Background. The leflunomide analog, FK778, is a selective pyrimidine synthesis inhibitor. In rodent models, FK778 is efficacious in the prevention of allograft and xenograft rejection, and a combination of FK778 and cyclosporine has synergistic immunosuppressive efficacy. Methods. Heterotopic renal transplantation was performed in 20 dogs. Dogs were randomly assigned to three treatment groups: Neoral alone (n=6), FK778 alone (n=7), or a combination of Neoral and FK778 (n=7). Dogs were killed when the plasma creatinine concentration exceeded 7 mg/dL. A complete postmortem examination was performed and the type of acute-active allograft rejection described. Results. A combination of Neoral and FK778 significantly prolonged allograft survival (P=0.0007), with median survival times of 14.5 days for Neoral alone, 7 days for FK778 alone, and 36 days for Neoral and FK778. Allograft histologic changes were consistent with acute-active allograft rejection in 19 of 20 dogs: in the Neoral-alone group, four dogs were type IB, and two were type IIA; in the FK778-alone group, five dogs were type IB, and one was type IIB; and in the Neoral and FK778 group, three dogs were type IB, three were IIA, and one dog was type III. The dog with type III rejection appeared to experience acute sepsis before rejection. Vomiting, diarrhea, and histologic gastritis and enteritis were commonly observed in dogs treated with the combination of Neoral and FK778. Conclusions. A combination of Neoral and FK778 prolonged allograft survival in a robust rejection model. Further investigation of FK778 in organ transplantation is warranted.
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