塞来昔布治疗骨关节炎的有效性和安全分析

目的 探讨塞来昔布治疗骨关节炎患者的临床有效性和安全性.方法 收集本院2014年1月至2015年5月入院的76例骨关节炎患者,随机分为对照组和实验组.对照组给予基础治疗+硫酸氨基葡萄糖胶囊治疗,实验组加服塞来昔布胶囊,比较两组整体治疗效果、治疗前后LequesneMG积分、VAS评分、不良反应、复发率等.结果 实验组治疗总有效率明显高于对照组,差异有统计学意义(94.74％vs.78.95％,x 2=4.145,P＜0.05).治疗后,实验组LequesneMG积分(3.90±0.61)与VAS评分(1.75±0.38)显著低于对照组[(4.49±0.68)与(3.15±0.57)],差异有统计学意义(t=3.981、12.597,P＜0.01).两组总体不良反应发生率差异无统计学意义(23.68％ vs.18.42％,x2=0.317,P＞0.05).实验组停药3月复发率明显低于对照组,差异有统计学意义(5.26％ vs.23.68％,x2=5.208,P＜0.05).结论 塞来昔布治疗骨关节炎临床效果显著,安全性高,复发率低,具有借鉴性.     

Current and emerging paradigms in the therapeutic management of atherosclerosis

Background: The pathogenesis of atherosclerosis lies in abnormalities in lipoprotein metabolism leading to pathological interactions with vessel walls and the release of inflammatory components, which further aggravate the disease condition. Objective: To elucidate current and emerging trends in drug discovery towards the development of new entities regulating lipoprotein metabolism and inflammatory components to combat the progression of atherosclerosis. Methods: Research/review articles in the public domain and press releases were employed. Results/conclusion: With the recent failure of torcetrapib and succinobucol, drug discovery and development efforts towards the treatment of atherosclerosis have received a big jolt and have been slowed down to certain extent. But this could be a starting point for several new mechanisms that are emerging to discover new drugs to combat the disease.     

Celecoxib but not the combination of celecoxib+atorvastatin prevents the development of monocrotaline-induced pulmonary hypertension in the rat

The present study aimed to assess the effects of a COX-2 inhibitor, celecoxib, a HMG-CoA reductase inhibitor, atorvastatin, and the association of both on monocrotaline (MC)-induced pulmonary hypertension in rats. Celecoxib (Cib, 25 mg kg(-1) day(-1)), atorvastatin (AS, 10 mg kg(-1) day(-1)) or vehicle, were given orally, separately or in combination, for 26 days to Wistar male rats injected or not with MC (60 mg/kg intraperitoneally). At 4 weeks, MC-injected rats developed a severe pulmonary hypertension, with an increase in lung to body weight ratio (L/BW), right ventricular pressure (RVP in mmHg, 31 +/- 3 and 14 +/- 1 for MC and control groups, respectively, P < 0.05) and right ventricle/left ventricle + septum weight ratio (RV/LV+S) associated with a decrease in acetylcholine- and sodium-nitroprusside-induced pulmonary artery vasodilation in vitro. Hypertensive pulmonary arteries exhibited an increase in wall thickness (wall thickness to external diameter ratio, 0.42 +/- 0.01 vs 0.24 +/- 0.01 for MC and control groups, respectively, P < 0.001). Whole lung eNOS expression was decreased, and an increase in apoptosis, evaluated by cleaved caspase-3 expression, was evidenced by Western blotting. Cib (RVP in mmHg, 19 +/- 3 and 31 +/- 3 for MC+Cib and MC groups, respectively, P < 0.05), but neither AS nor AS+Cib significantly limited the development of pulmonary hypertension (P < 0.05), although the three treatments exhibited protective effects against MC-induced lung and right ventricle hypertrophy evaluated by L/BW and RV/(LV+S) ratios, respectively (P < 0.05). AS, Cib and AS+Cib treatments reduced MC-induced thickening of small intrapulmonary artery wall (0.42 +/- 0.01, 0.24 +/- 0.01, 0.26 +/- 0.01 and 0.28 +/- 0.01 for MC, MC+AS, MC+Cib and MC+AS+Cib groups, respectively, P < 0.001). In control rats, Cib reduced acetylcholine-induced pulmonary artery vasorelaxation. Treatment of MC rats by either Cib or AS did not modify acetylcholine-induced pulmonary artery relaxation, whereas combination of both drugs significantly worsened it (P < 0.05). AS, but neither Cib nor the combination of both, prevented apoptosis (AS, P < 0.05) and partially restored eNOS expression (AS, P < 0.05) in whole lung of MC rats. In conclusion, celecoxib exhibited beneficial effects against the development of monocrotaline-induced pulmonary artery hypertension and right ventricular hypertrophy. These beneficial effects of celecoxib might be, at least partly, explained by its effects on pulmonary artery thickening and pulmonary hypertrophy, even if it did not show any effect on pulmonary artery vasorelaxation and whole lung eNOS expression or apoptosis. The combination of celecoxib and atorvastatin was unable to prevent MC-induced pulmonary hypertension, decreased endothelium-dependent vasorelaxation and showed a trend toward an increased in RVP that deserves further studies.     

