Thrombolysis with human extrinsic (tissue-type) plasminogen activator in dogs with femoral vein thrombosis.

Korninger, C; Matsuo, Osamu; Suy, R; Stassen, Jean Marie; Collen, D.

doi:10.1172/jci110483

Cited by 162 publications

(47 citation statements)

References 26 publications

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“…A slight but significant decrease (14%) in plasma fibrinogen occurred only with YM866 at 1 mg/kg. Enhancement of systemic fibrinolytic activity was minimal in this study as com pared with streptokinase (22) and urokinase (23), which lack affinity for fibrin, thus suggesting the high affinity of YM866 and t-PA for fibrin.…”

Section: Discussionmentioning

confidence: 52%

Experimental Model of Carotid Artery Thrombosis in Rats and the Thrombolytic Activity of YM866, a Novel Modified Tissue-Type Plasminogen Activator

Kawasaki¹,

Kawamura²,

Katoh³

et al. 1993

Japanese Journal of Pharmacology

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ABSTRACT-We compared the thrombolytic activity of a novel modified t-PA, YM866, with that of t-PA in a rat model of electrically-induced thrombosis. Histological examination revealed the thrombus to be composed mainly of platelet clumps. Measurement of the decrease in carotid blood flow showed that com plete occlusion occurred within 14 min. At 10 min after the induction of thrombus, a test drug (YM866, t PA, or saline) was administered by i.v. bolus injection under heparinization (300 IU/kg, i.v.). Both YM866 and t-PA exhibited dose-dependent thrombolytic activity; the reperfusion rate of YM866 was twice that of t-PA. There was no significant difference in time to reperfusion between the agents, but YM866 showed a greater improvement in patency status after successful thrombolysis than t-PA. Plasma fibrinogen fell slight ly but significantly (14% of baseline value) in animals given 1 mg/kg of YM866. All groups of rats showed a significant decrease in carotid artery blood flow at 1 hr after successful reperfusion or injection of the drug, but this decrease showed significant recovery in animals given 1 mg/kg of YM866. These results suggest that YM866 by single bolus injection is a superior thrombolytic agent to t-PA, and that YM866 can improve the patency status after successful thrombolysis. Furthermore, this platelet-rich thrombosis model permits con tinuous observation of the process of thrombus formation and subsequent thrombolysis and provides a useful tool for the screening and evaluation of efficacy of new antithrombotic agents.

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Section: Discussionmentioning

confidence: 52%

Experimental Model of Carotid Artery Thrombosis in Rats and the Thrombolytic Activity of YM866, a Novel Modified Tissue-Type Plasminogen Activator

Kawasaki¹,

Kawamura²,

Katoh³

et al. 1993

Japanese Journal of Pharmacology

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“…infusion of t-PA at 0.6 mg/kg. The changes appeared to generally parallel the relative in vivo thrombolytic activity of YM866 and t-PA; such changes may not lead to enhanced systemic fibrinolysis, since the decrease was minimal as compared with that seen following the administration of urokinase (29) or streptokinase (30). The changes that oc curred early after the bolus injection of YM866 or t-PA could be attributed to a sharp rise in plasma concentra tion after i.v.…”

Section: Discussionmentioning

confidence: 86%

Thrombolytic Activity of a Novel Modified Tissue-Type Plasminogen Activator, YM866, in a Canine Model of Coronary Artery Thrombosis

Kawasaki¹,

Katoh²,

Kaku³

et al. 1993

Japanese Journal of Pharmacology

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ABSTRACT-The thrombolytic activity of a novel modified t-PA, YM866, was compared with that of a recombinant t-PA in a canine model of copper coil-induced coronary thrombosis. The coronary thrombus was allowed to age for 1, 3 or 6 hr before either drug was administered. YM866 was administered by i.v. bolus injection, while t-PA was given by the same method, as well as by 60-min i.v. infusion. YM866 show ed thrombolytic activity 2 to 4 times as potent as that of t-PA when administered by bolus injection, the difference in thrombolytic effect being obvious in the 3 and 6-hr-old thrombi. Coronary reperfusion was achieved more rapidly with YM866 than with i.v. infusion of t-PA. In animals injected with doses of more than 0.1 mg/kg of YM866, no acute reocclusion occurred. Depletion of plasma fibrinogen to 70% of baseline levels was observed in animals given 0.2 mg/kg YM866, 0.4 mg/kg t-PA by bolus, and 0.6 mg/kg t-PA via infusion. The residual plasma YM866 and t-PA antigen 30 min after bolus injection was 2570 and 310 of the peak levels, respectively. YM866, administered by i.v. bolus injection, was thus confirmed to exert a thrombolytic effect superior to that of bolus injection and infusion of t-PA, without systemic fibrinolytic activation. These results suggest the potential clinical applicability of YM866 as a thrombolytic agent that can be administered by i.v.bolus injection for acute myocardial infarction.

