title: Inhibition of thrombin generation by the oral direct thrombin inhibitor ximelagatran in shed blood from healthy male subjects.
abstract: 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.
authors.affiliation: AstraZeneca R&D Mölndal, Sweden. troy.sarich@astrazeneca.com
authors.forename: Troy C
authors.initials: TC
authors.lastname: Sarich
authors.forename: Ulf G
authors.initials: UG
authors.lastname: Eriksson
authors.forename: Christer
authors.initials: C
authors.lastname: Mattsson
authors.forename: Michael
authors.initials: M
authors.lastname: Wolzt
authors.forename: Lars
authors.initials: L
authors.lastname: Frison
authors.forename: Gunnar
authors.initials: G
authors.lastname: Fager
authors.forename: David
authors.initials: D
authors.lastname: Gustafsson
mesh_terms: 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
chemical_list: 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