Thrombolysis of Canine Femoral Artery Thrombus by a Novel Modified Tissue-Type Plasminogen Activator (E6010).

Abstract

ABSTRACT-The thrombolytic activity of a novel modified tissue-type plasminogen activator (t-PA) (E6010) was examined in a canine model with copper coil-induced femoral artery thrombus. This model, in which thrombolytic activity can be easily and directly quantified by determining changes in thrombus weight, should be useful for comparing the activities of various thrombolytic agents. Using this model, the present study showed that the thrombolytic activity of bolus intravenous injection of E6010 was identical to that of continuous intravenous infusion of recombinant t-PA at the same dose. This thrombolytic activity can be explained by changes in blood concentrations of the administered thrombolytic agents. On the other hand, administration of the thrombolytic agents dose-dependently caused significant changes in the levels of hemostatic and fibrinolytic factors. These changes were not so marked with administration of E6010, and therefore we concluded that E6010 is unlikely to cause bleeding complications after administration Keywords: E6010 (novel modified t-PA), Plasminogen activator (tissue-type), Femoral artery thrombus model, Thrombolytic activity, Plasma concentrationRecently, coronary artery angiography has been com monly used and safely performed during early stages of acute myocardial infarction.As a result, coronary thrombi have been found in many patients with acute myocardial infarction, suggesting its involvement in the pathogenesis of myocardial infarction (1). In 1979, Rentrop et al. succeeded in lysing a coronary thrombus by direct intracoronal infusion of streptokinase (2). In Japan, percutaneous transluminal coronary recanaliza tion (PTCR) with urokinase has been commonly per formed (3). These drugs can lyse fibrin that is a compo nent of thrombi by converting plasminogen into the ac tive form, plasmin, in the circulating blood. The resulting plasmin lyses not only fibrin but also fibrinogen. The effect of plasmin is regulated by a2-plasmin inhibitor, which binds to plasmin to inactivate it. The increase in plasmin caused by these drugs results in the subsequent decrease in blood concentrations of fibrinogen and a2 plasmin inhibitor, frequently leading to bleeding compli cations. Therefore, it is necessary to develop drugs that have a high affinity with thrombi so that the production of plasmin will be localized near the thrombi.Compared to intracoronary administration, intra venous administration has been found to produce more rapid recanalization of the coronary artery by throm bolytic therapy. A large dose of urokinase must be admin istered for thrombolysis, with a high risk of bleeding com plications. In 1982, tissue-type plasminogen activator (t-PA), which has a high affinity to thrombi, was isolated and purified from human melanoma cells (4). The genetic recombinant technology has enabled the large-scale production of t-PA (5). T-PA has been used as an effective thrombolytic agent against acute myocardial infarction (6 8) and other diseases (9). However, pharmacokinetic studies revealed th...

Fibrinolytic Agents: Mechanisms of Activity and Pharmacology

“…One of such t-PA molecules in which Cys84 in the E-domain is replaced by Ser, has a half-life in man of more than 20 min, as compared to 6 min for native t-PA. This molecule has been used successfully for bolus administration in a canine femoral artery thrombosis model (14) and in a multicenter trial in patients with acute myocardial infarction (15).…”

Efficacy evaluation of reteplase in a novel canine acute pulmonary thromboembolism model developed by minimally invasive surgery and digital subtraction angiography

“…Recovery to the level before injection in both groups 24 hours after the operation suggested that thrombolytic drugs only had a temporary, rather than long-term, influence on blood coagulation, similar to studies of alteplase in other canine femoral artery thrombus models. 47 …”