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)

Tissue plasminogen activator (tPA), the serine protease that converts inactive plasminogen to the protease plasmin, was recently shown to mediate neurodegeneration in the mouse hippocampus. Mice deficient in tissue plasminogen activator (tPA) display a dramatic resistance to a paradigm of excitotoxic neuronal death that involves intrahippocampal injection of the excitotoxin. This model is thought to reproduce the mechanism of neuronal death observed during acute (such as ischemic stroke) and degenerative (such as amyotrophic lateral sclerosis) diseases of the nervous system. The requirement for the proteolytic activity of tPA to mediate neuronal death is acute in the adult mouse. Serine protease inhibitors, specific for tPA or the tPA/plasmin proteolytic cascade, are effective in conferring extensive neuroprotection following the excitotoxic injection. These findings suggest possible new ways for interfering with the neuronal death observed in the hippocampus as a result of excitotoxicity. In addition, tPA is produced in the hippocampus primarily by microglial cells, which become activated in response to the neuronal injury. Blocking microglial activation has been shown in other injury paradigms to protect against neuronal death, therefore suggesting another way to retard neurodegeneration in the CNS. Furthermore, after the insult has been inflicted and in the presence of a compromised blood-brain barrier macrophages (cells deriving from the same lineage as microglia) migrate into the brain, where they are thought to contribute to the neuronal cell loss by secreting neurotoxic molecules. If these macrophages/microglia expressed, however, a tPA inhibitor, rather than the possibly neurotoxic tPA, they might be able to protect the neurons from dying.
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PMID:Clinical implications of the involvement of tPA in neuronal cell death. 918 75

Following the initial report of the clinical use of plasminogen activators (PAs) in cerebrovascular thrombosis in 1958, interest in the efficacy of this approach accelerated only when the need for acute intervention in stroke was recognized. The use of PAs in acute ischemic stroke is based on the observation that approximately 80-90% of focal cerebral ischemic events presenting as strokes within 8 hr of symptom onset are due to atherothrombotic and embolic occlusions.
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PMID:Antithrombotic therapy of acute stroke: thrombolytic agents. 919 50

Stroke stands as the third leading cause of death. It makes great demands on patients, who must not only survive the complications of the acute stages, but must cope then with the great physical and economic costs of long-term disabilities. Therefore, there is urgent need to establish generally useful regimens for the acute treatment of ischaemic stroke. Three treatment approaches are based upon pathophysiologic concepts derived from experimental work with focal cerebral ischaemia. These include pharmacologic strategies for arterial recanalisation, inhibition of inflammatory processes and neural protection. Focal cerebral ischaemia secondary to occlusion of a brain-supplying artery initiates neuronal and microvascular events, and the simultaneous processes of inflammation which further injure tissue. The use of plasminogen activators to mediate thrombus and lysis in the acute setting has been shown to be clinically beneficial. Further work with arterial reperfusion strategies is under way. Early clinical studies with polymorphonuclear leukocyte-dependent endothelial adhesion receptor antagonists are being completed, but a strategy has yet to emerge. A large effort examining the potential efficacy of agents which may stabilise or protect neurons from ischaemic injury has shown promise in experimental models, and has been translated into clinical trials. Experimental work, and limited clinical experience, have indicated that: (a) the time window for intervention is important in limiting ischaemic and inflammatory injury, and for reducing the risk of haemorrhagic transformation; (b) putative neuroprotective strategies may potentially elongate the time interval for treatment; and (c) limitations from the adverse effects of plasminogen activators and of agents which beneficially affect neuronal dysfunction during ischaemia must yet be overcome. This review surveys pharmacological approaches currently undergoing evaluation which provide the goal of establishing effective strategies for the treatment of patients with acute cerebral ischaemia.
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PMID:Trends and future developments in the pharmacological treatment of acute ischaemic stroke. 921 Oct 77

Atherosclerosis is a degenerative pathology of blood vessels leading to coronary heart disease, myocardial infarction and stroke. The basic lesion of atherosclerosis is the fibrous plaque, which consists of lipids, smooth muscle cells, macrophages and connective tissue matrix. Data derived from experimental and clinical studies indicate the crucial role of elevated serum LDL-cholesterol concentration in the formation of atherosclerotic lesions. HDL removes cholesterol from the arterial wall, stimulates arterial prostacyclin synthesis, inhibits adhesion molecules expression, has antioxidant properties and protects against atherosclerosis. Lipoprotein (a) competes with plasminogen for its binding site, leading to reduced fibrinolysis and is an important link between thrombogenesis and atherosclerosis. The pathogenic role of lipids in atherogenesis is discussed.
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PMID:[Lipids and atherosclerosis]. 924 11

