title: Nafamostat attenuated the impairment of fibrinolysis in animal sepsis model by suppressing the increase of plasminogen activator inhibitor type 1.
abstract: BACKGROUND
  In endotoxemia, plasminogen activator inhibitor-1 (PAI-1) increases and develops clinical symptoms by suppressing fibrinolysis. We analyzed therapeutic advantage of nafamostat, a broad-range protease inhibitor, on fibrinolysis in an animal sepsis model.
  
  
  METHODS
  Male Wister rats infused with lipopolysaccharide (LPS) (50 mg/kg) alone or together with nafamostat (0.1 mg/kg/hr) for 4 hours were analyzed.
  
  
  RESULTS
  Plasma PAI-1 (4.2: 4.0-5.0 ng/mL, median and interquartile range) increased after LPS infusion (3700: 3400-4000), which was attenuated by nafamostat (2300: 2100-2600, p < 0.05). Fibrin(ogen) degradation products after LPS injection (173: 152-182 microg/mL) were further elevated by nafamostat (205: 205-228, p < 0.05), Nafamostat attenuated polymorphonuclear neutrophils infiltration in the liver, and tended to suppress plasma tumor necrosis factor-alpha levels. Nafamostat did not affect thrombin generation, platelet count, markers of liver and kidney function, and overall mortality.
  
  
  CONCLUSIONS
  Nafamostat appeared to improve impaired fibrinolysis by suppressing the increase of PAI-1 in plasma, though it did not largely improve clinical parameters.
authors.affiliation: Department of Physiology, Hamamatsu University School of Medicine, Handa-yama, Japan.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Hryszko
authors.forename: Keisuke
authors.initials: K
authors.lastname: Inaba
authors.forename: Hayato
authors.initials: H
authors.lastname: Ihara
authors.forename: Yuko
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Hideo
authors.initials: H
authors.lastname: Mogami
authors.forename: Tetsumei
authors.initials: T
authors.lastname: Urano
mesh_terms: D000818:Animals; D001550:Benzamidines; D004347:Drug Interactions; D005340:Fibrinogen / Q000378:metabolism*; D005342:Fibrinolysis / Q000187:drug effects*; D006146:Guanidines / Q000494:pharmacology*; D016753:Interleukin-10 / Q000097:blood; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001550:Benzamidines; D006146:Guanidines; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D011480:Protease Inhibitors; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D005340:Fibrinogen; C032855:nafamostat