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

The Cochrane Database of Systematic Reviews summarizes all the existing randomized evidence of all treatments for all diseases, so that doctors can quickly access the most up-to-date information. The trials for the Cochrane systematic review of thrombolytic therapy in acute ischemic stroke were identified from extensive searching of the literature and contact with trial investigators. Data on several prespecified outcomes (death and symptomatic intracranial hemorrhages within the first 7 to 10 days after treatment, and death and poor functional outcome at long-term follow-up) were sought in each identified randomized, controlled trial. There have thus far been 17 completed randomized, controlled trials of thrombolytic therapy versus control in 5,216 patients (including the provisional data from the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke [ATLANTIS] A and B and Recombinant Prourokinase in Acute Cerebral Thromboembolism [PROACT] II trials). Of these, eight trials tested recombinant tissue plasminogen activator (rt-PA) in 2,889 patients (56% of all data). Overall, there was an increase in the odds of death within the first 10 days (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.48 to 2.32) and symptomatic intracranial hemorrhage (OR 3.53, 95% CI 2.79 to 4.45) with thrombolysis (slightly less with rt-PA). The odds of death at the end of follow-up were also slightly increased with thrombolysis (OR 1.31, 95% CI 1.13 to 1.52), although this increase was not significant in patients receiving rt-PA. Despite this, overall there was a significant reduction in the number of patients with a poor functional outcome (combined death or dependency) at the end of follow-up (OR 0.83, 95% CI 0.73 to 0.94), which was slightly better in patients receiving rt-PA. Most of the data came from trials testing thrombolysis up to 6 hours after stroke, but the subgroup of patients treated within 3 hours showed a greater reduction in poor functional outcome with thrombolysis (OR 0.58, 95% CI 0.46 to 0.74) with a less adverse effect on death. The available data do not allow much further subgroup analysis, although there is reasonable evidence to indicate that aspirin or heparin given within 24 hours of thrombolytic therapy causes a significant increase in intracranial hemorrhage and death. It is hoped that a meta-analysis using individual patient data may be able to address the effect of thrombolysis in further specific subgroups and examine the interaction between the severity of stroke and the effect of thrombolysis.
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PMID:Overview of Cochrane thrombolysis meta-analysis. 1187 75

While thrombolytic agents have demonstrated improved mortality over the use of placebo, this has come at the expense of bleeding complications such as intracranial hemorrhage (ICH). Tenecteplase (TNK-tPA) is a novel thrombolytic agent engineered to improve upon the ease of use and safety of alteplase (t-PA). Given its longer half-life, TNK-tPA can be administered as a single bolus. The dosing of TNK-tPA has been weight optimized to enhance both safety and efficacy outcomes. Weight-optimized TNK-tPA dosing requires body weight estimation, which may introduce the potential for medication error. However, data from TNK-tPA clinical trials suggest that body weight estimates can err by up to 20 kg (44 lb) without an increased risk of ICH or death. Furthermore, the results of TNK-tPA clinical trials showed that even at the highest weight-optimized dosage of 50 mg, ICH rates were among the lowest reported in clinical trials of thrombolytics for acute myocardial infarction. In elderly female patients of low body weight, the use of weight-optimized TNK-tPA lowered the risk of ICH compared with the use of t-PA, expanding the potential use of thrombolytics to this high-risk patient population. Tenecteplase has demonstrated clinical equivalence to t-PA, but with a wider therapeutic margin of safety.
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PMID:Issues in the assessment of the safety and efficacy of tenecteplase (TNK-tPA). 1155 38

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

An international collaborative study was organised to replace the 2nd International Standard (IS) for tissue plasminogen activator (tPA). The 2nd IS for tPA (86/670) was used to calibrate the replacement Standard, which was selected from two candidate materials included in the collaborative study. Participants were provided with five sets of four samples (A, B, C, D) and asked to use sample A (2nd IS, 86/670, 850 IU/ml) to determine the activity of B (86/624, approximately 850 IU/ml), C and D (coded duplicates of the same material, 98/714 approximately 11,000 IU/ml). A total of 14 laboratories returned results from Europe, USA, Japan and Australia, providing data from 60 independent assays. Four laboratories used a reference method based on a published monograph from the European Pharmacopoeia for Alteplase for Injection, 1998, and the remaining 10 used their own method. Fibrin was used as promoter of tPA activity by 12 out of the 14 laboratories, the remaining two used kits where fibrinogen fragments were the promoter. Data from this collaborative study and the previous study to establish the 2nd IS for tPA show that tPA from melanoma cells and recombinant tPA from CHO cells are both suitable materials as International Standards. It was agreed that sample C, D, recombinant tPA, 98/714, be established as the 3rd International Standard for tPA with a potency of 10,000 IU per ampoule, calculated as the mean value from laboratories using fibrin as a promoter of tPA activity. The standard was established by WHO in November 2000.
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PMID:A collaborative study to establish the 3rd International Standard for tissue plasminogen activator. 1219 3

Tenecteplase is a novel fibrinolytic protein bioengineered from human tissue plasminogen activator (alteplase) for the therapy of acute ST-segment elevation myocardial infarction. Specific mutations at three sites in the alteplase molecule result in 15-fold higher fibrin specificity, 80-fold reduced binding affinity to the physiological plasminogen activator inhibitor PAI-1 and 6-fold prolonged plasma half-life (22 vs 3.5 minutes). Consequently, tenecteplase can be administered as a single intravenous bolus of 30-50mg (0.53 mg/kg bodyweight) over 5-10 seconds, in contrast to the 90-minute accelerated infusion regimen of alteplase. Tenecteplase plasma concentration-time profiles have been obtained from a total of 179 patients with acute myocardial infarction. Tenecteplase exhibited biphasic disposition; the initial disposition phase was predominant with a mean half-life of 17-24 minutes, and the mean terminal half-life was 65-132 min. Over the clinically relevant dose range of 30-50mg, mean clearance (CL) was 105 ml/min. The mean initial volume of distribution V(1) was 4.2-6.3L, approximating plasma volume, and volume of distribution at steady state was 6.1-9.9L, suggesting limited extravascular distribution or binding. Bodyweight and age were found to influence significantly both CL and V(1). Total bodyweight explained 19% of the variability in CL and 11% of the variability in V(1), and a 10kg increase in total bodyweight resulted in a 9.6 ml/min increase in CL. This relationship aided the development of a rationale for the weight-adjusted dose regimen for tenecteplase. Age explained only a further 11% of the variability in CL. The percentage of patients who achieved normal coronary blood flow was clearly related to AUC. More than 75% of patients achieved normal flow at 90 minutes after administration when their partial AUC(2-90) exceeded 320 microg.min/ml, corresponding to an average plasma concentration of 3.6 microg/ml. Systemic exposure to tenecteplase at all times after bolus administration of 30-50mg was higher than for alteplase 100mg. Tenecteplase has demonstrated equivalent efficacy and improved safety compared with the current gold standard alteplase in a large mortality trial (ASSENT-2). This suggests that the reduced clearance, greater fibrin specificity and higher PAI-1 resistance of tenecteplase allow higher plasma concentrations and thus a more rapid restoration of coronary patency to be attained, while providing a reduction in major non-cerebral bleeding events.
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PMID:Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction. 1245 36

Previous studies have shown that Japanese taxi drivers are exposed to more risk factors and have a higher mortality rate due to cardiovascular disease than other occupational groups. We investigated the effect of night taxi driving with a view to preventing acute events of cardiovascular disease among aged taxi drivers. Twenty-nine taxi drivers (41-67 years old) were examined for urine normetanephrine/creatinine, von Willebrand factor, anti-thrombin III, t-plasminogen activator-plasminogen activator inhibitor 1-complex, hematocrit, blood glucose and blood pressure in the morning and at midnight during a duty day and in the following morning. At the same time, the blood pressure and blood glucose of 46 taxi drivers (43-67 years old) in the morning after a night duty with little sleep and in the morning after daytime work and subsequent night sleep were compared. The results obtained indicate that the aggravation of sympathetic nervous system functions with disturbed circadian rhythms, increased blood coagulation and blood concentration, endothelial injury and the elevation of blood glucose at midnight or the next morning were induced by their night work. These conditions are supposed to favour acute vascular events in aged taxi drivers. Preventive measures considered include social support for anticoagulant food and water intake, short exercise and walking as well as taking a rest and a nap during night work.
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PMID:Searching for preventive measures of cardiovascular events in aged Japanese taxi drivers--the daily rhythm of cardiovascular risk factors during a night duty day. 1456 2

