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)

High-risk patients with dyslipidemias resistant to diet and single-agent pharmacotherapy may require combination therapy to achieve target levels of low density lipoprotein, triglycerides, and high density lipoprotein. Combinations of fibrates and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are effective, but because of safety concerns related to myopathy and rhabdomyolysis, it is important to consider the possibility of pharmacokinetic interactions when such combinations are used. In this study, the area under the curve, maximum plasma concentration, and time to maximum concentration for fluvastatin and gemfibrozil are compared, when used alone and in combination, in patients with hyperlipidemia and either coronary or carotid atherosclerosis, or a family history of coronary artery disease. A total of 17 patients were studied in a random sequence, open-label, crossover study of fluvastatin at 20 mg twice daily, gemfibrozil at 600 mg twice daily, and the combination of the 2 drugs. No significant difference was observed in area under the curve, maximum plasma concentration, and time to maximum concentration when comparing the combination with each drug alone. These pharmacokinetic data add support to the clinical observations that the combination of fluvastatin and gemfibrozil is both effective and safe.
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PMID:Pharmacokinetics of the combination of fluvastatin and gemfibrozil. 760 6

Our purpose was to assess the effect of apolipoprotein (apo) E and apo A-IV isoform variation on low density lipoprotein (LDL) cholesterol lowering response to the HMG CoA reductase inhibitor, pravastatin. Plasma samples were obtained from participants (apo E, n = 97; apo A-IV, n = 144) in the PLAC-I (Pravastatin Limitation of Atherosclerosis in Coronary Arteries Study-1). The mean LDL cholesterol reduction in these subjects who were randomized to pravastatin 40 mg/day was 28%. Subjects with the APOE*2 allele (n = 12) had significantly (P = 0.04) greater reductions at 36% than subjects homozygous for the APOE*3 allele (n = 66, 27%) or those with the APOE*4 allele (n = 19, 26%). No significant effect of apo A-IV phenotype on LDL cholesterol lowering in response to pravastatin was noted. A meta-analysis utilizing published data from 4 previously published studies as well as our own data with a total sample size of 625 subjects was carried out. This analysis indicates that the presence of the APOE*2 allele was associated with a significantly greater (P < 0.05) LDL-cholesterol lowering response at 37% than those subjects homozygous for the APOE*3 allele at 35%, while those with the APOE*4 allele had a significantly lower response (P < 0.05), at 33%. These data are consistent with the concept that apo E phenotype modulates the LDL cholesterol lowering response observed with the use of HMG CoA reductase inhibitors.
Atherosclerosis 1995 Mar
PMID:Effect of apolipoprotein E and A-IV phenotypes on the low density lipoprotein response to HMG CoA reductase inhibitor therapy. 760 54

This study was conducted to define progression of atherosclerosis in both homozygous and heterozygous Watanabe heritable hyperlipidemic (WHHL) rabbits and to investigate the ability of the HMG CoA reductase inhibitor simvastatin to attenuate progression of the disease. We examined contractile responses to phenylephrine and endothelium-dependent relaxation in response to carbachol in thoracic aorta at 3, 6, 9, and 12 months in control New Zealand White (NZW) rabbits, homozygous WHHL rabbits, and heterozygous WHHL rabbits. Homozygous and heterozygous rabbits were treated with simvastatin (10 mg/kg per day) from 3 to 6 months and from 9 to 12 months of age. Simvastatin significantly reduced serum cholesterol levels in young heterozygotes, with a nonsignificant trend toward a reduction in older heterozygotes. In homozygotes, no significant fall was observed. Contractile function declined progressively with age in all groups--most in homozygotes and least in NZW rabbits. Relaxation was unaffected by age in NZW rabbits; relaxation declined in the heterozygotes and declined to a greater extent in homozygotes. Simvastatin retarded the loss of function in the young heterozygotes. Similar trends were observed in young homozygotes and older heterozygotes, with no effect in older homozygotes. Histological studies revealed the progressive development of early atherosclerosis in heterozygotes, and more advanced atherosclerosis was observed in homozygotes. Simvastatin did not inhibit development of atheroma. A correlation was observed between vascular function and structure. However, functional changes preceded the development of atheroma. In addition, we have demonstrated that simvastatin can help to reduce the loss of vascular function associated with the progression of atherosclerosis in the heterozygous WHHL rabbit.
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PMID:Development and progression of atherosclerosis in aorta from heterozygous and homozygous WHHL rabbits. Effects of simvastatin treatment. 762 9

Agents that inhibit hepatic cholesterol biosynthesis reduce circulating cholesterol levels in experimental animals and humans, and may be of pharmacological importance in the prevention of atherosclerosis. Azalanstat (RS-21607), a synthetic imidazole, has been shown to inhibit cholesterol synthesis in HepG2 cells, human fibroblasts, hamster hepatocytes and hamster liver, by inhibiting the cytochrome P450 enzyme lanosterol 14 alpha-demethylase. When administered orally to hamsters fed regular chow, RS-21607 (50 mg/kg/day) lowered serum cholesterol in a dose-dependent manner (ED50 = 62 mg/kg) in a period of 1 week. It preferentially lowered low density lipoprotein (LDL) cholesterol and apo B relative to high density lipoprotein (HDL) cholesterol and apo A-1. It also lowered plasma cholesterol levels in hamsters fed a high saturated fat and cholesterol diet. RS-21607 inhibited hepatic microsomal hydroxymethylglutaryl-CoA (HMG-CoA) reductase activity in hamsters in a dose-dependent manner (ED50 = 31 mg/kg), and this was highly correlated with serum cholesterol lowering (r = 0.97). Cholesterol lowering by azalanstat and cholestyramine was additive, and the increase in HMG-CoA reductase brought about by cholestyramine was attenuated significantly by azalanstat. In vitro studies with HepG2 cells indicated that this modulation of reductase activity was indirect, occurring at a post-transcriptional step, and it is proposed that a regulatory oxysterol derived from dihydrolanosterol (or lanosterol) may be responsible for this regulation. Azalanstat does not appear to lower circulating cholesterol in the hamster by up-regulation of the hepatic LDL receptor, suggesting that other mechanisms are involved. Orally administered azalanstat (50-75 mg/kg) stimulated hepatic microsomal cholesterol 7 alpha-hydroxylase activity by 50-400% in hamsters, and it is postulated that this may result from modified cholesterol absorption and bile acid synthesis.
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PMID:Azalanstat (RS-21607), a lanosterol 14 alpha-demethylase inhibitor with cholesterol-lowering activity. 764 60

Patients with non-insulin-dependent diabetes mellitus (NIDDM) have a greater risk of developing coronary heart disease than would be expected from a similar degree of hyperlipidemia in nondiabetic populations. Accelerated transfer of cholesteryl esters (CET) from high-density lipoprotein (HDL) to low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL), a process that is associated with atherosclerosis, may be a possible explanation for this. CET, plasma lipoprotein concentration, and mass in the fasting and postprandial state have been examined in 31 hyperlipidemic patients with NIDDM before and after 8 weeks of treatment with the hydroxymethylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitor pravastatin in a double-blind, placebo-controlled, parallel group study. Body mass index, glycemic control, and blood pressure remained unaltered during the study period. Compared with placebo, pravastatin decreased fasting serum cholesterol (P < 0.001) and LDL cholesterol (P < 0.002) levels. The high basal CET (34.4 +/- 13.1 nmol.ml-1.h-1) was decreased significantly by pravastatin treatment (27.5 +/- 13.7 nmol.ml-1.h-1, P = 0.013). There was a fall in the total cholesterol, free cholesterol, and phospholipid content of the Sf 0-12, 20-60, and 60-400 lipoproteins (all P = 0.001). Lecithin: cholesterol acyl transferase activity was not altered. The postprandial increase in VLDL cholesterol 5 h after a standardized mixed meal was attenuated after pravastatin treatment (P = 0.011). Inhibition of hepatic cholesterol synthesis with an HMG-CoA reductase inhibitor in hyperlipidemic patients with NIDDM decreased serum cholesterol content of triglyceride-rich lipoprotein, thereby decreasing the transfer of cholesteryl ester from HDL to LDL and VLDL.
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PMID:Effect of treatment with a hydroxymethylglutaryl coenzyme A reductase inhibitor on fasting and postprandial plasma lipoproteins and cholesteryl ester transfer activity in patients with NIDDM. 769 16

The effect of l-triiodothyronine on 3-hydroxy-3-methylglutaryl CoA (HMG CoA) reductase activity was measured in cultured skin fibroblasts from patients with homozygous familial hypercholesterolemia (FH). The tested strains were obtained from 13 receptor-negative and 6 receptor-defective type homozygotes and 3 heterozygotes. Eleven out of 19 strains of cultured fibroblasts from FH homozygotes demonstrated high levels of the HMG CoA reductase activity when l-triiodothyronine was present in the culture medium. All the 11 strains that responded to l-triiodothyronine were the receptor-negative type in which the binding of LDL on the cell surface was completely lacking. Two receptor-negative type strains showed no response to the addition of l-triiodothyronine. In these strains, partially active receptors were synthesized and rapidly degraded. The effect of l-triiodothyronine on HMG CoA reductase was abolished by cycloheximide, and not by actinomycin D. Furthermore, the effect was abolished by the pre-loading of the cells with free cholesterol. The results indicate that the effect of l-triiodothyronine on HMG CoA reductase activity was a post-transcriptional event, required de novo protein synthesis, and was successful only when cholesterol was depleted from the cells. The difference in the responsiveness of HMG CoA reductase activity to l-triiodothyronine treatment can be utilized to judge the state of impairment of LDL-receptors in the FH homozygote from the viewpoint of ability to incorporate cholesterol into the cells.
Atherosclerosis 1995 Feb
PMID:Response of 3-hydroxy-3-methylglutaryl CoA reductase to l-triiodothyronine in cultured fibroblasts from FH homozygotes. 775 59

Atherosclerosis and its complications are the main cause of death and disability in affluent nations, especially in the elderly population. Lipids and lipoproteins play an important role in its pathogenesis. The authors treated a group of elderly patients with Simvastatin (20 mg/day for 1 year), a HMG CoA reductase inhibitor and observed a significant reduction in total cholesterol (p < 0.001). LDL (p < 0.001) and beta apolipoproteins (p < 0.05). They also achieved regression of the atherosclerotic plaque in 5 patients and arrested the atherosclerotic process in 8. The authors intend to conduct further studies in this field to better define the action of Simvastin on the atherosclerotic plaque.
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PMID:Effects of treatment with Simvastatin in elderly patients with primary hypercholesterolemia. 776 64

The recent guidelines for detection and treatment of hypercholesterolemia together with specific therapeutic goals have stimulated interest in, and use of, lipid lowering agents. The last decade has seen an explosive growth in the drug discovery area which is now translating into clinical trials with many new lipid lowering agents. In addition, clinical trials assessing clinical outcomes and cost effectiveness are resulting in a changing approach to how current lipid lowering drugs are used, especially in terms of dosing and combination therapies. At present only four classes of lipid altering agents remain in wide use; bile acid binding resins, niacin, fibrates and HMG CoA reductase inhibitors. Although only a decade has passed since the first HMG CoA reductase inhibitor, lovastatin, entered clinical trials this group of compounds are not only the most widely used lipid lowering agents, but more than six such agents have been or are currently being developed. In addition to pharmacological therapies, there have been significant advances in the non-pharmacological treatment of hypercholesterolemia, the most important being LDL-receptor gene replacement and selective LDL-apheresis.
Atherosclerosis 1994 Aug
PMID:Drug and alternative therapies for hyperlipidemia. 780 17

Atherosclerotic lesion development was assessed in the thoracic aorta and chronically denuded iliac-femoral artery of hypercholesterolemic New Zealand White rabbits using inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which have previously been shown to possess varying degrees of hepatoselectivity in rats. Atorvastatin, previously known as CI-981 (2.5 mg/kg), PD135022 (1.0 mg/kg), simvastatin (2.5 mg/kg), lovastatin (2.5 mg/kg), PD134965 (1.0 mg/kg), pravastatin (2.5 mg/kg) and BMY22089 (2.5 mg/kg) were added to a 0.5% cholesterol, 3% peanut, 3% coconut oil diet and fed for 8 weeks. Although reductions in plasma total cholesterol of 27% to 60%, VLDL-cholesterol of 31% to 71% and plasma total cholesterol exposure of 37% to 43% were obtained, no correlation between these parameters and vascular lipid content, lesion size or monocyte-macrophage content was noted. Iliac-femoral lipid content was unchanged; however, atorvastatin and simvastatin significantly reduced the cholesterol content of the thoracic aorta by 45%-62%. Atorvastatin and PD135022 reduced the size of the iliac-femoral lesion by 67% and monocyte-macrophage content by 72%. Simvastatin, lovastatin and PD134965 decreased the monocyte-macrophage content; however, lesion size was unchanged. Pravastatin and BMY22089 had no effect on lesion size or content. No compound significantly reduced the extent of thoracic aortic lesions. We concluded that changes in plasma lipids and lipoproteins noted with the various HMG-CoA reductase inhibitors did not account for the beneficial effect on atherosclerotic lesion development. The antiatherosclerotic potential of the HMG-CoA reductase inhibitors was compound-specific and clearly not a class effect.
Atherosclerosis 1994 Nov
PMID:Antiatherosclerotic activity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in cholesterol-fed rabbits: a biochemical and morphological evaluation. 784 Aug 8

Dietary measures, including calorie restriction and reduced fat intake, remain the mainstay of management in prevention of coronary heart disease (CHD). When this fails, drug therapy should be considered. Fibrates, a family of lipid lowering drugs, decrease plasma triglycerides and inhibit their synthesis. They are also reported to suppress cholesterol production in the liver. A disadvantage of fenofibrate is the poor solubility of the principal ingredient, with subsequent incomplete absorption after oral administration. Micronized fenofibrate, a new formulation chemically identical to the parent compound, has improved pharmacokinetic parameters which increase absorption, provide more stable plasma levels, and thus dosage can be decreased. The micronized formulation has been shown to be effective in reducing LDL cholesterol and triglycerides in patients with types IIa and IV hyperlipidemia, with increasing responsiveness to therapy in proportion to elevated baseline values of these parameters. This formulation has also been compared to simvastatin, an HMG-CoA reductase inhibitor. Results of a double-blind crossover study showed that both drugs reduced plasma cholesterol levels by similar amounts, and both produced similar increases in HDL cholesterol. The micronized formulation of fenofibrate thus provides improved efficacy in the prevention of CHD. In comparison to the standard formulation, micronised fenofibrate thus provides improved efficacy in the control of dyslipidemia and the prevention of CHD.
Atherosclerosis 1994 Oct
PMID:The fibrates in clinical practice: focus on micronised fenofibrate. 785 86


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