Potentiation of immunosuppressive efficacy by combining the novel leflunomide analog, HMR 279, with microemulsion cyclosporine in a rat lung transplant model.
BACKGROUND
The novel leflunomide (LFM) analog, HMR 279, potentiates the immunosuppressive efficacy of microemulsion cyclosporine (Neoral) in rodent heart transplantation. The present study was designed to evaluate the immunosuppressive efficacy of this combination in comparison to the combination of Neoral and LFM in a stringent allogeneic rodent lung transplant model.


METHODS
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 (Neoral), 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 Neoral (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 Neoral given simultaneously (n=13); and VI, 10 mg/kg/day HMR 279 plus 7.5 mg/kg/day Neoral given simultaneously (n=6). Drugs were given daily by oral gavage.


RESULTS
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 Neoral monotherapy and the combination groups showed no signs of opacification in the radiographs. Combination therapies of Neoral plus HMR 279 or Neoral plus LFM were most successful in preventing histologic allograft rejection. Combining Neoral and HMR 279 resulted in a significant decrease in the cyclosporine trough levels. Co-administration of LFM plus Neoral resulted in significantly higher LFM trough levels when compared to LFM monotherapy. Of all treatments studied, the combination of HMR 279 plus Neoral was tolerated best as assessed by percentage of weight change.


CONCLUSIONS
This study showed for the first time in a stringent rodent lung transplant model that combined treatment of LFM or HMR 279 plus Neoral potentiates the immunosuppressive efficacies of these drugs and successfully prevents allograft rejection.
Hausen
B
B
Department of Cardiothoracic Surgery, Stanford University, Palo Alto, California 94305-5407, USA.
Boeke
K
K
Berry
G J
GJ
Gummert
J F
JF
Christians
U
U
Morris
R E
RE
D000577:Amides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000814:Aniline Compounds / Q000493:pharmacokinetics; D000818:Animals; D001711:Biotransformation; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003437:Crotonates; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004655:Emulsions; D006885:Hydroxybutyrates / Q000493:pharmacokinetics; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007555:Isoxazoles / Q000737:chemistry; D000077339:Leflunomide; D016040:Lung Transplantation / Q000276:immunology*; D008297:Male; D009570:Nitriles / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship; D014052:Toluidines
D000577:Amides; D000814:Aniline Compounds; D003437:Crotonates; D004655:Emulsions; C117594:HMR 279; D006885:Hydroxybutyrates; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; D014052:Toluidines; C527525:teriflunomide; D016572:Cyclosporine; D000077339:Leflunomide