| Abstract: |
The effects of cyclosporine (CsA), sirołimus (RAPA), ] and/or brequinar (BQR) were examined in a vascularized heterotopic heart transplant model in mice. Un- treated C3H (H-2k) recipients reject C57 BL/10 (H-2b) heart allografts at a mean survival time (MST) of 7.7± 1.4 days. A 7-d intravenous (i.v) infusion by osmotic pump of CsA at doses of 5.0, 10.0, or 20.0 mg/kg extended heart allograft survival to 9.8±1.3 d (NS), 15.0± 5.1d (P<O.Ol) or 15.0 ±1.9 d CP<0.01), respectively. RAPA delivered i.v. for 7 d at a dose of 0.1 mg/kg produced an MST of 13.0±7.5 d; 0.2mg/kg, 20.0±10.9 d; and 0.4mg/kg, 15.8±4.1 d (all P<O.Ol). A 7-d altenate-day (q.o.d.) course of oral gavage with BQR (0.5,1.0, or 2.0 mg/kg) produced survivals of 12.0±2.4 d, 17.6±3.4 d, and 20.0± 4.1d, respectively (all P<O.Ol). The combination of 2.5 mg/kg CsA with 0.05 mg/kg RAPA extended graft survival to 18.2±2.9 d (P<O.Ol), and 5.0 mg/kg CsA with 0.1 mg/kg RAPA prolonged survival to 23.0±9.0 d (P<O.Ol). These combinations represent synergistic interactions based upon combination index (Cl) values of 0.1-0.6. Although 7-d courses of 0.5 mg/kg CsA (7.3 ±1.0 d; NS), 0.01 mg/kg RAPA (7.6±0.9 d; NS), or 0.125 mg/kg BQR (7.6±0.9 d; NS) were individually ineffective, the triple-drug combination prolonged the MST to 64.6± 32.7 d (Pc0.005; CI=0.001), with 2/5 grafts beating for more than 100 d. Similar results were produced by 14-day therapy in the BALB/c (H-2d) to C3H combination. © 1995 by Williams & Wilkins. |
| Keywords: |
controlled study; surgical technique; dose response; drug potentiation; nonhuman; mouse; animal; mice; models, biological; animal experiment; drug effect; dose-response relationship, drug; mice, inbred balb c; mice, inbred c57bl; drug synergism; survival time; drug antagonism; graft rejection; graft survival; immunosuppressive treatment; cyclosporin a; rapamycin; sirolimus; cyclosporine; immunosuppressive agents; intravenous drug administration; oral drug administration; mice, inbred c3h; heart transplantation; osmotic pump; biphenyl compounds; female; priority journal; article; support, u.s. gov't, p.h.s.; polyenes; brequinar
|
