SYNERGISTIC EFFECTS OF MYCOPHENOLATE MOFETIL (MMF) AND SIROLIMUS(RAPAMYCIN, RAPA) IN PREVENTION OF ACUTE HEART, PANCREAS AND KIDNEY ALLOGRAFT REJECTION AND IN REVERSAL OF ONGOING HEART ALLOGRAFT REJECTION IN THE RAT

Abstract

676 Results from preclinical studies predict that use of selected combinations of immunosuppressants in patients will be more efficacious with less side-effects. The aim of this study was to evaluate the combined effect of MMF and RAPA in prevention of acute allograft rejection and in reversal of ongoing acute rejection in the rat. Both drugs were given orally for up to 30 days. Eleven groups (n=6) were involved in the first part of the study. Lewis(LEW, RT11) recipients rejected Brown Norway (BN, RT1n) heart allografts with a mean survival time (MST) of 6.5 ± 0.6 days. There were graded dose-responses to MMF 10mg/kg (12.5 ± 2.6 days, p=0.01), 20mg/kg (19.3 ± 9.0 days, p=0.001), and RAPA 0.2mg/kg (19.2 ± 2.0 days, p=0.001), 0.4mg/kg (30 ± 7.3 days, p=0.001), 0.8mg/kg (50.8±12.5 days, p=0.001), 1.2mg/kg (51.2 ± 2.6 days, p=0.001) respectively. Results with combined use of drugs were: MMF 10 mg/kg + RAPA 0.2mg/kg (52.7 ± 5.7 days, combination index (CI)=0.189), MMF 20mg/kg + RAPA 0.4mg/kg (50.2 ± 13.5 days, CI=0.453), and MMF 20 mg/kg + RAPA 0.4 mg/kg(51.5 ± 6.8 days, CI=0.858) respectively. The results indicate that a synergistic or very strong synergistic interaction was produced when compared with monotherapy of MMF or RAPA. In the second part of the study (reversal of ongoing acute rejection model), concomitant administration of MMF 10mg/kg + RAPA 0.2mg/kg (35.5± 5.7 days, CI=0.794), and MMF 20mg/kg + RAPA 0.2mg/kg (57.2 ± 4.7 days, CI=0.310) represented synergistic interaction compared with monotherapy of MMF 10mg/kg (10.8 ± 0.8 days), and 20mg/kg (24.3± 6.2 days), or RAPA 0.2mg/kg (11.7 ± 2.4 days), and RAPA 0.4mg/kg (27.2 ± 8.5 days). The results were repeatable in reversal of ongoing pancreas and kidney allograft rejection. In conclusion, concomitant therapy of MMF and RAPA produces synergistic effect in prevention of heart, pancreas and kidney allograft rejection and in reversal of ongoing heart allograft rejection in the rat.