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 cyclophosphamide in the prolongation of heterotopic cardiac xenograft survival in a discordant neonatal pig to rabbit model.


METHODS
Animals were randomly assigned to receive rapamycin intravenously (1.0 mg/kg/day) or RS-61443 subcutaneously (160 mg/kg/day) commencing five days before surgery until rejection occurred. Cyclophosphamide, 20 mg/kg/day, was administered from one day prior to surgery. Combination of the above drugs (rapamycin 1.0 mg/kg/day and RS-61443 80 mg/kg/day) with and without treatment with cyclophosphamide was also evaluated. Trough blood concentrations of rapamycin and mycophenolic acid as well as rabbit antiporcine endothelial cell antibodies (immunoglobulin [Ig]M) were measured every 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), with the majority of animals (n = 6) rejecting their grafts in less than 1 h. Rapamycin (11.5 +/- 9.5 h), RS-61443 (9.8 +/- 6.1 h), cyclophosphamide (17.9 +/- 16 h) alone, or the three drugs in combination (16.6 +/- 9.1 h) resulted in a trend to increase graft survival, which did not reach significance. In contrast, rapamycin and RS-61443 in combination (24.3 +/- 11.9 h) significantly (P < 0.05) prolonged graft survival. No significant (P > 0.05) decrease in rabbit antiporcine endothelial cell IgM concentrations was observed in all drug-treated groups; however, considerable variation was noted within each group. No relationship was found between trough concentrations of rapamycin and mycophenolic acid and xenograft survival or with a decrease in antibody concentrations.


CONCLUSIONS
The data suggest that treatment modalities, in addition to the above drugs, is required for prolonged survival in cardiac xenografts in the discordant animal model used here.
Yatscoff
R W
RW
Department of Laboratory Medicine, University of Alberta, Edmonton.
Wang
S
S
Keenan
R
R
Chackowsky
P
P
Lowes
N
N
Koshal
A
A
D000818:Animals; D000831:Animals, Newborn; D003520:Cyclophosphamide / Q000494:pharmacology*; D004727:Endothelium / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D007075:Immunoglobulin M / Q000032:analysis; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009173:Mycophenolic Acid / Q000494:pharmacology; D011090:Polyenes / Q000494:pharmacology*; D011817:Rabbits; D011897:Random Allocation; D020123:Sirolimus; D013552:Swine; D014183:Transplantation, Heterologous
D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D011090:Polyenes; D003520:Cyclophosphamide; D009173:Mycophenolic Acid; D020123:Sirolimus