本文選題：乙酰水楊酸聯(lián)合雙氯芬酸　切入點：骨關(guān)節(jié)炎　出處：《山東大學(xué)》2016年博士論文　論文類型：學(xué)位論文

【摘要】：骨關(guān)節(jié)炎(osteoarthritis, OA)是一種慢性疾病,關(guān)節(jié)軟骨的退變和骨質(zhì)增生是其常見的表現(xiàn),一些活動多、磨損大、承受壓力較大的關(guān)節(jié)部位較早受累。OA發(fā)病率逐年增加,患者的醫(yī)療費用年年遞增,尤其是老年人關(guān)節(jié)肌肉組織退化導(dǎo)致外傷比例也越來越高,膝關(guān)節(jié)OA成為老年人致殘的頭號殺手,從而使OA逐漸由醫(yī)學(xué)問題進(jìn)展到社會問題,在老齡化社會的今天,OA成為影響公共健康的重點疾病。中華醫(yī)學(xué)會骨科學(xué)分會制定的“骨關(guān)節(jié)炎診治指南”中,治療骨性關(guān)節(jié)炎的目標(biāo)就是減輕關(guān)節(jié)疼痛,抑制關(guān)節(jié)的進(jìn)一步損壞,盡可能地保留及提高關(guān)節(jié)的運動功能,使得患者生活質(zhì)量能夠大幅度提高,以非藥物與藥物聯(lián)合的治療方法為主常用藥物包括非甾體類消炎藥(NSAIDS)、止痛藥、黏彈性補充藥物、氨基葡萄糖等。各種藥物治療只能緩解癥狀,因此目前研究的重點是通過靶向OA的各種生物學(xué)和生物力學(xué)因素來最大程度減緩OA病程。大量研究表明,OA病理機(jī)制是各種原因?qū)е碌年P(guān)節(jié)軟骨細(xì)胞凋亡和胞外基質(zhì)降解而引起關(guān)節(jié)系統(tǒng)損傷疾病。治療靶點減緩或者逆轉(zhuǎn)軟骨細(xì)胞凋亡。而軟骨細(xì)胞和滑膜細(xì)胞高表達(dá)基質(zhì)金屬蛋白酶系(MMPs),該酶類與基質(zhì)金屬蛋白酶組織抑制(TIMPs)之間的動態(tài)平衡被打破,在力學(xué)負(fù)荷作用和炎性因子的影響等共同作用下,出現(xiàn)軟骨中基質(zhì)成分的游離、蛋白多糖、軟骨膠原的持續(xù)性破壞,最終導(dǎo)致軟骨的降解和破壞。FDA在1999年發(fā)布了骨關(guān)節(jié)炎研究指南,其中包括了動物模型的應(yīng)用。建立OA模型的目的是重現(xiàn)關(guān)節(jié)疾病,研發(fā)潛在的治療方法。在本研究中,選擇新西蘭大白兔,復(fù)制人類外傷后OA模式,建立兔骨關(guān)節(jié)炎模型。對建模成功的動物進(jìn)行藥物治療。實驗中選用的藥物有兩種,乙酰水楊酸和雙氯芬酸鈉。乙酰水楊酸是一種解熱鎮(zhèn)痛藥,可用于骨關(guān)節(jié)炎和風(fēng)濕性疾病,還能抑制血小板聚集。雙氯芬酸,屬于非甾體抗炎藥。自20世紀(jì)60年代開始,就有兩種藥物聯(lián)合治療骨關(guān)節(jié)炎以及類風(fēng)濕性關(guān)節(jié)炎的報道,但是,對聯(lián)合用藥的機(jī)理以及治療靶點,都沒有詳細(xì)的報道。本研究推測,OA發(fā)病過程中,涉及MMP、TIMPs、IL-1β、 NO等因子的變化,擬對OA治療過程中幾個細(xì)胞因子的活性及表達(dá)進(jìn)行相關(guān)研究。本研究將分為五部分。1. Hulth法建立兔骨性關(guān)節(jié)炎模型的實驗研究2.乙酰水楊酸聯(lián)合雙氯芬酸對兔關(guān)節(jié)炎軟骨組織學(xué)方面的影響3.乙酰水楊酸聯(lián)合雙氯芬酸對兔關(guān)節(jié)炎關(guān)節(jié)滑液中IL-1β、NO含量的影響4.乙酰水楊酸聯(lián)合雙氯芬酸對兔關(guān)節(jié)炎軟骨細(xì)胞中MMP-3、MMP-13表達(dá)的影響5.乙酰水楊酸聯(lián)合雙氯芬酸對兔關(guān)節(jié)炎軟骨細(xì)胞中TIMP-1表達(dá)的影響研究目的：探討不同濃度乙酰水楊酸聯(lián)合雙氯芬酸對兔骨關(guān)節(jié)炎模型關(guān)節(jié)軟骨影響的實驗研究。方法：乙酰水楊酸聯(lián)合雙氯芬酸按照不同濃度分成三組5mg/kg,10mg/kg, 20mg/kg,將32新西蘭大白兔建立兔骨關(guān)節(jié)炎模型,對各組大白兔進(jìn)行評分,利用試劑盒測定各組關(guān)節(jié)液中的NO. IL-1β含量,WB法測定MMP-3, MMP-13的蛋白的表達(dá),PCR法測定TIMP-1的mRNA表達(dá),觀察各項指標(biāo)的變化。結(jié)果：不同濃度的藥物對兔骨關(guān)節(jié)炎有很好的治療作用,能夠降低評分分?jǐn)?shù),降低NO、IL-1β的含量,WB法可以看到MMP-3, MMP-13的蛋白表達(dá)下調(diào),PCR法發(fā)現(xiàn)TIMP-1的mRNA表達(dá)上調(diào)。結(jié)論：不同濃度的乙酰水楊酸聯(lián)合雙氯芬酸能夠有效抑制兔骨關(guān)節(jié)炎的發(fā)展,并能抑制NO、IL-1β、MMP-3、MMP-13,同時增加TIMP-1的表達(dá),進(jìn)而起到治療作用。通過對OA治療過程中幾個細(xì)胞因子的活性及表達(dá)進(jìn)行相關(guān)檢測,本研究對兩者聯(lián)合用藥的分子機(jī)制進(jìn)行了探討,從而為聯(lián)合治療奠定了堅實基礎(chǔ)。而且這兩種藥物都是質(zhì)優(yōu)價廉的藥品,大大減少了患者的經(jīng)濟(jì)負(fù)擔(dān)。本研究的重點就在此。
[Abstract]:Osteoarthritis (osteoarthritis, OA) is a chronic disease, the degeneration of articular cartilage and bone hyperplasia is the common manifestation of some activities, wear, pressure large joints involved earlier incidence of.OA increased year by year, the medical cost of the patients is increasing year after year, especially the elderly joint muscle tissue degradation cause trauma ratio is also more and more high, knee joint OA become the number one killer of elderly disabled, so that OA gradually from medical problems to social problems in the aging society, OA has become key diseases of public health. The Chinese Medical Association orthopedics society established the "guidelines for the diagnosis and treatment of osteoarthritis." the treatment of osteoarthritis of the goal is to reduce joint pain, inhibit the further damage of the joint, as far as possible to keep and improve the joint function, which can greatly improve the quality of life of patients with. Non drug treatments combined with drugs most commonly used drugs include non steroidal anti-inflammatory drugs (NSAIDS), painkillers, viscosupplemetation drugs, glucosamine. Drug therapy can alleviate the symptoms, so the focus of the research is to slow the course of OA to the greatest degree of various biological and biomechanical factors of OA through lots of research target. OA showed that the pathological mechanism of apoptosis cell and cartilage extracellular matrix degradation