title: Combination effect of antithrombin and recombinant human soluble thrombomodulin in a lipopolysaccharide induced rat sepsis model.
abstract: BACKGROUND
  Recombinant human soluble thrombomodulin (rhsTM) is newly developed for the treatment of DIC. The purpose of this study was to evaluate the efficacy of the concomitant administration of rhsTM and antithrombin (AT).
  
  
  METHODS
  In the first series, rats were treated with either 62.5, 125, 250 or 500 IU/kg (n = 6, each) of AT or 0.125, 0.25, 0.5 or 1.0 mg/kg (n = 6, each) of rhsTM followed by lipopolysaccharide (LPS) injection. 8 h later, the fibrinogen level was examined. In the second series, TM group was pretreated with 0.25 mg/kg of rhsTM, AT group was pretreated with 125 IU/kg of AT, AT/TM group was pretreated with both AT and rhsTM, and control group was pretreated with saline (n = 7, each). The platelet count, fibrinogen, ALT, LDH and high-mobility group box 1 (HMGB1) levels were measured. In addition, histologic changes in liver were examined. In the third series, survival was calculated up to 24 h.
  
  
  RESULTS
  Both AT and rhsTM produced a linear dose-response with regard to the fibrinogen level, with 125 IU/kg of AT and 0.25 mg/kg of rhsTM producing equivalent effects. The combined administration of AT and rhsTM significantly reduced the decrease in the platelet count and the fibrinogen level (P < 0.05, 0.01, respectively). The elevations in ALT and LDH were significantly suppressed in all treatment groups. The HMGB1 level and the histologic changes tended to indicate damage reduction. Survival was significantly better only in AT/TM group (P < 0.01).
  
  
  CONCLUSIONS
  The coadministration of AT and rhsTM might be effective for the treatment of severe sepsis.
authors.affiliation: Department of Emergency and Disaster Medicine, Juntendo University, Hongo Bunkyo-ku, Tokyo, 113-8421, Japan. toshiiba@cf6.so-net.ne.jp
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Iba
authors.forename: Etsuro
authors.initials: E
authors.lastname: Nakarai
authors.forename: Toshio
authors.initials: T
authors.lastname: Takayama
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakajima
authors.forename: Tetsumasa
authors.initials: T
authors.lastname: Sasaoka
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ohno
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D010976:Platelet Count; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000627:therapeutic use; D018805:Sepsis / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D018180:Thrombomodulin / Q000627:therapeutic use*
chemical_list: D000991:Antithrombins; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D018180:Thrombomodulin; D005340:Fibrinogen; D001219:Aspartate Aminotransferases