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PubMed1988

[Pharmacological investigation of bezafibrate, a hypolipidemic agent (2). Mechanism of the hypolipidemic action of bezafibrate in rats].

The mechanism of the hypolipidemic action of bezafibrate was investigated in rats. Bezafibrate decreased the incorporation of 14C-acetic acid into the liver and serum triglyceride and inhibited liver acetyl CoA carboxylate activity. Bezafibrate increased liver beta-oxidation, but it had no effect on lipolysis and triglyceride secretion from the liver. Bezafibrate accelerated the elimination of serum triglyceride in Intralipid injected rats and increased tissue lipoprotein lipase activity. Bezafibrate decreased the incorporation of 14C-acetic acid into liver cholesterol and inhibited liver HMG-CoA reductase activity. Bezafibrate had no effect on cholesterol absorption and excretion. These results suggest that the hypotriglyceridemic actions of bezafibrate are due to inhibition of triglyceride synthesis and acceleration of triglyceride elimination and that the hypocholesterolemic action of bezafibrate is mainly due to inhibition of liver HMG-CoA reductase activity.

Acetates↗
PubMed1986

Long-term effects of bezafibrate and of a bezafibrate and cholestyramine combination on lipids and lipoprotein lipids in type IIa hypercholesterolaemic patients.

Eighteen hypercholesterolaemic patients have been treated for four months with bezafibrate 200 mg thrice daily. After one month of therapy, total cholesterol (T-C) decreased on the average by 19%, total triglycerides (T-TG) by 28%, very low density lipoprotein-TG by 47%, LDL-C by 25% and HDL3-C increased by 16%. At the fourth month of therapy the lipoprotein pattern was unchanged as compared to the one observed at the first month. In 12 patients T-C was normalized by bezafibrate and the patients continued the treatment for one year without experiencing further changes in lipoprotein pattern. Six patients with severe hypercholesterolaemia (mean baseline T-C of 11.51 +/- 0.63 mmoles/l) failed to adequately respond to bezafibrate treatment and were put on the combined bezafibrate 600 mg/day and cholestyramine 16g/day therapy. During bezafibrate their T-C decreased on the average by 21% and LDL-C by 23% and during the combined therapy by 33% and by 37% respectively, as compared to the baseline values. Combined bezafibrate and cholestyramine treatment seems then to be more effective than bezafibrate alone in decreasing serum cholesterol and may be useful in patients with severe hypercholesterolaemia.

Adult↗
PubMed1988

[Pharmacological investigation of bezafibrate, a hypolipidemic agent (1). Effects of bezafibrate on normal and experimental hyperlipidemia in rats].

The hypolipidemic effects of bezafibrate were examined in normal rats and an experimentally induced hyperlipidemic model of rats. Oral administration of bezafibrate at 1 mg/kg/day or more to normal rats for 7 days significantly decreased serum triglyceride (TG) and at 3 mg/kg/day or more for 7 days caused significant reduction of serum total cholesterol (TC). A single oral dose of 100 mg/kg of bezafibrate significantly inhibited the increase of serum TC and TG in hyperlipidemic rats induced by Triton WR-1339. When normal rats were given 75% fructose solution for 7 days, serum TG increased in concentration about four times. Oral administration of bezafibrate for 7 days at 1 mg/kg/day or more inhibited the increase of serum TG in this model. Serum TC increased in concentration about twice in 1% cholesterol diet-fed rats for 8 weeks. Oral administration of bezafibrate at 30 mg/kg/day or more inhibited the increase of serum TC. These results suggest that bezafibrate is effective in the treatment of hyperlipidemia.

Administration, Oral↗
PubMed1997

Effect of bezafibrate treatment over five years on coronary plaques causing 20% to 50% diameter narrowing (The Bezafibrate Coronary Atherosclerosis Intervention Trial [BECAIT]).