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“…38 Briefly, the femoral vein was isolated between the inguinal ligament and the distal bifurcation and all side branches were carefully ligated except for a predominant musculocutaneous branch, which was cannulated. After introduction of a woolen thread into the lumen, a 4-cm segment of the femoral vein was isolated between two vessel clamps, emptied, and flushed with saline via the side branch catheter.…”

Section: Methodsmentioning

confidence: 99%

Thrombolytic and pharmacokinetic properties of chimeric tissue-type and urokinase-type plasminogen activators.

Collen

Lijnen

et al. 1991

Circulation

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BACKGROUND Chimeric molecules comprising the A-chain of tissue-type plasminogen activator (t-PA) and the catalytic domain of urokinase-type plasminogen activator (u-PA) have intact enzymatic characteristics of u-PA, partial fibrin-binding properties of t-PA, and thrombolytic properties in animal models comparable with but not superior to those of single-chain u-PA (scu-PA). Deletion of the finger and growth factor domains (t-PA-delta FE/scu-PA-e) in such chimeras further reduces their affinity for fibrin. METHODS AND RESULTS A detailed investigation of the thrombolytic potency and the pharmacokinetics of t-PA and u-PA chimeras was performed in quantitative animal models for thrombolysis. In hamsters with pulmonary embolism, in rabbits with jugular vein thrombosis, and in baboons with femoral vein thrombosis, the thrombolytic potency (percent lysis per milligram of compound administered per kilogram of body weight) of t-PA-delta FE/scu-PA-e was significantly higher than that of recombinant scu-PA (rscu-PA, Saruplase) as shown by a maximal rate of 720 +/- 170% versus 45 +/- 5% lysis per milligram of compound per kilogram of body weight (mean +/- SEM, p less than 0.01) in hamsters, 210 +/- 18% versus 49 +/- 3% lysis per milligram of compound per kilogram of body weight (mean +/- SEM, p less than 0.01) in rabbits, and 310 +/- 73% versus 90 +/- 0.3% lysis per milligram of compound per kilogram of body weight (p less than 0.01) in baboons. However, the specific thrombolytic activity (percent lysis per microgram per milliliter steady-state plasma antigen level) of t-PA-delta FE/scu-PA-e was not significantly different from that of rscu-PA in hamsters (210 +/- 57% versus 160 +/- 27% lysis per microgram per milliliter antigen level) and was lower than that of rscu-PA in rabbits (37 +/- 4% versus 130 +/- 5% lysis per microgram per milliliter antigen level; p less than 0.01). In dogs with a combined femoral vein blood clot and a platelet-rich femoral arterial eversion graft thrombosis, 0.25 mg/kg body wt bolus injections of t-PA-delta FE/scu-PA-e produced significantly more venous clot lysis (90 +/- 5%, n = 10) than 0.25 mg/kg rscu-PA (26 +/- 3%, n = 10) (p less than 0.001) and, at the arterial side, more frequent (10 of 10 dogs versus three of 10 dogs) and more persistent (six of 10 dogs versus none of 10 dogs) recanalization (p = 0.002). After bolus injection in hamsters, rabbits, or baboons, t-PA-delta FE/scu-PA-e had a fourfold to sixfold longer initial half-life than rscu-PA and a slower plasma clearance of sixfold in hamsters, 10-fold in rabbits, and more than 10-fold in baboons. CONCLUSIONS These results indicate that t-PA-delta FE/scu-PA-e has a markedly enhanced thrombolytic potency toward venous and arterial thrombi caused by a delayed in vivo clearance with relatively maintained specific thrombolytic activity. These properties suggest that the chimera may be clinically useful for thrombolytic therapy by bolus administration in patients with thromboembolic disease.

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Thrombolysis with human extrinsic (tissue-type) plasminogen activator in dogs with femoral vein thrombosis.

Cited by 162 publications

References 26 publications

Experimental Model of Carotid Artery Thrombosis in Rats and the Thrombolytic Activity of YM866, a Novel Modified Tissue-Type Plasminogen Activator

Experimental Model of Carotid Artery Thrombosis in Rats and the Thrombolytic Activity of YM866, a Novel Modified Tissue-Type Plasminogen Activator

Thrombolytic Activity of a Novel Modified Tissue-Type Plasminogen Activator, YM866, in a Canine Model of Coronary Artery Thrombosis

Thrombolytic and pharmacokinetic properties of chimeric tissue-type and urokinase-type plasminogen activators.

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