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)

ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, significantly reduced both serum cholesterol and phospholipid levels in dogs, when used at a dosage higher than 10 mg/kg per day. Triglyceride levels were not consistently changed, but beta- and pre-beta-lipoproteins were preferentially reduced. Serum cholesterol levels were reduced by 44--45% at the higher dosage of 100--400 mg/kg per day (for 5 weeks) but ML-236B caused no significant changes in the cholesterol content of the liver and aorta and in the activities of serum GOT, GPT, CPK and lecithin : cholesterol acyltransferase. Fecal excretion of neutral sterols was unaffected but that of bile acids was markedly elevated by the drug. Under these conditions, hepatic cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis, showed no detectable changes.
Atherosclerosis 1979 Mar
PMID:Hypolipidemic effects in dogs of ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. 22 90

The attempts to find a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which catalyzes the rate limiting step of cholesterol biosynthesis were started from 1971. The first potent inhibitor, ML-236B (compactin), was found from the culture broth of Penicillium citrinum. Among many derivatives of ML-236B, pravastatin sodium (hereafter refer to pravastatin) was finally selected because of its potency and tissue selectivity. Since pravastatin has a hydroxyl group at 6 beta position in the skeleton of decaline of ML-236B, the microbial hydroxylation was adopted for the production of pravastatin. Streptomyces carbophilus was finally chosen as a potent converter with the formation of a lesser amount of by-products. For the sake of industrial production of pravastatin, many devices and improvements were performed for selecting high potent strains and for culturing conditions both with ML-236B and pravastatin. Pravastatin strongly inhibited the sterol synthesis in freshly isolated rat hepatocytes, but only weakly inhibited in the cells from nonhepatic tissues. This selective inhibition of pravastatin in sterol synthesis was further confirmed by ex vivo and in vivo experiments by using rats and mice. Pravastatin markedly reduced serum cholesterol levels in dogs, monkeys and rabbits, including Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia. Pravastatin showed the preventive effect on the development of coronary atherosclerosis and xanthoma in young WHHL rabbits in consequence of maintaining the serum cholesterol levels low. In the clinical trials, pravastatin significantly reduced serum cholesterol and low density lipoprotein cholesterol levels, whereas inversely increased high density lipoprotein cholesterol levels.
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PMID:[Research and development of pravastatin]. 176 49

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

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

ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase, was administered to 11 patients with primary hypercholesterolemia. After 4--8 weeks of drug treatment at doses of 50--150 mg/day, serum cholesterol levels were reduced by 11--37% (27% on average) in cases of heterozygous familial hypercholesterolemia and combined hyperlipidemia. A marked reduction in tuberous xanthomas was noticed in a homozygous case of familial hypercholesterolemia, but here the drug was less effective in reducing the serum cholesterol level and a higher dose was required for treatment. Softening of Achilles tendon xantomas was observed in a case of combined hyperlipidemia.
Atherosclerosis 1980 Mar
PMID:Therapeutic effects of ML-236B in primary hypercholesterolemia. 736 99