Recent reports indicate that most coronary events originate from plaques causing <50% diameter stenosis. A subgroup analysis of the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) data was undertaken to determine the effects of bezafibrate in relation to baseline narrowing. BECAIT included 92 male postacute myocardial infarction patients <45 years of age. Each received double-blind treatment with bezafibrate (200 mg 3 times daily) or placebo for 5 years, together with a low-fat diet. Coronary angiography was performed at baseline and after 2 and 5 years. The mean minimum lumen diameter of lesions causing 20% to <50% diameter stenosis at baseline did not narrow over 5 years in the bezafibrate group and decreased by 0.15 mm in the placebo group (p <0.05). In segments with > or =50% diameter stenosis at baseline, no change was seen in either of the 2 groups. In the analysis including only segments with 20% to <50% stenosis at baseline, coronary events were seen in 7 of 40 patients with a progression in minimum lumen diameter of more than the median value and in 3 of 41 patients with a change less than the median value. Thus, bezafibrate had a preferential effect in slowing the progression of narrowings causing <50% stenosis at baseline in young men followed up for a 5-year period after acute myocardial infarction.

Adult↗
PubMed1996

Bezafibrate. An update of its pharmacology and use in the management of dyslipidaemia.

The lipid-modifying profile of bezafibrate is characterised by marked decreases in elevated triglyceride levels, increases in high density lipoprotein (HDL) cholesterol levels and decreases in total and low density lipoprotein (LDL) cholesterol levels. Bezafibrate also reduces elevated levels of lipoprotein(a) [Lp(a)] and fibrinogen, which are independent cardiovascular risk factors. Bezafibrate is effective in most types of primary and secondary dyslipidaemia. It is of greatest benefit in conditions featuring hypertriglyceridaemia and/or HDL cholesterol deficiency. This is particularly true for patients with diabetes mellitus, notably those with non-insulin-dependent diabetes mellitus (NIDDM) who are also likely to have increased fibrinogen levels. In the limited comparisons available, there appear to be few consistent differences in lipid-modifying effects between bezafibrate and other fibrates. Compared with HMG-CoA reductase inhibitors, bezafibrate causes larger changes in triglyceride and, in general, HDL cholesterol levels, and has a lesser influence on LDL and total cholesterol levels. These differences are advantageous when bezafibrate and HMG-CoA reductase inhibitors are used as combined therapy in patients with severe dyslipidaemia unresponsive to either modality alone. The combination of bezafibrate plus an HMG-CoA reductase inhibitor in clinical trials has not led to the predicted increase in myalgia. Indeed, bezafibrate is generally free of serious unwanted effects: rhabdomyolysis is rare and has occurred mainly in patients with renal dysfunction given excessive dosages. Other patient groups in whom bezafibrate has improved serum lipid profiles are those with isolated HDL cholesterol deficiency, dyslipidaemia secondary to renal insufficiency, and following cardiac surgery or other procedures. However, data for these indications are not extensive. Evidence is now available to show a beneficial effect of bezafibrate on retarding atherosclerotic processes and in reducing risk of coronary heart disease. The 5-year Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) in young male survivors of myocardial infarction demonstrated a smaller decrease in luminal diameter and a reduction in coronary events with bezafibrate compared with placebo. The Bezafibrate Infarction Prevention (BIP) study is expected to provide mortality data which is currently lacking for bezafibrate. In conclusion, bezafibrate is a useful and well-tolerated lipid-modifying agent in the management of primary and secondary dyslipidaemia. It has particularly beneficial effects in patients with hypertriglyceridaemia and/or low HDL cholesterol levels, and reduces fibrinogen levels. Together with its ability to sustain or improve glycaemic control, these properties make it a logical choice for treating patients with diabetes mellitus and dyslipidaemia. Additionally, the drug may be of value as combination therapy in patients with severe dyslipidaemia. Importantly, there is evidence that the drug can slow the atherosclerotic process and reduce cardiovascular morbidity. The ongoing BIP secondary intervention study and other investigations will help clarify the effects of bezafibrate on cardiovascular mortality and morbidity.

Angina Pectoris↗
PubMed1992

Effects of combined bezafibrate-simvastatin appraised in healthy subjects.

