RS-61443--a new, potent immunosuppressive agent.
The immunosuppressive activity of RS-61443, a semisynthetic derivative of mycophenolic acid, was examined in 33 canine renal allografts. Initial studies established that triple therapy consisting of 20 mg/kg RS-61443 in combination with 5 mg/kg cyclosporine and 0.1 mg/kg methylprednisolone was the optimal combination to prevent graft rejection. The median survival time was 8.1 +/- 1.2 days in dogs without treatment (n = 5), 8.5 +/- 1.7 days in the treatment control group (CsA 5 mg/kg, MP 0.1 mg/kg; n = 6), 36.0 +/- 9.6 days with RS-61443 monotherapy (40 mg/kg; n = 6); and 122.4 +/- 38.75 days with triple therapy (n = 16). Graft prolongation was statistically significant when compared with controls (P less than 0.05 and 0.002, respectively). Six recipients in the triple therapy group survived over 150 days without major adverse effects. Long-term administration of RS-61443 (20 mg/kg/day) did not cause nephrotoxicity, hematotoxicity, or hepatotoxicity, with the exception of a slight elevation of the alkaline phosphatase levels. Gastrointestinal symptoms including gastritis, diarrhea, and anorexia were common, especially under 40 mg/kg RS-61443 monotherapy, and appeared to be dose-related. Despite its immunosuppressive activity, an increased susceptibility to bacterial or viral infections was not observed. Histological studies of the kidney grafts revealed slight interstitial cell infiltration without vascular or glomerular damage.
Platz
K P
KP
Department of Surgery, University of Wisconsin School of Medicine, Madison 53792.
Sollinger
H W
HW
Hullett
D A
DA
Eckhoff
D E
DE
Eugui
E M
EM
Allison
A C
AC
D000818:Animals; D004285:Dogs; D005260:Female; D006084:Graft Rejection; D007166:Immunosuppressive Agents / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D016030:Kidney Transplantation; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology / Q000633:toxicity; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid