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PubMed2001

A prospective study of plasma fibrinogen levels and the risk of stroke among participants in the bezafibrate infarction prevention study.

PURPOSE: Plasma fibrinogen has emerged as an important predictor of cardiovascular disease, but few data are available on its association with stroke. We sought to determine if plasma fibrinogen is a marker of increased risk or a direct causative risk factor for stroke. SUBJECTS AND METHODS: Patients from the Bezafibrate Infarction Prevention Study, a placebo-controlled, randomized clinical trial of secondary prevention of coronary heart disease by lipid modification with bezafibrate retard (400 mg daily), were studied. Plasma fibrinogen levels were measured at baseline and yearly thereafter. Stroke, a prospectively monitored endpoint, was systematically assessed regarding stroke type, subtype, and functional outcome. RESULTS: Mean baseline fibrinogen levels were significantly higher in patients subsequently having a cerebrovascular event (140 strokes, 36 transient ischemic attacks; mean follow-up, 6.2 years) than in patients who did not (375 vs. 349 mg/dL, P <0.0001). Fibrinogen levels did not differ significantly by the type, subtype, or severity of the cerebrovascular event. Risk of ischemic stroke increased from 3.3% in the lowest tertile (baseline fibrinogen <314 mg/dL) to 7.% in the middle tertile (fibrinogen 314 to 373 mg/dL) to 10% in the upper tertile (fibrinogen >373 mg/dL, P <0.001). Adjusting for age, blood pressure, and other covariates, fibrinogen levels in the upper tertile were associated with more than a twofold increase in risk of ischemic stroke compared with in the lowest tertile (hazard ratio = 2.6; 95% confidence interval: 1.5 to 4.3). We did not find fibrinogen change from baseline to be related to subsequent ischemic stroke events. CONCLUSION: Plasma fibrinogen is a strong predictor of, rather than a direct causative factor for, subsequent stroke among patients at increased risk owing to manifest coronary heart disease.

Aged↗
PubMed1986

Diurnal lipid and lipoprotein profiles in hypertriglyceridemic patients with bezafibrate and clofibrate.

Thirty hypertriglyceridemic patients were treated under metabolic ward conditions for 10 days with either placebo, clofibrate (500 mg t.i.d.) or bezafibrate (200 mg t.i.d.) in a randomized, double-blind study. In addition, patients received an isocaloric prudent diet. On day 10 a diurnal lipid and lipoprotein profile was carried out. Compliance to medication was good. Each treatment led to significant reductions of fasting triglycerides and cholesterol. Lowering of fasting and integrated diurnal triglycerides was greatest with bezafibrate. HDL-cholesterol profiles were highest with this drug. A strong correlation between fasting and diurnal triglycerides was observed. Triglyceride-lowering therapy must therefore aim at fasting triglyceride values as low as possible.

Adult↗
PubMed1982

Bezafibrate: lack of effect on creatinine excretion and muscular proteins.

The effect of bezafibrate (200 mg t.i.d.) on renal and, to some degree, on muscular function was studied in nine patients with primary hyperlipoproteinemia. No signs of a reduction in creatinine excretion or an increase in muscular proteins could be found serving as a possible explanation for the slight increase in serum creatinine observed in a bezafibrate long-term study in more than 1,000 patients. Further studies are necessary for clarification.

Bezafibrate↗
PubMed1993

Rationale and design of a secondary prevention trial of increasing serum high-density lipoprotein cholesterol and reducing triglycerides in patients with clinically manifest atherosclerotic heart disease (the Bezafibrate Infarction Prevention Trial).

