Significant prolongation of renal allograft survival by delayed combination therapy of FK778 with tacrolimus in nonhuman primates.
BACKGROUND
Malononitrilamide 715 (FK778) is a new class of low-molecular-weight immunosuppressant that is a derivative of the active metabolite of leflunomide, A77 1726. In this study, the authors evaluated the combined effect of FK778 with tacrolimus in prevention of renal allograft rejection in Vervet monkeys.


METHODS
Male Vervet monkeys were obtained from Caribbean Primates Ltd. Donor and recipient monkeys were from different breeding colonies. Eleven groups (n>or=4 per group) were involved in this study. FK778 and tacrolimus were administered orally for 60 days according to protocol.


RESULTS
Naive controls rejected renal grafts, with a median survival time (MST) of 8.0 days in group 1. When recipient monkeys were treated with tacrolimus 1.0 mg/kg/day in group 2 or FK778 2.5 mg/kg/day in group 3, the MST was 16.0 days (P=0.001) and 11.0 days (P=0.266), respectively. Combination therapy of these two agents at the same doses immediately after transplantation resulted in an MST of 25.0 days (P=0.016) in group 4. When tacrolimus was initiated immediately after transplantation and FK778 treatment was delayed until day 7 after surgery in group 5, recipient survivals were significantly prolonged to 38.0 days (P=0.02). These results were repeatable when FK778 5.0 mg/kg/day (9.0 days, P=0.544 in group 6) was combined with tacrolimus 1.0 mg/kg/day immediately after transplantation (8.0 days, P=0.339) in group 7, or when FK778 was delayed 7 days (60.0 days, P=0.002) in group 8. Furthermore, it was also repeatable when FK778 10 mg/kg/day was combined with tacrolimus 1.0 mg/kg/day with a 7-day delay.


CONCLUSIONS
A significant prolongation of renal allograft survival was produced when FK778 administration was delayed by 7 days combined with tacrolimus in Vervet monkeys.
Qi
Shijie
S
Laboratory of Experimental Surgery, Research Center of CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
Zhu
Shengyun
S
Xu
Dasheng
D
Wang
Xiang
X
Ouyang
Jun
J
Jiang
Wenlei
W
Vu
Minh Diem
MD
Bilolo
Kupa
K
Ma
Anlun
A
Johnson
Stephane
S
Daloze
Pierre
P
Bekersky
Ihor
I
Fitzsimmons
William E
WE
Chen
Huifang
H
D000410:Alanine Transaminase / Q000097:blood; D000480:Alkynes; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001835:Body Weight; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007555:Isoxazoles / Q000008:administration & dosage*; D007668:Kidney / Q000503:physiopathology; D016030:Kidney Transplantation; D008099:Liver / Q000503:physiopathology; D008297:Male; D009570:Nitriles; D016559:Tacrolimus / Q000008:administration & dosage*; D013997:Time Factors
D000480:Alkynes; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D016559:Tacrolimus