Tissue plasminogen activator, therapeutic enzyme

Mechanism of Action A tissue plasminogen activator that activates the fibrinolytic system by directly cleaving plasminogen to generate plasmin, an enzyme that degrades the fibrin ot the thrombus. Therapeutic Effect Exerts CV-thrombolytic action. Pharmacokinetics Rapidlycleared from plasma. Eliminated primarilyby the liverand kidney. Haif-Hfe 13-16 min. 

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... 

The potential utility of enzymes as pharmaceuticals was noted many decades ago, and since then, nearly two dozen enzymes have been developed to treat a variety of diseases. Almost all enzyme therapies developed to date are used to deal with a loss of function defect (a mutation that diminishes activity, a low level of production, a deletion). Hence, most enzyme drugs are used as enzyme replacement therapies (ERT) for relatively rare, inborn errors of metabolism (lEMs). As a result, many enzyme therapeutics fall under the FDA s Orphan Drug Designation. However, a few enzyme therapies can also be used to treat much more common conditions such as cancer, heart attacks, and stroke. In the United States, the first enzyme to receive FDA approval was a tissue plasminogen activator called alteplase. This protein, which is now commonly used to treat strokes, was introduced in 1987 as Activase. Since then at least 16 other enzyme drugs have been introduced into the marketplace. Some of these are described in more detail below and in Table 6.1-3. 

E. Fibrinolytic Enzymes. Some snake venom proteolytic enzymes can dissolve blood clots, fibrin, without causing hemorrhage. Unlike tissue plasminogen activator (tPA) which liberates plasmin from plasminogen, venom fibrinolytic enzymes hydrolyze fibrin directly. These enzymes have potential therapeutic use in dissolving thrombi. Many such enzymes have been isolated (Retzios and Markland, 1988 Willis and Tu, 1988 Siigur and Siigur, 1991). 

Some of the previously unavailable enzymes for therapeutic use include domase (Pulmozyme), imiglucerase (Cerezyme), asparaginase, tissue-type plasminogen activator (Activase), and related drugs (Retavase). Detailed information about these products and their clinical use is provided in Part II in the form of monographs. Information relevant to pharmacokinetics and molecular characteristics can be found in Appendixes I and II. 

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