Tissue plasminogen activator alteplase

Tissue plasminogen activator (alteplase t-PA) is a serine protease that is released into the circulation from vascular endothelium under conditions of injury or... 

The Arst therapeutic sAategy attempted for sAoke victims was to disrupt the embolus and thus attack the cause of ischaemia/hypoxia. This approach appeared in 1996 with the advent of a tissue plasminogen activator, alteplase, to be administered... 

The American Heart Association/American Stroke Association (AHA/ ASA) Stroke Council guidelines for the management of acute ischemic stroke give grade A recommendations (i.e., evidence supported by data from randomized trials) to only two pharmacologic therapies (1) IV tissue plasminogen activator (alteplase) within 3 hours of onset and (2) aspirin within 48 hours of onset. Evidence-based reconnmendations for pharmacotherapy of ischemic stroke are given in Table 13-1. 

The recombinant tissue plasminogen activator alteplase has recently been shown to be an effective alternative for restoring line patency [39]. In addition, a recent randomized trial demonstrated that the use of alteplase instead of heparin once weekly, as compared with the use of heparin three times a week, as a locking solution for central venous catheters significantly reduced the incidence of catheter malfunction and bacteremia [40]. It is also significantly more expensive than heparin and urokinase, but it can reduce the costs of unblocking or replacing clotted CVCs [41]. 

Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA 1999 282 2019-2026 [see comment]. 

With alteplase, another endogenous plasminogen activator (tissue plasminogen activator, tPA) is available. With physiological concentrations this activator preferentially acts on plasminogen bound to fibrin. In concentrations needed for therapeutic fibrinolysis this preference is lost and the risk of bleeding does not differ with alteplase and streptokinase. Alteplase is rather short-Liillmann, Color Atlas of Pharmacology... 

The advent of recombinant DNA technology has allowed the isolation of genes and expression of proteins that are found in biologic tissues in exceedingly small quantities. This has permitted large-scale production of enzymes such as tissue plasminogen activator (i.e., tPA, alteplase) that cannot be extracted from tissues in quantities required for therapeutic use. Table 9.2... 

E Role in therapy Thrombolytic agents currently licensed for the treatment of AMI in the United States include streptokinase, tissue plasminogen activator, anistreplase, reteplase, and tenecteplase. TNKase and alteplase have similar clinical efficacy for thrombolysis after myocardial infarction (i.e., similar mortality and intracranial hemorrhage rates). However, advantages of TNKase include ease and rapidity of administration, longer half-life, greater fibrin specificity, and lower noncerebral bleeding rates. Reteplase shares some characteristics of tenecteplase (e.g., similar half-life, rapid onset, and ease of administration). 

Plasminogen can also be activated endogenously by tissue plasminogen activators (t-PAs). These activators preferentially activate plasminogen that is bound to fibrin, which (in theory) confines fibrinolysis to the formed thrombus and avoids systemic activation. Human t-PA is manufactured as alteplase by means of recombinant DNA technology. 

Activase (Alteplase) [CHO-expressed glycoprotein-recombinant human tissue plasminogen activator] Genentech Lyophilized (50 mg single-dose vial 100 mg single dose vial) 50 and 100 mg doses to be reconstituted with 50 or lOOmL of WFI, respectively Per 50 mg vial 1.7 g L-arginine 0.5 g phosphoric acid < 4 mg polysorbate 80 (under vacuum) Per 100 mg vial 3.5 g L-arginine 1 g phosphoric acid <11 mg polysorbate 80 (without vacuum) IV... 

Recombinant tissue plasminogen activator (or alteplase) TNK t-PA (tenecteplase)... 

Reteplase is a second-generation recombinant tissue plasminogen activator, which lacks portions of the original alteplase. The chemical structure results in a smaller molecule having less fibrin specificity and a longer half-life than alteplase. Studies from Ouriel et al. and Castaneda et al. demonstrated... 

Abciximab in Ischemic Stroke Investigators (2000) Abciximab in acute ischemic stroke a randomized, double-blind, placebo-controlled, dose-escalation study. Stroke 31 601-609 Albers GW, Clark WM (1999) For the ATLANTIS Study Investigators. The ATLANTIS rt-PA (Alteplase) acute stroke trial final results. Cerebrovasc Dis 9 126 Alexandrov AV, Burgin WS, Demchuk AM, El-Mitwalli A, Grotta JC (2001) Speed of intracranial clot lysis with intravenous tissue plasminogen activator therapy sonographic classification and short-term improvement. Circulation 103 2897-2902... 

Twenty-seven out of 44 FDA-approved biopharmaceuticals have been tested in a battery of genotoxicity assays. Eighty-five different assays performed yielded negative results. The most commonly performed assays were the Ames test, the chromosomal aberration assay in human lymphocytes, the mouse lymphoma gene mutation assay, and the mammalian in vivo erythrocyte micronucleus test. Examples of the range of biopharmaceutical products tested include, domase alfa (deoxyribonuclease I-DNAse), trastuzumab (mAb to human epidermal growth factor receptor 2), alteplase (tissue plasminogen activator), infliximab (mAb to the human tumor necrosis factor a). 

Alteplase is a recombinant tissue plasminogen activator (rt-PA). As a result of its production in eukaryotic Chinese hamster ovary (CHO) cells, carbohydrate residues are present as in the native substance. At the therapeutically used dosage, alteplase loses its fibrin dependence and thus also activates circulating plasminogen. In fresh myocardial infarctions, alteplase appears to produce better results than does streptokinase. 

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