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PubMed1978

Dose-response study of bezafibrate on serum lipoprotein concentrations in hyperlipoproteinanemia.

The effect of bezafibrate in the dosages 450, 900 and 1350 mg daily on serum lipoprotein concentrations were studied in 20 subjects with primary hyperlipoproteinaemia (16 of type IV, 2 of type II B, 1 of type III). Except for LDL cholesterol maximum effects were obtained with 450 mg daily. Total serum cholesterol and triglycerides (TG) fell significantly. Mean very low density lipoprotein (VLDL) TG fell by 54%. The maximum effect on low density lipoprotein was obtained with 900 mg daily. The effect was highly dependent on initial concentrations, decreases being observed above 4 mmoles/l and increases below that concentration. High density lipoprotein cholesterol increased by 31% (P less than 0.01) independently of the VLDL decrease. Three subjects suffered gastrointestinal side-effects on 1350 mg daily. Only benign reversible changes were noted on non-lipid measurements. Bezafibrate is a well-tolerated drug with a good VLDL TG lowering effect. It is particularly effective in increasing HDL cholesterol concentrations.

Cholesterol↗
PubMed2002

Low- and high-density lipoprotein cholesterol and ischemic cerebrovascular disease: the bezafibrate infarction prevention registry.

BACKGROUND: Despite increasing evidence that beta-hydroxy-beta-methyglutaryl coenzyme A reductase inhibitors reduce the incidence of stroke in patients with coronary heart disease (CHD), the associations between blood lipid levels and cerebrovascular disease (CVD) are not clear. OBJECTIVE: To evaluate whether blood cholesterol level and its fractions are risk factors for stroke in a large group of patients with CHD. METHODS: We followed up 11 177 patients with documented CHD who were screened for but not included in the Bezafibrate Infarction Prevention study, a secondary prevention randomized clinical trial of lipid modification, and had no history of stroke for subsequent CVD. During a 6- to 8-year follow-up period, 941 patients were identified as having nonhemorrhagic CVD, of whom 487 had verified ischemic stroke or transient ischemic attack (TIA). RESULTS: Increases in age-adjusted rates of both nonhemorrhagic CVD and verified ischemic stroke or TIA were identified with increasing cholesterol and low-density lipoprotein cholesterol levels, decreasing high-density lipoprotein cholesterol levels, and decreasing percentage of total serum cholesterol contained in the HDL moiety. In logistic regression models, adjusting for clinical covariates, the following odds ratios (95% confidence intervals) were identified for lipid values in the upper vs lower tertile for the end point of nonhemorrhagic CVD: total cholesterol, 1.43 (1.20-1.70); low-density lipoprotein cholesterol, 1.52 (1.27-1.81), high-density lipoprotein cholesterol, 0.84 (0.70-1.00); and percentage of serum cholesterol contained in HDL, 0.69 (0.58-0.83). Similar trends appeared for the end point of verified ischemic stroke or TIA. CONCLUSION: These findings clearly support the role of total cholesterol and its fractions in prediction of ischemic CVD among patients with established CHD.

Adult↗
PubMed2004

Predictive value of elevated white blood cell count in patients with preexisting coronary heart disease: the Bezafibrate Infarction Prevention Study.

BACKGROUND: Inflammation is implicated in the pathogenesis of atherosclerosis and acute coronary syndromes. White blood cell (WBC) count increases during infections and inflammatory illnesses and has been shown to predict coronary heart disease (CHD) independent of traditional cardiovascular risk factors. This apparent association may reflect a relationship between the WBC count and other coronary risk factors. Studies in patients with CHD are scarce and give conflicting results. The aim of the present study was to investigate the association between WBC count and subsequent coronary events and total mortality in a large cohort of patients with CHD. METHODS: We evaluated the relationship between WBC count and 6-year risk of coronary events and mortality in a large cohort of patients with chronic CHD who were enrolled in a secondary prevention study of bezafibrate. RESULTS: In univariate analysis, WBC count was associated with an elevated 6-year risk of myocardial infarction, cardiac death, and total mortality. On multivariate adjustment, the positive association with risk of myocardial infarction and cardiac death was eliminated, but WBC count remained predictive of total mortality: relative risk, 1.47; 95% confidence interval, 1.13 to 1.92, in the upper tertile of WBC count (as compared with the lowest). For every 1000/ microL increase in WBC count, risk of total death increased by 6% (relative risk, 1.06; 95% confidence interval, 1.03-1.10). CONCLUSIONS: Elevated WBC count in patients with CHD was associated with higher long-term risk of all-cause mortality. This excess risk of mortality was not due to cardiac causes.

