Synergistic effects of malononitrilamides (FK778, FK779) with tacrolimus (FK506) in prevention of acute heart and kidney allograft rejection and reversal of ongoing heart allograft rejection in the rat.
BACKGROUND
The effects of tacrolimus (FK506) and malononitrilamides (MNA) (FK778 and FK779) monotherapy and combination therapy were examined in prevention of acute heart and kidney allograft rejection and reversal of ongoing acute heart allograft rejection in the rat.


METHODS
Brown Norway (RT1n)-to-Lewis (RT11) and ACI (RT1a)-to-Lewis (RT11) combinations were used, respectively, for heart and kidney transplantation models. Immunosuppressants were administered orally from day 1 to day 14 for preventing acute rejection and from day 4 to day 34 after transplantation for the reversal of ongoing acute rejection.


RESULTS
In the prevention of acute heart rejection model, recipient rats treated with monotherapy of tacrolimus or MNA (FK778, FK779) showed a dose-related prolongation of mean survival time (MST) compared with naive control rats (P<0.01). The mean survival time in combination therapy of tacrolimus (FK506) and FK778 indicated that an additive to synergistic interaction was produced when compared with the respective monotherapies (combination index [CI]=0.631-1.022). These results were reproducible with tacrolimus and FK779 combination therapy (CI=0.572-0.846). Furthermore, similar results were also found in the prevention of acute kidney allograft rejection in the rat (CI=0.137-0.516). In the reversal of ongoing acute heart allograft rejection, combination therapy of tacrolimus and FK778 demonstrated a strong synergistic interaction (CI=0.166-0.970) compared with monotherapy of tacrolimus or FK778.


CONCLUSIONS
Combination therapy of tacrolimus and MNA (FK778, FK779) produces synergistic effects in prevention of acute heart and kidney rejection and reversal of ongoing heart allograft rejection in the rat.
Bilolo
Kupa K
KK
Laboratory of Experimental Surgery, Research Center of CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
Ouyang
Jun
J
Wang
Xiang
X
Zhu
Shengyun
S
Jiang
Wenlei
W
Qi
Shijie
S
Xu
Dasheng
D
Hebert
Marie J
MJ
Bekersky
Ihor
I
Fitzsimmons
William E
WE
Chen
Huifang
H
D000208:Acute Disease; D000480:Alkynes; D000818:Animals; D004357:Drug Synergism; D006084:Graft Rejection / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D007668:Kidney / Q000473:pathology / Q000502:physiology / Q000601:surgery; D016030:Kidney Transplantation; D008297:Male; D009206:Myocardium / Q000473:pathology; D009570:Nitriles; D051381:Rats; D011912:Rats, Inbred ACI; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000494:pharmacology*; D014184:Transplantation, Homologous
D000480:Alkynes; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D016559:Tacrolimus