title: Different antithrombotic properties of factor Xa inhibitor and thrombin inhibitor in rat thrombosis models.
abstract: We compared the antithrombotic properties of a factor Xa inhibitor (DX-9065a) with those of a thrombin inhibitor (melagatran) in a rat disseminated intravascular coagulation model and a rat venous thrombosis model. Rat disseminated intravascular coagulation and venous thrombosis models were produced by injection of tissue factor and platinum wire placement, respectively. DX-9065a exerted antithrombotic effects dose dependently in both models. Melagatran was also effective in the venous thrombosis model, whereas it showed an aggravation in the disseminated intravascular coagulation model at low but not high doses. In the in vitro study, DX-9065a decreased the C(max) of the thrombin generation curve in plasma irrespective of whether protein C was present or not. However, melagatran increased the C(max) at low concentrations when protein C was present. This increase was not detected in protein C-deficient plasma. These results suggest that, unlike DX-9065a, melagatran in low doses aggravates disseminated intravascular coagulation by increasing thrombin generation, which may be partly due to suppression of negative feedback by activated protein C.
authors.affiliation: New Product Research Laboratories II, Tokyo R & D Center, Daiichi Pharmaceutical Co. Ltd., 16-13, Kita-kasai 1-chome Edogawa-ku, Tokyo 134-8630, Japan.
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Furugohri
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shiozaki
authors.forename: Sumie
authors.initials: S
authors.lastname: Muramatsu
authors.forename: Yuko
authors.initials: Y
authors.lastname: Honda
authors.forename: Chikako
authors.initials: C
authors.lastname: Matsumoto
authors.forename: Koji
authors.initials: K
authors.lastname: Isobe
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Sugiyama
mesh_terms: D000818:Animals; D001384:Azetidines; D001596:Benzylamines; D001777:Blood Coagulation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013925:Thromboplastin / Q000633:toxicity; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*
chemical_list: C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D001384:Azetidines; D001596:Benzylamines; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D009281:Naphthalenes; D011422:Propionates; C109573:melagatran; D013925:Thromboplastin; D013917:Thrombin; D005998:Glycine