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

Thrombolysis today has become a routine option not only in the treatment of acute myocardial infarction but also in many other manifestations of thromboembolic disease. Until one decade ago, only two plasminogen activators, streptokinase and urokinase, were available for clinical use. They were characterized by limited thrombolytic potencies and major side effects including systemic fibrinogen breakdown, bleeds and stroke. This has prompted the search for new plasminogen activators with better pharmacological and clinical profiles. The first such new plasminogen activators were Anistreplase, a chemically modified version of the streptokinase-plasminogen-activator-complex and tissue-type plasminogen-activator produced by recombinant technology. Both new substances have fueled the development in modern thrombolytic treatment. While the clinical progress with t-PA was confirmed in large, double-blind, randomized, multicenter trials, no real superiority of anistreplase over the traditional plasminogen activators urokinase and streptokinase has been substantiated. While the clinical use of t-PA today has been established for acute myocardial infarction, pulmonary embolism and deep vein thrombosis, current research is focused on further plasminogen activators with further improved thrombolytic properties. This review summarizes the current knowledge on the biochemical and pharmacological properties of the first, second and future generation of plasminogen activators.
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PMID:Thrombolytic agents--an overview. 885 12

The clinical effects were compared between a thrombolytic agent (urokinase) and a thromboxane synthetase inhibitor (sodium ozagrel) in patients with acute lacunar infarction. All patients had some degree of neurological deficits, which corresponded to the lesions on computerized tomography or magnetic resonance imaging. Urokinase of 420,000 units was given over two days in 11 patients, 160 mg/day of sodium ozagrel was administered for two weeks in 23 patients. The study was followed up to one month after the onset. Urokinase treatment improved motor paresis in 45.5-62.5% of the patients, sodium ozagrel in 68.4-86.7%. Using the combined score of motor paresis and conscious disorder, urokinase group revealed 44.4-45.5% improvement, but sodium ozagrel group 81.0-89.5% (p < 0.05). The rates of suppressive effect in progressing stroke and complete recovery were higher in sodium ozagrel group. Sodium ozagrel was clinically more efficient than urokinase in patients with lacunar infarction.
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PMID:[Clinical effects of urokinase and sodium ozagrel in patients with acute symptomatic lacunar infarction]. 888 28

Operative stroke complicating carotid endarterectomy is traditionally treated by reexploration of the operative site to correct a potentially causative lesion; however, attempts are not made to diagnose or treat the intracranial arterial occlusion. A 65-year-old man had a right hemiplegia during a left carotid endarterectomy that was caused by premature reversal of heparin, which resulted in thrombosis of his left anterior cerebral artery. On reexploration, the patient was treated with a 1-hour infusion of 1 million U urokinase through an indwelling carotid shunt. A repeat arteriogram demonstrated patency of the left anterior cerebral artery, with complete clot dissolution and resolution of the right hemiplegia on awakening. Natural history studies of stroke and prospective, angiographically controlled clinical trials of intraarterial thrombolytic therapy for acute stroke support the use of intraoperative intraarterial infusion of urokinase as part of a therapeutic approach to patients who have an ischemic stroke during carotid endarterectomy.
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PMID:Intraoperative high-dose regional urokinase infusion for cerebrovascular occlusion after carotid endarterectomy. 897 54

The blood clotting enzyme thrombin plays a central role in the aetiology of occlusive disorders such as stroke and acute myocardial infarction. During fibrinolytic therapy with plasminogen activators, thrombin is neutralized by anticoagulative drugs. In order to combine plasminogen-activating and thrombin-inhibitory activities we constructed chimeric derivatives of recombinant single-chain, urokinase-type plasminogen activator (rscu-PA) which comprise the kringle and protease domain of rscu-PA fused via a linker sequence to a thrombin-inhibitory domain. The inhibitory domain contains a sequence element directed to the active site of thrombin and a sequence taken from either hirudin or the human thrombin receptor both binding to the fibrinogen recognition site of thrombin. Analysing different sets of point mutants showed that the linker between the protease domain and the active site-directed sequence is contributing significantly to the thrombin-inhibitory potential. Kinetic analysis of thrombin inhibition revealed that most of the chimeras tested competitively inhibit the thrombin-mediated cleavage of a peptide substrate in a concentration-dependent manner; however, in two examples the insertion of one glycine residue into the active site directed-sequence abolished the blockade of the active site. This supports the conclusion that the chimeras with high thrombin-inhibitory potential interact with the active site and the fibrinogen recognition site of thrombin.
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PMID:Construction and structure-activity relationships of chimeric prourokinase derivatives with intrinsic thrombin-inhibitory potential. 900 43

