Effects Of Bezafibrate Research Articles

Effect of bezafibrate and clofibrate on the heme-iron geometry of ferrous nitrosylated heme-human serum albumin: an EPR study.

The effect of bezafibrate (BZF) and clofibrate (CF), two therapeutic drugs displaying anticoagulant and antihyperlipoproteinemic activities, on the EPR-spectroscopic properties of ferrous nitrosylated heme-human serum albumin (HSA-heme-NO) has been investigated. In the absence of BZF and CF, HSA-heme-NO is a five-coordinate heme-iron system, characterised by an X-band EPR spectrum with a three-line splitting in the high magnetic field region. Addition of BZF and CF to HSA-heme-NO induced the transition towards a six-coordinate heme-iron species characterised by an X-band EPR spectrum with an axial geometry. These data indicate that HSA-heme-NO is a five-coordinate heme-iron system, BZF and CF acting as allosteric effectors, and show that the primary heme binding site and the CF cleft of HSA are conformationally-linked, regardless of their different location.

Effect of bezafibrate on soluble adhesion molecules and platelet activation markers in patients with connective tissue diseases and secondary hyperlipidemia.

We evaluated the plasma concentrations of soluble adhesion molecules, platelet activation markers, and platelet-derived microparticles (PMPs) in patients with connective tissue diseases who had secondary hyperlipidemia caused by long-term steroid administration (n = 22) before and after treatment with bezafibrate. There were differences in levels of platelet activation markers both before and after treatment (platelet CD62p: 15.11+/-2.03 vs 10.38+/-8.53%, P < 0.05; platelet CD63: 12.12+/-9.17 vs 9.90+/-7.20%, P < 0.05). There were also differences in the levels of PMPs and soluble adhesion molecules both before and after treatment (PMP: 514+/-273 vs 401+/-201 /10(4) platelet. P < 0.05; soluble vascular cell adhesion molecule-1: 724+/-191 vs 666+/-157 ng/mL, P < 0.01). After 6 months of treatment, serum lipid concentrations were reduced by 9% for total cholesterol (TC) and 32% for triglyceride (TG). The level of PMPs, activated platelets, and soluble adhesion molecules were all significantly decreased after treatment with bezafibrate. These findings suggest that bezafibrate may be useful for inhibiting both PMP-dependent and -independent vascular damage in patients with connective tissue diseases complaining of secondary hyperlipidemia.

Bezafibrate attenuates the overexpression of plasminogen activator inhibitor-1 messenger RNA by a combination of mono-unsaturated fatty acid and insulin in HepG2 cells

The effects of bezafibrate (PPARα activator) and troglitazone (PPARγ activator) on the expression of plasminogen activator inhibitor type-1 (PAI-1) in HepG2 cells were investigated. Exposure of the cells for 24 hours to either oleic acid or insulin showed no obvious effects on PAI-1 synthesis, whereas the combination of the two agents induced a 2.3-fold increase in PAI-1 synthesis, which was accompanied by a 3-fold increase in both the 2.2 kb and 3.2 kb forms of PAI-1 mRNA. This up-regulation of PAI-1 synthesis was attenuated by bezafibrate in a dose-dependent manner (1–100 μM) with 30 % reversal at 100 μM. In contrast, troglitazone further stimulated PAI-1 synthesis to 140 % of the level obtained in the presence of both oleic acid and insulin. This attenuation by bezafibrate and enhancement by troglitazone required the presence of both oleic acid and insulin. It is interesting that PAI-1 expression was affected so differently by these two PPAR activators.

Differential induction of stearoyl-CoA desaturase and acyl-CoA oxidase genes by fibrates in HepG2 cells

1 We studied whether two typical effects of fibrates, induction of stearoyl-CoA desaturase (EC 1.14.99.5) and peroxisome proliferation, are related. The effect of bezafibrate on the activity and mRNA of stearoyl-CoA desaturase and acyl-CoA oxidase in the liver and epididymal white adipose tissue of male Sprague–Dawley rats was determined. The same parameters were measured in HepG2 cells, a cell line resistant to peroxisome proliferation, following incubation with ciprofibrate. Bezafibrate increased the hepatic mRNA levels (14.5-fold on day 7) and activity (9.3-fold on day 15) of acyl-CoA oxidase. Stearoyl-CoA desaturase mRNA levels were transiently increased (2.7-fold on day 7)), while its activity remained increased at the end of the treatment (2.4-fold). In white adipose tissue, bezafibrate increased the mRNA (5-fold) and activity (1.9-fold) of acyl-CoA oxidase, while stearoyl-CoA desaturase was not modified. Ciprofibrate addition to HepG2 cells cultured in 7% fetal bovine serum (FBS) only increased the stearoyl-CoA desaturase mRNA (1.9-fold). When cells were cultured in 0.5% FBS, ciprofibrate increased acyl-CoA oxidase mRNA (2.2-fold), while the increase in stearoyl-CoA desaturase mRNA was identical (1.9-fold). Further, its activity was also increased (1.5-fold). Incubation of HepG2 cells in the presence of cycloheximide did not alter the capacity of ciprofibrate to induce stearoyl-CoA desaturase mRNA, whereas the presence of actinomycin abolished the induction. In addition, preincubation of HepG2 cells with ciprofibrate increased the rate of stearoyl-CoA desaturase mRNA degradation. The results presented in this study suggest that fibrates induce stearoyl-CoA desaturase activity and mRNA levels independently of peroxisome proliferation.

Effect of bezafibrate on relationship between insulin resistance and fatty acids

Effect of bezafibrate on relationship between insulin resistance and fatty acids

Effect of bezafibrate or pravastatin on serum lipid levels and albuminuria in NIDDM patients.

Lipid abnormalities in diabetic patients, particularly in those with nephropathy, may be partially due to deteriorating atherosclerosis. Therefore, strict control of the lipid metabolism in addition to glycemic control is desirable. Whether or not lipid lowering drugs prevent albuminuria in diabetic patients in the long term remains unclear. This study involved 71 NIDDM patients with hypercholesterolemia (group A: n = 37, group B: N = 34). The effect of bezafibrate (group A) or pravastatin (group B) on the cholesterol (CH) content of apolipoprotein AI, B100 containing particles or remnant-like particles (RLP) or urinary albumin excretion was studied over 4 years. The CH content in apolipoprotein B100 particles after treatment with either bezafibrate or pravastatin decreased significantly (group A: 24.7%, group B: 26.6%). The CH content in RLP after treatment with bezafibrate showed a significant decrease (67.9%). Apolipoprotein AI after treatment with bezafibrate showed a significant increase (10.9%). Apolipoprotein B100 after treatment with either drug decreased significantly (group A: 19.8%, group B: 23.4%). The urinary albumin excretion rate after treatment with either drug showed no significant change over 4 years. Bezafibrate and pravastatin appear to be useful in the preventive treatment of albuminuria as well as in lowering lipid levels in NIDDM patients.

Angioscopic Evaluation of Stabilizing Effects of Bezafibrate on Coronary Plaques in Patients With Coronary Artery Disease

Background Since long-term administrations of anti-hyperlipidemic agents result in reduction in % stenosis or increase in minimum lumen diameter (MLD) of stenotic coronary segments, it is generally believed that anti-hyperlipidemic agents stabilize vulnerable coronary plaques. However, recent pathologic and angioscopic studies revealed that vulnerability of coronary plaques is not related to severity of stenosis and the rims rather than top of the plaques disrupt, and therefore, angiography is not adequate for evaluation of vulnerability. Angioscopy enables macroscopic pathological evaluation of the coronary plaques. Therefore, we carried out a prospective angioscopic open trial for evaluation of the stabilizing effects of bezafibrate on coronary plaques. Methods From April, 1997 to December, 1998, 24 patients underwent coronary angioscopy of the plaques in the non-targeted vessels during coronary interventions and 6 months later. The patients were divided into control (10 patients, 14 plaques) and bezafibrat (14 patients, 21 plaques) groups. Oral administration of bezafibrate (Bezatol SR, 400mg/day) was started immediately after the interventions and was continued for 6 months. The vulnerability score was determined based on angioscopic characteristics of plaques and it was compared before and 6 months later. Results Six months later, vulnerability score was reduced (from 1.6 to 0.8;p < 0.05) in bezafibrate group and unchanged (from 1.4 to 1.3; NS) in control group. In bezafibrate group, the changes in vulnerability score was not correlated with those in % stenosis or MLD. Conclusion The results indicate that bezafibrate can stabilize coronary plaques.

