Toxicity of Five-Hour Intravenous Infusion of Penclomedine (NSC-338720) in Beagle Dogs.

摘要

The target organ toxicity and its reversibility following 5-h continuous i.v. infusions of penclomedine at 2.5, 12.5, 18, and 25 mg/kg/h were studied in male and female beagle dogs. Drug-related mortalities were seen on day 1 in both dogs (one per sex) treated with PEN at 25 mg/kg/h. In surviving dogs in the 12.5 and 18 mg/kg/h dose groups, hematology results showed a drug-induced, dose-dependent leukopenia, and thrombocytopenia on days 5 through 12 or 15, followed by a recovery to baseline or normal values on day 29. Males and females appear to be similarly affected. Drug-induced microscopic lesions included minimal to moderate lymphoid atrophy and necrosis in the secondary lymphoid organs (lymph nodes, lymphoid, thymus, spleen, tonsils, and intestinal lymphoid tissue-peyer's patches) in male and/or female dogs in the 12.5, 18, and 25 mg/kg/h dose groups on day 8. In addition, a marked bone marrow atrophy was observed in one female dog in both 12.5 and 18 mg/k/h dose groups on day 8. The lack of drug-induced lesions in animals sacrificed on day 29 (with the exception of thymic atrophy in the male dog in the 12.5 mg/kg/h dose group on day 29) suggests the reversibility of effects seen on days 1 and or 8. During a 5-h infusion of the drug, plasma or blood concentrations of PEN increased progressively with time, reaching maximum values at the end of the 5-h infusion.