塞来昔布联合奥氮平治疗难治性抑郁症的随机双盲对照

目的：探讨塞来昔布联合奥氮平治疗难治性抑郁症的临床效果。方法：采用双盲对照研究,将66例诊断为难治性抑郁症的患者随机分为观察组和对照组,每组各33例,观察组采用塞来昔布联合奥氮平治疗,对照组采用塞来昔布治疗,两组在治疗后1、2、4、8周末采用汉密顿抑郁量表（HAMD）,副反应量表（TESS）评定两组的药物副作用。结果：观察组的总有效率为87.88%,对照组为60.61%,两组差异有统计学意义（P〈0.05）,药物副作用两组间差异无统计学意义（P〉0.05）。结论：塞来昔布联合奥氮平治疗难治性抑郁症起效快、安全性高,并能迅速改善睡眠障碍和焦虑。     

塞来昔布对肺癌的抑制作用机制研究

目的探讨环氧化酶抑制剂（COX-2）抑制剂塞来昔布对于A549肺癌细胞增殖及其小鼠移植瘤生长的抑制作用及可能机制。方法加不同浓度塞来昔布与A549肺癌细胞共培养,MTT法检测细胞增殖。流式细胞仪法检测细胞凋亡情况。A549细胞移植入BALB／c裸小鼠皮下后,随机分为实验组和对照组,实验组隔日腹腔注射塞来昔布30mg．kg^-1,对照组隔日腹腔注射等体积生理盐水,24d后处死移植瘤小鼠,计算抑瘤率,RT-PCR检测移植瘤组织中COX一2和VEGFmRNA表达水平,同时酶联免疫检测小鼠血清中MMP-9浓度,免疫组化检测瘤组织中微血管密度（MVD）。结果塞来昔布在体外对细胞株A549的生长抑制作用呈剂量、时间依赖性,且经塞来昔布作用后,A549细胞G0／G1期比例增加,S、G2／M期比例下降。在体实验显示,塞来昔布具有明显的抑制A549肺癌移植瘤增殖的作用,同时能抑制移植瘤组织中COX-2、VEGF表达,降低血清MMP-9浓度,减少移植瘤中微血管密度（P〈0．05）。结论塞来昔布在体内外均可显著抑制A549肺癌细胞的增殖,而诱导肿瘤细胞凋亡,抑制肿瘤血管生成和降低癌细胞侵袭能力是其可能的作用机制。     

