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)

Rabbits fed a diet enriched in casein develop an endogenous hypercholesterolemia (EH) due both to an increased low density lipoprotein (LDL) synthetic rate and decreased LDL receptor activity. Pre-established EH in this model was used to assess the ability and mechanism by which atorvastatin lowers total plasma cholesterol (TPC) compared to the reference agent lovastatin. Rabbits were fed a casein diet for 6 weeks, obtaining average TPC levels above 200 mg/dl. To ensure equivalent mean cholesterol concentrations, animals were randomized into treatment groups based on the 6-week TPC levels, and fed the casein diet alone or in combination with either atorvastatin or lovastatin for an additional 6 weeks. Under these conditions, new steady-state cholesterol values were established. Lipoprotein concentrations and distributions were determined at this point. Compared to pretreatment values, TPC were similar in untreated animals. Atorvastatin, however, significantly reduced TPC by 38%, 45%, and 54% at the 1, 3, and 10 mg/kg doses, respectively. Statistically significant lowering of TPC (35%) by lovastatin was only achieved at the 10 mg/kg dose. To determine the mechanism by which atorvastatin lowered TPC in the EH rabbits, kinetic studies using human [125I]-LDL were performed in a subset of animals maintained on the casein diet alone (n = 5), or those treated with 3 mg/kg of atorvastatin (n = 5) or lovastatin (n = 7). In this set of studies, atorvastatin significantly lowered TPC compared to control and lovastatin-treated rabbits by 57% and 46%, respectively. Lovastatin treatment resulted in a 20% decrease in TPC as compared to untreated controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1995 Jun
PMID:Comparative effects of HMG-CoA reductase inhibitors on apo B production in the casein-fed rabbit: atorvastatin versus lovastatin. 766 76

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

Since inhibitors of HMG-CoA reductase lower plasma triglycerides rather than cholesterol in rats, we compared the triglyceride-lowering activity of lovastatin in rats to that of atorvastatin, a more potent synthetic inhibitor, prior to evaluating these drugs in established animal models in which low density lipoproteins (LDL) rather than high density lipoproteins (HDL) are the major transporters of plasma cholesterol. Atorvastatin was more efficacious than lovastatin in normal, chow-fed rats, and more potent in rats with endogenous hypertriglyceridemia (sucrose-fed). In hypertriglyceridemic rats plasma apoB concentrations decreased only with atorvastatin (30 mg/kg), and VLDL-triglyceride secretion (Triton method) was also decreased more by atorvastatin. The inactive enantiomer of atorvastatin did not lower plasma triglycerides. Thus, triglyceride-lowering was dependent upon inhibition of HMG-CoA reductase. Liver unesterified cholesterol and cholesteryl esters (mg/g) were increased by both drugs in normal rats but remained unchanged in hypertriglyceridemic rats. In normal, chow-fed guinea pigs atorvastatin was a more potent cholesterol-lowering drug, and unlike lovastatin, lowered plasma triglycerides and VLDL-cholesterol. In casein-fed rabbits with endogenous hypercholesterolemia and in chow-fed rabbits atorvastatin lowered LDL-cholesterol more potently than lovastatin, but in chow-fed rabbits neither drug had an effect on the in vivo rate of VLDL-lipid secretion, suggesting that efficacy was due to inhibition of direct LDL production and/or enhanced LDL clearance. We conclude that normal rats can be used as a preclinical tool to assess the efficacy of HMG-CoA reductase inhibitors since triglyceride-lowering correlates with cholesterol-lowering in LDL animal models. In this regard atorvastatin is a more potent hypolipidemic agent than lovastatin in animals. A common but not sole mechanism for these drugs may be direct inhibition of the hepatic production of the major apoB-containing lipoprotein in a given species, e.g. VLDL in rats and LDL in guinea pigs and rabbits.
Atherosclerosis 1995 Oct
PMID:Lipid-lowering activity of atorvastatin and lovastatin in rodent species: triglyceride-lowering in rats correlates with efficacy in LDL animal models. 880 69

