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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent pharmacological studies confirmed the role of hypercholesterolemia in the pathogenesis of coronary atherosclerosis. A 10% reduction in cholesterol levels can reduce the risk of coronary heart disease by 15%. However many hypercholesterolemic patients often suffer from arterial hypertension and drugs such as thiazide diuretics cause an imbalance in lipid metabolism. The efficacy and the tolerability of simvastatin (a inhibitor of HGM-CoA reductase) with that of gemfibrozil (a fibric acid derivative, which can reduce the VLDL level) were compared in a placebo-controlled study in 2 groups of patients with primary hypercholesterolemia and mild-to-moderate essential hypertension treated with hydrochlorothiazide. After 10 weeks standard hypolipidemic diet and hydrochlorothiazide (25 mg od) therapy, 30 patients whose cholesterol levels were still greater than or equal to 250 mg/100 ml and whose diastolic blood pressure was less than 95 mmHg were randomized to one of the following treatments: simvastatin, 20 mg od, gemfibrozil, 600 mg bid or placebo, while continuing dietetic and diuretic treatment. After 24 weeks treatment, simvastatin induced a 37% reduction in cholesterol plasma levels, a 9% increase of HDL and a 16% reduction of LDL. APO-A1 showed a 4% increase, while APO-B showed a 3% reduction. Gemfibrozil induced a 20% reduction in plasma triglycerides and a 13% decrease in plasma cholesterol, with a significant 19% increase in HDL and a 11% reduction in LDL. No significant variations in any of the lipid parameters monitored were observed in the placebo group. Treatment with simvastatin or gemfibrozil in hypertensive patients in hydrochlorothiazide monotherapy can reduce total cholesterol and LDL-cholesterol plasma levels, while significantly increasing HDL plasma levels compared to placebo. Simvastatin, however, resulted more efficient than gemfibrozil on total cholesterol or cholesterol fractions.
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PMID:[Simvastatin versus gemfibrozil in the treatment of primary hypercholesterolemia in hypertensive patients treated with hydrochlorothiazide]. 224 35

CL 277,082 is an inhibitor of acyl-CoA: cholesterol acyltransferase (ACAT). The effects of this drug on lipoprotein metabolism have been examined in cholesterol-fed rats. An optimal dose of drug incorporated into the diet (0.1% w/w) for 7 days reduced plasma cholesterol by 48% and plasma triglycerides by 72%. The decrease in plasma cholesterol was due to a reduction in triglyceride-rich lipoproteins and in HDL cholesterol. There was a significant 72% reduction in intestinal ACAT activity, accompanied by a 41% reduction in hepatic cholesterol content. There was a smaller 21% reduction in hepatic ACAT activity. Hepatic HMG-CoA reductase activity increased 3-fold. HDL binding activity by liver membranes was not altered significantly. The decrease in plasma cholesterol with this ACAT inhibitor is most likely due to decreased absorption of dietary cholesterol resulting from inhibition of intestinal ACAT.
Atherosclerosis 1990 May
PMID:On the mechanism by which an ACAT inhibitor (CL 277,082) influences plasma lipoproteins in the rat. 236 Sep 13

Patients with heterozygous familial hypercholesterolemia (FH) constitute a unique population at high risk for the premature development of coronary artery disease (CAD) and in whom long-term hypocholesterolemic therapy to reduce elevated levels of low density lipoprotein (LDL) cholesterol is most clearly indicated. Optimal therapy invariably requires diet regulation plus hypolipidemic drug therapy. When used as single agents, the bile-acid sequestrants, cholestyramine and colestipol, lower LDL cholesterol concentrations by 20% to 35% in compliant patients, whereas decreases of 20% to 30% can be achieved with nicotinic acid in doses of 3 to 6 g/day. Bezafibrate, fenofibrate, and ciprofibrate have also been shown to lower LDL cholesterol levels by 20% to 30%, and these drugs are more effective than gemfibrozil and clofibrate. Probucol, neomycin, and D-thyroxine reduce LDL cholesterol concentrations by 10% to 15% in single-drug use. Clinical trials with a new class of drugs that inhibit the rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, and that includes lovastatin, simvastatin, and pravastatin indicate that these drugs lower LDL cholesterol concentrations by 30% to 50% in patients with heterozygous FH. Combined drug therapy with a bile-acid sequestrant and nicotinic acid lowers LDL cholesterol by 40% to 55%, whereas fenofibrate, bezafibrate, or probucol plus a bile-acid sequestrant results in reductions varying from 25% to 50%. The combinations of an HMG CoA reductase inhibitor with either a bile-acid sequestrant or nicotinic acid appears to be the most promising, and these regimens reduce LDL cholesterol levels by 45% to 60%. With appropriate use, the currently available hypocholesterolemic drugs have the potential to markedly change the natural history of premature atherosclerosis that occurs in untreated patients with FH.
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PMID:Treatment of heterozygous familial hypercholesterolemia with lipid-lowering drugs. 249 89

The aim of this study was to characterize the plasma lipoprotein pattern and some aspects of cholesterol metabolism in a line of hyperlipemic male rats. Plasma cholesterol and triglycerides were increased about 3-fold as compared to control animals (238 vs. 75 and 185 vs. 59 mg/dl respectively). The plasma lipoprotein distribution and the chemical composition of the isolated lipoproteins was unaffected. Plasma triglyceride production rate was increased (40%, P less than 0.01) and post-heparin lipoprotein lipase activity in plasma decreased (-28%, P less than 0.01) in the hyperlipemic rat. The activity of 3 enzymes involved in cholesterol metabolism (HMG-CoA reductase, cholesterol 7 alpha-hydroxylase, and acyl-CoA cholesterol-acyltransferase) did not differ from control values. 3H2O incorporation into digitonin-precipitable sterols, however, was significantly higher than in controls. This finding was due, in part, to an increased liver weight in the hyperlipemic animals. Furthermore kinetic data using 125I-LDL showed that the fractional catabolic rate of lipoprotein was within the normal range, while the synthetic rate of LDL protein was increased (0.67 vs. 0.3 mg/kg/h, P less than 0.01) in the hyperlipemic rat. These observations suggest that multiple metabolic defects underline the hyperlipemia observed in this animal model.
Atherosclerosis 1989 Apr
PMID:Plasma lipoproteins and cholesterol metabolism in spontaneously hyperlipemic rats. 273 Jul 13

Elevated serum cholesterol is an established risk factor for the development of atherosclerosis but the effect of high dietary cholesterol in early life on subsequent arterial response to atherogenic diet in adult life is unknown. Weanling rabbits were exposed for 6 wk to a diet containing 0.25% cholesterol, allowed to recover for 9 wk (at least 3 wk after normalization of plasma cholesterol), and subsequently rechallenged with cholesterol to determine atherogenic response. Enhanced activity of acyl-CoA-cholesterol-acyl-transferase in aorta induced by cholesterol feeding persisted even after normalization of serum cholesterol. When rechallenged with cholesterol for 3 mo, these animals displayed significantly (p less than 0.05) increased development of aortic atherosclerosis and accumulation of cholesterol esters when compared with control animals. Exposure to cholesterol in early life appears to cause persistent changes in cholesterol ester synthetic enzyme activity in aorta after normalization of plasma cholesterol and these residual effects might increase aortic response to subsequent cholesterol challenge in adult life.
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PMID:Short-term exposure to high dietary cholesterol in early life: arterial changes and response after normalization of plasma cholesterol. 275 Jun 98

The effects of 5 micrograms/ml of 25-hydroxycholesterol; cholestane-3 beta,5 alpha,6 beta-triol; and cholesterol on acyl CoA cholesterol acyltransferase, acid cholesteryl ester hydrolase and neutral cholesteryl ester hydrolase was studied in cultured rabbit aortic smooth muscle cells. After 1 hour incubation, 25-hydroxycholesterol resulted in a fourfold stimulation of acyl CoA cholesterol acyltransferase activity. No stimulation by 25-hydroxycholesterol was noted before 15 minutes or after 5 hours of incubation. Neither cholestane-3 beta,5 alpha,6 beta-triol nor cholesterol influenced acyl CoA cholesterol acyltransferase activity at any time interval. No significant effects of any of the sterols were noted on acid cholesteryl ester hydrolase or neutral cholesteryl ester hydrolase activity. The imbalance between acyl CoA cholesterol acyl transferase and hydrolase activities induced by 25-hydroxycholesterol could result in cholesteryl ester accumulation by arterial smooth muscle cells, which may be associated with atherosclerosis.
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PMID:Effects of cholesterol oxidation derivatives on cholesterol esterifying and cholesteryl ester hydrolytic enzyme activity of cultured rabbit aortic smooth muscle cells. 276 54

Platelet-activating factor (PAF-acether), a phospholipid mediator involved in inflammatory reactions, has been reported to induce endovascular surface lesions. We investigated the possible involvement of PAF-acether in the mechanism of arterial cholesterol deposition. Rabbits fed a normal or hypercholesterolic diet were treated orally for 1 month with BN 52021 (20 mg/kg per day), a specific PAF-acether antagonist, and killed at the end of treatment. Cholesterol feeding resulted in a marked (50-fold) increase in plasma cholesterol. However, the drug had no significant effect on the diet-induced hypercholesterolemia. Free and esterified cholesterol were markedly increased (635%) in the aorta of animals receiving the atherogenic diet. This accumulation was reduced by 36% upon simultaneous administration of BN 52021 (P less than 0.02, n = 15). This decrease essentially affected the esterified cholesterol content. Conversely, BN 52021 showed no effect on the cellular cholesterol esterification, since liver acyl-CoA: cholesterol acyltransferase activity remained unchanged. This study indicates that BN 52021 is effective in reducing cholesterol accumulation in rabbit atherosclerotic aorta, without changing the plasma cholesterol levels.
Atherosclerosis 1989 Aug
PMID:Protective effect of BN 52021, a specific antagonist of platelet-activating factor (PAF-acether) against diet-induced cholesteryl ester deposition in rabbit aorta. 278 99

Following the recent demonstration that both cholestyramine and nicotinic acid decrease mortality from coronary heart disease, there is a new enthusiasm for hypolipidaemic therapy. The agents in current use are, however, insufficiently active or are accompanied by unacceptable side effects. An understanding of the mode of action is necessary, both to optimize treatment guidelines (e.g. regarding combination therapy or use in specific subsets of patients) and to develop new agents with preferred actions on rate-limiting steps. A reduction in LDL cholesterol concentration remains the principal desired action, although an elevation in HDL may also be beneficial. The main categories of commercially available agent comprise the anion exchange resins (inhibitors of bile acid absorption); cholesterol absorption inhibitors; fibrates (probably acting by enhancing lipoprotein lipase); and probucol (affecting LDL clearance). The most interesting of the new agents in clinical trials are the beta-hydroxy-beta-methylglutaryl-CoA reductase inhibitors, but other types of agent are at an earlier stage of evaluation, e.g. acyl-CoA: cholesterol acyltransferase inhibitors and peptide cofactors. It is not yet certain whether all the approaches to cholesterol lowering have equal validity, although an effect on biological endpoints is obtained for a variety of agents. Future evaluation will be aided by the implementation of noninvasive methods to quantify atherosclerosis and by the use of simple, 'dry-chemistry', cholesterol assays to screen populations.
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PMID:Mode of action of lipid-lowering drugs. 289 41

2-(2,4-Dimethylphenyl)indan-1,3-dione was shown to be a potent hypolipidemic agent in rodents, lowering significantly both serum cholesterol and triglyceride levels at 20 mg/kg/day. The agent in vivo inhibited the enzymatic activities of ATP-dependent citrate lyase, acetyl-CoA synthetase, cholesterol-7-alpha-hydroxylase, acyl-CoA cholesterol acyl transferase, sn-glycerol-3-phosphate acyl transferase and phosphatidylate phosphohydrolase. Tissue lipid levels of liver and small intestine also were reduced by the agent. The rat serum lipoprotein lipid content was modulated by the drug, which should be favorable for the removable of cholesterol from peripheral tissue for conduction to the liver for clearance from the body. Low density lipoprotein (LDL) cholesterol levels were reduced after treatment, which suggests that the agent potentially reduces deposition of cholesterol in plaques. If chemotherapy for atherosclerosis is to be successful, then the high density lipoprotein (HDL) cholesterol level needs to be elevated more than 16% to 25%, the level produced by current hypolipidemic agents. 2-(2,4-Dimethylphenyl)indan-1,3-dione offers a 75% increase in HDL cholesterol levels and a 30% reduction of LDL cholesterol levels with a suppression of de novo synthesis of lipids and a reduction of tissue cholesterol deposition.
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PMID:Effects of 2-(2,4-dimethylphenyl)indan-1,3-dione on serum lipoprotein and lipid metabolism of rodents. 318 7

Hypocholesterolaemic agents are powerful modifiers of the plasma lipoprotein pattern. In addition to lowering plasma low density lipoprotein (LDL) cholesterol, such drugs may elevate, decrease or have no effect on high density lipoprotein (HDL) cholesterol. Bile acid binding resins and 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors cause a reduction in hepatic cholesterol content resulting in stimulation of LDL receptor activity. This decreases the plasma LDL level, while HDL cholesterol levels remain unchanged or increase. Probucol, on the other hand, lowers both LDL and HDL cholesterol. It does not act by stimulating LDL receptor activity and is effective in some patients with homozygous familial hypercholesterolaemia who virtually lack LDL receptors. Despite their different lipoprotein-modifying effects, both HMG-CoA reductase inhibitors and probucol are regarded useful in the prevention and retardation of atherosclerosis.
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PMID:Treatment of familial and non-familial hypercholesterolaemia: a review of HMG-CoA reductase inhibitors and probucol. 331 84


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