Bezafibrate↗
PubMed1986

Lipid lowering treatment with bezafibrate in patients on chronic haemodialysis: pharmacokinetics and effects.

Hyperlipidaemia may contribute to the high rate of cardiovascular complications in patients on chronic haemodialysis (CHD). However, possibilities of lipid lowering therapy in CHD are still limited. The applicability of bezafibrate (BF), a recently developed clofibrate analogue, was investigated in patients on CHD with triglyceride and/or total cholesterol levels above 300 mg/dl. The lipid lowering effect was studied in a placebo-controlled trial over 6 months in 19 patients. Long-term effect was followed in six patients over a mean period of 29 months. Elimination half-life and mean therapeutic serum concentration were calculated by 72-h BF serum profiles, obtained after the first drug administration of a single 200-mg dose and during steady state after 12 weeks of treatment. Elimination half-lives were 17 h at start and 22 h after 12 weeks compared with 2 h in subjects with normal renal function. Dose reduction to 200 mg every 3rd day was necessary and resulted in a mean therapeutic serum concentration of 3.4 mg/l, which was similar to 3.0 mg/l of normal subjects, who received the dose optimal for lowering of lipids (200 mg 3 X/day). The protein-bound serum fraction of BF was decreased to 8% in CHD patients, compared with 95% found in normal subjects. BF therapy resulted in a marked reduction of serum triglycerides from 478 mg/dl by 31% and total cholesterol levels from 311 mg/dl by 19% as well as beta-Lp-cholesterol from 178 mg/dl by 17%, whereas the initially low alpha-Lp-cholesterol increased significantly from 18.3 mg/dl by 58%.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed2000

Properties of a fluorescent bezafibrate derivative (DNS-X). A new tool to study peroxisome proliferation and fatty acid beta-oxidation.

The first peroxisome proliferator-activated receptor (PPAR) was cloned in 1990 by Issemann and Green. Many studies have reported the importance of this receptor in the control of gene expression of enzymes involved in lipid metabolic pathways including mitochondrial and peroxisomal fatty acid beta-oxidation, lipoprotein structure [apolipoprotein (apo) A2, apo CIII], and fatty acid synthase. By using radiolabeled molecules, it was shown that peroxisome proliferators bind and activate PPAR. As an alternative method, we developed a fluorescent dansyl (1-dimethylaminonaphthalene-5-sulfonyl) derivative peroxisome proliferator from bezafibrate (DNS-X), a hypolipidemic agent that exhibits an in vitro peroxisome proliferative activity on rat Fao-hepatic derived cultured cells. However, until now, the effect of this new compound on the liver of animals and subcellular localization was unknown. In addition to in vivo rat studies, we present a more efficient large-scale technique of DNS-X purification. Treating rats (DNS-X in the diet at 0.3% w/w) for 6 d leads to a hepatomegaly and a marked increase in liver peroxisomal palmitoyl-CoA oxidase activity. We also developed a method to localize and quantify DNS-X in tissues or cell compartment organelles. The primarily cytosolic distribution of DNS-X was confirmed by direct visualization using fluorescence microscopy of cultured Fao cells. Finally, transfection assay demonstrated that DNS-X enhanced the PPAR alpha activity as well as other peroxisome proliferators do.

Animals↗
PubMed1985

The effect of bezafibrate and long-chain fatty acids on peroxisomal activities in cultured rat hepatocytes.

Peroxisomal activities have been evaluated in cultured rat hepatocytes in the presence of bezafibrate or long-chain fatty acids added to the culture medium. All activities decreased continuously over a time period of 100 h in culture but selected activities were relatively increased as a function of the added effectors. This relative increase in peroxisomal activities was dose-dependent, discernible within the first 24 h in culture and consisted of activities related specifically to peroxisomal fatty acyl beta-oxidation, e.g., cyanide-insensitive palmitoyl-CoA oxidation, H2O2-forming palmitoyl-CoA oxidase and heat-labile enoyl-CoA hydratase. Peroxisomal catalase or mitochondrial fatty acyl beta-oxidation (cyanide-sensitive) remained relatively unchanged. The relative increase in peroxisomal activities was accompanied by a respective increase in the number of peroxisomes as well as in thymidine incorporation rate.

