Beneficial effect of JTV-803, a new synthetic inhibitor of activated factor X, against both lipopolysaccharide-induced and tissue factor-induced disseminated intravascular coagulation in rat models.
We examined whether JTV-803, a specific activated factor X inhibitor independent of antithrombin III (ATIII), is effective against disseminated intravascular coagulation (DIC) in rat models induced by tissue factor (TF) or lipopolysaccharides (LPS). In male Wistar rats, DIC was induced by a 4 h infusion of thromboplastin (3.75 U/kg) or LPS (50 mg/kg). The rats were given JTV-803 (0.3 or 3 mg/kg, bolus intravenously) (JTV-803 groups) or low molecular weight heparin (LMWH groups) (200 U/kg, bolus intravenously) prior to an injection of TF or LPS. The results showed that JTV-803 was dose-dependently effective against DIC in both TF-induced and LPS-induced rat models. This anti-DIC effect of JTV-803 at higher doses was almost equivalent to that of LMWH in both types of DIC. Plasma ATIII activity was more prominent in the group treated with JTV-803 than in that treated with LMWH. None of rats died in the TF-induced DIC model with or without drug administration. On the contrary, seven of 22 rats died (mortality rate, 31.8%) in the LPS-induced DIC model without drug administration. Although the mortality rate of rats induced with LPS and treated with LMWH was quite high (6/16, 37.5%), none of the LPS-induced rats treated with JTV-803 died. These findings suggested that JTV-803 can treat both TF-induced and LPS-induced DIC models, and that this drug has greater potential in preserving ATIII and in improving the prognosis of DIC.
Asakura
H
H
Department of Internal Medicine (III), Kanazawa University School of Medicine, Kanazawa, Ishikawa, Japan. hasakura@med3.m.kanazawa-u.ac.jp
Ichino
T
T
Yoshida
T
T
Suga
Y
Y
Ontachi
Y
Y
Mizutani
T
T
Kato
M
M
Ito
T
T
Yamazaki
M
M
Aoshima
K
K
Morishita
E
E
Saito
M
M
Miyamoto
K-I
KI
Nakao
S
S
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D000990:Antithrombin III / Q000032:analysis; D015415:Biomarkers; D001798:Blood Proteins / Q000032:analysis; D017985:Dalteparin / Q000627:therapeutic use; D004211:Disseminated Intravascular Coagulation / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005170:Factor X / Q000037:antagonists & inhibitors*; D006487:Hemostasis / Q000187:drug effects; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007678:Kidney Glomerulus / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D044005:Tetrahydroisoquinolines; D013925:Thromboplastin / Q000633:toxicity*
C442639:4-((2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)methyl)-1-(4-pyridinyl)piperidine-4-carboxylic acid monomethanesulfonate trihydrate; D000925:Anticoagulants; D015415:Biomarkers; D001798:Blood Proteins; D007546:Isoquinolines; D008070:Lipopolysaccharides; D010880:Piperidines; D011725:Pyridines; D044005:Tetrahydroisoquinolines; D000990:Antithrombin III; D005170:Factor X; D013925:Thromboplastin; D017985:Dalteparin