Urokinase-type plasminogen activator (uPA) is an inducible extracellular serine protease implicated in fibrinolysis and in tissue remodeling. Recently, we have localized uPA mRNA strictly in limbic structures and the parietal cortex of the adult mouse brain. Here, we tested whether the systemic treatment of mice with kainic acid (KA), an amino acid inducing limbic seizures, could elevate in the brain mRNAs encoding uPA and its specific inhibitor, plasminogen activator inhibitor-1 (PAI-1), a major antifibrinolytic agent. Brain sections encompassing the hippocampus were tested through in situ hybridization using radiolabeled riboprobes specific for the two mRNA species. The results showed that KA greatly enhanced both mRNA species in sites of limbic structures and cortex. However, in the hypothalamus and brain blood vessels only PAI-1 mRNA was elevated. Those were also the only two locations where PAI-1 mRNA was detected in the non-treated control brain, although at a low level. For both mRNAs, KA enhancement was first evident 2-4 h after treatment, and it was most prolonged in the hippocampal area, where prominent hybridization signals persisted for three days. Here, both mRNAs were initially elevated in the hilar region of the dentate gyrus and in the molecular and oriens layers; however, PAI-1 mRNA became evident throughout the area, while uPA mRNA became especially pronounced in the CA3/CA4 subfield. In the cortex both mRNA types were induced, but only uPA mRNA was elevated in the retrosplenial cortex, and also in the subiculum. In the amygdaloid complex, uPA mRNA was restricted to the basolateral nucleus, whereas PAI-1 mRNA was seen throughout the structure, however, excluding this nucleus. These data show that seizure activity enhances the expression of uPA and PAI-1 genes in the brain; the patterns of enhancement suggest that the protease and its inhibitor may act in brain plasticity in synchrony, however, also independently of each other. Furthermore, the results suggest that by elevating PAI-1 mRNA in brain blood vessels, limbic seizures generate a risk for stroke.
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PMID:mRNAs encoding urokinase-type plasminogen activator and plasminogen activator inhibitor-1 are elevated in the mouse brain following kainate-mediated excitation. 922 13

The past year has seen tremendous progress in developing new therapies aimed at reversing the effects of acute stroke. Thrombolytic therapy with various agents has been extensively studied in stroke patients for the past 7 years. Tissue plasminogen activator (t-PA) received formal US Food and Drug Administration approval in June 1996 for use in patients within 3 hours of onset of an ischemic stroke. Treatment with t-PA improves neurologic outcome and functional disability to such a degree that, for every 100 stroke patients treated with t-PA, an additional 11-13 will be normal or nearly normal 3 months after their stroke. The downside of t-PA therapy is a 6% rate of symptomatic intracerebral hemorrhage (ICH) and a 3% rate of fatal ICH. Studies are under way to determine whether t-PA can be administered with an acceptable margin of safety within 5 hours of stroke, to evaluate the therapeutic benefits of intraarterial pro-urokinase, and to assess the use of magnetic resonance spectroscopy to identify which patients are most likely to benefit from thrombolysis. Combination thrombolytic-neuroprotectant therapy is also being studied. In theory, patients could be given an initial dose of a neuroprotectant by paramedics and receive thrombolytic therapy in the hospital. We are now entering an era of proactive, not reactive, stroke therapies. These treatments may reverse some or all acute stroke symptoms and improve functional outcomes.
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PMID:Hyperacute stroke therapy with tissue plasminogen activator. 928 41

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

Approximately 80 to 90% of cerebral ischaemic events that occur within 24 hours of symptom onset are due to atherothrombotic or thromboembolic occlusions. This forms the rationale for the use of thrombolytic agents in patients with acute ischaemic stroke. Early studies determined that recanalisation occurred in approximately 21 to 72% of patients with occluded cerebral arteries after intra-arterial or intravenous administration of streptokinase, urokinase, alteplase (recombinant tissue-type plasminogen activator; rt-PA) or duteplase (a 2-chain rt-PA). Initial reports suggested that frequencies of haemorrhagic transformation and parenchymatous haematoma in the carotid territory were similar whether patients with middle cerebral artery stroke received thrombolysis via intra-arterial or intravenous administration. The Multicentre Acute Stroke Trial-Europe (MAST-E), the Australia Streptokinase (ASK), and the Multicentre Acute Stroke Trial-Italy (MAST-I) trials, which evaluated intravenous streptokinase 1.5 x 10(6) IU in patients with acute ischaemic stroke, were terminated prematurely because of excessive early mortality and symptomatic intracranial haemorrhage in streptokinase recipients compared with those treated with placebo. However, those studies had not been preceded by dose-ranging trials. Intravenous administration of alteplase 0.9 mg/kg within 3 hours [National Institute of Neurological Disorders and Stroke (NINDS) trial], or 1.1 mg/kg within 6 hours [European Cooperative Acute Stroke Study (ECASS)], of symptom onset in patients with acute ischaemic stroke resulted in an absolute 11 to 13% treatment-associated improvement in clinical measurement scales; such as the modified Rankin scale and Barthel index, compared with placebo recipients. In the ECASS trial, those results were limited to a 'target population' restricted to those who satisfied all entry criteria. In both trials, the frequency of symptomatic haemorrhage was greater in patients treated with alteplase than with placebo and reinforced the importance of careful patient selection. Strict patient selection remains central to the success of this approach.
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PMID:Thrombolytic therapy in the treatment of stroke. 936 Aug 56

