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)

After an extensive searching for a microbial product that inhibits cholesterol synthesis, compactin and a series of related metabolites like monacolin K (mevinolin) have been isolated from molds as active agents. These compounds, which were structurally related to hydroxymethylglutaryl coenzyme A, were potent competitive inhibitors of hydroxymethylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. The inhibition was reversible and the inhibitor constant Ki for compactin was around 10(-9) M. Compactin inhibited cholesterol synthesis in mammalian cells at 10(-9) M. Sterol synthesis in vivo was also reduced when compactin was given orally to rats at a dose of 50 mg/kg. Hydroxymethylglutaryl coenzyme A reductase activity of both cultured cells and rat liver was elevated when sterol synthesis was strongly inhibited by compactin. Both the growth inhibition and reductase induction could be overcome by the presence of mevalonate. A compactin-resistant cell line of mouse FM3A cells, called CR200, was developed by stepwise selection. CR200-cells had an abnormally high level of reductase activity and amplified reductase gene. Compactin was not able to lower plasma cholesterol levels in mice, rats, and hamsters. However, it was highly effective in rabbits, dogs, and monkeys; plasma cholesterol of dogs was reduced by 30%-40% at a dose of 20-50 mg/kg. The low-density lipoprotein cholesterol, which is responsible for atherosclerosis, was preferentially lowered. Compactin was also highly effective in hypercholesterolemic patients at a small dose. The results of the current studies have proved that compactin and related compounds are far more effective in lowering plasma cholesterol than any other drugs available.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Chemistry, biochemistry, and pharmacology of HMG-CoA reductase inhibitors. 329 93

A new class of drugs, which inhibit de novo cholesterol biosynthesis, significantly reduces the blood cholesterol concentrations in hypercholesterolemic patients. Four separate inhibitors have lowered plasma total cholesterol and low-density lipoprotein (LDL) levels in humans by 20% to 40%: mevastatin (Compactin), lovastatin (mevinolin), pravastatin (CS-514, Eptastatin, and SQ 31000), and simvastatin (Synvinolin, MK-733). In addition to lowering total and LDL cholesterol concentrations, the plasma concentration of the potentially atherogenic B apolipoprotein is also reduced by 20% to 40%. The reduction in the levels of circulating atherogenic lipoprotein particles occurs as a result of decreased synthesis and enhanced removal of LDLs by the LDL receptor pathway in hepatocytes. Moreover, the levels of high-density lipoprotein cholesterol, which are inversely related to atherosclerosis, increase in concentration with treatment by these drugs. If the short-term safety of these drugs extends to ongoing long-term studies and if cardiovascular morbidity and mortality are affected by their use, this class of hypolipidemic agent will markedly facilitate the effective treatment of hypercholesterolemia.
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PMID:3-Hydroxy-3-methylglutaryl--coenzyme A reductase inhibitors in the treatment of hypercholesterolemia. 331 27

The reduction of elevated low density lipoprotein (LDL) cholesterol concentrations in patients with Type II hyperlipoproteinemia leads to improved cardiovascular morbidity and mortality. Two agents which may be of value in treating hypercholesterolemia are mevinolin and neomycin. Since these drugs lower cholesterol levels through complementary mechanisms, we evaluated the effects of mevinolin and combined mevinolin-neomycin treatment on plasma lipoprotein concentrations in 21 type II hyperlipoproteinemic patients. Mevinolin reduced total and LDL cholesterol concentrations by 24% and 31% respectively (P less than 0.001) and 81% of the patients reduced their LDL cholesterol levels to less than 200 mg/dl. Although the addition of neomycin to mevinolin treatment further lowered total (5%) and LDL (4%) cholesterol concentrations, it also reduced HDL cholesterol levels (19%) (P less than 0.05). Therefore mevinolin normalizes the plasma lipid concentrations in patients with type II hyperlipoproteinemia and combined mevinolin and neomycin treatment offers no advantage over mevinolin-only therapy. In addition, these findings emphasize the importance of determining the HDL cholesterol level to fully evaluate the effects of hypolipidemic therapy.
Atherosclerosis 1986 Jun
PMID:The effects of mevinolin and neomycin alone and in combination on plasma lipid and lipoprotein concentrations in type II hyperlipoproteinemia. 352 86

Mevinolin inhibited the incorporation of [14C]acetate into cholesterol by human monocyte-derived macrophages (HMD macrophages) when both mevinolin and [14C]acetate were added simultaneously to the culture medium. Longer incubation with mevinolin, 24 h, led to a marked increase in the degradation of [125I]low density lipoprotein (LDL) via the high affinity receptor for LDL by HMD macrophages. Furthermore, this increased LDL receptor activity in cells incubated for 24 h with mevinolin and lipoprotein-depleted serum (LPDS) led to a nearly 3-fold increase in the formation of cholesteryl esters when these cells were then incubated with LDL for 24 h. Continuous exposure to mevinolin did not result in a constant increase in LDL receptor activity. Cells exposed to mevinolin for 24 h on day 3 had increased LDL receptor activity, but continuous exposure to mevinolin with 5% human serum (HS) from day 3-9 resulted in degradation of [125I]LDL at the same rate as observed in cells incubated with 5% HS alone. Cholesterol synthesis from [14C]acetate was decreased in cells incubated for 24 h in 5% HS + mevinolin compared with 5% HS alone, and in 10% LPDS + mevinolin compared with 10% LPDS alone; however, cells incubated with LPDS + mevinolin synthesized cholesterol at higher rates than did cells cultured in 5% HS alone. Continuous culture with 5% HS + mevinolin for 5 days resulted in cholesterol synthesis at control levels. These data show that following inhibition of cholesterol synthesis by mevinolin, HMD macrophages maintain cholesterol homeostasis by increasing LDL receptor activity to obtain cholesterol from LDL.
Atherosclerosis 1984 Jul
PMID:Inhibition of cholesterol synthesis by mevinolin stimulates low density lipoprotein receptor activity in human monocyte-derived macrophages. 608 38

Mevinolin (MK-803) is a potent inhibitor of HMG-CoA reductase. After a placebo run-in period, mevinolin 5,15 or 50 mg, or placebo was given twice daily for 7-11 days under double -blind conditions ot 4 groups of 6 normocholesterolemic male volunteers. After 7 days, mean serum cholesterol fell 14%, 25% and 24% on 5, 15 and 50 mg, respectively, which was significantly greater than the fall on placebo (4%) in the case of the two higher doses (P less than 0.01). Serum triglycerides did not change significantly. Mevinolin was generally well-tolerated and there were no serious adverse effects.
Atherosclerosis 1982 Jan
PMID:Rapid and substantial lowering of human serum cholesterol by mevinolin (MK-803), an inhibitor of hydroxymethylglutaryl-coenzyme A reductase. 691 20

Mevinolin, a fungal metabolite isolated from cultures of Aspergillus terreus, is a potent competitive inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase, the rate-controlling enzyme in cholesterol biosynthesis. In the current studies we demonstrate that mevinolin significantly lowers serum cholesterol in rabbits fed a cholesterol free, low-fat semi-synthetic diet. Rabbits maintained on this diet developed endogenous hypercholesterolemia with average cholesterol concentrations of 310 mg/dl over a 66-day period. Treatment with mevinolin for 39 days at a dose of 2 mg/kg per day lowered serum cholesterol levels by an average of 37% (P less than 0.05), while a dose of 6 mg/kg per day resulted in a 48% (P less than 0.05) decrease when compared with the control group. When the administration of mevinolin was discontinued, serum cholesterol levels of the 6 mg/kg per day group increased significantly to a maximum post-treatment value of 319 mg/dl (P less than 0.0001). The results of this study demonstrate that rabbits with endogenous hypercholesterolemia are a useful animal model for the study of cholesterol biosynthesis inhibitors like mevinolin.
Atherosclerosis 1982 Jul
PMID:The effects of mevinolin on serum cholesterol levels of rabbits with endogenous hypercholesterolemia. 692 95

Compactin, [7-(1,2,6,7,8,8a-hexahydro-2-methyl-8-(2-methylbutyrylox)naphthyl)-3-hydroxyheptan-5-olide], a potent competitive inhibitor of the rate-determining step in cholesterol biosynthesis, was used to study the influence of changes in cholesterogenesis on serum cholesterol levels. Up to 3 h after a single oral dose (20 or 50 mg/kg) or after the last of a series of daily oral doses (50 mg/kg for 7 or 28 days) to young, male normolipidaemic rats, compactin consistently inhibited cholesterogenesis measured using 3H20 in liver, ileum and other extrahepatic tissues without affecting fatty acid synthesis. Compactin did not reduce serum or tissue cholesterol nor affect the serum concentration of other lipids nor the ratio between lipoprotein classes. A diurnal variation in the effect of compactin on cholesterogenesis was observed. For example, by 12--20 h after dosing, cholesterogenesis at all sites was increased above the comparable control value, indicating the induction of enzyme synthesis and overall there was little effect on the mass of cholesterol synthesized per day. Similar results were obtained using male chicks. Inhibition of cholesterogenesis by compactin was also observed in cholestyramine-treated rats, in which cholesterol turnover was markedly increased, and even in cholesterol-fed rats, in which cholesterogenesis already was repressed. In neither case, however, was inhibition of cholesterogenesis accompanied by a hypocholesterolaemic effect. It is concluded that a more persistent suppression of cholesterogenesis, than that observed with compactin in the rat, may be required in order to affect serum cholesterol concentrations.
Atherosclerosis 1980 Apr
PMID:The effect of compactin, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme-A reductase activity, on cholesterogenesis and serum cholesterol levels in rats and chicks. 718 61

