title: The effects of AEB071 (sotrastaurin) with tacrolimus on rat heterotopic cardiac allograft rejection and survival.
abstract: BACKGROUND
  AEB071 (sotrastaurin) is a specific inhibitor of protein kinase C that prevents T-cell activation. Our previous study demonstrated that AEB071 monotherapy could prevent acute cardiac allograft rejection in rats. Herein, we investigated the effects of AEB071 combined with various doses of tacrolimus (Tac) on the allograft rejection and survival in a rat heart transplantation model.
  
  
  METHODS
  Heterotopic cardiac transplantation from Brown-Norway to Lewis rats was performed. Cardiac allograft survival was assessed by monitoring heartbeats in six recipients of each experimental group. Another four recipient rats were selectively sacrificed in each group at d 7 post-transplantation for histologic examination. Serum transaminases, blood urea nitrogen, and creatinine concentrations were measured.
  
  
  RESULTS
  AEB071 monotherapy prolonged allograft mean survival time (MST) compared with the untreated control group. Also a combination of AEB071 and Tac prolonged MST compared with monotherapy groups with higher dose of Tac. In the cardiac graft histology, AEB071 combined with Tac 0.6 mg/kg/d significantly decreased the rejection grade as indicative of decreased inflammatory cell infiltration into the graft. No experimental group was found with any abnormal histologic or serologic evidence of liver and kidney toxicity.
  
  
  CONCLUSIONS
  AEB071 combined with a smaller dosage of Tac may be clinically possible to establish calcineurin inhibitor (CNI) minimization protocol in solid organ transplantation.
authors.affiliation: The Research Institute for Transplantation, Yonsei University, Seoul, South Korea.
authors.forename: Yu Hui
authors.initials: YH
authors.lastname: Fang
authors.forename: Dong Jin
authors.initials: DJ
authors.lastname: Joo
authors.forename: Beom Jin
authors.initials: BJ
authors.lastname: Lim
authors.forename: Kyu Ha
authors.initials: KH
authors.lastname: Huh
authors.forename: Myoung Soo
authors.initials: MS
authors.lastname: Kim
authors.forename: Hwal
authors.initials: H
authors.lastname: Suh
authors.forename: Yu Seun
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000208:Acute Disease; D000818:Animals; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000188:drug therapy*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007668:Kidney / Q000502:physiology; D008099:Liver / Q000502:physiology; D008297:Male; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000494:pharmacology*; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; C543528:sotrastaurin; D016559:Tacrolimus