1、西乐葆西乐葆对关节软骨作用研究对关节软骨作用研究内容提要内容提要n研究背景nCelebrex的相关研究报道n关于双氯芬酸研究背景研究背景q非甾体类抗炎药：对骨关节炎病人的炎性表现如关节肿胀、疼痛、积液及活动受限有较好的治疗作用.q但有的非甾体类抗炎药物如阿司匹林：消炎痛等，对软骨基质的合成有抑制作用，长期应用虽然关节疼痛改善，但是骨关节炎的基本病变反会加重。(文献）q西乐葆是目前治疗骨关节炎和类风湿关节炎的首选药物，不会对患者胃肠道造成严重伤害。最新研究表明西乐葆对关节软骨不仅最新研究表明西乐葆对关节软骨不仅没有损伤，还有良好的保护和促进作用。（文献）没有损伤，还有良好的保护和促进作用。（文献
2、）Normal healthy and osteoarthritic cartilage histology.Representive light micrographs of condylar cartilage obtained post mortem from joints with(a)normal healthy cartilage and(b)cartilage obtained at joint replacement surgery.Simon C et al.,Differential direct effects of cyclo-oxygenase-1/2 inhibit
3、ion on proteoglycan turnover of human osteoarthritic cartilage:an in vitro studyArthritis Research&Therapy 2006,8 骨关节炎的软骨细胞的缺失在显微镜下清晰可见。软骨细胞的缺失现象软骨细胞的缺失现象西乐葆对于西乐葆对于关节软骨的相关报道关节软骨的相关报道内容内容q有利于蛋白聚糖的合成有利于蛋白聚糖的合成q降低软骨成分的缺失降低软骨成分的缺失q促进透明质酸的合成促进透明质酸的合成q对类风湿滑液的调节作用对类风湿滑液的调节作用q对骨折恢复的影响对骨折恢复的影响塞来昔布可以加强软骨蛋白聚糖的
4、合成，减少软骨蛋白聚糖本身的损耗。Celebrex能加强软骨蛋白的合成能加强软骨蛋白的合成比利时比利时LouvainLouvain大学的大学的Daniel-Henri Daniel-Henri ManicourtManicourt博士及其研究小组发现，博士及其研究小组发现，塞来昔布可以加强软骨蛋白聚糖的合成，减少软骨蛋白聚糖本身的损耗。塞来昔布可以加强软骨蛋白聚糖的合成，减少软骨蛋白聚糖本身的损耗。ManicourtManicourt博士指出这项发现有可能会有助于骨关节炎患者的恢复。博士指出这项发现有可能会有助于骨关节炎患者的恢复。英国路透新闻社2003.12.25报道 媒体的关注媒体的关注M
5、astbergen SC.Selective COX-2 inhibition prevents proinflammatory cytokine-induced cartilage damage.Rheumatology(Oxford).2002 Jul;41(7):801-8.Fig.3.The effect of celecoxib on human articular cartilage explants under the influence of inflammation-related cytokines.(A)Sulphate incorporation rate as a m
6、easure of proteoglycan synthesis.(B)(B)Release of newly formed proteoglycans(normalized to the synthesis of these proteoglycans.(C)(C)Percentage release of proteoglycans as measured by the percentage release of GAG(normalized to the GAG content.(D)(D)GAG content as a measure of proteoglycan content.
