Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 3-hydroxy-3-methyl coenzyme A (HMG-CoA) reductase inhibitors or statins, specifically inhibit the enzyme HMG-CoA in the liver, thereby inhibiting the rate limiting step in cholesterol biosynthesis and so reducing plasma cholesterol levels. Numerous studies have consistently demonstrated that cholesterol lowering with statin therapy reduces morbidity and mortality from coronary heart disease, whilst recent evidence has demonstrated that benefits of statin therapy may also extend into stroke prevention. Since hypercholesterolaemia is a chronic condition, the long-term safety and tolerability of these agents is an important issue. Numerous large-scale clinical trials have consistently demonstrated a positive safety and tolerability profile for statins. Hepatic, renal and muscular systems are rarely affected during statin therapy, with adverse reactions involving skeletal muscle being the most common, ranging from mild myopathy to myositis and occasionally to rhabdomyolysis and death. Postmarketing data supports the positive safety and tolerability profile of statins, with an overall adverse event frequency of less than 0.5% and a myotoxicity event rate of less than 0.1%. The recent withdrawal of cerivastatin from the world market due to deaths from rhabdomyolysis has, however, focused attention on the risk of adverse events and in particular myotoxicity associated with statins. Indeed, initial clinical trial data supports postmarketing data, demonstrating a higher incidence of myotoxicity associated with cerivastatin, particularly when used in combination with fibrates. The potential mechanisms underlying statin-induced myotoxicity are complex with no clear consensus of opinion. Candidate mechanisms include intracellular depletion of essential metabolites and destabilisation of cell membranes, resulting in increased cytotoxicity. Cytochrome P450 3A4 is the main isoenzyme involved in statin metabolism. Reduced activity of this enzyme due to either reduced expression or inhibition by other drugs prescribed concomitantly such as cyclosporin or itraconazole may increase drug bioavailability and the risk of myotoxicity. Such factors may partly account for the interindividual variability in susceptibility to statin-induced myotoxicity, although other as of yet unclarified, genetic factors may also be involved. The risk of rhabdomyolysis is increased with combination fibrate-statin therapy, with initial evidence suggesting that gemfibrozil-statin combination may particularly increase the risk of myotoxicity, with pharmacodynamic as well as pharmacokinetic mechanisms being involved.
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PMID:Effects of HMG-CoA reductase inhibitors on skeletal muscle: are all statins the same? 1213 59

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been described as the principal and the most effective class of drug to reduce serum cholesterol levels. Statin therapies have been shown to reduce cardiovascular events, including myocardial infarction, stroke, and death, significantly, by altering vascular atherosclerosis development in patients with or without coronary artery disease symptoms. Extensive use of statins has led to the increase of some undesirable effects that are heavily counterbalanced by the benefits. Indeed, pleiotropic effects extend far beyond cholesterol reduction and involve non-lipid-related mechanisms that modify endothelial functions, immunoinflammatory responses, smooth muscle cell activation, proliferation and migration, atherosclerotic plaque stability, and thrombus formation. In this review, we describe in detail the targets and mechanisms of action of statins.
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PMID:Statins: the new aspirin? 1253 May 13

Statins reduce cholesterol levels through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme that regulates cholesterol synthesis. The cholesterol-lowering effect of statins is also due to an increase in the uptake of cholesterol by cells as a result of intracellular cholesterol depletion and enhanced expression of low-density lipoprotein (LDL) receptors. The use of statins as lipid-lowering agents has lead to remarkable changes in the treatment and prevention of ischemic heart disease. Results of large clinical trials of patients with ischemic heart disease have demonstrated that statins reduce inflammatory markers such as C-reactive protein, an independent risk factor in the disease. Statins exhibit properties that are beyond their lipid-lowering effects. These non-lipid-lowering properties involve the inhibition of the isoprenoid pathway through decreased synthesis of many nonsteroidal isoprenoid compounds. The focus on the immunomodulatory effect of statins is the result of the positive outcome of pravastatin treatment in cardiac transplantation patients, as well as angiographic regression studies showing insignificant changes in the degree of coronary stenosis despite a large reduction in cardiac events. Statin treatment reduces the risk of ischemic stroke despite the fact that LDL cholesterol is not directly associated with the risk of stroke. This observation lead to the investigation of the role of statins in inflammation and the immune system. Recent research data demonstrated that statins inhibit the induction of the major histocompatibility (MHC) class II expression by interferon-gamma (IFN-gamma), leading to repression of MHC II-mediated T-cell activation. Furthermore, statins inhibit the expression of specific cell surface receptors on monocytes, adhesion molecules and also integrin-dependent leucocyte adhesion. While statins may stimulate the secretion of caspase-1, IL-1beta and IL-18 in peripheral mononuclear cells in response to Mycobacterium tuberculosis, they exhibit additional effects on inflammation by decreasing IL-6 synthesis in human vascular smooth muscle cells (VSMC) in vitro. The focus of this monograph is to highlight the role of statins in the modulation of the immune system and inflammatory processes.
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PMID:Modulation of the inflammatory process by statins. 1269 8