The Kuopio Atherosclerosis Prevention Study is the first population-based, double-blind trial in the primary prevention of carotid and femoral atherosclerosis. A total of 447 subjects with serum low density lipoprotein (LDL) cholesterol levels > or = 155 mg/dl (> or = 4.0 mmol/liter) and total cholesterol levels < 290 mg/dl (< 7.5 mmol/liter) were randomly assigned to receive either pravastatin 40 mg/day or placebo for 3 years. Atherosclerotic progression in 424 men was assessed with B-mode ultrasonography. Pravastatin reduced the rate of progression by 45% (95% confidence interval [CI]: 16-69%, p = 0.005) in carotid arteries and by 66% (95% CI: 30-90%, p = 0.002) in the common carotid arteries. The treatment effect in the carotid arteries was greater in subjects with thick arterial walls at baseline, in smokers, and in subjects with low plasma alpha-tocopherol. Subjects who received pravastatin had a higher antioxidative capacity of LDL, a longer oxidation lag of very low density lipoprotein (VLDL) plus LDL, and a reduced oxidation rate of VLDL plus LDL in vitro. These data establish the antiatherogenic effect of lowering LDL cholesterol levels by pravastatin therapy in hypercholesterolemic men in a primary prevention setting and suggest that part of the antiatherogenic effect of pravastatin may be due to an improvement in the resistance of atherogenic lipoproteins to oxidation.
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PMID:The Kuopio Atherosclerosis Prevention Study (KAPS): effect of pravastatin treatment on lipids, oxidation resistance of lipoproteins, and atherosclerotic progression. 757 84

The Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries trial (PLAC-II) was initiated in 1987 and was the first double-blind, randomized clinical trial with progression of early extracranial carotid atherosclerosis as an outcome variable. We randomized 151 coronary patients to placebo or pravastatin and treated them for 3 years. B-mode ultrasound quantification of carotid artery intimal-medial thickness (IMT) was obtained at baseline and sequentially during this period. The primary outcome was the change in the mean of the maximum IMT measurements over time. Effects on individual carotid artery segments (common, bifurcation, internal carotid artery) and on clinical events were also investigated. During follow-up, plasma concentrations of total cholesterol were lower in pravastatin-treated patients compared with those of placebo-treated patients (4.81 vs 6.08 mmol/liter [186 vs 235 mg/dl]) as were concentrations of low density lipoprotein (LDL) cholesterol (3.10 vs 4.29 mmol/liter [120 vs 167 mg/dl]). Plasma concentrations of high density lipoprotein2 (HDL2) cholesterol were higher in pravastatin-treated patients than in placebo-treated patients (0.16 vs 0.14 mmol/liter [6.1 vs 5.5 mg/dl]). Active treatment resulted in a nonsignificant 12% reduction in progression of the mean-maximum IMT (from 0.068 mm/yr placebo to 0.059 mm/yr pravastatin) and a statistically significant 35% reduction in IMT progression in the common carotid (p = 0.03). Active treatment was also associated with a 60% reduction of nonfatal myocardial infarction plus death caused by coronary artery disease (p = 0.09), a 61% reduction of any fatal event plus any nonfatal myocardial infarction (p = 0.04), and an 80% reduction of fatal plus any nonfatal myocardial infarction (p = 0.03).
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PMID:Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II). 757 88

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are more efficacious than older lipid-lowering agents and therefore may be more effective in reducing the incidence of coronary events. The objective of this prespecified analysis was to examine in coronary patients the effect of the lipid-lowering agent pravastatin on 3-year rates of coronary event incidence, all-cause mortality, and nonfatal myocardial infarction (MI), and to determine whether any observed benefit was also evident in patients > or = 65 years of age. The design of this analysis was to pool the data from 2 concurrent 3-year placebo-controlled clinical trials of pravastatin monotherapy in coronary patients (Pravastatin Limitation of Atherosclerosis in the Coronary Arteries [PLAC I] and the Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries [PLAC II]). This pooled database included 559 coronary patients with moderately elevated levels of low density lipoprotein cholesterol (between the 60th and 90th percentiles for age and gender in the United States). Over the 3 years of follow-up, use of pravastatin was associated with a 55% reduction in coronary incidence (p = 0.014). Pravastatin was also associated with a 67% reduction in nonfatal MI (p = 0.006). Eleven placebo patients died over the 3 years of follow-up compared with 7 in the pravastatin groups (a 40% reduction). Among older patients (age > or = 65 years), pravastatin therapy was associated with a 79% reduction in coronary event incidence (95% confidence interval [CI] 33-100%) and with a 86% reduction in nonfatal myocardial infarction (CI, 35-100%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reduction in coronary events during treatment with pravastatin. PLAC I and PLAC II Investigators. Pravastatin Limitation of Atherosclerosis in the Coronary Arteries. 757 89


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