Molecular mechanism of action of newer thrombolytic agents.
Recombinant tissue-type plasminogen activator (rt-PA) and single chain urokinase-type plasminogen activator (scu-PA) are thrombolytic agents, characterized by a high but not absolute degree of fibrin specificity that is mediated through different molecular mechanisms. Both activators are still under clinical investigation but it has become apparent that their therapeutic dose in humans is high and associated with a variable degree of systemic activation of the fibrinolytic system and fibrinogen breakdown. Therefore, the quest for further improvement of agents and therapeutic schemes continues. Research is being pursued in this area along the following lines: 1) tissue-type plasminogen activator (t-PA) and single chain urokinase-type plasminogen activator in molar ratios of 4:1 to 1:4 do not act synergistically on thrombolysis in a plasma environment in vitro, but display significant synergism in animal models of thrombosis. In pilot studies in patients with coronary artery occlusion, rt-PA and scu-PA are markedly synergistic and efficient thrombolysis can be obtained with a fivefold lower combined dose than that of the separate agents. The combined dose does not seem to induce systemic fibrinogen breakdown. 2) Deletion mutants of rt-PA can be constructed with a significantly prolonged half-life in vivo, and a better thrombolytic potential after bolus intravenous injection. 3) Cleavage site-specific mutants of scu-PA that abolish the conversion to urokinase may have a higher fibrin specificity. The mutants constructed thus far, however, seem to have a lower specific thrombolytic activity.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D004357:Drug Synergism; D005342:Fibrinolysis / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009154:Mutation; D010960:Plasminogen Activators / Q000145:classification / Q000494:pharmacology / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D010959:Tissue Plasminogen Activator / Q000494:pharmacology / Q000627:therapeutic use; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology / Q000627:therapeutic use
D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator