吉非罗齐中有机溶剂残留量的顶空毛细管GC测定

建立了顶空毛细管GC法测定吉非罗齐中甲酸乙酯、THF和甲基环己烷3种有机溶剂的残留量。采用HP-1毛细管柱，溶剂DMA，内标乙酸乙酯。平均同收率分别为99．8％、100．3％、100．0％，RSD分别为0．71％、1．51％和1．76％。     

Therapeutic effects of bezafibrate and gemf ibrozil in hyperlipoproteinaemia Type IIa and IIb

Summary

Fifty-nine patients with hyperlipoproteinaemia Type IIa and IIb who had failed to respond to 1-month's dietary therapy were treated over a 4-month period with either bezafibrate (600?mg/day) or gemfibrozil (1200?mg/day) in addition to their diet. Fasting serum lipid (cholesterol, HDL-cholesterol and triglycerides) and blood glucose levels were measured on entry and at monthly intervals, and routine laboratory investigations were carried out before and after treatment to monitor hepatic, renal and haematic tolerance. The results showed that whilst both drugs produced significant reductions from baseline in total cholesterol, LDL-cholesterol and triglyceride levels from Day 30 onwards, the reductions were more marked in the bezafibrate group. There was a trend for HDL-cholesterol levels to increase. Fasting blood glucose levels decreased significantly in the bezafibrate group and to a greater extent than in patients on gemfibrozil. Only 1 patient on bezafibrate did not tolerate bezafibrate whereas 13 patients on gemfibrozil reported side-effects, mainly gastro-intestinal, and 4 had to withdraw from the study during the first or second month.     

A proteomic evaluation of the effects of the pharmaceuticals diclofenac and gemfibrozil on marine mussels (Mytilus spp.): evidence for chronic sublethal effects on stress‐response proteins

Human pharmaceuticals (e.g. the lipid regulator gemfibrozil and the non‐steroidal anti‐inflammatory drug diclofenac) are an emerging environmental threat in the aquatic environment. This study aimed to evaluate sublethal effects of these two commonly found pharmaceuticals on the protein profiles of marine mussels (Mytilus spp.). Mytilus spp. was exposed to environmentally relevant and elevated concentrations (1 and 1000 µg/l respectively) of both drugs for 14 days. In addition, mussels were maintained for seven days post treatment to examine the potential of blue mussels to recover from such an exposure. Differential protein expression signatures (PES) in the digestive gland of mussels were obtained using two‐dimensional gel electrophoresis after 7, 14, and 21 days of exposure. Twelve spots were significantly increased or decreased by gemfibrozil and/or diclofenac, seven of which were successfully identified by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) analysis. These proteins were involved in energy metabolism, oxidative stress response, protein folding, and immune responses. Changes in the PES over time suggested that mussels were still experiencing oxidative stress for up to seven days post exposure. In addition, a suite of biomarkers comprising glutathione transferase, lipid peroxidation, and DNA damage were studied. An oxidative stress response was confirmed by biomarker responses. To our knowledge, this is the first investigation using proteomics to assess the potential effects of human pharmaceuticals on a non‐target species in an environmentally‐relevant model. The successful application of this proteomic approach supports its potential use in pollution biomonitoring and highlights its ability to aid in the discovery of new biomarkers. Copyright © 2013 John Wiley & Sons, Ltd.     

药物刺激肝细胞合成分泌载脂蛋白AI的分子生物学机制

本文检测了Gemfibrozil(GF，商品名Lopid降脂灵是一种常用的抗动脉硬化药物，具有降低甘油三脂和升高高密度脂蛋白（HDL）的作用）对肝细胞载脂蛋白AI的合成与分泌的作用以及可能的作用机制。在本研究中我们使用了ELISA，免疫沉淀，分子生物学技术（如mRNA定量，半寿期和新mRNA合成率等）和特异性抗体。结果发现，GF可增载载脂蛋白AI(apoAI)的分流行性及放射标记蛋氨酸的掺入（合成）。与对照组相比使用200μm的GF可以增加apoAI的分泌及合成分别达158％和130％（短期冲击）。分子生物学结果显示，使用不同浓度的GF可以增加稳定状态的mRNA表达（最高达204）％。mRNA的半寿期由14．5h延长到35h。而新的mRNA的合成率无变化。结论：GF的心脏保护作用是因为该药刺激肝脏增加apoAI的合成及分泌。其机制则为延长apoAI mRNA的半寿期从使mRNA在肝细胞内的含量增加，而与新的mRNA的生成无关。     

吉非贝齐对血脂异常兔血清脂肪细胞型脂肪酸结合蛋白的影响

目的观察吉非贝齐短期干预对高胆固醇血症兔血清及脂肪组织分泌脂肪细胞型脂肪酸结合蛋白(AFABP)的影响。方法 15只新西兰大白兔随机分为3组:对照组.高胆固醇组.吉非贝齐组,每组5只。用RT-PCR法测定脂肪组织AFABP mRNA的表达;ELISA法检测血清及脂肪组织培养液中AFABP水平。结果高胆固醇组和吉非贝齐组兔饲养第8周及第12周血清总胆固醇、低密度脂蛋白胆固醇水平明显高于对照组(P<0.01);吉非贝齐组兔第12周体重较第8周明显下降(P<0.05),同时血清和脂肪组织培养的上清液中AFABP水平明显低于高胆固醇组(P<0.05);高胆固醇组和吉非贝齐组脂肪组织AFABP mRNA的表达明显高于对照组,但吉非贝齐组兔脂肪组织AFABP mRNA的表达明显低于高胆固醇组(P<0.05)。结论吉非贝齐能降低高胆固醇饮食饲养兔体重,并降低血清及脂肪组织分泌的AFABP,这一作用可能有利于防治动脉粥样硬化及肥胖。     

吉非罗齐对实验性糖尿病大鼠的降糖作用及其机制研究

 目的观察吉非罗齐(gemfibrozil,Gem)对实验性2型糖尿病(type 2 diabetes mellitus,T2DM)大鼠的降糖、降脂作用及其可能机制。方法采用高糖高脂膳食4周诱导大鼠胰岛素抵抗后,腹腔注射亚致病剂量链脲佐菌素(streptozotocin,STZ)的方法制备T2DM模型,并观察Gem对其血脂、血糖代谢的影响及其可能机制。结果连续灌胃给药8周后,Gem显著降低实验性糖尿病大鼠的空腹血糖(fasting blood glucose,FBG)和三酰甘油(triglyceride,TG)、总胆固醇(totalcholesterol,TC)、低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)及游离脂肪酸含量(nonesterified fatty acid,NEFA)(P<0.05或P<0.01),显著增高实验性糖尿病大鼠血清SOD活力(superoxide dismutase,SOD),降低模型组大鼠MDA(maleic dialdehyde,MDA)含量(P<0.05或P<0.01)。结论Gem不仅对实验性T2DM大鼠血脂具有良好的调节作用,还能改善实验性T2DM大鼠的血糖代谢,显著降低FBG。     

Self-Micellization of Gemfibrozil 1-O-β Acyl Glucuronide in Aqueous Solution

Purpose. Phase II metabolism involves the conjugation of a polar moiety, such as sulfate or glucuronic acid, to a (relatively) nonpolar xenobiotic. Although it might be expected that such conjugates may exhibit amphiphilic character (e.g., surface activity and potential to form micelles), no detailed study of the micellization characteristics of any drug-glucuronide conjugates has yet been reported. Therefore, the aim of this study was to investigate the solution behavior and amphiphilic characteristics of gemfibrozil 1-O- glucuronide (GG), a model drug-glucuronide conjugate. Methods. Crude GG was extracted from the urine of volunteers dosed with 600 mg of gemfibrozil, and this material was then purified by reversed-phase high-performance liquid chromatography to yield a white solid. The amphiphilic properties of GG within the bulk aqueous phase were studied by isothermal titration microcalorimetry and ¹H-NMR spectrometry, whereas those at the aqueous/air interface were studied by surface tensiometry. Results. The results of each independent analytical technique were consistent with GG in aqueous solution exhibiting amphiphilic properties typical of a hydrophilic surfactant. The titration microcalorimetry and ¹H-NMR spectrometry data were in excellent agreement with each other, yielding critical micellization concentrations (cmc) for GG in 0.1 M acetate buffer of 18.1 ± 0.4 mM and 18.3 ± 0.3 mM, respectively. The profile and results of the surface tension measurements were consistent with GG localizing at the aqueous/air interface. Conclusion. These results confirm the hypothesis that a glucuronide conjugate of a relatively nonpolar xenobiotic, such as gemfibrozil, behaves as an amphiphile in aqueous solution. The implications of this observation include a likely basis for the previously observed concentration-dependence in the degradation rate of the acyl glucuronides of 2-phenylpropionic acid, as well as identifying a possible broader contributory effect to the structural dependencies in biliary choleresis of different glucuronide conjugates of xenobiotics.     

Comparative studies on the influence of different fibrates on serum lipoproteins in endogenous hyperlipoproteinaemia

Summary Two trials have been performed in the same patients with hyperlipoproteinaemia Types IIb (12 cases), III (6 cases) and IV (11 cases). In the first study the lipid-lowering properties of bezafibrate, fenofibrate, gemfibrozil, etofibrate and etofylline clofibrate were compared and in a separate trial the influence of combined treatment with gemfibrozil plus colestipol and bezafibrate plus probucol on lipoproteins were investigated. The mean percentage lipid-lowering effect of each fibrate on serum and VLDL fraction was significant in the Types IIb, III and IV patients, but there were significant differences between the fibrates. In general, gemfibrozil and bezafibrate decreased plasma lipid levels more than etofibrate and etofylline clofibrate in Type IIb patients. In Type IV cases gemfibrozil and bezafibrate were significantly potent in reducing the triglyceride level than fenofibrate, etofibrate or etofylline clofibrate. All the fibrates produced an increase in HDL cholesterol, but there were significant differences between them were in the Type IV patients. The influence of fibrates on the LDL fraction was much more variable. In hyperlipoproteinaemia Type IIb, a decrease in both LDL cholesterol and LDL apolipoprotein B was observed. In Type III and IV patients, however, an increase in LDL concentration occurred. The addition of colestipol to gemfibrozil therapy led to a further decrease in total cholesterol, LDL cholesterol and LDL apolipoprotein B in Type IIb patients. In patients with hyperlipoproteinaemia Types III and IV colestipol prevented the increase in LDL concentration after treatment with gemfibrozil alone. The effect of probucol on LDL cholesterol was comparable to that of colestipol. Combined treatment with gemfibrozil and colestipol caused an increase in HDL cholesterol concentration in contrast to combined treatment with bezafibrate and probucol. It is concluded that combined therapy with fibrates plus bile acid sequestrant would be of practical value in patients with hyperlipoproteinaemia Types IIb, III and IV.     

益多酯治疗高脂血症并发高尿酸血症

目的　比较益多酯与吉非贝齐治疗高脂血症并发高尿酸血症的疗效及其安全性。方法　高脂血症并发高尿酸血症 82例 ,分为益多酯组 40例 ,男 2 7例 ,女 1 3例 ,年龄 (65± 6)岁 ,口服益多酯 2 50mg ,2 /d ,疗程 8周 ;吉非贝齐组 42例 ,男 2 8例 ,女 1 4例 ,年龄 (64±5)岁 ,口服吉非贝齐 30 0mg ,3/d ,疗程 8周。结果　 2组降TC总有效率分别为 83 % ,74% (P >0 .0 5) ,降TG总有效率分别为 85 % ,83 % (P >0 .0 5) ,升LDL -C的总有效率分别为 73 % ,67% (P >0 .0 5) ,降UA总有效率分别为 83 % ,2 6 % (P <0 .0 5)。益多酯组有 2例出现胃部不适 ,吉非贝齐组有 1 2例ALT轻度升高。结论　益多酯与吉非贝齐治疗高脂血症的疗效相近 ,益多酯降高尿酸作用确切 ,且安全。