Animals↗
PubMed1982

The effect of bezafibrate and clofibrate on microsomal ACAT and lysosomal cholesterol ester hydrolase activity in the cholesterol-fed rabbit aorta.

Bezafibrate markedly reduced the activity of fatty acyl CoA:cholesterol acyltransferase (ACAT) in the microsomal fraction of aortas from cholesterol-fed rabbits, while clofibrate was a less potent inhibitor. The activity of lysosomal cholesterol ester hydrolase (LCEH) was not significantly affected by either agent, indicating that inhibition of ACAT rather than stimulation of LCEH is a mechanism whereby these agents may decrease the cholesterol ester content of atherosclerotic aorta.

Acyltransferases↗
PubMed1988

Effect of short-term treatment with bezafibrate on plasma fibrinogen, fibrinopeptide A, platelet activation and blood filterability in atherosclerotic hyperfibrinogenemic patients.

The effect of bezafibrate (BZF) on plasma fibrinogen levels has been studied in 62 patients with atherosclerotic vasculopathy and hyperfibrinogenemia (643 +/- 15 (SEM) mg/dl). In a preliminary study, 15-30 days of BZF therapy (400-600 mg/day) normalized fibrinogen values in 16 subjects were compared to 16 controls. The effect was rapid and dose-dependent, and discontinuation in 6 patients who could not complete the study was followed by a rebound increase. A controlled study with 400 mg/day in the other 24 patients for 15 days showed that BZF lowered fibrinogen, PF4, blood filterability and platelet aggregating thresholds to the normal range. BTG and FpA decreased significantly compared to the placebo group (12 and 12 patients randomly distributed) without any variation in potentially biassing hematologic values (WBC, PLTS, Ht, lipids and plasma glucose). BZF may be of value in chronic treatment of hyperfibrinogenemia in atherosclerotic patients with a view to improving the haemorheologic pattern and, hence, reducing activation of the coagulation pathway.

Adult↗
PubMed1989

Modification of low density lipoproteins from hypertriglyceridemic patients by macrophages in vitro and the effect of bezafibrate treatment.

After 30 days of bezafibrate administration to 5 patients with hypertriglyceridaemia and hyperapobetalipoproteinaemia a rise was found in the concentrations of cholesterol and vitamin E in the LDL fraction. In consequence the susceptibility of the LDL fraction to oxidation by macrophages was reduced. The uptake of modified LDL by these cells was decreased in relation to the uptake before treatment.

Adult↗
PubMed1990

Effect of ciprofibrate, bezafibrate, and LY171883 on peroxisomal beta-oxidation in cultured rat, dog, and rhesus monkey hepatocytes.

Cultured rat hepatocytes have been used extensively to study the mechanisms of chemically induced peroxisome proliferation. Hepatocytes from nonrodent species have been used on a limited scale to study interspecies differences in the response. Because of their importance in pharmaceutical safety assessment, we have developed a model to study the response of beagle dog and rhesus monkey hepatocytes to peroxisome proliferators. Treatment of the hepatocytes with peroxisome proliferators was begun after 20 hr in culture and continued for 72 hr. Untreated rat, dog, and monkey hepatocytes retained 62, 42, and 43% of their initial (20 hr) peroxisomal beta-oxidation activity throughout 92 hr of culture. Ciprofibrate, bezafibrate, and LY171883 caused a dose-related increase in beta-oxidation in rat hepatocytes to a maximum of 10-, 8-, and 5-fold, respectively. In dog and monkey hepatocytes the increases in beta-oxidation were less than 2-fold. Peroxisome morphology in dog and monkey hepatocytes appeared to be unchanged by the drugs. Morphometric analysis in monkey hepatocytes showed no increase in peroxisome volume fraction in response to the chemicals. Treatment of dog and monkey hepatocytes with dexamethasone and glucagon during the final 24 hr in culture caused a 4- to 6-fold increase in tyrosine aminotransferase activity. This induction is characteristic of the in vivo response. The small increase in beta-oxidation reflects the relative insensitivity of the dog and monkey liver to peroxisome proliferators in vivo rather than a loss of sensitivity during culture. Cultured hepatocytes from beagle dog and rhesus monkey may provide a model for studying the mechanisms underlying the interspecies differences. Such information would help clarify the relevance of rodent data in human risk assessment.