Bezafibrate as differentiating factor of human myeloid leukemia cells.

Bezafibrate belongs to the class of fibric acid derivatives usually used as antihyperlipidemia agents. From the biochemical point of view, these drugs show intriguing properties which leads one to think they may promote a differentiation process in tumour cells. This new pharmacological activity of fibrates could partially depend on the induction of an oxidative stress. To test this hypothesis, the effect of bezafibrate, as well as of clofibric acid and gemfibrozil, on growth, functional and cytochemical characteristics of human leukaemia-derived cell lines HL-60, U-937 and K-562 has been studied in some details. The results show that bezafibrate, gemfibrozil and clofibric acid, do induce differentiation in human myeloid leukaemia cell lines as indicated by several differentiation markers. Moreover fibrates, in dose dependent manner, significantly alter the cell cycle distributions, mainly leading to G0/G1 phase increment and G2/M phase reduction. The differentiating activity of fibrates could have significant implications both for the pharmacotoxicological profile of this class of compounds and for the pathophysiology of neoplastic disease.

Serum Lp(α), insulin resistance, metabolic risk factors for cardiovascular disease, and the long term effects of bezafibrate in type 2 diabetes

Serum Lp(α), insulin resistance, metabolic risk factors for cardiovascular disease, and the long term effects of bezafibrate in type 2 diabetes

Effects of two different fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb hyperlipoproteinaemia

We have investigated the effects of two fibric acid derivatives, bezafibrate mono (400 mg daily) and gemfibrozil (600 mg b.d.), in 29 patients with type IIb hyperlipoproteinaemia. All patients received placebo and each drug for 8 weeks in randomised order in a double-blind, cross-over study designed to evaluate any different effects of the drugs on serum lipoproteins, cholesteryl ester transfer protein (CETP), cholesteryl ester transfer activity (CETA), plasma fibrinogen, plasminogen activator inhibitor-I (PAI-1) or paraoxonase. Serum cholesterol decreased ( P<0.05) with gemfibrozil, but the effect of bezafibrate on serum cholesterol did not achieve statistical significance (placebo 8.34±1.05 (mean±S.D.), gemfibrozil 7.70±1.23 and bezafibrate 7.8±1.37 mmol/l). Both drugs decreased the serum triglyceride concentration (both P<0.001) (placebo 4.39 (3.13–5.75) (median (interquartile range)), bezafibrate 2.26 (1.89–3.89) and gemfibrozil 2.00 (1.30–3.30) mmol/l) and very low density lipoprotein (VLDL) cholesterol (both P<0.001) (placebo 1.18 (0.74–2.30), bezafibrate 0.59 (0.34–0.85) and gemfibrozil 0.48 (0.34–0.68) mmol/l). Discontinuous gradient ultracentrifugation (DGU) revealed that Sf 60–400 (large VLDL) decreased by more than 50% and Sf 20–60 (small VLDL) by more than 30% with each of the drugs (both P<0.001), neither of which affected the composition of these lipoproteins. Gemfibrozil decreased the concentration of Sf 12–20 lipoprotein (intermediate density lipoprotein; IDL) by 23% ( P<0.01), whereas the effect of bezafibrate on this lipoprotein did not achieve statistical significance. Neither drug altered the concentration of apolipoprotein B or of total Sf 0–12 lipoproteins (low density lipoprotein, (LDL)). Both, however, significantly increased the quantity of free cholesterol in Sf 0–12 lipoproteins ( P<0.05). Overall the concentration of triglycerides decreased significantly in all lipoproteins isolated by DGU (Sf 0–12, Sf 12–20, Sf 20–60, Sf 60–400) on gemfibrozil treatment, but only in Sf 20–60 and Sf 60–400 on bezafibrate (all P<0.05). Both drugs also increased serum high density lipoprotein (HDL) cholesterol (placebo 1.15±0.29, bezafibrate 1.27±0.38 ( P<0.01) and gemfibrozil 1.26±0.49 ( P<0.05) mmol/l) and HDL 3 cholesterol concentration (placebo 0.59±0.12, bezafibrate 0.72±0.23 ( P<0.001) and gemfibrozil 0.70±0.24 ( P<0.01) mmol/l). Serum apolipoprotein A1 (apo A1) was increased ( P<0.05) by bezafibrate compared to gemfibrozil (placebo 103±26, bezafibrate 111±28 and gemfibrozil 102±25 mg/dl) and CETA from HDL to VLDL and LDL was decreased ( P<0.05) by bezafibrate compared to placebo, but the apparent decrease with gemfibrozil did not achieve statistical significance (placebo 39.6±17.7, bezafibrate 32.3±14.7 and gemfibrozil 33.8±15.0 nmol/ml/h). Neither drug affected the circulating concentration of CETP. Plasma fibrinogen was increased ( P<0.05) by gemfibrozil (placebo 4.16 (3.38–4.71) and gemfibrozil 4.65 (4.05–5.77) g/l) and was significantly lower ( P<0.001) on bezafibrate (3.60 (3.18–4.54) g/l) than on gemfibrozil treatment. There was a significant ( P<0.05) increase in PAI-1 activity with bezafibrate and a similar trend with gemfibrozil (placebo 41.2 (25.6–64.5), bezafibrate 50.5 (35.1–73.9) and gemfibrozil 48.5 (31.5–5.4 U/l). Neither fibrate influenced plasma concentrations of PAI-1 nor were the activities of lecithin:cholesterol acyl transferase or paraoxonase affected. The major difference in the action of the two drugs on lipoprotein metabolism was the greater effect of gemfibrozil in decreasing the overall serum concentration of Sf 12–20 lipoproteins and the triglycerides in Sf 12–20 and 0–12 lipoproteins. Bezafibrate, however, increased serum apo A1 concentration and significantly decreased CETA. The two drugs also had different effects on the plasma fibrinogen levels, which increased with gemfibrozil and tended to decrease with bezafibrate. These differences may be of importance in the interpretation of trials with clinical end-points. The effect of fibric acid derivatives on CETA in type IIb hyperlipoproteinaemia may be less than previously reported in type IV hyperlipoproteinaemia.

Acute effects of bezafibrate on blood pressure and renal haemodynamics in SHR and WKY rats

Acute effects of bezafibrate on blood pressure and renal haemodynamics in SHR and WKY rats

2.P.39 Effect of bezafibrate on atherogenic lipoproteins in Japanese familial combined hyperlipidemic patients with or without impaired glucose tolerance

2.P.39 Effect of bezafibrate on atherogenic lipoproteins in Japanese familial combined hyperlipidemic patients with or without impaired glucose tolerance

Dual Effects of Bezafibrate on Lipid Metabolism and Hepatobiliary Enzymes

We encountered a patient with Sjogren’s syndrome showing high levels of serum alkaline phosphatase (ALP) and gamma glutamyl transpeptidase (γ-GTP) whose hepatobiliary function was considerably improved by treatment with bezafibrate. In order to clarify the mechanism by which bezafibrate decreases these hepatobiliary enzymes, 400mg of this drug was administered daily to 26 patients with hyperlipidaemia for 7 months, and biochemical and haematological parameters were determined. Serum ALP decreased significantly (p < 0.001) from the baseline level of 174.5 IU/L to 116.7 IU/L (−26.5%), and γ-GTP from 64.4 IU/L to 34.4 IU/L (−29.5%). Other biochemical and haematological parameters remained unchanged. We compared bezafibrate-induced changes in serum lipids with those in serum ALP and γ-GTP. There was a slight correlation between γ-GTP and triglyceride levels, but not between ALP and total cholesterol, triglycerides or high density lipoprotein cholesterol. A close correlation was observed between ALP and γ-GTP (r = 0.81, p < 0.001).

