Experimental studies on a recombinant hirudin, CGP 39393.
The in vitro anticoagulant activities of recombinant desulphatohirudin (r-hirudin) were studied in the activated partial thromboplastin time (APTT) and the thrombin generation test systems. In the APTT, at concentrations below 5 micrograms/ml, r-hirudin showed a dose-response curve. At concentrations above 5 micrograms/ml, the plasma became unclottable, but in the thrombin generation test, at least 10 micrograms/ml of r-hirudin was required for full inhibition of thrombin generation. The antithrombotic effect was assessed using a rabbit venous stasis model; 150 micrograms/kg r-hirudin completely prevented thrombus formation at 10 and 20 min stasis. At this full antithrombotic dose, the mean bleeding time ratio measured in a rabbit ear template model, was not prolonged over control values. At higher doses, the bleeding time ratios were higher than those observed for the same dosage of heparin. These data indicate that while r-hirudin is an effective antithrombotic agent, antithrombotic doses have to be carefully titrated to avoid excessive bleeding.
Gray
E
E
National Institute for Biological Standards and Control, South Mimms, Potters Bar, Hertfordshire, UK.
Watton
J
J
Cesmeli
S
S
Barrowcliffe
T W
TW
Thomas
D P
DP
D000818:Animals; D005343:Fibrinolytic Agents; D006470:Hemorrhage / Q000139:chemically induced; D006493:Heparin / Q000494:pharmacology; D006629:Hirudins / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D010314:Partial Thromboplastin Time; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D013918:Thrombin Time; D013924:Thrombophlebitis / Q000517:prevention & control
D005343:Fibrinolytic Agents; D006629:Hirudins; D011994:Recombinant Proteins; D006493:Heparin; C060225:desirudin