Progress 01/01/01 to 12/31/03
Outputs
This collaborative study with Fujisawa Healthcare, Inc. evaluated a combination of FK778 and microemulsified cyclosporine for the prevention of renal allograft rejection. Dr. Kyles used a canine model, MLR-mismatched mongrel dogs, to study allograft rejection. He used a sub-therapeutic dose rate and target plasma concentration of microemulsified cyclosporine, modifying the surgical procedure to reduce the risks of intestinal intussusception and including a control group of FK778 alone treated animals. This study aimed to evaluate the efficacy of a combination of FK778 and cyclosporine to test whether a combination of FK778 and cyclosporine will significantly prolong renal allograft survival compared to either FK778 or cyclosporine administered alone.
Impacts
Ultimately this information could lead to improved survival rates and better clinical management of patients following renal transplantation.
Publications
- No publications reported this period
|
Progress 01/01/02 to 12/31/02
Outputs
Background: The leflunomide analog, FK778, is a selective pyrimidine synthesis inhibitor. In rodent models, FK778 is efficacious in the prevention of allo- 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: Neoralr alone (n=6), FK778 alone (n=7) or a combination of Neoralr and FK778 (n=7). Dogs were euthanized when the plasma creatinine concentration exceeded 7 mg/dL. A complete post mortem 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 Neoralr alone, 7 days for FK778 and 36 days for Neoralr and FK778. Allograft histologic changes were consistent with acute/active allograft rejection in 19 of 20 dogs: in the
Neoralr 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 Neoralr 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 prior to rejection. Vomiting, diarrhea and histologic gastritis and enteritis were commonly observed in dogs treated with the combination of Neoralr and FK778. Conclusions: A combination of Neoralr and FK778 prolonged allograft survival in a robust rejection model. Further investigation of FK778 in organ transplantation is warrented. The study has been presented at the merican Transplant Congress, Washington D.C. 2002, the XIX International Congress of the Transplantation Society, Miami, Fl, 2002 and the American College of Veterinary Surgeons Symposium, San Diego, 2002.
Impacts
FK778 is in phase II clinical trials for humans.
Publications
- Kyles A.E., Gregory C.R., Griffey S.M., Bernsteen L and Morris R.A. 2003 Enteroplication for the prevention of intestinal intussusception after renal transplantation in dogs. Journal of Investigative Surgery (In Press)
- Kyles A.E., Gregory C.R., Griffey S.M., Bernsteen L., Pierce J., Lilja H.S. and Morris R.E. 2003 Immunosuppression with a combination of the leflunomide analog, FK778, and microemulsified cyclosporine for renal transplantation in mongrel dogs. Transplantation (In Press)
|
|