Thrombolytic agent

The natural process of thrombosis functions to plug a damaged blood vessel, thus maintaining haemostasis until the damaged vessel can be repaired. Subsequent to this repair, the clot is removed via an enzymatic degradative process known as fibrinolysis. Fibrinolysis normally 

Ecokinase (rtPA differs from human tPA in that three of its five domains have been deleted) 

Tenecteplase (also marketed as Metalyse) (TNK-tPA, modified rtPA) 

TNKase (Tenecteplase modified rtPA see Tenecteplase) Streptokinase (produced by Streptokinase haemolyticus) Urokinase (extracted from human urine) 

Staphylokinase (extracted from Staphylococcus aureus and produced in various recombinant systems) 

In situations where inappropriate clot formation results in the blockage of a blood vessel, the tissue damage that ensues depends, to a point, upon how long the clot blocks blood flow. Rapid removal of the clot can often minimize the severity of tissue damage. Thus, several thrombolytic (clot-degrading) agents have found medical application (Table 12.5). The market for an effective thrombolytic agent is substantial. In the USA alone, it is estimated that 1.5 million people suffer acute myocardial infarction each year, and there are another 0.5 million suffer strokes. 

CH12 RECOMBINANT BLOOD PRODUCTS AND THERAPEUTIC ENZYMES 

Retavase (rtPA see Ecokinase) Boehringer Manheim/Centocor 

Cardiovascular diseases, comprising acute myocardial infarction, stroke, and venous thromboembolism, have, as their immediate underlying cause, thrombosis of critically situated blood vessels with loss of blood flow to vital organs. One approach to the treatment of thrombosis consists of pharmacologic dissolution of the blood clot via the intravenous infusion of plasminogen activators that activate the blood fibrinolytic system. 

Despite their widespread use in patients with acute myocardial infarction, all currently available thrombolytic agents suffer from a number of significant limitations, including resistance to reperfusion, the occurrence of acute coronary reocclusion, and bleeding complications. Therefore, the quest continues for thrombolytic agents with a higher thrombolytic potency, specihc thrombolytic activity, and/or a better fibrin selectivity. 

Thyroid USP is contraindicated in patients with thyrotoxicosis, acute myocardial infarction, or uncorrected adrenal insufficiency. 

Thyroid USP should be used cautiously in pahents with angina or other cardiovascular disease because of the risk of increased metabolic demands. 

Use with tricyclic antidepressants or sympathomimet-ics may increase the effects of these medications or of thyroid USP, possibly leading to coronary insufficiency or cardiac arrhythmias. Use with oral antidiabetic agents or insulin may affect dosage requirements of these agents. Estrogens, which increase serum thyroxine-binding globulin levels, raise thyroid USP requirements. 

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Thromb o cy top athy Thrombocytopenia Thromboembolism Thrombolytic agents... 

The success of thrombus lysis depends mainly on how large the thrombus is and whether any blood flow stiU remains. The outcome is better the larger the surface of the entire thrombus exposed to the thrombolytic agent. As the clot ages, the polymerization of fibria cross-linking and other blood materials iacreases and it becomes more resistant to lysis. Therefore, the eadier the thrombolysis therapy starts, the higher the frequency of clot dissolution. Thrombolytic agents available are Hsted ia Table 7 (261—276). 

PA S1 S01.232 /-Plasminogen activator Used as therapeutic thrombolytic agent... 

This section will review the phase III clinical trials of IV thrombolytic agents for acute ischemic stroke, organized by the type of agent and the time window from stroke onset to study drug delivery (Table 3.1). The 1995 National Institute of Neurological Disorders and Stroke (NINDS) rt-PA trial is presented first because it showed that IV rt-PA, given within 3 hours of stroke onset, reduced stroke-related disability. This trial was the basis for the United States Food and Drug Administration (FDA) approval for rt-PA for use in acute ischemic stroke. 

No direct comparison trials have been reported between the different thrombolytic agents in acute ischemic stroke. In a retrospective review of the results for acute stroke lAT performed at our center, we have found significantly higher rates of recanalization and good clinical outcome in the era in which lA UK was used versus the era in which UK was not available and lAT with rt-PA was the primary treatment. Conversely, in another retrospective study, Eckert et al. found no major difference between the recanalization rates of UK and rt-PA. 

Suarez Jl, Zaidat OO, Sunshine JL, Tarr R, Selman WR, Landis DM. Endovascular administration after intravenous infusion of thrombolytic agents for the treatment of patients with acute ischemic strokes. Neurosurgery 2002 50 251-259 [discussion 259-260]. 

The administration of aspirin as an adjunctive therapy, within 24 hours of the use of thrombolytic agents, is not recommended (grade A evidence). 

Pharmacologic management of thrombosis includes local administration of thrombolytic agents. Alteplase (2 mg per port) and reteplase (0.5 unit per port) are the two most commonly used agents today. Urokinase has been used in the past, but after its reintroduction to the United States market, the larger dosed vial size makes it less cost effective than the newer agents. 

Enzymes Thrombolytic agents, digestive aids, debriding agents (i.e. cleansing of wounds)... 

Genentech was founded in 1976 by scientist Herbert Boyer and the venture capitalist Robert Swanson. Headquartered in San Francisco, it employs almost 5000 staff worldwide and has 10 protein-based products on the market. These include hGHs (Nutropin, Chapter 11), the anti-body-based products Herceptin and Rituxan (Chapter 13) and the thrombolytic agents Ac-tivase and TNKase (Chapter 12). The company also has 20 or so products in clinical trials. In 2004, it generated some US 4.6 billion in revenues. 

Monoclonal antibodies for in vivo use Cytokines (e.g. interferons and interleukins) Therapeutic enzymes Thrombolytic agents Hormones Growth factors Additional miscellaneous proteins Blood Blood proteins (e.g. albumin and blood factors) Vaccines Cell- and tissue-based products Gene therapy products Antitoxins, venoms and antivenins Allenergic extracts... 

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