7、Celebrex有利于蛋白聚糖的合成有利于蛋白聚糖的合成塞来昔布能显著地改善软骨中蛋白聚糖合成受到的抑制作用。El Hajjaji H.Celecoxib has a positive effect on the overall metabolism of hyaluronan and proteoglycans in human osteoarthritic cartilage.J Rheumatol.2003 Nov;30(11):2444-51.塞来昔布能显著地促进软骨的蛋白聚糖（PG）合成，而双氯芬酸则没有这种作用。Celebrex促进蛋白聚糖的合成促进蛋白聚糖的合成塞来昔布能显著提高
8、骨关节软骨中蛋白聚糖的合成，而吲哚乙酸和萘普生则对蛋白聚糖的合成有明显抑制作用。Celebrex促进蛋白聚糖的合成促进蛋白聚糖的合成Simon C et al.,Differential direct effects of cyclo-oxygenase-1/2 inhibition on proteoglycan turnover of human osteoarthritic cartilage:an in vitro studyArthritis Research&Therapy 2006,8 El Hajjaji H.Celecoxib has a positive effect on
9、 the overall metabolism of hyaluronan and proteoglycans in human osteoarthritic cartilage.J Rheumatol.2003 Nov;30(11):2444-51.Celebrex有利于软骨成分的合成有利于软骨成分的合成塞来昔布能有效地阻止传统NSAIDs对PG和HA合成的抑制作用。Mastbergen SC.Selective COX-2 inhibition is favorable to human early and late-stage osteoarthritic cartilage:a hum
10、an in vitro study.Osteoarthritis Cartilage.2005 Jun;13(6):519-26.Fig.2.The effect of celecoxib on degenerated and OA human articular cartilage explants.加入塞来昔布后，蛋白聚糖的各项指标都有显著提高。Celebrex促进蛋白聚糖的各项指标促进蛋白聚糖的各项指标塞来昔布能显著减少骨关节软骨中蛋白聚糖的缺失。而吲哚乙酸和萘普生则对蛋白聚糖的缺失没有有明显作用，甚至加剧了蛋白的缺失。Celebrex抑制蛋白聚糖的缺失抑制蛋白聚糖的缺失Simon C
11、et al.,Differential direct effects of cyclo-oxygenase-1/2 inhibition on proteoglycan turnover of human osteoarthritic cartilage:an in vitro studyArthritis Research&Therapy 2006,8 El Hajjaji H.Celecoxib has a positive effect on the overall metabolism of hyaluronan and proteoglycans in human osteoarth
12、ritic cartilage.J Rheumatol.2003 Nov;30(11):2444-51.塞来昔布能降低PG和HA分子结构的缺失，而双氯芬酸则没有这种作用。Celebrex降低软骨成分结构的缺失降低软骨成分结构的缺失体内短期培养条件下，塞来昔布有利于蛋白聚糖（PG）和透明质酸酶（HA）的合成。因此长期使用这种药物不可能对关节软骨产生危害，相反地，塞来昔布可能会减少关节软骨中透明质酸的损耗。Celebrex促进软骨成分的代谢促进软骨成分的代谢Celebrex促进透明质酸酶的合成促进透明质酸酶的合成El Hajjaji H.Celecoxib has a positive effec
13、t on the overall metabolism of hyaluronan and proteoglycans in human osteoarthritic cartilage.J Rheumatol.2003 Nov;30(11):2444-51.塞来昔布能显著地促进软骨的透明质酸酶（HA）合成，而双氯芬酸则没有这种作用。Fig.3 Effect of three NSAIDs on PGE2 production in OA cartilage.Simon C et al.,Differential direct effects of cyclo-oxygenase-1/2 in
14、hibition on proteoglycan turnover of human osteoarthritic cartilage:an in vitro studyArthritis Research&Therapy 2006,8 塞来昔布能显著减少骨关节软骨炎软骨中前列腺素E2的释放。Celebrex减少前列腺素减少前列腺素E2的释放的释放Jacques C et al.Cyclooxygenase activity in chondrocytes from osteoarthritic and healthy cartilage.Rev Rhum Engl Ed 1999;66:70
15、1-704 qCOX-2蛋白的表达和前列腺素E2(PGE2)的产生会阻碍蛋白聚糖的合成过程。q塞来昔布能抑制PGE2的产生，从而促进蛋白聚糖的合成。050100150200250300control0.1110normaldegenerativeOAPGE2(g/ml)PGE2 production of cartilageFig.3.The effect of celebrex on PGE2 of normal,degenerated and OA human articular cartilage explants.Celebrex抑制抑制PGE2的合成的合成Mastbergen SC.
16、Selective COX-2 inhibition is favorable to human early and late-stage osteoarthritic cartilage:a human in vitro study.Osteoarthritis Cartilage.2005 Jun;13(6):519-26.Celebrex对对RASFs的的调节调节n日本科学家在关节炎和风湿病杂志12月号中报道：高剂量选择性环氧化酶2抑制剂（cox-2）celecoxib能诱发培养中的类风湿关节炎滑液纤维原细胞（RASFs）调亡。Celecoxib可能不仅有消炎的作用，还对类风湿滑液增加有
