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)

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

The development of promising acute stroke treatments is the fruit of the growing appreciation for the complex biochemical processes within neuronal tissue that commence immediately after the onset of ischemia. These biochemical cascades can be modified either by direct pharmacologic mitigation or by rapid restoration of perfusion and oxygenation. With both interventions, the ischemic tissue can remain viable and regain neurologic function rather than progress to infarction. Today the two major pharmacologic approaches to stroke therapy are neuroprotectants and thrombolytics. Neuroprotectants enable neuronal tissues to tolerate periods of minimal perfusion better, whereas thrombolytics facilitate reperfusion by disrupting the fresh thrombus. Important classes of neuroprotectants include calcium channel antagonists, N-methyl-D-aspartate (NMDA) receptor antagonists, benzothiazoles, and free radical scavengers. Pro-urokinase is a potentially important investigational thrombolytic. Ancrod, a defibrinogenating agent, is also currently being evaluated in acute stroke.
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PMID:The stroke pharmacopeia: promising experimental therapies. 961 94

Tissue plasminogen activator (t-PA) is expressed by hypothalamic and peripheral sympathetic neurons. The sympathetic axons that permeate artery walls have not been investigated as possible sources of intramural t-PA. The plasmin produced by such a system would locally activate both fibrinolysis and matrix metalloproteinases that regulate arterial collagen turnover. To assess this neural t-PA production, we investigated the capacity of rat cervical sympathetic ganglion neurons to synthesize and release t-PA, and the expression of the enzyme in carotid artery and the iris-choroid microvascular tissues that receive the ganglion axon distribution. Functional studies confirmed that (i) the ganglion neuron cell bodies synthesize t-PA mRNA, (ii) cultured ganglion carotid artery and iris-choroid microvascular explants predominantly release t-PA rather than urokinase, (iii) microvascular tissues release approximately 20 times more t-PA per milligram than carotid explants (which accords with the higher innervation density of small vessels), and (iv) removal of the endothelium did not cause major reductions in the t-PA release from carotid and microvascular explants. Immunolocalization studies then confirmed a strong expression of the enzyme within the ganglion axons, the carotid adventitia that receives these axons, and the predominantly sympathetic axon terminals in the iris-choroid microvasculature. These data indicate the existence of a previously undescribed system for the delivery of neural t-PA to vessel walls. The intramural production of plasmin induced by this system represents a novel principle for the regulation of arterial matrix flexibility, especially in the media of densely innervated small arteries and resistance arterioles involved in the pathogenesis of stroke, hypertension, and vascular aging. Thus, the data suggest an important new interface between neuroscience and vascular biology that merits further exploration.
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PMID:Functional and morphologic evidence of the presence of tissue-plasminogen activator in vascular nerves: implications for a neurologic control of vessel wall fibrinolysis and rigidity. 971 Feb 64

In the management of acute major vessel occlusion, the use of fibrinolytic agents such as recombinant tissue plasminogen activator (rt-PA), urokinase or streptokinase is widely accepted. Today, the spectrum of indications for thrombolytic drugs comprises acute myocardial infarction, lung embolism, ischaemic stroke, deep vein thrombosis and acute arterial occlusions of the lower limbs. In view of the histopathological and clinical features of retinal vessel occlusion, fibrinolysis aimed at early restoration of blood flow appears to be a promising therapeutic approach. Basically, it is of some concern that the systemic administration of fibrinolytic agents is associated with a haemorrhagic risk. Since this includes cerebral haemorrhage or gastrointestinal bleeding, the choice of an appropriate intravenous thrombolytic therapy in a non-life threatening situation such as central retinal artery occlusion (CRAO) or central retinal vein occlusion (CRVO) should be based on minimising the risk of adverse events. Furthermore, the fibrinolytic treatment of choice should be able to produce rapid and complete restoration of retinal capillary and arterial or venous blood flow and maintain patency long enough for retinal salvage to take place. In this article, we review several studies of fibrinolytic therapy in patients with retinal vessel occlusion to determine whether this treatment is likely to improve major clinical outcomes. Moreover, we review the large scale trials of fibrinolysis in myocardial infarction and acute ischaemic stroke to evaluate safety and efficacy of various thrombolytic regimens. Furthermore, we report on our results of fibrinolytic therapy with low dose rt-PA in patients with retinal artery occlusion and ischaemic central retinal vein occlusion. In light of the fact that the occurrence of bleeding complications constitutes a dose dependent problem, we conclude that the use of low dose regimens should be the ideal approach to fibrinolysis in retinal vessel occlusion. Although the results of our pilot studies must be interpreted with caution, we believe that the administration of low-dose rt-PA (50 mg) in a frontloaded manner (= simultaneous administration of rt-PA and intravenous heparin) constitutes a reasonable treatment option in patients with central retinal artery occlusion (CRAO) or ischaemic retinal vein occlusion (RVO), recent onset of symptoms (CRAO < or = 12 h, RVO < or = 11 d) and severe visual loss (< or = 20/50). Because of these limitations and the numerous contraindications of fibrinolytic therapy, only a limited number of patients will be suitable for this treatment. In view of the poor visual and ocular prognosis in severe retinal vessel occlusion, controlled clinical trials are needed to determine the benefit of thrombolysis in the management of this disease.
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PMID:[Systemic lysis therapy in retinal vascular occlusions]. 978 35

The treatment options and management of ischemic and hemorrhagic stroke are expanding. Neuroradiologic interventions are being used in acute care settings to change the course of these devastating processes. These interventions include the injection of intra-arterial urokinase for ischemic stroke, use of coils to secure aneurysms, and balloon angioplasty for increasing the lumen of spastic cerebral arteries in patients with cerebral vasospasm. Using a case study approach, these three options for managing stroke patients will be integrated, and nursing strategies for delivering care to the stroke patient will be profiled.
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PMID:Case presentations of neuroradiologic interventions for acute cerebrovascular disease. 978 1

This study investigates retrospectively, in selected patients, the ischemic outcome (reversible ischemia, infarction, and hemorrhage) and neurologic outcome of acute stroke treated with intra-arterial thrombolysis and the predictive value of pretreatment single-photon emission-computed tomography (SPECT). Thirty patients with complete recanalization within 12 hours were analyzed. The extent of ischemia was outlined on SPECT, and two CBF parameters were calculated: the ratio of ischemic regional activity to CBF in the cerebellum and the asymmetry index. Reversible ischemia, infarction, and hemorrhage were identified by comparing SPECT and follow-up computed tomography. Nine patients (30%) had no or small infarction, 14 (47%) had medium or large infarction, and seven (23%) had hemorrhage. Forty-two lesions were identified (22 reversible ischemia, 13 infarction, and 7 hemorrhage). Duration of ischemia, urokinase dose, disease type, and occlusion site were nonsignificant factors, whereas neurologic outcome and CBF parameters were significant among the three patient groups and three types of ischemic lesions. Ischemic tissue with CBF greater than 55% of cerebellar flow still may be salvageable, even with treatment initiated 6 hours after onset of symptoms. Ischemic tissue with CBF greater than 35% of cerebellar flow still may be salvageable with early treatment (less than 5 hours). Ischemic tissue with with CBF less than 35% of cerebellar flow may be at risk for hemorrhage within the critical time window. Pretreatment SPECT can provide useful parameters to increase the efficacy of thrombolysis by reducing hemorrhagic complications and improving neurologic outcome.
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PMID:Outcome in acute stroke with successful intra-arterial thrombolysis and predictive value of initial single-photon emission-computed tomography. 988 60

Urokinase-type plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA) play important roles in fibrinolysis, cell migration, tissue destruction, angiogenesis and tissue remodeling. u-PA and t-PA activity in tissue are tightly regulated by plasminogen activator inhibitor-1 (PAI-1). However, little is known of the activity of endogenous plasminogen activators (PAs) and PAI-1 in ischemic brain. To evaluate whether cerebral ischemic injury induces endogenous PAs and PAI-1, we measured PA activity from brain homogenates, and examined the expression of t-PA mRNA, u-PA mRNA and PAI-1 mRNA from brain homogenates in C57BL/6J mice (n=45) weighing 29-35 g in which the middle cerebral artery (MCA) was occluded by a fibrin-rich clot. Brain homogenates were prepared for direct casein zymography from control non-ischemic mice (n=4) and mice at 2 h (n=5), 4 h (n=5), and 24 h (n=4) after MCA occlusion (MCAO). Also, u-PA and t-PA knockout mice at 4 h (n=2, each) after MCAO were used as a negative control for direct casein zymography. Frozen sections for in situ zymography were obtained from control mice (n=2) and mice at 2 h, 4 h, and 24 h (n=2, per time point) after clot occlusion. Brain homogenates were prepared for reverse transcriptase-polymerase chain reaction (RT-PCR) to examine t-PA mRNA, u-PA mRNA and PAI-1 mRNA expression from control non-ischemic mice (n=4) and mice at 2 h (n=5), 4 h (n=5), and 24 h (n=5) after MCAO. By direct casein zymography, u-PA activity increased at 4 h (P<0.05), and 24 h (P<0.05) after stroke in the ischemic hemisphere compared with the non-ischemic mice. Activity of t-PA in ischemic brain was not significantly different from the control group. As measured by in situ zymography, PA activity, most likely u-PA, was present in the ischemic hemisphere. By RT-PCR, expression of PAI-1 mRNA, but not u-PA mRNA and t-PA mRNA, increased 3-, 15- and 25-folds in the ischemic hemisphere at 2 h, 4 h and 24 h after stroke, respectively, compared with control mice. This study demonstrates that PAI-1 mRNA and u-PA activity increase in mouse brain after stroke.
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PMID:Endogenous plasminogen activator expression after embolic focal cerebral ischemia in mice. 1043 99

Saruplase (unglycosylated human-type high molecular weight single-chain urokinase-type plasminogen activator) was given to 1698 patients in the open-label Practical Applicability of Saruplase Study (PASS), which assessed the safety and efficacy of saruplase in the treatment of acute myocardial infarction. Thirty-seven hospitals in Europe participated in the study. All patients received 20 mg saruplase as a bolus followed by an infusion of 60 mg saruplase over 1 hour. Prior to the infusion of saruplase, 62% of the patients received a bolus of 5000 U of heparin, and after saruplase a 24-hour intravenous infusion of heparin was given to 95% of patients. The mean age of the patients was 59 years and 80.1% were male. The median delay from the onset of chest pain to the start of saruplase infusion was 145 minutes. Acute angiography was performed in 8 of the participating 37 centers in 350 patients (20.6%), on average 85 minutes (median) after the start of the saruplase infusion. TIMI 3 flow was obtained in 186 patients (53.1%) and TIMI 2 flow in 61 patients (17.4%). Patency rates were similar for patients with anterior and inferior infarction. ECG signs suggestive of reperfusion were seen in 63% of the patients. In-hospital mortality was low (92 patients; 5.4%), and nonfatal recurrent myocardial infarction was seen in 60 patients (3.5%). Severe bleeding complications occurred in 92 patients (5.4%), 21 of whom (1.2%) needed a blood transfusion. An intracerebral hemorrhage was observed in eight patients (0.5%), and seven patients (0.4%) suffered from a thromboembolic stroke. At discharge 85.9% of the patients were in NYHA functional class I. One-year mortality was low (142 patients; 8. 4%). Mortality was high in patients with TIMI 0 or 1 flow at the acute angiography who did not undergo rescue PTCA (9/39; 23.1%), lower in patients with TIMI 0 or 1 flow followed by successful rescue PTCA (7/64; 10.9%), and low in patients with TIMI 2 flow (1/61; 1.6%) or with TIMI 3 flow (2/186; 1.1%). Patency rates and (bleeding) complications did not differ between patients with a body weight greater than or less than 70 kilograms. No antibodies against saruplase were detected in samples from 455 patients. In conclusion, it can be stated that saruplase, given in combination with aspirin and intravenous heparin, can be given safely and effectively to patients with acute myocardial infarction.
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PMID:Saruplase is a safe and effective thrombolytic agent; observations in 1,698 patients: results of the PASS study. Practical Applications of Saruplase Study. 1043 45

The purpose of this study was to determine the efficacy of intraoperative intraarterial urokinase (UK) in patients who suffered an acute stroke immediately following carotid endarterectomy (CEA). From January 1995 to March 1998, 823 carotid endarterectomies were performed. The subsequent results showed that intraarterial UK in the setting of early post-CEA neurologic events appears to be safe and may be a useful adjunct to re-exploration in improving neurologic outcomes.
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PMID:Intraoperative intraarterial urokinase in early postoperative stroke following carotid endarterectomy: a useful adjunct. 1054 7

This study was designed to investigate possible diurnal fluctuations in the efficacy of thrombolysis with streptokinase and whether they follow the circadian periodicity which has already been well documented for the time of onset of acute myocardial infarction, transient myocardial ischaemia, sudden cardiac death, thrombotic stroke, and for the efficacy of thrombolysis with tissue-type plasminogen and urokinase. A total of 156 consecutive patients treated with streptokinase were studied retrospectively; success or failure of thrombolysis was determined according to accepted clinical and angiographic criteria. A definite time peak for successful thrombolysis could be detected at the late afternoon and early evening hours; between 16.00 and 20.00 h, 30.2% of all successful thrombolysis cases were observed compared with 7.0% between 20.00 and 24.00 (p < 0.05) or 10.5% between 00.00 and 04.00 (p < 0.05). Between 16.00 and 20.00 h, 75.8% of treated patients had successful thrombolysis compared to 15.2% of failed treatments and 9% equivocal results (p < 0.001). Multiple regression analysis showed that the independent factor with the major impact on successful reperfusion was the actual time of thrombolysis (p = 0.037), followed by the time delay from pain onset to streptokinase administration (p = 0.020), while age and gender had much lesser impact (p = 0.328 and 0.215, respectively) and the individual risk factors even less. These findings may have several clinical implications; dose adjustment for the time of day may be required, with higher doses during morning hours, or preference for primary coronary angioplasty in order to avoid the increase in bleeding complications related to higher doses of thrombolytic agents.
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PMID:Circadian fluctuations in the efficacy of thrombolysis with streptokinase. 1062 77


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