Preclinical Pharmacodynamic and Pharmacokinetic Studies of Investigational New Drugs.

摘要

A study was conducted to investigate the pharmacodynamic effects, as assessed by signs of clinical and pathological toxicity, of artelinate (AL; given as an L-lysine salt) and artesunate (AS) in male and female Sprague-Dawley rats given single or multiple intravenous (iv) doses via a tail vein; intramuscular (im) administered arteether (AE) served as the positive control for the formation of neurotoxicological lesions. For rats given single iv doses, mortality was observed at AL doses of greater than or equal to 160 mg/kg and at an AS dose of 400 mg/kg. Following 7 consecutive days of iv dose administration, no mortality was observed for male and female rats given less than or equal to 37.5 mg/kg/day of AL (total dose: less than or equal to 262.5 mg/kg) or less than or equal to 75 mg/kg/day of AS (total dose: less than or equal to 525 mg/ kg). Due to the difficulty encountered during the iv administration of AL, no conclusions could be drawn relative to the lethality produced by higher multiple iv doses of AL. Single or multiple iv dose administration of AL produced a possible dose-dependent venotoxicity that was characterized by black and/or dark discoloration of the tail, which in some instances was accompanied by necrosis. Clinical pathological changes observed for rats given iv doses of 80 mg/kg/day of AL for less than or equal to 4 days or 150 mg/kg/day of AS for 7 consecutive days were consistent with an effect on hematopoiesis. No evidence was obtained for the presence of histopathological lesions in the hindbrains of rats given less than or equal to 37.5 mg/kg/day of AL for 7 consecutive days or less than or equal to 150 mg/kg/day of AS for 7 consecutive days.