Accession Number:

ADA383328

Title:

Preclinical Pharmacodynamic and Pharmacokinetic Studies of Investigational New Drugs

Descriptive Note:

Annual rept. 8 Sep 1999-7 Sep 2000

Corporate Author:

SOUTHERN RESEARCH INST BIRMINGHAM AL

Personal Author(s):

Report Date:

2000-10-01

Pagination or Media Count:

44.0

Abstract:

Individual studies have been conducted to determine the identity of the urinary metabolites of artelinic acid eliminated by dogs and to investigate the dose-related pharmacodynamic effects of artelinic acid, as assessed by signs of clinical and pathological toxicity, in male and female rats and dogs. Using LCMSMS methodology, glucuronides of artelinic acid, hydroxy artelinic acid, DQHS, and hydroxy DQHS were tentatively identified in urine collected from dogs dosed with artelinic acid. In rats given 14 consecutive daily oral doses of artelinic acid of 0, 10, 20, 40, SO, or 320 mgkgday or IM doses of 12.5 mgkgday of arteether, body weight loss and mortality were observed at an artelinic acid dose of 320 mgkgday. Biologically relevant changes in hematology parameters observed on Day 21 included increases in mean reticulocyte counts at artelinic acid doses of 20, 40, 80, and 320 mgkgday and mild increases in erythrocyte MCV values at artelinic acid doses of 20 and 80 mgkgday. A biologically relevant decrease in mean ALP activity was also observed in rats in the 320 mgkgday dose group. At artelinic acid doses of 40 and 80 mgkgday and an arteether dose of 12.5 mgkgday, neuropathological lesions observed in the hind brain consisted of neuronal degeneration of the trapezoid nucleus at an artelinic acid dose of 320 mgkgday, the lesions also included multiple nuclei in the hind brain. In dogs given 14 consecutive daily oral doses of artelinic acid of 0, 20, 40, 80, or 320 mgkgday or IM doses of 20 mgkgday of arteether, body weight loss was noted for dogs in the 320 mgkgday artelinic acid and the arteether dose groups. Potentially drug-related decreases in RBC, hemoglobin, hematocrit, andor reticulocyte counts were observed in the 20, 40, 80, and 320 mgkgday artelinic acid and the arteether dose groups.

Subject Categories:

  • Medicine and Medical Research
  • Pharmacology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE