普伐他汀钠治疗原发性高脂血症疗效观察

报道普伐他汀钠治疗原发性高脂血症的疗效，以吉非罗齐为对照。结果显示：服普伐他汀钠４周后，ＴＣ值下降１６％，第８、１２周末下降幅度分别为２０％及１９％，与对照组比Ｐ＜０．０５；ＬＤＬ─Ｃ第４周末下降２０％，第８周末下降２５％，第１２周末下降２４％，Ｐ＜０．０１。ＴＧ亦下降，ＨＤＬ─Ｃ略有上升，但无统计学意义。     

吉非贝齐对吡格列酮及其主要活性代谢产物的药物动力学影响

目的研究吉非贝齐对吡格列酮及其主要活性代谢产物药物动力学的影响,为临床合理用药提供参考。方法12名健康男性受试者随机分为2组,分别服用吉非贝齐(GEM)或安慰剂(PLA)600 mg,2次.d-1,连续1周;第3日在服用吉非贝齐或安慰剂1 h后口服单剂量吡格列酮(PIO)30 mg;第2周期2组交叉服用安慰剂或吉非贝齐,其余给药方案不变。采用HPLC-MS法测定吡格列酮及其代谢产物M-Ⅲ和M-Ⅳ的血药浓度,HPLC-RIF法测定吉非贝齐的血药浓度。结果与安慰剂组相比,合用吉非贝齐后:PIO的AUC0~∞增加239%(P<0.01),而M-Ⅲ和M-Ⅳ的AUC0~∞均无显著性改变,M-Ⅲ和M-Ⅳ与PIO的AUC0~∞比值分别减小71%和65%(P<0.01);PIO的Cmax在两组间无显著性差别,M-Ⅲ的Cmax减小51%(P<0.05),M-Ⅳ的Cmax也有减小趋势;三者的半衰期均延长约1倍;总活性成分(TAC)的AUC0~∞增加59%(P<0.01);Cmax无显著变化,t1/2由24.3 h延长至30.2 h(P<0.01)。结论吉非贝齐可同时抑制吡格列酮活性代谢产物M-Ⅲ和M-Ⅳ的生成和进一步代谢。吉非贝齐使吡格列酮及其总活性成分的AUC显著增加、清除减慢,因此临床上两药合用需谨慎,必要时需减少吡格列酮剂量。     

Species‐related exposure of phase II metabolite gemfibrozil 1‐O‐β‐glucuronide between human and mice: A net induction of mouse P450 activity was revealed

Gemfibrozil is a fibrate drug used widely for dyslipidemia associated with atherosclerosis. Clinically, both gemfibrozil and its phase II metabolite gemfibrozil 1‐O‐β‐glucuronide (gem‐glu) are involved in drug–drug interaction (DDI). But the DDI risk caused by gem‐glu between human and mice has not been compared. In this study, six volunteers were recruited and took a therapeutic dose of gemfibrozil for 3 days for examination of the gemfibrozil and gem‐glu level in human. Male mice were fed a gemfibrozil diet (0.75%) for 7 days, following which a cocktail‐based inhibitory DDI experiment was performed. Plasma samples and liver tissues from mice were collected for determination of gemfibrozil, gem‐glu concentration and cytochrome p450 enzyme (P450) induction analysis. In human, the molar ratio of gem‐glu/gemfibrozil was 15% and 10% at the trough concentration and the concentration at 1.5 h after the 6th dose. In contrast, this molar ratio at steady state in mice was 91%, demonstrating a 6‐ to 9‐fold difference compared with that in human. Interestingly, a net induction of P450 activity and in vivo inductive DDI potential in mice was revealed. The P450 activity was not inhibited although the gem‐glu concentration was high. These data suggested species difference of relative gem‐glu exposure between human and mice, as well as a net inductive DDI potential of gemfibrozil in mouse model.     

吉非罗齐对游离脂肪酸和脂肪型脂肪酸结合蛋白在血脂异常兔中影响

目的观察吉非罗齐短期干预对高胆固醇血症兔血清游离脂肪酸（FFA）及脂肪组织分泌脂肪细胞型脂肪酸结合蛋白（AFABP）的影响,并阐明其可能机制。方法 15只新西兰大白兔随机分为3组,每组5只。①对照组：给予普通饮食12周。②高胆固醇组：给予高胆固醇饲料12周。③吉非罗齐组：在饲以高胆固醇饲料8周的基础上给予吉非罗齐200 mg·kg^-1·d^-1 4周。酶联免疫吸附测定（ELISA）法检测血清FFA、AFABP水平,应用反转录聚合酶链反应（RT-PCR）法测定脂肪组织AFABPmRNA的表达。结果高胆固醇组和吉非罗齐组兔饲养第8周及第12周血清总胆固醇、低密度脂蛋白胆固醇、FFA水平均明显高于对照组（P〈0.01）;第12周时高胆固醇组和吉非罗齐组兔饲养血清总胆固醇、低密度脂蛋白胆固醇、FFA水平均明显高于对照组（P〈0.01）;吉非罗齐组兔第12周末体质量较第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）;高胆固醇组和吉非罗齐组脂肪组织AFABPmRNA的表达明显高于对照组（P〈0.05）,但吉非罗齐组兔脂肪组织AFABPmRNA的表达明显低于高胆固醇组（P〈0.05）。结论吉非罗齐能降低高胆固醇饮食饲养兔体质量,并降低FFA、血清及脂肪组织分泌AFABP,这一作用可能有利于肥胖及动脉粥样硬化的防治。     

Possible increased risk of rhabdomyolysis during concomitant use of simvastatin and gemfibrozil

The occurrence of rhabdomyolysis is one of the rare side-effects of the cholesterol-lowering agent simvastatin. During the use of lovastatin, an agent related to simvastatin, the risk of this side-effect might be increased when cyclosporin or gemfibrozil are used concomitantly. It is possible that this also applies for simvastatin. We present two patients who developed rhabdomyolysis during the concomitant use of simvastatin and gemfibrozil.     

Gemfibrozil treatment of the high triglyceride-low high-density lipoprotein cholesterol trait in men with established atherosclerosis

Abstract. Objective. To study the short-term efficacy, tolerability and safety of the treatment with gemfibrozil 600 mg twice daily or placebo in male patients with established atherosclerosis, with a lipid profile matching the ‘high triglyceride-low high-density lipoprotein (HDL) cholesterol trait”. Design. Double-blind randomized placebo controlled prospective trial. Setting. Amsterdam Lipid Research Clinic at the Academic Medical Centre of the University of Amsterdam and the Slotervaart Training Hospital affiliated to the University of Amsterdam, Amsterdam, the Netherlands. Subjects. Thirty-five male patients, age 30–70, with established atherosclerosis and the high triglyceride-low HDL cholesterol trait. Main outcome measures. Plasma total cholesterol, triglycerides, lipoproteins, apolipoproteins A₁ and B₁₀₀, clinical and laboratory safety parameters. Results. Seventeen patients in the gemfibrozil group and 16 patients in the placebo group completed the study period. Compliance was considered adequate. Mean (± standard deviation) plasma HDL cholesterol levels increased 20.3% (±12.22) from 0.82 to 0.99 mmol L^?1 in the gemfibrozil group against 9.9% (±18.31) from 0.79 to 0.87 mmol L^?1 in the placebo group (P = 0.001). Mean plasma triglyceride level fell 49.5% (±14.27) from 3.65 to 1.82 mmol L^?1 in the gemfibrozil group against an increase of 13.6% (±40.31) from 3.62 to 4.01 mmol L^?1 in the placebo group (P < 0.001). Although plasma HDL cholesterol and triglyceride levels improved in all patients, normalization of these lipoproteins was only observed in approximately half of them. Plasma total and low-density lipoprotein (LDL) cholesterol levels, as well as plasma levels of apolipoprotein (apo) A₁, B₁₀₀ and lipoprotein [Lp(a)], did not show significant alterations compared to the placebo. All safety parameters were comparable between the two groups and remained within the reference limits. Gemfibrozil was well tolerated during treatment. Minor inconveniences were equally distributed between the two treatment groups. Conclusions. Gemfibrozil is an effective and safe drug in patients with coronary heart disease (CHD) and the high triglyceride-low HDL cholesterol trait.     

Effect of modest vitamin E supplementation on blood glycated hemoglobin and triglyceride levels and red cell indices in type I diabetic patients.

The glycation of proteins and elevated triglyceride (TG) levels are two of the major risk factors in the development of complications of diabetes. Previous studies have found some beneficial effects of supplementation of pharmacological doses (900-2000 IU/day) of vitamin E in Type II diabetic patients. This study examined whether supplementation with a modest dose of vitamin E (100 IU/day) had any effect on blood glucose, glycated hemoglobin (GHb), TG or red cell counts in Type I diabetic patients.

35 diabetic patients were supplemented with either DL-alpha-tocopherol (vitamin E) capsules (orally, 100 IU/day) or a placebo for 3 months in a double-blind clinical trial. Fasting blood was collected from each diabetic patient before and after vitamin E or placebo supplementation. Data were analyzed using paired “t” tests and the Wilcoxon Signed Rank Test.

Levels of GHb (mean +/? SEM) were 11.5 +/? 0.4 and 12.8 +/? 0.9% (p < 0.05); glucose, 8.8 +/? 1.2 and 11.6 +/? 1.3 mM; and TG, 2.2 +/? 0.2 and 2.9 +/? 0.3 mM (p < 0.03) after vitamin E supplementation versus before supplementation. There were no differences in these parameters after supplementation with the placebo. There was no effect on blood RBC, hematocrit, and hemoglobin levels after supplementation of vitamin E or the placebo. There were no differences in ages and duration of diabetes between placebo and vitamin E-supplemented groups.

This study suggests that modest vitamin E supplementation (100 IU/day) can significantly lower blood GHb and TG levels and does not have any effect on red cell indices in Type I diabetic patients.     

The Helsinki Heart Study: coronary heart disease incidence during an extended follow-up

Abstract. Objectives . To confirm that coronary heart disease (CHD) can be prevented by gemfibrozil treatment and to estimate the long-term effect of the treatment. Design . All participants of the Helsinki Heart Study, a controlled 5-year CHD primary prevention trial with gemfibrozil and placebo, were offered gemfibrozil treatment and biannual follow-up for 3.5 more years. Setting . By the end of the multi-clinic double-blind trial, a 34% difference in definite cardiac events (56 vs. 84; P < 0.2) had developed between the gemfibrozil and placebo groups. Subjects . There were 2046 dyslipidaemic men in the gemfibrozil group at randomization, 1961 started the extended follow-up; the comparison group comprised 2035 men, and 5 years later 1928 men. Interventions . Gemfibrozil was selected by 66.3% of gemfibrozil and 68.5% of placebo men without previous CHD end-points. Main outcome measures . Definite fatal and non-fatal CHD events are reported, possible CHD events were recorded but reported selectively. Results . During the post-trial period the numbers of definite CHD events in both groups (54 vs. 47; NS) were smaller than expected without treatment, namely a reduction of around 40% for the original treatment groups. The mean incidence rates were in fact similar to that in the placebo group 5 years earlier. The post-trial CHD incidence was lowest amongst the placebo group men who later selected gemfibrozil. Cardiovascular mortality over the entire study period was similar but all-cause mortality was slightly higher amongst men of the original gemfibrozil group compared to the placebo group men (P = 0.19). Conclusions . Thus prolonged gemfibrozil treatment postpones cardiac events. This protective effect presumably involves both attenuation of atherosclerosis and mechanisms related to acute cardiac events.     

Serum ferritin and ceruloplasmin as coronary risk factors

Iron and copper catalyze lipid peroxidation in vitro, and recentepidemiological data suggest that these metal ions might alsobe involved in human coronary heart disease. We tested the hypothesisby investigating whether the storage proteins ferritin and ceruloplasminwere coronary risk factors. A nested case-control study was set up in middle-aged dyslipidaemicparticipants of the Helsinki Heart Study: a placebo-controlledcoronary primary prevention trial with gemfibrozil Of the 140subjects with cardiac end-points (non-fatal myocardial infarctionor cardiac death) 136 were matched with controls for geographicalarea and drug treatment (gemfibrozil-placebo). Frozen baseline serum samples were used in the analyses of ferritinand ceruloplasmin. Using logistic regression analyses no incrementin coronary risk was detected with increasing ferritin levels(P=0.8 for trend). Ceruloplasmin was higher 349 ± 86vs 317 ± 77mg. l^–1 (P<0.001) in cases than incontrols and the risk in the highest fertile was two-fold (oddsratio 21; 95% CI 1.3-4.2) compared to the lowest (P<0.005for trend). The risk of high ceruloplasmin was influenced bylipoprotein cholesterol concentrations, with an odds ratio of2.4 (95% CI 1.3-4.4) in subjects with high low density lipoproteincholesterol and of 11.3 (95% CI 2.5-52.2) in subjects with lowhigh density lipoprotein cholesterol. It was concluded that ferritin was not associated with coronaryheart disease in dyslipidaemic, middle-aged men, while therewas a continuous and graded increment in coronary risk withelevating ceruloplasmin level.     

Association of Serum Triglyceride Level and Gemfibrozil Consumption With Periodontal Status

Background: Hyperlipidemia is a major risk factor for cardiovascular diseases. Considering the suggested association between periodontal and cardiovascular diseases, this study sought to assess the association, if any, between serum triglyceride (TG) levels and gemfibrozil consumption with periodontal parameters. Methods: This cross‐sectional study was conducted on 90 participants, including 30 individuals with a normal lipid profile (group H), 30 patients with hypertriglyceridemia and not on medication (group N), and 30 patients with hypertriglyceridemia and taking gemfibrozil over a 3‐month period (group M). Periodontal parameters including probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), and plaque index were measured at four sites of each tooth. Serum levels of total cholesterol (TC), TG, low‐density lipoprotein, and high‐density lipoprotein were measured. Results: Mean values for PD and CAL in the two hypertriglyceridemic groups were significantly higher than those of the H group (P <0.001). After controlling for confounding variables, significant linear correlations were noted between PD and BOP, PD and TC, PD and TG, and CAL and TG in each group (P <0.01). Conclusions: Patients with hypertriglyceridemia had worse periodontal status than healthy controls. Patients with hypertriglyceridemia who were taking gemfibrozil did not show significant differences in CAL and PD compared with untreated patients with hypertriglyceridemia.