The mechanism of action of currently available thrombolytic agents, such as streptokinase, urokinase, alteplase (recombinant tissue-type plasminogen activator; rt-PA) and anistreplase (anisoylated plasminogen streptokinase activator complex; APSAC), involves conversion of inactive plasminogen to plasmin, a potent fibrinolytic. However, the relatively weak substrate specificity of first generation agents (streptokinase and urokinase) can result in a state of systemic fibrinolysis and associated bleeding complications. The second generation drugs such as alteplase were developed in an attempt to enhance fibrin specificity, so that only enzymatic conversion of fibrin-complexed plasminogen would take place, thus avoiding systemic fibrinolysis. Results from large clinical trials have failed to consistently show any significant differences between first and second generation thrombolytic agents in the incidence of bleeding. In the clinical setting, thrombolytic agents have been evaluated primarily in patients with acute myocardial infarction and have been shown to significantly reduce morbidity and mortality compared with conservative treatment. The focus of current and future research is to investigate these agents in patients with other vaso-occlusive or ischaemic conditions (e.g. stroke), and also to evaluate different drug administration regimens and the use of adjunctive therapies such as aspirin (acetylsalicylic acid) and heparin.
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PMID:Evaluation of thrombolytic agents. 936 Aug 48

The nature of the relationship between inherited abnormalities of the clotting system and the occurrence of cerebrovascular accidents in young subjects is controversial. To evaluate the risk of cerebrovascular disease associated with such abnormalities, we analyzed a series of 23 consecutive patients in a case-control study with ischemic stroke proven by computerised tomography and aged below 45 years at admission, and a control group of 115 age- and sex-matched controls from the general population. No differences in antithrombin, protein C, protein S, heparin cofactor II, plasminogen or response to activated protein C were observed between cases and controls. None of the patients had a history of personal or familial thrombosis, and none had a reduction in the considered clotting factor below the reference range. We conclude that abnormalities of the clotting system are not associated with the occurrence of cerebrovascular abnormalities in the young and that routine screening for inherited thrombophilia is not appropriate in young patients with cerebrovascular disease.
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PMID:Inherited abnormalities of blood coagulation in juvenile stroke. A case-control study. 939 20

Postmenopausal hormone replacement therapy is associated with a reduction in the incidence of coronary heart disease. However, inconclusive results have been reported with respect to the risk of stroke, and recent studies consistently showed an increased risk of venous thromboembolism in postmenopausal women using oral estrogen. There are surprisingly few interventional studies to assess the true effects of estrogen-progestin regimens on blood coagulation and fibrinolysis, and the impact of the route of estrogen administration on hemostasis has not been well documented. Therefore, we investigated the effects of oral and transdermal estradiol/progesterone replacement therapy on hemostatic variables. Forty-five healthy postmenopausal women, aged 45 to 64 years, were assigned randomly to one of the three following groups: cyclic oral or transdermal estradiol, both combined with progesterone, or no hormonal treatment. Hemostatic variables were assayed at baseline and after a 6-month period. Pairwise differences in the mean change between the three groups were compared using nonparametric tests. Oral but not transdermal estradiol regimen significantly increased the mean value of prothrombin activation peptide (F1 + 2) and decreased mean antithrombin activity compared with no treatment. Differences in fragment F1 + 2 levels between active treatments were significant. The oral estrogen group was associated with a significant decrease in both mean tissue-type plasminogen (t-PA) concentration and plasminogen activator inhibitor (PAI-1) activity and a significant rise in global fibrinolytic capacity (GFC) compared with the two other groups. A transdermal estrogen regimen had no significant effect on PAI-1, t-PA, and GFC levels. There were no significant changes in mean values of fibrinogen, factor VII, von Willebrand factor, protein C, fibrin D-dimer, and plasminogen between and within the three groups. We conclude that oral estrogen/progesterone replacement therapy may result in coagulation activation and increased fibrinolytic potential, whereas opposed transdermal estrogen appears without any substantial effects on hemostasis. Whereas these results may account for an increased risk of venous thromboembolism in users of oral postmenopausal estrogen, they emphasize the potential importance of the route of estrogen administration in prescribing hormone replacement therapy to postmenopausal women, especially to those at high risk of thrombotic disease.
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PMID:Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. 940 95

