Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical trials in the 1990s of intravenous thrombolysis for ischaemic stroke have involved over 3000 patients. Alteplase given within 3 hours of onset significantly reduces the combined end-point of death and disability. Although alteplase appears safe when given up to 6 hours after onset, individual trials have failed to confirm efficacy beyond 3 hours. Meta-analysis indicates that intravenous alteplase given up to 6 hours after stroke onset significantly reduces death or dependence 3 months after stroke. Two trials of intra-arterial pro-urokinase confirm benefits of treatment up to 6 hours in highly selected patients with angiographically confirmed proximal middle cerebral occlusion. Streptokinase increased the risk of early death significantly in 3 trials, with no overall reduction in eventual death and disability. Patients over 80 years have been excluded from most trials of alteplase, and experience in this age group is minimal. Increased incidence and poorer functional outcome in the elderly mean that thrombolysis may have greater absolute benefit in this group than in the young, but there is also a higher prevalence of absolute or relative potential contraindications to treatment (ranging from increased use of anticoagulant drugs to higher prevalence of atrial fibrillation). Further trials are necessary to address age restrictions and other important issues in the use of alteplase. Thrombolysis is likely to remain feasible for a minority of stroke patients of all ages, and there is a need for other acute treatment options.
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PMID:Thrombolytic therapy for stroke: a review with particular reference to elderly patients. 1073 63

The removal of urokinase from the market has created a dilemma for interventionists and vascular surgeons treating patients with acute limb threatening ischemia due to arterial thrombosis or embolization. Reteplase is a newer, fibrin-specific thrombolytic agent with properties that make it an attractive alternative to urokinase. We report two cases of successful treatment of acute, limb threatening ischemia with intra-arterial Reteplase therapy.
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PMID:Intra-arterial reteplase for the treatment of acute limb ischemia. 1074 80

Intraoperative intraarterial thrombolysis is a valuable adjunct for the removal of residual arterial thrombi after mechanical thromboembolectomy. Early reports by some investigators indicated high rates of bleeding complications, most likely caused by inappropriately high doses of plasminogen activators infused over long periods of time, which led to systemic lytic effects. Animal models and controlled human experiments subsequently have shown the potential efficacy and safety of intraarterial thrombolysis. Since urokinase (UK) has been withdrawn from the market, recombinant tissue-type plasminogen activator (rt-PA) has become the plasminogen activator of choice. Reteplase and other plasminogen activators may be beneficial (and safe); however, data on intraoperative use currently are not available. The most common methods of delivery into the distal arterial tree are bolus infusion with inflow occlusion, drip infusion after restoration of arterial inflow, and the isolated limb perfusion technique. The number of distal vessels involved, the amount of residual thrombus, and severity of ischemia guide the dose of plasminogen activator, volume of perfusate, and the technique and duration of infusion.
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PMID:Intraoperative lytic therapy: agents and methods of administration. 1140 89

Alteplase (t-PA), a recombinant analogue of human tissue plasminogen activator, became the first genetically engineered thrombolytic approved by the Food and Drug Administration in 1987 for acute myocardial infarction (AMI). In addition to AMI, alteplase is currently approved for the treatment of acute ischemic stroke and pulmonary embolism, and we anticipate approval for catheter clearance in late 2001 in a 2-mg vial configuration. With the withdrawal of human neonatal kidney cell-derived urokinase, alteplase has become an alternative agent in peripheral vascular applications. Because few interventionalists had prior experience with the handling and dosage of alteplase, the Advisory Panel to the Society of Cardiovascular and Interventional Radiology established practice guidelines for use in noncoronary applications. Emerging clinical experience with contemporary dosing regimens shows a safety and efficacy profile similar to urokinase but with significantly reduced drug costs. Tenecteplase (TNK) is a genetically modified version of alteplase. TNK is the only plasminogen activator available that has shown a significantly enhanced safety profile versus alteplase in AMI. Approved for a 5-second, single-bolus injection in AMI, TNK possesses a longer half-life, increased resistance to plasminogen activator inhibitor, and improved fibrin specificity compared with alteplase. Because of its enhanced safety profile, TNK may be a desirable agent for peripheral vascular applications. Initial clinical studies with TNK in acute arterial and venous disease are ongoing. This article outlines the Advisory Panel guidelines for using alteplase and highlights features of tenecteplase.
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PMID:Alteplase and tenecteplase: applications in the peripheral circulation. 1198 95