A well-recognized complication of the anatomic correction (arterial switch operation) of transposition of the great arteries is obstruction of the translocated coronary arteries. Myocardial reperfusion has previously been achieved by surgical revascularization or percutaneous balloon angioplasty. We report the case of a 3-month-old infant who suffered myocardial infarction 11 weeks after the arterial switch operation, in whom myocardial reperfusion was established following infusion of recombinant tissue-type plasminogen activator (Alteplase).
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PMID:Recombinant t-PA in myocardial ischemia after switch operation. 1505 63

Even with the benefit of cardiopulmonary resuscitation, the prognosis of cardiac arrest remains poor. Multiple case series describe survival with the use of thrombolytic therapy for refractory cardiac arrest. Presumably thrombolysis treats that subset of cardiac arrest cases resulting from fulminant pulmonary embolism, or perhaps massive myocardial infarctions. Published reports to date have dealt exclusively with streptokinase, urokinase, reteplase, or recombinant tissue plasminogen activator. The authors report the first case of return of spontaneous circulation with the administration of tenecteplase. Tenecteplase is a recently developed reengineered isomer of tissue plasminogen activator that possesses many properties of the ideal cardiac arrest thrombolytic agent. It is bolus dosed, stable at room temperature before reconstitution, and is compatible with most other advanced cardiac life support medications. Because of clinical equivalency and its logistical advantages, tenecteplase should be evaluated as an alternative to other thrombolytics in future trials involving cardiac arrest.
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PMID:Tenecteplase and return of spontaneous circulation after refractory cardiopulmonary arrest. 1555 35

Veno-occlusive disease (VOD) of the liver occurs in 10% to 50% of patients after hematopoietic stem cell transplantation (HSCT), ranging from a mild reversible disease to a fulminant course with a mortality rate close to 100%. We retrospectively evaluated the clinical signs, diagnosis, prognosis, therapy, and outcome of 13 hepatic VOD cases which developed after HSCT. A total of 193 consecutive patients (age: 15-62 years; median 33 years) with various hematologic diseases underwent 197 HSCT (allogeneic HSCT, n = 128; autologous HSCT, n = 69). In general, the conditioning regimen consisted of cyclophosphamide combined either with total body irradiation or busulfan. Since 2000, to reduce hepatic complications, all patients received ursodexycolic acid and discontinuation of norethisterone which inhibits ovulation. VOD diagnosed clinically was mainly managed in supportive fashion. Five patients received thrombolytic therapy (t-plasminogen activator [t-PA], n = 3; defibrotide [DF], n = 2). VOD developed in 13 of 197 cases (6.6%). All except one were in the allogeneic group who had received a busulfan-containing conditioning regimen; Ten (77%) were severe. Thirty-three of 197 (17%) cases died before day 100 with VOD as the cause in eight (24%). All of the t-PA administered patients died with significant hemorrhagic complications. DF patients improved completely, even after renal and respiratory failure, despite high total bilirubin levels. Only one patient who received DF became a long-term survivor; the other died with sepsis during the following days. The dramatic improvement with regard to VOD during DF therapy was encouraging.
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PMID:Time-related changes in the incidence, severity, and clinical outcome of hepatic veno-occlusive disease in hematopoietic stem cell transplantation patients during the past 10 years. 1596

Alteplase (recombinant human tissue type plasminogen activator, rt-PA) was identified as a naturally occurring plasminogen activator in 1975, cloned from a human melanoma cell line in 1981, introduced into clinical trials in 1982, and received a product licence for the treatment of acute myocardial infarction in 1986. The present review will concentrate on assessing its current status as a clinically effective thrombolytic agent, but will touch briefly on its biochemical, physiological and pharmacological properties. Since alteplase is an approved pharmaceutical name, the term tPA will be used to refer to the naturally occurring substance in its physiological context.
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PMID:Alteplase. 1598 66


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