the experimental group and 64 cases of ADRs/ADEs.3 Qingkailing Injection in the control group for the treatment of epidemic parotitis: 7 studies, 580 cases of cumulative patients, and Qingkailing Injection combined with symptomatic treatment. The time of reducing the fever of epidemic parotitis was better than that of Leigh Bhave Lin injection combined with symptomatic treatment or only symptomatic treatment (MD =-1.16,95%CI:-1.36 to -0.96, P0.000 01); 3 studies did not occur ADRs/ADEs, 4 studies did not report ADRs/ADEs. study conclusion 1 the key node analysis of each drug pair of Qingkailing injection, gene GO function injection. The results of the analysis of the concentration and analysis of the KEGG pathway were focused, reflecting the differences in the efficacy of each drug and the interaction between the drugs and the mechanism of the action between each drug, reflecting the significance of the combination of medicine and compound medicine of traditional Chinese medicine (.2), the key of the Qingkailing injection may be affected by many components through the action on LXR, COX-2, HSP86 and PPAR gamma. Target, regulation of cholesterol metabolism and its internal balance, amino acid metabolism, cell proliferation, cell apoptosis and other biological processes involved in multiple signaling pathways, metabolic pathways and cancer pathways, and play a role in.3 injection in diseases such as tumors, cardiovascular diseases, diabetes, Alzheimer's disease, schizophrenia and inflammation. The drug is mainly used in cerebrovascular disease, and there are few reports on the treatment of cardiovascular diseases. However, this study found that many target targets, related pathways are closely related to myocardial infarction, ischemic heart disease and other cardiovascular diseases. It is worthwhile to further study the "drug composition target disease" and the overall prescription of.4 Qingkailing injection. The disease "network has a part of scale-free and small world characteristics, the module attribute is very low, the method of identifying key nodes is suitable for network analysis. The method of module analysis can choose.5 in clinical application according to the specific situation, compared with only conventional treatment of Western medicine or symptomatic treatment, combined with Qingkailing injection can improve the acute effect. The treatment effect of upper respiratory tract infection, pneumonia and mumps. However, the safety of Qingkailing injection has not been given by the analysis of the literature.
【學位授予單位】：北京中醫(yī)藥大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R286

【參考文獻】

相關期刊論文 前10條

1 王青海;;納美芬聯(lián)合清開靈注射液治療重度安眠藥中毒臨床觀察[J];河南醫(yī)學研究;2017年01期

2 梁華;彭小寶;楊軍平;楊建安;周愛明;;清開靈、雙黃連聯(lián)合頭孢哌酮-舒巴坦鈉對產ESBLs肺炎克雷伯菌抗菌作用研究[J];實驗與檢驗醫(yī)學;2016年06期

3 楊維;吳思s，

本文編號：2141941