Additive improvement induced by bezafibrate in patients with primary biliary cirrhosis showing refractory response to ursodeoxycholic acid

Background and Aim: Ursodeoxycholic acid (UDCA) has been widely used in the treatment of patients with primary biliary cirrhosis (PBC). However, some patients are refractory to UDCA. The aim of this study is to clarify the additive improvement induced by bezafibrate in patients refractory to UDCA. Methods: This study was a prospective analysis of 37 consecutive PBC patients. All patients were treated first for 6 months with UDCA, and then with bezafibrate, if their alkaline phosphatase (ALP) levels did not decrease more than 40% or within the normal range after 6 months' treatment with UDCA. Clinical parameters were monitored for the subsequent 24 months. Result: Twenty‐two patients (59%) achieved improvement of ALP levels after the treatment with UDCA. Those patients (Group A) had significantly lower levels of ALP at diagnosis than those with abnormal ALP levels after 6 months' treatment with UDCA (Group B; P = 0.020). They continued UDCA monotherapy, and maintained normal ALP levels at subsequent follow ups. However, immunoglobulin M (IgM) levels remained abnormal in eight patients, whose IgM levels at the time of diagnosis were significantly higher than those whose IgM were normalized after 6 months' treatment with UDCA (P = 0.026). Those in Group B were treated additionally with bezafibrate, and 12 patients (80%) achieved normal ALP and IgM levels within 12 months of commencement of therapy. Conclusion: Higher ALP level at diagnosis is one of the predictors for UDCA failure. Combination treatment of bezafibrate in addition to UDCA may be an effective treatment for PBC patients refractory to UDCA.     

苯扎贝特通过过氧化物酶体增殖物激活受体α信号途径对人横纹肌RD细胞的毒性作用

目的探讨苯扎贝特对人骨骼肌细胞的毒性作用及其作用机制。方法人横纹肌RD细胞与苯扎贝特0(对照组),10,30,100,300和1000μmol·L-1作用24h,WST-1法检测细胞存活;苯扎贝特与MK8861μmol·L-1共同作用RD细胞24h,实时荧光定量PCR检测过氧化物酶体增殖物激活受体α(PPARα)与丙酮酸脱氢酶激酶4(PDK4)mRNA的表达。结果苯扎贝特10～100μmol·L-1对RD细胞存活率无影响,300和1000μmol·L-1明显抑制RD细胞的生长,抑制率分别为13%和31%(P<0.01)。苯扎贝特300和1000μmol·L-1可明显升高PPARαmRNA表达,分别为对照组的2和3倍(P<0.05);苯扎贝特联合MK886组,PPARαmRNA表达与正常对照组无差异,但可显著抑制苯扎贝特300和1000μmol·L-1的升高作用(P<0.05)。与正常对照组相比,苯扎贝特单独或与MK886联合组,PDK4mRNA的表达均显著增加(P<0.01);与苯扎贝特单独组比较,苯扎贝特30,100,300和1000μmol·L-1与MK886合用组PDK4mRNA表达分别下降了44%,60%,69%和63%(P<0.05)。结论苯扎贝特对RD细胞具有明显的毒性作用,其作用机制可能是PPARα发挥了重要的调节作用。     

Disposition pharmacokinetics of bezafibrate in man

Summary The disposition kinetics of bezafibrate, a newly developed drug of great lipid-lowering potency, were investigated in normal male subjects. Five male volunteers received¹⁴C-labelled bezafibrate orally in solution, and a further 10 were given the same dose (300 mg) of un-labelled drug as tablets. The concentration of bezafibrate in serum and urine from the latter was determined by GC, and in the former total radioactivity in serum, urine and feces was followed for 48 h, and urinary excretion products were analysed by TLC and GC-MS. Rapid absorption from the gastrointestinal tract led to peak serum levels 30 min and 2 h after administration of solution and tablets, respectively. Since approximately 95% of the administered¹⁴C-bezafibrate was excreted in urine within 48 h, and almost all the remainder was detected in feces, absorption can be regarded as complete after administration in solution. The relative optimal bioavailability from the tablets was also complete, since in both cases approximately 50% of the administered dose was detected as unchanged bezafibrate in urine within 24 h by GC in the tablet study, and by TLC in the solution study. Of the decomposition products, more than 20% of the dose was present as glucuronides and the remainder consisted of several more polar compounds, one of which was identified as a hydroxyderivative of bezafibrate. Since the apparent halflife of bezafibrate in serum was 2.1 h, this new drug possesses favourable pharmacokinetic features: rapid and complete absorption, even from tablets, combined with a conveniently short half-life, and clearance which is half renal (56 ml/min) and half metabolic (43 ml/min), giving a total clearance of 99 ml/min.     

