PATHOLOGICAL CHANGES DEVELOPING IN THE RAT DURING A 3-WEEK COURSE OF HIGH DOSAGE CYCLOSPORIN A AND THEIR REVERSAL FOLLOWING DRUG WITHDRAWAL

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Abstract
Adult Sprague-Dawley rats given [the immunologic drug] cyclosporin A (Cy A) orally in a dose of 100 mg/kg every 48 h for 21 days displayed pronounced suppression of humoral immunity to sheep red blood cells. They showed hair loss and failure to gain weight and exhibited a progressive increase in serum urea, serum creatinine and urinary N-acetyl-.beta.-D-glucosaminidase (NAG) activity, with a fall in urea clearance rate. Hypoalbuminemia and hyperbilirubinemia were observed in combination with a significant decrease in serum aspartate aminotransferase (AAT) and alkaline phosphatase levels. At 2 wk there was significant lymphopenia with the appearance of atypical lymphocytes in the peripheral blood. Autopsies performed on animals killed at 3 wk revealed no light microscopic or ultrastructural differences between test and control animals, apart from some reduction in overall bone marrow cellularity in the former. During the 3 wk period following withdrawal of Cy A, renal and hepatic function reverted to normal and a rebound lymphocytosis occurred. Only 1 of 6 rats autopsied 3 wk after cessation of Cy A administration showed reduced bone marrow cellularity. The rat may be a useful experimental model for further investigation of the functional and structural changes which may be encountered in the clinical use of Cy A.