The novel immunosuppressive agents malononitrilamides (MNA) 279 and 715 are
derivatives of A77 1726, the primary metabolite of leflunomide. The effect
s of these agents have been previously demonstrated in rat skin and cardiac
allo- and xenotransplant models. The aim of this study was to evaluate the
combination of MNA and tacrolimus in a high-responder rat cardiac allotran
splant model.
Graft survival was evaluated following 10 days of post-transplant oral ther
apy of MNA or tacrolimus alone and the drugs combined in PVG recipients of
DA grafts. An iso-effect curve of single and combined drugs was constructed
. Histological changes in grafts were evaluated at 10 days.
MNA (20 mg/kg) or tacrolimus (2.4 mg/kg) alone prolonged graft survival wit
h median survival of 14 and 13.5 days, respectively. Combined therapy of MN
A (10 mg/kg) and tacrolimus 1.6 mg/kg likewise resulted in a median surviva
l of 13.25 days and an iso-effect curve for these doses was constructed. An
other iso-effect curve for median graft survival of 18-19 days, including M
NA (10 mg/kg) + tacrolimus (3.2 mg/kg) in combination, MNA (30 mg/kg) alone
and tacrolimus (4.8 mg/kg) alone, was constructed and both isoboles showed
a straight line, demonstrating additive effects (zero interaction). In add
ition, histological analysis of grafts confirmed the benefit of the drug co
mbination. No additional toxicity was noted with combined therapy.
Optimal doses of MNA or tacrolimus had comparative effects on graft surviva
l and histological changes, and a combination of the two drugs was benefici
al with respect to both these parameters. The iso-effect curves Verified ad
ditive effects of the drug combination.