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)

To examine the effects of gemfibrozil on very-low-density lipoprotein (VLDL) composition and low-density lipoprotein (LDL) size, five men with hypertriglyceridemia (HTG) alone and five men with HTG and hypercholesterolemia (combined hyperlipidemia, CHLP) were randomized for 8 weeks to Lopid SR (slow-release gemfibrozil; two 600-mg tablets once per day) or placebo in a crossover study. Drug therapy versus placebo significantly decreased plasma triglyceride (68%), and VLDL (77%), and significantly increased high-density lipoprotein cholesterol (25%); total cholesterol, apolipoprotein B and lipoprotein[a] concentrations did not change significantly. With drug, mean total apoE in plasma was 53% lower in patients with HTG and 39% lower in patients with CHLP. Gemfibrozil significantly affected VLDL composition: protein increased 26%, molar ratio of apoE to apoB reduced 48%, apoC-II increased 19%, and apoC-III decreased 9%. LDL cholesteryl ester significantly increased with drug treatment. VLDL subfractions were separated and classified as heparin binding (VLDLR, apoE rich) or nonbinding (VLDLNR-1 and VLDLNR-2, both apoE poor). All VLDL subfractions were significantly lower with drug therapy, and the differences for total VLDL and for VLDL subfractions were greater in patients with HTG. With placebo, VLDLR accounted for 41.8% of VLDL in HTG and 49.0% of VLDL in CHLP, reduced to 27.6% and 38.6%, respectively, with gemfibrozil. Taken together, these results suggest that treatment with gemfibrozil reduces plasma concentrations of VLDL and alters the apoprotein composition of VLDL in a manner that may favor LDL- and VLDL-receptor-mediated clearance of the apoE-rich VLDL subfraction, thereby reducing TG-rich particle concentrations, and possibly reducing risk for coronary heart disease.
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PMID:Effects of gemfibrozil on very-low-density lipoprotein composition and low-density lipoprotein size in patients with hypertriglyceridemia or combined hyperlipidemia. 887 39

Diet and drug therapy are two of the principal approaches to lipid management. The aim of both is to reduce low-density-lipoprotein (LDL) cholesterol to goal levels established by the National Cholesterol Education Program Expert Panel in its second report, based on a patient's short-term risk of a coronary event. In prescribing diet therapy, it is important to determine patients' willingness to initiate and adhere to dietary modifications, their skill at reading nutritional labels, adapting recipes, and ordering "heart-healthy" foods when eating out. Diet therapy should be directed at modifying dietary factors known to adversely influence blood cholesterol-saturated fats, cholesterol, and obesity. Diet therapy (with exercise) is not always adequate. High risk individuals with no overt coronary artery disease but with >/=2 risk factors, as well as patients with coronary artery disease, are potential candidates for drug therapy, depending on their LDL cholesterol levels. The "statins" are the drug of choice for patients with coronary disease and elevated LDL cholesterol or familial LDL-cholesterol abnormalities. These drugs increase high-density-lipoprotein (HDL) cholesterol and reduce LDL cholesterol, coronary artery disease, and total mortality. Bile acid resins lower LDL cholesterol and are often used to augment the effects of the statins and niacin. Niacin is particularly useful in the management of patients with combined hyperlipidemia and low HDL cholesterol levels. Gemfibrozil is effective in familial dysbetalipoproteinemia and is the drug of choice for patients with severely elevated serum triglycerides.
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PMID:Lipid management: current diet and drug treatment options. 890 Mar 36

