title: Effects of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and dalteparin on the endogenous thrombin potential in venous blood from healthy male subjects.
abstract: The effect of the oral direct thrombin inhibitor ximelagatran and its active form, melagatran, on thrombin generation was investigated in vitro and ex vivo using a thrombin generation assay. In-vitro thrombin generation was triggered in human platelet-poor plasma by the addition of tissue factor, and the endogenous thrombin potential (ETP) was measured. The ETP IC(50) values for melagatran and the low-molecular-weight heparin dalteparin were 0.44 micromol/l and 0.06 IU/ml, respectively. In contrast to dalteparin, melagatran increased the time-to-thrombin peak in a concentration-dependent manner. ETP was also studied ex vivo in platelet-poor plasma collected from healthy male subjects (n = 54) at pre-dose and 2 h post-dose, with ximelagatran (60 mg) orally, dalteparin (120 IU/kg) subcutaneously, or control (water) orally. After ximelagatran or dalteparin administration, the time-to-thrombin peak was prolonged by 41 and 95%, and the ETP was decreased by 61 and 77%, respectively. Thus, melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, efficiently delays and inhibits the generation of thrombin in plasma both in vitro and ex vivo.
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden. stig-lennart.bostrom@astrazeneca.com
authors.forename: Stig L
authors.initials: SL
authors.lastname: Boström
authors.forename: Göran F
authors.initials: GF
authors.lastname: Hansson
authors.forename: Magnus
authors.initials: M
authors.lastname: Kjaer
authors.forename: Troy C
authors.initials: TC
authors.lastname: Sarich
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology*; D001384:Azetidines / Q000008:administration & dosage / Q000493:pharmacokinetics; D001596:Benzylamines; D017985:Dalteparin / Q000008:administration & dosage / Q000494:pharmacology*; D065427:Factor Xa Inhibitors; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007279:Injections, Subcutaneous; D008297:Male; D012016:Reference Values; D013917:Thrombin / Q000032:analysis / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013997:Time Factors; D014680:Veins
chemical_list: D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D065427:Factor Xa Inhibitors; C109573:melagatran; C426686:ximelagatran; D013917:Thrombin; D017985:Dalteparin; D005998:Glycine