Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the serine protease, tissue plasminogen activator (tPA), is approved by the US Food and Drug Administration for therapy to combat focal cerebral infarction, the basic concept of thrombolytic tPA therapy for stroke was challenged by recent studies that used genetically manipulated tPA-deficient (tPA-/-) mice, which suggested that tPA mediates ischemic neuronal damage. However, those studies were potentially flawed because the genotypes of tPA-/- and wild-type control mice were not entirely clear, and ischemic neuronal injury was evaluated in isolation of tPA effects on brain thrombosis. Using mice with appropriate genetic backgrounds and a middle cerebral artery occlusion stroke model with nonsiliconized thread, which does lead to microvascular thrombus formation, in the present study we determined the risk for cerebrovascular thrombosis and neuronal injury in tPA-/- and genetically matched tPA+/+ mice subjected to transient focal ischemia. Cerebrovascular fibrin deposition and the infarction volume were increased by 8.2- and 6. 7-fold in tPA-/- versus tPA+/+ mice, respectively, and these variables were correlated with reduced cerebral blood flow up to 58% (P<0.05) and impaired motor neurological score by 70% (P<0.05). Our findings indicate that tPA deficiency exacerbates ischemia-induced cerebrovascular thrombosis and that endogenous tPA protects the brain from an ischemic insult, presumably through its thrombolytic action. In addition, our study emphasizes the importance of appropriate genetic controls in murine stroke research.
 ...
PMID:Tissue plasminogen activator (tPA) deficiency exacerbates cerebrovascular fibrin deposition and brain injury in a murine stroke model: studies in tPA-deficient mice and wild-type mice on a matched genetic background. 1089 28

Thrombolytic therapy with recombinant tissue plasminogen activator (rt-RA) is now an accepted treatment for acute ischemic stroke if the patient can be treated within 3 hours of onset of symptoms, and if the clinical presentation justifies use of the medication, and if there are no contraindications to the use of rt-PA. The non-contrast CT brain scan is mandatory to rule out an intracerebral hemorrhage, evidence of subarachnoid hemorrhage, or significant evolution of a large cerebral infarction. The later the patient is treated, within the 3-hour therapeutic window, the less likely there is to be clinical benefit of the treatment and the greater risk of hemorrhagic transformation of the cerebral infarction with potentially catastrophic consequences. There is approximately a 30% greater chance of full recovery from the stroke, at 3 months out from the infarct, with rt-PA compared to no rt-PA. On the other hand, there is a 6.4% risk of symptomatic intracerebral hemorrhage, within 36 hours, associated with the use of rt-PA compared to a 0.6% risk in the placebo group. The greater the neurological deficit at the time of presentation and the greater the evolution of the infarct by the admission CT brain scan, the greater the risk of intracerebral hemorrhage complicating the use of rt-PA.
 ...
PMID:Thrombolytic therapy for acute ischemic stroke. 1087 15

It has been suggested that subtle signs of early cerebral infarction on CT are important indicators of outcome and of the effect of thrombolytic treatment in acute ischaemic stroke. We studied these signs prospectively, in 260 patients with an anterior circulation stroke from a European-Australian randomised trial of lubeluzole in acute ischaemic stroke. Interobserver reliability was assessed by means of the chi statistic. The validity of the early signs was assessed by comparing the assessments of the first CT with another CT at 1 week after the onset of stroke, and with stroke outcome at 12 weeks. Each initial CT study was assessed by two of a group of five reviewers, who were blinded to each other's assessments and to the findings on the follow-up CT. The images were assessed twice, once without clinical information and again after disclosure of the side (left or right hemisphere) of the lesion. All reviewers were experienced clinicians with a special interest and training in vascular neurology and CT. The median time between stroke onset and the first CT was 3.2 h; 59% of the patients were imaged within 3 h and 77% within 6 h. More than half of the patients (52%) had a large middle cerebral artery territory (MCA) infarct on follow-up CT. Chance-adjusted interobserver agreement (chi) for any early infarct was 0.27 (95% confidence interval (CI): 0.15 to 0.39). Agreement (chi) on the extent of a middle cerebral artery (MCA) infarct and on the indication for treatment with recombinant tissue plasminogen activator (rt-PA) was fair: 0.37 and 0.35, respectively. Patients with early signs of an infarct of more than 1/3 of the MCA territory were more likely to have a large MCA infarct on follow-up CT (odds ratio 5.7, 95% confidence interval 2.8-11.5); the positive and negative predictive value of these signs was 81% and 57%, respectively. Chance-adjusted interobserver agreement on early, subtle signs of a large MCA territory infarct on CT by neurologists was thus no more than fair, and the accuracy of prediction of actual infarct size on the basis of these signs only moderate, under circumstances which resemble everyday clinical practice.
 ...
PMID:The validity and reliability of signs of early infarction on CT in acute ischaemic stroke. 1107 32

