PROLONGATION OF HETEROTOPIC CARDIAC ALLOGRAFTS IN RATS BY CYCLOSPORIN-A

  • 1 January 1980
    • journal article
    • research article
    • Vol. 88  (4) , 594-600
Abstract
Cyclosporin A (CsA), an investigational immunosuppressive drug, was tested for its ability to prevent rejection of heterotopic rat heart allografts transplanted across a major histocompatibility barrier (ACI to Lewis). The relative efficacy of CsA was compared to a combination of azathioprine and prednisolone. Various dose-schedule combinations of CsA as a single drug were evaluated in regard to duration of grafts beating, recipient mortality rate and histology of long-term functioning grafts. A daily dose of CsA of 10 mg/kg prevented rejection, but was associated with a 40% recipient mortality rate from infection. CsA in 5 mg/kg per day doses resulted in long-term graft function (> 100 days); histological examination of these grafts showed mild rejection. A dose-schedule of CsA in 10 mg/kg per day for 7-35 days followed by a reduction to 5 mg/kg per day, prolonged the survival rate of all grafts to > 100 days; no rats died from this treatment and there was no evidence of rejection on graft histology. A combination of 4 mg/kg per day azathioprine and 4 mg/kg per day prednisolone did not prolong graft survival rates. Azathioprine in 30 mg/kg and prednisolone in 12 mg/kg, prolonged allograft survival (50-60 days), but was associated with significant recipient morbidity (> 25% weight loss) and histological evidence of acute and chronic rejection. A nontoxic dose of CsA is superior to a combination of azathioprine and prednisolone in preventing the rejection of heterotopic rate heart allografts. The therapeutic index of cyclosporin A in rats can be increased by using a tapering dose schedule, as opposed to a fixed dose schedule. CsA has good potential for clinical application to organ transplantation.

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