Gemfibrozil reduces the plasmal levels of cholesterol and triglyceride in patients with hyperlipidemia by a mechanism that is not well understood. The present study evaluated the effect of gemfibrozil on the LDL receptor in human hepatoma cells compared with that of pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Exposure to gemfibrozil, 40 mumol/L, for 3 days increased the binding of 125I-LDL to the surface of three lines of human hepatoma cell, HepG2, HuH7, and HLE by 1.5- to 2.0-fold. Similar findings were observed with pravastatin. Scatchard analysis with 125I-LDL indicated an increased number of LDL receptors on the cell surface of HepG2 cells when treated with gemfibrozil and pravastatin. However, the gemfibrozil-treated cells exhibited no increase in the binding of 125I-epidermal growth factor (EGF). Gemfibrozil increased the levels of LDL receptor mRNA and protein in HepG2 cells. The increase in LDL receptor activity induced by pravastatin was abolished by concomitant administration of mevalonic acid, 770 mumol/L. This effect was not seen with gemfibrozil, suggesting the mechanism differs for the two lipid-lowering drugs. To determine whether this increase in mRNA was due to transcriptional activation, we prepared HepG2 cells transfected with an LDL receptor promoter-reporter construct that contained a sterol regulatory element. The expression of LDL receptor regulated by the sterol regulatory element was increased by pravastatin, but not by gemfibrozil. We evaluated the stability of the mRNA in the presence of actinomycin D to explain the increase in the LDL receptor mRNA. Gemfibrozil prolonged the half-life of the mRNA for LDL receptor but not that for the EGF receptor. Stabilization of the LDL receptor mRNA is suggested to be the novel mode of action of gemfibrozil.
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PMID:Upregulation of low density lipoprotein receptor by gemfibrozil, a hypolipidemic agent, in human hepatoma cells through stabilization of mRNA transcripts. 940 46

It was suggested that postprandial lipoproteins (PPLp) may play an important role in atherogenesis. To examine this hypothesis, we studied PPLp metabolism in normolipidemic individuals and hyperlipoproteinemic (HLP) patients on various diets, physical activity programs and hypolipidemic drugs as well as in patients with coronary artery disease (CAD). We used the vitamin A-fat loading test, which labels intestinally derived lipoproteins with retinyl palmitate. Type IV HLP patients demonstrated a severe defect in chylomicron clearance. Type III HLP patients showed severely disordered clearance of chylomicron remnants. Compared to the saturated fatty acid enriched diet, the omega 6 polyunsaturated acid enriched diet reduced chylomicrons and their remnant levels by 56% and 38%, respectively. The diet enriched in omega 3 polyunsaturated acid decreased chylomicrons and their remnant levels by 67% and 53%, respectively. Physical conditioning reduced chylomicron levels by 37%. Gemfibrozil decreased chylomicron levels in type IV HLP patients. Cholestyramine increased chylomicron levels by 88%. Bezafibrate reduced chylomicrons and their remnants levels and increased fasting HDL-C in patients with isolated low HDL-C levels. Continuous prolonged intravenous heparin administration inhibited chylomicron clearance. Normolipidemic patients with CAD had significantly higher plasma levels of chylomicron remnants than matched controls with normal coronary arteries. The studies reported here demonstrate that both chylomicrons and their remnants are present in the plasma of normolipidemic people and more so for hyper- or dyslipidemic patients for a prolonged period of time after fat ingestion. The duration and magnitude of this postprandial lipemia can be regulated or altered by such interventions as diet, physical activity, and drugs. Our case control studies strongly support the hypothesis that PPLp may play a crucial part in atherogenesis, and therefore justify measuring their levels in high risk patients. We believe that in selected patient groups the use of one or more of the interventions mentioned here is warranted.
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PMID:Disturbances in dietary fat metabolism and their role in the development of atherosclerosis. 943 21

Subjects with diabetes have a greatly increased risk of CHD, which is only partially related to their elevated glucose. Other factors such as insulin resistance and dyslipidemia are likely to be important. The type of dyslipidemia that is most characteristic of type 2 diabetic subjects is elevated triglycerides and decreased HDL cholesterol levels, although all lipoproteins have compositional abnormalities. Surprisingly few good prospective studies of lipoprotein levels in relation to CHD have been done in diabetic subjects. Available studies suggest that low HDL cholesterol may be the most important risk factor for CHD in observational studies. In studies in which total cholesterol and triglyceride were done, cholesterol and triglycerides were risk factors for CHD, although triglycerides were often a stronger predictor. However, the strength of triglyceride as a risk factor for CHD may depend partially on its association with other variables (e.g., hypertension, plasminogen activator inhibitor 1 [PAI-1], etc.). In clinical trials in diabetic subjects, LDL reduction with statins has led to significant reductions in CHD incidence. In addition, overall mortality was reduced with statin therapy, although the results were not statistically significant. Gemfibrozil has led to reductions in CHD incidence in diabetic subjects, although the results were not statistically significant perhaps because of low sample size. Regarding lipoproteins and CHD risk in diabetic patients, the very positive results of statin trials point to LDL cholesterol being more important than previous realized. Apparently, having a borderline high LDL cholesterol (between 130 and 160 mg/dl) in a diabetic patient is equivalent to a much higher LDL cholesterol in terms of CHD risk for a nondiabetic subject. Therefore, the primary target of therapy in diabetic patients is lowering LDL cholesterol (or possibly, non-HDL cholesterol). Statins are the preferred pharmacological agent in this situation. Once LDL cholesterol levels have been lowered, attention can be given to treatment of residual hypertriglyceridemia and low HDL. The goal here is weight reduction and increased exercise. However, for selected patients, combining a fibric acid (or low-dose nicotinic acid) with a statin also can be considered. Reduction of LDL levels should take priority over reduction of triglycerides in combined hyperlipidemia because of the proven safety of the statin class of drugs as well as greater reduction in CHD incidence.
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PMID:Management of dyslipidemia in adults with diabetes. 953 88

Apolipoprotein (APO) E*3-Leiden mice with impaired chylomicron and VLDL (very low density lipoprotein) remnant metabolism display hyperlipidaemia and atherosclerosis. In the present study, these mice were used for testing the hypolipidaemic effect of two marketed agents, lovastatin (CAS 75330-75-5) and gemfibrozil (CAS 25812-30-0) as well as a novel compound, SB 204990 (the 5-ring lactone of +/-(3R*,5S*) 3-carboxy-11-(2,4-dichlorophenyl)-3,5-dihydroxyundecanoic acid, CAS 154566-12-8), a potent inhibitor of cholesterol and fatty acid synthesis at the level of ATP-citrate lyase. APOE*3-Leiden mice were fed a saturated fat and cholesterol-rich diet supplemented with either 0.05 or 0.1% w/w of lovastatin, 0.1 or 0.2% w/w of gemfibrozil or 0.1 or 0.2% w/w of SB 204990. Lovastatin showed a dose-related decrease in plasma cholesterol levels (up to -20%) due to a lowering of LDL and HDL (low density resp. high density lipoprotein)-cholesterol (-20 and -18%, respectively), while plasma triglyceride levels were unaffected. Gemfibrozil had no effect on plasma total cholesterol levels but gave significant dose-dependent decreases in plasma (VLDL) triglyceride levels (up to -53%). SB 204990 resulted in a dose-dependent reduction of plasma cholesterol (up to -29%) by lowering VLDL, LDL and HDL-cholesterol (-50, -20 and -20%, respectively). In addition, a strong dose dependent reduction of plasma (VLDL) triglycerides up to -43% was observed with this compound. Although the effects of gemfibrozil and SB 204990 were not simply explained by changes in a single determinant of VLDL metabolism--no effects of these drugs were seen on post-heparin plasma lipoprotein lipase activity, in vivo rate of VLDL synthesis or hepatic apoC-III mRNA levels--APOE*3-Leiden mice were found to give robust hypolipidaemic responses to these test compounds. The responsiveness to hypolipidaemic therapy combined with a clear relationship between aortic lesion size and plasma cholesterol exposure, as demonstrated previously, makes this mouse an attractive model for the testing of anti-atherosclerotic properties of hypolipidaemic drugs.
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PMID:Apolipoprotein E*3-Leiden transgenic mice as a test model for hypolipidaemic drugs. 960 83

Previous reports have shown that administration of fibrates can reduce coronary events and also improve plasma lipid levels. Oxidative modification of low density lipoprotein has been implicated in the pathogenesis of atherosclerosis, and the resistance of low density lipoprotein (LDL) to in vitro oxidation has been found to be correlated with the extent of atherosclerosis. We performed a double-blind, placebo-controlled intervention trial to establish whether gemfibrozil could improve resistance of LDL to oxidation in patients with hyperlipidemia. Patients were randomly assigned to treatment with gemfibrozil (450 mg, twice a day, n = 10) or placebo (n = 9) for 8 weeks. Blood samples were obtained after an overnight (12 h) fast. Gemfibrozil administration significantly reduced total plasma cholesterol and triglyceride levels and changed the LDL from small, dense particles (pattern B, < or = 25.5 nm) to larger, more buoyant particles (pattern A, > 25.5 nm). Gemfibrozil significantly increased the lag time of LDL oxidation in vitro by 18.2% from 45.5 +/- 8.0 min at week 0 to 53.4 +/- 11.4 min at week 8, but did not change LDL vitamin E and beta-carotene concentrations. Surprisingly, gemfibrozil significantly decreased LDL lipid peroxides by -33.1% and increased the LDL vitamin E/lipid peroxide ratio by 67.6% from 1.3 +/- 0.5 at week 0 to 2.1 +/- 0.9 at week 8. These results demonstrate that gemfibrozil treatment can render LDL less susceptible to oxidative modification while reducing plasma cholesterol and triglyceride and improving LDL subclass pattern. This antioxidative effect of gemfibrozil on LDL may be one of the factors which could delay the progression of atherosclerosis.
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PMID:Beneficial effect of gemfibrozil on the chemical composition and oxidative susceptibility of low density lipoprotein: a randomized, double-blind, placebo-controlled study. 969 6

According to the NCEP resins and nicotinic acid were selected as drugs of choice to treat hypercholesterolemia. Gemfibrozil and nicotinic acid were recommended for patients with HDL cholesterol below 35 mg/dl. Current concepts of efficacy and side effects lead to the following recommendations. a) type IIa severe hypercholesterolemia (LDL > 220 mg/dl): HGMC inhibitors or combined therapy with resins and nicotinic acid, fenofibrate, or bezafibrate. b) Moderate hypercholesterolemia (LDL < 220 mg/dl): bezafibrate and/or acipimox if HDL is < 35 mg/dl; fenofibrate, bezafibrate and/or acipimox if HDL > 35 mg/dl. As second line drugs, the HGMC inhibitors. c) Type IIb hyperlipidemia: first line, acipimox; second line, fibrates associated to acipimox. d) Type III hyperlipidemia: first line, fibrates; second line, an association of HGMC inhibitors and fibrates or acipimox. e) Type IV moderate hyperlipidemia (TG < 500 mg/dl): first line, acipimox, second line, fibrates alone or in association with acipimox. As general remarks, lovastatin has been effective and well tolerated in 98% of cases. Pravastatin seems to have very little side effects. Acipimox, a nicotinic acid derivative is especially effective in elevating HDL2b levels and decreasing LDL III. Given its adequate tolerance, acipimox has replaced nicotinic acid.
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PMID:[Pharmacologic treatment of dyslipidemias: Analysis of initiation recommendations and drug selection]. 972 1