The occurrence of clinical and biochemical side effects of bezafibrate (400 mg daily) or simvastatin (20 mg daily) alone or combined was appraised in 13 healthy male normolipidemic subjects according to a single blind design. Each period of 2 weeks of treatment with bezafibrate or simvastatin or bezafibrate plus simvastatin was followed by a period of placebo (1 week). No subjects experienced myalgia or muscle weakness. Plasma creatine kinase (CK) elevations, particularly skeletal muscle CK (CK-MM), were observed in 6 subjects: 11 times during different placebo periods, 5 times on bezafibrate, 4 times on simvastatin, and 4 times on combined bezafibrate-simvastatin, but never reached 1,600 IU/L. Only a trend to an increase of CK mean values on combined bezafibrate-simvastatin was shown. The hepatic transaminase and gamma-glutamyltransferase activities remained unmodified throughout the trial, unlike alkaline phosphatase activity, which fell on bezafibrate and on bezafibrate plus simvastatin. The low-density lipoprotein cholesterol level was more reduced with simvastatin than with bezafibrate. The addition of bezafibrate to simvastatin did not decrease it further. Lecithin:cholesterol acyltransferase activity expressed as fractional esterification rate was enhanced only on simvastatin and bezafibrate-simvastatin.

Adult↗
PubMed1994

Effects of bezafibrate therapy on subfractions of plasma low-density lipoprotein and high-density lipoprotein, and on activities of lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein in patients with hyperlipoproteinemia.

We investigated the effects of 12 weeks of bezafibrate treatment on plasma lipoprotein subfraction levels and on activities of LCAT and CETP in 25 patients with hyperlipoproteinemia. Bezafibrate reduced plasma levels of VLDL-TC and VLDL-TG by 69% and 66% (P < 0.001) and plasma levels of IDL-TC and IDL-TG were decreased by 37% and 31% (P < 0.01). Bezafibrate had no significant effects on plasma levels of LDL1 (1.019 < d < 1.045)-TC and LDL1-TG in the study population as a whole but significantly increased the plasma level of LDL1-TC in the subgroup of 9 patients with type IV hyperlipoproteinemia. Bezafibrate reduced plasma levels of LDL2 (1.045 < d < 1.063)-TC, LDL2-TG by 48% and 44% (P < 0.001) in both type II and type IV hyperlipoproteinemic patients. Gradient polyacrylamide gel electrophoresis revealed a decrease in small LDL particles. Bezafibrate did not affect the plasma level of HDL2-TC but reduced the HDL2-TG concentration significantly (P < 0.001). Bezafibrate increased the plasma level of HDL3-TC by 37% and reduced the HDL3-TG level significantly by 20% (P < 0.001). Gradient polyacrylamide gel electrophoresis revealed an increase in HDL3a and a decrease in HDL2a. Bezafibrate suppressed the activities of LCAT and CETP by 21% (P < 0.001) and 17% (P < 0.01), respectively. The bezafibrate-induced decrease in plasma levels of small, heavy LDL might be related to its inhibition of LCAT and CETP activities which resulted in suppression of heteroexchange of HDL-EC with triglyceride in large, light LDL. The bezafibrate-induced increase in large HDL3 (HDL3a) could not be explained solely by its suppression of LCAT and CETP activities. The decrease of plasma small, heavy LDL as well as TG-rich lipoproteins by bezafibrate seems to be beneficial for prevention of atherosclerotic diseases.

Adult↗
PubMed1998

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

BACKGROUND: Bezafibrate, a fibric acid analogue, has well-established lipid- and fibrinogen-lowering properties. Some data exist pointing towards a blood-pressure-lowering effect of bezafibrate. Thus the aim of this study was to examine the acute effect of bezafibrate on blood pressure and renal haemodynamics in hypertensive and normotensive rats. METHODS: 8 Wistar-Kyoto (WKY) and 12 spontaneously hypertensive rats (SHR) were treated with i.v. bolus injections of vehicle and 1-10 mg of bezafibrate in increasing doses every 15 min. Mean arterial pressure (MAP), renal blood flow (RBF), cortical blood flow (CBF), and medullary blood flow (MBF) were monitored continuously, together with plasma renin activity (PRA), urine volume and urinary Na+, K+, and protein concentration (15-min intervals). RESULTS: Bezafibrate reduced MAP in a dose-dependent manner (mean +/- SEM): in WKY, 1 mg bezafibrate, -1.13 +/- 0.61 mmHg and after 10 mg bezafibrate, -7.25 +/- 1.10 mmHg; in SHR, -0.60 +/- 0.43 and -5.83 +/- 0.90 mmHg respectively. In contrast to vehicle, bezafibrate induced a dose-dependent increase in RBF (WKY, 0.21 +/- 0.10 and 0.83 +/- 0.48 ml/min; SHR, 0.38 +/- 0.10 and 3.09 +/- 0.45 ml/min respectively) and a corresponding decrease in renal vascular resistance which was significantly greater in SHR than in WKY. The increase in RBF was paralleled by an increase in CBF. No effect of bezafibrate on MBF, PRA, urine flow, or urinary Na+, K+ or protein excretion was observed. The observed effects could not be attributed to one of the classic vasodilating mechanisms. CONCLUSIONS: We conclude that in rats bezafibrate is a potent hypotensive drug exhibiting additional effects on renal haemodynamics.