Acetophenones↗
PubMed1992

Effect of bezafibrate and clofibric acid on the spectroscopic properties of the nitric oxide derivative of ferrous human hemoglobin.

The effect of bezafibrate (BZF) and clofibric acid (CFA) on the spectroscopic (EPR and absorbance) properties of the nitric oxide derivative of ferrous human hemoglobin (HbNO) has been investigated quantitatively. In the presence of BZF and CFA, the X-band EPR spectra and the absorption spectra in the Soret region of HbNO display the same basic characteristics described in the presence of inositol hexakisphosphate (IHP) and 2, 3-diphosphoglycerate (2,3-DPG). Next, in the presence of these allosteric effectors, the oxygen affinity for ferrous human hemoglobin (Hb) is reduced. These findings indicate that BZF and CFA, as already reported for IHP and 2, 3-DPG, induce the stabilization of a low affinity conformation of the ligated hemoprotein (i.e., HbNO). Values of the apparent equilibrium constant for BZF and CFA binding to HbNO (K) are 1.5(+/- 0.2) x 10(-2) M and 2.8(+/- 0.3) x 10(-2) M, respectively, at pH 7.0 (in 0.1 M N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid]/NaOH buffer system plus 0.1 M NaCl) and 20 degrees C. The results reported here represent clearcut evidence for BZF and CFA specific (i.e., functionally relevant) binding to a ligated derivative of Hb (i.e., HbNO).

2,3-Diphosphoglycerate↗
PubMed1993

Cooperative effect of inositol hexakisphosphate, bezafibrate, and clofibric acid on the spectroscopic properties of the nitric oxide derivative of ferrous human hemoglobin.

The cooperative effect of inositol hexakisphosphate (IHP), bezafibrate (BZF), and clofibric acid (CFA) on the spectroscopic (EPR and absorbance) properties of the nitric oxide derivative of ferrous human hemoglobin (HbNO) has been investigated quantitatively. In the presence of IHP, BZF, and CFA, the X-band EPR spectra and the absorption spectra in the Soret region of HbNO display the same basic characteristics described in the presence of 2,3-diphosphoglycerate (2,3-DPG), which have been attributed to a low affinity conformation of the tetramer. Addition to HbNO of two allosteric effectors together (such as IHP and BZF, or IHP and CFA) further stabilizes the low affinity conformation of the ligated hemoprotein (i.e., HbNO). Moreover, in the presence of saturating amounts of IHP, the affinity of BZF and CFA for HbNO increases by about fifteenfold. Likewise, in the presence of both IHP and BZF, as well as in IHP and CFA, the oxygen affinity for ferrous human hemoglobin (Hb) is reduced with respect to that observed in the presence of IHP, BZF, or CFA alone, which in turn is lower than that reported in the absence of any allosteric effector. All the data were obtained at pH 7.0 (in 1.0 x 10(-1) M N-[2-hydroxyethyl]-piperazine-N'-[2-ethanesulfonic acid]/NaOH buffer system plus 1.0 x 10(-1) M NaCl), as well as at 100 K and/or 20 degrees C. The results here reported represent clearcut evidence for the cooperative and specific (i.e., functionally relevant) binding of IHP, BZF, and CFA to Hb.

Bezafibrate↗
PubMed1995

Plasma fibrinogen levels and their correlates in 6457 coronary heart disease patients. The Bezafibrate Infarction Prevention (BIP) Study.