Thrombolytic therapy in acute ischemic stroke is safe and effective in a defined subgroup of stroke patients. Until now, different fibrinolytic substances including urokinase, streptokinase and recombinant tissue plasminogen activator (rt-PA) have been tested regarding safety, efficacy, dosage and economic parameters in patients suffering from both carotid and basilar artery territory strokes. Recently, two large multicenter placebo-controlled intravenous rt-PA studies were published. The results show that thrombolysis of acute carotid territory strokes (European Cooperative Acute Stroke Study) and of strokes with a deficit measurable on the NIH Stroke Scale (National Institute of Neurological Disorders and Stroke rt-PA Stroke Study) improves clinical and economic outcome parameters in patients who were treated within 6 hours of the onset of symptoms and had that no signs of extended early infarction on the initial CT-scan. The occurrence of intracranial hemorrhages is more frequent after thombolytic therapy, but the majority of bleeding complications referred to petechial or more confluent hemorrhage limited to the infarcted tissue, without clinical deterioration. However, the identification of the appropriate patients is difficult and depends on the level of clinical and diagnostic experience. In vertebrobasilar artery territory stroke, local intraarterial thrombolysis with urokinase or streptokinase is performed in most cases. Thrombolytic treatment within twelve hours of the onset of symptoms was associated with significantly better results concerning both survival and neurological recovery.
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PMID:[Thrombolytic therapy in ischemic infarct]. 945 30

In this study, the clinical effects were compared between a thromboxane synthetase inhibitor (sodium ozagrel) and a thrombolytic agent (urokinase) in patients with acute cerebral infarction. The subjects consisted of 598 patients admitted on the day of the onset of the cerebral infarction in the territory of the internal carotid artery who showed a low density area on CT images within 5 days. Of these patients, 300 were treated with sodium ozagrel and classified as Group Oz, while the remaining 298 were treated with urokinase and classified as Group Ur. The results were as follows: 1. In group Oz, complete recovery of motor impairment was seen in 209 (69.7%) patients. Complete recovery within 3 weeks after onset was seen in 186 (62.0%) patients. In group Ur, complete recovery of motor impairment was seen in 175 (58.7%) patients. Complete recovery within 3 weeks after onset was seen in 120 (40.3%) patients. Therefore, a higher incidence of complete recovery of the motor impairment was noted in group Oz [p < 0.001: chi 2 test]. Similarly, complete recovery within 3 weeks after onset was more frequent in group Oz [p < 0.001: chi 2 test]. 2. In group Oz, complete recovery was made contribution statistically by Anosognosia (Ag) and unilateral neglect (UN) on admission [multivariate analysis: p < 0.01]. In group Ur, complete recovery was made contribution statistically by Ag (p < 0.01), UN (p < 0.01) and aphasia (p < 0.05). 3. Progressive stroke was observed in 29 (9.5%) patients in the group Oz and in 71 (23.0%) patients in group Ur. There was a higher incidence of progressive stroke in group Ur [p < 0.001: chi 2 test] 4. All patients with progressive stroke had initial evidence of deterioration of neurological deficits within 6 days after the onset in group Oz, and within 5 days after the onset in group Ur. The maximal period from the beginning to the end of the deterioration of neurological deficit was 7 days. 5. In group Oz, progressive stroke was only seen in 29 (29.9%) of the patients who were admitted with motor disturbances and unilateral neglect. In group Ur, progressive stroke was seen in 8 (4.3%) of the 187 patients with motor disturbances without higher cortical dysfunction, in 17 (47.2%) of the 36 patients with motor disturbances and higher cortical dysfunction without unilateral neglect and was seen in 46 (61.3%) of the patients with motor disturbances and unilateral neglect. 6. Hemorrhagic infarction was observed in 14 (4.6%) patients in group Oz and in 31 (10.0%) patients in group Ur. There was a higher incidence of hemorrhagic infarction in group Ur [p < 0.001: chi 2 test]. 7. In group Oz, there was a higher incidence of hemorrhagic infarction among patients with atrial fibrillation (Af) on the ECG [p < 0.001: chi 2 test]. Similarly, in group Ur, hemorrhagic infarction was more frequent among patients with atrial fibrillation (Af) on the ECG [p < 0.001: chi 2 test]. Therefore, sodium ozagrel was clinically more efficient and safer than urokinase in patients with acute cerebral infarction.
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PMID:[Clinical effects of sodium ozagrel and urokinase in patients with acute cerebral infarction in the territory of the internal carotid artery]. 951 4


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