Controlled clinical trials have demonstrated the efficacy of reducing the blood levels of low-density lipoprotein cholesterol in reducing the incidence of coronary artery disease in hypercholesterolemic middle-aged men. However, a similar reversibility of the risk of coronary artery disease has not been demonstrated for high-density lipoprotein cholesterol elevation and triglyceride reduction. Therefore, the effect of administering 400 mg of bezafibrate retard daily versus placebo (double blind) to patients with myocardial infarction preceding randomization by 6 months to 5 years, or a clinically manifest anginal syndrome documented by objective evidence of dynamic myocardial ischemia, or both, is being investigated. Three thousand subjects (aged 45 to 74 years) are being enrolled from 19 cardiac departments in Israel, with total serum cholesterol between 180 and 250 mg/dl, high-density lipoprotein cholesterol < or = 45 mg/dl and triglycerides < or = 300 mg/dl. In addition, low-density lipoprotein cholesterol concentrations are required to be < or = 180 mg/dl (< or = 160 mg/dl for patients aged < 50 years). Patients needing lipid-modifying therapy, exhibiting > or = 1 prespecified exclusion criterion or not giving informed consent, or a combination, are not randomized. The primary end points for evaluating efficacy are the incidence of fatal and nonfatal myocardial infarction, and sudden death. The hypothesized effect of bezafibrate administration under the aforementioned protocol is to reduce an estimated cumulative end point event incidence of > or = 15% by 20 to 25% over an average follow-up period of 6.25 years, through early 1998, when the last patient recruited will have completed 5 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1983

The effect of bezafibrate and clofibrate on cholesterol ester metabolism in rabbit peritoneal macrophages stimulated with acetylated low density lipoproteins.

Bezafibrate and clofibrate reduce the quantity of esterified cholesterol, decrease the incorporation of 14C-labeled oleic acid into cholesterol ester and inhibit acyl coenzyme A cholesterol acyltransferase activity in rabbit peritoneal macrophages stimulated with acetylated low density lipoprotein. In all cases, the effect of bezafibrate was more marked than that of clofibrate. The activity of lysosomal cholesterol ester hydrolase in these cells was not affected by these drugs. It is suggested that these drugs exert an anti-atherogenic activity not only by their action on serum lipids, but by influencing cellular cholesterol ester metabolism.

Animals↗
PubMed1993

Transcriptional induction of the fatty acid binding protein gene in mouse liver by bezafibrate.

The mechanism by which hypolipidemic peroxisome proliferators of the fibrate family induce the liver fatty acid binding protein in liver of rodents is unknown. In order to delineate the level at which this protein is induced, the transcriptional activity of the specific gene encoding for liver fatty acid binding protein was measured in isolated hepatocyte nuclei obtained from male Swiss mice daily force-fed during 7 days with 400 mg/kg body weight bezafibrate. This treatment induced a 4-fold increase in the liver fatty acid binding protein transcription rate. Liver fatty acid binding protein mRNA level, measured by Northern blot analysis and cytosolic content of this protein, analyzed by immunoblotting, increased concurrently. From these results we conclude that the increase in the cytosolic liver fatty acid binding protein level by bezafibrate is due to an enhancement of the transcription rate of the liver fatty acid binding protein gene. Whether the transcriptional effect is mediated by peroxisome proliferator-receptor remains to be elucidated.

Animals↗
PubMed1982

Effects of bezafibrate on receptor-mediated and receptor-independent low density lipoprotein catabolism in type II hyperlipoproteinaemic subjects.

This study examines the effects of bezafibrate (200 mg t.i.d.) on LDL metabolism in 7 type II hyperlipoproteinaemic subjects. Eight weeks of treatment lowered plasma cholesterol and triglyceride by 10% and 30%, respectively (P less than 0.02). These reductions were associated with a fall in circulating VLDL (31%, P less than 0.02) and LDL (11%, P less than 0.05), while HDL cholesterol stayed the same. LDL metabolism changed during therapy. The plasma fractional clearance rate (FCR) of autologous [125I]LDL normalized from a low value of 0.256 +/- 0.048 (mean +/- SD) to 0.298 +/- 0.040 pools/day (P less than 0.001). This was attributable to a 65% increase (P less than 0.01) in receptor-mediated LDL catabolism since the clearance of simultaneously injected 1,2-cyclohexanedione-modified [131I]LDL, which measures the receptor-independent pathway, was unaltered (FCR of [131I]cyclohexanedione/LDL in control phase = 0.194 +/- 0.030 pools/day; during drug treatment = 0.194 +/- 0.024 pools/day). We conclude that bezafibrate lowers plasma LDL in type II hyperlipoproteinaemia by promoting its degradation via high affinity receptors.

Adult↗
PubMed1982

Elevated lipoprotein lipase activity in skeletal muscle tissue during treatment of hypertriglyceridaemic patients with bezafibrate.

