Repeated Dose Toxicity Studies Including Plasma Levels on Nsc 109229 Following Daily I. V. Administration to Monkeys and Dogs. Range Finding Toxicity Studies in Mice Following Single I. V. Administration and Antigenic Studies in Guinea Pigs and Rabbits

摘要

The preclinical toxicity of L-Asparaginase (Squibb), was investigated following I. V. administration to Rhesus monkeys in dosages of 175-500 I. U./kg, B.I.D. x 5 and 1,000 I. U./kg/day x 5. The major effects produced by L-Asparaginase in the monkeys independent of S.A. and dose, consisted of BSP retention and fatty liver; anemia and decrease in WBC; weight loss and mild pyrogenicity, associated with a transient leucocytosis and elevation in BUN. These parameters were reversible within 30 days post Rx except for single instances of nonreversibility of leucopenia, weight loss and fatty liver. L-Asparaginase, TAD-4R was not hepatotoxic in beagle puppies as in the primate. Hematological changes were comparable in the two species as were plasma levels following equivalent dosage. E.Coli Endotoxin Bacto Lipopolysaccharide B, when administered I. V. to a single monkey in a dose of 5 mg/kg (total dose 28.8 mg/kg) resulted in BSP retention, leucopenia, anemia, elevations in SGOT, SGPT, BUN and loss of weight. The histopathology noted in the liver of this animal was quite different than that seen in animals treated with L-Asparaginase. It is believed that on the basis of this single study that the toxicity noted with L-Asparaginase is not due to E.Coli Endotoxin. (Author)