Post-prandial metabolism of triglyceride-rich lipoproteins in non-insulin-dependent diabetic patients before and after bezafibrate treatment.

Retarded post-prandial (pp) lipid clearance is potentially a major component of the increased cardiovascular risk incurred by hypertriglyceridaemic non-insulin-dependent diabetic mellitus (NIDDM) patients. The effect of bezafibrate (Bz, 400 mg per day for 5 weeks on chylomicron (CM) and remnant clearance after loads of 100 g of fat and vitamin A was therefore explored in 10 male patients (glycaemia 11.9 +/- 3.3 TG 4.5 +/- 2.4 mmol L(-1)). In all subjects CM-TG and retinyl palmitate (RP) were reduced by 50%, but 8-h non-CM (remnant) RP decreased only in initially mildly hypertriglyceridaemic subjects (-35%, P < 0.05), while in three patients with very elevated initial TG (epsilon3/3, epsilon3/2 and epsilon2/2 genotypes) 8-h remnant RP increased by 100%. The decrease in pp CM-TG correlated with that of fasting Sf 20-400 (r = 0.686, P = 0.026), suggesting that improved lipolysis was a major determinant of hypolipidaemic effect. Apo CIII synthesis is known to be depressed by Bz: concentrations were lower under Bz (P < 0.05). A positive correlation (r = 0.880, P < 0.001) with fasting TG before treatment and its disappearance after treatment suggested an involvement of high concentrations with hypertriglyceridaemia. Post-prandial non-esterified fatty acids were decreased by 35 in correlation with a significant (-19%, P < 0.05) improvement in fasting glycaemia (r = 0.801, P < 0.005). These results suggest that Bz acts both on lipolysis and on removal of CM remnants, but that removal can become saturated when lipolysis is massively improved.

Effects of bezafibrate on ethanol oxidation in rats.

Bezafibrate is used to lower serum lipid levels in humans. Fibrate derivatives induce an enzyme participating in the beta-oxidation by peroxisomes. We gave ethanol (2 g/kg) orally to bezafibrate-treated (300 mg/kg) male rats of the Wistar strain. Blood ethanol levels were remarkably lower and ethanol elimination stood at 432.6 mg/kg/hr (control, 336.6 mg/kg/hr) in the bezafibrate group (p < 0.01). Blood acetate levels were conversely higher in the bezafibrate group. The fatty acid beta-oxidation activity of liver peroxisome in bezafibrate-treated, clofibrate-treated, or gamma-linolenic acid-treated rats for 4 days was assayed. The activity was 5.8-fold higher in rats given bezafibrate, 5.4-fold in the clofibrate (p < 0.01), and 2.0-fold in the gamma-linolenic acid (p < 0.05). Alcohol dehydrogenase and aldehyde dehydrogenase activity of cytosol in the liver was not induced by the hypolipidemic drugs, but aldehyde dehydrogenase activity in the liver homogenate was induced. From foregoing results, bezafibrate induced in the organism beta-oxidation by peroxisomes and increased H2O2 production, which led to augmented ethanol metabolism by catalase.

Bezafibrate and clofibric acid are novel inhibitors of phosphatidylcholine synthesis via the methylation of phosphatidylethanolamine

The effects of bezafibrate and clofibric acid, fibrate hypolipidemic agents, on phosphatidylcholine (PC) synthesis via the phosphatidylethanolamine (PE) methylation pathway were studied. In cultured rat hepatocytes, bezafibrate and clofibric acid added to the medium rapidly and markedly reduced the conversion of ethanolamine-labeled PE to PC (IC 50 30 and 150 μM, respectively). Furthermore, the methylation of PE derived from serine was also blocked by bezafibrate, as was the secretion of PC derived from either serine or ethanolamine. The microsomal activity of PE N-methyltransferase was inhibited by these agents. Perfluorooctanoic acid but not DCQVA, though both are potent peroxisome proliferators comparable to fibrates, produced this inhibition. The inhibitory effects produced by these agents were diminished by dithiothreitol (DTT) added to the assay or alkaline pH assay condition. Inhibition by oleic acid was also attenuated under these conditions, suggesting a common mechanism of inhibition. However, unlike fatty acids, fibrates did not have rapid stimulatory effects on the CDP-choline pathway in hepatocytes. These results suggest that fibrates may mimic fatty acids in regulating PC synthesis from the PE methylation pathway but not the CDP-choline pathway.

