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The effects of AEB071 (sotrastaurin) with tacrolimus on rat heterotopic cardiac allograft rejection and survival

 Yu Hui Fang  ;  Dong Jin Joo  ;  Beom Jin Lim  ;  Kyu Ha Huh  ;  Myoung Soo Kim  ;  Hwal Suh  ;  Yu Seun Kim 
 JOURNAL OF SURGICAL RESEARCH, Vol.171(1) : 131-137, 2011 
Journal Title
Issue Date
Acute Disease ; Animals ; Disease Models, Animal ; Drug Therapy, Combination ; Graft Rejection/drug therapy* ; Graft Survival/drug effects* ; Heart Transplantation* ; Immunosuppressive Agents/pharmacology ; Kidney/physiology ; Liver/physiology ; Male ; Protein Kinase Inhibitors/pharmacology ; Pyrroles/pharmacology* ; Quinazolines/pharmacology* ; Rats ; Rats, Inbred BN ; Rats, Inbred Lew ; Tacrolimus/pharmacology* ; Transplantation, Heterotopic ; Transplantation, Homologous
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. MATERIALS AND 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. CONCLUSION: AEB071 combined with a smaller dosage of Tac may be clinically possible to establish calcineurin inhibitor (CNI) minimization protocol in solid organ transplantation.
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1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Medical Engineering (의학공학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kim, Myoung Soo(김명수) ORCID logo https://orcid.org/0000-0002-8975-8381
Kim, Yu Seun(김유선) ORCID logo https://orcid.org/0000-0002-5105-1567
Fang, Yu Hui(방우휘)
Suh, Hwal(서활)
Lim, Beom Jin(임범진) ORCID logo https://orcid.org/0000-0003-2856-0133
Joo, Dong Jin(주동진) ORCID logo https://orcid.org/0000-0001-8405-1531
Huh, Kyu Ha(허규하) ORCID logo https://orcid.org/0000-0003-1364-6989
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