Despite dramatic improvement in treatments for reducing risk for coronary heart disease (CHD), it is still the leading cause of mortality in the developed world. In the past decade, a major improvement in reducing low-density lipoprotein (LDL) cholesterol has been achieved with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). This approach has been shown to be beneficial in both primary and secondary prevention of CHD. On the other hand, while a reduced high-density lipoprotein (HDL) cholesterol level is an independent CHD risk factor, no HDL cholesterol goal has yet been established. The Helsinki Heart Study and the Veterans Affairs High-density Lipoprotein Intervention Trial documented that increasing HDL cholesterol with gemfibrozil significantly decreases coronary events or stroke in CHD patients either with elevated non-HDL cholesterol or normal LDL cholesterol levels plus low HDL cholesterol. Investigations with statins have focused on their efficacy not only in significantly decreasing total cholesterol, LDL cholesterol, and triglyceride levels but also in increasing HDL cholesterol concentrations. The two different classes of drugs (statins and fibrates) have different effects on the various HDL subspecies. As new members of these drug classes and other novel drugs are emerging, there is interest in clarifying whether HDL is only a bystander (an indicator for other CHD risk factors) or it has an active role in the development of CHD. If HDL has an active role, there is a need to determine if any HDL subspecies are protective. It is now clear that HDL plays a pivotal role in cellular cholesterol efflux via the interaction of apolipoprotein A-I with the ATP binding cassette transporter A-1. Thereafter the cholesterol is esterified by lecithin:cholesterol acyltransferase; HDL is remodeled by cholesterol ester transfer protein (CETP) and hepatic lipase. The cholesterol in HDL can either be transferred to apolipoprotein B-containing particles via CETP or delivered directly to the liver with the help of scavenger receptor B1.
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PMID:HDL in atherosclerosis: actor or bystander? 1271 34

We demonstrate that the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors atorvastatin and simvastatin enhance functional outcome and induce brain plasticity when administered after stroke to rats. With atorvastatin treatment initiated 1 day after stroke, animals exhibited significant increases in vascular endothelial growth factor, cyclic guanosine monophosphate, angiogenesis, endogenous cell proliferation and neurogenesis, and an increase in the synaptic protein, synaptophysin. Atorvastatin-induced angiogenesis in a tube formation assay was reduced by an antibody against the vascular endothelial growth factor receptor 2 (FIK-1) and by the nitric oxide synthase inhibitor, N-mono-methyl-L-arginine (L-NAME). Atorvastatin also induced phosphorylation of Akt and Erk in cultured primary cortical neurons. These data indicate that atorvastatin induced brain plasticity and has neurorestorative activity after experimental stroke.
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PMID:Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. 1278 20

(3S)-(+)-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one) (MaxiPost, BMS-204352) is a potent and specific opener for maxi-K channels and has potential to prevent and treat ischemic stroke. Following single intravenous doses of [14C]BMS-204352 to rats, only 10 to 12% of radioactivity was extractable from plasma with organic solvents. The unextractable radioactivity remained associated with the proteins (mostly albumin) after SDS-polyacrylamide gel electrophoresis or dialysis. Following acid hydrolysis in 6 M HCl for 24 h at 110 degrees C from plasma proteins collected from nine rats dosed with [14C]BMS-204352, one major radioactive product was isolated and identified as a lysine-adduct of des-fluoro des-O-methyl BMS-204352 by liquid chromatography/mass spectrometry and NMR analyses as well as by comparison with the synthetic analog, lysine-adduct of des-fluoro BMS-204352 (BMS-349821). The covalent binding of BMS-204352 results from the displacement of the ring-fluorine atom of des-O-methyl BMS-204352 with the epsilon-amino group of a lysine residue. Microsomal incubations of [14C]BMS-204352 resulted in low levels of covalent binding of radioactivity to proteins. This in vitro covalent binding required cytochrome P450-reductase cofactor NADPH and was attenuated by glutathione. P4503A inhibitors ketoconazole and troleadomycin selectively prevented the covalent binding in vitro. Based on these observations, a two-step bioactivation process for the protein covalent binding of BMS-204352 was postulated: 1) P4503A-mediated O-demethylation leading to spontaneous release of HF and the formation of an ortho-quinone methide reactive metabolite and 2) nucleophilic addition of the epsilon-amino group of protein lysine residue(s) in protein to form des-fluoro des-O-methyl BMS-204352 lysine adduct.
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PMID:Protein covalent binding of maxipost through a cytochrome P450-mediated ortho-quinone methide intermediate in rats. 1281 59

The development of statins improved the therapy of hypercholesterolemia and atherosclerotic disease tremendously. The beneficial effects of statins were clearly demonstrated in large scale primary and secondary prevention studies. In addition to the reduction of plasma cholesterol, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase also results in the depletion of intermediates of cholesterol biosynthesis that are important for cellular integrity. The so called pleiotrophic effects of statins and probably also their adverse events can be attributed to the inhibition of synthesis of these intermediates. The review article describes the pathogenesis of atherosclerosis, the pharmacokinetic and pharmacodynamik of statins, and their pleiotrophic effects concerning endothelial function, LDL (low density lipoprotein) oxidation, macrophages, smooth muscle cell proliferation, atherosclerotic plaque, platelets, thrombosis, proinflammatory factors, haemorheology, hypertension, venous thrombosis, bone metabolism, stroke, and the possible influence on the prevention of Alzheimer's disease.
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PMID:[Pleiotrophic effect of statins (3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors)]. 1367 44

Statins, 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors, inhibit the rate-limiting enzyme in cholesterol synthesis and lead to a significant reduction of plasma lipid concentrations. As a clear correlation exists between serum cholesterol and cardiovascular risk, statins have become increasingly important in current preventive medicine. Studies prompted by the extraordinary benefits afforded by these drugs have reported minimal changes in the vasculature of hypercholesterolemic patients when compared with clinical benefits and have led to further investigations to determine the underlying reasons for these clinical benefits. The purpose of this review is to present the wide array of systems that HMG-CoA reductase inhibitors are known to influence, which range from adverse events due to coronary artery disease, stroke risk, platelet function, endothelial function, and inflammatory effects to intracellular signaling pathways that control vascular cell migration, proliferation, and differentiation.
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PMID:Noncholesterol-lowering effects of statins. 1452 75

Paediatric patients with systemic lupus erythematosus (SLE) and antiphospholipid antibodies (aPL), specifically lupus anticoagulants (LAC) are at high risk of developing thromboembolic events (TE). Our objectives were to determine the prevalence of TE in paediatric SLE patients with LAC and to determine if anticoagulation was effective to decrease morbidity, and prevent recurrent TE. We reviewed data on 149 paediatric SLE patients treated over 10 years. In all, 24 patients (16%) were LAC positive, and 21 TE occurred in 13 of these LAC positive patients (54% incidence of TE in LAC positive patients). The events were cerebral venous thrombosis (9), arterial stroke (3), deep venous thrombosis (4), pulmonary embolism (2), other venous event (1) and other arterial events (2). The median duration between SLE diagnosis and first TE was 15.2 months (range 0-62), and the median age at first TE was 15.1 years (range 11.4-18.4). Long-term anticoagulation was prescribed, and eight patients (62%) were transferred to adult care on lifelong oral warfarin; four (31%) remain under our care on lifelong warfarin, and one patient died of causes unrelated to her TE. No patient has been identified with deficiencies of protein C, protein S or antithrombin III. One patient is heterozygous for Factor V Leiden, and one is heterozygous for both the Prothrombin 20210A mutation and the MTHFR (methylene tetrahydrofolate reductase) mutation. Four patients had recurrent TE (31%), and three were not anticoagulated at the time of their second event. One patient had two recurrences on therapeutic anticoagulation. Thromboembolic events are prevalent in the LAC positive paediatric SLE population, and consideration for lifelong anticoagulation must occur after an initial TE.
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PMID:Thromboembolism in paediatric lupus patients. 1459 22

Stroke is a heterogeneous disorder with significantly high morbidity and mortality. The relationship between serum cholesterol level and the incidence of stroke remains controversial. Recent evidence from primary and secondary prevention trials suggests that treatment with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors may reduce the incidence of stroke in patients with coronary artery disease (CAD). In this review, we attempt to outline and describe the potential mechanisms of HMG-CoA reductase inhibitors in the prevention of stroke. In addition to their lipid-lowering action HMG-CoA reductase inhibitors appear to exert their beneficial effects by various nonlipid-lowering mechanisms including anti-inflammatory effects, effect on endothelial function and coagulation cascade. Treatment with HMG-CoA reductase inhibitors is associated with decreased progression, plaque stablization and even regression of atheromatous plaque in the carotid arteries. HMG-CoA reductase inhibitors also inhibit the coagulation cascade at various levels such as activation of prothrombin, factor V, factor X and liberation of tissue factor in response to vascular injury. Inhibition of fibrinolysis occurs secondary to inhibition of plasmin generation. Pravastatin therapy is associated with a reduction in the size of aortic atheroma which is an independent risk factor for stroke. Lastly, left ventricular dysfunction after acute myocardial infarction is associated with an increased risk of stroke and HMG-CoA reductase inhibitors may indirectly decrease the incidence of stroke by reducing coronary events. Most of these effects are independent of the cholesterol-lowering effects of HMG-CoA reductase inhibitors. In conclusion, HMG-CoA reductase inhibitors may have a role in primary prevention of stroke in patients with CAD.
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PMID:How do HMG-CoA reductase inhibitors prevent stroke? 1472 94


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