mna-715 and teriflunomide

Topics: Alkynes; Aniline Compounds; Animals; Autoimmune Diseases; Biological Availability; Crotonates; Drug Design; Graft Rejection; Graft Survival; Graft vs Host Disease; Graft vs Host Reaction; Heart Transplantation; Humans; Hydroxybutyrates; Immunosuppressive Agents; Isoxazoles; Nitriles; Skin Transplantation; Toluidines; Transplantation, Homologous

Malononitrilamides (MNAs) are a new class of immunomodulatory drug highly effective in in vivo models of allo- and xenotransplantation. Knowledge of their effects on immune cells, however, is limited and has been derived solely from investigations using isolated mononuclear cells. This use of purified cells to investigate drug activity is not ideal, so we have combined the analytical power of flow cytometry with our mitogen-driven, whole blood lymphocyte activation and proliferation assays to investigate the in vitro mechanism of action of MNAs. We first show that MNAs (A77 1726, HMR1279, and HMR1715), as well as brequinar (BQR) and cyclosporine (CsA), effectively inhibit cell activation antigen expression and lymphocyte proliferation. We next show that the inhibitory effects of MNAs and BQR, but not CsA, are reversed by the addition of uridine to the culture. These results suggest that inhibition of pyrimidine biosynthesis may be a mechanism by which MNAs suppress both lymphocyte activation and proliferation since these effects were reversed when uridine nucleotide pools were replenished. This novel finding of suppression of activation antigen expression by MNAs in whole blood expands our understanding of the effects of this new class of drug.

Topics: Acrylamides; Alkynes; Aniline Compounds; Animals; Biphenyl Compounds; Caproates; Crotonates; Cyclosporine; Dose-Response Relationship, Drug; Flow Cytometry; Hydroxybutyrates; Immunosuppressive Agents; Isoxazoles; Leflunomide; Lymphocyte Activation; Lymphocytes; Male; Nitriles; Rats; Rats, Inbred Lew; Receptors, Interleukin-2; Receptors, OX40; Receptors, Tumor Necrosis Factor; Toluidines; Tumor Necrosis Factor Receptor Superfamily, Member 7

Topics: Acrylamides; Alkynes; Aniline Compounds; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Caproates; Crotonates; Dose-Response Relationship, Drug; Hydroxybutyrates; Immunosuppressive Agents; Isoxazoles; Nitriles; Rats; Rats, Inbred Lew; Toluidines

Topics: Acrylamides; Alkynes; Aniline Compounds; Animals; Caproates; Cell Division; Crotonates; Hydroxybutyrates; Immunosuppressive Agents; Isoxazoles; Muscle, Smooth, Vascular; Nitriles; Platelet-Derived Growth Factor; Rats; Toluidines; Uridine

A77 1726 is a malononitrilamide (MNA) and the active metabolite of leflunomide, which has been extensively investigated and shown to be a potent immunosuppressive drug. However, the half-life of A77 1726 is about 15-18 days in humans and leflunomide is therefore currently being developed for the treatment of autoimmune disease and not for transplantation. Search for analogues has led to the discovery of MNA 715 and 279, derivatives of A77 1726. Previous experimental experience of these compounds is still limited. The aim of the present study was to verify the efficacy of these MNAs concerning prevention and reversal of rejection, inhibition of antibody production and interaction with cyclosporin A (CsA). Heterotopic cardiac transplantation in DA to PVG rats was used. Subgroups of rats were given either CsA, MNA 715 or MNA 279 for 10 days, starting at either day 0 or day 4, or received no treatment. Titres of allospecific immunoglobulin M (IgM) and immunoglobulin G (IgG) were quantified by flow cytometry. Ten days of induction with MNA 715 or 279 produced significantly longer graft survival than in controls. Treatment from day 4 onwards, when acute rejection was established, rescued all grafts. Allospecific production of IgM or IgG was absent during MNA induction and was suppressed in animals receiving a rescue course of MNA. The transplant model was potentiated by addition of the immunomodulator quinolone-3-carboxamide (Linomide), which eliminates the effect of CsA and other immunosuppressants. The combined treatment with MNA and CsA was successful in overcoming the challenge of Linomide, demonstrating the additive effects of the two drugs. In conclusion, MNA 715 and 279 were shown to be potent immunosuppressants, preventing and reversing acute allograft rejection, inhibiting and suppressing allospecific antibody production, and the drugs interacted positively with CsA.

Topics: Alkynes; Aniline Compounds; Animals; Antibody Formation; Crotonates; Cyclosporine; Drug Interactions; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Hydroxybutyrates; Immunoglobulin Allotypes; Immunosuppressive Agents; Isoxazoles; Nitriles; Rats; Rats, Inbred Strains; Toluidines; Transplantation, Homologous