【摘要】：目的：1.通過對應(yīng)用中醫(yī)補腎強督法治療強直性脊柱炎(ankylosing spondylitis, AS)的療效和安全性進行文獻的系統(tǒng)評價及meta分析,為補腎強督法治療AS提供初級循證醫(yī)學(xué)證據(jù)。2.采用隨機、對照、前瞻性臨床研究,客觀評價中醫(yī)補腎強督法綜合方案治療AS在關(guān)節(jié)功能狀態(tài)及影像學(xué)方面的臨床療效,揭示其抗骨化潛能,并為后期大樣本、多中心的隨機對照研究提供參考。3.以Connexin43 (Cx43)為靶點,研究補腎強督方藥對體外培養(yǎng)的大鼠成纖維細胞增殖及成骨分化的影響,初步探討補腎強督法抗AS異位骨化的機制,為其臨床療效提供科學(xué)證據(jù)。方法：1.系統(tǒng)評價系統(tǒng)評價近30年間發(fā)表的應(yīng)用補腎強督法治療AS的臨床隨機對照研究的文獻,通過分析文獻確定檢索主題詞,計算機檢索PubMed (1985/2015-5)、Embase (1985/2015-5)、ScienceDirect (1985/2015-5)、CBM (1985/2015-5)、VIP (1985/2015-5)、CNKI (1985/2015-5)和WANFANG(1985/2015-5),使用Note express V3.0.2.6367進行文獻數(shù)據(jù)庫的管理,通過Excel進行數(shù)據(jù)的提取,采用Cochrane Review Manager 5.2進行偏倚風(fēng)險評價和Meta分析。2.臨床研究納入腎虛督寒證AS患者30例,隨機分為中醫(yī)試驗組及西醫(yī)對照組,兩組各15例,均采用功能鍛煉作為基礎(chǔ)治療,試驗組服用補腎強督治僂湯加減,并聯(lián)合督灸,對照組服用塞來昔布,療程均為48周,采用ASAS工作組推薦的基于CRP的AS疾病活動指數(shù)(ASDAS-CRP)為主要療效評價標準,并通過巴氏AS功能指數(shù)(BASFI),巴氏AS測量指數(shù)(BASMI)和胸廓活動度,AS生活質(zhì)量問卷(ASQoL)及骶髂關(guān)節(jié)核磁(MRI)評價補腎強督綜合方案治療AS在關(guān)節(jié)功能狀態(tài)及影像學(xué)方面的臨床療效,初步探討其抗骨化潛能。3.實驗研究以體外培養(yǎng)的大鼠髖關(guān)節(jié)周圍韌帶成纖維細胞為研究對象,采用MTS法觀察補腎強督治僂湯對成纖維細胞增殖的影響,并采用免疫印跡(WB)法探究補腎強督治僂湯對成纖維細胞成骨標志蛋白及Cx43蛋白表達的影響。結(jié)果：1.系統(tǒng)評價初檢出相關(guān)文獻923篇,排除重復(fù)文獻214篇,排除非隨機對照試驗、動物試驗、綜述、經(jīng)驗論述673篇,排除研究設(shè)計、干預(yù)措施、結(jié)局指標等不符合納入／排除標準的文獻23篇,納入可分析文獻13篇,共972例病例。結(jié)果顯示,以補腎強督法治療方案/基于補腎強督法的中西醫(yī)結(jié)合治療方案治療AS, AS療效評價標準20(ASAS20)達標率、中醫(yī)證候改善率、血沉(ESR)、疼痛視覺模擬評分法(Visual Analogue Scale/Score, VAS)、腰椎活動度(Schober)均高于西醫(yī)治療組(RR= 1.19 [1.03, 1.24],Z=2.37,P=0.02; RR= 1.17 [1.07,1.28],Z=3.44,P=0.0006; MD=-0.62 [-1.08,-0.17], Z=2.67, P=0.008; MD=-14.23 [-22.58,-5.88], Z=3.34, P=0.0008; MD=0.36 [0.20,0.53], Z=4.41, P0.0001)。2.臨床研究中醫(yī)補腎強督法綜合方案和西醫(yī)綜合方案均可顯著降低AS患者ASDAS-CRP、 BASFI、ASQoL并改善骶髂關(guān)節(jié)骨髓水腫評分(SPARCC評分)(P0.05),但對BASMI和胸廓活動度無明顯改善作用(P0.05),兩組差異無顯著性意義(P0.05)；在改善AS關(guān)節(jié)面硬化、侵蝕及骨贅的形成情況的骨質(zhì)病變方面中醫(yī)試驗組優(yōu)于西醫(yī)對照組(P0.05)。3.實驗研究補腎強督方藥對大鼠成纖維細胞增殖具有抑制作用,且呈現(xiàn)出一定的濃度依賴性,隨藥物濃度升高而抑制作用增強,500μg/ml的補腎強督方藥對大鼠成纖維細胞增殖的抑制率達(18.791±4.637)%(P0.001)；補腎強督方藥以及塞來昔布可同時下調(diào)成纖維細胞核心結(jié)合因子(Core Binding Factorα1, Cbfα1)、Cx43及磷酸化的Cx43(pCx43)蛋白的表達(P0.05或P0.001),兩組比較,差異無統(tǒng)計學(xué)意義(P0.05)。結(jié)論：1.中醫(yī)補腎強督法治療方案/基于補腎強督的中西醫(yī)結(jié)合治療方案治療AS與單純西醫(yī)治療AS比較,療效較好,為中醫(yī)補腎強督法應(yīng)用于AS治療提供了有力證據(jù)。2.補腎強督法綜合方案治療AS可有效改善患者關(guān)節(jié)功能狀態(tài),糾正患者骶髂關(guān)節(jié)骨髓水腫,且在骨質(zhì)改善上展現(xiàn)出較西醫(yī)對照組更好的療效,提示中醫(yī)補腎強督法綜合方案治療AS療效肯定,且可能在抗骨化作用上具有一定潛能和優(yōu)勢。3.補腎強督法可能通過抑制成纖維細胞的增殖并調(diào)節(jié)Cx43半通道而抑制韌帶成纖維細胞的成骨分化,起到抗AS骨化、延緩AS骨質(zhì)病變的作用。
[Abstract]:Objective: 1. through the systematic evaluation and meta analysis of the curative effect and safety of ankylosing spondylitis (AS) in the treatment of ankylosing spondylitis (AS) by using Chinese traditional Chinese medicine for tonifying kidney and governor, to provide primary evidence-based evidence for the treatment of AS by reinforcing kidney and governor method,.2. is random, contrast, forward-looking clinical study and objective evaluation of traditional Chinese medicine. The therapeutic effect of AS on joint functional status and imaging, and to reveal its anti ossification potential, and to provide reference.3. to Connexin43 (Cx43) as a target for large sample and multi center randomized controlled study, to investigate the effect of tonifying kidney and governor prescription drugs on the proliferation and osteogenic differentiation of rat fibroblasts cultured in vitro. To discuss the mechanism of reinforcing kidney and governor method against AS heterotopic ossification and providing scientific evidence for its clinical efficacy. Methods: 1. systematic evaluation system was used to evaluate the literature of the clinical randomized controlled study on the treatment of AS by reinforcing kidney and governor method in the last 30 years. Through the analysis of the literature, the subject words were retrieved, and the computing machine retrieved PubMed (1985/2015-5), Embase (1985/2015-5). ScienceDirect (1985/2015-5), CBM (1985/2015-5), VIP (1985/2015-5), CNKI (1985/2015-5) and WANFANG (1985/2015-5), use Note express to carry out the management of the literature database. 