title: Effect of RS61443 in combination with leflunomide or FK506 on rat heart allograft survival.
abstract: Mycophenolate Mofetil (RS61443) is a potent inhibitor of de novo purine synthesis and lymphocyte proliferation. It is known to prevent ongoing rejection and even reverse established rejection, alone and in combination with, cyclosporin. We investigated whether RS61443 in combination with leflunomide (Lef) or FK506 (FK) could prolong allograft survival in a rat heart model, since combination therapy might help to overcome drug toxicity. Abdominal heart grafting was performed from DA to LEW rats (250 g) and RS61443, 10 mg/kg or 30 mg/kg monotherapy or combination treatment (RS 10 mg/kg with Lef 5 mg/kg or FK 0.5 mg/kg) was begun orally at transplantation and continued daily until the ninth posttransplant (post-Tx) day. Ventricular motion was graded daily and rejection was defined as lack of contractions, confirmed by histology. Results were analysed using non-parametric tests. A two-tail P value < 0.05 was considered significant. RS at 10 mg/kg was ineffective and all grafts were rejected under immunosuppression between 5 and 6 post-Tx day, whereas RS at 30 mg/kg was immunosuppressive for as long as it was given. The combinations of RS at 10 mg/kg with either Lef at 5 mg/kg or FK at 0.5 mg/kg were immunosuppressive in the majority of cases, for as long as they were given. However, the combination of RS at 10 mg/kg with FK at 0.5 mg/kg was attendant with graft vein anastomosis rupture (3/5). The combination of RS with Lef was clinically therapeutic for as long as it was given; grafts were rejected 3-4 days after withdrawing immunosuppression. The combination of RS with FK resulted in over-immunosuppression, leading to graft vein anastomosis non-healing and rupture within 5 days of grafting; histology demonstrated evidence of bacterial infection with complete destruction of the vein wall. These data suggest that the combination of RS with Lef or FK in subtherapeutic doses might be a potentially promising strategy for combination therapy in solid organ transplantation.
authors.affiliation: Transplantation Microsurgery Laboratory, Queen Elizabeth Hospital and Medical Center, Edgbaston, Birmingham, UK.
authors.forename: E
authors.initials: E
authors.lastname: Antoniou
authors.forename: A
authors.initials: A
authors.lastname: DeRoover
authors.forename: Y
authors.initials: Y
authors.lastname: Nishimura
authors.forename: A J
authors.initials: AJ
authors.lastname: Howie
authors.forename: P
authors.initials: P
authors.lastname: McMaster
authors.forename: M
authors.initials: M
authors.lastname: D'Silva
mesh_terms: D000818:Animals; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007555:Isoxazoles / Q000008:administration & dosage*; D000077339:Leflunomide; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051381:Rats; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000008:administration & dosage*; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D007555:Isoxazoles; D000077339:Leflunomide; D009173:Mycophenolic Acid; D016559:Tacrolimus