POTENTIATION OF IMMUNOSUPPRESSIVE EFFICACY BY COMBINING THE NOVEL LEFLUNOMIDE ANALOG, HMR 279, WITH MICROEMULSION CYCLOSPORINE IN A RAT LUNG TRANSPLANT MODEL1

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Abstract
The novel leflunomide (LFM) analog, HMR 279, potentiates the immunosuppressive efficacy of microemulsion cyclosporine (NeoralR) in rodent heart transplantation. The present study was designed to evaluate the immunosuppressive efficacy of this combination in comparison to the combination of NeoralR and LFM in a stringent allogeneic rodent lung transplant model. Donor lungs from Brown Norway rats were implanted into Lewis recipients and were followed for 21 days. Postoperative monitoring included daily weight assessment, chest radiographs, drug trough levels measured by high-performance liquid chromatography (LFM/HMR 279) and high-performance liquid chromatography/mass spectrometry (NeoralR), and blinded histology assessment of the transplanted lung on the day of death based on the International Society for Heart and Lung Transplantation working formulation. Untreated lung recipients served as controls (group I, n=5). Rats were assigned to the following treatment groups: II, 7.5 mg/kg/day NeoralR (n=6); III, 10 mg/kg/day LFM (n=6); IV, 10 mg/kg/day HMR 279 (n=6); V, 10 mg/kg/day LFM plus 7.5 mg/kg/day NeoralR given simultaneously (n=13); and VI, 10 mg/kg/day HMR 279 plus 7.5 mg/kg/day NeoralR given simultaneously (n=6). Drugs were given daily by oral gavage. All rats except for one in the HMR 279 monotherapy group survived the follow-up period. The chest radiographs in the control, LFM, and HMR 279 monotherapy groups showed moderate to complete opacification of the left chest by postoperative day 7 (controls) and day 14 (LFM, 279). At postoperative day 21, the NeoralR monotherapy and the combination groups showed no signs of opacification in the radiographs. Combination therapies of NeoralR plus HMR 279 or NeoralR plus LFM were most successful in preventing histologic allograft rejection. Combining NeoralR and HMR 279 resulted in a significant decrease in the cyclosporine trough levels. Co-administration of LFM plus NeoralR resulted in significantly higher LFM trough levels when compared to LFM monotherapy. Of all treatments studied, the combination of HMR 279 plus NeoralR was tolerated best as assessed by percentage of weight change. This study showed for the first time in a stringent rodent lung transplant model that combined treatment of LFM or HMR 279 plus NeoralR potentiates the immunosuppressive efficacies of these drugs and successfully prevents allograft rejection.