This paper aimed to investigate the effect of lumbrokinase on the anticoagulation and fibrinolysis in treating cerebral infarction. Lumbrokinase was used in patients with cerebral infarction. Patients were randomly divided into treatment group (n = 31) and control group (n = 20). Single blind method was used in this investigation. The Chinese stroke score was used to evaluate the results of treatment before and after administration of lumbrokinase. Kaolin partial thromboplastin time (KPTT), prothrombin time (PT), fibrinogen content, vWF content were analyzed, and tissue plasminogen activator (t-PA) activity, plasminogen activator inhibitor (PAI) activity, D-dimer level were assayed. In both groups, the stroke score decreased after administration, but in the treatment group, it was more obvious. In the treatment group, KPTT was prolonged, t-PA activity and D-dimer level increased, while the content of fibrinogen decreased significantly. There were no significant changes of PT and PAI activity in both groups. It is concluded that lumbrokinase is beneficial to the treatment of cerebral infarction. The effect of lumbrokinase is related to the inhibition of intrinsic coagulation pathway and the activation of fibrinolysis via an increase of t-PA activity.
 ...
PMID:Changes in coagulation and tissue plasminogen activator after the treatment of cerebral infarction with lumbrokinase. 1132 42

An 8-month-old boy presented with right hemiplegia of sudden onset after 20 days of Kawasaki disease, which was not initially treated by gamma globulin. Cranial X-ray computed tomography confirmed cerebral infarction as the cause of the right hemiplegia. In subsequent weeks, he developed multiple thromboses in coronary aneurysms. He successfully underwent intracoronary thrombolysis using tissue plasminogen activator without haemorrhagic complications. Cerebral infarction as a complication of Kawasaki disease is rare, and is a difficult clinical situation to manage.
 ...
PMID:Kawasaki disease complicated by cerebral infarction. 1269 Dec 96

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

The binding of platelet glycoprotein (GP) IIb/IIIa to fibrinogen is the final common pathway in platelet aggregation, a process known to play a key role in the pathogenesis of ischemic brain damage. We compared the effects of FK419, a novel nonpeptide GPIIb/IIIa antagonist, with recombinant tissue plasminogen activator (rt-PA) on middle cerebral artery (MCA) patency and ischemic brain damage in a thrombotic stroke model in squirrel monkeys. FK419 not only inhibited in vitro platelet aggregation (IC50: 88 nmol/L), but also showed disaggregatory activity to aggregated platelet (EC50: 286 nmol/L). FK419 dose-dependently reduced the time to first reperfusion and total occlusion time of MCA blood flow when administered immediately after the termination of photoirradiation. FK419 reduced cerebral infarction and ameliorated neurologic deficits with similar dose-dependency. Although rt-PA reduced the time to first reperfusion, total occlusion time, and cerebral infarction, it did not significantly ameliorate neurologic deficits and induced petechial intracerebral hemorrhages. These results indicate: (1) FK419 restored cerebral blood flow after thrombotic occlusion of MCA, (2) FK419 reduced ischemic brain injury by its thrombolytic actions in a non-human primate stroke model, and (3) FK419 has superior antithrombotic efficacy and is safer than rt-PA.
 ...
PMID:FK419, a nonpeptide platelet glycoprotein IIb/IIIa antagonist, ameliorates brain infarction associated with thrombotic focal cerebral ischemia in monkeys: comparison with tissue plasminogen activator. 1567 17

The role of endogenous tissue-type plasminogen activator (tPA) on focal cerebral ischemic injury (FII) after middle cerebral artery (MCA) occlusion was studied by using tPA gene deficient (KO) mice and wild type (WT) mice. MCA was occluded by thrombosis induced by 3 different intensities of photochemical damage of MCA. FII size in KO mice was smaller than in WT mice in mild damage whereas it was larger in severe damage. These results suggested that endogenous tPA protected FII through its thrombolytic action on transient occlusion with mild damage, but deteriorated on persistent occlusion with severe damage. Cerebral hemorrhage associated with antithrombotic and thrombolytic therapy in acute stroke is a major clinical problem. We investigated the roles of endogenous tPA and MMPs in hemorrhagic cerebral infarction associated with heparin. We demonstrated that heparin administration caused cerebral hemorrhage in WT but not in KO. Heparin administration increased tPA activity and its mRNA expression in WT. We also observed an induction of MMP9 and its mRNA expression by heparin administration in WT but not in KO. Our findings suggest that endogenous tPA plays an important role in heparin-produced cerebral hemorrhage via MMP9 induction and activation.
 ...
PMID:[Role of endogenous tPA in stroke]. 1619 Mar 67

A 79-year-old man with a cardiac pacemaker for bradycardia fell down and presented with sudden onset of right hemiplegia and aphasia. Initial computed tomography (CT) showed no cerebral infarction but angiography revealed occlusion of the left middle cerebral artery (MCA). Local intra-arterial thrombolysis with tissue plasminogen activator (tPA; tisokinase, 1,600,000 units) was performed 3 hours after the onset, and the MCA was partially recanalized. Further administration of tPA was suspended because of nosebleed. However, the patient's neurological findings did not improve. His consciousness gradually deteriorated to coma and quadriplegia with dilation of the left pupil 2.5 hours after thrombolysis. CT disclosed marked mass effect with a left acute subdural hematoma and a small intracerebral hematoma in the left frontal lobe. He underwent urgent craniotomy and removal of the subdural hematoma. The subdural hematoma originated in a frontal cerebral contusion. He died of severe brain edema 2 days after surgery. Acute subdural hematoma is a very rare complication of intra-arterial thrombolysis. Presumably he had suffered head trauma at the first onset. Evidence of head trauma should be considered a contraindication for the use of thrombolytic agents in a patient with acute stroke.
 ...
PMID:Acute subdural hematoma after intra-arterial thrombolysis for acute ischemic stroke--case report. 1672 23

The extent of cerebral infarction correlates with increased risk of intracerebral hemorrhage (ICH) following recombinant tissue plasminogen activator (rt-PA) administration. The Alberta Stroke Program Early CT Score (ASPECTS) is a widely used, validated method which assesses involvement of 10 selected regions of the MCA territory. An ASPECTS score >7 is associated with a higher risk of ICH following thrombolysis than lower scores. To understand the internal structure of the ASPECTS template better, we estimated the infarct volume corresponding to each region. We hypothesized that, in the ASPECTS scoring system, the striatocapsular region is weighted disproportionally. Four experienced radiologists rated individual ASPECTS regions on subacute CT images (day 5-day 10) of 19 patients with MCA territory stroke. Infarct volume was determined from manual segmentation of infarcts on CT images. Linear regression was used to estimate the regional volume associated with each ASPECTS region. The ASPECTS regions are weighted unequally with the striatocapsular region accounting for 21% of the MCA territory infarct volume. Together, the 10 ASPECTS regions account for approximately 51% of the maximum MCA infarct territory volume. These findings should provide impetus for research to develop a scoring system explicitly based on regional hemorrhage risk as an aid to selecting patients for thrombolysis.
 ...
PMID:The ASPECTS template is weighted in favor of the striatocapsular region. 1650 41


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