CARDIOVASCULAR ENGINEERING Journal for Extracorporeal Circulation, Assist Devices,Transplantation and Artificial Organs
	Volume 2, 1997, No 2

Effect of Combination Schedules of Leflunomide with Cyclosporin or FK506 in Rat Cardiac Allografting

D. Candinas, C. Mills, S. Lee, A. Dalgic, E. Antoniou, A. Germenis, C. Stavropoulos, T. C. Chou, P. McMaster, M. D’Silva

Abstract:
Background: The undesirable and troublesome adverse effects of cyclosporin(CsA)- or FK506-based immunosuppression protocols determine long term graft residence and patient survival. Combining immunosuppressive agents in decreased doses which act at different points in the cell cycle may benefit by preventing acute rejection by potentiating the effects of the drugs in the combination and concomitantly raising drug tolerability. The aim of this study was to describe the immunomodulating effects of leflunomide(LEF) in combination with CsA or FK506 using a strongly histoincompatible cardiac allograft model. The present study applied the available knowledge of optimal doses of each immunosuppressive agent and employed them in dual combination treatment such that one of the two agents was given in reduced dose. The survival data were analyzed using the dose-effect analysis of the Chou-Talalay method which has been proposed as a suitable model for testing novel drug combinations. Methods: Heterotopic cardiac transplantation (TX) was performed from DA (RT1a)-to-Lewis-RT11 (LEW) rats. Six dose combinations were studied for LEF+CsA and 5 for LEF+FK506. Immunosuppressive agents were given daily for 10 days from TX and withdrawn thereafter. Graft survival, drug tolerability, renal and liver biochemistry were assessed. Analysis of drug interactions was performed using the median-effect method of Chou. Results: Apparently, LEF+FK506 combinations are antagonistic, whereas LEF+CsA results are nearly additive with some data points showing synergism and some points showing antagonism. Interestingly, the results for LEF+CsA at high effect levels demonstrate a trend toward synergism. These results suggest that treatments for longer than 10-day periods would improve the outcomes. The results also showed that both combinations with LEF above 10 mg/kg are counterproductive (probably due to toxicity). Thus, increasing the dose of CsA but keeping the dose of LEF low might also improve results. Conclusion: In a strongly allogeneic TX model, certain combinations of LEF+CsA demonstrate additive and even synergistic interactions whereas, LEF+FK506 combinations are antagonistic. Such knowledge (synergism, additive effect, or even slight antagonism) may lead to desirable dose-reduction index (DR)) (i.e., DRI > 1) for one or both drugs and prove beneficial in reducing toxicity when the toxicity of the two drugs are not overlapping. "Secondary" undesirable effects are difficult to define.

Keywords:
Rat, heterotopic cardiac graft, allograft, combination immunosuppression, adverse effects, median-effect analysis, combination index analysis, leflunomide, cyclosporin, FK506

Address for Correspondence:

Reference:
(CVE. 1997; 2 (2): 145-153)

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