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)

The availability of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has revolutionised the treatment of lipid abnormalities in patients at risk for the development of coronary atherosclerosis. The relatively widespread experience with HMG-CoA therapy has allowed a clear picture to emerge concerning the relative tolerability of these agents. While HMG-CoA reductase inhibitors have been shown to decrease complications from atherosclerosis and to improve total mortality, concern has been raised as to the long term safety of these agents. They came under close scrutiny in early trials because ocular complications had been seen with older inhibitors of cholesterol synthesis. However, extensive evaluation demonstrated no significant adverse alteration of ophthalmological function by the HMG-CoA reductase inhibitors. Extensive experience with the potential adverse effect of the HMG-CoA reductase inhibitors on hepatic function has accumulated. The effect on hepatic function for the various HMG-CoA reductase inhibitors is roughly dose-related and 1 to 3% of patients experience an increase in hepatic enzyme levels. The majority of liver abnormalities occur within the first 3 months of therapy and require monitoring. Rhabdomyolysis is an uncommon syndrome and occurs in approximately 0.1% of patients who receive HMG-CoA reductase inhibitor monotherapy. However, the incidence is increased when HMG-CoA reductase inhibitors are used in combination with agents that share a common metabolic path. The role of the cytochrome P450 (CYP) enzyme system in drug-drug interactions involving HMG-CoA reductase inhibitors has been extensively studied. Atorvastatin, cerivastatin, lovastatin and simvastatin are predominantly metabolised by the CYP3A4 isozyme. Fluvastatin has several metabolic pathways which involve the CYP enzyme system. Pravastatin is not significantly metabolised by this enzyme and thus has theoretical advantage in combination therapy. The major interactions with HMG-CoA reductase inhibitors in combination therapy involving rhabdomyolysis include fibric acid derivatives, erythromycin, cyclosporin and fluconazole. Additional concern has been raised relative to overzealous lowering of cholesterol which could occur due to the potency of therapy with these agents. Currently, there is no evidence from clinical trials of an increase in cardiovascular or total mortality associated with potent low density lipoprotein reduction. However, a threshold effect had been inferred by retrospective analysis of the Cholesterol and Recurrent Events study utilising pravastatin and the role of aggressive lipid therapy is currently being addressed in several large scale trials.
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PMID:Comparative tolerability of the HMG-CoA reductase inhibitors. 1100 3

Statins are generally considered as safe drugs with a very favorable cost-efficacy-ratio. Calculation of health expenses limits the prescription of statins in primary prevention to persons on high risk (i.e. 20% risk of a coronary infarction within the next 10 years). Prescription of statins in secondary prevention of atherosclerosis is mandatory. Advanced age, impairment of renal function or polypharmacotherapy increase the incidence of severe side-effects, especially myopathy and rhabdomyolysis. These patients should be given statins with lesser risk of these side-effects. Combination of statins with fibrates has attracted public concern, but may be indicated in persons with otherwise not treatable hyperlipidemia. These patients need intensive monitoring, just as patients on other drugs that are metabolized via the enzyme CYP3A4. Patients on statins should get dietary counseling, as an appropriate diet increases the effect of statins.
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PMID:[Prevention of coronary heart disease with statins. Which patients profit?]. 1289 51

Dyslipidemia, characterized by elevated serum levels of triglycerides and reduced levels of total cholesterol, low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol, has been recognized in patients with human immunodeficiency virus (HIV) infection. It is thought that elevated levels of circulating cytokines, such as tumor necrosis factor-alpha and interferon-alpha, may alter lipid metabolism in patients with HIV infection. Protease inhibitors, such as saquinavir, indinavir and ritonavir, have been found to decrease mortality and improve quality of life in patients with HIV infection. However, these drugs have been associated with a syndrome of fat redistribution, insulin resistance, and hyperlipidemia. Elevations in serum total cholesterol and triglyceride levels, along with dyslipidemia that typically occurs in patients with HIV infection, may predispose patients to complications such as premature atherosclerosis and pancreatitis. It has been estimated that hypercholesterolemia and hypertriglyceridemia occur in greater than 50% of protease inhibitor recipients after 2 years of therapy, and that the risk of developing hyperlipidemia increases with the duration of treatment with protease inhibitors. In general, treatment of hyperlipidemia should follow National Cholesterol Education Program guidelines; efforts should be made to modify/control coronary heart disease risk factors (i.e. smoking; hypertension; diabetes mellitus) and maximize lifestyle modifications, primarily dietary intervention and exercise, in these patients. Where indicated, treatment usually consists of either pravastatin or atorvastatin for patients with elevated serum levels of LDL-C and/or total cholesterol. Atorvastatin is more potent in lowering serum total cholesterol and triglycerides compared with other hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, but it is also associated with more drug interactions compared with pravastatin. Simvastatin and lovastatin are significantly metabolized by cytochrome P450 enzymes (CYP3A4) and are therefore not recommended for coadministration with protease inhibitors. A fibric acid derivative (gemfibrozil or fenofibrate) should be used in patients with primary hypertriglyceridemia. However, it must be kept in mind that protease inhibitors, such as nelfinavir and ritonavir, induce enzymes involved in the metabolism of the fibric acid derivatives and may, therefore, reduce the lipid-lowering activity of coadministered gemfibrozil or fenofibrate. In certain patients HMG-CoA reductase inhibitors may be used in combination with fibric acid derivatives but patients should be carefully monitored for liver and skeletal muscle toxicity. Select patients may experience improvements in serum lipid levels when their offending protease inhibitor(s) is/are exchanged for efavirenz, nevirapine, or abacavir; however each patient's virologic and immunologic status must be taken closely into consideration.
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PMID:Management of protease inhibitor-associated hyperlipidemia. 1472 85

Statins are widely used in clinical practice for lowering of levels of atherogenic blood plasma lipids and treatment of atherosclerosis. Variability of response of the body to these drugs might be determined by genetic factors (gene polymorphisms) related to metabolism of drugs. Among them central place belongs to enzymes of subfamily 3A of cytochrome P450 (CYP). In this review we present results of studies assessing effect of various allele variants of CYP3A4 and CYP3A5 on efficacy and tolerability of atorvastatin, lovastatin,, and simvastatin in different populations of patients. We also present data on populational frequency of genetic polymorphisms under study. In addition we cover the problem of possible influence of apoE genotype on efficacy of statins. The available data do not allow yet to recommend pharmacogenetic testing for wide clinical practice.
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PMID:[Effect of polymorphisms of cytochrome P450 and apolipoprotein E genes on therapeutic efficacy of statins]. 2110 32

Statins represent a major advance in the treatment of hypercholesterolemia, a significant risk factor for atherosclerosis. There is, however, notable interindividual variation in the cholesterolemic response to statins, and the origin of this variability is poorly understood; pharmacogenetics has attempted to determine the role of genetic factors. Myopathy, further, has been reported in a considerable percentage of patients, but the mechanisms underlying muscle injury have yet to be fully characterized. Most statins are the substrates of several cytochrome P450s (CYP). CYP polymorphisms may be responsible for variations in hypolipidemic activity; inhibitors of CYPs, e.g. of CYP3A4, can significantly raise plasma concentrations of several statins, but consequences in terms of clinical efficacy are not uniform. Pravastatin and rosuvastatin are not susceptible to CYP inhibition but are substrates of the organic anion-transporting polypeptide (OATP) 1B1, encoded by the SLCO1B1 gene. Essentially all statins are, in fact, substrates of membrane transporters: SLCO1B1 polymorphisms can decrease the liver uptake, as well as the therapeutic potential of these agents, and may be linked to their muscular side-effects. A better understanding of the mechanisms of statin handling will help to minimize adverse effects and interactions, as well as to improve their lipid-lowering efficiency.
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PMID:Clinical response to statins: mechanism(s) of variable activity and adverse effects. 2162 98