EFFICACY OF RAPAMYCIN, RS-61443 AND CYCLOPHOSPHAMIDE IN THE PROLONGATION OF SURVIVAL OF DISCORDANT PIG TO RABBIT CARDIAC XENOGRAFTS

Objective: To evaluate the efficacy of two new immunosuppressive drugs , RS-61443 and rapamycin, alone and in combination with cyclophosphami de in the prolongation of heterotopic cardiac xenograft survival in a discordant neonatal pig to rabbit model. Design: Animals were randomly assigned to receive rapamycin intravenously (1.0 mg/kg/day) or RS-614 43 subcutaneously (160 mg/kg/day) commencing five days before surgery until rejection occurred. Cyclophosphamide, 20 mg/kg/day, was administ ered from one day prior to surgery. Combination of the above drugs (ra pamycin 1.0 mg/kg/day and RS-61443 80 mg/kg/day) with and without trea tment with cyclophosphamide was also evaluated. Trough blood concentra tions of rapamycin and mycophenolic acid as well as rabbit antiporcine endothelial cell antibodies (immunoglobulin [Ig]M) were measured ever y second day from the commencement of drug therapy. Results: The mean +/- SD survival time in control animals was 7.98+/-13.85 h (n = 11), w ith the majority of animals (n = 6) rejecting their grafts in less tha n 1 h. Rapamycin (11.5+/- 9.5 h), RS-61443 (9.8+/-6.1 h), cyclophospha mide (17.9+/-16 h) alone, or the three drugs in combination (16.6+/-9. 1 h) resulted in a trend to increased graft survival, which did not re ach significance. In contrast, rapamycin and RS-61443 in combination ( 24.3+/-11.9 h) significantly (P<0.05) prolonged graft survival. No sig nificant (P>0.05) decrease in rabbit antiporcine endothelial cell IgM concentrations was observed in all drug-treated groups; however, consi derable variation was noted within each group. No relationship was fou nd between trough concentrations of rapamycin and mycophenolic acid an d xenograft survival or with a decrease in antibody concentrations. Co nclusion: The data suggest that treatment modalities, in addition to t he above drugs, is required for prolonged survival in cardiac xenograf ts in the discordant animal model used here.