Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the last decades, transplantation has become an established tool for the treatment of terminal organ failure. Beside immunological factors, hyperlipidemia is the main problem after heart transplantation, causing rapid transplant coronary artery disease (TxCAD) and poor long-term prognosis at the beginning of the transplantation. Heart transplant recipients are now effectively treated with lipid lowering substances, of which HMG-CoA-reductase inhibitors are the most potent. However, treatment with these substances correlates with an increased risk for the development of rhabdomyolysis due to therapy with the immunosuppressive cyclosporine A. Our study monitored the safety and efficacy of treatment with the HMG-CoA reductase inhibitor fluvastatin in heart transplant recipients compared to healthy controls. We investigated 10 patients receiving immunosuppressive therapy consisting of cyclosporine A, prednisone, and azathioprine who had increased concentrations of LDL-cholesterol (LDL-C), and 10 age-matched healthy controls. The patients were treated with 40 mg/day fluvastatin for 4 weeks and 20 mg/day for 4 additional weeks. Control individuals received 40 mg/day fluvastatin for 4 weeks only. Parameters of fluvastatin pharmacokinetics (maximum concentration of the drug (C(max.)), time (t(max.)) to reach C(max.), area under the concentration vs. time curve (AUC(0h-24h)), elimination half-life time (t(1/2))), apparent total body clearance (CL), blood cyclosporine A concentration, plasma lipids, and safety parameters were determined in both study groups at the beginning of the study and after 4 weeks. The latter were determined in the patient group also after 8 and 12 weeks. Treatment with 40 mg/day fluvastatin caused a significant decrease in total cholesterol (patients: 5.47 +/- 1.32 mmol/L vs. 7.30 +/- 1.83 mmol/L; controls: 4.69 +/- 0.64 mmol/L vs. 5.81 +/- 0.72 mmol/L), LDL-C (patients: 3.28 +/- 1.25 mmol/L vs. 5.00 +/- 1.85 mmol/L; controls: 2.58 +/- 0.63 mmol/L vs. 3.50 +/- 0.70 mmol/L), and triglycerides (patients: 1.99 +/- 0.77 mmol/L vs. 2.50 +/- 1.00 mmol/L; controls: 1.24 +/- 0.46 mmol/L vs. 1.72 +/- 0.67 mmol/L) in both study groups, whereas HDL-C was not significantly changed (patients: 1.29 +/- 0.35 mmol/L vs. 1.17 +/- 0.32 mmol/L; controls: 1.55 +/- 0.30 mmol/L vs. 1.53 +/- 0.26 mmol/L). Values of C(max.) and AUC(0h-24h) were higher in the patient group than in the control group (day 1, patients vs. controls, C(max.): 869.4 +/- 604.0 ng/mL vs. 211.9 +/- 113.9 ng/mL; AUC(0h-24h): 1948.8 +/- 1347.9 ng/mL*h vs. 549.4 +/- 247.4 ng/mL*h), whereas the corresponding value of CL was lower in the patient group (33.3 +/- 24.5 L/h vs. 107.9 +/- 95.8 L/h), and the values of t(max.) and t(1/2) showed no differences. In addition, values of C(max.) and AUC(0h-24h) after administration of 40 mg/day fluvastatin for 4 weeks in both groups were slightly higher than at the beginning, whereas the value of CL was slightly lower (day 28, patients vs. controls, C(max.): 1530.4 +/- 960.4 ng/mL vs. 254.7 +/- 199.8 ng/mL; AUC(0h-24h): 2615.3 +/- 1379.4 ng/mL*h vs. 841.8 +/- 421.4 ng/mL*h; CL: day 28, 21.4 +/- 15.3 L/h vs. 61.5 +/- 36.6 L/h). Except for an intermittent increase of creatine kinase, safety parameters showed no increases within the observation period. Our data suggest that fluvastatin effectively lowers plasma concentrations of cholesterol and LDL-C in patients after heart transplantation, however, the metabolism of fluvastatin is affected by concomitant therapy with cyclosporine A. Serum concentrations of fluvastatin should be monitored in cases of concomitant therapy with other substances interfering in the metabolism by competing cytochrome enzymes.
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PMID:Pharmacokinetics and pharmacodynamics of fluvastatin in heart transplant recipients taking cyclosporine A. 1190 37

