Immunosuppression with FK778 and mycophenolate mofetil in a rat cardiac transplantation model
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Immunosuppression with FK778 and mycophenolate mofetil in a rat cardiac transplantation model. / Deuse, Tobias; Schrepfer, Sonja; Reichenspurner, Hermann.
In: TRANSPLANTATION, Vol. 76, No. 11, 15.12.2003, p. 1627-9.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Immunosuppression with FK778 and mycophenolate mofetil in a rat cardiac transplantation model
AU - Deuse, Tobias
AU - Schrepfer, Sonja
AU - Reichenspurner, Hermann
PY - 2003/12/15
Y1 - 2003/12/15
N2 - 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.
AB - 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.
KW - Alkynes
KW - Animals
KW - Drug Therapy, Combination
KW - Graft Survival/drug effects
KW - Heart Transplantation/immunology
KW - Immunosuppressive Agents/therapeutic use
KW - Isoxazoles/therapeutic use
KW - Models, Animal
KW - Mycophenolic Acid/analogs & derivatives
KW - Nitriles
KW - Rats
KW - Transplantation, Homologous
U2 - 10.1097/01.TP.0000092006.43818.B0
DO - 10.1097/01.TP.0000092006.43818.B0
M3 - SCORING: Journal article
C2 - 14702537
VL - 76
SP - 1627
EP - 1629
JO - TRANSPLANTATION
JF - TRANSPLANTATION
SN - 0041-1337
IS - 11
ER -
