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)

Lymphatic absorption and transport of cholesterol and triacylglycerols were examined in rats treated with pravastatin, an inhibitor of 3-hydroxy-3-methyglutaryl-CoA (HMG-CoA) reductase. Pravastatin-treatment for 1, 7 and 28 days did not affect the recovery of cholesterol and triacylglycerols during 24 h after the lipid administration: the recovery was 52-59% and 82-93% for cholesterol and triacylglycerols, respectively. Rats treated with pravastatin for 28 days had a higher lymphatic recovery of the lipids during 3-6 h after the lipid administration than did control rats. Pravastatin treatment did not affect the ratio of phospholipid to cholesterol in the gut mucosa, the fatty acid composition of the lymph and mucosal lipids. We concluded that an inhibitor of HMG-CoA reductase would exert no adverse effect on absorption of fat-soluble nutrients by gut.
Atherosclerosis 1996 Jul
PMID:Lymphatic transport of cholesterol in normocholesterolemic rats treated with pravastatin, an inhibitor of HMG-CoA reductase. 880 Apr 97

Treatment with hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors has gained considerable success in the management of hypercholesterolemia. A large number of studies have shown the efficacy of these drugs in lowering plasma total and low density lipoprotein (LDL) cholesterol levels, but there have been less studies evaluating their effectiveness in standard clinical practice, particularly relating to the maintenance of hypocholesterolemic activity. In the present study, the long-term effectiveness of HMG CoA reductase inhibitors has been tested in 177 patients with familial hypercholesterolemia (FH) who had been on statin therapy (simvastatin or pravastatin) for at least 12 months and up to 5 years or longer. The mean 'dose normalized' LDL cholesterol reduction in the whole group was around 20%. However, in spite of a generally good efficacy of both statins in lowering total and LDL cholesterol, a wide variety of responses, either after short- or long-term treatment, was noted. Individual responses were calculated and patients classified into three different groups: (a) responders, (b) non-responders, and (c) response losers. Of the 177 patients, 4% did not respond to treatment and a further 10% showed an initial unsatisfactory response (LDL cholesterol reduction < or = 10%). Another 10% experienced a progressive loss of response over time. There appeared to be little difference between the two treatments in the long-term efficacy and no predictive index could be established. Treatment with HMG CoA reductase inhibitors is generally effective and well tolerated, but a non-negligible number of patients may show a primary non-response or a progressive loss of response.
Atherosclerosis 1995 Oct
PMID:Therapy with HMG CoA reductase inhibitors: characteristics of the long-term permanence of hypocholesterolemic activity. 880 64

Heterozygotes for familial defective apolipoprotein B-100 (FDB) have two populations of low density lipoprotein (LDL), one bearing normal apolipoprotein B-100 (apo B) and the other bearing defective apo B which exhibits a much lower affinity for the LDL-receptor. If HMGCoA reductase inhibitors such as simvastatin lowered LDL mainly by up-regulating LDL-receptor mediated clearance, they should decrease the overall binding affinity of LDL from an FDB heterozygote by selectively decreasing LDL bearing normal apo B. We compared how LDL from FDB heterozygotes competed with normal 125I-labelled LDL for binding to LDL-receptors while on and off therapy with simvastatin. The LDL of FDB heterozygotes had 40% (n = 10) the affinity of normal LDL (n = 12) for the LDL receptor on cultured fibroblasts, and 55% (n = 6) of normal LDL (n = 6) for that on HepG2 cells. Treatment of FDB subjects with simvastatin (n = 10) decreased serum LDL by 22% but had no effect on its binding affinity for LDL receptors, indicative of lowering of LDL containing both normal and defective apo B. This is consistent with the major LDL lowering effect being associated with decreased synthesis of LDL, rather than enhanced LDL-receptor clearance.
Atherosclerosis 1996 Aug 23
PMID:Familial defective apolipoprotein B-100 (FDB): effect of simvastatin therapy on LDL-receptor binding. 883 32

Macrophage cholesterol accumulation and foam cell formation, the hallmark of early atherosclerosis, is the result of enhanced cellular uptake of plasma low density lipoprotein (LDL). Native LDL, has to undergo oxidative modifications in order to be taken up at an enhanced rate by macrophages, leading to foam cell formation. Macrophage uptake of oxidized LDL involves its binding to scavanger receptors (including cellular proteoglycans) and this is followed by an impaired cellular cholesterol metabolism. Cells of the arterial wall including macrophages can oxidize LDL in a process that involves activation of cellular oxygenases, such as NADPH oxidase and 15-lipoxygenase. This process, however, also depends on the macrophage antioxidant environment, where glutathione peroxidase and reduced glutathione play an important protective role against cell-mediated oxidation of LDL. Macrophage phospholipids peroxidation under oxidative stress can also contribute to macrophage-mediated oxidation of LDL. Evidence for the occurrence of oxidized LDL in vivo is as follows: 1) In the atherosclerotic lesion [in humans, as well as in the transgenic, apolipoprotein E-deficient mice], LDL is oxidized (and as a result, it is also aggregated), in comparison to plasma LDL which is normally not oxidized. 2) Plasma LDL from patients at high risk for atherosclerosis (such as hypercholesterolaemic, hypertensive, diabetic and renal failure patients), as well as from the apolipoprotein E-deficient mice, demonstrates increased susceptibility to oxidation in comparison to normal LDL. In some groups of these patients LDL is minimally oxidized already in plasma. 3) Supplementation of nutritional antioxidants, which are rich in polyphenols (red wine, licorice, olive oil), or of selenium to humans or to the apolipoprotein E-deficient mice, as well as therapy with beta-hydroxy-beta-methyl-glutaryl-CoA reductase inhibitors (so-called "statins") in hyperocholesterolaemic patients, were shown to reduce the susceptibility of LDL to oxidation. This effect could be associated with a reduction in the size of the atherosclerotic lesion and may thus contribute to attenuation of the atherosclerotic process.
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PMID:Interaction of oxidized low density lipoprotein with macrophages in atherosclerosis, and the antiatherogenicity of antioxidants. 887 34

