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)

SK&F 97426-A is a novel bile acid sequestrant which was selected for comparison with cholestyramine in vivo because of its superior in vitro bile acid binding properties. The effects of the two sequestrants on faecal bile acid excretion, plasma total cholesterol, VLDL + LDL and HDL cholesterol and triglyceride concentrations and on liver enzymes involved in the synthesis and metabolism of cholesterol were investigated in normocholesterolaemic hamsters. Four studies were conducted to determine the relative potencies of the two resins using a range of doses of the sequestrants over treatment periods of up to 2 weeks. Curves fitted to the resulting data allowed common maximum responses and separate ED50s to be calculated for each sequestrant. The maximum response of both sequestrants was to increase bile acid excretion by 352% and lower plasma total cholesterol by 37-58%. LDL + VLDL and HDL cholesterol were reduced by 56-75% and 25-41%, respectively. SK&F 97426-A was 3 times more potent than cholestyramine at increasing the excretion of bile acids in the faeces and 2.1-3.4-fold and 2.3-3.2-fold more potent at lowering total plasma cholesterol and LDL plus VLDL cholesterol, respectively. In some of the experiments SK&F 97426-A was also more potent than cholestyramine at lowering HDL cholesterol. Plasma triglycerides were also lowered by both sequestrants by up to 31% after 1 week but the relative potency could not be determined. These HDL cholesterol and total triglyceride lowering effects of bile acid sequestrants in the hamster are known not to occur in people treated with cholestyramine. There were minimal differences between hamsters treated for 1 or 2 weeks in the relative potencies or ED50s calculated for the total plasma cholesterol, LDL + VLDL and HDL cholesterol. Both sequestrants may have been slightly more efficacious on these parameters after 2 weeks of treatment. Liver weights were reduced by about 15% by both sequestrants at 2% (w/w) in the diet for 1 week. The activities of the liver HMG-CoA reductase and cholesterol 7 alpha-hydroxylase were increased as expected, whilst the activity of the acyl-CoA:cholesterol acyltransferase was reduced by both sequestrants at this dose. SK&F 97426-A was, therefore, 2-3-fold more potent as a bile acid sequestrant and hypocholesterolaemic agent than cholestyramine when tested in the hamster.
Atherosclerosis 1993 Jun
PMID:SK&F 97426-A a more potent bile acid sequestrant and hypocholesterolaemic agent than cholestyramine in the hamster. 821 2

Epidemiologic evidence linking elevated cholesterol concentrations and coronary heart disease (CHD) through the eighth decade of life provides a rationale for lowering cholesterol concentrations to reduce morbidity and mortality from CHD. Pravastatin, a well tolerated HMG CoA reductase inhibitor with a convenient once-daily dosing regimen, has been shown to effectively lower total and low density lipoprotein (LDL) cholesterol. Individual data from more than 1800 hypercholesterolemic patients enrolled in six double-blind, randomized, multicenter studies were pooled and then analyzed to compare the safety and efficacy of pravastatin in the elderly (i.e., patients at least 65 years old) and the non-elderly. In short-term studies (8-16 weeks), response was dose-related and similar in elderly and non-elderly subjects. Pravastatin 20 or 40 mg daily lowered total cholesterol 19-25%, LDL-cholesterol 25-33%, and triglycerides 14-23%; high density lipoprotein (HDL) cholesterol increased 5-10%. During long-term studies, improvements were sustained for more than 24 months in both the non-elderly and elderly. The incidences of adverse drug events and laboratory abnormalities were similar in the elderly and non-elderly patients in all groups (active treatment control with resin, pravastatin alone, or combination therapy). In short-term studies, treatment was discontinued because of adverse events in < 1% of all patients treated with pravastatin (all doses) or placebo. The frequency and profile of adverse events were similar among patients treated with pravastatin or placebo. In long-term studies, treatment was discontinued in 0.4% of patients in the pravastatin group and in 0.3% of the patients in the bile-acid-binding resin group. If drug therapy is warranted, pravastatin appears to be safe and effective for long-term use in elderly patients with hypercholesterolemia.
Atherosclerosis 1993 Jun
PMID:Pravastatin experience in elderly and non-elderly patients. 821 7

Primary cultures of vascular smooth muscle cells (SMC) were incubated with hyperlipidemic rabbit serum (HLRS) to produce intracellular lipid accumulation. Cultures were exposed to different concentrations of the test compounds and their effects upon cell proliferation and intracellular lipid accumulation were measured. The in vitro results obtained with different Ca2+ antagonists, a HMG-CoA reductase inhibitor and other hypolipidemic substances showed a strong correlation with the in vivo activities of these compounds, suggesting that cultured SMC may be a useful initial in vitro model to detect new chemical entities active upon atherosclerosis related parameters.
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PMID:An in vitro method using vascular smooth muscle cells to study the effect of compounds on cell proliferation and intracellular lipid accumulation. 823 54

It has been postulated that oxidatively modified low-density lipoprotein (LDL) contributes to the genesis of atherosclerosis. Ubiquinone has been suggested to be an important physiological lipid-soluble antioxidant and is found in LDL fractions in the blood. We measured plasma level of ubiquinone using high-performance liquid chromatography and plasma levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides in 245 normal subjects (186 males, 59 females) and in 104 patients (55 males, 49 females) who had coronary artery disease not receiving pravastatin and 29 patients (12 males, 17 females) receiving pravastatin. In the normal subjects, the plasma ubiquinone levels did not vary with age. In the patient groups, the plasma total cholesterol and LDL levels were higher and the plasma ubiquinone level lower than in the normal subject group. The LDL/ubiquinone ratio was higher in the patient groups. We found that ubiquinone level, either alone or when expressed in relation to LDL levels, was significantly lower in the patient groups compared with the normal subject group. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor is thought to prevent atherosclerosis, however, it also inhibits ubiquinone production. The present study revealed that HMG CoA reductase inhibitor decreased plasma cholesterol level, and that it did not improve either the ubiquinone level or the LDL/ubiquinone ratio. From these results, the LDL/ubiquinone ratio is likely to be a risk factor for atherogenesis, and administration of ubiquinone to patients at risk might be needed.
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PMID:Coenzyme Q10 and coronary artery disease. 824 93

Atherosclerosis is the principal cause of diabetic morbidity and mortality. Diabetic dyslipidemia, obesity, and hypertension are significant contributing factors in the acceleration of the atherosclerotic process. Regardless of the type of diabetes, increased levels of very-low-density lipoprotein triglyceride, modified levels of low-density lipoprotein cholesterol, and decreased levels of high-density lipoprotein (HDL) cholesterol are the main lipoprotein abnormalities in diabetic patients. These abnormalities can be improved in part by glycemic control, but additional intervention may be needed. Diet and exercise are important elements in the management of dyslipidemia, but lipid-lowering drugs (especially fibrates and HMG-CoA reductase inhibitors) also may be necessary for the control of diabetic dyslipidemia. Based on these findings, the American Diabetes Association Consensus Panel and the revised treatment guidelines of the National Cholesterol Education Program recommend treatment of hypertriglyceridemia/low HDL cholesterol as a risk factor of coronary heart disease in diabetic and nondiabetic individuals alike. Aggressive treatment is recommended, therefore, particularly in diabetic patients and in all patients with existing vascular disease.
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PMID:Prevention of atherosclerosis in diabetes: emphasis on treatment for the abnormal lipoprotein metabolism of diabetes. 826 43

Human monocyte-derived macrophages treated with increasing concentrations of the HMG-CoA reductase inhibitor, simvastatin, showed a dose-dependent decrease in superoxide formation in response to activation by phorbol myristate acetate. As a consequence, they oxidized LDL much less than untreated cells. Addition of exogenous mevalonic acid to simvastatin-treated macrophages restored their ability for superoxide production and for oxidative modification of LDL. These results indicate that simvastatin might prevent atherosclerosis by additional mechanisms besides its hypocholesterolemic activity.
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PMID:Simvastatin inhibits the oxidation of low-density lipoproteins by activated human monocyte-derived macrophages. 838 Mar 38

This report describes the design and methodological features of a double-masked, randomized, placebo-controlled trial to determine whether administration of the HMG CoA reductase inhibitor lovastatin retards the progression or facilitates the regression of coronary atherosclerosis. The study population consists of coronary patients with a recent arteriogram that characterizes them as being at high risk for coronary progression and a baseline fasting total serum cholesterol > or = 5.7 mmol/L and < or = 7.8 mmol/L. Lovastatin, or matching placebo, are up-titrated from 20 mg to 40 mg to 80 mg/day during the first 16 weeks of the study in an attempt to attain a fasting serum LDL cholesterol level of 3.4 mmol/L; patients and study personnel remain masked as to cholesterol levels throughout the trial. Coronary arteriography is repeated at 2 years, or earlier if necessitated by worsening symptoms, and all segments are measured quantitatively using a computer-based system. The primary outcome of the trial is a comparison between the lovastatin and placebo groups for coronary change score, defined as the mean of the minimum lumen diameter changes for all lesions (follow-up minus baseline arteriogram) per patient. The advantages and limitations of coronary arteriographic trials and some of the issues related to outcome measurements are discussed. The question posed by this study is of clinical relevance because the consequences of progression of coronary disease, angina, myocardial infarction, and sudden cardiac death are leading causes of morbidity and mortality.
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PMID:Design features of a controlled clinical trial to assess the effect of an HMG CoA reductase inhibitor on the progression of coronary artery disease. Canadian Coronary Atherosclerosis Intervention Trial Investigators Montreal, Ottawa, and Toronto, Canada. 844 94

Simvastatin, an inhibitor of HMG CoA reductase, lowers the plasma total cholesterol and LDL-cholesterol concentration in familial hypercholesterolemic patients. The efficacy of the drug shows considerable inter-individual variation, however. In this study we have assessed the influence of certain LDL-receptor gene mutations on this variation. A group of 20 male and female heterozygotic familial hypercholesterolemic patients, all Afrikaners and each bearing one of two different LDL receptor gene mutations, FH Afrikaner-1 (FH1) and FH Afrikaner-2 (FH2), was treated with simvastatin (40 mg once daily) for 18 months. The average reduction in total plasma cholesterol was 35.3% in the case of the FH2 men but only 23.2% in that of the FH1 men (P = 0.005); the reduction in LDL cholesterol concentrations was also greater in the FH2 group (39% as opposed to 27.1%, P = 0.02). The better response of the FH2 group was also evident when men and women were considered together. Female FH1 patients responded better to simvastatin treatment, however, than did males with the same gene defect. Mutations at the LDL-receptor locus may thus play a significant role in the variable efficacy of the drug. The particular mutations in the males of this group may have contributed up to 35% of the variance in total cholesterol response and 29% of the variance in LDL-cholesterol response to simvastatin treatment.
Atherosclerosis 1993 Jan 04
PMID:Influence of specific mutations at the LDL-receptor gene locus on the response to simvastatin therapy in Afrikaner patients with heterozygous familial hypercholesterolaemia. 845 50

Non-insulin-dependent diabetes mellitus (NIDDM) is often characterized by an increase in VLDL-triglyceride, VLDL-cholesterol, LDL-cholesterol and a reduction in HDL-cholesterol. HMG-CoA reductase inhibitors significantly lower cholesterol rates and have an indirect effect on the LDL receptor. We measured the effect of simvastatin in 28 hypercholesterolemic subjects, including 14 with NIDDM in good metabolic control (HbAIc 7.8% +/- 1.3%). A 24-week treatment with 10 mg/day (weeks 1-4), 20 mg/day (weeks 5-8) and 40 mg/day (weeks 9-24) simvastatin revealed different responses in diabetic and non-diabetic patients. Total cholesterol, LDL-cholesterol and apo B decreased significantly in both groups (less in the diabetics), whereas only NIDDM patients displayed a significant reduction in VLDL-cholesterol and VLDL-apo B. In the non-diabetics, the reduction in plasma cholesterol was mainly confined to the LDL fraction (276 +/- 65 vs. 132 +/- 28 mg/dl), whereas a significant fall in VLDL-cholesterol (45 +/- 19 vs. 21 +/- 10 mg/dl) was more evident in the NIDDM patients. Simvastatin also influenced plasma apo B levels (221 +/- 33 vs 134 +/- 23 mg/dl in non-diabetics and 182 +/- 44 vs. 134 +/- 30 mg/dl in diabetics). Significant reduction of apo B, LDL-apo B (205 +/- 39 vs. 128 +/- 23 mg/dl) in the non-diabetics and VLDL-apo B (16 +/- 5 vs. 9 +/- 2 mg/dl) in the diabetics, indicates that the VLDL are primarily concerned when statins are administered in NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1993 Feb
PMID:Hypercholesterolemia in non-insulin-dependent diabetes mellitus: different effect of simvastatin on VLDL and LDL cholesterol levels. 846 Oct 59

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


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