mna-279 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

The novel leflunomide (LFM) analog, HMR 279, potentiates the immunosuppressive efficacy of microemulsion cyclosporine (Neoral) in rodent heart transplantation. The present study was designed to evaluate the immunosuppressive efficacy of this combination in comparison to the combination of Neoral and LFM in a stringent allogeneic rodent lung transplant model.. Donor lungs from Brown Norway rats were implanted into Lewis recipients and were followed for 21 days. Postoperative monitoring included daily weight assessment, chest radiographs, drug trough levels measured by high-performance liquid chromatography (LFM/HMR 279) and high-performance liquid chromatography/mass spectrometry (Neoral), and blinded histology assessment of the transplanted lung on the day of death based on the International Society for Heart and Lung Transplantation working formulation. Untreated lung recipients served as controls (group I, n=5). Rats were assigned to the following treatment groups: II, 7.5 mg/kg/day Neoral (n=6); III, 10 mg/kg/day LFM (n=6); IV, 10 mg/kg/day HMR 279 (n=6); V, 10 mg/kg/day LFM plus 7.5 mg/kg/day Neoral given simultaneously (n=13); and VI, 10 mg/kg/day HMR 279 plus 7.5 mg/kg/day Neoral given simultaneously (n=6). Drugs were given daily by oral gavage.. All rats except for one in the HMR 279 monotherapy group survived the follow-up period. The chest radiographs in the control, LFM, and HMR 279 monotherapy groups showed moderate to complete opacification of the left chest by postoperative day 7 (controls) and day 14 (LFM, 279). At postoperative day 21, the Neoral monotherapy and the combination groups showed no signs of opacification in the radiographs. Combination therapies of Neoral plus HMR 279 or Neoral plus LFM were most successful in preventing histologic allograft rejection. Combining Neoral and HMR 279 resulted in a significant decrease in the cyclosporine trough levels. Co-administration of LFM plus Neoral resulted in significantly higher LFM trough levels when compared to LFM monotherapy. Of all treatments studied, the combination of HMR 279 plus Neoral was tolerated best as assessed by percentage of weight change.. This study showed for the first time in a stringent rodent lung transplant model that combined treatment of LFM or HMR 279 plus Neoral potentiates the immunosuppressive efficacies of these drugs and successfully prevents allograft rejection.

Topics: Amides; Aniline Compounds; Animals; Biotransformation; Body Weight; Chromatography, High Pressure Liquid; Crotonates; Cyclosporine; Drug Therapy, Combination; Emulsions; Hydroxybutyrates; Immunosuppressive Agents; Isoxazoles; Leflunomide; Lung Transplantation; Male; Nitriles; Rats; Rats, Inbred BN; Rats, Inbred Lew; Structure-Activity Relationship; Toluidines

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