Mechanistic study of malononitrileamide FK778 in cardiac transplantation and CMV infection in rats.
BACKGROUND
FK778 is a malononitrilamide, a class of immune suppressive compounds with antiviral features and experimental activity in chronic rejection, a potentially interesting combination for organ transplantation. The goal of this project was to study the tolerability, immune suppressive efficacy, and anti-cytomegalovirus (CMV) activity of FK778 and to assess the in vivo relevance of its previously described inhibition of de novo pyrimidine synthesis.


METHODS
Heart transplants were performed in rats (Brown Norway [BN] to Lewis) and treated with varying doses of FK778 or leflunomide for 28 days. At 28 days, at the time of rejection or at the death of the animal, the allograft and other vital organs were obtained for study by light microscopy and immunohistochemistry. In separate experiments, Lewis rats were given sublethal irradiation, inoculated with rat CMV (Maastricht strain), and treated with varying doses of FK778 and leflunomide. In both the transplant and CMV studies, IP uridine was given at 250 mg/kg to cohorts or animals receiving FK778 and leflunomide.


RESULTS
FK778 controls acute rejection and inhibits CMV replication at 20 mg/kg but is toxic at 25 mg/kg. Toxicity is manifested as anemia, changes in hepatic and intestinal histology, and mortality. The toxicity but not the immune suppressive or antiviral efficacy, is reduced significantly by exogenous uridine administration.


CONCLUSIONS
FK778 has both immune suppressive and antiviral activities, neither of which is entirely dependent on inhibition of pyrimidine synthesis. These, and other published observations, suggest that the antiviral activity and a considerable part of the efficacy of the malononitrilamide family of drugs is attributable to activities other than drug induced pyrimidine deficiency.
Zeng
Huasong
H
Department of Surgery, University of Chicago, Chicago, IL 60637, USA.
Waldman
W James
WJ
Yin
Deng Ping
DP
Knight
Deborah A
DA
Shen
Jikun
J
Ma
Lianli
L
Meister
Gabriel T
GT
Chong
Anita S
AS
Williams
James W
JW
D000480:Alkynes; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D003586:Cytomegalovirus Infections / Q000188:drug therapy*; D006084:Graft Rejection / Q000517:prevention & control; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology*; D009570:Nitriles; D051381:Rats; D011914:Rats, Inbred BN; D014184:Transplantation, Homologous; D014529:Uridine / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D000480:Alkynes; D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D014529:Uridine