title: Factor Xa-inhibitor (DX-9065a) modulates the leukocyte-endothelial cell interaction in endotoxemic rat.
abstract: Abnormalities of vascular endothelial function and coagulation play important roles in the development of septic organ dysfunction. DX-9065a is a novel Factor Xa inhibitor that is expected to modulate both coagulation and endothelial function. The purpose of this study is to examine the effect of DX-9065a on leukocyte-endothelial interaction. Rats were injected with 1.0 mg/kg of endotoxin simultaneously with saline, (placebo group), 0.3 mg/kg DX-9065a (low-dose group), or 3.0 mg/kg DX-9065a (high-dose group; n = 6 in each group). At 1 and 3 h after injection, the mesenteric microcirculation was observed under intravital microscopy. In addition, TNF, IL-6, alanine aminotransferase (ALT), blood urea nitrogen (BUN), and lactate levels were measured. The number of leukocytes adhering to the endothelium was significantly reduced in both the high-dose and low-dose groups (P < 0.05 for both, compared to the control group). A comparison of the cytokine levels showed that the peak levels in the treatment groups tended to be lower. Markers of organ damage also showed less increase in the treatment groups (P < 0.05 for both treatment groups compared to the control group). In summary, the Factor Xa inhibitor DX-9065a showed a protective effect on the microcirculation of endotoxemic rats by attenuating leukocyte-endothelial interaction. Although the mechanism for this effect could not be fully elucidated, suppression of both excessive coagulation and cytokine production appear to play a role.
authors.affiliation: Department of Surgery, Juntendo University School of Medicine, Urayasu Hospital, Chiba, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Iba
authors.forename: Akio
authors.initials: A
authors.lastname: Kidokoro
authors.forename: Masaki
authors.initials: M
authors.lastname: Fukunaga
authors.forename: Shoichi
authors.initials: S
authors.lastname: Fuse
authors.forename: Masaru
authors.initials: M
authors.lastname: Suda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kunitada
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hara
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D019446:Endotoxemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D065427:Factor Xa Inhibitors; D005260:Female; D015850:Interleukin-6 / Q000097:blood; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects*; D009102:Multiple Organ Failure / Q000378:metabolism / Q000503:physiopathology; D009281:Naphthalenes / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010976:Platelet Count; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D065427:Factor Xa Inhibitors; D015850:Interleukin-6; D009281:Naphthalenes; D010975:Platelet Aggregation Inhibitors; D011422:Propionates; D014409:Tumor Necrosis Factor-alpha