Hemodialysis patients frequently require temporary venous catheters until suitable arteriovenous (AV) access can be placed and used for cannulation. However, these temporary catheters often occlude before the AV access has matured. The National Kidney Foundation (NKF) recommends using urokinase to clear the thrombus before progressing to the more invasive and costly procedure of catheter replacement, but urokinase is not currently available. The recombinant tissue-plasminogen activator, reteplase (Retavase, Centocor, Inc., Malvern, PA) was used to clear catheters in 62 patients (a total of 199 doses) at two for-profit outpatient hemodialysis centers with an overall success rate of 91.4% and a minimal cost of $44 per dose. Reteplase was found to be an efficacious and cost-effective alternative to urokinase in the treatment of occluded dialysis venous catheters.
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PMID:The efficacy of reteplase in the treatment of thrombosed hemodialysis venous catheters. 1214 62

The effectiveness of alteplase and urokinase in restoring adequate hemodialysis blood-flow rates was examined. A retrospective review of the medical records of hemodialysis patients with central venous catheters receiving alteplase or urokinase for presumed catheter thrombosis between June 1997 and December 2000 was conducted. Patients received 1 mL of alteplase 1 mg/mL or 1 mL of urokinase 5000 units/mL in each catheter port. The choice of the thrombolytic agent was left to the prescriber. Effectiveness of thrombolysis was defined as achieving a posttreatment hemodialysis blood-flow rate of > 300 mL/min, maintained for at least 30 minutes during the dialysis session. Inclusion criteria included adherence to the thrombolytic protocol and the inability to achieve a hemodialysis blood-flow rate of > 300 mL/min during the first 60 minutes of the hemodialysis session despite at least one attempt to reposition the catheter. Both thrombolytic agents significantly increased the hemodialysis blood-flow rates. Patients with alteplase-treated catheters were twice as likely to achieve hemodialysis blood-flow rates of > 300 mL/min (p = 0.0134) and were more likely to complete hemodialysis during that session (93% versus 70%, p = 0.0234). The percentage of functioning catheters at a subsequent hemodialysis session did not significantly differ between groups (p = 0.0806). The majority of patients in both treatment groups required no further interventions. Hemodialysis blood-flow rates increased after either alteplase 1 mg/mL per port or urokinase 5000 units per port was used to clear presumed catheter thrombosis. Alteplase was more likely than urokinase to result in a hemodialysis blood-flow rate of > 300 mL/min.
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PMID:Alteplase versus urokinase in restoring blood flow in hemodialysis-catheter thrombosis. 1216 43

Amediplase (K(2) tu-PA) is a hybrid plasminogen activator, consisting of the kringle 2 domain of alteplase and the protease domain of urokinase. The objective of this study was to determine the in vitro clot penetration of amediplase in relation to its fibrin binding and to compare the properties with those of alteplase. The clot lysis activity of amediplase in internal clot lysis models (both purified system and plasma system) was about 10 times less than that of alteplase. The clot lysis activity of amediplase in an external clot lysis model (plasma system) was similar to that of alteplase at therapeutic concentrations around 1 micro g/ml. The fibrin-clot binding properties of amediplase and alteplase were studied in a purified system as well as in a plasma system. In both systems amediplase bound to fibrin although to a significantly lower extent than alteplase. The binding of amediplase or alteplase did not increase during plasmin-mediated degradation of fibrin. The binding of amediplase was fully inhibited by epsilon-aminocaproic acid, indicating that the observed binding was specific and occurred via the lysine binding site in the kringle of amediplase. Clot penetration was studied during pressure-driven fluid permeation using syringes containing plasma clots. Amediplase was able to enter the clot without significant hindrance, while alteplase was concentrated on the top of the plasma clot and hardly entered into the inner parts of the clot. Diffusion-driven clot penetration was studied during clot lysis using confocal microscopy. Alteplase was detected on or close to the clot surface, while two-chain urokinase, which has no affinity to fibrin, was also detected deep inside the clot. Amediplase showed a penetration behaviour, which was distinct from that of alteplase and similar to that of two-chain urokinase. We concluded that the fibrin binding of amediplase is moderate and does not hinder clot penetration under permeation-driven or diffusion-driven transport conditions. Enhanced clot penetration, especially in large clots, could allow a more efficient lysis during thrombolytic therapy.
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PMID:Clot penetration and fibrin binding of amediplase,a chimeric plasminogen activator (K2 tu-PA). 1469 68

In occluded hemodialysis catheters, thrombolytic agents are used to dissolve fibrin clots, reestablish blood flow and allow the patient to continue with hemodialysis treatment. Prior to 2001, urokinase was the indicated fibrinolytic for hemodialysis catheter thrombolysis. However, when urokinase became unavailable in the United States, New Hanover Regional Medical Center developed and implemented a protocol for the use of another fibrinolytic, reteplase, to lyse catheter occlusions. The purpose of this retrospective analysis was to assess the safety and efficacy of reteplase in opening occluded catheters in a series of patients receiving hemodialysis. Between January 1 and June 30, 2002, 59 patients could not complete dialysis, because of either poor arterial blood flow or elevated venous resistance. Reteplase, 0.4 U, was administered to the lumen of occluded catheters. After 30 min dwell times, the lumens were aspirated. If flow could not be sufficiently reestablished, a second reteplase dose was administered. Efficacy endpoints were defined as the ability to complete hemodialysis and achieve flow rates of > or =250 ml/min. Safety endpoints were defined as the occurrence of allergic reactions or bleeding. Eighty-five percent (50/59) of the patients were able to complete their hemodialysis session following reteplase administration, with 70% (41/59) able to sustain blood flow rates of > or =250 ml/min. Of the 50 patients who successfully completed dialysis, 66% (33/50) required only one 0.4-unit dose of reteplase per lumen while 34% (17/50) required a second dose. No instances of bleeding or allergic reactions were noted.
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PMID:The efficacy and safety of reteplase for thrombolysis of hemodialysis catheters at a community and academic regional medical center. 1498 96

Ischemic stroke is a major public health problem worldwide. The potential to cure stroke patients with intravenous thrombolytic therapy has evolved to the use of intra-arterial thrombolytic agents. Fewer than 200 patients have been enrolled in randomized trials of intra-arterial therapy. In this article the authors have reviewed the literature listed in MEDLINE and EMBase, and searched relevant articles to examine the role of fibrinolytic agents in acute interventional stroke therapy. Only English language articles reporting five or more patients were included. Outcomes were defined at 90 days. Good outcome was defined on the modified Rankin Scale. Symtpomatic hemorrhage was defined as hemorrhage in the setting of clinical deterioration in the first 24 to 48 h. The search identified 57 studies of which 44 reported usable data. Only three randomized trials were reported. Of a total of 1140 patients, most (73%) were treated open-label with urokinase (Abbokinase, Abbott Laboratories). The best outcomes were reported in case series and slightly worse outcomes were reported in clinical trials. Overall, it was not possible to distinguish whether one agent was superior to the others. There is a paucity of published evidence on intra-arterial therapy for acute ischemic stroke. Alteplase (Activase, Genentech Inc.) is currently the drug of choice simply because it is available and it is the current intravenous standard. Further trials and developments are anticipated.
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PMID:Intra-arterial thrombolysis in acute ischemic stroke: a review of pharmacologic approaches. 1515 76

The two main causes of peripheral arterial occlusion (PAO) are embolism and thrombosis. Surgical treatment of acute limb ischemia, because of related complications, has a 30-day mortality rate of 15% to 25%. Intra-arterial thrombolysis for lower extremity ischemia is a well-accepted and frequently used technique. It may offer definitive treatment without the need for major surgery in a significant series of patients with acute occlusion of a native leg artery or a by-pass graft. Thrombolysis can offer several potential advantages when compared with surgical therapy. Thrombolytic agents include streptokinase (SK), urokinase (UK), pro-UK and recombinant tissue plasminogen activators (rt-PA-Alteplase and r-PA-Reteplase). All these agents induce a systemic fibrinolytic state. Three prospective randomized trials, ROCHESTER, STILE, and TOPAS, which compared thrombolytic therapy with traditional surgical revascularization for lower limb ischemia, have recently been published. They suggest that thrombolysis, as an initial therapy, reduces the risk of subsequent surgery and improves limb salvage for patients with PAO. Using this approach, the underlying lesions can be identified and treated by transluminal balloon angioplasty or stenting, or by elective surgical revascularization. However, severe bleeding is still a non rare complication of intra-arterial thrombolysis and the risk of intracranial hemorrhage is 1-2%.
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PMID:Thrombolytic therapy in peripheral arterial disease. 1537 17


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