Thrombolytic activity of two chimeric recombinant plasminogen activators (FK2tu-PA and K2tu-PA) in rabbits.
The aim of this study was to evaluate the thrombolytic activity of two hybrid plasminogen activators (HPAs) in a rabbit jugular vein thrombosis model. In the two HPAs the kringle-2 domain (K2tu-PA) or the finger and the kringle-2 domains (FK2tu-PA) of tissue-type plasminogen activator (t-PA) are linked to the catalytic protease domain of single chain urokinase type plasminogen activator (scu-PA). The two HPAs were compared with rt-PA and scu-PA on a weight/weight basis. K2tu-PA, FK2tu-PA, rt-PA and scu-PA were infused at doses of 0.4, 0.8 and 1.2 mg/kg over 3 h. Saline served as control. Saline produced 11 +/- 2% thrombolysis. The three doses of K2tu-PA led to 38 +/- 4%, 66 +/- 5% and 89 +/- 7% thrombolysis, respectively; the three doses of FK2tu-PA: 18 +/- 3%, 29 +/- 5% and 33 +/- 6%, respectively; the three doses of rt-PA 32 +/- 2%, 49 +/- 3% and 68 +/- 6%, respectively; the three doses of scu-PA 16 +/- 2%, 24 +/- 3% and 32 +/- 4%, respectively. K2tu-PA and rt-PA showed a statistically significant higher thrombolytic activity than FK2tu-PA and scu-PA at the three tested doses (p less than 0.01). The thrombolytic activity of K2tu-PA was significantly higher than rt-PA at the two higher doses (p less than 0.01). Both K2tu-PA and rt-PA produced a statistically significant reduction of fibrinogen, alpha 2-antiplasmin and plasminogen 3 h after the start of the infusions of the two higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)
Agnelli
G
G
Istituto di Medicina Interna e di Medicina Vascolare, Università di Perugia, Italy.
Pascucci
C
C
Colucci
M
M
Nenci
G G
GG
Mele
A
A
Bürgi
R
R
Heim
J
J
D000818:Animals; D002384:Catalysis; D004195:Disease Models, Animal; D006487:Hemostasis / Q000187:drug effects; D007601:Jugular Veins; D010960:Plasminogen Activators / Q000302:isolation & purification / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D012015:Reference Standards; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
D011993:Recombinant Fusion Proteins; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator