罗格列酮对老年胰岛素抵抗患者血清C反应蛋白水平的影响

目的　观察罗格列酮对老年胰岛素抵抗患者C反应蛋白 (CRP)和胰岛素敏感性的影响。方法　 71例胰岛素抵抗患者分为罗格列酮治疗组 (4 6例 ,罗格列酮 ,4mg/d)和对照组 (2 5例 ,维生素C ,10 0mg/d) ,观察 2 4周 ,治疗前后检查空腹CRP、胰岛素、血脂和肝功能 ,测量血压、身高和体重。结果　 (1)与基础值相比 ,罗格列酮组CRP、胰岛素抵抗指数 (COMA -IR)、收缩压、舒张压、胆固醇 (TC)、甘油三脂 (TG)、低密度脂蛋白胆固醇 (LDL -C)明显降低 (P <0 .0 5 ) ,高密度脂蛋白胆固醇 (HDL -C)轻度升高 ,有统计学差异 (P <0 .0 5 ) ,对照组以上各指标无明显变化 ;(2 )CRP与HOMA -IR、BMI、TC、TG、LDL -C、收缩压和舒张压呈正相关 ,与HDL -C呈负相关。结论　IR患者存在低度炎症状态 ,罗格列酮在改善IR及其相关代谢指标的同时 ,可降低CRP。     

罗格列酮抑制HL-6O细胞增殖和诱导分化作用

目的:研究罗格列酮对人急性髓性白血病细胞(HL-60)增殖和诱导分化的作用。方法:用不同浓度的罗格列酮处理HL-60细胞24~72h,MTT观察细胞的增殖抑制作用,瑞特-姬姆萨染色法及硝基蓝四氮(NBT)还原比色法测定细胞分化,流式细胞仪检测细胞周期分布和凋亡率,免疫组化检测PPAR-γ表达。结果:不同浓度罗格列酮处理细胞后,HL-60细胞增殖明显受抑,抑制率最高达77%,抑制作用呈现时间、剂量和效应依赖性;细胞周期分析,罗格列酮能诱导HL-60细胞G1期阻滞;同时罗格列酮能促进HL-60细胞分化。免疫组化发现,HL-60细胞表达PPAR-γ,罗格列酮作用HL-60细胞后,发生核转位现象。结论:罗格列酮能抑制HL-60细胞增殖,诱导细胞分化和细胞周期G1期阻滞,其作用机制可能与激活PPAR-γ有关。     

罗格列酮逆转丝裂霉素对人胃癌 SGC7901／VCR祼鼠移植瘤耐药作用的研究

目的：探讨 PPARγ激动剂罗格列酮（ ROS ）逆转人胃癌 SGC7901／VCR 细胞裸鼠移植瘤对丝裂霉素（ MMC）的耐药作用及其可能机制。方法建立人胃癌SGC7901／VCR细胞裸鼠移植瘤模型,将48只裸鼠随机分为6组：空白对照组（生理盐水0．2 ml）、MMC组（ MMC 2．5 mg／kg）、ROS组（ ROS 100 mg／kg）、MMC＋ROS中剂量组（ MMC 2．5 mg／kg＋ROS 50 mg／kg）、MMC＋ROS高剂量组（MMC 2．5 mg／kg＋ROS 100 mg／kg）、MMC＋CSA组（MMC 2．5 mg／kg＋CSA 50 mg／kg）。每组8只裸鼠;用药40天后,观察各组裸鼠体重和移植瘤体积变化,计算抑瘤率,绘制移植瘤的生长曲线;Western-blot法检测P-gp和MGr1-Ag蛋白的表达。结果空白对照组、MMC组移植瘤瘤体积和抑瘤率差异无显著性,ROS组、MMC＋ROS中剂量组、MMC＋ROS高剂量组组、MMC＋CSA组与空白对照组、MMC组比较,移植瘤瘤体积和抑瘤率差异有显著性。空白对照组、MMC组中P-gp、MGr1-Ag蛋白表达最强,ROS组、MMC＋ROS中剂量组、MMC＋ROS大剂量组、MMC＋CSA组与空白对照组和MMC组P-gp、MGr1-Ag蛋白表达比较有统计学意义（ P＜0．05）,MMC＋ROS大剂量组、MMC＋CSA组中其表达最弱,组间差异无统计学意义（P＞0．05）。结论罗格列酮可抑制人胃癌SGC7901／VCR细胞祼鼠移植瘤瘤体生长,罗格列酮可下调人胃癌SGC7901／VCR细胞裸鼠移植瘤组织中P-gp和MGr1-Ag蛋白的表达。罗格列酮可部分逆转人胃癌SGC7901／VCR细胞祼鼠移植瘤对丝裂霉素的耐药性。     

Solubility enhancement of rosiglitazone by using melt sonocrystallization technique

The poor solubility and low dissolution rate in gastro-intestinal fluid, especially for class-II drugs according to Biopharmaceutics Classification System (BCS) the bioavailability enhanced by increasing the solubility and dissolution rate. A novel melt sonocrystallization technique of particle engineering to enhance solubility as well as dissolution of hydrophobic drug and to study its effect on crystal properties of drug. The present study leads to use investigate solubility of melt sonocrystallization technique to modify the undesirable properties of Rosiglitazone is antidiabetic drug in thiozolidione category with (BCS II) to forms agglomerates with number of shallow circular pits on the surface leads to increase solubility. Melt sonocrystallization process was developed for Rosiglitazone in which Rosiglitazone melt was poured in deionized water and simultaneously subjected to ultrasonic energy for 20 min at amplitude 80 %. The product obtained was evaluated using scanning electron microscopy, differential scanning calorimetry, X-ray powder diffractometry (XPRD), Fourier transformed infrared spectroscopy (FTIR), solubility and dissolution rate. The irregular agglomerates with porous surface were obtained having different crystal habit which increases solubility and dissolution rate. FTIR shows thermal behavior of untreated Rosiglitazone and treated Rosiglitazone have no significant difference low intensity peaks in XPRD of treated Rosiglitazone were noticed crystals habit changes and lattice defects during processing have causes favorable changes in the physicochemical properties of Rosiglitazone. The use of melt sonocrystallization technique is promising technique that may affords powder with improved flow as well as improved solubility and dissolution.     

Thiazolidinediones reduce the LDL binding affinity of non-human primate vascular cell proteoglycans

Aims/hypothesis Retention of atherogenic lipoproteins in the artery wall by proteoglycans is a key step in the development of atherosclerosis. Thiazolidinediones have been shown to reduce atherosclerosis in mouse models. The aim of this study was to determine whether thiazolidinediones modify vascular proteoglycan synthesis in a way that decreases LDL binding.Methods Primate aortic smooth muscle cells were exposed to troglitazone or rosiglitazone, or no stimulus at all for a 24-hour steady-state labelling period. Sulphate incorporation, size and LDL binding affinity of proteoglycans were determined. Proteoglycans secreted by cells in the presence or absence of troglitazone were separated into large and small classes by size exclusion chromatography, and LDL binding affinity was determined.Results Proteoglycans synthesised by cells exposed to troglitazone or rosiglitazone were smaller, with decreased sulphate incorporation and decreased LDL binding affinity. However, troglitazone had a greater effect than rosiglitazone. Troglitazone reduced the LDL binding affinities of both the large and small proteoglycans compared with control. The binding differences persisted when glycosaminoglycan chains released from proteoglycans were incubated with LDL, indicating that troglitazone affects the glycosaminoglycan synthetic machinery of these cells.Conclusions/interpretation Thiazolidinediones decrease the LDL binding affinity of the proteoglycans synthesised by primate aortic smooth muscle cells. This could, in part, account for the reduced atherosclerosis observed in animal models.Abbreviations PPAR peroxisome proliferator-activated receptor - K_d binding constantPresented in part at the 3rd Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology, Salt Lake City, Utah, USA, 6 April 2002     

罗格列酮对2型糖尿病合并高血压患者血压的作用

目的：运用胰岛素增敏剂罗格列酮治疗2型糖尿病伴高血压患者，研究其降压作用及降压机理。方法：38例2型糖尿病伴高血压患者，口服罗格列酮（文迪雅）4～8mg／d，共12周，观察治疗前后的血压、瘦素、血糖和胰岛素水平，计算胰岛素敏感指数和胰岛素抵抗指数，并进行分析比较。结果：罗格列酮治疗后收缩压和舒张压明显下降（P〈0．05）；甘油三酯（TG）、空腹血糖（FBG）、餐后血糖（PBG）、空腹胰岛素（FINS）和餐后胰岛素（PINS）均明显降低（P均〈0．05）；瘦素水平明显升高（P〈0．01）；胰岛素敏感性指数（ISI）显著升高（P〈0．05），胰岛素抵抗指数（IR）显著下降（P〈0．05）。结论：罗格列酮在降低血糖、改善胰岛索抵抗、提高胰岛素敏感指数的同时，具有升高瘦素水平和降低血压的作用。     

罗格列酮对老年胰岛素抵抗小鼠骨骼肌细胞葡萄糖转运体4转位的影响

目的 探讨罗格列酮对胰岛素刺激的老年胰岛素抵抗（IR）小鼠骨骼肌细胞葡萄糖转运体4（GLUT4）转位的影响.方法 18月龄雌性C57BL/6J老年小鼠30只,随机平均分成三组：老年普通膳食组,老年IR组喂养高脂肪膳食（58%脂肪,21%蛋白,21%碳水化合物）,罗格列酮组给予高脂肪膳食的同时服用罗格列酮,同时设立青年组.16 w后提取各组小鼠完整的骨骼肌束,在胰岛素浓度为10-7的缓冲液中孵育30min.用超速蔗糖梯度离心方法分离细胞内膜和外膜的匀浆,用Western blot方法检测各组小鼠骨骼肌细胞内、外膜GLUT4蛋白水平.结果 老年对照组小鼠胰岛素刺激的GLUT4转位功能较青年组明显下降（P＜0.05）,老年IR组的内、外膜GLUT4蛋白总量及GLUT4转位均较老年对照组降低（P＜0.05）,而罗格列酮组的GLUT4转位较IR组有明显的上升（P＜0.05）.结论 罗格列酮增加了细胞内膜GLUT4向细胞外膜的转位.     

罗格列酮对大鼠溃疡性结肠炎的疗效及其机制

目的观察罗格列酮对大鼠溃疡性结肠炎的疗效并探讨其可能存在的机制。方法应用三硝基苯磺酸(TNB)/乙醇灌肠制备大鼠溃疡性结肠炎模型。实验设正常对照组、模型对照组、阳性药物组(柳氮磺胺吡啶组,100 mg/kg)、罗格列酮给药组(2 mg、4mg、8 mg/kg),每天灌胃给药1次,给药时间从造模后第2天开始至实验结束共8 d,观察大鼠疾病活动指数(DAI)、结肠黏膜损伤指数(CMDI)及组织学评分(HS)。生化法检测大鼠结肠组织髓过氧化物酶(MPO)、超氧化物歧化酶(SOD)活性及丙二醛(MDA)的含量。结果与正常组相比,模型组大鼠DAI、CMDI、HS明显增加(P<0.01),结肠组织MPO活性、MDA水平显著升高(P<0.01),SOD活性下降(P<0.01)。罗格列酮4 mg、8 mg/kg和SASP可不同程度改善DAI、CMDI和HS(P<0.05,P<0.01),降低MPO活性和MDA水平(P<0.01),增加SOD活性(P<0.01)。结论罗格列酮对大鼠溃疡性结肠炎有保护作用,其机制可能与减少脂质氧化,增加清除氧自由基的能力有关。