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-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or "statins", are used as cholesterol-lowering agents worldwide. Statins inhibit cholesterol biosynthesis, leading to enhanced uptake of low-density lipoprotein (LDL) from the circulation via LDL receptors. This strong cholesterol-lowering action contributes to the beneficial effects of statins. For example, large clinical trials have demonstrated that statins significantly reduce cardiovascular risk. Recent research has shown that statins have other multiple actions involved in endothelial function, cell proliferation, inflammatory response, immunological reactions, platelet function, and lipid oxidation. These "pleiotropic actions" of statins probably provide a significant contribution to the reduction of cardiovascular events. This review summarizes the pleiotropic actions of statins in both basic and clinical studies. It also considers the potential for statin therapy in the treatment of stroke and dementia.
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PMID:Cholesterol-independent effects of statins and new therapeutic targets: ischemic stroke and dementia. 1555 7

Neuroimaging and management advances require review of indications for excluding cerebral venous sinus (sinovenous) thrombosis (CSVT) in children. Our goals were to examine (i) clinical presentations of CSVT, (ii) prothrombotic risk factors and other predisposing events, (iii) clinical and radiological features of brain lesions in CSVT compared with arterial stroke, and (iv) predictors of outcome. We studied 42 children with CSVT from five European paediatric neurology stroke registries. Patients aged from 3 weeks to 13 (median 5.75) years (27 boys; 64%) presented with lethargy, anorexia, headache, vomiting, seizures, focal signs or coma and with CSVT on neuroimaging. Seventeen had prior chronic conditions; of the 25 previously well patients, 23 had recent infections, eight became dehydrated and six had both. Two children had a history compatible with prior CSVT. Anaemia and/or microcytosis (21 probable iron deficiency, five haemolytic, including two with sickle cell disease and one with beta-thalassaemia) was as common (62%) as prothrombotic disorder (13/21 screened). High factor VIII and homozygosity for the thermolabile methylene tetrahydrofolate reductase polymorphism were the commonest prothrombotic disorders. The superficial venous system was involved in 32 patients, the deep in six, and both in four. Data on the 13 children with bland infarction and the 12 with haemorrhage in the context of CSVT were compared with those from 88 children with ischaemic (AIS) and 24 with haemorrhagic (AHS) arterial stroke. In multiple logistic regression, iron deficiency, parietal infarction and lack of caudate involvement independently predicted CSVT rather than arterial disease. Five patients died, three acutely, one after recurrence and one after 6 months being quadriparetic and blind. Follow-up ranged from 0.5 to 10 (median 1) years. Twenty-six patients (62%) had sequelae: pseudotumour cerebri in 12 and cognitive and/or behavioural disabilities in 14, associated with epilepsy in three, hemiparesis in two and visual problems in two. Eighteen patients, including six with haemorrhage, were anticoagulated. Older age [odds ratio (OR) 1.54, 95% confidence limits (CI) 1.12, 2.13, P = 0.008], lack of parenchymal abnormality (OR 0.17, 95% CI 0.02, 1.56, P = 0.1), anticoagulation (OR 24.2, 95% CI 1.96, 299) and lateral and/or sigmoid sinus involvement (OR 16.2, 95% CI 1.62, 161, P = 0.02) were independent predictors of good cognitive outcome, although the last predicted pseudotumour cerebri. Death was associated with coma at presentation. Of 19 patients with follow-up magnetic resonance (MR) venography, three had persistent occlusion, associated with anaemia and longer prodrome. A low threshold for CT or MR venography in children with acute neurological symptoms is essential. Nutritional deficiencies may be modifiable risk factors. A paediatric anticoagulation trial may be required, after the natural history has been further established from registries of cases with and without treatment.
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PMID:Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome. 1569 61

Previous studies have shown that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) protect the brain against ischemic injury by upregulating endothelial nitric oxide synthase (eNOS). Here, we tested the hypothesis that statins provide additional beneficial effects by also upregulating endogenous tissue plasminogen activator (tPA) and enhancing clot lysis in a mouse model of embolic focal ischemia. Heterologous blood clots (0.2 mm) were injected into the distal internal carotid artery to occlude blood flow in the middle cerebral artery territory after long-term (14 days) simvastatin, atorvastatin or vehicle treatment. Ischemic lesion volume, neurologic deficits, as well as residual blood clots were measured at 22 h. Reverse transcription-polymerase chain reaction assessed mRNA levels of eNOS, tPA, and the endogenous plasminogen activator inhibitor PAI-1. Ischemic lesion volumes and neurologic deficits were significantly reduced in wild-type mice by both simvastatin and atorvastatin. Statins increased eNOS and tPA mRNA levels but did not change mRNA levels of PAI-1. In eNOS knockout mice, atorvastatin reduced the volume of ischemic tissue and improved neurologic outcomes after arterial occlusion by blood clot emboli. In contrast, statins did not have protective effects in tPA knockout mice after embolic focal ischemia, but only in a filament model where focal ischemia was achieved via mechanical occlusion. These results suggest that statins protect against stroke by multiple mechanisms involving both eNOS and tPA. The involvement of each pathway may be revealed depending on the choice of experimental stroke model.
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PMID:Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia. 1571 55

Recently, it has been demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitor or statin can regulate the thrombogenesis beyond its lipid lowering effect. In this study, we investigated the beneficial effect of statin to reduce the platelet P-selectin expression in atherosclerotic ischemic stroke. Thirty-two (28 men, 4 women; mean age 59.8 +/- 9.6 years) patients with atherosclerotic ischemic stroke were assigned to receive simvastatin 20 mg per day for 12 weeks and discontinued for another 12 weeks. Then, administration of simvastatin was discontinued for the following 12 weeks. Using whole blood flow cytometry, we evaluated the change of platelet P-selectin expression of all the patients after the 12-weeks use and the 12-weeks discontinuance of simvastatin. The platelet P-selectin expression was significant reduced after treatment of simvastatin 20 mg for 12 weeks (p < 0.001). However, the effect of statin to reduce platelet P-selectin expression disappeared after 12 weeks of cessation of statin. In addition, the P-selectin changes induced by statin were independent of the changes of the LDL cholesterol (r = -0.311, p = 0.386). This study demonstrated that the use of statin might be a helpful add-on therapy to regulate the platelet related thrombogenesis in atherosclerotic ischemic stroke.
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PMID:Statin reduces the platelet P-selectin expression in atherosclerotic ischemic stroke. 1574 52

Besides aspirin several new drugs for inhibition of platelet aggregation and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibition are used in secondary stroke prevention. Pharmacology and clinical effects, however, are not fully explained by current understanding of underlying mechanisms. Population spike amplitude (PSAP), an established marker of slice integrity, was measured during hypoxia and recovery thereof in hippocampal slices from control CD1 mice (25-35 g) and animals pretreated in vivo with a single i.p. injection of clopidogrel, ticlopidine, or atorvastatine at different time intervals and dosages. Posthypoxic recovery of PSAP was 20 +/- 35% in control CD1 mice. Upon pretreatment with clopidogrel (1-24 h, 0.5-2 mg/kg body weight) an increase up to 81 +/- 20% (p < 0.01 to control) was observed at 1h interval and 1mg/kg. Application of ticlopidine (1-24 h, 1-4 mg/kg body weight) resulted in an improvement of posthypoxic recovery to 61 +/- 41% (p < 0.05 to control) while administration of atorvastatine (1-24 h, 1-4 mg/kg body weight) caused an increase up to 87 +/- 31% (p < 0.01 to control) at 1h interval and 2 mg/kg. On application of these substances in vitro the NADH autofluorescence spectrum in hippocampal slices is blue-shifted suggesting an alteration of oxidative metabolism. The present data demonstrate a shared neuroprotective effect of agents known to inhibit platelets (acetylsalicylic acid, clopidogrel, and ticlopidine) and HMG-CoA reductase (atorvastatine). The time course of this neuroprotective action in the current experimental study (onset within an hour, duration of several hours in contrast to several days) resembles clinical practice in dosing these substances. We hypothesize that an increase of hypoxic tolerance resulting from mild mitochondrial inhibition by these substances is a principal constituent of the effectiveness of these drugs.
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PMID:Improved posthypoxic recovery in vitro on treatment with drugs used for secondary stroke prevention. 1575 83

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. 1582 62

Methyl-coenzyme M reductase (MCR) catalyses the formation of methane from methyl-coenzyme M (CH(3)-S-CoM) and coenzyme B (HS-CoB) in methanogenic archaea. The enzyme has an alpha(2)beta(2)gamma(2) subunit structure forming two structurally interlinked active sites each with a molecule F(430) as a prosthetic group. The nickel porphinoid must be in the Ni(I) oxidation state for the enzyme to be active. The active enzyme exhibits an axial Ni(I)-based electron paramagnetic resonance (EPR) signal and a UV-vis spectrum with an absorption maximum at 385 nm. This state is called the MCR-red1 state. In the presence of coenzyme M (HS-CoM) and coenzyme B the MCR-red1 state is in part converted reversibly into the MCR-red2 state, which shows a rhombic Ni(I)-based EPR signal and a UV-vis spectrum with an absorption maximum at 420 nm. We report here for MCR from Methanothermobacter marburgensis that the MCR-red2 state is also induced by several coenzyme B analogues and that the degree of induction by coenzyme B is temperature-dependent. When the temperature was lowered below 20 degrees C the percentage of MCR in the red2 state decreased and that in the red1 state increased. These changes with temperature were fully reversible. It was found that at most 50% of the enzyme was converted to the MCR-red2 state under all experimental conditions. These findings indicate that in the presence of both coenzyme M and coenzyme B only one of the two active sites of MCR can be in the red2 state (half-of-the-sites reactivity). On the basis of this interpretation a two-stroke engine mechanism for MCR is proposed.
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PMID:Temperature dependence of methyl-coenzyme M reductase activity and of the formation of the methyl-coenzyme M reductase red2 state induced by coenzyme B. 1584 25

Peripheral artery disease (PAD) is a problem frequently encountered by physicians who care for patients with coronary heart disease, diabetes mellitus, renal insufficiency, congestive heart failure, or stroke. Patients with PAD are at heightened risk of myocardial infarction and stroke and are 6 times more likely to die of cardiovascular causes than persons without the disease. There is an urgent need for therapies that reduce the incidence of vascular complications among patients with PAD. In recent years, a number of risk-lowering therapies have been validated by randomized controlled trials enrolling large numbers of patients with PAD. The available evidence supports aggressive lifestyle modification as well as the provision of an antiplatelet agent, an HMGCoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitor, and an angiotensin-converting enzyme inhibitor for cardiovascular protection in patients with PAD. As a result of their high baseline risk and the proven effectiveness of these interventions, most patients with PAD will benefit substantially from aggressive medical therapy.
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PMID:Management of risk in peripheral artery disease: recent therapeutic advances. 1608 48

In the summer of 2004, an evidence-based update of the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines for management of hypercholesterolemia was published. This detailed assessment of 5 major clinical trials, published since the ATP III report in 2001, was designed to provide guidance for physicians in decision making for patients at high risk and very high risk. We have tried to summarize this assessment by suggesting the following to clinicians: (1) Calculate global risk of coronary artery disease (CAD) to determine an overall strategy for cholesterol management. (2) Emphasize the benefits of diet, exercise, and weight control or therapeutic lifestyle change, especially in those with lifestyle risk factors. (3) Use 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors (statins) as first-line drugs to reduce risk of CAD and stroke in those at moderate to high risk. (4) If statins are prescribed, use moderate doses that reduce plasma levels of low-density lipoprotein (LDL) cholesterol by > or = 30% to 40%. (5) Strongly consider statin therapy in those with diabetes (with the exception of severe hypertriglyceridemia). (6) Consider LDL cholesterol-lowering drug therapy for lipids in older patients at risk. (7) Consider adding either a fibrate or nicotinic acid in high-risk patients with elevated plasma triglyceride values or low levels of plasma high-density lipoprotein cholesterol after statin therapy has achieved the LDL cholesterol goal. (8) Continue to treat those at low risk in similar fashion as before. This update is to inform current physician judgment in this area. Further clinical trial data that may modify or extend these recommendations are eagerly awaited.
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PMID:Recent National Cholesterol Education Program Adult Treatment Panel III update: adjustments and options. 1609 45

Statin drugs inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and share the common mechanism of lowering circulating levels of low-density lipoprotein (LDL) cholesterol, a powerful indicator of risk for cardiovascular disease. Large clinical trials have documented the benefit of hypolipidemic therapy for both primary and secondary prevention of coronary artery disease and stroke. Recent clinical findings, including direct comparator studies, now indicate that certain statins may slow progression of disease at a rate and to an extent that cannot be solely attributed to LDL reduction. The proposed mechanisms for such pleiotropic actions include enhancement of endothelial-dependent nitric oxide bioavailability, anti-inflammatory activity, and inhibition of oxidative stress. To understand the biochemical basis for such differences among statins, this article reviews their physicochemical properties and pharmacology at the molecular level.
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PMID:Intermolecular differences of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors contribute to distinct pharmacologic and pleiotropic actions. 1612 19


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