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PubMed1997

A study to determine the response of coronary atherosclerosis to raising low high density lipoprotein cholesterol with a fibric-acid derivative in men after coronary bypass surgery. The rationale, design, and baseline characteristics of the LOCAT Study. Lopid Coronary Angiography Trial.

Several clinical trials have shown that reducing serum cholesterol levels retards the progression of coronary atherosclerosis assessed by serial angiography. By contrast, as yet no studies have addressed the impact of increasing high density lipoprotein (HDL) cholesterol levels on progression of coronary artery disease (CAD). As HDL cholesterol is inversely related to the risk of CAD, we hypothesize that an intervention that raises low HDL cholesterol concentrations may have a beneficial effect on the course of CAD. Lopid Coronary Angiography Trial (LOCAT) was designed to test this hypothesis. Three hundred and ninety-five men, aged < or = 70 years, all of whom had previously undergone coronary bypass surgery, were randomly assigned to receive either slow-release gemfibrozil, 1200 mg once daily, or a matching placebo for on average 2 1/2 years. The lipid inclusion criteria were HDL cholesterol concentration < or = 1.1 mmol/L, low density lipoprotein (LDL) cholesterol < or = 4.5 mmol/L, and serum triglyceride < or = 4.0 mmol/L. Subjects were not accepted if they had manifest diabetes, body mass index > 30 kg/m2, uncontrolled hypertension, or if they were regular smokers. All randomized subjects underwent baseline coronary angiography, which will be repeated at the end of the study. The angiograms will be analyzed using the Cardiovascular Measurement System, a validated computer-assisted image-analysis and quantitation package. The primary endpoints are the changes in the per-patient mean of 1) the average diameter of evaluable native coronary segments, and 2) the minimal luminal diameter of evaluable stenoses, and 3) the appearance of new lesions. Extensive lipoprotein and other metabolic studies and analyses of genetic polymorphisms are carried out to study the determinants of CAD progression. At baseline, the study subjects were 59.1 +/- 6.8 (mean +/- standard deviation) years old, had a body mass index 26.4 +/- 2.2 kg/m2, and serum triglyceride, serum cholesterol, HDL cholesterol, and LDL cholesterol concentrations 1.64 +/- 0.64, 5.17 +/- 0.64, 0.82 +/- 0.14, and 3.61 +/- 0.53 mmol/L, respectively.

Cholesterol, HDL↗
PubMed2006

Fibric acid derivatives in cardiovascular disease prevention: results from the large clinical trials.

PURPOSE OF REVIEW: Results from five large placebo-controlled trials with second-generation fibrates have shown varying success in reducing cardiovascular events. This review focuses on a number of extended analyses from these trials that may relate to the success or failure of fibrate therapy and indicate who might likely benefit from this therapy. RECENT FINDINGS: Results have been far from uniform and several trials have been adversely impacted by high off-trial statin use. Collective evidence suggests, however, that fibrates have optimum cardiovascular benefit in diabetes or other manifestations of insulin resistance. Much of this evidence comes from posttrial analysis in subgroups with more sharply defined clinical characteristics than in the overall trial population. Analyses also suggest that different fibrates have a different range of favorable clinical properties, that the cardiovascular benefit of fibrates may not be readily measured or mostly predicted by changes in traditional lipid measurements, and that other nonlipid properties of fibrates as peroxisome proliferator-activated receptor agents might explain some of the benefit of these drugs. SUMMARY: Results of major clinical endpoint trials with fibrates, although not uniformly positive, provide substantial evidence for a selective therapeutic role of these drugs in cardiovascular event reduction in diabetes or insulin resistance.

Cardiovascular Diseases↗
PubMed1993

Acyl-CoA synthetase mRNA expression is controlled by fibric-acid derivatives, feeding and liver proliferation.

Several enzymes of the beta-oxidation pathway have been shown to be induced after stimulation with peroxisomal proliferators, including several hypolipidemic drugs. We investigated the regulation of the long-chain-acyl-CoA synthetase (ACS) gene in the liver. Fenofibrate, a hypolipidemic drug and potent peroxisomal proliferator, induced ACS gene expression in several tissues. In liver, large increases in ACS mRNA levels and ACS activity were observed after fenofibrate administration. Adipose tissue ACS mRNA levels and ACS activity were also stimulated upon fibrate treatment but to a lesser extent in comparison with liver ACS mRNA. Kidney ACS mRNA was only weakly induced, except for the highest dose and the longest treatment period, where a strong induction was observed. In contrast to these tissues, heart ACS mRNA and ACS activity remained almost unchanged after fenofibrate treatment. These effects of fenofibrate could be reproduced by other fibrates such as clofibrate. In addition, it is demonstrated that both nutritional composition and liver proliferation trigger ACS gene expression in liver. Consequently, these data suggest that ACS is a highly regulated enzyme with a potentially important control function in lipid metabolism.

Adipose Tissue↗
PubMed2004

Co-induction of methyltransferase Rv0560c by naphthoquinones and fibric acids suggests attenuation of isoprenoid quinone action in Mycobacterium tuberculosis.

The superoxide generator menadione was previously demonstrated as an inducer of growth stage dependent protein patterns in Mycobacterium tuberculosis. The present study refines this observation by characterizing a novel 27-kDa protein that had not been observed in previous studies relying on younger cultures. A very similar response, based on two-dimensional gel electrophoretic analyses, was induced by the closely related naphthoquinone plumbagin. The 27-kDa protein was also induced by the pro-oxidant peroxisome proliferator gemfibrozil and to a lesser extent by the structurally related compounds fenofibrate and clofibrate. N-terminal sequence data of proteolytic fragments from the 27-kDa protein demonstrated its identity with protein Rv0560c, previously demonstrated to be inducible by salicylate, which also possesses peroxisome proliferating properties. Protein Rv0560c bears three conserved motifs characteristic of S-adenosylmethionine-dependent methyltransferases. Further sequence similarities suggest a function in the bio syn thesis of isoprenoid compounds, e.g., tocopherol, ubiquinone, and sterols. Such involvement is supported by the recognized yet unexplained widespread interference of menadione, salicylate, and fibrates with the isoprenoid quinones ubiquinone, menaquinone, and vitamin K. Induction of Rv0560c by fibrates, salicylate, and naphthoquinones is thus suggested to be caused by action on the plasma membrane, reminiscent of cytochrome P450BM-3 induction by fibrates in Bacillus megaterium, which catalyzes the hydroxylation of fatty acids and thus modulates membrane properties.

Amino Acid Motifs↗
PubMed2002

Induction of plasminogen activator inhibitor-1 in endothelial cells by basic fibroblast growth factor and its modulation by fibric acid.

Plasminogen activator inhibitor-1 (PAI-1) inhibits fibrinolysis and proteolysis. Basic fibroblast growth factor (bFGF) stimulates angiogenesis, which requires regional proteolysis. Because modulation of vasculopathy requires tight control of proteolysis, effects of bFGF on PAI-1 expression in endothelial cells (ECs) were characterized. bFGF increased PAI-1 mRNA and accumulation of PAI-1 protein in conditioned media in human umbilical vein ECs. The bFGF-mediated increase in PAI-1 mRNA was attenuated by inhibition of extracellular signal-regulated kinase kinase in human ECV304 cells. The rate of decrease in PAI-1 mRNA after actinomycin D treatment was not affected by bFGF. Transient transfection assays of the human PAI-1 promoter-luciferase construct demonstrated that bFGF-induced PAI-1 transcription was dependent on the elements within the -313 to -260 bp relative to the transcription start site. This region contains an E26 transformation specific 1 (Ets-1)-like site. Electrophoretic mobility shift assay showed that bFGF increased nuclear translocation or DNA binding of the Ets-1-like transcription factor to the PAI-1 promoter. Nucleotide substitution to disrupt the Ets-1-like site reduced bFGF-stimulated promoter activity. Fenofibric acid, an agonist ligand for the peroxisome proliferator-activated receptor-alpha, inhibited basal and bFGF-stimulated PAI-1 expression. By inducing PAI-1 expression from ECs, bFGF may control proteolysis and fibrinolysis in vessel walls.

5' Flanking Region↗
PubMed1989

[Efficacy of blood lipid normalization and tolerance in dyslipidemic patients treated for 18 months with fibric acid derivatives].

Three groups of hyperlipoproteinemia patients have been submitted to long term treatment (18 months) with bezafibrate, gemfibrate and fenofibrate evaluating efficacy and tolerability of the three drugs. A global improvement of lipemic profile with an increase in protective (HDL, APO-A1) and a reduction in atherogenic factors (TC, LDL, APO-B, TG) has been shown, particularly at the end of the 18 months of therapy. No pathological changes have been observed in SGOT, SGPT, GGT values. Echotomography of biliary tract excluded the development of gallstones during treatment. The Authors can conclude with a positive judgement about use of these drugs in long term treatment of primary hyperlipoproteinemias, resistant to diet alone.

Adult↗
PubMedDate not supplied

[The action of a fibric acid derivative on lipid metabolism].

The action of N-2 (p-chlorophenoxy isobutiril)-N-morpholino-methylureea on some serum lipids parameters in rats with normolipemia and tritonic hyperlipidemia was studied. In the animals with normolipidemia, the compound induces hypocholesterolemia beginning with the 5th day of treatment, hypotriglyceridemia during the entire investigation interval and an increase of phospholipid levels in the 9th day of treatment. In the rats with tritonic hyperlipidemia, the substance induces hypocholesterolemia, hypotriglyceridemia, increase of HDL-cholesterol levels, decrease of (VLDL + LDL)--cholesterol levels and the return to normal values of Glueck ratio.

Animals↗
PubMed1995

Modulation of cardiac intermediate filament proteins in the chick heart by fibric acid derivatives.

The effects of different fibrates (bezafibrate, fenofibrate and gemfibrozil) on intermediate filaments were studied in cultured chick embryo heart cells after treatment for 6 or 24 h. Treatment led to alterations in total protein levels, as well as changes in protein levels, in the cytoplasmic and cytoskeletal fractions of cultured cells. Desmin was increased in the cytoskeletal fraction of all cultures after 6 h of treatment regardless of the drug tested, whereas vimentin was decreased in the cytoskeletal fraction only in cells treated with fenofibrate. These findings suggest that the alterations caused by fibrates in desmin and vimentin protein content may be related with the secondary effects that these drugs have on the cardiovascular system in patients treated with fibrates.

Animals↗
PubMed1992

Cholesterol-lowering drugs as cardioprotective agents.

A detailed overview of the various forms of hyperlipidemia/dyslipidemia that constitute a major risk factor for coronary heart disease and a detailed discussion of the various types of cholesterol-lowering drugs are presented. The importance of identifying the type of dyslipidemia with respect to the choice of treatment is emphasized, as is the use of nonpharmacologic intervention, i.e., diet, exercise, and weight loss. The appropriate use and benefits of bile acid sequestrants, nicotinic acid, fibric acids, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, and probucol are individually discussed, whereas nonpharmacologic approaches used in conjunction with the drugs are recommended emphatically.

Anticholesteremic Agents↗
PubMed1995

Surgery, drugs, lifestyle, and hyperlipidemia.

Heart disease is the number-one cause of death in the United States, and more money is spent on its treatment each year than for any other condition. Both epidemiologic and experimental data clearly show that elevated plasma cholesterol levels increase the risk of death from coronary heart disease. Genetic insufficiencies can cause high blood cholesterol, but most people with high cholesterol do not have genetic abnormalities; rather, they have lifestyles that include high-fat diets and little exercise. Cholesterol can be managed aggressively with coronary artery bypass surgery, percutaneous transluminal coronary angioplasty, partial ileal bypass, and even liver transplant. Antihyperlipidemic drugs include bile-acid-binding resins, nicotinic acid, fibric acid derivatives, hydroxymethyglutaryl coenzyme A-reductase inhibitors, and the antioxidant probucol. Strict programs of low-fat diets and exercise are also effective for reducing cholesterol, lowering blood pressure, and preventing heart disease without the side effects associated with surgery and drug therapy. Such lifestyle changes are critical to reducing the incidence of heart disease in this country.

Adult↗
PubMedDate not supplied

Defining specific goals of therapy in treating dyslipidemia in the patient with low high-density lipoprotein cholesterol.

Because patients with low high-density lipoprotein (HDL) cholesterol (HDL-C) are at high risk for clinical coronary artery disease (CAD) events, these patients require aggressive treatment with lifestyle modifications-increased exercise, smoking cessation, and weight loss in overweight patients-and available pharmacological agents. Drugs that raise HDL-C include nicotinic acid, fibric acid derivatives, estrogens, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), alpha-blockers, and alcohol. However, all agents that increase HDL-C may not have the same clinical benefit, just as, as shown in genetic studies in humans and mice, genetic causes of high HDL-C do not always protect against CAD, nor do genetic causes of low HDL-C always increase risk for CAD. Better understanding of the complexities of HDL metabolism and the mechanisms by which HDL protects against CAD is needed to enable the development of new therapeutic strategies--novel drugs or gene delivery systems--to increase HDL-C and reduce CAD events. The statins are the agents with the greatest evidence for slowing progression of CAD and reducing clinical events in patients with low HDL-C, but additional research is needed to determine the potential benefits of additional interventions that increase HDL-C, including combination therapy, which may provide greater improvements in the entire lipid profile.

Animals↗