补肾强督法治疗强直性脊柱炎的疗效及抗骨化作用初探

发布时间：2018-08-09 14:11

【摘要】：目的：1.通过对应用中医补肾强督法治疗强直性脊柱炎(ankylosing spondylitis, AS)的疗效和安全性进行文献的系统评价及meta分析,为补肾强督法治疗AS提供初级循证医学证据。2.采用随机、对照、前瞻性临床研究,客观评价中医补肾强督法综合方案治疗AS在关节功能状态及影像学方面的临床疗效,揭示其抗骨化潜能,并为后期大样本、多中心的随机对照研究提供参考。3.以Connexin43 (Cx43)为靶点,研究补肾强督方药对体外培养的大鼠成纤维细胞增殖及成骨分化的影响,初步探讨补肾强督法抗AS异位骨化的机制,为其临床疗效提供科学证据。方法：1.系统评价系统评价近30年间发表的应用补肾强督法治疗AS的临床随机对照研究的文献,通过分析文献确定检索主题词,计算机检索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进行文献数据库的管理,通过Excel进行数据的提取,采用Cochrane Review Manager 5.2进行偏倚风险评价和Meta分析。2.临床研究纳入肾虚督寒证AS患者30例,随机分为中医试验组及西医对照组,两组各15例,均采用功能锻炼作为基础治疗,试验组服用补肾强督治偻汤加减,并联合督灸,对照组服用塞来昔布,疗程均为48周,采用ASAS工作组推荐的基于CRP的AS疾病活动指数(ASDAS-CRP)为主要疗效评价标准,并通过巴氏AS功能指数(BASFI),巴氏AS测量指数(BASMI)和胸廓活动度,AS生活质量问卷(ASQoL)及骶髂关节核磁(MRI)评价补肾强督综合方案治疗AS在关节功能状态及影像学方面的临床疗效,初步探讨其抗骨化潜能。3.实验研究以体外培养的大鼠髋关节周围韧带成纤维细胞为研究对象,采用MTS法观察补肾强督治偻汤对成纤维细胞增殖的影响,并采用免疫印迹(WB)法探究补肾强督治偻汤对成纤维细胞成骨标志蛋白及Cx43蛋白表达的影响。结果：1.系统评价初检出相关文献923篇,排除重复文献214篇,排除非随机对照试验、动物试验、综述、经验论述673篇,排除研究设计、干预措施、结局指标等不符合纳入／排除标准的文献23篇,纳入可分析文献13篇,共972例病例。结果显示,以补肾强督法治疗方案/基于补肾强督法的中西医结合治疗方案治疗AS, AS疗效评价标准20(ASAS20)达标率、中医证候改善率、血沉(ESR)、疼痛视觉模拟评分法(Visual Analogue Scale/Score, VAS)、腰椎活动度(Schober)均高于西医治疗组(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.临床研究中医补肾强督法综合方案和西医综合方案均可显著降低AS患者ASDAS-CRP、 BASFI、ASQoL并改善骶髂关节骨髓水肿评分(SPARCC评分)(P0.05),但对BASMI和胸廓活动度无明显改善作用(P0.05),两组差异无显著性意义(P0.05)；在改善AS关节面硬化、侵蚀及骨赘的形成情况的骨质病变方面中医试验组优于西医对照组(P0.05)。3.实验研究补肾强督方药对大鼠成纤维细胞增殖具有抑制作用,且呈现出一定的浓度依赖性,随药物浓度升高而抑制作用增强,500μg/ml的补肾强督方药对大鼠成纤维细胞增殖的抑制率达(18.791±4.637)%(P0.001)；补肾强督方药以及塞来昔布可同时下调成纤维细胞核心结合因子(Core Binding Factorα1, Cbfα1)、Cx43及磷酸化的Cx43(pCx43)蛋白的表达(P0.05或P0.001),两组比较,差异无统计学意义(P0.05)。结论：1.中医补肾强督法治疗方案/基于补肾强督的中西医结合治疗方案治疗AS与单纯西医治疗AS比较,疗效较好,为中医补肾强督法应用于AS治疗提供了有力证据。2.补肾强督法综合方案治疗AS可有效改善患者关节功能状态,纠正患者骶髂关节骨髓水肿,且在骨质改善上展现出较西医对照组更好的疗效,提示中医补肾强督法综合方案治疗AS疗效肯定,且可能在抗骨化作用上具有一定潜能和优势。3.补肾强督法可能通过抑制成纤维细胞的增殖并调节Cx43半通道而抑制韧带成纤维细胞的成骨分化,起到抗AS骨化、延缓AS骨质病变的作用。
[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.
【学位授予单位】：广州中医药大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R259

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