title: Rapamycin, a potent immunosuppressive drug for vascularized heart, kidney, and small bowel transplantation in the rat.
abstract: The effectiveness of rapamycin (RAPA) was examined for heart, kidney, and small bowel allografts in rats. Untreated or vehicle only-infused Wistar Furth (RT1u) recipients rejected Buffalo (RT1b) heart allografts within a mean survival time (MST) of 6.5 +/- 0.5 and 6.3 +/- 0.5 days, respectively. In contrast, a 14-day continuous intravenous (i.v.) infusion by an osmotic pump of 0.08 mg/kg/day RAPA to WFu recipients prolonged BUF heart allograft survival to an MST of 34.4 +/- 12.1 days (P = 0.0001). There was a graded dose-response to 0.16 mg/kg (39.0 +/- 8.7 days; P = 0.0001), 0.32 mg/kg (55.7 +/- 3.3 days; P = 0.0001) and 0.8 mg/kg (48.0 +/- 3.6; P = 0.0001). Furthermore, intraarterial/intragraft but not i.v. infusion of 0.02 mg/kg/day prolonged BUF heart allografts--namely, an MST of 14.6 +/- 1.4 days versus 8.6 +/- 2.6 days (P = 0.0001), respectively. Local delivery doses of RAPA were about as effective as the same dose delivered i.v.: 0.08 mg/kg MST 37.0 +/- 18.3 days (P = 0.0001); 0.32 mg/kg, 40.0 +/- 3.9 days (P = 0.0001); and 0.8 mg/kg, 54.8 +/- 8.2 days (P = 0.0001). Systemic i.v. RAPA therapy with 0.08 or 0.8 mg/kg/day prolonged the survival of BUF kidney grafts in WFu recipients--namely, an MST of 52.7 +/- 42.7 (NS) and 90.2 +/- 62.4 (P = 0.001) days, respectively, versus an MST of 11.6 +/- 1.5 days in control WFu recipients only infused with vehicle. While normal WFu rats reject heterotopic BUF small bowel allografts within an MST of 10.0 days, a 14-day course of i.v. RAPA treatment significantly (P = 0.0001) prolonged small bowel allograft survival to an MST of 26.8 +/- 3.7 days.
authors.affiliation: Department of Surgery, University of Texas Medical School, Houston 77030.
authors.forename: S M
authors.initials: SM
authors.lastname: Stepkowski
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: P
authors.initials: P
authors.lastname: Daloze
authors.forename: B D
authors.initials: BD
authors.lastname: Kahan
mesh_terms: D000818:Animals; D003524:Cyclosporins / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007421:Intestine, Small / Q000637:transplantation*; D016030:Kidney Transplantation; D008297:Male; D011090:Polyenes / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D020123:Sirolimus; D014184:Transplantation, Homologous
chemical_list: D003524:Cyclosporins; D007166:Immunosuppressive Agents; D011090:Polyenes; D020123:Sirolimus