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)

High-risk patients with dyslipidemias resistant to diet and single-agent pharmacotherapy may require combination therapy to achieve target levels of low density lipoprotein, triglycerides, and high density lipoprotein. Combinations of fibrates and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are effective, but because of safety concerns related to myopathy and rhabdomyolysis, it is important to consider the possibility of pharmacokinetic interactions when such combinations are used. In this study, the area under the curve, maximum plasma concentration, and time to maximum concentration for fluvastatin and gemfibrozil are compared, when used alone and in combination, in patients with hyperlipidemia and either coronary or carotid atherosclerosis, or a family history of coronary artery disease. A total of 17 patients were studied in a random sequence, open-label, crossover study of fluvastatin at 20 mg twice daily, gemfibrozil at 600 mg twice daily, and the combination of the 2 drugs. No significant difference was observed in area under the curve, maximum plasma concentration, and time to maximum concentration when comparing the combination with each drug alone. These pharmacokinetic data add support to the clinical observations that the combination of fluvastatin and gemfibrozil is both effective and safe.
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PMID:Pharmacokinetics of the combination of fluvastatin and gemfibrozil. 760 6

Patients with non-insulin-dependent diabetes mellitus (NIDDM) have a greater risk of developing coronary heart disease than would be expected from a similar degree of hyperlipidemia in nondiabetic populations. Accelerated transfer of cholesteryl esters (CET) from high-density lipoprotein (HDL) to low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL), a process that is associated with atherosclerosis, may be a possible explanation for this. CET, plasma lipoprotein concentration, and mass in the fasting and postprandial state have been examined in 31 hyperlipidemic patients with NIDDM before and after 8 weeks of treatment with the hydroxymethylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitor pravastatin in a double-blind, placebo-controlled, parallel group study. Body mass index, glycemic control, and blood pressure remained unaltered during the study period. Compared with placebo, pravastatin decreased fasting serum cholesterol (P < 0.001) and LDL cholesterol (P < 0.002) levels. The high basal CET (34.4 +/- 13.1 nmol.ml-1.h-1) was decreased significantly by pravastatin treatment (27.5 +/- 13.7 nmol.ml-1.h-1, P = 0.013). There was a fall in the total cholesterol, free cholesterol, and phospholipid content of the Sf 0-12, 20-60, and 60-400 lipoproteins (all P = 0.001). Lecithin: cholesterol acyl transferase activity was not altered. The postprandial increase in VLDL cholesterol 5 h after a standardized mixed meal was attenuated after pravastatin treatment (P = 0.011). Inhibition of hepatic cholesterol synthesis with an HMG-CoA reductase inhibitor in hyperlipidemic patients with NIDDM decreased serum cholesterol content of triglyceride-rich lipoprotein, thereby decreasing the transfer of cholesteryl ester from HDL to LDL and VLDL.
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PMID:Effect of treatment with a hydroxymethylglutaryl coenzyme A reductase inhibitor on fasting and postprandial plasma lipoproteins and cholesteryl ester transfer activity in patients with NIDDM. 769 16

The effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on the metabolism of apolipoprotein (apo) B-containing lipoproteins appear to differ according to the predominant lipoprotein profiles present and the condition being treated. In familial hypercholesterolemia, with isolated low density lipoprotein (LDL) elevations, the LDL-apoB elimination rate is increased by up-regulated LDL-receptors. In familial combined hyperlipidemia where very low density lipoprotein (VLDL) and LDL both may be increased and enhanced production of LDL-apoB may be present, HMG-CoA reductase inhibitors seem to diminish increased LDL-apoB production. The drug-induced decreases in LDL-apoB production could be due to decreased production of precursor VLDL-apoB or due to decreased conversion of VLDL-apoB to LDL-apoB after enhanced removal of VLDL by up-regulated LDL-receptors. To distinguish between these possibilities, we assessed the effects of HMG-CoA reductase inhibitors in another condition in which there is both apoB overproduction and accumulation of VLDL and LDL in plasma, the nephrotic syndrome. We used endogenous labeling of apoB with [13C]leucine and a multicompartmental model to calculate the metabolic parameters of apoB-containing lipoproteins. Only subjects with focal segmental glomerular sclerosis (FSGS) were included, as FSGS is a chronic, very slowly progressive form of nephrotic syndrome. A double-blind, randomized, placebo-controlled, crossover design was used. Treatment periods of 6 weeks were separated by a 2-week washout period. Of the four men studied, three had high triglyceride levels and four had high cholesterol levels. Lovastatin (20 mg/day) significantly decreased cholesterol (27.6 +/- 6%), LDL-cholesterol (27.6 +/- 9%) and plasma apoB (17.9 +/- 2.9%) (P < 0.01 for all). During the placebo period, calculation of kinetic parameters revealed VLDL-, intermediate density lipoprotein (IDL)-, and LDL-apoB overproduction and decreased VLDL-apoB fractional catabolic rate. Lovastatin significantly decreased LDL-apoB production rate in all cases (34.1 +/- 14%, P = 0.03). The decreased LDL-apoB was mainly due to a channelling of LDL precursors away from conversion to LDL (conversion of VLDL to LDL decreased from 80.6 +/- 8.3% to 55.9 +/- 17.2%, P = 0.05). Thus, lovastatin decreased LDL-cholesterol in nephrotic subjects mainly by inhibiting LDL-apoB production from VLDL.
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PMID:Physiologic mechanisms of action of lovastatin in nephrotic syndrome. 770 43

Dietary measures, including calorie restriction and reduced fat intake, remain the mainstay of management in prevention of coronary heart disease (CHD). When this fails, drug therapy should be considered. Fibrates, a family of lipid lowering drugs, decrease plasma triglycerides and inhibit their synthesis. They are also reported to suppress cholesterol production in the liver. A disadvantage of fenofibrate is the poor solubility of the principal ingredient, with subsequent incomplete absorption after oral administration. Micronized fenofibrate, a new formulation chemically identical to the parent compound, has improved pharmacokinetic parameters which increase absorption, provide more stable plasma levels, and thus dosage can be decreased. The micronized formulation has been shown to be effective in reducing LDL cholesterol and triglycerides in patients with types IIa and IV hyperlipidemia, with increasing responsiveness to therapy in proportion to elevated baseline values of these parameters. This formulation has also been compared to simvastatin, an HMG-CoA reductase inhibitor. Results of a double-blind crossover study showed that both drugs reduced plasma cholesterol levels by similar amounts, and both produced similar increases in HDL cholesterol. The micronized formulation of fenofibrate thus provides improved efficacy in the prevention of CHD. In comparison to the standard formulation, micronised fenofibrate thus provides improved efficacy in the control of dyslipidemia and the prevention of CHD.
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PMID:The fibrates in clinical practice: focus on micronised fenofibrate. 785 86

Chronic renal failure is associated with hyperlipidemia and atherosclerosis. The mechanism responsible for the observed increase of serum cholesterol in chronic renal disease is not certain. The objective of the present study was to characterize the effect of induced renal failure on 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) and cholesterol 7 alpha-hydroxylase, the two rate determining enzymes of the cholesterol and bile acid biosynthetic pathways, respectively. Studies were carried out in rats with subtotal (75%) nephrectomy, which resulted in a marked elevation of blood urea nitrogen (371 +/- 44% of control, P < 0.001), and was accompanied by significant increases in the levels of serum cholesterol (133 +/- 7%, P < 0.005) and triglycerides (185 +/- 25, P < 0.01). In nephrectomized rats, an increase in the specific activity of HMG-CoA reductase (219 +/- 30% above control levels, P < 0.02) was observed. This increase occurred in the presence of elevated hepatic microsomal cholesterol concentrations (150 +/- 13% of controls, P < 0.01). Surprisingly, the increase in HMG-CoA reductase specific activity was not associated with parallel increases in HMG-CoA reductase steady-state mRNA levels and gene transcriptional activity. These uremic rats also exhibited a marked increase in the specific activity of cholesterol 7 alpha-hydroxylase (240 +/- 559% of controls, P < 0.05). There was no concomitant increase in cholesterol 7 alpha-hydroxylase steady-state mRNA levels or gene transcriptional activity. The factors responsible for the observed increases in HMG-CoA reductase and cholesterol 7 alpha-hydroxylase specific activity in renal failure remain to be determined.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Post-transcriptional regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase and cholesterol 7 alpha-hydroxylase in rats with subtotal nephrectomy. 796 47

Patients with non-insulin-dependent diabetes mellitus (NIDDM) are at high risk of cardiovascular disease for many reasons and especially due to the fact that dyslipidemias are more frequent in this group of patients. Fibrate derivatives are the drugs of choice when hypertriglyceridemia is the main lipid anomaly. When hypercholesterolemia is predominant, the use of resins and nicotinic acid has been advocated but these drugs are poorly tolerated on a long-term basis. We assessed the effect of simvastatin, a recent HMG-CoA reductase inhibitor in 12 NIDDM patients with hypercholesterolemia. After 4 weeks of placebo, which did not significantly modify the lipid values, patients were given simvastatin at increasing dosages (from 10 to a maximum of 40 mg daily) during 24 weeks. Compliance and clinical tolerance were excellent. There was no major biological side effect, but a significant deterioration of glucose control was noted at the end of the study. Simvastatin reduced total cholesterol by 28%, LDL-cholesterol by 36% and apo B by 31%. Concomitantly, there was an increase of HDL-cholesterol by 15%. This improvement of lipid profile persisted during the 24 weeks of treatment. Comparing the patients with pure hypercholesterolemia to those presenting combined hyperlipidemia, it was evident that the hypolipidemic effect was more marked in the diabetic subjects with combined hyperlipidemia.
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PMID:Efficacy of simvastatin for lowering cholesterol in non-insulin dependent diabetic patients with hypercholesterolemia. 806 75

Many experimental results support the hypothesis that increased plasma lipid concentrations may have a deleterious effect on the course of chronic renal diseases. Until now a clear causal relationship has not been proved. Because reliable results of prospective controlled trials are not available that would demonstrate a beneficial effect of lipid-lowering interventions on the course of chronic renal diseases, it is not possible at this time to provide a general recommendation for a lipid-lowering drug therapy. Nevertheless, I would support the prescription of HMG CoA reductase inhibitors for patients with extremely increased total cholesterol and LDL cholesterol concentrations despite the restricted data of already existing experimental and clinical studies. It should be stressed that every patient with glomerular disease and concomitant hyperlipidemia constrains us to weigh advantages and side-effects of a lipid-lowering regimen. We have to wait for the results of prospective and controlled multicenter studies to give a final recommendation for therapeutic consequences in patients with chronic renal disease and hyperlipidemia.
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PMID:[Is hyperlipidemia a factor in the progression of renal failure?]. 814 60

The effect of the sulfur-substituted fatty acid analogue 1,10 bis(carboxymethylthio)decane, also known as 3-thiadicarboxylic acid, on puromycin aminonucleoside-induced nephrotic hyperlipidemia was studied in rats. Treatment with 3-thiadicarboxylic acid (250 mg/kg) for 5 days reduced plasma levels of triglycerides from 5.8 to 2.7 mmol/L and cholesterol from 11.0 to 7.7 mmol/L. This was accounted for by decreases in very-low-density lipoprotein triglycerides, very-low-density lipoprotein cholesterol, and low-density lipoprotein cholesterol, without any major changes in the composition of plasma lipoproteins. The activities of two enzymes involved in fatty acid synthesis (ATP:citrate lyase and fatty acid synthetase) were inhibited by 3-thiadicarboxylic acid treatment, whereas acetyl-coenzyme A carboxylase activity was unchanged. In contrast, treatment with the sulfur-substituted fatty acid analogue induced the peroxisomal beta-oxidation of fatty acids ninefold and the mitochondrial beta-oxidation by 54% to 73%, depending on the substrate used. This was accompanied by a 26% reduction in hepatic triglyceride secretion rate. The hepatic phosphatidate phosphohydrolase activity was unchanged. 3-Thiadicarboxylic acid treatment suppressed the activity of the rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, by 58%, whereas hepatic LDL receptor expression was unaltered. The activities of lipoprotein lipase and hepatic lipase were unchanged by treatment. These results demonstrated that treatment with 3-thiadicarboxylic acid ameliorates hyperlipidemia in experimental nephrosis primarily by decreasing the overproduction of very-low-density lipoprotein present. The data also indicate that hepatic very-low-density lipoprotein synthesis and secretion is strongly influenced by the availability of the fatty acid substrate under the same hyperlipidemic conditions.
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PMID:Effect of 3-thiadicarboxylic acid on lipid metabolism in experimental nephrosis. 821 98

This study compared the effects of a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, fish oil, and placebo on plasma lipids and lipoproteins in patients with mixed hyperlipidemia. After an initial run-in phase, 32 patients were randomized for 6 weeks to either (1) pravastatin 40 mg/d, n = 10; (2) fish oil (himega 6 g/d, equivalent to 3 g omega-3 fatty acids/d), n = 10; or (3) placebo. After single drug therapy, in the pravastatin group mean total plasma cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein (apo) B fell significantly by 23% (P < .001), 30% (p < .001), and 26% (P < .01), respectively. LDL Stokes' diameter did not change. In the fish oil group mean plasma triglycerides (TG) fell 30% (P < .05), LDL Stokes' diameter increased from 25.0 to 25.9 nm (P < .05), and there was a nonsignificant increase in LDL-C. There were no changes in the placebo group. To assess the effect of the combination of pravastatin plus fish oil therapy, all patients, except one woman from the placebo group who developed nausea on fish oil, then took combined therapy of pravastatin 40 mg/d plus fish oil 6 g/d for an additional 12 weeks. In each case, there were no clinically significant episodes of muscle tenderness or elevation of creatine phosphokinase or alanine aminotransferase. After 12 weeks of combined therapy of pravastatin plus fish oil, there were significant reductions in the mean TC, TG, LDL-C, and apoB in the three groups compared with baseline levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of pravastatin and omega-3 fatty acids on plasma lipids and lipoproteins in patients with combined hyperlipidemia. 824 Oct 95

Lowering serum cholesterol levels in patients with hyperlipidemia has been shown to decrease deaths due to coronary heart disease. While diet is the mainstay of treatment for hyperlipidemia, drug therapy is necessary to achieve treatment goals in certain patients. The HMG CoA reductase inhibitors are the most effective cholesterol-lowering agents currently available. These agents are well tolerated and have few serious side effects. Their major disadvantage is their high cost.
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PMID:HMG CoA reductase inhibitors for treatment of hyperlipidemia. 850 48


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