依那西普联合来氟米特治疗强直性脊柱炎的疗效观察及安全性分析

目的:探究依那西普联合来氟米特治疗强直性脊柱炎(AS)的疗效及安全性。方法:收集2015年1月-2016年6月间我院收治的AS患者90例,按随机数字表法分为观察组和对照组,每组各45例。观察组采用依那西普联合来氟米特治疗,对照组则单纯采用来氟米特治疗。记录两组治疗前后的晨僵时间、AS活动性指数(BASDAI)和AS测量指数(BASMI),比较两组治疗总有效率及不良反应发生情况。结果:治疗后,两组患者晨僵时间、BASDAI及BASMI较治疗前均有所下降,且观察组上述各指标均显著低于对照组,差异有统计学意义(P0.05);观察组总有效率显著高于对照组,差异有统计学意义(P0.05);治疗过程中,患者发生的主要不良反应为肝功能损伤、腹泻和过敏性皮疹,但两组不良反应发生率差异无统计学意义(P0.05)。结论:依那西普联合来氟米特可获得比较理想的疗效,且不良反应发生率较低,值得在临床上推广使用。     

依那西普联合甲氨蝶呤治疗类风湿关节炎疗效分析

目的:探讨依那西普联合甲氨蝶呤治疗类风湿关节炎的疗效。方法:选取2011年至2013年风湿免疫科的60例类风湿关节炎患者,分为对照组和治疗组,其中对照组15例,治疗组45例,两组患者都应用甲氨蝶呤治疗,治疗组患者联合使用依那西普治疗,总疗程12周。比较两组患者治疗前后的临床及实验室指标。采用美国风湿病学会的核心标准作为疗效评定标准。结果:治疗组患者肿瘤坏死因子(tumor necrosis factor,TNF)和白细胞介素(interleukin,IL-1)下降明显,与对照组患者相比差异均有统计学意义(P0.05);治疗后两组患者超敏C反应蛋白(hs-CRP)均较治疗前明显降低,差异均有统计学意义(P0.05);治疗组患者关节疼痛、关节肿胀和晨僵情况较对照组均有显著的改善(P0.05);治疗组患者的休息痛、患者评分以及HAQ评分均显著优于对照组(P0.05);治疗组患者ACR20和ACR70缓解的比例均高于对照组,且治疗组患者达ACR50缓解的比例显著高于对照组(P0.05)。结论:依那西普联合甲氨蝶呤治疗类风湿关节炎的疗效优于单纯的甲氨蝶呤治疗。     

局部应用依那西普治疗强直性脊柱炎髋关节受累的临床疗效分析

目的：评价局部应用依那西普治疗强直性脊柱炎髋关节受累的短期疗效。方法：选择我科2001-2011年收治的强直性脊柱炎髋关节受累的患者50例,在高频超声引导下于髋关节局部注射依那西普50mg,每周1次,连用4次。分别在注射前、注射后2、4、8周观察患者的BASDAI、BASFI、脊柱痛VAS、患者总体评价（PGA）VAS、夜间痛VAS、血沉、CRP和Harris功能评分,同时记录患者出现的不良反应。结果：依那西普治疗2周时,30例达ASAS20的缓解（60％）,13例（26％）达到ASAS50的缓解,8例（16％）达到ASAS70的缓解;治疗8周时,ASAS20／50／70的缓解率分别为38例（64％）、21例（42％）、15例（30％）,其中Harris评分达70以上者占总人数的90％,80分60％,90分30％,1例患者缓解不明显,4例患者处于70分以下,但疾病活动度情况改善。结论：依那西普可有效改善强直性脊柱炎髋关节受累患者的关节症状,降低疾病活动强度,且无明显药物不良反应。     

髓核突出模型大鼠背根神经节中Wnt5a的表达

目的:观察Wnt5a在大鼠髓核突出模型的表达变化,探索Wnt5a在神经根病中的作用。方法:将80只成年雄性大鼠随机分为假手术组(Sham组,n=20)、髓核突出组(NP组,n=20)、髓核突出+生理盐水组(NP+Saline组,n=20)、髓核突出+益赛普组(NP+Etanercept组,n=20)。从大鼠尾椎椎间盘中取髓核,将髓核种植于L5背根神经节旁,制作髓核突出大鼠模型。采用免疫组织化学法分别检测各组大鼠背根神经节中的Wnt5a蛋白的表达,利用RT-PCR的方法分别检测各组大鼠背根神经节中Wnt5a m RNA的表达。结果:免疫组化结果显示,各组大鼠背根神经节的大中小神经元均有Wnt5a的表达,NP组较Sham组在3天、7天时Wnt5a表达量均增加(P0.01),3天和7天时NP+Etanercept组大鼠背根神经节中Wnt5a的表达量较NP+Saline组均减少(P0.01)。RT-PCR的结果与免疫组化的结果相符,表现为NP组较Sham组在3天、7天时Wnt5a mRNA的相对表达量增加(P0.01),NP+Etanercept组大鼠背根神经节中Wnt5a的相对表达量较NP+Saline组均减少(P0.01)。结论:髓核突出并压迫背根神节时,可引起背根神经节Wnt5a的表达增加,且阻断肿瘤坏死因子α(TNF-α)时,背根神经节的Wnt5a表达减少。     

Manufacturing history of etanercept (Enbrel®): Consistency of product quality through major process revisions

Etanercept (ETN) (Enbrel®) is a soluble protein that binds to, and specifically inhibits, tumor necrosis factor (TNF), a proinflammatory cytokine. ETN is synthesized in Chinese hamster ovary cells by recombinant DNA technology as a fusion protein, with a fully human TNFRII ectodomain linked to the Fc portion of human IgG1. Successful manufacture of biologics, such as ETN, requires sophisticated process and product understanding, as well as meticulous control of operations to maintain product consistency. The objective of this evaluation was to show that the product profile of ETN drug substance (DS) has been consistent over the course of production. Multiple orthogonal biochemical analyses, which included evaluation of attributes indicative of product purity, potency, and quality, were assessed on >2,000 batches of ETN from three sites of DS manufacture, during the period 1998–2015. Based on the key quality attributes of product purity (assessed by hydrophobic interaction chromatography HPLC), binding activity (to TNF by ELISA), potency (inhibition of TNF-induced apoptosis by cell-based bioassay) and quality (N-linked oligosaccharide map), we show that the integrity of ETN DS has remained consistent over time. This consistency was maintained through three major enhancements to the initial process of manufacturing that were supported by detailed comparability assessments, and approved by the European Medicines Agency. Examination of results for all major quality attributes for ETN DS indicates a highly consistent process for over 18 years and throughout changes to the manufacturing process, without affecting safety and efficacy, as demonstrated across a wide range of clinical trials of ETN in multiple inflammatory diseases.     

Immunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute-phase response

TNF-α has proved to be a successful target in the treatment of many peripheral inflammatory diseases, but the same interventions worsen immune-mediated CNS disease. However, anti-TNF-α strategies may offer promise as therapy for non-immune CNS injury. In this study, we have microinjected IL-1β or lipopolysaccharide (LPS) into the rat brain as a simple model of brain injury and have systemically administered the TNF-α antagonist etanercept to discover whether hepatic TNF-α, produced as part of the acute-phase response to CNS injury, modulates the inflammatory response in the brain. We report a significant reduction in neutrophil numbers recruited to the IL-1β- or LPS-challenged brain as a result of TNF-α inhibition. We also show an attenuation in the levels of hepatic mRNA including TNF-α mRNA and of TNF-α-induced genes, such as the chemokines CCL-2, CXCL-5, and CXCL-10, although other chemokines elevated by the injury were not significantly changed. The reduction in hepatic chemokine synthesis results in reduced numbers of circulating neutrophils, and also a reduction in the numbers recruited to the liver as a consequence of brain injury. These findings suggest that TNF-α inhibitors may reduce CNS inflammatory responses by targeting the hepatic acute-phase response, and thus therapies for brain injury need not cross the blood–brain barrier to be effective.     

来氟米特联合依那西普对佐剂性关节炎大鼠免疫功能的影响

目的:研究来氟米特和依那西普联合使用对佐剂性关节炎(AA)大鼠的治疗作用及其可能的作用机制。方法:建立AA大鼠关节炎模型,分为正常对照组、模型组、来氟米特组、依那西普组、来氟米特联合依那西普配伍组;采用关节炎指数评分法评价大鼠关节炎症程度,半定量RT-PCR和放射免疫法检测滑膜组织及血清中IL-1β、TNF-α表达水平,免疫组化方法检测滑膜组织中MMP-3含量。结果:①相较于AA模型组,来氟米特组、依那西普组和配伍组中大鼠的AI评分均显著下降(P<0.01),其中以配伍组关节炎指数为最低(P<0.05)。②模型组大鼠血清及滑膜组织的IL-1β和TNF-α水平明显高于正常对照组(P<0.01),用药后各组的IL-1β和TNF-α水平均有所下降,并以配伍组降低最为明显(P<0.01或P<0.05);③模型组大鼠滑膜组织MMP-3表达阳性密度显著高于正常对照组(P<0.01),用药后各组的MMP-3阳性密度降低(P<0.01),其中配伍组下降程度明显高于来氟米特组和依那西普组(P<0.01)。结论:来氟米特和依那西普联合使用可明显减轻AA大鼠的关节炎症,降低血清和滑膜组织中IL-1β和TNF-α水平,减少滑膜中MMP-3的表达,疗效优于单独使用来氟米特或依那西普。     

来氟米特联合依那西普对佐剂性关节炎大鼠免疫功能的影响

目的：研究来氟米特和依那西普联合使用对佐剂性关节炎（AA）大鼠的治疗作用及其可能的作用机制。方法：建立AA大鼠关节炎模型,分为正常对照组、模型组、来氟米特组、依那西普组、来氟米特联合依那西普配伍组;采用关节炎指数评分法评价大鼠关节炎症程度,半定量RT-PCR和放射免疫法检测滑膜组织及血清中IL-1β、TNF-α表达水平,免疫组化方法检测滑膜组织中MMP－3含量。结果：①相较于AA模型组,来氟米特组、依那西普组和配伍组中大鼠的AI评分均显著下降（P〈0．01）,其中以配伍组关节炎指数为最低（P〈0．05）。②模型组大鼠血清及滑膜组织的IL-1β和TNF-α水平明显高于正常对照组（P〈0．01）,用药后各组的IL-1β和TNF-α水平均有所下降,并以配伍组降低最为明显（P〈0．01或P〈0．05）;③模型组大鼠滑膜组织MMP-3表达阳性密度显著高于正常对照组（P〈0．01）,用药后备组的MMP-3阳性密度降低（P〈0．01）,其中配伍组下降程度明显高于来氟米特组和依那西普组（P〈0．01）。结论：来氟米特和依那西普联合使用可明显减轻AA大鼠的关节炎症,降低血清和滑膜组织中IL-1β和TNF-α平,减少滑膜中MMP-3的表达,疗效优于单独使用来氟米特或依那西普。     

痹祺胶囊联合依那西普对强直性脊柱炎患者急性时相反应物指标、血清疼痛介质和骨代谢指标的影响

摘要 目的：探讨痹祺胶囊联合依那西普对强直性脊柱炎（AS）患者急性时相反应物指标、血清疼痛介质和骨代谢指标的影响。方法：纳入西安市第五医院2020年4月~2022年3月期间收治的96例AS患者。按照随机数字表法分为对照组（n=48）和研究组（n=48）,对照组接受依那西普治疗,研究组接受痹祺胶囊联合依那西普治疗。对比两组疗效、临床症状指标[Bath强直性脊柱炎活动指数（BASDAI）、Bath强直性脊柱炎功能指数（BASFI）、Bath强直性脊柱炎计量学指数（BASMI）、视觉疼痛模拟（VAS）评分]、急性时相反应物指标[红细胞沉降率（ESR）、C反应蛋白（CRP）]、血清疼痛介质指标[前列腺素E₂ (PGE₂) 、P物质( SP)、多巴胺（DA）,五羟色胺（5-HT）]和骨代谢指标[骨形态发生蛋白-2（BMP-2）、骨钙素（BGP）],观察两组不良反应发生情况。结果：研究组（95.83%）的临床总有效率高于对照组（79.17%）,差异有统计学意义（P<0.05）。两组治疗后PGE₂、SP、DA、5-HT下降,且研究组的下降程度更大（P<0.05）。两组治疗后CRP、ESR下降,且研究组的下降程度更大（P<0.05）。两组治疗后BMP-2、BGP升高,且研究组的升高程度更大（P<0.05）。两组治疗后BASDAI、BASFI、BASMI、VAS评分下降,且研究组的下降程度更大（P<0.05）。两组不良反应发生率对比无差异（P>0.05）。结论：痹祺胶囊联合依那西普治疗AS患者,疗效较好,可改善临床症状,调节急性时相反应物指标、血清疼痛介质和骨代谢指标水平,安全性较高。