Animals↗
PubMed1987

Bezafibrate. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hyperlipidaemia.

Bezafibrate is a lipid-lowering drug, chemically related to clofibrate. At its recommended dosage of 200 mg 3 times daily, or alternatively 400 mg once daily as a sustained-release preparation, it produces substantial reductions in plasma triglyceride and cholesterol concentrations in patients with hypertriglyceridaemia and hypercholesterolaemia, respectively. Preliminary investigations indicate that a single daily dose of 400 mg in a sustained-release preparation is as effective as 200 mg 3 times daily. In patients with any type of hyperlipoproteinaemia bezafibrate also increases the plasma HDL-cholesterol concentration. These effects are equivalent in patients with primary hyperlipoproteinaemia or hyperlipoproteinaemia secondary to diabetes or renal disease, although dosage adjustment is important in the latter group. During long term therapy (2 to 4 years) the influence of bezafibrate on the lipid profile is sustained. The lipid-lowering effects of bezafibrate are at least equivalent to those of clofibrate, fenofibrate, colestipol, probucol or sustained release etofibrate. In addition, the increase in HDL-cholesterol tends to be at least as great as with all alternative treatments studied. Bezafibrate is rapidly eliminated, and thus does not accumulate during prolonged administration in patients with normal renal function. Experimental studies have shown bezafibrate to have a complex range of effects on lipoproteins and on the enzymes and receptors involved in lipid metabolism. However, its exact mechanism of lipid-lowering action is unclear. Bezafibrate enhances anticoagulation in hyperlipoproteinaemic patients requiring anticoagulant therapy, and preliminary investigations indicate that it reduces the plasma fibrinogen concentration, especially in patients with hyperfibrinogenaemia. These properties of bezafibrate could contribute to an antiatherogenic effect of the drug, but further investigation is required to establish the drug's potential as chronic therapy in patients with hyperfibrinogenaemic atherosclerosis. Adverse reactions to bezafibrate have largely been restricted to gastrointestinal disturbances, with some cutaneous reactions and central nervous system effects. The incidence of side effects has been no greater than with comparative lipid-lowering drugs. In patients with renal disease, a few cases of marked elevation of serum creatine phosphokinase and myoglobin, and associated muscle cramps, have been reported (diagnosed as rhabdomyolysis). Hepatic enzyme induction by bezafibrate in rats results in hepatomegaly, but there has been no case of significant hepatotoxicity in man.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2000

Efficacy and safety of a combination of fluvastatin and bezafibrate in patients with mixed hyperlipidaemia (FACT study).

Preliminary data suggest that fluvastatin may be safely combined with fibrates. The Fluvastatin Alone and in Combination Treatment Study examined the effects on plasma lipids and safety of a combination of fluvastatin and bezafibrate in patients with coronary artery disease and mixed hyperlipidaemia. A total of 333 patients were randomly allocated in this multicentre double-blind trial to receive 40 mg fluvastatin alone (n=80), 400 mg bezafibrate (n=86), 20 mg fluvastatin+400 mg bezafibrate (n=85) or 40 mg fluvastatin+400 mg bezafibrate (n=82) for 24 weeks. Low-density lipoprotein (LDL)-cholesterol decreased >20% in all fluvastatin-containing regimens, with significantly greater decreases compared with bezafibrate alone (P<0.001). Bezafibrate alone and fluvastatin+bezafibrate combinations resulted in greater increases in high-density lipoprotein (HDL)-cholesterol and decreases in triglycerides compared with fluvastatin alone (P<0.001). Fluvastatin (40 mg)+bezafibrate was the most effective for all lipid parameters with a decrease from baseline at endpoint in LDL-cholesterol of 24%, a decrease in triglycerides of 38% and an increase in HDL-cholesterol of 22%. All treatments were well tolerated with no increase in adverse events for combination therapy versus monotherapy, or between combination regimens. No clinically relevant liver (aspartate aminotransferase [ASAT] or alanine aminotransferase [ALAT]) greater than three times the upper limit of normal) or muscular (creatine phosphokinase (CPK) greater than four times the upper limit of normal) laboratory abnormalities were reported. This large study shows 40 mg fluvastatin in combination with 400 mg bezafibrate to be highly effective and superior to either drug given as monotherapy in mixed hyperlipidaemia, and to be safe and well tolerated.

Adult↗
PubMed2000

Bezafibrate reduces blood glucose in type 2 diabetes mellitus.

The clinical efficacy of bezafibrate was examined with special reference to glucose metabolism in patients with type 2 diabetes mellitus (DM2). In protocol 1, 342 patients with DM2 and hyperlipidemias were randomly divided into 2 groups, 16-week bezafibrate treatment (n = 174) and no bezafibrate treatment (n = 168). In protocol 2, 20 DM2 patients were randomly divided into 2 groups, 8-week bezafibrate treatment (n = 10) and no bezafibrate treatment (n = 10), and a meal tolerance test (MTT) was performed. In protocol 1, bezafibrate treatment significantly reduced the fasting levels of triglyceride (TG) by 50% +/- 1.6%, total cholesterol (TC) by 12% +/- 1.1%, plasma glucose (PG) from 151.3 +/- 3.5 to 128.6 +/- 3.4 mg/dL, and hemoglobin A1c (HbA1c) from 7.2% +/- 0.1% to 6.9% +/- 0.1%, and significantly increased high-density lipoprotein cholesterol (HDL-C) by 20% +/- 0.8%. In protocol 2, fasting TG, PG, and insulin levels were significantly reduced by bezafibrate treatment. Moreover, in the MTT, postprandial increments of TG were significantly blunted after bezafibrate treatment, whereas postprandial PG and insulin levels were not significantly changed. Leptin levels were significantly decreased, while tumor necrosis factor alpha (TNF-alpha) levels were not changed. In conclusion, both hyperglycemia and hyperlipidemia can be improved by bezafibrate treatment in DM2.

Bezafibrate↗
PubMed1996

Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients.

BACKGROUND: Bezafibrate has effects on lipid metabolism and haemostatic function. We undertook a double-blind, placebo-controlled intervention trial, the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT), to establish whether bezafibrate (200 mg three times daily) could retard or prevent the progression of atherosclerotic lesions in dyslipidaemic male survivors of myocardial infarction who were younger than 45 years at the time of the event. METHODS: 92 patients completed an initial 3-month period of dietary intervention and were randomly assigned to treatment with bezafibrate or placebo. Dietary intervention continued throughout the trial. Coronary angiography was done at baseline and after 2 and 5 years. 81 patients (42 bezafibrate treated and 39 placebo treated) who underwent baseline angiography and at least one post-treatment angiogram were included in the efficacy analysis. The primary endpoint was change in mean minimum lumen diameter. FINDINGS: The mean minimum lumen diameter decreased from baseline to the last angiographic assessment (2 or 5 years) by 0.06 mm (95% CI 0.15 reduction to 0.01 increase) in the bezafibrate group and by 0.17 mm (0.33 reduction to 0.09 increase) in the placebo group. The treatment effect was therefore 0.13 mm (95% CI 0.10 to 0.15; p=0.049). Parallel treatment effects, although not statistically significant, were observed for the secondary angiographic endpoints (mean segment diameter 0.02 mm [0.01-0.04] and percentage stenosis -3.41% [-4.00 to -2.98]). The cumulative coronary event rate was significantly lower among bezafibrate-treated than among placebo-treated patients (three vs 11 patients; p=0.02). There were significant treatment effects of bezafibrate for serum concentrations of cholesterol (-9%; p<0.001), very-low-density-lipoprotein (VLDL) cholesterol (-35%; p<0.001), serum triglycerides (-31%; p<0.001), VLDL triglycerides (-37%; p<0.001), and plasma fibrinogen (-12%; p=0.001), whereas low-density (LDL) cholesterol concentrations did not change. High density lipoprotein (HDL) cholesterol increased significantly with bezafibrate (9%; p=0.02). INTERPRETATION: The results show that bezfibrate improves dyslipidaemia, lowers plasma fibrinogen, slows the progression of focal coronary atherosclerosis, and reduces coronary events in young survivors of myocardial infarction.

Adult↗
PubMed1996

Chemoprevention of radiation-induced mammary tumors in rats by bezafibrate administered together with diethylstilbestrol as a promoter.

Pregnant Wistar-MS strain rats were irradiated with 2.6 Gy of gamma-rays at day 20 of pregnancy. Rats in the control group (n = 48) were then implanted with a diethylstilbestrol (DES) pellet at 35 days after weaning, while being fed a control (MB-1) diet. The incidence of mammary tumors was 89.6% within 1 year. In the experimental group (n = 22), a bezafibrate (0.15%) diet was initiated immediately after weaning, and 35 days after weaning a DES pellet was implanted. Administration of dietary bezafibrate together with DES-implantation continued for a period of 1 year, at which time the experiment was terminated. The incidence (27.3%) of the mammary tumors in the bezafibrate-fed rats was less than one-third of that in the control rats. Compared with the control group, the number of mammary tumors per tumor-bearing rat in the bezafibrate-treated group was reduced. For clarification of the mechanism of the chemopreventive effects of bezafibrate, lipid and hormone concentrations in serum were measured. Bezafibrate-fed rats showed a significant decrease in serum prolactin (56%) and triglyceride (63%) concentrations, and a significant increase in serum estradiol-17beta (3.8-fold), cholesterol ester (2.0-fold) and TSH (2.0-fold) concentrations in comparison with the control rats. The bezafibrate diet inhibited the formation of DES-induced pituitary tumors. However, the development of mammary glands in the bezafibrate-fed rats was stimulated more than that in the control rats treated with DES alone. The present results demonstrate that bezafibrate is effective in preventing mammary tumors induced by radiation together with DES, possibly by reducing prolactin and triglyceride concentrations.

Animals↗
PubMed1995

Atherogenic risk reduction in patients with dyslipidaemia. comparison between bezafibrate and lovastatin.

OBJECTIVE: To examine the atherogenic risk-reducing effect of bezafibrate and lovastatin. DESIGN, SETTING, PATIENTS, INTERVENTIONS: Double-blind, randomized clinical trial of male and female patients with moderate hypercholesterolaemia with or without hypertriglyceridaemia. Two months dietary treatment followed by 400 mg sustained release bezafibrate every day or 20 mg lovastatin every day for 6 months. Patients recruited (n = 561) and treated (n = 524) by primary care physicians throughout Austria. MAIN OUTCOME MEASURES: Multifactorial assessment of atherogenic risk profile. RESULTS: Bezafibrate increased high density lipoprotein cholesterol by 16%, lovastatin by 10% (P < 0.05). Bezafibrate decreased low density lipoprotein cholesterol by 20%, lovastatin by 27% (P < 0.001). Bezafibrate decreased total cholesterol by 15%, lovastatin by 18% (P < 0.001). Bezafibrate reduced triglycerides by 29%, lovastatin by 13% (P < 0.001); and fibrinogen by 9.4% and 3.0%, respectively. Fibrinogen reduction as a result of bezafibrate administration was dependent on starting levels. The risk ratio cholesterol:high density lipoprotein cholesterol (baseline both 6.1) reduction was 27% in both groups. The low:high density lipoprotein ratio (baseline: 4.1/4.2) reduction reached 31% and 34% respectively. Coronary events' probability (calculated from multifactorial risk functions) were greatly reduced by both agents (41%/33%). Hypertriglyceridaemic patients had a higher initial global coronary risk and profited more from treatment. Bezafibrate was significantly better tolerated (P < 0.001) than lovastatin; most events were gastrointestinal (6 vs 14, ns) or as a result of creatine phosphokinase elevations (3 vs 12, P < 0.05). CONCLUSIONS: Both treatments significantly reduced the risk parameters for developing coronary heart disease, and calculated multifactorial coronary risk was similarly decreased. When selecting a drug for moderate dyslipidaemia and if haemostatic regulation is disturbed, the additional effect of bezafibrate on elevated fibrinogen levels should be considered.

