title: Mycophenolate mofetil, azathioprine and cyclophosphamide enhanced efficacy combined with cyclosporine in rat cardiac transplantation.
abstract: Anti-proliferative drugs have been used for immunosuppression since the introduction of clinical transplantation. Most transplant centres include azathioprine (Aza) and cyclosporine (CyA) in their standard regimens, despite several controlled studies having failed to confirm the benefit of this combination. Aza is still the most commonly used anti-proliferative drug, although no major differences in immunosuppressive or toxic effects have been shown between Aza and cyclophosphamide (Cph). Cph as an adjunct to CyA has never been tested in a randomized study. Recently, mycophenolate mofetil (MMF) has been developed as the most selective inhibitor of T- and B-cell proliferation and promoted as an adjunct to CyA treatment. In the present study, the additive or synergistic effects of these three anti-proliferative agents in combined treatment with CyA have been investigated using a rat cardiac transplantation model in which the immunomodulator linomide (Lin) was included as a potentiator of rejection. As single drug treatment, CyA, Cph and MMF, but not Aza, exerted a beneficial effect on graft survival. This prolongation of graft survival was abrogated when any one drug was administered together with Lin. The addition of MMF, Aza or Cph to CyA plus Lin treatment improved the graft survival significantly, thus demonstrating each of the anti-proliferative drugs to exert additive or synergistic effects in conjunction with cyclosporine. MMF seemed to be the most effective and least toxic of the drugs tested.
authors.affiliation: Department of Surgery, Gothenburg University, Sahlgren's Hospital, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Ostraat
authors.forename: Z
authors.initials: Z
authors.lastname: Qi
authors.forename: M
authors.initials: M
authors.lastname: Olausson
authors.forename: G
authors.initials: G
authors.lastname: Tufveson
authors.forename: H
authors.initials: H
authors.lastname: Ekberg
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001379:Azathioprine / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology / Q000379:methods*; D006912:Hydroxyquinolines / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D011921:Rats, Inbred WKY
chemical_list: D000276:Adjuvants, Immunologic; D006912:Hydroxyquinolines; D007166:Immunosuppressive Agents; C045282:roquinimex; D016572:Cyclosporine; D003520:Cyclophosphamide; D009173:Mycophenolic Acid; D001379:Azathioprine