Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Doctors prescribe patients more and more medications. This predominantly affects elderly people. Polypharmacy is more and more frequent and predominantly affects elderly people. It may lead to many harmful and virtually life threatening drug interactions. There is pressing need to investigate new remedies, which would be applied in many different and coexisting medical conditions. It is vital particularly in case of elderly people who usually suffer from many different diseases which have numerous common pathogenetic pathways. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are a widely prescribed drug class for treatment of dyslipidemias and their complications such as coronary artery disease, stroke and peripheral arteriosclerosis. Now, there is accumulating evidence that statins also have beneficial pleiotropic effects that may make them useful in treatment of such diseases as dementia, osteoporosis, some forms of cancer, diabetes mellitus and its microangiopathic complications, hypertension and prevent deep vein thrombosis. Should we call statins "21st century aspirin?" This paper reviews recent data concerning the possibility of using statins in new indications; particularly in dementia (including Alzheimer's disease), osteoporosis, cardiovascular accidents and some forms of neoplasms.
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PMID:[Statins--"21st century aspirin"?]. 1619 42

C-reactive protein (CRP) is a non-specific biomarker of inflammation. Recent research has shown that inflammation is an important step in the genesis of atherosclerosis, and is involved in the development of unstable plaques. Measurement of serum levels of CRP using a high sensitivity assay (hsCRP) can demonstrate subclinical inflammatory states, which may reflect vascular inflammation. Clinical studies have shown that elevated hsCRP levels in healthy populations predict vascular events such as myocardial infarction (MI) and stroke as well as the development of diabetes. In patients with acute coronary syndromes, higher hsCRP levels are associated with adverse outcomes and subsequent vascular events. There is data to suggest that aspirin, angiotensin converting enzyme (ACE) inhibitors and HMG Co-A reductase inhibitors (statins), which all reduce vascular event rates, also reduce serum levels of hsCRP and therefore hsCRP levels may potentially guide therapy. As well as having a critical role in risk prediction, recent evidence has emerged implicating CRP directly in atherogenesis. CRP has been found in human atherosclerotic plaque and CRP has been shown to cause endothelial cell dysfunction, oxidant stress and intimal hypertrophy in experimental models. We review the postulated roles of CRP in atherogenesis and prediction of vascular events, as well as discussing current recommendations for CRP testing in patients.
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PMID:The novel role of C-reactive protein in cardiovascular disease: risk marker or pathogen. 1633 36

The aim of the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial was to determine whether intensive low-density lipoprotein (LDL)-cholesterol lowering to a level of approximately 70 mg/dL (1.8 mmol/L) with atorvastatin 80 mg/day was more efficacious than standard LDL cholesterol lowering to 100 mg/dL (2.6 mmol/L) with pravastatin 40 mg/day in reducing the incidence of cardiovascular events in patients with acute coronary syndrome (ACS). In total, 4,162 men and women aged >18 years, who had been hospitalized for an ACS within the preceding 10 days, were randomized to receive either pravastatin 40 mg/day or atorvastatin 80 mg/day. The median LDL cholesterol levels achieved during follow-up were 95 mg/dL (2.5 mmol/L) in the pravastatin group and 62 mg/dL (1.6 mmol/L) in the atorvastatin group (P <0.001). Standard treatment (statin) with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (pravastatin 40 mg/day) resulted in a 22% reduction in LDL cholesterol levels at 30 days compared with a 51% reduction with intensive therapy (atorvastatin 80 mg/day). At 2 years, a relative risk reduction of 16% (95% confidence interval, 5%-26%; P = 0.005) in the primary end point rate (death, myocardial infarction, documented unstable angina requiring hospitalization, coronary revascularization, or stroke) was seen in patients receiving intensive statin treatment compared with standard statin therapy. The benefit of intensive treatment was apparent as early as 30 days and was consistent over time. The PROVE IT-TIMI 22 data indicate that patients recently hospitalized for an ACS benefit from early and continued lowering of LDL cholesterol to levels substantially below current guideline recommendations.
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PMID:Improved outcome after acute coronary syndromes with an intensive versus standard lipid-lowering regimen: results from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial. 1635 5

Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase used in the prevention of cardiovascular disease (CVD). In addition to their cholesterol-lowering activities, statins exert pleiotropic antiinflammatory effects, which might contribute to their beneficial effects not only on CVD but also on lipid-unrelated immune and inflammatory diseases, such as rheumatoid arthritis, asthma, stroke, and transplant rejection. However, the molecular mechanisms involved in these antiinflammatory properties of statins are unresolved. Here we show that the peroxisome proliferator-activated receptor (PPAR) alpha mediates antiinflammatory effects of simvastatin in vivo in models of acute inflammation. The inhibitory effects of statins on lipopolysaccharide-induced inflammatory response genes were abolished in PPARalpha-deficient macrophages and neutrophils. Moreover, simvastatin inhibited PPARalpha phosphorylation by lipopolysaccharide-activated protein kinase C (PKC) alpha. A constitutive active form of PKCalpha inhibited nuclear factor kappaB transrepression by PPARalpha whereas simvastatin enhanced transrepression activity of wild-type PPARalpha, but not of PPARalpha mutated in its PKC phosphorylation sites. These data indicate that the acute antiinflammatory effect of simvastatin occurs via PPARalpha by a mechanism involving inhibition of PKCalpha inactivation of PPARalpha transrepression activity.
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PMID:Acute antiinflammatory properties of statins involve peroxisome proliferator-activated receptor-alpha via inhibition of the protein kinase C signaling pathway. 1639 46

Healthy endothelium is essential for undisturbed functioning of the cardiovascular system, while endothelial dysfunction leads to its various pathologies. For example endothelial dysfunction precedes clinical symptoms of atherothrombosis, such as acute coronary syndrome, ischemic stroke, peripheral arterial disease or diabetic microangiopathies e.g. retinopathy and nephropathy. Accordingly, pharmacological reversal of endothelial dysfunction may represent a new approach in preventing the aforementioned vasculopathies. In modern cardiovascular pharmacology, inhibitors of angiotensin converting enzyme (ACE-I) or inhibitors of HydroxyMethylGlutaryl-CoA (HMG-CoA) reductase (statins) are among the most widely used cardiovascular drugs. Originally, ACE-I and statins were introduced to clinical medicine to lower arterial blood pressure or to lower blood LDL cholesterol levels, respectively. They were respectively targeted to inhibit ACE in blood or to inhibit HMG-CoA reductase in the liver. Surprisingly, these two classes of drugs apart from their classic mechanisms of action exert pleiotropic endothelial actions, which involve the inhibition of ACE or HMG-CoA reductase within the endothelium, as well as other less understood endothelial mechanisms. Typically, therapeutic effectiveness of ACE-I by far exceeds the benefits expected from their hypotensive effect or as the matter of fact of other hypotensive drugs. Similarly, statins offer cardiovascular protection irrespective of initial LDL cholesterol levels in patients. In our view, it is the endothelial action of ACE-I or statins that contributes significantly to their anti-inflammatory, anti-thrombotic, and vasculoprotective actions. Importantly, actions of ACE-I or statins are not limited to the correction of functioning of a single endothelial mediator, but they do possess a broader spectrum of endotheliotropic properties that proved efficient in preventing atherothrombosis and other vasculopathies. Quite surprisingly, the history of ACE-I and statins has a major impact for the future development in pharmacology of endothelium.
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PMID:Angiotensin converting enzyme (ACE) and HydroxyMethylGlutaryl-CoA (HMG-CoA) reductase inhibitors in the forefront of pharmacology of endothelium. 1641 89

Homocyst(e)ine elevation is associated with a two- to threefold fold increased risk of ischemic stroke. Although most commonly associated with large-artery atherosclerosis and venous thrombosis, hyperhomocysteinemia may contribute to stroke by other mechanisms as well. Levels of homocysteine are determined by genetic regulation of the enzymes involved in homocyst(e)ine metabolism and by levels of the vitamin cofactors (folate, B (6), and B (12)) associated with those reactions. Emerging evidence suggests that genetic variation within this pathway, such as the methyleneterahydrofolate reductase and cystathionine beta-synthase and nicotinamide N-methyltransferase genes, increases the risk of ischemic stroke. The introduction of grain folate fortification in 1998 has reduced homocyst(e)ine concentrations in the U.S. population. However, it is important to screen for vitamin B (12) deficiency and be cognizant that vitamin B (6) levels may be low in the elderly and in individuals with inflammatory disorders. The Vitamin Intervention in Stroke Prevention study failed to prove that high-dose supplementation with folate, B (6), and B (12) reduced the risk of recurrent stroke or myocardial infarction at 2 years; however, there is an ongoing clinical trial evaluating the potential benefit of vitamin supplementation.
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PMID:Homocyst(e)ine and stroke. 1647 41

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are potent cholesterol-lowering drugs. In addition to their cholesterol-lowering properties, statins exert a number of so-called 'pleiotropic', vasculoprotective actions that include improvement of endothelial function, increased nitric oxide (NO) bioavailability, antioxidant properties, stabilisation of atherosclerotic plaques, regulation of progenitor cells, inhibition of inflammatory responses and immunomodulatory actions. Pleiotropic actions of statins may have potential clinical impact in vascular disease beyond cholesterol lowering. The ongoing Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), for example, tests the effects of statins in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol (LDL-C) and elevated high-sensitivity C-reactive protein (hs-CRP). Additionally, previous studies have shown that although cholesterol is not an established stroke risk factor, statin therapy is associated with a reduction in the incidence of strokes. It is known that sudden withdrawal of statin treatment may acutely impair vascular function and increase morbidity and mortality in patients with vascular disease. Furthermore, the anti-inflammatory effects of statins may have clinical impact in a number of non-vascular conditions including multiple sclerosis and rheumatoid arthritis.
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PMID:Statins: potential new indications in inflammatory conditions. 1650 22

The reduction of circulating atherogenic lipoproteins through lifestyle modification and pharmacologic intervention is an important therapeutic goal in patients at risk for acute cardiovascular events. A large number of clinical trials have demonstrated that the reduction of low-density lipoprotein cholesterol (LDL-C) is associated with significant decreases in the incidence of all cause mortality, stroke, fatal and nonfatal myocardial infarction, and the need for revascularization with coronary artery bypass grafting and percutaneous transluminal coronary angioplasty. Therapy with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (i.e., statins) are the agents of choice for treating a variety of dyslipidemias, particularly when LDL-C levels are elevated. The statins are highly efficacious; however, not all patients are able to tolerate the higher doses of these medications due to adverse side-effects such as hepatoxicity and myotoxicity. Moreover, many patients cannot achieve their various lipoprotein targets at even the highest doses of these medications. Ezetimibe is a novel cholesterol absorption inhibitor that blocks the translocation of dietary and biliary cholesterol from the gastrointestinal lumen into the intracellular space of jejunal enterocytes. Ezetimibe undergoes enterohepatic recirculation with minimal systemic exposure and not does not adversely impact the pharmacokinetic profile of statins. Ezetimibe significantly reduces serum LDL-C. It is safe when used as monotherapy or when used in combination with statins. Ezetimibe is indicated in the management of hyperlipidemia, familial hypercholesterolemia, and sitosterolemia and significantly increases the percentage of patients able to reach their lipid-lowering goals.
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PMID:Cholesterol absorption blockade with ezetimibe. 1650 65

Our objective was to characterize the etiologic factors and outcome for stroke in children. We retrospectively reviewed the charts of patients between the ages of 40 days and 94 months (36.5 +/- 23.7 months) with stroke seen at Istanbul Medical Faculty, Department of Pediatrics between January 1995 and December 2003. We found 79 cases of stroke: 57 ischemic and 22 hemorrhagic strokes. Seventeen children had vitamin K deficiency dependent hemorrhage. In 14 children stroke occurred as a complication of cardiac disease, 7 had moyamoya disease, 3 had protein C deficiency, 2 had thalassemia, 2 had hyperhomocysteinemia (methylene tetrahydrofolate reductase gene mutation), 2 were heterozygote for factor V Leiden, 3 had Down's syndrome, 1 was diagnosed with antiphospholipid syndrome, 1 had glycogen storage disease, and in 28 children no underlying cause could be found. Multiple risk factors were found in 4 children. The outcome in all 79 stroke patients was as follows: asymptomatic 60%; symptomatic epilepsy or persistent neurologic deficit 37%; death 3%; and recurrent stroke 5%. Thus, an underlying cause for stroke was identified in 65% of the children in the study group; 40% of the children either died or suffered motor and/or cognitive sequelae.
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PMID:Stroke in childhood: experience in Istanbul, Turkey. 1663 11

Coronary heart disease (CHD) and stroke share common risk factors and are the leading causes of death and disability in the United States. Although the impact of elevated cholesterol on stroke risk has been disputed, numerous trials using 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (ie, statins) in patients with CHD have demonstrated a significant reduction in stroke incidence as a secondary endpoint. It is likely that statins are pleiotropic in stroke prevention, providing benefits through both cholesterol reduction and cholesterol-independent mechanisms. In this article, we review the relationship between cholesterol and stroke, randomized trials of statins in patients with CHD and high risk for CHD that have assessed stroke risk, and the putative mechanisms of stroke prevention by statins.
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PMID:Statin therapy for coronary heart disease and its effect on stroke. 1682 1


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