SDZ RAD, a new rapamycin derivative: synergism with cyclosporine.
BACKGROUND
SDZ RAD is a new rapamycin analog with potent immunosuppressive activity. Compounds of the rapamycin class differ in their mode of action from cyclosporine, thus providing a rationale for potential synergism of these two potent immunosuppressants.


METHODS
The two-way mouse mixed lymphocyte reaction (BALB/c-CBA strain combination) was applied. Orthotopic kidney and heterotopic heart allografting was performed in the stringent DA-to-Lewis rat strain combination, with administration of compounds orally as microemulsion preconcentrate (i.e., Neoral in the case of cyclosporine).


RESULTS
Isobologram analysis of checkerboard titrations of SDZ RAD and cyclosporine in two-way mouse mixed lymphocyte reactions indicates a synergistic interaction in vitro. In vivo, the minimal effective dose of microemulsion cyclosporine giving long-term graft survival was 5.0 mg/kg/day; for SDZ RAD, the minimal effective dose was 5.0 mg/kg/day in kidney transplantation and >5.0 mg/kg/day in heart transplantation. Long-term allograft survival was noted for combinations of microemulsion cyclosporine administered at 1.0 or 2.0 mg/kg/day and SDZ RAD given at between 0.5 and 2.0 mg/kg/day. The index of synergy in different combinations ranged between 0.3 and 0.7.


CONCLUSIONS
SDZ RAD and cyclosporine show synergism in immunosuppression, both in vitro and in vitro. They form a promising synergistic drug combination in allotransplantation.
Schuurman
H J
HJ
Department of Preclinical Research/Transplantation, Novartis Pharma Inc., Basel, Switzerland.
Cottens
S
S
Fuchs
S
S
Joergensen
J
J
Meerloo
T
T
Sedrani
R
R
Tanner
M
M
Zenke
G
G
Schuler
W
W
D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology; D004357:Drug Synergism; D000068338:Everolimus; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D011090:Polyenes / Q000494:pharmacology*; D051381:Rats; D020123:Sirolimus / Q000031:analogs & derivatives
D007166:Immunosuppressive Agents; D011090:Polyenes; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus