Effects of a factor Xa inhibitor, DX-9065a, in a novel rabbit model of venous thrombosis.
The objective of this study was to evaluate the effects of DX-9065a, a nonpeptide, direct inhibitor of factor Xa (FXa), in a novel experimental model of venous thrombosis. The experiments were conducted on anesthetized rabbits in which a veno-venous shunt with cotton threads was inserted into the vena cava. DX-9065a was administered intravenously to the rabbits as an initial bolus followed by a maintenance infusion using the following dosing schedules: DX-I: 0.25 mg/kg + 3 micrograms/kg/min.; DX-II: 0.75 mg/kg + 9 micrograms/kg/min.; DX-III: 1.5 mg/kg + 18 micrograms/kg/min.; DX-IV: 3.0 mg/kg + 36 micrograms/kg/min.; DX-V: 6.0 mg/kg + 72 micrograms/kg/min. DX-9065a induced a dose-dependent increase in the time to occlusion and a dose-dependent decrease in thrombus weight. Because of the unique character of the model, we were also able to show a dose-dependent increase in blood flow through the shunt. In addition, there were dose-dependent increases in prothrombin time (PT) and activated coagulation time (ACT) with more variable responses in the activated partial thromboplastin time (APTT). DX-9065a had little effect on thrombin time (TT) or bleeding time at all doses tested. In conclusion, dose-dependent antithrombotic efficacy was documented with DX-9065a in this new model of venous thrombosis. Although the in vivo potency of the compound was not striking, the results support the utility of FXa inhibition in venous thrombosis and demonstrate the utility of this experimental model for evaluating the efficacy of novel anticoagulants.
Rogers
K L
KL
Department of Pharmacokinetics, Dynamics & Metabolism, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105, USA. Karen.Rogers@wl.com
Chi
L
L
Rapundalo
S T
ST
Kramer
J B
JB
Gallagher
K P
KP
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D065427:Factor Xa Inhibitors; D006487:Hemostasis; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011422:Propionates / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D020246:Venous Thrombosis / Q000378:metabolism*
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D009281:Naphthalenes; D010975:Platelet Aggregation Inhibitors; D011422:Propionates; D015842:Serine Proteinase Inhibitors