Adult↗
PubMed2001

Bezafibrate reduces mRNA levels of adipocyte markers and increases fatty acid oxidation in primary culture of adipocytes.

The molecular mechanisms by which peroxisome proliferator-activated receptor (PPAR) activation by fibrates reduces fat deposition and improves insulin sensitivity are not completely understood. We report that exposure of a rat primary culture of adipocytes for 24 h to the PPAR activator bezafibrate increased the mRNA levels of crucial genes involved in peroxisomal and mitochondrial beta-oxidation. The mRNA levels of the peroxisomal beta-oxidation rate-limiting enzyme acyl-CoA oxidase and of the muscle-type carnitine palmitoyl transferase I (M-CPT-I), which determines the flux of mitochondrial beta-oxidation, increased by 1.6-fold (P < 0.02) and 4.5-fold (P = 0.001), respectively. These changes were accompanied by an increase in the transcript levels of the uncoupling protein-2 (UCP-2; 1.5-fold induction; P < 0.05) and UCP-3 (3.7-fold induction; P < 0.001), mitochondrial proteins that reduce ATP yield and may facilitate the oxidation of fatty acids. Furthermore, bezafibrate increased the mRNA levels of the fatty acid translocase (2-fold induction; P < 0.01), suggesting a higher fatty acid uptake into adipocytes. In agreement with these changes, bezafibrate caused a 1.9-fold induction (P < 0.02) in 9,10-[(3)H]palmitate oxidation. Moreover, bezafibrate reduced the mRNA expression of several adipocyte markers, including PPARgamma (30% reduction; P = 0.05), tumor necrosis factor-alpha (33% reduction; P < 0.05), and the ob gene (26% reduction). In contrast, adipocyte fatty acid binding protein mRNA levels increased (1.5-fold induction; P < 0.01), pointing to a mobilization of fatty acids to mitochondria and peroxisomes. The reduction of the adipocyte markers caused by bezafibrate was accompanied by an increase in the mRNA levels of the preadipocyte marker Pref-1 (1.6-fold induction; P < 0.01). Some of the changes observed in the primary culture of rat adipocytes also were studied in the epididymal white adipose tissue of bezafibrate-treated rats for 7 days. In vivo, M-CPT-I mRNA levels increased (4.5-fold induction; P = 0.001) in epididymal white adipose tissue of bezafibrate-treated rats. Similarly, fatty acid translocase (2.6-fold induction; P = 0.002) and Pref-1 (5.6-fold induction) mRNA levels increased, although differences in the latter were not significant because of huge individual variations. These results indicate that exposure of adipocytes to bezafibrate, independent of its hepatic effects, increases the degradation of fatty acids, reducing their availability to synthesize triglycerides. As a result, some degree of dedifferentiation of adipocytes to preadipocyte-like cells is achieved. These changes may be involved in the reduction in fat depots and in the improvement of insulin sensitivity observed after bezafibrate treatment.

Acyl-CoA Oxidase↗
PubMed1980

[Comparative double-blind investigation of bezafibrate and clofibrate in patients with primary hyperlipoproteinaemia].

