mna-279 and Acute-Disease

Topics: Acute Disease; Alkynes; Animals; Graft Rejection; Immunization; Immunoglobulin G; Immunoglobulin M; Immunosuppressive Agents; Isoantigens; Isoxazoles; Leflunomide; Lymphocyte Transfusion; Nitriles; Rats; Rats, Inbred Lew; Rats, Inbred Strains; Skin Transplantation; Structure-Activity Relationship; Time Factors; Transplantation, Homologous

Topics: Acute Disease; Alkynes; Animals; Antibodies, Heterophile; Antibody Formation; Cyclosporine; Graft Rejection; Graft Survival; Immunosuppressive Agents; Isoxazoles; Mice; Mice, Inbred BALB C; Nitriles; Rats; Rats, Inbred Lew; Skin Transplantation; Time Factors; Transplantation, Heterologous

The low molecular weight malononitrilamides (MNAs), a new class of immunosuppressive agents, belong to the derivatives of leflunomide's active metabolite, A771726. They have been shown to bind specifically to dehydroorotate dehydrogenase and inhibit de novo pyrimidine biosynthesis, thereby blocking T- and B-cell proliferation and strongly suppressing IgM and IgG antibody production. Here we evaluated their efficacy together with cyclosporine (CyA) in rat skin allotransplantation models, using different strain combinations. Monotherapy of transplanted animals in these models with the MNAs HMR 1279 and HMR 1715 resulted in a significant and dose-dependent prolongation of the graft survival time. Even a short-term application showed efficacy in the prevention of acute rejection. The MNAs were also effective when treatment was started at the time of expected rejection crisis, demonstrating strong therapeutic activity to reverse ongoing acute rejection, whereas CyA was ineffective for the treatment of ongoing allograft rejection episodes. Combination therapy of MNAs with CyA proved to be very effective for the prevention of acute skin graft rejection. Interestingly, whereas CyA alone was unable to treat ongoing acute rejection episodes, comedication of MNAs and CyA, even after a short-term application, was synergistically effective and significantly suppressed ongoing allogeneic skin graft rejection. These results demonstrate that MNAs are potent and well tolerated immunosuppressants with a potential comparable to that of CyA, but they are superior to CyA in their ability to reverse acute rejection episodes. They represent powerful rescue drugs and demonstrate synergistic activity with CyA to prevent acute and treat ongoing skin allograft rejection.

Topics: Acute Disease; Alkynes; Animals; Cyclosporine; Drug Synergism; Graft Rejection; Immunosuppressive Agents; Isoxazoles; Nitriles; Rats; Rats, Inbred F344; Rats, Inbred Lew; Skin Transplantation

Topics: Acute Disease; Alkynes; Animals; Chronic Disease; Encephalomyelitis, Autoimmune, Experimental; Immunosuppressive Agents; Isoxazoles; Kinetics; Nitriles; Rats; Rats, Inbred Lew; Recurrence

Due to their immunosuppressive mode of action, we examined the therapeutic effects of the malononitrilamides MNA 279 and MNA 715 in acute EAE, and two models of chronic relapsing EAE in Lewis rats and Biozzi mice. In the first model, sensitization of adult Lewis rats with guinea pig spinal cords results in an acute clinical episode of severe EAE, and by day 15 all animals had died. Treatment of these sensitized rats with the MNAs was most effective in delaying and reducing the onset of clinical symptoms, and mortality of acute EAE was prevented in a dose-dependent manner. The protection afforded by the two MNAs was long-lasting and no subsequent relapse was observed. Similarly, in the chronic relapsing disease, aged Lewis rats were immunized with rabbit myelin basic protein, and all untreated animals developed a disease with up to three relapses. The second and third episodes were both milder and shorter in duration than the first. All animals treated with the MNAs survived the first attack, which also was delayed. Pathological signs were reduced and relapses did not occur. Inhibition of chronic relapsing EAE in aged Lewis rats was observed, even when the MNA-treatment was started after the first appearance of clinical symptoms. All treated animals recovered completely and mortality was prevented. Also in the second model of chronic relapsing EAE in Biozzi AB/H mice, MNA treated animals showed only one acute and delayed episode and no further relapses. All these results qualify both MNA 279 and MNA 715 as powerful immunosuppressants with therapeutic potential in human multiple sclerosis (MS).

Topics: Acute Disease; Alkynes; Animals; Chronic Disease; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Guinea Pigs; Immunosuppressive Agents; Isoxazoles; Mice; Mice, Inbred Strains; Nitriles; Rabbits; Rats; Rats, Inbred Lew

Topics: Acute Disease; Alkynes; Animals; Cyclosporine; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Graft Rejection; Graft Survival; Immunosuppressive Agents; Isoxazoles; Nitriles; Rats; Rats, Inbred F344; Rats, Inbred Lew; Rats, Inbred Strains; Skin Transplantation; Time Factors