title: FK778 and FK506 combination therapy to control acute rejection after rat liver allotransplantation.
abstract: BACKGROUND
  In organ transplantation, several immunosuppressants are currently used to control graft rejection. Clinically, no single immunosuppressive agent can completely prevent posttransplantation immunoreaction; thus, combination therapy is usually performed. Novel agents with more powerful immunosuppressive activity and less toxicity need to be developed.
  
  
  METHODS
  Lewis rat livers were orthotopically transplanted into Brown-Norway recipients. FK778 was administered orally from day 0 to day 6 to prevent acute rejection and from day 7 to day 13 to rescue ongoing rejection. To assess the combined effects, recipients were treated with intramuscular injection of FK506 and oral administration of FK778 from day 0 to day 6. Blood chemistry and histopathologic findings were measured to determine the patient's general condition and the graft condition. Allospecific antibodies were measured using enzyme-linked immunosorbent assays. The FK778 trough concentration was examined by using high-performance liquid chromatography.
  
  
  RESULTS
  The acute immune response was suppressed by FK778 alone in a dose-dependent manner. The optimal FK778 dosage was determined to be 20 mg/kg per day, because adverse effects (weight loss and intestinal bleeding) occurred at 30 mg/kg per day. FK778 treatment from day 7 to day 13 rescued liver grafts from ongoing rejection. The intramuscular FK506 (0.125 mg/kg per day) injection and the oral FK778 (20 mg/kg per day) gavages suppressed acute liver graft rejection effectively and maintained better graft condition compared with monotherapy. CONCLUSIONS.: FK778 treatment effectively prevented acute rejection and rescued ongoing rejection after liver transplantation. The optimal dosage was determined to be 20 mg/kg per day. Combination therapy with FK506 was more beneficial than FK778 monotherapy.
authors.affiliation: Department of Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. m7577175@msic.med.osaka-cu.ac.jp
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Toyokazu
authors.initials: T
authors.lastname: Okuda
authors.forename: Keiichi
authors.initials: K
authors.lastname: Yamasaki
authors.forename: Hiromu
authors.initials: H
authors.lastname: Tanaka
authors.forename: Shoji
authors.initials: S
authors.lastname: Kubo
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Takemura
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ikeda
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Minamiyama
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hirohashi
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Suehiro
mesh_terms: D000208:Acute Disease; D000480:Alkynes; D000818:Animals; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000517:prevention & control*; D007075:Immunoglobulin M / Q000097:blood; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007555:Isoxazoles / Q000008:administration & dosage*; D008099:Liver / Q000473:pathology; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D009570:Nitriles; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000008:administration & dosage*; D014184:Transplantation, Homologous
chemical_list: D000480:Alkynes; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D016559:Tacrolimus