Pharmacokinetics and Thrombolytic Properties of a Nonglycosylated Mutant of Human Tissue-Type Plasminogen Activator, Lacking the Finger and Growth Factor Domains, in Dogs with Copper Coil-Induced Coronary Artery Thrombosis

1988 ◽  
Vol 11 (4) ◽  
pp. 468-472 ◽  
Author(s):  
P. Cambier ◽  
F. Van de Werf ◽  
G. R. Larsen ◽  
D. Collen
Keyword(s):  
Coronary Artery ◽  
Growth Factor ◽  
Plasminogen Activator ◽  
Human Tissue ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Artery Thrombosis ◽  
Type Plasminogen Activator ◽  
Coronary Artery Thrombosis ◽  
Copper Coil

CORONARY THROMBOLYSIS IN DOGS WITH A NONGLYCOSYLATED VARIANT OF HUMAN TISSUE-TYPE PLASMINOGEN ACTIVATOR LACKING THE FINGER AND GROWTH FACTOR DOMAINS

1987 ◽  
Author(s):  
P Cambier ◽  
F van de werf ◽  
D collen
Keyword(s):  
Coronary Artery ◽  
Growth Factor ◽  
Plasminogen Activator ◽  
Human Tissue ◽  
Bolus Injection ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Significant Difference ◽  
Plasma Peak

A variant of human tissue-type plasminogen activator (t-PA-AΔFE3X), with deletion of the NH2-terminal fibronectin-like finger (F) and epidermal growth factor (E) domains, and with amino acid substitution of Gin for Asn at all known N-linked glycosylation sites was expressed in Chinese Hamster Ovary Cells and purified to homogeneity. The thrombolytic and pharmacokinetic properties of this variant were studied in a canine model with copper coil induced thrombosis of the left anterior descending coronary artery. Infusion of t PAΔFE3X at a rate of 5 pg/kg/min for 30 min in 3 dogs resulted in a plateau level in plasma of 0.66 ± 0.08 ug/ml and induced recanalization of the coronary artery within 24 ± 4 min (mean ± SEM). Bolus injections over 2 min of 0.15 mg/kg in 3 dogs resulted in peak antigen levels in plasma of 1.6 ± 0.72 μg/ml and caused reperfusion within 14 ± 6 min. Bolus injection of 0.075 mg/kg in 3 dogs gave plasma antigen levels of 0.81 + 0.20 μg/ml and induced lysis in 31 ±15 min. Further reduction of the bolus to 0.038 mg/kg yielded plasma peak levels of 0.43 ± 0.20 μg/ml but did not cause reperfusion within 3 hours. Bolus injection of 0.075 mg/kg of natural t-PA isolated from melanoma cell culture fluid (Mel-t-PA) resulted in plasma peak levels of 0.46 ± 0.09 μg/ml and caused recanalization within 3 hours in only 1 of 4 dogs. None of the injections was associated with systemic fibrinolytic activation and fibrinogen degradation. The disposition of t-PAΔ related antigen from plasma following bolus injection could be described by a sum of two exponential terms with t1/2α: 17 min and t1/2β: 100 min. No significant difference in disposition rates for the different bolus injections were observed. Corresponding values for t1/2α of Mel-t-PA are 3 min.It is concluded that the deletion mutant t-PAΔFE3X has a markedly slower disposition rate from plasma than intact t-PA, which renders it relatively more effective than natural t-PA after bolus injection.

Thrombin inhibition enhances tissue-type plasminogen activator-induced thrombolysis and delays reocclusion

1992 ◽  
Vol 262 (2) ◽  
pp. H374-H379 ◽  
Author(s):  
S. K. Yao ◽  
J. McNatt ◽  
H. V. Anderson ◽  
J. Eidt ◽  
K. X. Cui ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Plasminogen Activator ◽  
Thrombin Inhibitors ◽  
Tissue Type ◽  
Thrombin Inhibitor ◽  
Tissue Type Plasminogen Activator ◽  
Blood Flows ◽  
Thrombin Inhibition ◽  
Type Plasminogen Activator ◽  
Copper Coil

The objectives of this study were to test the hypotheses that thrombin inhibitors 1) enhance tissue-type plasminogen activator (t-PA)-induced coronary thrombolysis and 2) prevent or delay coronary artery reocclusion. Seventy-one dogs developed occlusive coronary thrombi after introducing a copper coil into the left anterior descending coronary artery (LAD). Coronary blood flows were monitored by an externally positioned pulsed Doppler flow probe. t-PA was given with or without heparin at different times after LAD occlusions. In some experiments, hirugen, a synthetic hirudin-based peptide and specific thrombin inhibitor, was given as 4 mg/kg i.v. bolus and 3 mg.kg-1.h-1 i.v. infusion at 30 min after LAD occlusion with t-PA and a bolus of heparin. Thrombolysis times were significantly shorter in t-PA- and heparin-treated dogs than in dogs treated with t-PA alone. Reocclusion times were significantly longer in t-PA- and heparin-treated dogs than in dogs treated with t-PA alone. Continuous heparin infusions prolonged reocclusion times to greater than 180 min in all treated dogs. The addition of hirugen to t-PA plus one bolus heparin prolonged reocclusion times to 90 +/- 6 min in dogs with 30-min thrombi. Thus heparin enhances t-PA-induced thrombolysis and delays reocclusion. Addition of a specific thrombin inhibitor, such as hirugen, to heparin enhances its effect on delaying reocclusion.

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