Determination of the dosage of recombinant hirudin to inhibit arterial thrombosis in baboons.
Recombinant hirudin, a potent and direct inhibitor of thrombin, effectively inhibits platelet-dependent thrombosis. Our aim was to establish the plasma concentration at which r-hirudin expresses its optimal antithrombotic effect. We measured the extent of inhibition of (111)In-labeled platelet deposition onto 0.6 cm(2) segments of Dacron vascular grafts. These grafts were incorporated as extension segments into exteriorized permanent femoral arteriovenous shunts in baboons. In six control studies a mean of 1.99 +/- 0.26 x 10(9) platelets were deposited at the end of 120 min. In the treatment studies, a thrombus was allowed to form for 10 min in six animals. Treatment for 30 min with r-hirudin at dosages of 140, 70, and 35 microgram/kg/min, but not 14 microgram/kg/min, dose dependently interrupted platelet deposition. The relationship between the percent inhibition of platelet deposition caused by r-hirudin and the plasma concentration of hirudin was exponential (i.e., % Inhibition = 95(1-e(0.23 x [r-hirudin])) (R(2) = 0.76). From this, we estimated that 50% inhibition of platelet deposition will occur at a plasma concentration of approximately 3.3 microgram r-hirudin/mL and 80% at 8.1 microgram/mL. The relationship between the inhibition of platelet deposition and the plasma concentration of hirudin makes it possible to estimate the dose of hirudin that will result in a given level of inhibition of platelet deposition.
Kotzé
H F
HF
Department of Haematology and Cell Biology, Faculty of Health Sciences, University of the Orange Free State, P.O. Box 339 (G2), Bloemfontein, 9300 Republic of South Africa.
Lamprecht
S
S
Van Wyk
V
V
Roodt
J P
JP
Badenhorst
P N
PN
D000818:Animals; D000991:Antithrombins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D006207:Half-Life; D024764:Hirudin Therapy; D006629:Hirudins / Q000493:pharmacokinetics; D008297:Male; D010215:Papio; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use; D013927:Thrombosis / Q000188:drug therapy* / Q000378:metabolism
D000991:Antithrombins; D006629:Hirudins; D011994:Recombinant Proteins