The effect of simvastatin and bezafibrate on bile composition and gall-bladder emptying in female non-insulin-dependent diabetics

Abstract Female non-insulin-dependent diabetics have a high prevalence of gallstones. Treatment of hyperlipidaemia in these patients may modify the risk. Seventeen female non-insulin-dependent diabetics (age 35–65) were treated with simvastatin ( n = 10) or bezafibrate ( n = 7) and had the cholesterol saturation index (CSI) of bile and gall-bladder emptying measured before and after 3 months therapy. In both groups, there was a significant reduction in serum cholesterol following treatment. The mean pretreatment cholesterol saturation indices of bile did not differ between the two groups but, after 3 months therapy, there was a highly significant difference in CSI between the bezafibrate group (2.0 ± 0.33) and the simvastatin group (1.1 ± 0.14) P < 0.002. Whereas the increase in the CSI (42%) observed with bezafibrate therapy was significant, the decrease in the simvastatin group (14%) was only significant in those whose pretreatment cholesterol saturation indices were elevated. Despite the differences in CSI observed between the two treatment groups, no changes in gall-bladder emptying were detected.     

Clinical pharmacokinetics of bezafibrate in patients with impaired renal function

Summary The pharmacokinetics of the new lipidlowering drug bezafibrate has been investigated in patients with impaired renal function and hyperlipoproteinaemia. 12 patients received a single oral dose of bezafibrate 300 mg. Plasma and urine samples were collected and bezafibrate was analyzed by gas chromatography. Eight of the patients had moderately impaired renal function, with a creatinine clearance between 20 and 40 ml/min; the mean plasma half-life of bezafibrate in them was 7.8±3.9 h (SD) and the plasma clearance was 0.03±0.02 l/kg · h. Three of the patients had a creatinine clearance>40 ml/min; in them the plasma half-life was shorter, 4.6±1.2 h, and the plasma clearance was higher, 0.06±0.01 l/kg · h. The slowest elimination of bezafibrate was found in a patient with a creatinine clearance of only 13 ml/min. This patient had a plasma half-life of 20.1 h, which is ten times longer than has been reported in healthy volunteers. Thus, when treating hyperlipoproteinaemia in patients with impaired renal function, the dosage of bezafibrate must be individualized because of its reduced renal elimination.     

Simvastatin and bezafibrate: Effects on serum lipoproteins and lecithin: Cholesterol acyltransferase activity in familial hypercholesterolaemia

Summary Sixteen subjects with familial hypercholesterolaemia were randomly assigned to treatment with simvastatin 20–40 mg/day (an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase) or with bezafibrate 600 mg/day (a clofibrate analogue) for 12 weeks.Both drugs produced significant reductions in serum and LDL cholesterol; mean percentage fall –30.5% and –38.1% (simvastatin) and –17.8% and –20.6% (bezafibrate), respectively. Both drugs also caused a decrease in VLDL cholesterol, while only bezafibrate decreased the serum and VLDL triglyceride levels and increased HDL cholesterol and serum apolipoprotein A-I and A-II levels. Serum apolipoprotein B fell by 33.3% (simvastatin) and 15.7% (bezafibrate). Simvastatin and bezafibrate produced significant increases in the mean fractional esterification rate of LCAT, by +124,1% and +20.6%, respectively.Thus simvastatin was clearly more effective than bezafibrate in lowering LDL by enhancing its turnover, but bezafibrate had specific effects on VLDL and HDL that might be favourable in combined treatment regimens.     

EFFECT OF BEZAFIBRATE ON HYPERCOAGULABILITY ASSESSED BY FLUOROGENIC PROTHROMBIN TIME IN HYPERLIPIDEMIC PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES MELLITUS

We investigated the usefulness of the fluorogenic prothrombin time (FPT) for detection of hypercoagulability and its association with hyperlipidemia in 19 patients with non-insulin-dependent diabetes mellitus (NIDDM) and 10 healthy control subjects, compared with plasma levels of fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and D-dimer. We also evaluated the effect of bezafibrate on hypercoagulability in 10 hyperlipidemic NIDDM patients. The plasma levels of FPT and fibrinogen were significantly higher in hyperlipidemic NIDDM patients than in normolipidemic NIDDM patients and controls. Plasma levels of PAI-1 and D-dimer were significantly higher in normolipidemic and hyperlipidemic NIDDM patients compared with controls. The FPT was correlated with the HbA1c, the body mass index, and levels of total cholesterol, fibrinogen and PAI-1. Six-months therapy with bezafibrate reduced the levels of FPT, triglycerides and basal insulin, but did not alter levels of fibrinogen, PAI-1 and D-dimer. Our results showed that the FPT was useful for detection of hypercoagulability and evaluation of the effect of drugs. The increased FPT in patients with NIDDM suggested that hypercoagulability was present in association with hyperlipidemia. © 1997 Elsevier Science Ltd     

Stimulation of decreased lipoprotein lipase activity in the tumor-bearing state by the antihyperlipidemic drug bezafibrate

The activity of lipoprotein lipase (LPL), a key regulatory enzyme for triglyceride (TG) clearance from plasma, is reported to decrease as the tumor burden increases in tumor-bearing animals and patients with lung cancer; therefore, it is believed to play a key role in inducing cancer cachexia. We attempted to reverse cancer cachexia by stimulating LPL activity with an antihypertriglyceridemic drug, bezafibrate. Bezafibrate, which reduces circulating TG levels by stimulating tissue LPL activity, has been used clinically in patients with hypertriglyceridemia. Bezafibrate was administered subcutaneously to 24 rats at a dose of 30 mg/kg per day from the 8th day after tumor inoculation with methylcholanthrene-induced sarcoma until they were killed on either the 25th or 33rd day, at the precachectic and cachectic stages, respectively. The animals were divided into the following three groups: treated tumor-bearing rats (treated TBR group), untreated TBRs (untreated TBR group), and a control (CTR) group. LPL activities in both the adipose tissue and cardiac muscle were measured by the method of Nilsson-Ehle and Schotz. Both TG and nonesterified fatty acid (NEFA) became elevated as the size of the tumor increased in the TBRs; however, this increment was quantitatively less in the treated TBR group than in the untreated TBR group. The administration of bezafibrate resulted in preservation of the epididymal fat pad mass at the cachectic stage. A significant decrease in LPL activity in the epididymal fat was observed in the untreated TBR group at the cachectic stage, but this was prevented in the treated TBR group, the values being 2.97±1.37 U/whole tissue in the untreated TBR group, 4.03±1.11 in the treated TBR group, and 10.15±6.61 in the CTR group. Thus, tumor growth in the treated TBR group at the cachectic stage was significantly suppressed compared with that of the untreated TBR group. These results suggest that the decreased LPL activity that occurs in the tumor-bearing state can be stimulated by the antihyperlipidemic drug bezafibrate, which may modulate some of the tumor-induced metabolic alterations leading to cancer cachexia.     

PPARoL／Υ激动剂对糖尿病伴冠心病患者血浆炎症因子的影响△

目的探讨联合应用过氧化物酶体增殖物激活受体（peroxisomeproliferator-activatedreceptor,PPAR）α／Υ激动剂对糖尿病伴冠状动脉粥样硬化性心脏病（冠心病）患者血浆炎症因子的影响。方法将80例伴有糖尿病的冠心病患者分为马来酸罗格列酮组（n=20）、苯扎贝特组（n=20）、马来酸罗格列酮和苯扎贝特联合组（n=20）、常规治疗组（n=20）。治疗后,对所有患者随访12周。治疗前后均对所有患者采血,并用酶联免疫吸附法测定患者血浆C反应蛋白、单核细胞趋化蛋白-1（monocytechemotacticprotein-1,MCP-1）,观察患者空腹血糖、空腹胰岛素、胰岛素抵抗指数、糖化血红蛋白-Alc（HbAlc）、血脂、体质量指数的改变。结果联合组、马来酸罗格列酮组、苯扎贝特组血浆C反应蛋白、MCP-1、空腹血糖、糖化血红蛋白、胰岛素、总胆固醇、三酰甘油、低密度脂蛋白胆固醇浓度和胰岛素抵抗指数治疗12周后比治疗前明显降低,高密度脂蛋白胆固醇明显升高．差异有统计学意义（P〈0．05）,且联合组上述指标改善最显著。马来酸罗格列酮组、苯扎贝特组、联合组的单核细胞在脂多糖诱导下分泌MCP-1浓度较治疗前降低,以联合组降低最为显著。C反应蛋白的降低与空腹胰岛素和胰岛素抵抗指数的降低呈正相关（r=0．498,P〈0．001和r=O．496,P〈0．001）,与其他因素的变化无相关性（P〉0．05）;而MCP-1的变化与糖、脂代谢无相关性（P〉0．05）;C反应蛋白与MCP-1之间也无明显相关性（P〉0．05）。结论联合应用马来酸罗格列酮、苯扎贝特能够降低血浆C反应蛋白和MCP-1浓度,降低血糖和血浆胰岛素浓度,减轻胰岛素抵抗,改善辛伐他汀治疗后残存的高三酰甘油和低高密度脂蛋白胆固醇,效果优于单用马来酸罗格列酮或苯扎贝特。