Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fenofibrate is clinically successful in treating hypertriglyceridemia and mixed hyperlipidemia presumably through peroxisome proliferator-activated receptor alpha (PPARalpha)-dependent induction of genes that control fatty acid beta-oxidation. Lipid homeostasis and cholesterol metabolism also are regulated by the nuclear oxysterol receptors, liver X receptors alpha and beta (LXRalpha and LXRbeta). Here we show that fenofibrate ester, but not fenofibric acid, functions as an LXR antagonist by directly binding to LXRs. Likewise, ester forms, but not carboxylic acid forms, of other members of the fibrate class of molecules antagonize the LXRs. The fibrate esters display greater affinity for LXRs than the corresponding fibric acids have for PPARalpha. Thus, these two nuclear receptors display a degree of conservation in their recognition of ligands; yet, the acid/ester moiety acts as a chemical switch that determines PPARalpha versus LXR specificity. Consistent with its LXR antagonistic activity, fenofibrate potently represses LXR agonist-induced transcription of hepatic lipogenic genes. Surprisingly, fenofibrate does not repress LXR-induced transcription of various ATP-binding cassette transporters either in liver or in macrophages, suggesting that fenofibrate manifests variable biocharacter in the context of differing gene promoters. These findings provide not only an unexpected mechanism by which fenofibrate inhibits lipogenesis but also the basis for examination of the pharmacology of an LXR ligand in humans.
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PMID:A chemical switch regulates fibrate specificity for peroxisome proliferator-activated receptor alpha (PPARalpha ) versus liver X receptor. 1244 42

The effect of fluvastatin and fenofibrate on antioxidative enzymatic activity in patients with stable angina and mixed hyperlipidaemia was investigated. Thirty-five patients (13 men and 22 women) aged 40-77 years, were randomly divided into two groups. The first group comprised 20 patients who were administered fluvastatin 40 mg once daily at bedtime for 30 days. The second group consisted of 15 patients who were administered fenofibrate 200 mg once daily at bedtime for 30 days. The control group comprised 11 clinically healthy persons aged 21-54 years. The activities of SOD-1, CAT and GSH-Px in erythrocytes were measured. Fluvastatin induced an increase of the activities of all investigated enzymes. Fenofibrate caused no change of enzyme activities in patients with dyslipidaemia.
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PMID:[Effect of fluvastatin and fenofibrate on the antioxidative barrier enzyme activity in patients with dyslipidemia]. 1286 85

Kinetics of apo B and apo AI were assessed in 8 patients with mixed hyperlipidemia at baseline and after 8 weeks of atorvastatin 80 mg q.d. and micronised fenofibrate 200 mg q.d. in a cross-over study. Both increased hepatic production and decreased catabolism of VLDL accounted for elevated cholesterol and triglyceride concentrations at baseline. Atorvastatin significantly decreased triglyceride, total, VLDL and LDL cholesterol and apo B concentrations (-65%, -36%, -57%, -40% and -33%, respectively, P<0.05). Kinetic analysis revealed that atorvastatin stimulated the catabolism of apo B containing lipoproteins, enhanced the delipidation of VLDL1 and decreased VLDL1 production. Fenofibrate lowered triglycerides and VLDL cholesterol (-57% and -64%, respectively, P<0.05) due to enhanced delipidation of VLDL1 and VLDL2 and increased VLDL1 catabolism. Changes of HDL particle composition accounted for the increase of HDL cholesterol during atorvastatin and fenofibrate (18% and 23%, P<0.01). Only fenofibrate increased apo AI concentrations through enhanced apo AI synthesis (45%, P<0.05). We conclude that atorvastatin exerts additional beneficial effects on the metabolism of apo B containing lipoproteins unrelated to an increase in LDL receptor activity. Fenofibrate but not atorvastatin increases apo AI production and plasma turnover.
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PMID:Effects of atorvastatin versus fenofibrate on apoB-100 and apoA-I kinetics in mixed hyperlipidemia. 1452 53

Both atorvastatin and fenofibrate are known to lower postprandial chylomicrons and chylomicron remnants. However, until now it has not been investigated which of the two drugs is more effective in one and the same patient and, secondly, whether these drugs exert different effects on chylomicron remnants of different sizes. To this end 12 patients with mixed hyperlipidemia were treated in a crossover study with 40 mg atorvastatin or with 200 mg micronized fenofibrate once daily for 6 weeks. Oral fat loading was given before and after each treatment. Chylomicron remnants of various sizes were determined by fluorometric determinations of retinyl palmitate after lipoprotein separation by size-exclusion chromatography. As expected, atorvastatin was more effective than fenofibrate on total and LDL-cholesterol (P < 0.05). Fenofibrate, in contrast, was more effective on all triglyceride-rich lipoproteins in both the fasting and the postprandial state. The stronger effect of fenofibrate affected not only chylomicrons and VLDL but also chylomicron remnants. It reduced large chylomicron remnants by 66% at 6h and by 74% at 8 h. The action of atorvastatin was less pronounced, with corresponding reductions of 42 and 65% (P < 0.05 only after 8 h). Fenofibrate was even more effective on small chylomicron remnants, yielding reductions of 47, 74, and 66% at 4, 6, and 8 h. Atorvastatin, in contrast, gave reductions of 30 and 26% after 6 and 8 h, the effect reaching statistical significance only after 6h. Fenofibrate is therefore more effective than atorvastatin in lowering all triglyceride-rich lipoproteins, including large and small chylomicron remnants.
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PMID:Chylomicron remnants of various sizes are lowered more effectively by fenofibrate than by atorvastatin in patients with combined hyperlipidemia. 1464 9

The effects of cerivastatin and fenofibrate on proteins involved in haemostasis and on markers of inflammation were investigated in otherwise healthy middle-aged males with combined hyperlipidemia. Besides classical risk factors, other so-called novel risk factors for coronary artery disease are seen to be playing an increasingly important role in the development and progression of atherosclerosis. Thirty-eight males, aged 49 +/-5 years were randomised to 12 weeks treatment either with cerivastatin at a daily dose of 0.2 mg to 0.4 mg to achieve the LDL cholesterol goal of <3.0 mM, or with fenofibrate 250 mg daily. Fasting serum lipids, homocysteine, total and free tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor (PAI-1) and tissue plasminogen activator (t-PA) antigen and activity, C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured. No change in homocysteine level was observed in the cerivastatin group, while after fenofibrate administration it increased (p <0.0001). Total TFPI decreased significantly after cerivastatin (p = 0.002), but not after fenofibrate. Free TFPI did not decrease after either drug. Neither drug affected (t-PA) antigen and activity, while fenofibrate increased PAI-1 antigen (p <0.05) and activity (p <0.05). Cerivastatin decreased serum CRP values by 49.5% (p = 0.001), and fenofibrate by 29.8% (p = 0.03). The decreases of CRP in the two groups differed significantly (p = 0.04). IL-6 levels decreased significantly in the fenofibrate group (39%; p <0.0001), but not in the cerivastatin group (15%; p = 0.24) No significant decreases were observed for TNF-alpha. Cerivastatin had neutral effects on fibrinolysis, homocysteine or coagulation. On the other hand, fenofibrate increased PAI-1 antigen and activity and homocysteine, and did not affect coagulation. Both cerivastatin and fenofibrate reduced CRP levels, the decrease being significantly greater after cerivastatin. Fenofibrate also significantly decreased IL-6.
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PMID:Statin and fibrate treatment of combined hyperlipidemia: the effects on some novel risk factors. 1554 43

Apolipoprotein (apo) A-II has been biochemically and genetically linked to familial combined hyperlipidemia. Human ApoA-II transgenic mice and peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice share some similar phenotypic characteristics. The aim of this study was to determine whether a fibrate-induced PPARalpha activation corrects the combined hyperlipidemia present in human apoA-II transgenic mice. ApoA-II transgenic mice were treated with fenofibrate (250 mg/kg) for 13 days. After this period, they presented a remarkable 8-fold increase in plasma triglycerides. This was concomitant with a 4-fold increase in non-high-density lipoprotein (non-HDL) cholesterol, a quantitatively similar decrease in HDL cholesterol and a severe reduction in mouse plasma apoA-I and apoA-II. Fenofibrate stimulated liver fatty acid beta-oxidation, increased the transcriptional expression of carnitine palmitoyltransferase 1 and phospholipid transfer protein, and decreased expression of apoA-I and apoC-III. However, very-low-density lipoprotein (VLDL)-triglyceride production and lipoprotein lipase (LPL) activities and the expression of other PPARalpha target genes were similar in mice treated with vehicle and fenofibrate. Further, fenofibrate-treated mice presented decreased in vivo [3H]VLDL catabolism and decreased VLDL-triglyceride hydrolysis by exogenous LPL. Therefore, the paradoxical enhancement of hyperlipidemia in fenofibrate-treated apoA-II transgenic mice is mainly due to decreased VLDL catabolism and, also, to a partial impairment in PPARalpha-signaling.
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PMID:Paradoxical exacerbation of combined hyperlipidemia in human apolipoprotein A-II transgenic mice treated with fenofibrate. 1622 89

Abnormalities in glucose and lipid regulation have been reported in schizophrenia during antipsychotic medications. The objectives of the present study were to evaluate the effect of various peroxisome proliferator-activated receptor modulators viz. glimepiride, rosiglitazone and fenofibrate on chlorpromazine, clozapine and ziprasidone induced hyperglycemia and hyperlipidemia in mice. Male Swiss albino mice were orally treated with chlorpromazine, clozapine and ziprasidone concurrently with the antidiabetic medications for 7 days. Plasma glucose, insulin and triglyceride levels were determined at the end of the study. Chlorpromazine and clozapine elevated the glucose and triglyceride levels in normal mice, with no effect on insulin but ziprasidone increased the basal triglyceride and insulin levels and did not have any effect on glucose. Glimepiride and rosiglitazone showed beneficial glucose and triglyceride lowering effects in chlorpromazine and clozapine animals and no effect on insulin levels. Fenofibrate significantly reduced the glucose levels only in animals treated with clozapine, and exhibited significant reduction of triglyceride levels in chlorpromazine, clozapine and ziprasidone treated animals. All three antidiabetic/hypolipidemic agents lowered triglyceride and insulin levels in ziprasidone treated animals. The results of the present studies suggest that hyperglycemia, hyperinsulinemia and hypertriglyceridemia induced by various antipsychotics may involve diverse mechanisms.
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PMID:Antipsychotic induced metabolic abnormalities: an interaction study with various PPAR modulators in mice. 1682 8

