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

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

HMG-CoA reductase inhibitors are a new class of drugs, which inhibit de novo cholesterol biosynthesis and significantly reduces the blood cholesterol concentrations. Three separate inhibitors, lovastatin, simvastatin and pravastatin can lower plasma total cholesterol and low-density lipoprotein (LDL) levels in hypercholesterolemic humans by 20 to 30% and 30 to 40%, respectively. 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 (HDL-)cholesterol, which are inversely related to atherosclerosis, increase with treatment by these drugs. If the short-term safety of these drugs extends to ongoing longterm studies and if cardiovascular morbidity and mortality are improved by their use, these hypolipidemic agents will facilitate the effective treatment of hypercholesterolemia.
 ...
PMID:[HMG-CoA-reductase inhibitors: a new principle in the treatment of hypercholesterolemia]. 237 7

Extracorporeal procedures to eliminate LDL from plasma now allow us to drastically lower the plasma LDL-concentrations to virtually every desired level. In a new therapeutic approach the combination of HMG-CoA reductase inhibitors with an LDL/fibrinogen apheresis procedure (the HELP-system) was evaluated in hypercholesterolemic CAD-patients. HELP treatment alone can lower the mean plasma LDL-cholesterol by about 50-60%, HMG-CoA reductase inhibitor therapy reduces the LDL-cholesterol by about 40%. The combination of both treatments resulted in a lowering of mean LDL-cholesterol to about 80% of baseline values. Improvement of blood rheology by lowering plasma viscosity and inhibiting erythrocyte aggregation became apparent. No relevant adverse effects were noted over a period of two years. This therapeutic strategy for maximal LDL-cholesterol lowering may be useful in secondary prevention of coronary heart disease in hypercholesterolemic patients if plasma LDL-C cannot be reduced by diet and drug treatment to desirable plasma levels (LDL-cholesterol less than 120 mg/dl). Preliminary data show an improvement in the symptoms of our CAD-patients treated with this combined therapy. Furthermore, within the near future a combined HELP and dialysis unit will be available for patients with terminal renal insufficiency and progressive atherosclerosis.
 ...
PMID:[Maximal therapy of hypercholesterolemia in coronary heart disease]. 237 8

We examined the relationship between cholesterol biosynthesis and total and high affinity LDL binding in liver specimens from two sitosterolemic and 12 healthy control subjects who died unexpectedly and whose livers became available when no suitable recipient for transplantation was identified. Accelerated atherosclerosis, unrestricted intestinal sterol absorption, increased plasma and tissue plant sterol concentrations, and low cholesterol synthesis characterize this disease. Mean total microsomal HMG-CoA reductase (rate-control controlling enzyme for cholesterol biosynthesis) activity was sevenfold higher (98.1 +/- 28.8 vs. 15.0 +/- 2.0 pmol/mg protein per min) and microsomal enzyme protein mass was eightfold larger (1.43 +/- 0.41 vs. 0.18 +/- 0.04 relative densitometric U/mg protein) in 11 controls than the average for two sitosterolemic liver specimens. HMG-CoA reductase mRNA probed with pRED 227 and pHRED 102 was decreased to barely detectable levels in the sitosterolemic livers. In addition, there was a 50% decrease in the rate [2-14C]mevalonic acid was converted to cholesterol by sitosterolemic liver slices compared with controls (112 vs. 224 +/- 32 pmol/g liver per h). In contrast, average total LDL binding was 60% greater (326 vs. 204 +/- 10 ng/mg), and high affinity (receptor-mediated) binding 165% more active (253 vs. 95.1 +/- 8.2 ng/mg) in two sitosterolemic liver membrane specimens than the mean for 12 controls. Liver morphology was intact although sitosterolemic hepatocytes and microsomes contained 24 and 14% less cholesterol, respectively, and 10-100 times more plant sterols and 5 alpha-stanols than control specimens. We postulate that inadequate cholesterol biosynthesis is an inherited abnormality in sitosterolemia and may be offset by augmented receptor-mediated LDL catabolism to supply cellular sterols that cannot be formed.
 ...
PMID:A molecular defect in hepatic cholesterol biosynthesis in sitosterolemia with xanthomatosis. 239 40

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.
 ...
PMID:Treatment of heterozygous familial hypercholesterolemia with lipid-lowering drugs. 249 89

Lp(a) is a plasma lipoprotein particle consisting of a plasminogenlike protein [apo(a)] disulfide bonded to the apo B moiety of low-density lipoprotein (LDL). Increased plasma levels of Lp(a), either independently or interactively with LDL levels, have been shown to be a risk factor for atherosclerosis. Recently, a new class of lipid-lowering drugs, HMG CoA reductase inhibitors, have been introduced. These drugs act by decreasing liver cholesterol synthesis resulting in up-regulation of LDL receptors, increased clearance of LDL from plasma, and diminution of plasma LDL levels. In this study, we examined the effect of HMG CoA reductase inhibitors on Lp(a) levels in three groups of subjects, five volunteers and two groups of five and 14 patients. In all 24 subjects, mean decreases were observed in total cholesterol (43 +/- 5%), total triglyceride (35 +/- 8%), very low-density lipoprotein (45 +/- 9%), and LDL cholesterol (43 +/- 5%). The mean change in high-density lipoprotein cholesterol was an increase of 7 +/- 8%. Despite the very significant decrease in LDL cholesterol levels (p less than 0.001), Lp(a) levels increased by 33 +/- 12% (p less than 0.005). This was not associated with a measurable change in the chemical composition or size of the Lp(a) particle. This emphatically suggests that Lp(a) particles, despite consisting principally of LDL, are cleared from plasma differently than LDL. The surprising finding of an increase in Lp(a) levels suggests this class of drugs may have a direct effect on Lp(a) synthesis or clearance independent of its effect on LDL receptors.
 ...
PMID:HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels. 253 5

The effects of exercise on hypocholesterolemia, one of the risk factors of cerebrovascular disorders, were examined. 47-51-day-old stroke-prone spontaneously hypertensive rats (stroke-prone SHRs) were assigned to 2 groups, sedentary or exercise, and raised for 8 weeks. The total serum cholesterol level of the exercised group was 17-18% higher (P less than 0.01) than the control group, and the level of cholesterol synthesis in the liver of the former group significantly higher than in the latter. On the other hand, the level of intestinal cholesterol synthesis in the exercised group was significantly lower. The activity of HMG-CoA reductase in the liver microsomes was significantly increased by exercise, but the activity of this enzyme in the small intestine was not affected. A significant correlation was observed between the rate of cholesterol synthesis in the liver and the amount of radiolabeled cholesterol released into the serum. From these results, we conclude that the enhancement of the synthesis and the release of cholesterol in the liver by exercise is a major cause of the exercise-induced increase in serum cholesterol of stroke-prone SHRs.
Atherosclerosis 1989 Oct
PMID:Effects of exercise on hypocholesterolemia of stroke-prone spontaneously hypertensive rats. 259 21

Bezafibrate was given for 15 days at a dose of 200 mg t.i.d. to 4 normolipidemic subjects, to 5 patients with putative heterozygous familial hypercholesterolemia, and to 6 patients with primary hypercholesterolemia of the non-familial type. At the end of the treatment, the rate of incorporation of labelled acetate into non-saponifiable lipids in freshly isolated blood mononuclear cells decreased in all subjects. On the average, acetate incorporation decreased by 31% in cells from normolipidemic subjects, 41% in cells from familial, and 45% in cells from non-familial hypercholesterolemia patients. Results of the present study suggest that the lowering effect of bezafibrate on serum cholesterol is mainly due to the inhibition of cholesterol synthesis through the suppression of HMG-CoA reductase as was demonstrated in rat hepatocytes and in cultured human blood mononuclear cells.
Atherosclerosis 1989 Oct
PMID:Inhibition of cholesterol biosynthesis in freshly isolated blood mononuclear cells from normolipidemic subjects and hypercholesterolemic patients treated with bezafibrate. 259 33

Simvastatin, an inhibitor of HMG-CoA reductase was given to 7 normolipidemic healthy volunteers for 1 month at a dose of 20 mg/day. Measurements of turnover of low density lipoprotein apolipoprotein B (LDL-apo B) were determined before and after drug treatment using intravenous injection of 125I-labeled LDL and 131I-labeled cyclohexanedione-treated LDL to quantify the receptor pathway. In addition to a 13% increase in HDL cholesterol and apolipoprotein A-I concentrations, plasma cholesterol was reduced by 20%, LDL-cholesterol by 32%, and apolipoprotein B by 23%. Assuming a heterogeneous pool of LDL, the new model presented in the companion paper was built to calculate the contribution of the receptor-dependent and the receptor-independent pathways and the corresponding fractional catabolic rates. Simvastatin did not modify constantly the synthetic rate of LDL-apo B but increased the fractional catabolic rate of the receptor-dependent pathway and the contribution of this pathway in the catabolism. The fall in LDL plasma levels observed in normocholesterolemic subjects can be then entirely explained by an enhanced fractional removal of LDL from the circulation by the receptor route.
Atherosclerosis 1989 Dec
PMID:Effect of simvastatin on receptor-dependent low density lipoprotein catabolism in normocholesterolemic human volunteers. 261 Jul 23

The reduction of total and LDL cholesterol (TC and LDLc), apoprotein B (ApoB) and in some instances triglycerides (TG) and the increase of HDL cholesterol (HDLc) and apoprotein A (ApoA) seem to be associated to a reduced coronary risk. Aim of our work was to evaluate the effects of a chronic treatment with the HMG-CoA reductase inhibitor simvastatin (MK-733), in a group of 8 dyslipidemic patients, 5 women and 3 men, aged between 48 and 69 years (mean age 59 +/- 8 years) at high risk being already affected by clinical compliances of atherosclerosis and not previously controlled by diet and/or other antidyslipidemic drugs. At the beginning and at the end (6 months) of this open study it was performed a clinical, ECG and ophthalmological examination, as well as an evaluation of the routine laboratory parameters. The initial dosage of simvastatin was a tablet of 10 mg/day, increased after a month to 20 mg and then to 40 mg/die. The mean dosage was 26.25 mg at the 3rd month and 21.25 mg at the 6th. Long-term simvastatin treatment was well tolerated (lack of important side effects as well as of significant changes of other clinical and laboratory parameters) and effective, reducing significantly (p less than 0.01) TC (317.9 +/- 30.8 vs 238.5 +/- 37.9 mg/dl), LDLc (210.6 +/- 48 vs 147.9 +/- 52 mg/dl), ApoB (144.7 +/- 17.5 vs 104.5 +/- 18), and TG (272.9 +/- 184 vs 200.5 +/- 117.6 mg/dl) and increasing in contrast HDL and ApoA values.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Effect of a long-term treatment with simvastatin, an inhibitor of HMG-CoA reductase, in dyslipidemic patients at high risk]. 263 79


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>