Cardiovascular disease (CVD) remains a major cause of death in industrialised societies, and elevated serum lipids are a significant, highly prevalent and undertreated risk factor for this condition. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have revolutionised the treatment of hyperlipidaemia, and results from large-scale, long-term clinical trials have shown that the substantial reductions in low-density lipoprotein cholesterol (LDL-C) achieved with these drugs are associated with dramatic decreases in cardiovascular risk. Results from recent comparative clinical trials that have included a new drug in this class, rosuvastatin (Crestor), have demonstrated that it is significantly superior to atorvastatin, pravastatin and simvastatin in reducing total cholesterol, LDL-C and apolipoprotein B (Apo B). It is also significantly more effective than atorvastatin in increasing high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (Apo A-I). Rosuvastatin was also superior to all these agents in helping patients meet European Atherosclerosis Society (EAS) and National Cholesterol Education Programme (NCEP) goals for LDL-C. The results of an increasing number of studies indicate that statins have a wide range of pleiotropic properties that almost certainly contribute to their ability to decrease cardiovascular risk and may also make them valuable for treatment of other diseases. These actions include plaque stabilisation, improvement of endothelial function, inhibition of smooth muscle cell proliferation and migration, reduction of expression of adhesion molecules, prevention of cholesterol esterification and accumulation, reduction of secretion of matrix metalloproteinases by macrophages, reduction of platelet activity, reduction of formation of thrombogenic factors, chemoprotection and induction of bone morphogenic protein-2 (BMP-2). Further exploration of these actions will provide key information about class effects and properties of specific members of this highly useful group of drugs.
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PMID:Statin therapy: rationale for a new agent, rosuvastatin. 1213 48

The triglyceride-lowering effect of pitavastatin, a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, was investigated in a rat model of postprandial lipemia. Plasma triglyceride levels started to increase 4 h after the fat load, reached the maximum at 6 h and then gradually decreased. A single dose of pitavastatin (1 mg/kg) significantly suppressed chylomicron-triglyceride secretion into the lymph by 40% and delayed the elevation of plasma triglyceride. Pitavastatin at 1 mg/kg decreased the 6-h plasma triglyceride levels by 53% and at 0.5 mg/kg decreased the 0-12 h area under the curve (AUC) of triglyceride levels by 56%. Atorvastatin also caused decreases, but to a lesser extent. Pitavastatin, and atorvastatin to a lesser extent, reduced the activity of the intestinal microsomal triglyceride transfer protein (MTP) at 6 h. These results suggested that a single dose of pitavastatin lowered postprandial triglyceride levels in rats by decreasing chylomicron-triglyceride secretion, probably through a reduction of intestinal MTP activity and triglyceride droplet formation in the endoplasmic reticulum.
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PMID:Triglyceride-lowering effect of pitavastatin [corrected] in a rat model of postprandial lipemia. 1219 89

The triglyceride (TG)-lowering effect of pitavastatin (CAS 147526-32-7), a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, was investigated in a guinea pig model of post-prandial lipemia. Plasma TG levels started to rise 2 h after the fat load, reached the maximum at 8 h and then gradually decreased. A 14-day dose of pitavastatin at 3 mg/kg decreased the 8 h plasma TG levels by 59%, and the 0-12 h area under the curve (AUC) of TG levels above the initial levels, by 77%. This effect was also shown with 30 mg/kg of atorvastatin (CAS 134523-00-5), and the same dose of simvastatin (CAS 79902-63-9). The intensity of the action was equivalent for pitavastatin and atorvastatin, but weaker with simvastatin. In order to clarify the mechanism of this action, the effect of pitavastatin exerted on the activity of microsomal triglyceride transfer protein (MTP), which participates in the secretion to the lymph vessel of chyromicron (CM)-TG in the small intestine, and the activity of lipoprotein lipase (LPL), which is the hydrolysis enzyme of the very low density lipoprotein (VLDL)-TG and CM-TG, was examined. However, an influence on the activity of MTP or LPL by pitavastatin was not shown. These results suggested that pitavastatin lowered the postprandial TG levels in guinea pigs by accelerating the remnant clearance, probably through the enhancement of the low density lipoprotein (LDL) receptor. This effect is expected to improve postprandial lipemia.
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PMID:Triglyceride-lowering effect of pitavastatin in a guinea pig model of postprandial lipemia. 1270 69

The statins reduce cholesterol synthesis through inhibition of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase and are widely prescribed for hyperlipidaemia to reduce the risk of atherosclerotic complications. The beneficial effect of lipid lowering by statins in the treatment of coronary heart disease has been demonstrated in large clinical trials. However, statins appear to have additional benefits on vascular function above and beyond their lipid lowering effects. Through inhibition of L-mevalonate synthesis, statins also prevent the synthesis of isoprenoid intermediates, including farnesylpyrophosphate and geranylgeranylpyrophosphate. Isoprenylation is important in the post-translational modification of a variety of proteins, including the small GTPases Rho, Rac and Ras, and hence plays an integral role in cellular signalling. Moreover, interference with isoprenylation underlies many of the beneficial actions of the statins on vascular endothelium, which include increased endothelial nitric oxide synthase expression, pro-angiogenic effects, increased fibrinolytic activity, immunomodulatory and anti-inflammatory actions, including increased resistance to complement. This has led to interest in the use of this class of drugs outside the realm of cardiovascular disease.
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PMID:Statins and their role in vascular protection. 1279 55

HIV protease inhibitors decrease mortality and improve quality of life in patients with HIV infection. However, these drugs have been associated with serum lipid elevations, which may pose an increased risk of cardiovascular disease and pancreatitis. Treatment of protease inhibitor-related hyperlipidaemia (PIH) is complicated by drug interactions, which significantly increase concentrations of most 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins). Although pravastatin and atorvastatin effectively lower cholesterol and triglyceride concentrations in HIV-infected patients, a significant number of patients did not achieve their National Cholesterol Education Program low density lipoprotein concentration goals. Nonetheless, due to the increased risk of rhabdomyolysis with elevated statin concentrations, atorvastatin should be considered a second-line agent. The limited available PIH data supports the fact that pravastatin and atorvastatin are well-tolerated in HIV-infected individuals. More data are needed on the appropriate starting doses, maximum safe doses, role of combination statin-fibrate therapy, documentation of coronary heart disease benefit and incidence of myotoxicity and hepatotoxicity. Pravastatin has an acceptable risk-benefit ratio in PIH, while theoretical toxicity concerns exist with atorvastatin.
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PMID:Risk-benefit of HMG-CoA reductase inhibitors in the treatment of HIV protease inhibitor-related hyperlipidaemia. 1290 55

The most important side effects of fibrate and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) treatment are hepatic toxicity and myopathy. Obese individuals may have higher levels of serum transaminases than their lean counterparts. The main purpose of this study was to examine the effects of statins and fibrates on liver enzymes in obese patients and to compare them with their effects on patients with various body mass indexes (BMI). Two hundred and sixty-three hyperlipidemic patients of both sexes aged 31-74 years were studied for 24 weeks. One hundred and three patients received fluvastatin (40 mg/day), 62 atorvastatin (10-20 mg/day), 45 micronized fenofibrate (200 mg/day), 44 ciprofibrate (100 mg/day) and nine patients received gemfibrozil (900 mg/day). Laboratory determinations were performed at baseline, after 8 weeks of treatment and at the end of the follow-up period. At baseline, obese patients tended to exhibit elevated liver enzymes more frequently than their lean counterparts (12 of 105 vs. 5 of 67). At the end of the study period, 11 obese, seven overweight and six lean subjects exhibited elevated liver enzymes. Twelve patients who experienced a moderate elevation of serum liver enzymes at baseline had their liver enzyme profile normalized at the end of the study. Furthermore, in 12 patients who had normal serum liver enzyme levels at baseline, abnormal levels of at least one enzyme were observed after 24 weeks of treatment. Fibrates and statins are safe drugs for the treatment of hyperlipidemia in obese patients as well as in those with moderately increased liver enzymes.
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PMID:Lipid-lowering drugs and serum liver enzymes: the effects of body weight and baseline enzyme levels. 1291 53

Several intervention studies have shown that some hypolipidemic and hypotensive drugs such as fibrates, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, angiotensin converting enzyme (ACE) inhibitors and calcium (Ca)-antagonists prevent atherosclerosis. The main pathological findings in atherosclerosis include abnormal reactions of neutrophils, lymphocytes and monocytes/ macrophages, vascular smooth muscle cells and vascular endothelial cells, and the accumulation of cholesterol ester in the arterial wall. Therefore, investigating the effects of these drugs on the arterial wall may improve understanding of the mechanisms underlying atherosclerosis. Here, based on recent studies including our own, we describe the relationships between risk factors for atherosclerosis, especially hyperlipidemia and hypertension, and the molecular mechanisms that govern lipid metabolism in the arteries.
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PMID:The possible therapeutic actions of peroxisome proliferator-activated receptor alpha (PPAR alpha) agonists, PPAR gamma agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, angiotensin converting enzyme (ACE) inhibitors and calcium (Ca)-antagonists on vascular endothelial cells. 1503 51

Asymmetric dimethylarginine (ADMA), a guanidino-substituted analogue of L-arginine, is a potent endogenous competitive inhibitor of the endothelial nitric oxide synthase and therefore a potentially atherogenic amino acid. Hyperlipidemia and hyperhomocysteinemia have both been reported to be associated with elevated ADMA concentrations. Therefore, we investigated the influence of micronized fenofibrate (200 mg/day, 6 week treatment) on the L-arginine:ADMA ratio in 25 hypertriglyceridemic men. ADMA was neither associated to serum triglycerides, serum cholesterol, LDL-cholesterol or HDL-cholesterol or plasma total homocysteine at baseline. Treatment with fenofibrate did not alter plasma ADMA level, in contrast to serum triglycerides which were significantly lowered and plasma total homocysteine which was significantly increased. In addition, serum L-arginine levels significantly increased, leading to a higher L-arginine:ADMA ratio after treatment. The null effect of fenofibrate on plasma ADMA levels is in line with reported effects of other lipid-lowering agents (HMG-CoA-reductase inhibitors), but fenofibrate treatment elevated the plasma L-arginine:ADMA ratio, suggesting an improvement of endogenous NO formation and endothelial function. The results do not support the view that in vivo ADMA metabolism itself is directly influenced by cholesterol or homocysteine.
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PMID:Fenofibrate increases the L-arginine:ADMA ratio by increase of L-arginine concentration but has no effect on ADMA concentration. 1506 97

The purpose of this study was to investigate the lipid-lowering and anti-oxidative effects of fluvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, in type 2 diabetic patients. Six patients (3 men and 3 women, mean age = 56.2) took 20 mg of fluvastatin once daily (at night) for 12 weeks. Several markers of oxidative stress were then measured in these patients including plasma cholesterol oxidation products, i.e. oxysterols, and the levels of circulating adhesion molecules. Plasma total cholesterol levels were reduced by 12.3% in these individuals after 4 weeks of treatment, with levels remaining below 220 mg/dl for the entire treatment period. LDL levels were significantly reduced at 4 (18.1%) and 12 weeks (16.1%), and triglyceride levels were significantly reduced after 8 (22.5%) and 12 (37.7%) weeks of treatment. HDL-C levels increased from 50.7 +/- 15.4 prior to treatment to 63.8 +/- 24.3 mg/dl after 12 weeks of treatment, though this increase was not statistically significant. Lipid hydroperoxide, thiobarbituric acid-reactive substance (TBARS), and oxysterol levels were also reduced, suggesting that fluvastatin also had anti-oxidative effects. Finally, VCAM-1 levels were similarly reduced by fluvastatin treatment. We conclude that fluvastatin safely improves the plasma lipid profile in type 2 diabetic patients with hyperlipidemia. We speculate that this drug might be doubly effective in reducing atherosclerosis and cardiac events in these patients as a result of its demonstrated anti-oxidative effects and its ability to reduce VCAM-1 levels.
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PMID:Effects of fluvastatin in type 2 diabetic patients with hyperlipidemia: reduction in cholesterol oxidation products and VCAM-1. 1515 64


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