Angiographic Assessment of Effects of Bezafibrate on Progression of Coronary Artery Disease in Young Male Postinfarction Patients

Angiographic Assessment of Effects of Bezafibrate on Progression of Coronary Artery Disease in Young Male Postinfarction Patients

30. Effect of Bezafibrate on fibrinogen binding to platelets in patients with hyperlipidemia

30. Effect of Bezafibrate on fibrinogen binding to platelets in patients with hyperlipidemia

Evidence for transcriptional induction of the liver fatty-acid-binding-protein gene by bezafibrate in the small intestine.

The effect of bezafibrate on cytosolic fatty-acid-binding-protein (FABPc) production along the small intestine has been investigated in mice. This drug increased the intestinal fatty-acid-binding-protein (I-FABPc) and liver fatty-acid-binding-protein (L-FABPc) mRNA levels in the duodenum. The extents of induction in the duodenum and in the liver are similar. However, the degree of stimulation gradually decreases along the length of the gut, no effect being found in the ileum. An efficient absorption of this drug as early as the proximal part of the small intestine may explain this phenomenon. The L-FABPc gene is silent in terminal ileum of mice, but a direct infusion of bezafibrate into the ileum switches it on. We used this original model to follow the time course of induction of the L-FABPc gene by bezafibrate. L-FABPc mRNA was first detected 4 h after fibrate infusion, reached a maximum level at 16 h and subsequently decreased at 24 h. This induction was totally blocked by cycloheximide. Sunflower oil also caused small increases in the L-FABPc mRNA levels. The transcriptional origin of the induction triggered both by bezafibrate and sunflower oil was demonstrated by run-on assays. These data indicate that (a) the transcription of the L-FABPc gene is induced by bezafibrate via de novo protein synthesis and (b) components of sunflower oil can transcriptionally activate the L-FABPc gene. Our results also demonstrate that the mouse terminal ileum is a useful system for studying the regulation of L-FABPc gene expression both in vivo and in vitro.

The effects of clofibrate and bezafibrate on cholesterol metabolism in the liver of the male rat.

Fibric acid derivatives are used to treat hyperlipidemia and have wide ranging effects on lipid metabolism. The action of these compounds on cholesterol esterification, catalyzed by acyl-coenzyme A:cholesterol acyltransferase (ACAT), has been quite widely studied, but their effect on cholesteryl ester hydrolysis and the enzyme neutral cholesteryl ester hydrolase (nCEH) has been largely ignored. Male rats were therefore fed for 10 d on a standard chow diet supplemented with either clofibrate or bezafibrate, to study their effects on plasma lipid levels and hepatic cholesterol metabolism. Plasma triacylglycerols were not significantly altered by these diets, but bezafibrate significantly lowered plasma cholesterol levels (29.7%, P < 0.01). When expressed per unit weight of DNA, both fibrates reduced the hepatic content of triacylglycerol, cholesterol and cholesteryl esters (40, 18.7, 16.5 and 66.7, 28.6, 34.2% for clofibrate and bezafibrate, respectively). ACAT activity was significantly reduced by both drugs, but clofibrate (65% inhibition) was more effective than bezafibrate (35% inhibition). The most dramatic effect of the diets was a marked increase in the activity of both the microsomal and the cytosolic nCEH. When expressed on a whole liver basis, the effect of bezafibrate on the cytosolic enzyme (13.6-fold increase in activity) was much greater than that of clofibrate (4.8-fold increase). Increases in the activity of a cytosolic protein that inhibits the activity of nCEH were also noted, but these changes were relatively small. The results suggest that the activation of nCEH, in combination with the inhibition in ACAT activity, contributes to a decrease in the cholesteryl ester content of the liver which may influence the secretion of very low density lipoprotein.