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

Stroke is a disease of the elderly and, as a result of the expected demographic changes in many industrialised countries, its incidence is likely to increase in the future. A first-ever stroke significantly increases the likelihood of further events; thus, secondary prevention is of major importance. Only a minority of recurrent strokes can be prevented by surgical or other invasive methods, meaning that most secondary preventive measures involve drug treatment, which has become increasingly sophisticated in recent years. Ischaemic stroke constitutes the vast majority of all strokes; effective secondary prevention depends on a variety of factors, of which the correct classification in terms of subtypes and aetiological mechanisms is a pivotal prerequisite, as is the assessment of the patient's cardiovascular risk profile. In addition to the evaluation of pathomechanisms, stratification of subtypes of brain infarction is mainly based on morphology seen with brain imaging techniques, which provides additional evidence for the presumed cause of the stroke. Inhibitors of platelet function and anticoagulants are the two major groups of antithrombotic drugs used for the secondary prevention of stroke. Antiplatelet agents are still indicated in the majority of patients after ischaemic stroke, especially if an arterial origin is presumed. In addition to aspirin (acetylsalicylic acid), the position of which as the first-line antiplatelet drug is increasingly being questioned, other compounds with antiplatelet activity have been developed and have proven effective in secondary stroke prevention, including ticlopidine, clopidogrel and dipyridamole. Anticoagulants are principally indicated after cardioembolic ischaemic stroke; however, their inherent bleeding risks render their use in many cases rather difficult, in particular for elderly patients. Patient compliance with the recommended treatment is of major importance, given the somewhat limited efficacy of antithrombotic agents in stroke prevention. Since 'real world' experience does not match the circumstances under which clinical trials are conducted, this article will also deal with problems not covered by specific studies, such as risk stratification for anticoagulant treatment and how to proceed in cases of unknown stroke aetiology. The management of major cardiovascular risk factors is the other mainstay of secondary stroke prevention. Recent evidence indicates that antihypertensive treatment may be as effective as antithrombotic drugs for secondary prevention of stroke. This still needs to be proven for the treatment of other cardiovascular risk factors, such as diabetes mellitus and hypercholesterolemia. Nevertheless, the results of recent studies investigating the effect of HMG-CoA reductase inhibitors ('statins') on cardiovascular events strongly suggest a stroke-preventive effect.
 ...
PMID:Secondary prevention of stroke: a practical guide to drug treatment. 1501 3

Nitric oxide (NO) generated by endothelial NO synthase (eNOS) plays a crucial role in vascular function and homeostasis. NO possesses vasodilatory, anti-inflammatory, antithrombotic and antiproliferative properties. Augmentation of NO production increases cerebral blood flow, which can lead to neuroprotection during brain ischaemia. Several modalities that upregulate eNOS expression and/or activity have recently been identified, including HMG-CoA reductase inhibitors (statins), steroid hormones, nutrients and physical activity. They all increase NO bioavailability, leading to enhanced cerebral blood flow and protection from ischaemic stroke. Thus, therapeutic modalities that target eNOS not only serve as preventive measures to reduce stroke incidence but also could represent novel treatment strategies for reducing brain injury during cerebral ischaemia.
 ...
PMID:Targeting eNOS for stroke protection. 1511 Oct 11

Neurological sequela which occur with the medication and procedure to treat or prevent cerebrovascular diseases are reviewed. The report by the NINDS upon the recombinant tissue plasminogen activator (rt-PA) for cerebral infarction showed overall improved prognosis and increased number of cerebral hemorrhage from 1 to 9. Individual approach rather than statistical analysis should be applied to the adverse effect of the treatment. The rhabdomyolysis by statin, the HMG-CoA reductase inhibitor, is well known. The frequency of elevation in serum creatine kinase activity increases from water-soluble statin to lipid-soluble statin and to statin of longer half-life and with entero-hepatic recirculation. All of the interventional procedure such as embolization, stent, intravascular thrombolysis, endarterectomy and EC-IC bypass are possibly complicated by bleeding, arterial occlusion, distal embolism and so on. Guidelines are also a possible source of iatrogenic diseases. For example, 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension recommend at least 3 months of non-pharmacological treatment before starting the anti-hypertensive medications. The possibility to develop stroke within 3 months after the initial examination, however, is not zero. This is what can be called as guideline-induced neurological disease, of which practical physician should be reminded.
 ...
PMID:[Neurological complication due to the drug and the maneuver for the treatment and prevention of cerebrovascular diseases: iatrogenic neurology]. 1515 91

Significant amounts of di(2-ethylhexyl) phthalate (DEHP) leach out into blood stored in DEHP plasticized polyvinyl chloride (PVC) bags resulting in the exposure of recipients of blood transfusion to this compound. The aim of this study was to find out whether DEHP at these low levels has any effect on the activity of membrane Na(+)-K+ ATPase, since a decrease in this enzyme activity has been reported to take place in a number of disorders like neurodegenerative and psychiatric disorders, coronary artery disease and stroke, syndrome-X, tumours etc. DEHP was administered (ip) at a low dose of 750 microg/100 g body weight to rats and the activity of membrane Na(+)-K+ ATPase in liver, brain and RBC was estimated. Histopathology of brain, activity of HMG CoA reductase (a major rate limiting enzyme in the isoprenoid pathway of which digoxin, the physiological inhibitor of Na(+)-K+ ATPase is a product), intracellular concentration of Ca2+ and Mg2+ in RBC (which is altered as a result of inhibition of Na(+)-K+ ATPase) were also studied. (In the light of the observation of increase of intracellular Ca2+ load and intracellular depletion of Mg2+ when Na(+)-K+ ATPase is inhibited). Histopathology of brain revealed areas of degeneration in the rats administered DEHP. There was significant inhibition of membrane Na(+)-K+ ATPase in brain, liver and RBC. Intracellular Ca2+ increased in the RBC while intracellular Mg2+ decreased. However activity of hepatic HMG CoA reductase decreased. Activity of Na(+)-K+ ATPase and HMG CoA reductase, however returned to normal levels within 7 days of stopping administration of DEHP. The inhibition of membrane Na(+)-K+ ATPase activity by DEHP may indicate the possibility of predisposing recipients of transfusion of blood or hemodialysis to the various disorders mentioned above. However since this effect is reversed when DEHP administration is stopped, it may not be a serious problem in the case of a few transfusion; but in patients receiving repeated blood transfusion as in thalassemia patients or patients undergoing hemodialysis, possibility of this risk has to be considered. This inhibition is a direct effect of DEHP or its metabolites, since activity of HMG CoA reductase, (an enzyme which catalyses a major rate limiting step in the isoprenoid pathway by which digoxin, the physiological inhibitor of Na(+)-K+ ATPase is synthesized) showed a decrease.
 ...
PMID:Inhibition of membrane Na(+)-K+ Atpase of the brain, liver and RBC in rats administered di(2-ethyl hexyl) phthalate (DEHP) a plasticizer used in polyvinyl chloride (PVC) blood storage bags. 1524 77

There has been recent concern regarding the potential for certain HMG CoA reductase inhibitors (statins) to interfere with the activation of clopidogrel, thereby leaving patients susceptible to thrombotic events. Ex vivo studies have both supported and refuted an interaction, likely a result of heterogeneity in study design and methodology. More recent reports have been more consistent in demonstrating no increase in thrombotic event rates (myocardial infarction, stroke, etc) in patients receiving clopidogrel with a statin compared with clopidogrel alone, although these reports have all been retrospective in nature. Until a prospective study shows detriment when clopidogrel and statins are given together compared with either drug being administered alone, the debate regarding whether this interaction is of practical importance will continue. Until then, the weight of the evidence does not currently support a change in prescribing patterns for the sole purpose of avoiding a potential statin-clopidogrel interaction.
 ...
PMID:Clopidogrel--statin interaction. 1531 4

We investigated the neuroprotective effects of a novel 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (pitavastatin) on ischemic neuronal damage in gerbils using immunohistochemistry. The animals were allowed to survive for 14 days after 5 min of ischemia induced by bilateral occlusion of the common carotid arteries. Five days after ischemia, severe neuronal cell loss was observed in the hippocampal CA1 sector. Prophylactic treatment with pitavastatin dose-dependently prevented the hippocampal CA1 neuronal cell loss 5 days after ischemia. Immunohistochemical study did not show the change of nNOS and iNOS expression in the hippocampus except for, in a few regions, up to 1 day after ischemia. Thereafter, the expression of iNOS was observed in the hippocampal CA1 sector 5 and 14 days after ischemia. In contrast, the expression of nNOS and eNOS gradually decreased in the hippocampal CA1 sector up to 14 days after ischemia. Prophylactic treatment with pitavastatin also prevented the expression of iNOS and the decrease of eNOS expression and the number of nNOS-positive cells in the hippocampal CA1 sector 5 days after ischemia. However, prophylactic treatment with pitavastatin at a dose of 10 mg kg(-1) did not change the immunoreactivity of iNOS and nNOS in the hippocampus at an early phase after ischemia. In contrast, this drug prevented the reduction of eNOS immunoreactivity in the hippocampal CA1 neurons at an early phase after ischemia. These findings demonstrate that the HMG-CoA reductase inhibitor pitavastatin can protect hippocampal CA1 neurons after transient forebrain ischemia through up-regulation of eNOS expression in this region. Thus pharmacological modulation of eNOS expression may offer a novel therapeutic strategy for cerebral ischemic stroke.
 ...
PMID:Protective effect of pitavastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, on ischemia-induced neuronal damage. 1532 60

3-Hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, "statins," are widely used oral cholesterol-lowering drugs. Statins competitively inhibit HMG-CoA reductase, the enzyme that catalyzes conversion of HMG-CoA to L-mevalonate, a key intermediate in cholesterol synthesis. Certain metabolites of L-mevalonate are also involved in posttranslational modifications of specific proteins with cell proliferation and differentiation properties. Thus, statins have important biologic effects beyond their cholesterol-reducing properties. Here we discuss recent experimental and clinical data that may support a potential role for statins in the treatment of three central nervous system (CNS) neurological diseases: Multiple sclerosis (MS), Alzheimer's disease (AD), and ischemic stroke. Despite their considerable pathogenic differences, in animal models of these disorders statins have shown beneficial effects. In both stroke and AD cohort studies suggest a beneficial treatment effect in humans; in MS, results from small open-label studies look encouraging. Multicenter, randomized, placebo-controlled clinical trials are in the planning or recruiting stage to evaluate the therapeutic effects of statins in all three disorders.
 ...
PMID:[Statins for treatment of CNS diseases. Status report from research and clinical practice]. 1544 14

Grapefruit juice can alter oral drug pharmacokinetics by different mechanisms. Irreversible inactivation of intestinal cytochrome P450 (CYP) 3A4 is produced by commercial grapefruit juice given as a single normal amount (e.g. 200-300 mL) or by whole fresh fruit segments. As a result, presystemic metabolism is reduced and oral drug bioavailability increased. Enhanced oral drug bioavailability can occur 24 hours after juice consumption. Inhibition of P-glycoprotein (P-gp) is a possible mechanism that increases oral drug bioavailability by reducing intestinal and/or hepatic efflux transport. Recently, inhibition of organic anion transporting polypeptides by grapefruit juice was observed in vitro; intestinal uptake transport appeared decreased as oral drug bioavailability was reduced. Numerous medications used in the prevention or treatment of coronary artery disease and its complications have been observed or are predicted to interact with grapefruit juice. Such interactions may increase the risk of rhabdomyolysis when dyslipidemia is treated with the HMG-CoA reductase inhibitors atorvastatin, lovastatin, or simvastatin. Potential alternative agents are pravastatin, fluvastatin, or rosuvastatin. Such interactions might also cause excessive vasodilatation when hypertension is managed with the dihydropyridines felodipine, nicardipine, nifedipine, nisoldipine, or nitrendipine. An alternative agent could be amlodipine. In contrast, the therapeutic effect of the angiotensin II type 1 receptor antagonist losartan may be reduced by grapefruit juice. Grapefruit juice interacting with the antidiabetic agent repaglinide may cause hypoglycemia, and interaction with the appetite suppressant sibutramine may cause elevated BP and HR. In angina pectoris, administration of grapefruit juice could result in atrioventricular conduction disorders with verapamil or attenuated antiplatelet activity with clopidrogel. Grapefruit juice may enhance drug toxicity for antiarrhythmic agents such as amiodarone, quinidine, disopyramide, or propafenone, and for the congestive heart failure drug, carvediol. Some drugs for the treatment of peripheral or central vascular disease also have the potential to interact with grapefruit juice. Interaction with sildenafil, tadalafil, or vardenafil for erectile dysfunction, may cause serious systemic vasodilatation especially when combined with a nitrate. Interaction between ergotamine for migraine and grapefruit juice may cause gangrene or stroke. In stroke, interaction with nimodipine may cause systemic hypotension. If a drug has low inherent oral bioavailability from presystemic metabolism by CYP3A4 or efflux transport by P-gp and the potential to produce serious overdose toxicity, avoidance of grapefruit juice entirely during pharmacotherapy appears mandatory. Although altered drug response is variable among individuals, the outcome is difficult to predict and avoiding the combination will guarantee toxicity is prevented. The elderly are at particular risk, as they are often prescribed medications and frequently consume grapefruit juice.
 ...
PMID:Interactions between grapefruit juice and cardiovascular drugs. 1544 71

Atorvastatin (Lipitor) is an HMG-CoA reductase inhibitor with well documented lipid-lowering effects. It has recently been evaluated for the primary prevention of major cardiovascular events in patients with type 2 diabetes mellitus without elevated serum low-density lipoprotein (LDL)-cholesterol levels. Atorvastatin 10mg daily for 4 years was effective at reducing the risk of a first major cardiovascular event, including stroke, in a large, placebo-controlled, multicentre trial in patients with type 2 diabetes and at least one other coronary heart disease (CHD) risk factor, but without markedly elevated LDL-cholesterol levels. In this trial, known as CARDS (the Collaborative AtoRvastatin Diabetes Study), atorvastatin had a similar tolerability profile to that of placebo. Thus, atorvastatin has a potential role in the primary prevention of cardiovascular events in diabetic patients at risk of CHD, irrespective of pre-treatment LDL-cholesterol levels.
 ...
PMID:Atorvastatin: a review of its use in the primary prevention of cardiovascular events in patients with type 2 diabetes mellitus. 1561 62

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.
 ...
PMID:Improved posthypoxic recovery in vitro on treatment with drugs used for secondary stroke prevention. 1575 83


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>