塞来昔布对兔动脉粥样硬化组织中环氧合酶-2的作用研究

目的:观察环氧合酶-2(COX-2)在兔主动脉粥样硬化(AS)组织中的表达,探讨COX-2与AS的关系及其抑制剂塞来昔布抗AS的作用。方法:取新西兰兔18只,随机分为对照组、高胆固醇组(HC)和塞来昔布组(20mg·kg·d-1)。喂养14周后测兔主动脉AS斑块面积及主动脉内膜/中膜厚度值,用逆转录聚合酶链反应(RT-PCR)、免疫组化、蛋白印记法检测COX-2 mRNA和蛋白的表达。结果:与HC组比较,塞来昔布AS斑块面积、内膜/中膜厚度值、COX-2 mRNA及蛋白表达明显降低(P<0·01);COX-2 mRNA和蛋白的表达(免疫组化、蛋白印记)强弱与AS斑块面积显著正相关(r=0·98、0·97、0·96,P均<0·01)。结论:COX-2在AS斑块中表达增强,且与AS的严重程度相关,提示COX-2可作为AS治疗的新靶点,塞来昔布可抑制其表达从而发挥抗AS作用。     

HDL as a prognostic biomarker for coronary atherosclerosis: the role of inflammation

Introduction: Emerging evidence suggests that the role of high density lipoprotein (HDL) in the atherosclerotic process is not as clear as previously thought, since atheroprotective HDL becomes atherogenic in states of increased inflammatory processes.

Areas covered: In this review we aim to elucidate the role of HDL as a prognostic biomarker and we discuss therapeutic approaches that aim to increase HDL and their possible clinical benefit.

Expert opinion: Given the structural variability and biological complexity of the HDL particle, its role in the atherosclerotic process is far from clear. According to current evidence, the atheroprotective role of HDL turns atherogenic in states of increased inflammatory processes, while even minor alterations in systemic inflammation are likely to hinder the endothelial protective effects of HDL. In accordance, significant data have revealed that HDL-related drugs may be effective in reducing cardiovascular mortality; however they are not as encouraging or unanimous as expected. Possible future goals could be to quantify either HDL subclasses or functions in an attempt to reach safer conclusions as to the prognostic importance of HDL in coronary atherosclerosis. Having achieved that, a more targeted therapy that would aim to raise either HDL functionality or to remodel HDL structure would be more easily designed.     

动脉粥样硬化炎症信号转导通路研究进展

炎症是动脉粥样硬化(atheroscle rosis,AS)疾病关键的病理环节之一。AS发病相关的多个危险因素均与炎症信号调节密切相关。深入研究AS炎症信号通路,并研制有效的干预药物,可能成为影响AS炎症反应乃至AS病变过程的有效途径。     

高效液相色谱法测定塞来昔布胶囊中塞来昔布的含量

目的 　建立测定塞来昔布胶囊中塞来昔布含量的反相高效液相色谱法。 方法 　以美国 Dikma公司 Diamonsil TMC1 8反相柱 ( 2 5 0 mm×4.6mm,5 μm)为色谱柱 ,流动相为甲醇 -超纯水 ( 85∶ 15 ,V/V) ,流速为 0 .8m L· min- 1 ,检测波长 2 5 4nm,柱温 40℃ ,进样量为 5 μL。考察了流动相不同配比对塞来昔布色谱行为的影响。 结果 　塞来昔布与胶囊剂辅料及其杂质可完全分离 ;分析方法的定量测定下限为 2 5μg· m L- 1 ,线性范围 :2 5～ 10 0 0 μg·m L- 1 ,回归方程为 C=1.86× 10 - 2 F+1.84× 10 - 1 ,r=0 .999( n=8) ,平均回收率为 98.2 3 %,RSD=0 .47%。 结论 　该方法灵敏、准确、简单、快速、可用于塞来昔布胶囊的含量测定     

Lipid pharmacotherapy for treatment of atherosclerosis

Introduction: For more than two decades, lowering levels of low-density lipoprotein cholesterol has formed the cornerstone of management of patients with atherosclerotic cardiovascular disease. The substantial residual risk of clinical events in patients treated with statin therapy highlights the need to develop more effective strategies to reduce cardiovascular risk.

Areas covered: Current and future approaches targeting dyslipidemia and inflammatory factors implicated in atherosclerosis are discussed.

Expert opinion: Considerable efforts to further reduce levels of atherogenic lipoproteins provide additional strategies to lower cardiovascular risk. In contrast, it remains to be determined whether targeting protective lipid factors or inflammatory mediators of atherosclerosis will be clinically beneficial.     

塞来昔布对膀胱癌细胞T24 增殖的影响

目的观察塞来昔布对人膀胱癌细胞T24增殖的影响,并探讨其可能的作用机制。方法不同浓度塞来昔布（25、50、100和200μmoL·L^-1）分别作用于人膀胱癌细胞T24不同时间（24h、48h和72h）,MTT检测T24细胞增殖抑制率,半定量RT-PCR和Western-blot检测T24细胞中COX-2表达的变化。结果塞来昔布对膀胱癌T24细胞抑制作用存在剂量、时间依赖性,200μmoL·L^-1塞来昔布作用72h时抑制率达75.7±1.9%,明显高于其它各组（P〈0.05或0.01）;半定量RT-PCR和Western-blot方法显示塞来昔布可显著降低T24细胞中COX-2mRNA和蛋白水平（P〈0.05）,且呈时间依赖性。结论塞来昔布可通过减少COX-2的表达抑制人膀胱癌细胞T24的增殖,并呈时间和剂量依赖性。     

塞来昔布凝胶剂的制备及含量测定

目的：制备塞来昔布凝胶并建立测定塞来昔布凝胶剂含量的方法。方法：以卡波姆940为凝胶基质制备塞来昔布凝胶剂;采用高效液相色谱法测定主药含量。结果：本法制得的凝胶均匀细腻,易涂布;塞来昔布在2．05～205．20μg·ml^-1浓度范围内线性关系良好（r=0．9999）,平均回收率为100．01％,RSD=0．18％。结论：该方法操作简便,准确可靠。     

内质网应激与动脉粥样硬化

在动脉粥样硬化的病理机制的研究中,内质网应激的作用越来越受到关注。本文拟就内质网应激与动脉粥样硬化的关系作一综述。内质网应激通过在炎症反应、脂质代谢异常、细胞凋亡中起的潜在作用,可能参与动脉粥样硬化发生和发展的机理。同时,血浆高半胱氨酸、高血糖等独立危险因子与内质网应激过程相互作用而诱导动脉粥样硬化。     

极谱催化氢波法测定塞来昔布的含量

目的建立一种灵敏快速测定塞来昔布的新方法。方法采用线性单扫描极谱法实现快速测定。结果在0.05 mol.L-1磷酸二氢钾-磷酸氢二钠(KH2PO4-Na2HPO4)缓冲溶液(pH值6.81±0.10)中,塞来昔布于?1.25 V处产生一灵敏的极谱催化氢波,其二阶导数峰电流与塞来昔布浓度在1.0×10-7~2.6×10-6mol.L-1范围内呈线性关系(r=0.997 0,n=6),检出限为5.0×10-8mol.L-1。结论该方法可用于药剂中塞来昔布的测定。     

低浓度Celecoxib对卵巢癌细胞SKOV3侵袭的抑制作用的研究

目的探讨低浓度环氧化酶-2(COX-2)选择性抑制剂Celecoxib对人卵巢癌细胞系SKOV3侵袭的影响及其相关机制。方法10μmol/L Celecoxib作用SKOV3细胞24h后,细胞外基质黏附试验检测细胞黏附能力,Transwell侵袭小室测定细胞的侵袭力,划痕试验检测细胞的迁移能力,明胶酶谱法(Zymography)检测细胞基质金属蛋白酶(MMP)-2、MMP-9活性,Western blot检测MMP-2、MMP-9和E-cadherin的表达;同时利用RNAi技术特异性沉默SKOV3细胞中COX-2的表达,观察上述指标的变化情况。结果10μmol/L Celecoxib作用SKOV3细胞24h后,细胞外基质黏附试验结果表明:SKOV3细胞黏附于matrigel的细胞数明显增加(P<0.05);Transwell侵袭小室实验结果表明:SKOV3细胞穿膜数明显减少(P<0.05),划痕试验结果表明:SKOV3细胞迁移到损伤区的细胞数明显减少(P<0.05)。进一步探讨机制,Zymography结果显示Celecoxib作用SKOV3细胞后,MMP-2、MMP-9的活性降低,Western blot结果显示MMP-2、MMP-9的表达量降低,而E-cadherin的表达量增强。而经特异性沉默COX-2表达的SKOV3/COX-2i细胞未出现上述分子的变化。结论10μmol/L Celecoxib能够增强SKOV3的黏附力,抑制其侵袭和转移能力,其机制可能与增加E-cadherin的表达,抑制MMP-2、MMP-9的活性和表达有关,而这一过程可能是COX-2非依赖的。     

An evaluation of RVX-208 for the treatment of atherosclerosis

Introduction: RVX-208 is a first-in-class, orally active, novel small molecule in development by Resverlogix Corporation (Calgary, AB, Canada). It acts through an epigenetic mechanism by inhibiting the bromodomain and extraterminal (BET) family of proteins, increasing apolipoprotein A-I (apoA-I) and targeting high-density lipoprotein (HDL) metabolism, including generating of nascent HDL and increased larger HDL particles, resulting in the stimulation of reverse cholesterol transport. RVX-208 also has a beneficial effect on inflammatory factors known to be involved in atherosclerosis and plaque stability. New therapeutic strategies are needed for patients with atherosclerosis.

Areas covered: In this review, the authors evaluate the use of RVX-208 as an agent for the treatment of atherosclerosis. The article is based on a literature search considering both animal and human studies available on PubMed as well as Media Releases from the Resverlogix Corporation.

Expert opinion: The current evidence suggests promising beneficial effects of this novel drug in the prevention and treatment of atherosclerosis and other metabolic disorders. Its unique mechanism of action is encouraging; it affects several pathways and has a modest effect on HDL levels. There is also a shift in particle size to larger HDL particles, which may have potent atheroprotective effects. Future clinical development is needed, including safety assessment.     

塞来昔布对非小细胞肺癌放疗的增敏作用

目的 探讨塞来昔布对非小细胞肺癌(NSCLC)放疗增敏作用的影响.方法 回顾性分析2012年5月-2013年10月收治的NSCLC患者90例,按治疗方法分为研究组44例和对照组46例,对照组予以同步放化疗方案,研究组在对照组基础上给予塞来昔布口服,观察2组临床疗效、不良反应发生情况,比较治疗前后KPS评分及治疗后2年内生存情况.结果 研究组治疗总有效率及1年、2年生存率均高于对照组,差异有统计学意义(P＜0.05).2组严重不良反应发生率比较差异无统计学意义(P＞0.05).治疗6个周期后,2组KPS评分较治疗前提高,且研究组高于对照组,差异有统计学意义(P＜0.05).结论 同步放化疗同时联合塞来昔布口服能有效增加NSCLC患者放疗敏感性,可提高临床疗效、延长患者生存时间.     

血管内皮细胞炎症反应与动脉粥样硬化的关系对药物研究的启示

动脉粥样硬化病 (AS)是一种具有慢性炎症反应特征的病理过程。血管内皮细胞在引发和扩大动脉炎症反应中起了关键的作用。以NF κB转录因子家族为调控中心的内皮细胞活化及炎症基因诱导途径有可能成为有关危险因子促动脉粥样硬化形成的的共同途径。选择性保护内皮细胞 ,调节内皮细胞的炎症反应 ,可能是合理的AS治疗靶点之一     

塞来昔布的合成、药理作用和临床应用研究进展

综述了近10多年来具有代表性的COX-2抑制剂塞来昔布合成方法,并对合成方法的优缺点进行了剖析,同时阐述了制备塞来昔布过程中常形成的晶型与杂质;对于塞来昔布的药理学作用、临床疗效和副作用作了归纳总结。