Immunosuppression with FK778 and mycophenolate mofetil in a rat cardiac transplantation model.
FK778 blocks the dihydro-orotate dehydrogenase, necessary for pyrimidine synthesis, and mycophenolate mofetil (MMF) inhibits the inosine monophosphate dehydrogenase, a crucial enzyme for purine biosynthesis. Beneficial immunosuppressive effects have been suggested for the combination of both drugs. The Brown Norway-Lewis rat heterotopic heart transplantation model was used. FK778 (5 and 20 mg/kg/day), MMF (10 and 40 mg/kg/day), or a combination of both drugs for 10 days was used for prevention of acute graft rejection. Grafts of untreated animals were rejected after 6.2 +/- 0.4 days. Low-dose FK778 and low-dose MMF administration did not result in a significantly prolonged graft survival (6.7 +/- 0.8 and 8.7 +/- 1.4 days; P=not significant). Grafts of rats treated with high-dose FK778 or high-dose MMF survived significantly longer (17.0 +/- 2.8 and 20.7 +/- 3.8 days; P<0.01). Concomitant use of low-dose FK778 with low-dose MMF produced synergistic interactions (mean survival time 12.3 +/- 2.9 days; P<0.01; combination index=0.85). High-dose drug combination (mean survival time 24.0 +/- 1.4 days) showed antagonistic drug interaction (combination index=1.55) with increased toxic side effects.
Deuse
Tobias
T
Department of Cardiovascular Surgery, University Hospital Hamburg-Eppendorf, Germany.
Schrepfer
Sonja
S
Reichenspurner
Hermann
H
D000480:Alkynes; D000818:Animals; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology*; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007555:Isoxazoles / Q000627:therapeutic use*; D023421:Models, Animal; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D009570:Nitriles; D051381:Rats; D014184:Transplantation, Homologous
D000480:Alkynes; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D009173:Mycophenolic Acid