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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathophysiology of stroke in humans is much more complex than what is typically studied in animal models. Embolic stroke models are more complex than pure ischemia models, but are more representative of human disease and may be particularly useful in the study of new therapeutic strategies. Vascular damage is a prominent feature of embolic stroke, and may be a useful therapeutic target. Serotonin antagonists, adenosine-regulating agents, free radical scavengers, matrix metalloproteinase inhibitors, and HMG-CoA reductase inhibitors are all potentially valuable agents in treating vascular damage after stroke. These agents facilitate decreased infarction volume, hemorrhage, and improved cerebral bloodflow.
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PMID:Endothelium-targeted pharmacotherapeutics for the treatment of stroke. 1213 9

During the last decade, the development of the HMG CoA reductase inhibitors, commonly referred to as 'statins', has contributed greatly to cholesterol lowering therapy and cardiovascular risk reduction. These agents are well tolerated and efficacious. Data on nearly 30,000 patients from five long-term randomised, placebo-controlled trials of statins have clearly demonstrated that a broad range of individuals can benefit from such therapy. These include men or women, younger or older individuals, those with elevated or normal cholesterol levels, with or without myocardial infarction or symptomatic coronary heart disease, with or without hypertension or diabetes mellitus, and those who are smokers or non-smokers. Benefits include reductions in the risks for myocardial infarction, and coronary, cardiovascular and all-cause mortality, stroke and the need for coronary revascularisation. Results of the recently completed Heart Protection Trial have clearly confirmed the results of the earlier trials and support the use of statin therapy in secondary prevention. The role of statins in acute coronary syndromes is being actively evaluated and appears promising. In primary prevention, the data are not as convincing and generalisations cannot be made as to whether, and in which subgroup, drug therapy to lower low density lipoprotein (LDL) cholesterol should be initiated. There are important cost implications to consider and the use of statin therapy has to be judged on an individual basis, particularly in those with high or very high LDL cholesterol levels and/or with multiple risk factors rendering them at high short- and long-term risk of coronary heart disease. There is evidence of a 'care gap' in translating trial data into practice, even in secondary prevention, and this needs closing in order to improve patient outcomes.
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PMID:Who should receive HMG CoA reductase inhibitors? 1214 41

Many of the wide-ranging health benefits conferred by statin therapy are mediated, not by reductions in LDL cholesterol, but rather by inhibition of isoprenylation reactions essential to the activation of Rho family GTPases; this may be the mechanism primarily responsible for the favorable impact of statins on risk for ischemic stroke, senile dementia, and fractures, as well as the anti-hypertensive and platelet-stabilizing actions of these drugs. Indeed, the extent of these benefits is such as to suggest that most adults would be wise to take statins; however, owing to the significant expense of statin therapy, as well as to the potential for dangerous side effects that mandates regular physician follow-up, this strategy appears impractical. However, policosanol, a mixture of long-chain aliphatic alcohols extractable from sugar cane wax, has shown cholesterol-lowering potency comparable to that of statins, and yet appears to be devoid of toxic risk. Recent evidence indicates that policosanol down-regulates cellular expression of HMG-CoA reductase, and thus has the potential to suppress isoprenylation reactions much like statins do. Consistent with this possibility, the results of certain clinical and animal studies demonstrate that policosanol has many effects analogous to those of statins that are not likely explained by reductions of LDL cholesterol. However, unlike statins, policosanol does not directly inhibit HMG-CoA reductase, and even in high concentrations it fails to down-regulate this enzyme by more than 50% - thus likely accounting for the safety of this nutraceutical. In light of the fact that policosanol is quite inexpensive and is becoming available as a non-prescription dietary supplement, it may represent a practical resource that could enable the general public to enjoy health benefits comparable to those conferred by statins. In a long-term clinical study enrolling patients with significant symptomatic coronary disease, Esselstyn has demonstrated that a low-fat, whole-food vegan diet, coupled with sufficient statin therapy to maintain serum cholesterol below 150 mg/dL, can stop the progression of coronary disease and virtually eliminate further risk for heart attack. A comparable regimen, in which policosanol is used in place of statins, may represent a practical strategy whereby nearly everyone willing to commit to health-protective eating can either prevent coronary disease, or prevent pre-existing coronary disease from progressing to a life-threatening event.
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PMID:Policosanol safely down-regulates HMG-CoA reductase - potential as a component of the Esselstyn regimen. 1220 52

Stroke is a major cause of morbidity and mortality. Full assessment of stroke or transient ischaemic attack (TIA) patients is required to identify all risk factors and apply appropriate secondary preventative strategies. Antiplatelet therapies are effective in the secondary prevention of ischaemic stroke and can be justified despite adverse effects such as gastrointestinal haemorrhage. Aspirin (acetylsalicylic acid), aspirin plus dipyridamole, ticlopidine and clopidogrel are all of value but their adverse effect profiles vary significantly. Combinations of antiplatelet agents may offer additional benefit but not all combinations have been studied in stroke patients. Anticoagulation with agents such as warfarin is effective with coexisting atrial fibrillation and other conditions predisposing to cardioembolic stroke. Antihypertensive agents have been extensively studied in the primary prevention of stroke; however, relatively few trials of antihypertensive agents in the secondary prevention of stroke are available. The incidence of adverse effects of antihypertensive agents is relatively low and the benefit-risk profile would tend to favour their use in the secondary prevention of stroke. Recent studies of ACE inhibitors have identified an important role for these agents in the secondary prevention of stroke even in those who are normotensive and in those who have had a haemorrhagic stroke. The incidence of serious adverse effects with ACE inhibitors appears relatively low. Lipid-lowering agents may have a role to play in certain groups of patients with stroke. The incidence of adverse effects is relatively low with HMG-CoA reductase inhibitors. Cigarette smoking is an important risk factor for stroke and evidence is available that smoking cessation does reduce the individual's risk of stroke. Pharmacological agents are available to help smoking cessation. In patients with diabetes mellitus, intensive regimens with insulin and oral hypoglycaemic agents have so far not definitively been shown to reduce the incidence of macrovascular complications such as stroke. Tight glycaemic control has been shown to improve microvascular complications such as retinopathy, nephropathy and neuropathy and hence this is reason enough to advocate the use of these agents. Future developments in the treatment of diabetes may help. Secondary prevention of stroke has improved greatly over the past decade and hopefully will continue to improve. The use of pharmacological agents available currently and in the future will be clarified and refined as further clinical trials report.
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PMID:A benefit-risk assessment of agents used in the secondary prevention of stroke. 1238 Dec 15

HMG-CoA reductase is the rate-limiting enzyme for cholesterol synthesis and its inhibition exerts profound effects on cellular metabolism. Inhibitors of this enzyme are used in clinical practice to lower plasma cholesterol levels and are commonly collectively referred to as 'statins'. A number of in vitro, in vivo animal, and clinical studies suggest that properties of statins other than cholesterol lowering may be of biological importance. These diverse properties are often referred to as 'pleiotropic' and suggest that statins may affect a number of diseases of ageing. In this article we review the biological plausibility and clinical evidence of a role for statins in modulating two diseases of ageing: osteoporosis and dementia (including Alzheimer's disease). In both diseases, there is a sound cellular and laboratory basis for a plausible therapeutic effect of statins. In the case of osteoporosis, there are conflicting data regarding clinical benefit, with both negative and positive results reported. In particular, secondary analyses of randomised, controlled studies have shown no reduction of fracture risk by statins. In the case of dementia there are fewer clinical studies but there is clear anticipated benefit in macrovascular dementias attributable to statin-mediated reduction of the risk of stroke. Overall, there are a lack of prospective, placebo-controlled, randomised data testing statins and modulation of the risk of osteoporosis-related fracture or of clinical dementia, where these are primary outcomes. Until such data are available, the use of statins appears promising but cannot be recommended as a primary therapeutic modality for either condition.
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PMID:The pleiotropic effects of HMG-CoA reductase inhibitors: their role in osteoporosis and dementia. 1251 62

HMG-CoA reductase inhibitors (statins) have been established as the dominant treatment for coronary heart disease (CHD). This dominance is based on an impressive body of clinical trial evidence showing significant benefits in primary prevention of cardiovascular events in individuals at risk for CHD and in secondary prevention of such events in patients with CHD and high or normal plasma cholesterol levels. There is, however, significant room for improvement in the treatment of CHD with respect both to drug efficacy and to the disparity between evidence-based medicine and actual clinical practice particularly in relation to treatment strategies for the elderly. Current statins fall short of requirements for 'ideal' lipid-lowering treatment in several respects; 'super' statins and other agents currently in development may satisfy more of these requirements. Moreover, available therapies are not applied optimally, because of physician nonacceptance and/or patient noncompliance; thus, the majority of patients with CHD or its risk factors still have cholesterol levels that exceed guideline targets. There is also evidence that older patients with CHD, or at high risk of CHD, are undertreated - possibly because of concerns regarding the increased likelihood of adverse events or drug interactions or doubts regarding the cost effectiveness of statin therapy in this population. This group is of particular clinical relevance, since it is showing a proportionate rapid expansion in most national populations. To address their potential healthcare needs, the ongoing Pravastatin in the Elderly at Risk (PROSPER) study is assessing the effects of pravastatin in elderly patients (5804 men and women aged 70-82 years) who either have pre-existing vascular disease or are at significant risk for developing it, with the central hypothesis that statin therapy (pravastatin 40 mg/day) will diminish the risk of subsequent major vascular events compared with placebo. After a 3.2-year treatment period, a primary assessment will be made of the influence of statin treatment on major cardiovascular events (a combination of CHD death, nonfatal myocardial infarction, and fatal or nonfatal stroke). Optimal deployment of the currently available agents and of newer agents (no matter how well they satisfy requirements for ideal treatment) ultimately depends on the establishment of an evidence base and may require far-reaching educational programmes that change the way risk factor management is viewed by caregivers and patients alike.
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PMID:Statin therapy in the elderly: does it make good clinical and economic sense? 1264 82

Abstract Antithrombotic treatment has now been joined by other evidence-based drug interventions for prevention of stroke, including angiotensin-converting enzyme inhibitors and hydroxymethylglutaryl-CoA reductase inhibitors. The efficacy of oral anticoagulation in atrial fibrillation has not been seen in other stroke-prone groups, although trials are continuing. Diffusion-weighted magnetic resonance imaging improves diagnostic accuracy in acute stroke, which is important in arriving at the right secondary prevention strategy. Carotid endarterectomy has been shown to be beneficial for 50-69% symptomatic -stenosis but with a much narrower therapeutic index than for 70-99% stenosis. A comparison of endarterectomy with angioplasty and/or stent placement has been the subject of one small trial suggesting similar procedural stroke and mortality risks. Device closure of cardiac abnormalities increases in the absence of any trial data, and in spite of a low subsequent stroke risk for young patients with isolated patent foramen ovale treated with aspirin.
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PMID:Stroke prevention: what's new? 1268 Sep 84

Recent advances in the prevention and pharmacotherapy of cerebrovascular disease have provided more favorable clinical outcomes. For the treatment of an acute ischemic stroke, the early use of thrombolytic agents can reduce the degree of brain damage while improving functional outcomes. However, trials evaluating various classes of other neuroprotective agents have not shown benefit to date. For the prevention of second stroke, the use of antiplatelet drugs, HMG-CoA reductase inhibitors, and angiotensin-converting enzyme inhibitors with a diuretic have shown benefit in reducing new events. In patients with underlying heart disease or atrial fibrillation, warfarin appears to be the drug of choice in preventing stroke. Early treatment of hemorrhagic stroke with calcium channel blockers can improve the functional outcome. Innovative therapies are now available for the treatment of migraine and vascular dementia. Primary prevention of stroke remains the optimal therapeutic strategy and includes treatment of systemic hypertension and hypercholesterolemia.
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PMID:Drug therapy of neurovascular disease. 1270 43

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

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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