Eleven hypertriglyceridaemic patients were treated with 600 mg bezafibrate daily for 2 months. The mean serum triglyceride concentration decreased by 35% (P less than 0.01) corresponding to a reduction in the very low density lipoprotein triglycerides by 41% (P less than 0.01). The high density lipoprotein cholesterol concentration and the serum concentration of apolipoproteins AI and AII increased by 19% (P less than 0.02), 11% (N.S., P less than 0.08) and 24% (P less than 0.01), respectively. The fractional removal rate (K2) in the intravenous fat tolerance test (IVFTT) increased by 37% (P less than 0.001). This was associated with significant increase of the skeletal muscle lipoprotein lipase activity ( + 39%, P less than 0.05). The mean value for the adipose tissue lipoprotein lipase activity remained unchanged. The K2 at IVFTT was correlated highly significantly to the activity of skeletal muscle lipoprotein lipase (r = 0.85, P less than 0.01). The present study indicates that the main reason for the reduction of the serum triglycerides during treatment with bezafibrate may be an increased activity of the skeletal muscle tissue lipoprotein lipase activity.

Adipose Tissue↗
PubMed1983

Some comparative effects of gemfibrozil, clofibrate, bezafibrate, cholestyramine and compactin on sterol metabolism in rats.

Liver cholesterogenesis in rats was measured by giving [l-14C]octanoate i.p.; 1 h later digitonin-precipitable sterols were isolated and counted. In rats fed normal chow and given 7 daily p.o. doses of compounds and then fasted, at 20 h after the last dose, clofibrate or bezafibrate had no effect at lower doses or inhibited incorporation at higher doses, while compactin or gemfibrozil caused increases; cholestyramine added to the diet also caused marked increases. When rats were fed chow containing 0.1% cholesterol and 5.5% peanut oil, again at 20 h following the last of 7 daily doses, gemfibrozil caused increases of incorporation which diminished at higher levels of dosage, while clofibrate caused only inhibition. A single dose of gemfibrozil caused inhibition at 3 h postdose followed by increases over control at 36 and 48 h; a single dose of compactin caused inhibition at 3 h but not subsequent increase, and a single dose of clofibrate had no effect over the entire period. In rats fed chow containing 1.5% cholesterol and 5.5% peanut oil, gemfibrozil given orally or cholestyramine in the diet prevented the diet-induced decreases of plasma HDL cholesterol and increases of liver cholesterol content, while bezafibrate treatment did not have those effects. The effects of cholestyramine rapidly disappeared when it was withdrawn from the diet, while the effects of gemfibrozil persisted after dosage was stopped. These results suggest that some of the actions of gemfibrozil on rat sterol metabolism are quantitatively different from those of the other agents tested.

Animals↗
PubMed1985

Effect of bezafibrate during 4.5 years of treatment of hyperlipoproteinaemia.

Bezafibrate in a dosage of 200 mg 3 times daily was given to 24 patients with type II A (n = 8), II B (n = 1) and IV (n = 15) hyperlipoproteinaemia for 4.5 years. In type II A the content of total cholesterol and that of low density lipoprotein in serum decreased by 10-23 and 11-34 percent over the years compared to pretreatment. In type IV the content of total triglycerides and that of very low density lipoprotein decreased by 28-39 and 38-52 percent, respectively, over the years. High density lipoprotein cholesterol increased in both types. The "atherogenic index" was reduced by the drug. The effect remained through the 4.5 years of treatment. Compliance to the drug was good. Changes in safety laboratory parameters were minor and reversible. No subjective side-effects occurred and no cases of gallbladder disease or cancer were noted. It is concluded that bezafibrate is a safe, convenient and effective serum lipid-lowering drug suitable for the use in primary and secondary prevention of atherosclerotic disease.

Bezafibrate↗
PubMed1986

The fibrinolytic system and coagulation during bezafibrate treatment of hypertriglyceridemia.

Bezafibrate was given to 23 hypertriglyceridemic but otherwise healthy middle-aged men in a double-blind, cross-over study to evaluate its effect on the components of the fibrinolytic system as well as on ATIII, FVIIIR: Ag, FVIII: C and platelet aggregation. Fibrinogen dropped markedly (P less than 0.05) and there was a small but significant fall of ATIII. The second wave of platelet aggregation was found much less frequently than in controls (P less than 0.001). Bezafibrate seemed to decrease the rate of formation of the first wave platelet aggregation.

Adult↗
PubMed1989

Inhibition of cholesterol biosynthesis in freshly isolated blood mononuclear cells from normolipidemic subjects and hypercholesterolemic patients treated with bezafibrate.

Bezafibrate was given for 15 days at a dose of 200 mg t.i.d. to 4 normolipidemic subjects, to 5 patients with putative heterozygous familial hypercholesterolemia, and to 6 patients with primary hypercholesterolemia of the non-familial type. At the end of the treatment, the rate of incorporation of labelled acetate into non-saponifiable lipids in freshly isolated blood mononuclear cells decreased in all subjects. On the average, acetate incorporation decreased by 31% in cells from normolipidemic subjects, 41% in cells from familial, and 45% in cells from non-familial hypercholesterolemia patients. Results of the present study suggest that the lowering effect of bezafibrate on serum cholesterol is mainly due to the inhibition of cholesterol synthesis through the suppression of HMG-CoA reductase as was demonstrated in rat hepatocytes and in cultured human blood mononuclear cells.

Adult↗
PubMed1995

Effect of troglitazone (CS-045) and bezafibrate on glucose tolerance, liver glycogen synthase activity, and beta-oxidation in fructose-fed rats.

To clarify the relationship between lipid and glucose metabolism abnormalities in fructose-fed rats, we examined whether an improvement of insulin sensitivity by troglitazone (CS-045) or a decrease in plasma lipids by bezafibrate affects the relationship between serum levels of lipid and glucose. In addition, we also examined changes in liver glycogen metabolism and beta-oxidation in fructose-fed rats. Troglitazone ameliorated fasting hyperlipidemia, hyperglycemia, and hyperinsulinemia. In addition, it augmented glycogen synthase activity by 53%, and decreased the mitochondrial palmitic acid beta-oxidation rate and ketone body production rate by 27% and 55%, respectively. However, hyperglycemia and liver glycogen synthase activity were not improved by bezafibrate treatment despite a marked reduction of serum triglyceride (TG) levels resulting from a 1.76-fold increase in mitochondrial oxidation and a 2.04-fold increase in hepatic ketone body production. These results suggest that abnormalities in glucose and lipid metabolism in fructose-fed rats, which are ameliorated by troglitazone, may be closely linked to reduced glycogen synthase activity in the liver.

Animals↗
PubMed1985

Changes in serum lipoprotein pattern following bezafibrate. Differential effects in type IIa and in type IIb hyperlipoproteinemic patients.

Sixteen type IIb and 26 type IIa hyperlipoproteinemic patients were treated with bezafibrate 200 mg t.i.d. After 1 month VLDL-TG decreased by 54% in type IIb and by 43% in type IIa; LDL-C decreased by 13% in type IIb and by 23% in type IIa patients. HDL3-C rose in both group of patients, while HDL2-C significantly increased (52%) only in patients with phenotype IIb. The change in LDL-C and in HDL2-C concentrations resulted to be related to the pretreatment VLDL lipid concentration and to its change during the treatment. Twenty patients were treated with bezafibrate for 4 months. On the average, the changes in lipoprotein lipid concentration attained at the end of the first month of therapy remained substantially constant in the following 3 months.

Adult↗
PubMed1989

Altered radiosensitivity in a mouse carcinoma after administration of clofibrate and bezafibrate.

We have investigated the ability of the antilipidaemia drugs clofibrate and bezafibrate, to reduce the binding affinity of haemoglobin for oxygen and to sensitize an experimental tumour (the SCCVII/St carcinoma) in the mouse to radiation. Clofibrate at a high dose (4.1 mmol/kg, p.o.) increased the P50 of the blood by about 10 mm Hg. Its effect on tumour radiosensitivity was dependent on tumour size. Highly significant sensitization, equivalent to a 40-fold reduction in the number of hypoxic cells, was seen in small tumours; but in large tumours there was much less effect. At a low dose, which is close to that currently used clinically (0.3 mmol/kg), clofibrate produced a small and barely significant increase in P50. The effect of low dose clofibrate on tumour radiosensitivity also depended on tumour size, small tumours (200 mg) being significantly sensitized, while no significant effect was seen in large tumours. Bezafibrate, at the low dose of 0.3 mmol/kg, gave a significant increase in P50 (by approximately equal to 8 mm Hg), but sensitization to radiation in small tumours was not impressive and not statistically significant. We must gain a better understanding of the mechanisms involved in these effects before applying this approach to clinical radiotherapy.

Animals↗
PubMed1994

Improvement of glucose tolerance by bezafibrate in non-obese patients with hyperlipidemia and impaired glucose tolerance.

Glucose intolerance or diabetes mellitus, hyperlipidemia, obesity and hypertension may have a close interrelation based on insulin resistance. We selected 28 impaired glucose tolerance (IGT) patients with hyperlipidemia. The IGT patients demonstrated hypertriglyceridemia associated with hyperinsulinemia, a typical manifestation of insulin resistance. Administration of bezafibrate at 400 mg/day for 4 weeks to the IGT patients with hypertriglyceridemia resulted in an improvement of the plasma glucose level and insulin response to 75 g oral glucose loading associated with a concomitant decrease in non-esterified fatty acids. The ratio of the level of serum C-peptide to that of insulin after a 75 g oral glucose tolerance test (OGTT) was augmented after 4 weeks of bezafibrate administration. However, reduction of the cholesterol level with pravastatin did not alter these parameters. These results suggest that treatment to reduce the level of serum triglycerides, but not that of cholesterol, may have a beneficial effect for improving insulin resistance even in the non-obese subjects with IGT and decreasing the risk of coronary heart disease.

Bezafibrate↗
PubMed2007

Lipid-lowering drugs in the MPTP mouse model of Parkinson's disease: fenofibrate has a neuroprotective effect, whereas bezafibrate and HMG-CoA reductase inhibitors do not.

We tested the ability of simvastatin, atorvastatin, fenofibrate and bezafibrate (two synthetic peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonists) to prevent dopaminergic cell death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Tyrosine hydroxylase (TH) immunochemistry was performed 8 days after acute MPTP intoxication. When orally administered for the week prior to intoxication and a week thereafter, fenofibrate prevented the MPTP-induced dopaminergic cell loss in the substantia nigra pars compacta (SNpc) and attenuated the loss of tyrosine hydroxylase immunoreactivity in the striatum. The dosage of 1-methyl-4-phenyl pyridinium (MPP+) in the striatum by high-performance liquid chromatography indicated that fenofibrate did not affect MPTP metabolism. Bezafibrate had no effect and, strikingly, simvastatin and atorvastatin had a negative effect. We also demonstrated the presence of PPAR-alpha in the dopaminergic neurons of the murine substantia nigra. Our data suggest that PPAR-alpha activation by fenofibrate could have a neuroprotective effect in PD through inhibition of inflammation, oxidative stress and/or apoptosis.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1995

Open-label study to assess the efficacy, safety, and tolerability of fluvastatin versus bezafibrate for hypercholesterolemia.

Increased levels of total cholesterol and low density lipoprotein cholesterol (LDL-C) are associated with the development of coronary artery disease, which has become a worldwide public health problem. Clinical trials show that, in the long term, effective lowering of total cholesterol and raising of high density lipoprotein cholesterol (HDL-C) can slow atherosclerosis progression and reduce coronary artery disease risk. This study evaluated the efficacy, safety, and tolerability of fluvastatin versus bezafibrate (slow release) in patients with cholesterol > 241 mg/dL (6.2 mmol/liter) not responding to dietary treatment alone (cholesterol < 300 mg/day for 8 weeks). Patients were divided into 2 groups: group A (13 women, 7 men; mean age, 47.8 +/- 9.7 years; range, 30-70) received 40 mg fluvastatin once daily with their evening meal; group B (14 women, 6 men; mean age, 45 +/- 11 years, range, 25-68) received 400 mg bezafibrate once daily with either breakfast or their evening meal. After 12 weeks of treatment, the mean cholesterol decrease in group A was 27% (from 271 +/- 51.4 to 197.4 +/- 24.3 mg/dL; p < 0.001) versus 8% (from 278.6 +/- 33.2 to 255.8 +/- 20.3 mg/dL; p < 0.005) in group B. At the same time point, LDL-C was significantly decreased in group A (from 197.9 +/- 49 to 107.5 +/- 27.6 mg/dL; p < 0.001) but not in group B (from 181.6 +/- 39.6 to 173.3 +/- 24.3 mg/dL).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