The Cerivastatin Gemfibrozil Hyperlipidemia Treatment (RIGHT) study--a multicenter, randomized, double-blind, placebo-controlled study--compared the lipid-lowering effects of cerivastatin, once daily at doses of 0.1, 0.2, and 0.3 mg with those of twice-daily gemfibrozil 600 mg in 751 patients with primary mixed hyperlipidemia. Randomization to the first 16 weeks of treatment followed an initial 4-week washout period and subsequent 6-week diet-controlled, placebo run-in phase. Patients continued to receive study medication for a further 36 weeks, with those previously on placebo switched to 0.1 mg/day cerivastatin at the end of week 16. Additional cholestyramine therapy was permitted at week 36 in patients with uncontrolled low-density lipoprotein (LDL) cholesterol levels. Cerivastatin achieved significant dose-dependent reductions in LDL cholesterol of 15-24% after 16 weeks of treatment, compared with reductions of 7.5% with gemfibrozil. Over this period both cerivastatin (0.3 mg) and gemfibrozil (1,200 mg) significantly decreased levels of triglycerides (20.3% vs 50.3%, respectively) and very low-density lipoprotein (VLDL) cholesterol (30.8% vs 47.1%, respectively), as well as increasing high-density lipoprotein (HDL) cholesterol (11.3% vs 13.3%, respectively). The reductions in LDL cholesterol and other atherogenic lipids and lipoproteins at 16 weeks were sustained in the subsequent 36-week double-blind continuation phase, during which time <10% of patients received additional cholestyramine therapy. Both study drugs were well tolerated, with the incidence of adverse events similar to that of placebo treatment. Clinically significant increases in hepatic transaminases and creatine phosphokinase occurred at a similar low frequency of around 1%. This study demonstrated that cerivastatin is a safe, well-tolerated, and effective treatment for lowering elevated LDL cholesterol and triglycerides in patients with mixed hyperlipidemia.
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PMID:Cerivastatin in the treatment of mixed hyperlipidemia: the RIGHT study. The Cerivastatin Study Group. Cerivastatin Gemfibrozil Hyperlipidemia Treatment. 973 46

Although myopathy is considered an adverse effect of treatment with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors and fibrates in combined hyperlipidemia, the present study was performed to investigate whether combined hyperlipidemia itself is associated with skeletal muscle pathology and whether lipid-lowering intervention has beneficial effects. To investigate whether combined hyperlipidemia is associated with skeletal muscle pathology, 10 male patients and 15 normolipidemic controls underwent a 45-minute standardized bicycle ergometer test at a load of 2 W/kg lean body mass (parallel study). One- and 8-hour postexercise increments in the plasma level of the muscle proteins creatine kinase (CK), myoglobin (Mb), and fatty acid-binding protein (FABP) were assessed as parameters for (subclinical) skeletal muscle pathology. The 8-hour postexercise increments in CK and Mb and 1-hour postexercise increment in Mb were significantly higher in patients than in controls, thus indicating increased exercise-induced muscle membrane permeability in combined hyperlipidemia. To investigate the effects of lipid-lowering intervention on skeletal muscle in combined hyperlipidemia, 21 subjects with combined hyperlipidemia were randomized double-blindly to receive 6 weeks of treatment with fluvastatin 40 mg/d, gemfibrozil 600 mg twice daily, or combination therapy. All subjects underwent an ergometer test before and after treatment. Gemfibrozil treatment alone reduced the CK increments 8 hours postexercise by 47% and the FABP increments 1 and 8 hours postexercise by 83% and 101%, respectively (all P < .05). Combined treatment reduced Mb increments 1 hour postexercise by 54% and FABP increments 8 hours postexercise by 44% (all P < .05). A highly significant correlation existed between therapy-induced changes in plasma triglycerides and changes in postexercise increments of FABP and Mb. In conclusion, combined hyperlipidemia is associated with an increased exercise-induced release of muscle proteins, which is ameliorated by triglyceride-lowering intervention. As FABP is an indicator for ischemia-induced skeletal muscle pathology, a possible explanation is the impaired muscle blood flow during hypertriglyceridemia, which may be reversed by triglyceride-lowering intervention. The mechanism and clinical relevance of these findings remain to be investigated.
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PMID:Combined hyperlipidemia is associated with increased exercise-induced muscle protein release which is improved by triglyceride-lowering intervention. 1059 82


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