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)

Secondary prevention of stroke and other manifestations of atherothrombosis is essential if the burden of disease associated with these events is to be reduced. Therefore, it is important to identify patients most likely to benefit from antiplatelet therapy. There is a good rationale for combining antiplatelet agents with different modes of action, since different signalling pathways contribute to platelet activation. Based on the promising results obtained with an adenosine diphosphate receptor antagonist-aspirin combination in coronary stenting, several additional trials with clopidogrel plus aspirin are ongoing. They include CURE (Clopidogrel in Unstable angina to prevent Recurrent Events, in unstable angina and non-Q-wave myocardial infarction) and COMMIT (in acute myocardial infarction), which compare clopidogrel with placebo in patients receiving aspirin, and CREDO (Clopidogrel for Reduction of Events During extended Observation), a 1-year treatment follow-up to the clopidogrel arms of the CLASSICS trial (Clopidogrel Aspirin Stent International Cooperative Study). Planned trials with clopidogrel in neurology include SPS3 (Secondary Prevention of Small Subcortical Strokes, in patients with symptomatic lacunar stroke), and MATCH (Management of Atherothrombosis with Clopidogrel in High-risk patients, in patients with stroke or transient ischaemic attack plus one additional risk factor), which will compare the efficacy of clopidogrel plus aspirin versus clopidogrel in reducing important ischaemic events. Combination therapy with an oral glycoprotein (GP) IIb/IIIa receptor antagonist plus aspirin has so far been less promising. Trials of three compounds--orbofiban, xemilofiban and sibrafiban--in combination with aspirin for secondary prevention in cardiac patients have reported increased mortality compared with aspirin alone. A similar effect was seen when sibrafiban monotherapy was compared directly with aspirin alone. Trials of newer oral GP IIb/IIIa inhibitors are under way or are planned. The combination of dipyridamole plus aspirin appears to be superior to aspirin alone for the prevention of stroke in patients with stroke or transient ischaemic attack; the effectiveness of this combination is being further investigated in ESPRIT (European/Australian Stroke Prevention in Reversible Ischaemia Trial).
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PMID:Future perspectives for optimizing oral antiplatelet therapy. 1131 19

This is the first Hungarian paper on the platelet glycoprotein IIb/IIIa (LeuPro 33) polymorphism in stroke patients. There are conflicting data about the role of this polymorphism in the pathogenesis of arterial thrombosis. The aim of our study was to describe the prevalence of PLA1/PLA2 in healthy persons and in stroke patients. From the same study population other polymorphism (prothrombin gene 20210 G/A) also has been determined. Blood sample was investigated by polymerase chain reaction in 173 unrelated healthy donors and 234 stroke patients. Stroke was documented by CT and MRI. We used a rutin questionnaire to study previous vascular events and conventional risk factors of patients. Prevalence of PLA1/PLA2 was 23.5% among healthy persons. That is higher than in other European countries (15%). It was 30.4% in stroke patients (OR: 1.42, 95%; CI: 0.87-2.31; p = 0.15). Heterozigous PLA was found in patients older than 50 by 33.6% (OR: 1.65, 95%; CI: 0.94-2.87; p = 0.09). Previous vascular events and conventional risk profil were not significantly different between PLA1/PLA1 and PLA1/PLA2 groups of patients. In patients under 50 having 20-85% stenosis of internal carotid artery there was a higher prevalence (p = 0.09). Comparing stroke patients to control population there was a slight increase (OR: 7.0; p = 0.06) in the frequency of two polymorphisms (PLA and factor II) together in the stroke cases. Polymorphism of GP IIb/IIIa LeuPro 33 seemed to be increased in stroke patients above 50 years. Carotid stenosis with polymorphism is a risk factor for young patients. PLA variant together with prothrombin gene polymorphism results very high risk for stroke.
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PMID:[Platelet glycoprotein IIb/IIIa (LeuPro 33) polymorphism in stroke patients]. 1136 63

While thrombolytic therapy is approved in the United States and Canada for treatment of acute ischemic stroke, only a small number of patients are currently treated. Additional agents that could restore or improve cerebral flow are needed. Based on the experience in acute coronary syndromes, reperfusion agents such as platelet glycoprotein IIb/IIIa antagonists, alone or in combination with reduced doses of thrombolytic agents, have the potential for improving the safety and efficacy of recombinant tissue plasminogen activator (rt-PA). In addition, these newer agents may permit extension beyond the current 3-hour window from symptom onset used for systemic rt-PA.
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PMID:Platelet glycoprotein IIb/IIIa blockade in acute ischemic stroke. 1138 6

Recently, clinical depression has been identified as an independent risk factor for increased mortality in patients following acute coronary events. Although the underlying mechanisms of this link remain uncertain, increased platelet activity has been suggested but never proven as the mechanism responsible for this association. Sertraline hydrochloride is a selective serotonin reuptake inhibitor (SSRI), and is an effective antidepressant agent. Its major liver metabolite, N-desmethylsertraline (NDMS), is known to be neurologically inactive. We assessed the in vitro effects of escalating concentrations of sertraline and NDMS on human platelets by aggregometry in plasma and whole blood, by expression of major surface receptors with flow cytometry in washed cells and in the whole blood, and quantitatively by various platelet function analysers in healthy volunteers and patients with coronary artery disease. Pretreatment of blood samples with sertraline and NDMS resulted in a dose-dependent inhibition of platelet-rich plasma aggregation induced by 5 microM ADP (P =, 0.002), by 10 microM ADP (P = 0.0017), by collagen (P = 0.008), and by thrombin (P = 0.026). Whole blood platelet aggregability was also significantly reduced when induced by 20 microM ADP (P = 0.006), and by collagen (P = 0.01). Surface expression of CD9 (P = 0.004), GP Ib (P = 0.0001), GP IIb/IIIa (P = 0.007), VLA-2 (P = 0.01), P-selectin (P = 0.02), and PECAM-1 (P = 0.01), but not the vitronectin receptor, was also reduced in sertraline and NDMS pretreated washed platelets. Whole blood flow cytometry revealed significant inhibition of GP IIb/IIIa (P = 0.008), and P-selectin expression (P = 0.0001) in NDMS treated samples. Closure time was delayed for the collagen-ADP cartridge (P = 0.009), and for the collagen-epinephrin cartridge (P = 0.01), indicating platelet inhibition in whole blood under high shear conditions. Rapid platelet-function assay revealed a decreased (P = 0.002) ability of platelets to agglutinate fibrinogen-coated beads, suggesting GP IIb/IIIa inhibition. Both sertraline, and its neurologically inactive metabolite NDMS, exhibited significant dose-dependent inhibition of human platelets. The documented anti-platelet effects of sertraline and NDMS may be directly related to the mortality benefits of SSRIs after ischemic events including myocardial infarction and stroke.
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PMID:Platelet inhibition by sertraline and N-desmethylsertraline: a possible missing link between depression, coronary events, and mortality benefits of selective serotonin reuptake inhibitors. 1139 37

In acute ischemic stroke, reocclusion after an initially successful thrombolysis treatment can occur and is associated with increased morbidity and mortality. The authors present the successful use of abciximab, a platelet glycoprotein IIb/IIIa receptor inhibitor, in a patient with a thrombotic occlusion of the proximal middle cerebral artery, which was refractory to combined IV and intra-arterial thrombolysis and percutaneous intracranial balloon angioplasty.
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PMID:Rescue treatment with abciximab in acute ischemic stroke. 1140 23

Three platelet glycoprotein (GP) IIb/IIIa receptor antagonists have been approved as adjunctive therapy to decrease the ischemic complications of percutaneous coronary interventions (PCI) and/or unstable angina. They include the chimeric murine/human monoclonal antibody 7E3 Fab fragment (abciximab), a cyclic heptapeptide based on the KGD amino acid sequence (eptifibatide), and a nonpeptide mimetic of the RGD sequence (tirofiban). The agents are very effective in providing both short-term and long-term benefit after PCI, and one agent has also demonstrated a progressive long-term mortality benefit. The long-term mortality benefit is highly cost-effective when compared to other medical interventions. The benefits in treating unstable angina without PCI are less dramatic and robust, with some agents providing no benefit. Severe thrombocytopenia is an infrequent, but potentially serious, complication of therapy with all of the agents. The risk of major bleeding is increased only minimally or not at all by the drugs. Currently, a number of new indications for GPIIb/IIIa antagonists are under study, including acute myocardial infarction (+/- thrombolytic therapy, +/- PCI) and stroke. In addition to their impact on improving outcome, the results of clinical trials with these agents provide crucial insights into the contribution of GPIIb/IIIa-mediated platelet function in the pathophysiology of thrombotic vascular disease.
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PMID:Anti-GPIIb/IIIa drugs: current strategies and future directions. 1148 34

Information is lacking regarding dynamic platelet accumulation at the site of the occluded middle cerebral artery (MCA) and the relationship between platelet aggregation in downstream cerebral microvessels and loss of perfusion and vascular integrity of these microvessels. In the present study, we employed a model of embolic MCA occlusion in the rat to simultaneously measure temporal and spatial profiles of platelet accumulation at the site of the embolus occluding the MCA and within downstream cerebral microvessels. We also measured the integrity of microvessels and matrix metalloproteinase (MMP) activity in ischemic brain. Rats (n=36) were subjected to embolic MCA occlusion. Immunohistochemistry was used to detect microvascular integrity, plasminogen activator inhibitor 1 (PAI-1) and the deposition of fibrin. SDS-PAGE zymography was used to measure MMP2 and MMP9 activities. Accumulation of platelets and increases in PAI-1 immunoreactivity at the site of the embolus occluding the MCA were detected 1 h (n=7) and 4 h (n=7) after ischemia, respectively, and numbers of GPIIb/IIIa immunoreactive downstream cerebral microvessels increased significantly (209+/-59; n=7; P<0.05) 4 h after ischemia, suggesting dynamic platelet aggregation. A significant (n=7; P<0.01) diffuse loss of type IV collagen immunoreactivity in microvessels was temporally associated with platelet GPIIb/IIIa immunoreactivity within the vessels. Triple immunostaining revealed that microvessels containing platelet aggregates exhibited loss of type IV collagen immunoreactivity and both intra- and extra-vascular fibrin deposition, suggesting that intravascular platelet aggregation is associated with decreases in the integrity of the microvascular basal lamina and blood-brain barrier leakage. A significant increase (P<0.05) in MMP9 was detected at 4 h (n=3) and 24 h (n=3) after ischemia but levels of MMP2 were not significantly changed in ischemic brain. Our data suggest that dynamic platelet aggregation in ischemic brain may contribute to time-dependent resistance to fibrinolysis. In addition, platelet deposition and increased MMP9 coincided with degradation of type IV collagen and loss of vascular integrity. These data suggest an important role for post-occlusive distal platelet deposition in the pathophysiology of stroke.
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PMID:Dynamic platelet accumulation at the site of the occluded middle cerebral artery and in downstream microvessels is associated with loss of microvascular integrity after embolic middle cerebral artery occlusion. 1153 35

Although thrombolytic therapy is approved in several countries for treatment of ischemic stroke, only a small number of patients are eligible for treatment. Additional agents that could restore or improve cerebral flow are needed. Reperfusion agents such as platelet glycoprotein (GP) IIb/IIIa antagonists, alone or in combination with reduced doses of thrombolytic agents, have the potential for improving safety and efficacy compared with standard recombinant tissue plasminogen activator (rt-PA). In addition, GP IIb/IIIa antagonists may permit expansion beyond the current 3-hour window after symptom onset that is used for rt-PA. On the basis of experience in acute coronary syndromes, parenteral GP IIb/IIIa antagonists may have potential applications in the treatment of acute ischemic stroke and as adjunctive therapy to carotid angioplasty.
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PMID:Platelet glycoprotein IIb/IIIa antagonists for acute ischemic stroke. 1155 56

This study examined the influence of the Pl(A) polymorphism of glycoprotein IIIa (GPIIIa) in determining the response to an oral GPIIb/IIIa antagonist, orbofiban, in patients with unstable coronary syndromes. Genotyping for the Pl(A) polymorphism was performed in 1014 patients recruited into the OPUS-TIMI-16 (orbofiban in patients with unstable coronary syndromes-thrombolysis in myocardial infarction 16) trial, in which patients were randomized to low- or high-dose orbofiban or placebo for 1 year. The primary end point (n = 165) was a composite of death, myocardial infarction (MI), recurrent ischemia requiring rehospitalization, urgent revascularization, and stroke. Overall, orbofiban failed to reduce ischemic events when compared with placebo, but increased the rate of bleeding. In the whole population, Pl(A2) carriers had a significant increase in MI (n = 33) during follow up, with a relative risk (RR) of 2.71 (95% CI, 1.37 to 5.38; P =.004). There was a significant interaction between treatment (placebo and orbofiban) and the Pl(A) polymorphism for bleeding (n = 187; P =.05). Thus, while orbofiban increased bleeding in noncarriers (RR = 1.87, 1.29 to 2.71; P <.001) in a dose-dependent fashion, it did not increase bleeding events in Pl(A2) carriers (RR = 0.87, 0.46 to 1.64). There was no interaction between treatment (placebo and orbofiban) and the Pl(A) polymorphism for the primary end point (P =.10). However, in the patients receiving orbifiban there was a higher risk of a primary event (RR = 1.55, 1.03 to 2.34; P =.04) and MI (RR 4.27, 1.82 to 10.03; P <.001) in Pl(A2) carriers compared with noncarriers. In contrast, there was no evidence that Pl(A2) influenced the rate of recurrent events in placebo-treated patients. In patients presenting with an acute coronary syndrome, the Pl(A) polymorphism of GPIIb/IIIa may explain some of the variance in the response to an oral GPIIb/IIIa antagonist.
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PMID:Genetic variation in glycoprotein IIb/IIIa (GPIIb/IIIa) as a determinant of the responses to an oral GPIIb/IIIa antagonist in patients with unstable coronary syndromes. 1171 62

The possible mechanisms inducing acute coronary obstruction starting from the atherosclerotic plaque are illustrated. The effects of the inhibitors of the platelet's receptor GPIIb/IIIa and the results of the main trials performed using these inhibitors are reported. Finally, the results obtained immediately before their employment in the coronary angioplasty with or without stent's implantation are also reported. The first applications in acute ischemic stroke appear to be favourable too.
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PMID:[Inhibitors of the platelet's receptor GPIIb/IIIA. Progress in the treatment of acute myocardial ischemia and future trends]. 1173 37


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