Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Simvastatin (MK-733), a new inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, was administered to 38 patients with heterozygous familial hypercholesterolaemia for 24 weeks. A dose of 40 mg per day produced a mean reduction in low density lipoprotein cholesterol of 43-45% and in triglycerides of 21-31%. Mean high density lipoprotein cholesterol increased significantly by 10-13%. There were no major differences in response whether the drug was taken in one or two doses. MK-733 was tolerated well. Adverse effects were infrequent and limited to slight increases of alanine aminotransferase, creatine phosphokinase and bilirubin. This drug appears to be a potent inhibitor of cholesterol synthesis and has produced the largest therapeutic response as monotherapy in patients with familial hypercholesterolaemia.
Atherosclerosis 1988 Feb
PMID:Simvastatin (MK-733): a potent cholesterol synthesis inhibitor in heterozygous familial hypercholesterolaemia. 327 66

Hypercholesterolemia with increased plasma concentrations of low density lipoproteins (LDL) is a major risk factor for the premature development of coronary atherosclerosis in humans and is best exemplified by patients with familial hypercholesterolemia. The recent development of several specific competitive inhibitors of the rate-limiting enzyme in cholesterol biosynthesis (3-hydroxy-3-methylglutaryl-coenzyme A reductase, HMG CoA reductase) has opened up an important new avenue of therapy for patients with hypercholesterolemia who are not responsive to dietary treatment alone. Three drugs, lovastatin (mevinolin), simvastatin (synvinolin) and pravastatin (CS 514), are currently undergoing clinical trials in North America and Europe; the former has recently been approved for general use. Experience with lovastatin and simvastatin in the treatment of patients with primary and secondary causes of hypercholesterolemia is reviewed. The relative potency of simvastatin appears to be greater than that of lovastatin and pravastatin but, with each drug, decreases in the plasma concentrations of LDL cholesterol of 30% to 50% can be achieved. The hypocholesterolemic effects of HMG CoA reductase inhibitors can be potentiated by combination therapy with other approved lipid-lowering medications including the bile acid sequestrants and nicotinic acid. If long-term safety can be satisfactorily established, specific inhibitors of HMG CoA reductase represent a major advance in the therapy of hypercholesterolemia and afford the potential to reduce substantially the high incidence of premature atherosclerosis that occurs in patients with persistent hypercholesterolemia.
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PMID:Hypolipidemic effects of HMG-CoA reductase inhibitors in patients with hypercholesterolemia. 331 47

A brief description has been given of the major processes involved in the genesis of atherosclerosis, and of the morphological features of fatty streaks, gelatinous elevations and fibrolipid plaques. The effects of hyperlipidaemia, genetically and dietarily determined, are described, with special reference to the possible role of macrophages in the development of arterial lesions caused by such hyperlipidaemias. The administration of a competitive inhibitor of HMG-CoA reductase (lovastatin) to genetically hyperlipidaemic rabbits markedly reduced the extent of intimal surface involvement by lipid-rich lesions.
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PMID:The pathology of atherosclerosis with particular reference to the effects of hyperlipidaemia. 331 74

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

Prolonged exposure of rats to cigarette smoke resulted in significant alterations in the metabolism of lipids. There was a significant increase in the concentration of cholesterol, triglycerides and phospholipids in most of the tissues, particularly the heart, aorta and lungs. Cholesterol, triglycerides and phospholipids decreased in the serum HDL and increased in LDL + VLDL. There was increased cholesterogenesis in the heart, lungs and liver, as evidenced by increased activity of HMG-CoA reductase and increased incorporation of labelled acetate into cholesterol. Incorporation of label into the triglycerides also increased in these tissues. Activity of lipoprotein lipase in the extrahepatic tissues was decreased. Activity of glucose-6-phosphate dehydrogenase and malic enzyme increased in the heart and lungs. There was decreased concentration of bile acids in the liver.
Atherosclerosis 1988 Apr
PMID:Effect of exposure of rats to cigarette smoke on the metabolism of lipids. 336 90

The effects of plant constituents on lipid metabolism were examined in swine that had been fed for 4 weeks a standard diet containing, in addition, (per kg diet) 3.15 g of the methanol serial solvent fraction garlic bulbs or 3.5 g of the petroleum ether solubles high-protein barley flour or 5 mg of the plant growth regulator, AMO 1618. All treatments suppressed 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol 7 alpha-hydroxylase activities. Modest increases in serum triglycerides were associated with significantly increased hepatic lipogenic activities in response to all treatments except that of the barley extract. The methanol solubles of a second lot of garlic were fractionated by HPLC and tested in an avian hepatocyte system. One component, an isoprenoid metabolite, MW 358, suppressed HMG-CoA reductase.
Atherosclerosis 1987 Apr
PMID:Influence of minor plant constituents on porcine hepatic lipid metabolism. Impact on serum lipids. 360 7

1. The rat and rabbit are amongst the animal models most widely used in the study of human atherosclerosis, a disease state correlating with disturbances in cholesterol metabolism. 2. In order to relate the key regulatory enzymes of cholesterol synthesis, esterification and catabolism in the rat and rabbit to their differing degree of susceptibility to atherosclerosis, enzyme levels and their properties were determined in liver and intestine of both species. 3. Hepatic HMG CoA reductase and cholesterol 7 alpha-hydroxylase levels were significantly higher in the rat than in the rabbit, while intestinal HMG CoA reductase activity in the two species was comparable. Conversely, the capacity to esterify cholesterol as measured by ACAT activities was considerably greater in both sites in the rabbit compared to the rat. 4. The data suggest that differences in the key regulatory enzymes of cholesterol metabolism in both liver and intestine may reflect different methods of cholesterol utilization in the two species.
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PMID:A comparative study of the rate-limiting enzymes of cholesterol synthesis, esterification and catabolism in the rat and rabbit. 366 23

Ro 16-0521 is a newly synthesized benzodiazepine derivative which is devoid of reactivity with the brain benzodiazepine receptor. The effects of this drug on plasma lipids and lipoproteins and hepatic cholesterol metabolism have been examined in the cholesterol-fed rat. Drug therapy was associated with dose-related falls in plasma cholesterol concentration, liver cholesterol content, and the activity of the liver enzyme Acyl-CoA cholesterol acyltransferase. Drug therapy abolished the lipid and lipoprotein changes induced by cholesterol feeding, including those associated with a diet supplemented with olive oil to facilitate cholesterol loading. Drug therapy was also associated with an increased activity of the enzyme HMG-CoA reductase and reduced hepatic microsomal cholesterol content. It is suggested that the cholesterol-fed rat will be a suitable model for further mechanistic studies.
Atherosclerosis 1986 Jun
PMID:Effects of Ro 16-0521 on cholesterol metabolism in the rat. 373 45

Aortic smooth muscle cells from atherosclerosis-susceptible White Carneau (WC) pigeons lack a functional low density lipoprotein (LDL) receptor pathway. The purpose of the present study was to determine if atherosclerosis-resistant Show Racer pigeons (SR) shared this lack of an LDL receptor pathway and if LDL from normal and hypercholesterolemic pigeons were metabolized similarly. The amount of LDL bound, internalized, and degraded by skin fibroblasts, embryo fibroblasts, and aortic smooth muscle cells from WC and SR pigeons were similar and averaged from 2% to 25% of that seen with monkey smooth muscle cells incubated with the same LDL. LDL uptake by pigeon cells was due largely to nonspecific processes, while specific uptake predominated in monkey cells. A similar lack of specific uptake was obtained with LDL from normal and hypercholesterolemic pigeons. Sterol synthesis and HMG-CoA reductase activity were 10- to 35-fold higher in pigeon cells than in monkey cells incubated in serum-containing medium. LDL had little effect on cholesterol esterification and cholesteryl ester accumulation in pigeon cells. These results indicate that despite major changes in the size and composition of LDL from hypercholesterolemic pigeons, this LDL, like normal pigeon and monkey LDL, was not metabolized by specific uptake processes by pigeon cells. Cells from both WC and SR pigeons lack a functional LDL receptor pathway.
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PMID:Metabolism of low density lipoproteins by pigeon skin fibroblasts and aortic smooth muscle cells. Comparison of cells from atherosclerosis-susceptible and atherosclerosis-resistant pigeons. 395 71

The current results show that one can exploit the normal regulation of receptor synthesis to stimulate the single normal gene in FH heterozygotes to produce an increased number of LDL receptors. This stimulation can be achieved by drugs that inhibit HMG CoA reductase in the liver and by maneuvers that cause bile acid depletion. These two therapeutic approaches are most effective when they are combined. It seems reasonable to speculate that such a profound lowering of plasma cholesterol levels will minimize the development of atherosclerosis in FH heterozygotes. In a broader sense, the success of this regulatory manipulation raises the possibility that other genetic diseases may be treated through manipulation of regulatory signals that control the rates of synthesis of gene products.
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PMID:Mevinolin stimulates receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. 638 97


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