Prevention of vascularized allograft and xenograft rejection in rodents by brequinar sodium.
The data that has been obtained from preclinical studies in rodents demonstrate that BQR is an effective primary immunosuppressive agent with important advantages for use in transplantation immunotherapy. The drug is highly effective when used as a single agent to prevent the rejection of a variety of vascularized allografts and xenografts. BQR is easily administered orally, the drug displays a high level of bioavailability, and drug plasma levels and immunosuppressive activity can be directly measured. The adverse side effects seen with the drug are those normally associated with antiproliferative drugs and are predictable and easily reversed by treatment withdrawal. Most importantly, perhaps, is the broad range of synergistic activity when used in combination with new immunosuppressive drugs. We believe that the combination of these attributes separate BQR from many of the new drugs now under study. Some, for example, do not exhibit synergism (CsA and FK 506), others have may have problems with inadequate oral bioavailability (MPM and rapamycin), and some exhibit the potential for substantial toxicity (15-DSG, myzorbine). The data derived from the use of BQR in combination with other immunosuppressive drugs, such as the studies described above, are important. They provide direct evidence to support the concept that the next important advances in immunosuppressive therapy will involve the use of an effective multidrug approach to preventing organ graft rejection. Combination therapies with immunosuppressive drugs that exhibit different modes of action improve graft survival, widen therapeutic windows, and reduce the risk of toxic side effects. The experimental evidence that several of these combinations are potentially useful is solid, consistent, and exciting. It is our expectation from the rodent experiments described in this symposium that the treatment of allograft (and perhaps xenograft) rejection will consist of the use of CsA (or FK 506), BQR, and a third drug such as rapamycin or mycophenolate mofetil, the choice of which will be heavily influenced by the development of either analogues of these drugs or perhaps new compounds with improved bioavailability and effective monitoring techniques.
Department of Surgery, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
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Cramer
F A
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Chapman
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Makowka
D000818:Animals; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D003331:Coronary Vessels / Q000502:physiology; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007668:Kidney / Q000098:blood supply; D016030:Kidney Transplantation / Q000276:immunology; D008099:Liver / Q000098:blood supply; D016031:Liver Transplantation / Q000276:immunology; D014181:Transplantation Immunology / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology; D011798:Quinaldines
D001713:Biphenyl Compounds; D007166:Immunosuppressive Agents; C046943:brequinar; D011798:Quinaldines