Effects of activated factor X inhibitor, JTV-803, in a pig model of hemodialysis.
JTV-803 (4-[(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)methyl]-1-(4-pyridinyl)piperidine-4-carboxylic acid monomethanesulfonate trihydrate), a specific inhibitor of factor Xa, was evaluated in a pig hemodialysis model with ligation of renal arteries. In this model, JTV-803 administered into the dialysis circuit showed an anticoagulant effect (prolongation of dialysis time) at doses of 0.3 mg/kg + 0.3, 1.0 and 3.0 mg/kg/h. The prolongation of dialysis time in the 0.3 mg/kg + 1.0 mg/kg/h JTV-803 group was comparable to that in the 15 U/kg + 7.5 U/kg/h heparin group. The plasma concentrations of JTV-803 following 0.3 mg/kg + 1.0 mg/kg/h infusion of the drug into the dialysis circuit was 500 ng/ml or less, and prothrombin time was 1.5-fold or less than the pretreatment value. JTV-803 was removed by passing the blood through a dialyzer, resulting in a clearance rate of 53.4-81.8%. After the end of dialysis, plasma concentrations of JTV-803 decreased rapidly with time. These results suggest that human factor Xa inhibitor JTV-803 may have good potential as an antithrombotic agent during hemodialysis, with lower likelihood of bleeding after the end of dialysis.
Hayashi
Mikio
M
Central Pharmaceutical Research Institute, Japan Tobacco Inc, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Uesato
Naofumi
N
Aisaka
Kazuo
K
D000818:Animals; D005170:Factor X / Q000037:antagonists & inhibitors*; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D011517:Prothrombin Time; D011725:Pyridines / Q000494:pharmacology*; D006435:Renal Dialysis; D013552:Swine; D044005:Tetrahydroisoquinolines; D013927:Thrombosis / Q000097:blood*
C442639:4-((2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)methyl)-1-(4-pyridinyl)piperidine-4-carboxylic acid monomethanesulfonate trihydrate; D007546:Isoquinolines; D010880:Piperidines; D011725:Pyridines; D044005:Tetrahydroisoquinolines; D005170:Factor X