Acute antithrombotic effects of ximelagatran, an oral direct thrombin inhibitor, and r-hirudin in a human ex vivo model of arterial thrombosis.
BACKGROUND
Thrombin plays a major role in thrombus formation through activation of platelets and conversion of fibrinogen to fibrin.


OBJECTIVE
To investigate the antithrombotic effects of the oral direct thrombin inhibitor (DTI) ximelagatran and the parenteral DTI r-hirudin in humans.


METHODS
Healthy male volunteers randomized into four parallel groups each with 15 subjects received either ximelagatran (20, 40 or 80 mg orally) or r-hirudin (0.4 mg kg-1 intravenous bolus + infusion of 0.15 mg kg-1 h-1 for 2 h and 0.075 mg kg-1 h-1 for 3 h). Antithrombotic effects were assessed as changes in total thrombus area (TTA) and total fibrin area (TFA) from baseline, using the Badimon perfusion chamber model at baseline and 2 h and 5 h after drug administration.


RESULTS
Two hours postdosing, ximelagatran showed antithrombotic effects at both high and low shear rates (TTA% of mean baseline value +/- SEM was 76 +/- 13% and 71 +/- 17% [both P < 0.05] for the 20-mg dose, 85 +/- 11% [P > 0.05] and 62 +/- 15% [P < 0.05] for the 40-mg dose and 60 +/- 11% and 26 +/- 7% [both P < 0.05] for the 80-mg dose, respectively). r-Hirudin also showed a significant antithrombotic effect at high and low shear rates (76 +/- 11% [P = 0.05] and 57 +/- 17% [P < 0.05] of baseline values, 2 h postdosing, respectively). The inhibitory effects on TFA were similar to those on TTA.


CONCLUSIONS
The oral DTI ximelagatran shows antithrombotic effects under both high and low shear conditions. The antithrombotic effect of 40-80 mg ximelagatran appeared comparable to that of parenterally administered r-hirudin, which has been previously demonstrated to be clinically effective in acute coronary syndromes.
Sarich
T C
TC
Experimental Medicine, AstraZeneca LP, Wilmington, DE 19850, USA. troy.sarich@astrazeneca.com
Osende
J I
JI
Eriksson
U G
UG
Fager
G B
GB
Eriksson-Lepkowska
M
M
Ohlsson
L
L
Carlsson
S
S
Wåhlander
K
K
Gustafsson
D
D
Badimon
J J
JJ
D000328:Adult; D001157:Arterial Occlusive Diseases / Q000188:drug therapy / Q000517:prevention & control; D001384:Azetidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001596:Benzylamines; D001780:Blood Coagulation Tests; D005337:Fibrin / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D006629:Hirudins / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008297:Male; D010477:Perfusion; D010599:Pharmacokinetics; D013314:Stress, Mechanical; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000188:drug therapy / Q000517:prevention & control*; D014680:Veins
D001384:Azetidines; D001596:Benzylamines; D005343:Fibrinolytic Agents; D006629:Hirudins; C426686:ximelagatran; D005337:Fibrin; D013917:Thrombin