30 AS patients with cold syndrome were randomly divided into the traditional Chinese medicine test group and the western medicine control group, 15 cases in each of the two groups, all with functional exercise as the basic treatment. The test group took tonifying kidney and Qiang Du Zhi Tang Decoction plus subtraction, and the control group was treated with celecoxib for 48 weeks, using the CRP based AS disease activity index recommended by the ASAS working group (ASDAS-CRP For the main therapeutic evaluation criteria, and through the pasteurized AS function index (BASFI), the pasteurized AS measurement index (BASMI) and the thoracic activity degree, the AS life quality questionnaire (ASQoL) and the sacroiliac joint NMR (MRI), the clinical effect of the combination of the kidney and the strong governor (MRI) for the treatment of AS in the functional state and image of the joint was evaluated, and its anti ossification potential.3. experiment was preliminarily discussed. The effect of tonifying kidney and Qiang Du Zhi Zhi Decoction on fibroblast proliferation was studied by MTS method, and the effect of invigorating kidney and Qiang Du Zhi Zhi Decoction on the expression of osteoblast marker protein and Cx43 protein in fibroblasts was investigated by WB method. Results: 1. 923 articles were first detected, 214 articles were excluded, non randomized controlled trials, animal tests, review, 673 experiences, 23 articles that were excluded from the inclusion / exclusion criteria were excluded from research design, intervention measures and outcome indicators, including 13 articles and 972 cases. The combination of Chinese and Western medicine based on reinforcing the kidney and strengthening the kidney was treated for the treatment of AS, the standard 20 (ASAS20), the improvement rate of TCM syndrome, the ESR, the Visual Analogue Scale/Score, VAS, and the lumbar activity (Schober) higher than that of the western medicine group (RR= 1.19 [1.03, 1.24], VAS, 1.17). .28], Z=3.44, P=0.0006; MD=-0.62 [-1.08, -0.17], Z=2.67, P=0.008; MD=-14.23 [-22.58, -5.88], Z=3.34. (SPARCC score) (P0.05), but no significant improvement on BASMI and thoracic activity (P0.05), there was no significant difference between the two groups (P0.05). In the improvement of AS joint sclerosis, erosion and osteophyte formation, the traditional Chinese medicine test group was superior to the western medicine group (P0.05).3. experiment to study the fibroblast fineness of tonifying kidney and strong governor prescription drugs to rats. Cell proliferation had a inhibitory effect, and showed a certain concentration dependence. The inhibitory effect was enhanced with the increase of drug concentration. The inhibitory rate of 500 g/ml tonifying kidney strong governor on the proliferation of rat fibroblasts was (18.791 + 4.637)% (P0.001), and celecoxib could reduce the core binding factor of fibroblasts at the same time (Core The expression of Binding Factor alpha 1, Cbf alpha 1), Cx43 and phosphorylated Cx43 (pCx43) protein (P0.05 or P0.001), the difference between the two groups was not statistically significant (P0.05). Conclusion: 1. Chinese traditional Chinese medicine for tonifying kidney and strong governor method / based on the combination of traditional Chinese and Western medicine treatment scheme based on reinforcing kidney and governor is compared with pure western medicine for AS, and the curative effect is better, and it is the strengthening of kidney in traditional Chinese medicine. The application of the governor method to the treatment of AS provides strong evidence for the combination of.2. kidney and strong governor method in the treatment of AS, which can effectively improve the state of the joint function, correct the bone marrow edema of the sacroiliac joint, and show a better curative effect on the bone improvement than the western medicine control group. There is a certain potential and advantage in the ossification effect of.3., which may inhibit the proliferation of fibroblasts and regulate the Cx43 semi channel to inhibit the osteogenic differentiation of the ligament fibroblasts, and play an anti AS ossification and delay the effect of AS osteogenesis.
【學(xué)位授予單位】：廣州中醫(yī)藥大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R259

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