caused by various reasons caused by joint injury disease treatment targets. Slow or even reverse the apoptosis of cartilage cells and cartilage cells and synovial cells with high expression of matrix metalloproteinase system (MMPs), the enzymes and tissue inhibitor of metalloproteinases-1 (TIMPs) dynamic balance is broken, in the action of mechanical load and inflammatory factor influence, appear in the cartilage matrix free, proteoglycan, soft Persistent bone collagen destruction, resulting in degradation and destruction of cartilage.FDA released the osteoarthritis research guidelines in 1999, including the application of animal model. The OA model is to reproduce the joint disease, development of potential treatments. In this study, selection of New Zealand white rabbits, human reproduction after trauma OA model, the establishment of rabbit osteoarthritis model. Drug therapy for the successful modeling of the animal drug in the experiment. There are two kinds of acetylsalicylic acid and diclofenac sodium. Acetylsalicylic acid is a kind of antipyretic analgesics, can be used for osteoarthritis and rheumatoid disease, can inhibit platelet aggregation. Diclofenac, belongs to non steroidal anti-inflammatory drugs. Since the beginning of 1960s, there are two kinds of agents in the treatment of osteoarthritis and rheumatoid arthritis, but the mechanism of the combined use of drugs and therapeutic targets are not detailed Reported. This study hypothesizes that the pathogenesis of OA, involving MMP, TIMPs, IL-1 beta, NO changes and other factors, intends to OA treatment and the expression of several cytokines in the process of the activity of related research. This study will be divided into the establishment of rabbit osteoarthritis model five.1. Hulth method to the experimental research 2. acetylsalicylic acid combined with diclofenac on rabbit articular cartilage histological effects of 3. acetylsalicylic acid combined with diclofenac on IL-1 rabbit arthritis synovial beta, the effect of NO content of 4. acetylsalicylic acid combined with diclofenac on MMP-3 rabbit articular cartilage cells, MMP-13 expression of 5. acetylsalicylic acid combined with diclofenac on influence the expression of TIMP-1 in rabbit joint cartilage cells: Experimental Study on the effects of different concentrations of acetylsalicylic acid combined with diclofenac on cartilage in rabbit osteoarthritis models. Methods: the combination of acetylsalicylic acid According to the different concentration of diclofenac and divided into three groups: 5mg/kg, 10mg/kg, 20mg/kg, rabbit osteoarthritis model of 32 New Zealand rabbits were established, scoring for each group of rabbits, the determination of NO. content of each IL-1 beta in synovial fluid by using the reagent kit for determination of MMP-3, WB, protein expression of MMP-13, expression of TIMP-1 was measured by PCR method mRNA, to observe the changes of the indexes. Results: the different concentrations of the drug has good effects on treating osteoarthritis in rabbits, can reduce the score, reduce the content of NO, IL-1 beta, WB can see MMP-3, the expression of MMP-13 protein expression, PCR assay showed that the TIMP-1 expression of mRNA. Conclusion: the development of different concentrations of acetylsalicylic acid combined with diclofenac can effectively inhibit rabbit osteoarthritis, and can inhibit NO, MMP-3, MMP-13, IL-1 beta, and increase the expression of TIMP-1, which plays a role in the treatment of OA. Through the treatment process of several fine To detect the expression and activity of cytokines, the molecular mechanism of the combination are discussed, which lays a solid foundation for combination therapy. But the two drugs are cheap drugs, greatly reduce the economic burden of the patients. The focus of this study here.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R684.3;R-332

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