Combination effect of antithrombin and recombinant human soluble thrombomodulin in a lipopolysaccharide induced rat sepsis model.
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.
Iba
Toshiaki
T
Department of Emergency and Disaster Medicine, Juntendo University, Hongo Bunkyo-ku, Tokyo, 113-8421, Japan. toshiiba@cf6.so-net.ne.jp
Nakarai
Etsuro
E
Takayama
Toshio
T
Nakajima
Kenji
K
Sasaoka
Tetsumasa
T
Ohno
Yoichi
Y
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*
D000991:Antithrombins; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D018180:Thrombomodulin; D005340:Fibrinogen; D001219:Aspartate Aminotransferases