Prolongation of canine intestinal allograft survival with RS-61443, cyclosporine, and prednisone.
The efficacy of RS-61443 and cyclosporine utilized either alone or in combination was assessed in both a segmental heterotopic and total orthotopic canine intestinal transplant model. Twenty-eight dogs underwent segmental (150-cm) heterotopic intestinal transplants and five dogs total orthotopic transplants. Five heterotopic groups were compared: group 1, no immunosuppression; group 2, cyclosporine and prednisone; group 3, RS-61443, cyclosporine and prednisone; group 4, RS-61443 and prednisone; and group 5, RS-61443 and subtherapeutic cyclosporine. Group 3 animals achieved a median survival of 136 days, while the median survivals of groups 1, 2, 4, and 5 were < or = 10 days (P < .001). Twenty deaths in groups 1 through 5 were secondary to allograft rejection, two were due to infection, and two were unexplained. Four animals in group 3 were sacrificed, one at 83 days due to diarrhea and weight loss and three at the termination of the study. The median survival of five dogs undergoing total orthotopic transplantation (group 6) was 27.0 days and was significantly longer than groups 1, 4, and 5 (P < .01). No dog in this group had intestinal rejection--however, four were sacrificed due to weight loss and one died of malnutrition. The combination of RS-61443 and cyclosporine significantly prolonged intestinal allograft survival in both the heterotopic and orthotopic transplant models. Clinically, this combination may be promising for both combined liver-intestinal and isolated intestinal transplantation.
D'Alessandro
A M
AM
Department of Surgery, University of Wisconsin Medical School, Madison 53792.
Rankin
M
M
McVey
J
J
Hafez
G R
GR
Sollinger
H W
HW
Kalayoglu
M
M
Belzer
F O
FO
D000818:Animals; D016572:Cyclosporine / Q000097:blood / Q000494:pharmacology*; D004285:Dogs; D005965:Glucuronates / Q000097:blood; D006085:Graft Survival / Q000187:drug effects*; D007082:Ileum / Q000637:transplantation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007408:Intestinal Absorption; D007422:Intestines / Q000637:transplantation*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D011241:Prednisone / Q000494:pharmacology*; D014994:Xylose / Q000493:pharmacokinetics
D005965:Glucuronates; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D014994:Xylose; D009173:Mycophenolic Acid; D011241:Prednisone