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)

Inhibitors of HMG-CoA reductase (statins) are potent cholesterol-lowering drugs. Large clinical trials have shown that statins reduce the incidence of cerebrovascular events, which might be surprising because cholesterol is not an established risk factor for stroke. In addition to their cholesterol-lowering properties, statins exert a number of pleiotropic, vasculoprotective actions that include improvement of endothelial function, increased nitric oxide (NO) bioavailability, antioxidant properties, inhibition of inflammatory responses, immunomodulatory actions, regulation of progenitor cells, and stabilization of atherosclerotic plaques. In fact, statins augment cerebral blood flow and confer significant protection in animal models of stroke partly via mechanisms related to the upregulation of endothelial nitric oxide synthase. Retrospective clinical evidence suggests that long-term statin administration may not only reduce stroke risk but also improve outcome. Early secondary prevention trials are underway to test the hypothesis that statin treatment initiated immediately after an event improves short-term outcome. Lastly, recent evidence suggests that sudden discontinuation of statin treatment leads to a rebound effect with downregulation of NO production. Withdrawal of statin treatment may impair vascular function and increase morbidity and mortality in patients with vascular disease.
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PMID:Statins and stroke. 1581 80

Sir John Vane named vascular endothelium 'the maestro of blood circulation'. Recently, 'the maestro' has become a target for pharmacotherapy of atherothrombotic and diabetic vasculopathies with well known cardio-vascular drugs belonging to the families of Angiotensin Converting Enzyme inhibitors, HMG CoA reductase inhibitors or beta1-Adrenoceptor antagonists. These drugs became upgraded to a position of the pleiotropic endothelial drugs. It is not a simple verbal change in the nomenclature. It means that these drugs apart from their well defined mechanisms of action, as indicated in their regular names, in addition they act in an unknown mechanism at the level of vascular endothelium preventing angina, myocardial infarction and stroke. Many biochemical events take place in endothelial cells. I chose for a closer inspection the nitric oxide/prostacyclin defensive system to explain the endothelial pleiotropism of the drugs in question. I tried to examine the validity of this conception according to the general rule: in vitro cognitio sed in vivo veritas.
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PMID:Pharmacology of vascular endothelium. Delivered on 27 June 2004 at the 29th FEBS Congress in Warsaw. 1595 56

Statins, i.e. HMG-CoA reductase inhibitors, reduce the risk of stroke and may have therapeutic potential for other neurologic diseases, including multiple sclerosis and Alzheimer's disease. In addition to lowering cholesterol levels, statins exert a number of cholesterol-independent (pleiotropic) effects. While endothelial, anti-thrombotic, anti-inflammatory, and immunomodulatory, i.e. peripheral, effects of statins are well known, little is known about the direct effects on neurons. This may be of clinical relevance because some statins are able to cross the blood-brain barrier. Recent experimental studies demonstrate that statins reduce the activity of neuronal glutamate receptors and protect neurons from excitotoxic insults. At higher doses, however, statins may also inhibit neurite sprouting and even induce neuronal apoptosis.
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PMID:[Direct neuronal effects of statins]. 1602 81

Treatment with statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) reduces the risk of ischemic stroke among patients with increased risk of vascular disease. Recent experimental data point to neuroprotective properties of statins in acute cerebral ischemia. There is a proven link between bioavailability of nitric oxide and the activity of statins and ischemic stroke. Due to their ability to up-regulate nitric oxide synthase, statins have been considered in the therapy of a number of the central nervous system disorders, including cerebral ischemia, Alzheimer's disease, Parkinson's disease, tumors, and trauma. It has been claimed that they suppress inflammatory response and secondary injury after acute ischemia.
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PMID:Neuroprotective properties of statins. 1622 38

Stroke is the third leading cause of death in the US and a common cause of long-term disability worldwide. Ischemic strokes, which are often atherothrombotic, account for more than 80% of all strokes. Current stroke prevention focuses on optimizing the treatment of modifiable risk factors, such as hypertension, diabetes and dyslipidemia. The epidemiologic association between serum cholesterol levels and adjusted stroke rates is not as strong as the link between serum cholesterol levels and coronary heart disease. Clinical trials of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), which are potent inhibitors of cholesterol synthesis, have demonstrated, however, a marked reduction in stroke risk in hypercholesterolemic and atherosclerotic individuals, with benefits extending to normocholesterolemic individuals. These findings suggest that statins might have additional effects in stroke protection beyond cholesterol reduction. Because statins inhibit the synthesis of isoprenoid intermediates in the cholesterol biosynthetic pathway, which are important lipid attachments for intracellular signaling molecules, they might have direct noncholesterol-dependent effects on inflammatory and endothelial cells. Here we discuss data from clinical trials assessing the effects of statins on stroke risk, as well as outline the mechanisms underlying the cholesterol-independent effects of statins and provide evidence-based recommendations for stroke prevention, based on achieved serum cholesterol levels in patients at risk of stroke.
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PMID:Drug Insight: statins and stroke. 1625 69

Dyslipemia is a clear risk factor (RF) for ischemic heart disease and peripheral artery disease, but its relation with ischemic stroke (IS) is not so clear. HMG-CoA reductase inhibitor drugs or statins (simvastatin, atorvastatin, pravastatin) reduce the relative risk of IS by between 18 and 51% in patients with IHD, in patients with high vascular disease risk and in hypertensive patients with other RFs, acute coronary syndrome, and type 2 diabetes mellitus. According to the guidelines for use, statins are indicated in the majority of patients with IS since the risk is equivalent to that of IHD or high vascular disease risk. In view of the existing clinical evidence of benefit, it would not seem unreasonable to proceed with treatment of patients using statins while awaiting specific studies justifying their use. The non-lipid-lowering mechanisms of the statins and results of studies, such as the Heart Protection Study, provide evidence for widening the indications of statins beyond the prevention of dyslipemia, as a new therapeutic approach in the prevention of IS in patients with plasma levels of total cholesterol or low density lipoproteins currently considered within the normal distribution. The neuroprotective role, which these drugs may play in the acute phase of cerebral ischemia, remains to be clarified, but very recent evidence suggests that such patients may also benefit.
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PMID:Lipids and stroke: the opportunity of lipid-lowering treatment. 1632 54

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

Besides classical risk factors such as hypercholesterolemia and hypertension, chronic subacute inflammation has recently been recognized as an important force driving the development of atherosclerosis, the most common underlying cause of myocardial infarction and stroke. There is compelling evidence that a disturbance of cholesterol homeostasis contributes to the development of a chronic inflammatory state and that inhibitors of HMG-CoA reductase (statins) may dampen inappropriate inflammatory responses. We review the evidence and suggest mechanisms by which dietary cholesterol can induce an atherogenic inflammatory response in liver and vessel wall, with particular emphasis on the time course of this inflammatory response during atherogenesis and the interplay between these tissues. We discuss how statins interfere in this process, and whether they may reduce chronic subacute inflammation via a) their cholesterol-lowering effect, and/or b) their cholesterol-independent (pleiotropic) vasculoprotective activities. Recent studies performed in (humanized) animal models allow us to distinguish the lipid-lowering-dependent from the lipid-lowering-independent functions of statins. Using these data, we discuss the degree to which the lipid-lowering-dependent and lipid-lowering-independent effects of statins contribute to a reduction of inflammation, allowing estimation of the relevance of pleiotropic statin effects for the human situation.
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PMID:HMG-CoA reductase inhibitors: effects on chronic subacute inflammation and onset of atherosclerosis induced by dietary cholesterol. 1650 64

In the past years, statins have emerged as the most important class of lipid lowering agents. Through inhibition of HMG-CoA reductase, they restrict the rate-limiting step of cholesterol synthesis, which leads to upregulation of LDL receptors on the cell membrane and thus reduction of atherogenic LDLs. This effect translates into clinical benefit by reducing cardiovascular events both in primary and secondary prevention settings. As an approximate rule, statin therapy leads to a relative risk reduction of 25-30% in most of the large randomised controlled trials. Stroke risk is reduced to a similar degree. Despite initial concerns, the currently available statins have a favourable safety profile; however, potential interactions with other drugs must be considered. Recently, characteristics unrelated to LDL lowering have been intensively studied. These pleiotropic statin effects result from decreased levels of isoprenoid intermediates of cholesterol synthesis. They include--among others--anti-inflammatory, anti-proliferative, and immunomodulatory actions. Pleiotropic effects favourably influence pathomechanisms of plaque formation. Furthermore, they may prove beneficial in the prevention or treatment of diseases unrelated to atherosclerosis, eg rheumatoid arthritis, multiple sclerosis, or cancer.
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PMID:The role of statins in clinical medicine--LDL--cholesterol lowering and beyond. 1663 45

Vascular damage occurring after cerebral ischemia may lead to a worse outcome in patients with ischemic stroke, as it facilitates edema formation and hemorrhagic transformation. There are several phases in the development of vascular injury (acute, subacute and chronic) and different mediators act in each one. Therapeutic options to avoid vascular injury must be focused on acting in each phase. However, even though experimental studies have demonstrated the benefit of therapeutic interventions both in the acute and chronic phases of cerebral ischemia, only the chronic phase offers a therapeutic window sufficiently wide enough to provide vascular protection in clinical practice. Several drugs including erythropoietin and HMG-CoA reductase inhibitors (statins), antihypertensive (angiotensin modulators), antibiotics (minocycline) and antihyperglycemic drugs (thiazolidinediones) have been proved to provide vascular protection in patients with ischemic stroke. Anti-inflammatory, antioxidant, and antiapoptotic actions are responsible for the vascular protective effect related to these drugs.
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PMID:Vascular protection in brain ischemia. 1665 11


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