Lp(a) is a major inherited risk factor associated with premature heart disease and stroke. The mechanism of Lp(a) atherogenicity has not been elucidated, but likely involves both its ability to influence plasminogen activation as well as its atherogenic potential as a lipoprotein particle after receptor-mediated uptake. We demonstrate that fibroblasts expressing the human VLDL receptor can mediate endocytosis of Lp(a), leading to its degradation within lysosomes. In contrast, fibroblasts deficient in this receptor are not effective in catabolizing Lp(a). Lp(a) degradation was prevented by antibodies against the VLDL receptor, and by RAP, an antagonist of ligand binding to the VLDL receptor. Catabolism of Lp(a) was inhibited by apolipoprotein(a), but not by LDL or by monoclonal antibodies against apoB100 that block LDL binding to the LDL receptor, indicating that apolipoprotein(a) mediates Lp(a) binding to this receptor. Removal of Lp(a) antigen from the mouse circulation was delayed in mice deficient in the VLDL receptor when compared with control mice, indicating that the VLDL receptor may play an important role in Lp(a) catabolism in vivo. We also demonstrate the expression of the VLDL receptor in macrophages present in human atherosclerotic lesions. The ability of the VLDL receptor to mediate endocytosis of Lp(a) could lead to cellular accumulation of lipid within macrophages, and may represent a molecular basis for the atherogenic effects of Lp(a).
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PMID:The atherogenic lipoprotein Lp(a) is internalized and degraded in a process mediated by the VLDL receptor. 941 Aug 93

We analysed the results of coagulation studies in an unselected series of young adults with acute cerebral ischaemia. Our aims were (a) to determine the prevalence of coagulation disorders among these patients, (b) to investigate the relation between the presence of coagulation abnormalities and large vessel disease or potential sources of cardiac embolism and (c) to evaluate the occurrence of thrombotic events in patients with or without coagulation disorders. One hundred and twenty consecutively admitted patients (53 men, 67 women, median age 38 years, range 15-45) who presented with acute cerebral infarction (n = 89) or a transient ischaemic attack (n = 31) were evaluated. Diagnostic studies consisted of electrocardiography, echocardiography, duplex scanning, and/or angiography. Coagulation studies included activity tests of protein S, protein C, antithrombin, plasminogen, measurement of immunoglobulin G (IgG) anticardiolipin antibodies (ACLA), and a dilute prothrombin assay. Initially, 30 patients had increased ACLA titres and 28 had an abnormal dilute prothrombin assay, suggesting lupus anticoagulant. Decreased protein S, protein C and antithrombin activity were detected in 20, 3 and 3 patients, respectively, excluding patients in whom the abnormalities could be explained by the use of medication, by pregnancy or puerperium. We detected a decreased activity of plasminogen in 5 patients. The disorders could be confirmed by a second assessment in only 2 patients with a protein S deficiency, in none of the patients with a protein C or antithrombin deficiency and in 1 patient with plasminogen deficiency. However, the abnormalities persisted in 19 of 21 patients with increased anticardiolipin IgG titres and in 9 of 20 patients with lupus anticoagulant. A confirmed coagulation disorder was not associated with stroke type or vascular risk factors, but it was more common among patients with large vessel disease (odds ratio: 3.8, 95% confidence interval (CI): 1.1-12.8). Sixteen patients had a recurrent thromboembolic event, but the risk of recurrence was not increased among patients with a confirmed coagulation disorder. Our results suggest that idiopathic coagulation disorders are found in about a quarter of young stroke patients. They are difficult to predict and probably interact with other risk factors.
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PMID:Coagulation disorders in young adults with acute cerebral ischaemia. 945 24

Arterial thrombosis is the underlying cause of a wide variety of cardiovascular diseases such as myocardial infarction, stroke and pulmonary thromboembolism. All the currently used thrombolytic agents are plasminogen activators, which are very efficient in restoring the blood flow. The fibrinolytic system comprises an inactive proenzyme plasminogen, that is converted by plasminogen activators to the enzyme plasmin, that degrades fibrin. Despite the widespread use of established thrombolytic agents such as streptokinase, tissue-plasminogen activator and urokinase, all these agents suffer from a number of inadequacies including resistance to reperfusion, occurrence of acute coronary reocclusion and bleeding complications. The quest continues for thrombolytic agents with a higher potency, specific thrombolytic activity and fibrin selectivity. Several lines of research towards improvement of thrombolytic agents are being explored including the construction of mutants and variants of plasminogen activators, chimeric plasminogen activators and conjugates of plasminogen activators with monoclonal antibodies. Newer molecules such as pro-urokinase, saruplase, alteplase, K1K2Pu and staphylokinase have shown promise in animal models of arterial and venous thrombosis and also in pilot scale clinical studies in patients with myocardial infarction. However, more clinical trials are needed to determine whether these novel recombinant thrombolytic agents shows improved efficacy and fibrin specificity with minimal bleeding tendencies.
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PMID:Newer thrombolytic drugs for acute myocardial infarction. 953 45


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