A profound imbalance between oxidants and antioxidants has been suggested in uremic patients on maintenance hemodialysis. However, the respective influence of uremia and dialysis procedure has not been evaluated. Circulating levels of copper-zinc superoxide dismutase (CuZn SOD), glutathione peroxidase (GSH-Px), and reductase (GSSG-Rd), total GSH and GSSG were determined in a large cohort of 233 uremic patients including 185 undialyzed patients with mild to severe chronic renal failure, and 48 patients treated by peritoneal dialysis or hemodialysis. Compared to controls, erythrocyte GSH-Px and GSSG-Rd activities were significantly increased at the mild stage of chronic uremia (p < .001), whereas erythrocyte CuZn SOD activity was unchanged, total level of GSH and plasma GSH-Px activity were significantly decreased, and GSSG level and GSSG-Rd activity were unchanged. Positive Spearman rank correlations were observed between creatinine clearance and plasma levels of GSH-Px (r = .65, p < .001), selenium (r = .47, p < .001), and GSH (r = .41, p < .001). Alterations in antioxidant systems gradually increased with the degree of renal failure, further rose in patients on peritoneal dialysis and culminated in hemodialysis patients in whom an almost complete abolishment of GSH-Px activity was observed. In conclusion, such disturbances in antioxidant systems that occur from the early stage of chronic uremia and are exacerbated by dialysis provide additional evidence for a resulting oxidative stress that could contribute to the development of accelerated atherosclerosis and other long-term complications in uremic patients.
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PMID:Glutathione antioxidant system as a marker of oxidative stress in chronic renal failure. 890 30

Non-insulin-dependent diabetes mellitus is frequently associated with premature atherosclerosis. Abnormalities in lipid and lipoprotein metabolism contribute to the increased risk of coronary heart disease. One of the most common lipid abnormalities in non-insulin-dependent diabetes mellitus is hypertriglyceridaemia. In the present paper, the authors review the metabolism of triglyceride-rich lipoproteins, with special emphasis on the post-prandial state. Several studies have demonstrated that levels of atherogenic post-prandial lipoproteins are increased in patients with non-insulin-dependent diabetes mellitus. An increased supply of glucose and free fatty acids contributes to overproduction of very low-density lipoproteins, increasing the burden of triglyceride-rich lipoproteins on the common lipolytic pathway at the level of lipoprotein lipase. Low lipoprotein lipase activity and increased amounts of lipolysis-inhibiting free fatty acids further impair lipolysis of post-prandial lipoproteins. The clearance of atherogenic remnants is also delayed in non-insulin-dependent diabetes mellitus. There is evidence that a relative hepatic removal defect exists, secondary to impaired remnant-receptor interaction and increased competition with very low density lipoprotein remnants. Correction of the increased post-prandial lipaemia in non-insulin-dependent diabetes mellitus is advisable, as it may contribute to attenuation of the risk on premature atherosclerosis. When dietary measures and hypoglycaemic agents have failed to achieve acceptable lipid levels, lipid-lowering drugs should be advised. Fibric acids and hydroxymethyl-glutaryl coenzyme A (HMG CoA) reductase inhibitors are the drugs of choice.
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PMID:Triglyceride-rich lipoproteins in non-insulin-dependent diabetes mellitus: post-prandial metabolism and relation to premature atherosclerosis. 890 18

Treatment of hypercholesterolemia with HMG-CoA-reductase inhibitors has revolutionized medical intervention towards the prevention of coronary artery disease. There is a wide sprectrum of patients with diverse underlying clinical conditions that may benefit from treatment using these agents. These include patients with multiple risk factors, individuals following major vascular events, and those with special conditions that are associated with accelerated atherosclerosis. The latter include patients with severe, dominantly inherited hypercholesterolemia, patients with major organ dysfunction such as chronic renal failure, and individuals after transplantation. Multimodality intervention includes behavior modification and mechanical as well as pharmacological treatment. It is aimed at several important targets: cholesterol reduction, control of hypertension and diabetes, improvement of myocardial contractility, reduction of infarct size, and control of hemostasis. Most of these patients require multiple drugs, which may interact at the pharmacodynamic (efficacy and safety) as well as pharmacokinetic levels. These potential interactions should be considered while planning and implementing preventive measures for an individual as well as for the community. The beneficial effects and the potential hazardous interactions between HMG-CoA reductase inhibitors and other medications are presented and discussed using two models: heterozygous familial hypercholesterolemia and major organ transplantation. Although there is a partial overlap in the medications used for the treatment of these two conditions, some of them differ. The interaction between HMG-CoA reductase inhibitors and other cholesterol-lowering agents, mainly fibrates, is discussed in the first model summarizing data from controlled clinical trials. The interaction with cyclosporin A is presented using the second model. A potential benefit of fluvastatin, as compared with other currently available HMG-CoA reductase inhibitors, which may be related to its relatively short plasma half-life and low systemic exposure, is discussed.
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PMID:Targeted prevention of coronary artery disease: pharmacological considerations in multimodality treatment. 890 72

The introduction of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has provided an important new class of agents that reduce levels of total and low-density lipoprotein cholesterol more powerfully than any previously used drugs. Multiple clinical trials have shown a significant decrease in lipid values and cardiovascular events and a slowing of the progression of atherosclerosis in men and women of all ages. The Scandinavian Simvastatin Survival Study demonstrated a significant reduction in all-cause mortality as a result of reduced cardiovascular mortality. The HMG-CoA reductase inhibitors should be considered as first-line therapy for hypercholesterolemia in all patients with established atherosclerosis involving the coronary, carotid, or peripheral vessels.
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PMID:Advances in treatment of cholesterol abnormalities. The role of HMG-CoA reductase inhibitors. 891 25

1. The effects of fluvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on the vascular angiotensin converting enzyme (ACE) activity in hyperlipidaemic rabbits were compared with those of enalapril, an ACE inhibitor. 2. Rabbits were fed a 1.5% cholesterol containing diet or normal diet for 16 weeks and treated with either fluvastatin or enalapril in the diet at the respective doses of 2 and 10 mg kg-1 day-1. The total cholesterol, triglyceride and phospholipid levels in serum were significantly increased in rabbits fed the high cholesterol diet. Treatment with fluvastatin but not enalapril resulted in a decrease in serum lipids. 3. The vascular ACE activities assessed via the cleavage rate from synthetic substrate in the aortic arches and upper thoracic aortae were increased by 8 to 10 times when the rabbits were made hyperlipidaemic. Fluvastatin as well as enalapril significantly lowered the tissue ACE in the aortae. 4. The ACE activities in serum did not alter in hyperlipidaemic rabbits either in the presence or absence of fluvastatin. The serum ACE activity was lowered by enalapril. 5. The lipid peroxide in serum as well as the plaque area in the thoracic aorta was significantly increased in the cholesterol diet-fed rabbits. Treatment with fluvastatin or enalapril reduced both serum lipid peroxide and plaque formation. The relaxant responses to acetylcoholine (ACh) were significantly suppressed in the cholesterol-fed rabbits. Treatment with fluvastatin or enalapril significantly reversed the suppression of ACh-induced relaxation. 6. It seems that the reduction of vascular ACE is not coupled to lipids and ACE activity in serum, but rather to lipid peroxidation. Thus, the decrease in vascular ACE activity by fluvastatin as well as the lipid-lowering effect may reduce the risk of atherosclerosis progression in the vasculature.
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PMID:Inhibitory effects of fluvastatin, a new HMG-CoA reductase inhibitor, on the increase in vascular ACE activity in cholesterol-fed rabbits. 893 33

Proliferation of smooth muscle cells (SMCs) plays an important role in vascular pathobiology by being involved in the development of coronary atherosclerosis and restenosis. Competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase have shown antiproliferative properties on different cell types. We have assessed the relative effectiveness of three HMG-CoA reductase inhibitors (compactin, lovastatin and pravastatin) in blocking serum-induced replication of human and porcine SMCs. No effects were seen on DNA synthesis in porcine or human SMCs at the reported therapeutic lipid-lowering concentrations. The effectiveness of statins in blocking SMC proliferation was similar in both species; the IC50 values for porcine cells were 12.2 mumol L-1, 12.6 mumol L-1 and 1.16 mmol L-1 for lovastatin, compactin and pravastatin respectively. Inhibition of SMC proliferation was reversed by addition of mevalonate but not by low-density lipoprotein (LDL)-cholesterol. Statins showed high anti-proliferative efficiency against purified growth factors involved in human restenosis (1 nmol L-1 platelet-derived growth factor (PDGF), 1 nmol L-1 epidermal growth factor (EGF), 10 U mL-1 alpha-thrombin). The porcine model seems to be a suitable system, closely resembling the human model, for assaying in vivo new strategies, formulations and delivery systems targeted to the mevalonate pathway to inhibit local SMC response to percutaneous transluminal coronary angioplasty.
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PMID:Human and porcine smooth muscle cells share similar proliferation dependence on the mevalonate pathway: implication for in vivo interventions in the porcine model. 895 10


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