Cyclosporin A, FK506, rapamycin: the use of a quantitative analytic tool to discriminate immunosuppressive drug interactions.

Potent immunosuppressive agents display toxic complications at full therapeutic doses: cyclosporin A (CsA) produces pleiotropic mesenchymal effects with prominent vasculopathy, whereas FK506 displays severe neurotoxicity associated with a similar range of mesenchymal and possibly vasculitic reactions. The concept of drug synergy seeks to exploit combinations of agents that promote each other's immunosuppressive effects. This article presents a quantitative method to assess synergy in vitro and in vivo--the median-effect analysis. Application of this method revealed synergistic interactions of CsA with steroids, an additive effect with azathioprine, and antagonistic effects with FK506 and enisoprost. Clearly, a synergistic therapeutic combination can be clinically useful only if it is not associated with a similar potentiation of toxic complications. Clinical practice has documented the synergistic relation of CsA plus steroids and the antagonistic relation of CsA with FK506 or enisoprost. Clinical trials of rapamycin, which displays extremely potent synergistic effects with CsA both in vitro with human and in vivo with animal immune responses, may afford important new insights for clinical immunosuppression.