Plasma cholesterol and other lipoproteins play a significant role in the development of atherosclerosis and subsequent coronary heart disease (CHD). This 1 year study was designed to confirm the efficacy and safety of atorvastatin (Lipitor) compared to pravastatin, a marketed agent for low density lipoprotein cholesterol (LDL-C) reduction in hypercholesterolemic patients. Patients were recruited at 26 centers in six European countries. After a 6 week placebo baseline phase, patients were randomized to receive atorvastatin 10 mg or pravastatin 20 mg daily. The dose could be doubled at week 16, if LDL-C levels remained > or = 3.4 mmol/l (135 mg/dl). Atorvastatin significantly lowered LDL-C from baseline by 35% compared with 23% for pravastatin (P < 0.05). A total of 72% of atorvastatin patients attained the LDL-C target level of < 3.4 mmol/l, compared to 26% of pravastatin patients. Atorvastatin also significantly reduced TC, TG and apo B (P < 0.05). Safety was assessed by recording adverse events and measuring clinical laboratory parameters. The adverse event profile was similar for both treatment groups and neither treatment caused clinically relevant laboratory abnormalities. Atorvastatin 10 and 20 mg once daily is superior to pravastatin 20 and 40 mg once daily in treating patients with hypercholesterolemia.
Atherosclerosis 1997 Apr
PMID:Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia. 912 64

Preclinical and clinical data on atorvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, indicate that it has superior activity in treating a variety of dyslipidemic disorders characterized by elevations in low-density lipoprotein cholesterol (LDL-C) and/or triglycerides. Results for patients randomized in early efficacy and safety studies were combined in one database and analyzed. This analysis included a total of 231 atorvastatin-treated patients (131 with hypercholesterolemia (HC), 63 with combined hyperlipidemia (CH), 36 with hypertriglyceridemia (HTG), and 1 with hyperchylomicronemia (Fredrickson Type V)). Patients were treated with a cholesterol-lowering diet (National Institutes of Health National Cholesterol Education Program Step 1 diet or a more rigorous diet) and either 2.5, 5, 10, 20, 40, or 80 mg/day of atorvastatin or placebo. Efficacy was based on percent change from baseline in total cholesterol, total triglycerides, LDL-C, very low-density lipoprotein cholesterol (VLDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (apo B), and non-HDL-C/HDL-C. Safety was assessed in all randomized patients. Atorvastatin seemed to preferentially lower those lipid and lipoprotein component(s) most elevated within each dyslipidemic state: LDL-C in patients with HC, triglycerides and VLDL-C in patients with HTG, or all 3 in patients with CH. Atorvastatin was well-tolerated with a safety profile similar to other drugs in its class.
Atherosclerosis 1997 May
PMID:A brief review paper of the efficacy and safety of atorvastatin in early clinical trials. 918 Feb 40

The effects of atorvastatin (lipitor) on cholesterol-rich and triglyceride-rich lipoproteins were evaluated in this multicenter trial. Following a 6-week baseline period, 47 patients with elevated cholesterol and triglyceride levels were treated with atorvastatin 10 mg once daily (QD) for the initial 12 weeks (Period 1) increasing to 20 mg QD for the following 12 weeks (Period 2). At both the 10 and 20 mg doses, atorvastatin treatment resulted in significant reductions compared to pretreatment levels in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-C), apolipoprotein (apo) B, apoB in LDL (LDL-apo B), apo B in VLDL (VLDL-apo B), lipoprotein (Lp)B, lipoprotein B-complex (LpBc), triglycerides (TG), low-density lipoprotein triglycerides (LDL-TG), very low-density lipoprotein triglyceride (VLDL-TG), high-density lipoprotein triglycerides (HDL-TG), and apo C-III. Atorvastatin 10 and 20 mg QD also resulted in significant increases in high-density lipoprotein cholesterol (HDL-C), apo AI, and LpAII:B:C:D:E. Due to its unique ability to normalize both cholesterol-rich and triglyceride-rich particles, atorvastatin is a promising candidate for monotherapy in a broad range of patients including those with varying degrees of hypercholesterolemia and hypertriglyceridemia.
Atherosclerosis 1997 Aug
PMID:Effect of a new HMG-CoA reductase inhibitor, atorvastatin, on lipids, apolipoproteins and lipoprotein particles in patients with elevated serum cholesterol and triglyceride levels. 925 16

The focus of lipid-lowering therapy with drugs is prevention of complications of atherosclerosis. Landmark clinical trials have demonstrated that lowering low density lipoprotein cholesterol (LDL-C) may not only reduce coronary artery disease (CAD) risk but also may slow the progression and even induce regression of atherosclerosis in the coronary arteries. In addition, much attention has been given in recent years to the importance of triglyceride-rich lipoprotein (TRL) as a CAD risk factor, and the benefit of reducing plasma triglyceride levels and raising high density lipoprotein cholesterol (HDL-C) levels to prevent the recurrence of coronary events. Lipid-lowering drugs should be used within the framework of a systematic approach to treatment. Consideration must be given to the lipoprotein abnormality, the severity of disease, the role of combination therapy, and the spectrum of action of the drug and its pleiotropic effects (ie, effects beyond the expected action on lipoproteins). Five major agents have been used for the treatment of dyslipidemias. Three (resins, probucol and statins) target LDL-C, and two (fibrates and niacin) target primarily TRL and HDL-C. Fibrates and statins are the drugs of choice. Fibrates correct many abnormalities of lipoprotein metabolism in addition to having beneficial pleiotropic effects such as reducing fibrinogen and plasma viscosity. They inhibit the transcription of apolipoprotein (apo) CIII and enhance that of apoAI and lipoprotein lipase. Statins are safe and potent drugs for reducing LDL-C levels, and their efficacy in primary and secondary prevention of CAD has been amply demonstrated. They share a modes effect of raising HDL-C levels. Their pleiotropic effects, which include improvement of endothelial dysfunction, are numerous and may contribute to their spectacular beneficial effect of reducing CAD risk. They have effects that are complementary to those of fibrates, but the two drugs should be combined with caution because of the danger of myopathy. Atorvastatin is a major addition to this class of drugs because of its high efficacy and large spectrum of action. It lowers LDL-C levels effectively, not only in patients with severe forms of hypercholesterolemia but also in those with homozygous familial hypercholesterolemia. The effect of atorvastatin on LDL-C may be further enhanced by combining it with a resin. The ability of atorvastatin to lower triglyceride levels as well as LDL-C levels indicates that combined hyperlipidemia, a condition that, in the past, was best controlled with combination therapy, can now be treated with a single drug. It is also effective in patients with isolated hypertriglyceridemia and, although less potent than fenofibrate at reducing TRL and increasing HDL-C, it has a greater impact on the atherogenic risk ratios such as LDL-C:HDL-C. The profile of its pleiotropic effects is promising.
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PMID:Advances in drug treatment of dyslipidemia: focus on atorvastatin. 962 39

Endothelial dysfunction associated with atherosclerosis has been attributed to alterations in the L-arginine-nitric oxide (NO)-cGMP pathway or to an excess of endothelin-1 (ET-1). The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to ameliorate endothelial function. However, the physiological basis of this observation is largely unknown. We investigated the effects of Atorvastatin and Simvastatin on the pre-proET-1 mRNA expression and ET-1 synthesis and on the endothelial NO synthase (eNOS) transcript and protein levels in bovine aortic endothelial cells. These agents inhibited pre-proET-1 mRNA expression in a concentration- and time-dependent fashion (60-70% maximum inhibition) and reduced immunoreactive ET-1 levels (25-50%). This inhibitory effect was maintained in the presence of oxidized LDL (1-50 microg/ml). No significant modification of pre-proET-1 mRNA half-life was observed. In addition, mevalonate, but not cholesterol, reversed the statin-mediated decrease of pre-proET-1 mRNA levels. eNOS mRNA expression was reduced by oxidized LDL in a dose-dependent fashion (up to 57% inhibition), whereas native LDL had no effect. Statins were able to prevent the inhibitory action exerted by oxidized LDL on eNOS mRNA and protein levels. Hence, these drugs might influence vascular tone by modulating the expression of endothelial vasoactive factors.
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PMID:Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. 963 5

Diabetes mellitus type 2 (DM type 2) is a common disease that is associated with high mortality and morbidity due to macrovascular and microvascular complications. CHD mortality and morbidity is 2--3 times higher in diabetic than in non-diabetic patients/. There are many potentially atherogenic factors in diabetes these may underlie this problems. Except major risk factors (high serum cholesterol concentration, hypertension, cigarette smoking), insulin resistance is common in DM type 2 patients. The dyslipidemic component of insulin resistance is "atherogenic lipoprotein phenotype", its components include small LDL particles (pattern B) with higher atherogenic risk. Several recent studies have demonstrated the preponderance of small, dense LDL in patients with DM type 2 and IR. The question of whether small, dense LDL can be explained by triglyceride levels alone or whether it is directly related to DM type 2 and insulin resistance is still the subject of debate. If serum triglycerides exceed 1,3 mmol/l, small, dense LDL increases. The practical implication is that serum triglyceride levels should be maintained as low as possible to prevent the deleterious effects of triglycerides on LDL subclass distribution and size. There are several potential mechanisms to explain the increased atherogenicity of dense LDL (small dense LDL is more susceptible to lipid peroxidation and oxidation leading to its increased uptake by macrophages and subsequent removal by scavenger pathway, also has a lower binding affinity to LDL receptors). Theoretical grounds postulate that the treating of diabetic dyslipoproteinemias would reduce atherosclerosis disease. However, to date, there have been no intervention studies specifically designed to test this postulate in the diabetic population Such studies the Diabetes Atherosclerosis Intervention Study (DAIS), Fenofibrate Intervention and Event Lowering in Diabetes (FIELD), Collaborative Atorvastatin in Diabetes Study and lipid in Diabetes Study are currently in progress (Tab. 4, Fig. 2, Ref. 81.).
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PMID:[In Process Citation] 966 34

Diabetes mellitus type 2 (DM type 2) is a common disease that is associated with high mortality and morbidity due to macrovascular and microvascular complications. CHD mortality and morbidity is 2-3 times higher in diabetic than in non-diabetic patients. There are many potentially atherogenic factors in diabetes these may underlie this problems. Except major risk factors (high serum cholesterol concentration, hypertension, cigarette smoking), insulin resistance is common in DM type 2 patients. The dyslipidemic component of insulin resistance is "atherogenic lipoprotein phenotype", its components include small LDL particles (pattern B) with higher atherogenic risk. Several recent studies have demonstrated the preponderance of small, dense LDL in patients with DM type 2 and IR. The question of whether small, dense LDL can be explained by triglyceride levels alone or whether it is directly related to DM type 2 and insulin resistance is still the subject of debate. If serum triglycerides exceed 1.3 mmol/l, small, dense LDL increases. The practical implication is that serum triglyceride levels should be maintained as low as possible to prevent the deleterious effects of triglycerides on LDL subclass distribution and size. There are several potential mechanisms to explain the increased atherogenicity of dense LDL (small dense LDL is more susceptible to lipid peroxidation and oxidation leading to its increased uptake by macrophages and subsequent removal by scavenger pathway, also has a lower binding affinity to LDL receptors). Theoretical grounds postulate that the treating of diabetic dyslipoproteinemias would reduce atherosclerosis disease. However, to date, there have been no intervention studies specifically designed to test this postulate in the diabetic population. Such studies the Diabetes Atherosclerosis Intervention Study (DAIS), Fenofibrate Intervention and Event Lowering in Diabetes (FIELD), Collaborative Atorvastatin in Diabetes Study and Lipid in Diabetes Study are currently in progress. (Tab. 4, Fig. 2, Ref. 81.)
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PMID:[Relation between insulin resistance and small, dense lipoproteins with low density and the development of atherosclerosis in type 2 diabetes mellitus]. 991 42


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