The lipid-reducing effects of bezafibrate and clofibrate were investigated in a double-blind crossover trial. 3 x 200 mg/d bezafibrate and 3 x 500 mg/d clofibrate were administered for periods of 8 weeks each to 22 patients with primary hyperlipoproteinaemia (9 Type IIb, 13 Type IV). Placebo periods preceded and followed the periods of medication. Compliance was checked by determination of the serum concentrations of bezafibrate and clofibrate. As compared with the pre-therapy value under placebo, cholesterol was reduced by 14% with bezafibrate and 7% with clofibrate in the group as a whole. In Type IIb patients cholesterol was reduced by 16% with bezafibrate as against 10% with clofibrate, and in Type IV patients by 12% with bezafibrate and 6% with clofibrate. A similar response was found in triglyceride reduction: 36% vs. 18% for the group as a whole; 47% vs. 31% for Type IIb; and 29% vs. 9% for Type IV. The difference in triglyceride reduction for the group as a whole was significant at the p less than 0.05 level. Body weight, pulse rate, and blood pressure showed no changes during the entire period of investigation. Fasting blood glucose was somewhat lower under both substances than under the subsequent placebo period while urea-N and creatinine was increased for both as compared with both pre- and post-therapy placebo periods. Under bezafibrate there was an increase in CPK as compared with the second placebo phase. There were no changes in GOT and GPT. Reductions in gamma-GT, alkaline phosphatase, and bilirubin were observed under both bezafibrate and clofibrate, as were slight decreases in haemoglobin, erythrocytes, and leucocytes, and a small increase in thrombocytes. No changes in urinary excretion of protein or glucose were observed. No subjective side effects were reported, either for bezafibrate or for clofibrate.

Bezafibrate↗
PubMed1978

[Comparison of clofibrate and bezafibrate in type IIa and type IIb hyperlipoproteinemia].

In a randomized block-trial the comparative efficacy and side-effects of clofibrate (2 X 1 g), placebo and bezafibrate (3 X 150 mg) were tested in groups of 24 patients each with hyperlipoproteinemia type IIa and IIb. Each period of treatment was 2 months. Both bezafibrate and clofibrate as compared to placebo were associated with a significant lowering of triglycerides and cholesterol: triglycerides by 30% in type IIa and a 41% reduction in type IIb, whereas clofibrate lowered triglycerides by 23% in type IIa and 28% in type IIb. Bezafibrate reduced total cholesterol by 18% in type IIa and 12% in type IIb as opposed to clofibrate reducing cholesterol by 16% in type IIa and 8% in type IIb. Bezafibrate compared to clofibrate was shown to be significantly more effective in lowering triglycerides in type IIa correlating to a significant reduction of VLDL- and LDL-triglycerides in this type. Both substances significantly lowered LDL-cholesterol in type IIa; in type IIb only bezafibrate was effective. HDL-cholesterol increased significantly with bezafibrate. The effect of clofibrate raising LDL-cholesterol in dependence on the initial concentration of the VLDL-triglycerides was seen less frequently after bezafibrate and only with higher initial VLDL-concentrations as compared to clofibrate. Patients tolerated both bezafibrate and clofibrate equally well. It should be considered that bezafibrate was not given in the optimal dose of 3 X 200 mg.

Adult↗
PubMed1989

Effects of bezafibrate on insulin secretion and peripheral insulin sensitivity in hyperlipidemic patients with and without diabetes.

Although it has been reported that bezafibrate influences carbohydrate metabolism, this possibility has never been properly evaluated in a controlled clinical trial. In this study we attempted to evaluate the effects of bezafibrate on plasma lipoproteins, glucose tolerance, insulin secretion and peripheral insulin sensitivity in a group of hypertriglyceridemic patients with and without diabetes. Sixteen hyperlipidemic patients (10 males and 6 females) participated in the study. Eight had type IIB and 8 type IV hyperlipoproteinemia; 6 of them also had non-insulin dependent diabetes mellitus. The study was performed according to a double blind, crossover design: after 1 month wash-out period in which patients were on diet alone, they underwent, in a random order, a period of placebo therapy and another period in which they received a single daily dose of a long-acting bezafibrate preparation (400 mg) administered in the evening. Each treatment lasted 2 months. Total plasma and VLDL triglyceride concentrations were consistently reduced by bezafibrate (-46%, P less than 0.001; and -50%, P less than 0.001). Total and VLDL-cholesterol were also reduced by bezafibrate. The effects of bezafibrate on lipoproteins were similar in diabetic and non-diabetic subjects. Bezafibrate treatment did not influence fasting blood glucose concentration, glucose tolerance, peripheral insulin sensitivity or insulin secretion. In conclusion, the results of this controlled trial clearly indicate that bezafibrate can be successfully employed to lower plasma lipid levels in patients with non-insulin dependent diabetes mellitus and hyperlipidemia.

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