Tissue plasminogen activator tPA

Overall, therefore, activation of the thrombolytic cascade occurs exactly where it is needed— on the surface of the clot. This is important as the substrate specificity of plasmin is poor, and circulating plasmin displays the catalytic potential to proteolyse fibrinogen, factor V and factor VIII. Although soluble serum tPA displays a much reduced activity towards plasminogen, some free circulating plasmin is produced by this reaction. If uncontrolled, this could increase the risk of subsequent haemorrhage. This scenario is usually averted, as circulating plasmin is rapidly 

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Tissue Plasminogen Aetivator (tPA). While streptokinase and urokinase can effectively induce clot dissolution in the majority of patients if given early, they lack clot specificity. Treatment with these enzymes results in a systemic lytic state attributable to their degradative action on circulating fibrinogen. Tissue plasminogen activator (tPA) was developed to achieve rapid and specific thrombolysis. 

The antithrombotic factors produced by endothelial cells are thrombomodulin (TM) and protein S (PS), components of the vitamin K-dependent protein C (PC) anticoagulant pathway, inhibiting F-Va-F-Villa (E15) tissue plasminogen activator (tPA), responsible for fibrinolysis (N2, LI8) and the lipoprotein-associated coagulation inhibitor (LACI), which inhibits F-VIIa-TF complex and F-Xa (B51). 

The first large-scale process to circumvent these limitations was one developed by Genentech, Inc. (South San Francisco, CA) for production of recombinant tissue plasminogen activator (tPA). This protein dissolves blood clots and can be used to treat heart attacks and strokes. This process was developed in the mid-1980s, resulting in final product licensure in 1987. The process required both regulatory and technical breakthroughs. 

Faster acting insulins (Chapter 11) Slow acting insulins (Chapter 11) Modified tissue plasminogen activator (tPA Chapter 12)... 

The role of the fibrinolytic system is to dissolve any clots that are formed within the intact vascular system and so restrict clot formation to the site of injury. The digestion of the fibrin and hence its lysis is catalysed by the proteolytic enzyme, plasmin, another serine proteinase. Plasmin is formed from the inactive precursor, plasminogen, by the activity of yet other proteolytic enzymes, urokinase, streptokinase and tissue plasminogen activator (tPA) which are also serine proteinases. These enzymes only hydrolyse plasminogen that is bound to the fibrin. Any plasmin that escapes into the general circulation is inactivated by binding to a serpin (Box 17.2). 

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... 

Patients who have had a heart attack or stroke are frequently treated by intravenous administration of tissue plasminogen activator (tPA) or streptokinase, enzymes that break down fibrin clots that clog blood vessels. 

Biopharmaceutical products have not fallen neatly into either category and the decision to refer any biotech-derived drug to CBER or CDER is taken on a case-by-case basis. Tissue plasminogen activator (tPA Chapter 9), for example, is licensed as a biologic, whereas erythropoietin (EPO Chapter 6) comes under the auspices of CDER. The majority of biopharmaceuticals, however, are assessed by CBER. 

Tissue plasminogen activator (tPA) E. coli, CHO Follicle-stimulating hormone (FSH) CHO... 

AC VIII, adenylyl cyclase type VIII BDNF, brain-derived neurotrophic factor CamKII, calcium-calmodulin kinase II GIRK2, G protein-activated inward rectifying potassium 2 MAOA, monoamine oxidase A n.d., not determined NCAM, neural cell adhesion molecule nNOS, neuronal nitric oxide synthase Petl, ETS domain transcription factor tPA, serine protease tissue-plasminogen activator (tPA). t/ > Increase/decrease in anxiety-related behavior. No effect. 

While some potential therapeutic proteins can be isolated and purihed from natural sources, it may be impractical to extract a sufficient amount for therapeutic purposes. This is the case for tissue plasminogen activator (tPA). While its therapeutic potential was quickly recognized, the protein was present naturally in such small amount that it was not possible to obtain quantities sufficient for chnical evaluation. Advances in biotechnology, including the development of recombinant DNA engineering, permitted production of recombinant tPA in sufficient quantities to evaluate its effects on occluded coronary arteries and to eventually develop a product. 

Tenecteplase, human recombinant tissue plasminogen activator (tPA) produced in CHO cells... 

Figure 17.4 Antifibrinolytic action of the lysine analogues. Normally, plasminogen binds to fibrin at a lysine-binding site and is converted in the presence of tissue plasminogen activator (tPA) to piasmin. The lysine analogues block the lysine-bIndIng site and prevent access of plasminogen to tfie fibrin molecule. Reproduced from Dunn O, Goa KL. Drugs 1999 57 1005-32, with permission.)...

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