Lowering of low-density lipoprotein cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) is clearly efficacious in the treatment and prevention of coronary artery disease. However, despite increasing use of statins, a significant number of coronary events still occur and many of such events take place in patients presenting with type 2 diabetes and metabolic syndrome. More and more attention is being paid now to combined atherogenic dyslipidemia which typically presents in patients with type 2 diabetes and metabolic syndrome. This mixed dyslipidemia (or "lipid quartet"): hypertriglyceridemia, low high-density lipoprotein cholesterol levels, a preponderance of small, dense low-density lipoprotein particles and an accumulation of cholesterol-rich remnant particles (e.g. high levels of apolipoprotein B)--emerged as the greatest "competitor" of low-density lipoprotein-cholesterol among lipid risk factors for cardiovascular disease. Most recent extensions of the fibrates trials (BIP - Bezafibrate Infarction Prevention study, HHS - Helsinki Heart Study, VAHIT--Veterans Affairs High-density lipoprotein cholesterol Intervention Trial and FIELD--Fenofibrate Intervention and Event Lowering in Diabetes) give further support to the hypothesis that patients with insulin-resistant syndromes such as diabetes and/or metabolic syndrome might be the ones to derive the most benefit from therapy with fibrates. However, different fibrates may have a somewhat different spectrum of effects. Other lipid-modifying strategies included using of niacin, ezetimibe, bile acid sequestrants and cholesteryl ester transfer protein inhibition. In addition, bezafibrate as pan-peroxisome proliferator activated receptor activator has clearly demonstrated beneficial pleiotropic effects related to glucose metabolism and insulin sensitivity. Because fibrates, niacin, ezetimibe and statins each regulate serum lipids by different mechanisms, combination therapy--selected on the basis of their safety and effectiveness - may offer particularly desirable benefits in patients with combined hyperlipidemia as compared with statins monotherapy.
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PMID:Atherogenic dyslipidemia in metabolic syndrome and type 2 diabetes: therapeutic options beyond statins. 1700 98

The ezetimibe and fenofibrate combination regimen was recently approved by the U.S. Food and Drug Administration for treatment of mixed hyperlipidemia. This powerful lipid-modifying therapy takes advantage of the different mechanisms of action of the two individual components. Ezetimibe selectively inhibits intestinal uptake of dietary and biliary cholesterol, and exerts its effect most notably on the low-density lipoprotein cholesterol (LDL-C). Fenofibrate activates the peroxisome proliferators-activated receptor alpha (PPAR-alpha), thereby increasing the tissue lipoprotein lipase activity and breakdown of triglycerides in very low-density lipoproteins (VLDL). The combination therapy of ezetimibe and fenofibrate has an excellent safety profile and exhibits potent synergistic actions on multiple lipid risk factors and represents another alternative in the clinical management of mixed hyperlipidemia. Further studies are needed to determine the effectiveness and safety of the ezetimibe and fenofibrate combination therapy used in conjunction with other lipid-modifying agents such as statins. Finally, outcome trials are warranted to evaluate if combination therapy would result in additive effects on morbidity and mortality.
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PMID:Ezetimibe and fenofibrate combination therapy for mixed hyperlipidemia. 1731 51

Cardiovascular disease is the major cause of mortality worldwide and accounts for approximately 40% of all deaths. Dyslipidemia is one of the primary causes of atherosclerosis and effective interventions to correct dyslipidemia should form an integral component of any strategy aimed at preventing cardiovascular disease. Fibrates have played a major role in the treatment of hyperlipidemia for more than two decades. Fenofibrate is one of the most commonly used fibrates worldwide. Since fenofibrate was first introduced in clinical practice, a major drawback has been its low bioavailability when taken under fasting conditions. Insoluble Drug Delivery-Microparticle fenofibrate is a new formulation that has an equivalent extent of absorption under fed or fasting conditions. In this review, we will discuss the clinical pharmacology of fenofibrate, with particular emphasis on this novel formulation, as well as its lipid-modulating and pleiotropic actions. We will also analyze the major trial that evaluated fibrates for primary and secondary prevention of cardiovascular disease, the safety and efficacy profile of fibrate-statin combination treatment, and the current recommendations regarding the use of fibrates in clinical practice.
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PMID:Fenofibrate: a novel formulation (Triglide) in the treatment of lipid disorders: a review. 1772 29


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