17、调节作用。塞来昔布对于类风湿关节炎滑液纤维原细胞（RASFs）的增殖具有抑制作用。Natsuko Kusunoki,Induction of Apoptosis in Rheumatoid Synovial Fibroblasts by Celecoxib,but Not by Other Selective Cyclooxygenase 2 Inhibitors。ARTHRITIS&RHEUMATISM Vol.46,No.12,December 2002,pp 31593167 Celebrex对类风湿滑液增加有调节作用对类风湿滑液增加有调节作用塞来昔布能诱发培养中的类风湿关节炎滑液纤维原
18、细胞调亡。Natsuko Kusunoki,Induction of Apoptosis in Rheumatoid Synovial Fibroblasts by Celecoxib,but Not by Other Selective Cyclooxygenase 2 Inhibitors。ARTHRITIS&RHEUMATISM Vol.46,No.12,December 2002,pp 31593167 Celebrex对类风湿滑液增加有调节作用对类风湿滑液增加有调节作用图片显示了celebrex诱导RASFs分裂的作用。Natsuko Kusunoki,Induction of Ap
19、optosis in Rheumatoid Synovial Fibroblasts by Celecoxib,but Not by Other Selective Cyclooxygenase 2 Inhibitors。ARTHRITIS&RHEUMATISM Vol.46,No.12,December 2002,pp 31593167 Celebrex对类风湿滑液增加有调节作用对类风湿滑液增加有调节作用动物体的试验表明，塞来昔布对于腿骨骨折的手术后恢复不会产生抑制作用。Celebrex不影响骨折的恢复不影响骨折的恢复Brown KM.Effect of COX-2-specific inh
20、ibition on fracture-healing in the rat femur.J Bone Joint Surg Am.2004 Jan;86-A(1):116-23.024681012144 weeks8 weeks12 weeksFig.4 Graphic representation of the histological grades at each time-point.Untreated fracture control group Celecoxib Indomethacin无论是X光透视还是生化数据，塞来昔布对骨折的愈合与对照组相比没有显著的差别。Histologi
21、c GradeCelebrex不影响骨折的愈合不影响骨折的愈合关于双氯芬酸的报道关于双氯芬酸的报道双氯芬酸会导致骨关节炎加重双氯芬酸会导致骨关节炎加重双氯芬酸可能会导致臀部和膝关节的放射性骨关双氯芬酸可能会导致臀部和膝关节的放射性骨关节炎加重。节炎加重。M.Reijman et al.,Is there an association between the use of different types of nonsteroidal antiinflammatory drugs and radiologic progression of osteoarthritis?:The rotterda
22、m study.Arthritis&Rheumatism.52(10):3137-3142 051015DPM 10-2CELLS0-22-44-66-810-12Fig.2 Effect of diclofenac on the secretion of 35SO4-labelled proteoglycans by chondrocyte monodrocyte cultures and cartilage explant culture during the indicated 2-day culture intervals.00.111050100g/MLSimon Collier a
23、nd Peter Ghosh.Comprarion of the effect of non-steroidal anti-inflammatory drugs(NSAIDs)on proteoglycan synthesis by articular cartilage explant and chondrocyte monolayer cultures.Biochemical Pharmacology,41(9):1375-1384双氯芬酸在一定浓度（50和10 g/ML）下能起强烈地抑制软骨中蛋白聚糖的合成。双氯芬酸抑制软骨蛋白聚糖的合成双氯芬酸抑制软骨蛋白聚糖的合成Days024681
24、00-22-44-66-810-12CELL MATRIXEXPLANT MATRIX02468100-24-66-810-12Fig.6.Effect of diclofenac on the accumulation of 35SO4-labelled proteoglycans in the culture supernatanns(top panels)and the extra celluiar matrix(Botom panels)of chondrocyte monolayer(left)panels and articular cartilage explant(right
25、panels)culture during successive 2-day culture intervals.The durg was removed from the cultures on day 8.双氯芬酸抑制软骨蛋白聚糖的合成双氯芬酸抑制软骨蛋白聚糖的合成Contral10g/mL100g/mLContral10g/mL100g/mL双氯芬酸能抑制软骨细胞中蛋白聚糖的合成，而除去双氯芬酸后可得到恢复。Simon Collier and Peter Ghosh.Comprarion of the effect of non-steroidal anti-inflammatory d
26、rugs(NSAIDs)on proteoglycan synthesis by articular cartilage explant and chondrocyte monolayer cultures.Biochemical Pharmacology,41(9):1375-1384小结小结n临床研究证实，西乐葆对关节炎患者的关节软骨不仅没有损临床研究证实，西乐葆对关节炎患者的关节软骨不仅没有损伤，相反还能显著增强软骨组成成分的代谢功能，促进蛋白伤，相反还能显著增强软骨组成成分的代谢功能，促进蛋白聚糖、透明质酸酶等合成，减少损耗，并显著抑制前列腺素聚糖、透明质酸酶等合成，减少损耗，并显著抑制前列腺素等的释放，有利于患者软骨组织的健康恢复。等的释放，有利于患者软骨组织的健康恢复。n双氯芬酸、吲哚乙酸、萘普生、阿司匹林等传统双氯芬酸、吲哚乙酸、萘普生、阿司匹林等传统NSAIDs对对关节软骨基质的合成有抑制作用，长期服用关节炎基本病变关节软骨基质的合成有抑制作用，长期服用关节炎基本病变 反而会加重。反而会加重。西乐葆西乐葆更安心的保护更安心的保护您的健康首选您的健康首选
