Inhibition of thrombin generation by the oral direct thrombin inhibitor ximelagatran in shed blood from healthy male subjects.
Ximelagatran, an oral direct thrombin inhibitor, whose active form is melagatran, was studied using a model of thrombin generation in humans. Healthy male volunteers (18 per group) received ximelagatran (60 mg p.o.), dalteparin (120 IU/kg s.c.) or a control (water p.o.). Shed blood, collected after incision of the forearm with standardised bleeding time devices at pre-dose, and at 2, 4 and 10 h post-dosing, was analysed for markers of thrombin generation. Statistically significant reductions (p < 0.05) in levels of prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complex (TAT) in shed blood were detected at 2 and 4 h post-dosing in both the ximelagatran and dalteparin groups. Shed blood F1+2 and TAT levels had returned to pre-dose levels at 10 h post-dosing. Using a shed blood model, we demonstrate that the reversible thrombin inhibitor melagatran and, therefore, oral administration of ximelagatran, inhibits thrombin generation in humans after acute activation of coagulation.
Sarich
Troy C
TC
AstraZeneca R&D Mölndal, Sweden. troy.sarich@astrazeneca.com
Eriksson
Ulf G
UG
Mattsson
Christer
C
Wolzt
Michael
M
Frison
Lars
L
Fager
Gunnar
G
Gustafsson
David
D
D000284:Administration, Oral; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000990:Antithrombin III / Q000032:analysis; D001384:Azetidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001596:Benzylamines; D017985:Dalteparin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D005246:Feedback; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000032:analysis; D010447:Peptide Hydrolases / Q000032:analysis; D011516:Prothrombin / Q000032:analysis; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D010446:Peptide Fragments; C046193:antithrombin III-protease complex; C045879:prothrombin fragment 1.2; C426686:ximelagatran; D000990:Antithrombin III; D011516:Prothrombin; D010447:Peptide Hydrolases; D013917:Thrombin; D017985:Dalteparin