The association between fibrinogen measured in healthy individuals and subsequent development of ischemic heart disease is well established, but studies reporting fibrinogen levels in coronary heart disease patients are scarce. Plasma fibrinogen was determined for 5729 men and 728 women (aged 45 to 74) with established coronary heart disease, screened for participation in the Bezafibrate Infarction Prevention study, with the following lipid profile at the time of the first screening visit: total serum cholesterol < or = 270 mg/dl, high density lipoprotein cholesterol < or = 45 mg/dl and triglyceride < or = 300 mg/dl. Increased age was associated with augmented plasma fibrinogen values. Age-adjusted fibrinogen levels were higher in women than in men. A direct association was found between mean fibrinogen levels and low density lipoprotein cholesterol. On the other hand, the correlation with high density lipoprotein cholesterol was inverse. Fibrinogen was also associated with body mass index, behavioral variables and severity of coronary heart disease. In a multivariable linear regression analysis performed, risk factors considered explained merely 6 and 4% of fibrinogen variation for men and women, respectively. Therefore, most of the fibrinogen level variability in coronary heart disease patients is accounted for by factors that remain to be established by further research.

Age Factors↗
PubMed2003

Effects of baseline level of triglycerides on changes in lipid levels from combined fluvastatin + fibrate (bezafibrate, fenofibrate, or gemfibrozil).

This analysis was conducted to evaluate the effect of baseline triglyceride levels on lipid and lipoprotein changes after treatment with the combination of fluvastatin and fibrates. The analysis involved pooling data from 10 studies that included 1,018 patients with either mixed hyperlipidemia or primary hypercholesterolemia. Patients received a combination of fluvastatin and a fibrate (bezafibrate, fenofibrate, or gemfibrozil) from 16 to 108 weeks. The combination of fluvastatin and a fibrate improved lipid profiles, with reductions in triglycerides, low-density lipoprotein (LDL) cholesterol, and non-high-density lipoprotein (non-HDL) cholesterol that were dependent on baseline triglyceride levels. The greatest triglyceride reductions were observed in patients with high baseline triglyceride levels (> or =400 mg/dl) (41%, p <0.0001). The greatest LDL cholesterol and non-HDL cholesterol reductions occurred in patients with normal baseline triglyceride levels (<150 mg/dl) (35% and 33%, respectively; p <0.0001). The combined fluvastatin-fibrate therapy was well tolerated. Two patients (0.2%) (1 patient on fluvastatin 80 mg + gemfibrozil 1,200 mg and 1 patient on fluvastatin 20 mg + fenofibrate 200 mg) had creatine kinase levels > or =10 times the upper limit of normal, 11 patients (1.1%) had an elevation in alanine transaminase >3 times the upper limit of normal, and 7 patients (0.7%) had elevations in aspartate transaminase >3 times the upper limit of normal. Combined fluvastatin-fibrate therapy takes advantage of the complementary effects of the 2 agents, with the extent of triglyceride, LDL cholesterol, and non-HDL cholesterol lowering dependent on baseline triglyceride levels. The combination of fluvastatin and fibrates was well tolerated with no major safety concerns.

Age Factors↗
PubMed1996

Usefulness of beta-blocker therapy in patients with non-insulin-dependent diabetes mellitus and coronary artery disease. Bezafibrate Infarction Prevention (BIP) Study Group.

The benefit of beta-blocker therapy in patients after myocardial infarction is well established. The use of beta blockers in the high-risk subgroup of patients with combined diabetes mellitus (DM) and coronary artery disease (CAD) remains controversial. From a database of 14,417 patients with chronic CAD who had been screened for participation in the Bezafibrate Infarction Prevention (BIP) study, 2,723 (19%) had non-insulin-dependent DM. Baseline characteristics and 3-year mortality were analyzed in patients with DM receiving (n = 911; 33%) and not receiving (n = 1,812; 67%) beta blockers. Total mortality during a 3-year follow-up was 7.8% in those receiving beta blockers compared with 14.0% in those who were not (a 44% reduction). A reduction in cardiac mortality of 42% between the 2 groups was also noted. Three-year survival curves showed significant differences in mortality with increasing divergence (p = 0.0001). After multiple adjustment, multivariate analysis identified beta-blocker therapy as a significant independent contributor to improved survival (relative risk = 0.58; 90% confidence interval 0.46 to 0.74). Within the diabetic population, the main benefit associated with beta-blocker therapy was observed in older patients, in those with a history of myocardial infarction, those with limited functional capacity, and those at lower risk. Thus, therapy with beta blockers appears to be associated with improved long-term survival in the high-risk subpopulation of patients with DM and CAD.

Actuarial Analysis↗
PubMed2001

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.

Bezafibrate↗