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)

Previous work suggested an influence of etofibrate, a diester of nicotinic acid and clofibric acid, on lipoprotein receptors. Besides its beneficial effects on plasma lipoprotein levels of decrease in total cholesterol, LDL-cholesterol and triglycerides and increase in HDL-cholesterol, etofibrate was shown to inhibit platelet function. In order to further evaluate platelet-lipoprotein interactions, the effects of etofibrate on plasma lipids and lipoproteins on the specific binding of normal [111In]LDL and [111In]HDL onto platelets as well as its effect on platelet function were evaluated in 8 patients affected by Type II hyperlipoproteinemia (HLP). In all patients binding was saturable and indicated high affinity binding sites capable of binding 927 +/- 233 ng protein of [111In]LDL/10(9) platelets (Kd 12 +/- 3 micrograms protein/ml) and 1496 +/- 435 ng protein of [111In]HDL/10(9) platelets (Kd 14 +/- 3 micrograms protein/ml). The capacity of native LDL (HDL) to displace bound [111In]LDL ([111In]HDL) by half (IC50) amounted to 22 +/- 9 micrograms protein/ml (26 +/- 8 micrograms protein/ml). Following a 6-week treatment period with etofibrate (500 mg twice daily), decrease in plasma total cholesterol, LDL-cholesterol and apolipoprotein (apo) B and increase in HDL-cholesterol and apo AI was correlated to a significant (P < 0.01) increase in LDL- as well as HDL-receptor binding. The platelet binding capacity increased to 1085 +/- 212 ng protein/10(9) platelets (Kd 8 +/- 3 micrograms protein/ml) for [111In]LDL and to 1867 +/- 266 ng protein/10(9) platelets for [111In]HDL (Kd 11 +/- 3 micrograms protein/ml). Platelet function studies demonstrated significantly (P < 0.01) reduced platelet aggregation in response to ADP and thromboxane formation after 6 weeks of etofibrate therapy. These findings in patients with HPL Type II indicate in vivo upregulation of specific [111In]LDL as well as [111In]HDL binding sites on human platelets associated with reduced platelet activation following etofibrate therapy.
Atherosclerosis 1993 Sep
PMID:Etofibrate increases binding of low and high density lipoprotein to human platelets of patients with type II hyperlipoproteinemia. 825 Oct 8

Familial hypercholesterolaemia (FH) is caused by mutations in the gene for the low density lipoprotein (LDL) receptor. It is generally believed that homozygous FH patients do not respond well to lipid-lowering drug therapy with inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase because they cannot respond to an increased demand for hepatic cholesterol by up-regulation of LDL-receptor activity. In this paper we show that serum cholesterol in a homozygous FH patient with a receptor-negative LDL-receptor phenotype was reduced by 30% after treatment with simvastatin alone and by a further 11% with simvastatin in combination with probucol and nicotinic acid. The patient was a true homozygote, with two identical alleles of the LDL receptor gene in which a previously undescribed point mutation in exon 11 introduces a premature termination codon at residue 540 in the protein; the mutant protein is predicted to be truncated in the domain with homology to the epidermal growth factor precursor. Cultured cells from the patient were unable to bind, internalise or degrade LDL by the receptor pathway and there was no immunodetectable LDL receptor protein in the cells. Thus the lipid lowering effect of simvastatin in this individual must involve mechanisms other than stimulation of LDL receptors.
Atherosclerosis 1993 Nov
PMID:Cholesterol-lowering drug therapy in a patient with receptor-negative homozygous familial hypercholesterolaemia. 829 93

Five classes of lipid-lowering drugs are approved by the Food and Drug Administration (FDA) for use in the United States: nicotinic acid, bile acid sequestrants, fibric acid derivatives, reductase inhibitors, and probucol. None of the agents has an antiatherosclerotic indication. Cholestyramine and gemfibrozil have received indications for preventing complications of atherosclerosis, namely, myocardial infarction and coronary artery disease death. Foreseeable pharmacological strategies to reduce lipid-related cardiovascular risk might be divided into three categories. First, the present approach of lowering lipid and lipoprotein concentrations might be extended through modification of available agents (e.g., a more potent or soluble bile acid resin) or development of agents of novel mechanism (e.g., acyl-CoA:cholesterol acyltransferase [ACAT] inhibition or inhibition of cholesterol biosynthesis at a step other than HMG-CoA reductase). Second, blood lipids could be directly addressed outside of lipid-lowering strategies. Raising high density lipoprotein (HDL) cholesterol levels has not been fully explored, or the target might be modification of the lipoproteins themselves rather than their concentrations. Areas of particular interest in the latter regard are hepatic lipase activity, cholesteryl ester transfer protein activity, and differences between oxidized or otherwise modified low density lipoprotein (LDL) particles and normal LDL. Third, it may be possible to directly lessen the atherosclerotic potential of the vessel wall (e.g., through protecting it from the effects of certain growth factors or altering its state of relaxation.
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PMID:Dyslipidemia and atherosclerosis. A forecast of pharmaceutical approaches. 846 81

Since plasma high density lipoprotein (HDL) concentrations are inversely related to the development of atherosclerosis, induction of HDL after pharmacological treatment is considered of benefit. To study whether currently used hypolipidemic drugs affect HDL metabolism by modulating the expression of genes involved in HDL metabolism, liver and intestinal apolipoprotein (apo) AI, apo-AII and apo-AIV gene expression was evaluated in rats treated with different classes of hypolipidemic drugs, and correlated to the changes in plasma lipid and apolipoprotein concentrations. In rats, the most pronounced hypolipidemic effects were observed after treatment with the fibrates clofibrate and fenofibrate, which lowered plasma lipid, apo-AI and apo-AIV concentrations. This decrease was accompanied by lowered liver apo-AI, apo-AII and apo-AIV mRNA levels. None of the other compounds tested affected plasma cholesterol, whereas probucol and simvastatin decreased plasma triglyceride concentrations. Apo-AI and apo-AII mRNA remained constant after nicotinic acid and probucol, whereas liver apo-AIV mRNA levels decreased. Cholestyramine increased hepatic apo-AI and apo-AII, but not apo-AIV mRNA levels. Simvastatin treatment increased apo-AI mRNA nearly threefold, whereas apo-AII and apo-AIV decreased by more than 50%. Similarly as after cholestyramine, the alteration in hepatic apo-AI mRNA levels did not result in changed plasma apo-AI concentrations. Remarkably, none of the drugs tested significantly affected intestinal apolipoprotein mRNA levels. These results indicate that hypolipidemic drugs may act on plasma lipoprotein metabolism by regulating apolipoprotein gene expression. Further studies in humans and primates are therefore warranted.
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PMID:Effects of hypolipidemic drugs on the expression of genes involved in high density lipoprotein metabolism in the rat. 868 57

Current experience from coronary angiographic trials using different treatment regimens such as lifestyle changes, resins, nicotinic acid and statins, shows that progression of atheroma can be retarded, and that regression can sometimes be induced, by a marked lowering of LDL-cholesterol. Young post-myocardial infarction patients, however, usually exhibit a multiplicity of metabolic risk factors with dyslipidaemias, predominantly hypertriglyceridaemia, and disturbances of glucose-insulin homeostasis and of the haemostatic system. These factors, together coupled with coronary angiographic data showing that the degree of dyslipidaemia is related to the extent and degree of coronary atherosclerosis, and the fact that rapid progression of coronary atherosclerosis was foreseen in this group of patients, resulted in the initiation of the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) in 1985. BECAIT was a 5-year, double-blind, placebo-controlled study of bezafibrate (200 mg three times daily) and dietary intervention in dyslipidaemic male survivors of myocardial infarction below 45 years of age. The angiographic analysis included 81 patients (42 bezafibrate and 39 placebo) who underwent baseline and at least one post-treatment angiogram, at 2 and 5 years. Changes in mean minimum lumen diameter indicated that there was 0.13 mm less (95% Cl: 0.10; 0.15) disease progression in focal lesions in the bezafibrate group than in the placebo group (P = 0.049). Parallel, but non-statistically significant, treatment effects were observed for mean segment diameter and percent stenosis. Three patients treated with bezafibrate and 11 patients in the placebo group suffered coronary events during the course of the trial (P = 0.02 logrank test). The angiographic effects of bezafibrate were accompanied by statistically significant reductions in serum cholesterol and triglycerides. Furthermore, plasma fibrinogen levels were significantly reduced and HDL-cholesterol concentration increased but there was no net change in LDL-cholesterol. These findings show that bezafibrate slowed the progression of focal coronary atherosclerosis to a degree that is comparable to that achieved with the statins in angiographic trials such as MAAS and REGRESS. Bezafibrate also reduced the occurrence of coronary events in young post-infarction victims. Like BECAIT, analyses of data from the NHLBI type II study, CLAS, POSCH and MARS provide evidence for the role of triglyceride-rich lipoproteins in the progression of coronary artery disease. Retardation of progression of atherosclerosis and a reduction in coronary events is, therefore, possible without reducing LDL-cholesterol.
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PMID:Secondary preventive potential of lipid-lowering drugs. The Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT). 896 Apr 46

Usual risk factors for coronary artery disease account for only 25-50% of increased atherosclerotic risk in diabetes mellitus. Other obvious risk factors are hyperglycemia and dyslipidemia. However, hyperglycemia is a very late stage in the sequence of events from insulin resistance to frank diabetes, whereas lipoprotein abnormalities are manifested during the largely asymptomatic diabetic prodrome and contribute substantially to the increased risk of macrovascular disease. The insulin-resistant diabetes course affects virtually all lipids and lipoproteins. Chylomicron and very-low-density lipoprotein (VLDL) remnants accumulate, and triglycerides enrich high-density lipoprotein (HDL) and low-density lipoprotein (LDL), leading to high levels of potentially atherogenic particles and low levels of HDL cholesterol. Hyperglycemia eventually impairs removal of triglyceride-rich lipoproteins, the accumulation of which accentuates hypertriglyceridemia. As triglycerides increase-still within the so-called normal range-abnormalities in HDL and LDL became more apparent. Thus, when triglycerides are >200 mg/dL, LDL particles are small and dense (when they are <90 mg/dL, the particles are of the large, buoyant variety). The atherogenicity of small, dense LDL particles is attributed to their increased susceptibility to oxidation, but in many patients they may be a marker for insulin resistance or the presence of atherogenic VLDL. Hypertriglyceridemia is associated with atherosclerosis because (1) it is a marker for insulin resistance and atherogenic metabolic abnormalities; and (2) the small size of triglyceride-enriched lipoproteins enables them to infiltrate the blood vessel wall where they are oxidized, bind to receptors on macrophages, and ingested, leading to the development of the atherosclerotic lesion. Various studies (primary prevention with gemfibrozil: Helsinki Heart Study; secondary prevention with simvastatin and pravastatin: Scandinavian Simvastatin Survival Study [4S] and Cholesterol and Recurrent Events [CARE], respectively) have demonstrated that lipid-lowering therapy in type 2 diabetes is effective in decreasing the number of cardiac events. Risk reduction was 22% to 50% (statins) and approximately 65% (fibrate) relative to placebo. It was also noted (in 4S and CARE) that the risk of major coronary events in untreated diabetic patients was 1.5-1.7-fold greater than in untreated nondiabetic patients. Although gemfibrozil (fibric acid derivative) is more effective in decreasing triglycerides and increasing HDL cholesterol in diabetic patients than the statins, it does not change and may even increase LDL-cholesterol levels (fenofibrate may be an exception, decreasing LDL cholesterol by 20-25% in some studies). However, gemfibrozil does increase LDL particle size. Nevertheless, the statins are the current lipid-lowering drugs of choice because the change in LDL-cholesterol-to-HDL-cholesterol ratio is better than with gemfibrozil. Moreover, the diabetic patient may be more likely to benefit from statin therapy than the nondiabetic patient. It should be noted that, in theory, nicotinic acid can correct or improve all lipid or lipoprotein abnormalities in patients with type 2 diabetes. Unfortunately, it is relatively contraindicated because it causes insulin resistance and may precipitate or aggravate hyperglycemia (in addition to its other well-known side effects such as flushing, gastric irritation, development of hepatotoxicity, and hyperuricemia). It is unknown at present whether newer formulations such as once-daily Niaspan may be better tolerated in diabetes. In any case, most patients with type 2 diabetes have risk factors for coronary artery disease and qualify for aggressive LDL cholesterol-lowering therapy. At the same time, it is presently unknown whether improved glycemic control decreases coronary artery disease risk in such patients.
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PMID:Diabetic dyslipidemia. 991 65

Atherosclerosis can be defined as being a disease of coronary circulation. The present work evaluates the action of the naringenin, rutin, nicotinic acid, isolated and in association, on the metabolism of lipids. Cholesterol, cholesterol HDL, and triacylglycerols have been dosed after retreat of blood, following the administration of the compounds dissolved in propylene glycol by intraperitoneal route in doses of 5 mg kg-1 body wt. Results evidence that naringenin and nicotinic acid, isolated as well as their association with naringenin and nicotinic acid-rutin, present the largest percentual reduction of cholesterol. On the other hand, the best results for cholesterol-HDL have been obtained with naringenin, while rutin has shown the best triacylglycerols levels.
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PMID:Hypolipidaemic effects of naringenin, rutin, nicotinic acid and their associations. 1066 Sep 47

The hypertriglyceridemia attends the physiopathology of the atherosclerosis by various mechanisms: association of low levels of high density lipoprotein-cholesterol (HDL-c), modification of quality of low density lipoprotein-cholesterol (LDL-c), influence on hemostatic processes, association with other hazard's factors (obesity, hypertension, etc.). The hypertriglyceridemia distinguishes in primary and secondary. In primary forms the origin is essentially genetic, while the secondary ones are metabolic consequence of various pathologies (renal, thyroid, diabetes mellitus etc.). The hypertriglyceridemia's treatment is founded on a correct feeding and/or on eventual use of drugs. Apart from the secondary forms, in which is obligatory to treat at first the basal disease, the pharmacological therapy of the hypertriglyceridemia is suggested only in resistant cases to alone dietetic therapy and overall in presence of other factors of atherothrombotic hazard. The most utilized drugs are: omega-3 fatty acids, the nicotinic acid and its derivatives, the fibrates and the statins. The stronghold of alpha-glucosidases inhibitors is the acarbose. It reduces the biosynthesis of very low density lipoproteins (VLDL) by the reduction of substrata with an improvement of glucidic metabolism. Atorvastatin and cerivastatin develop a greater action to reduce serum levels of triglycerides as to the foregoing ones because of the better selectivity of receptor binding, the greater halflife and inhibition of the apolipoprotein's B100 synthesis.
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PMID:[Treatment of hypertriglyceridemia. Current aspects]. 1093 25

The authors share their experiences with using Solcoseryl in treatment of 158 patients with obliterating atherosclerosis of the lower extremity vessels. This treatment was found to be very effective. A scheme of the treatment is proposed after which the improved quality of life retains during not less than 6 months in 93% of the patients. The accessory maintenance therapy with minimum doses of aspirin and nicotinic acid is enough between the courses of treatment with Solcoseryl.
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PMID:[An assessment of the efficacy of intravenous monotherapy with the preparation solcoseryl in patients with arteriosclerosis obliterans of the vessels of the lower extremities]. 1098 50

Secondary prevention of coronary heart disease by antilipidemic therapy beginning at > or =3 months after an acute coronary syndrome is well documented. The impact, however, of immediate initiation of antilipidemic therapy on coronary stenoses and clinical outcome in patients with acute coronary syndrome is unknown. In our study, patients were randomized, on average, 6 days after an acute myocardial infarction and/or percutaneous transluminal coronary angioplasty secondary to unstable angina, to pravastatin (combined, when necessary, with cholestyramine and/or nicotinic acid) to achieve low-density lipoprotein cholesterol levels of < or =130 mg/dl (group A, n = 70). In controls (group B, n = 56), antilipidemic therapy was determined by family physicians. Quantitative coronary angiography was performed at inclusion, and at 6- and 24-month follow-up. The combined clinical end points were total mortality, cardiovascular death, nonfatal myocardial infarction, need for coronary intervention, stroke, and new onset of peripheral vascular disease. Minimal lumen diameter in group A increased by 0.05 +/- 0.20 mm after 6 months and 0.13 +/- 0.29 mm after 24 months, whereas it decreased by 0.08 +/- 0.20 mm and 0.18 +/- 0.27 mm, respectively, in group B (p = 0.004 at 6 months and p <0.001 at 24 months). After 2 years, 29 patients of 56 patients in group B, but only 16 of 70 patients in group A, experienced a clinical end point (p = 0.005; odds ratio 0.28, confidence intervals 0.13 to 0.6). We conclude that pravastatin-based therapy initiated immediately after an acute coronary syndrome is well tolerated and safe, lessens coronary atherosclerosis, and has a pronounced clinical benefit.
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PMID:Beneficial effects of pravastatin (+/-colestyramine/niacin) initiated immediately after a coronary event (the randomized Lipid-Coronary Artery Disease [L-CAD] Study). 1111 1


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