Thirteen Week Oral Toxicity Study of WR242511 with a Thirteen Week Recovery Period in Dogs. Volume 1 of 2
Abstract
This study evaluated the toxicity of WR242511 in male and female beagle dogs following thirteen weeks of daily oral administration by gelatin capsule. A thirteen week recovery period was included for all groups. WR242511 tartrate is being developed as an anticyanide agent. Dose levels studied were 0, 0.1, 0.3 and 1.0 mg base/kg/day and were based on a one month toxicity study in beagle dogs in which 1.0 mg base/kg/day resulted in toxicity to RBCs, lungs and platelets and a no-observed effect level (NOEL) of 0.1 mg base/kg/day was seen (UIC/TRL Study No. 134). The dogs were = 7-8 months old and weighed 10.3 - 13.6 kg (males) and 7.4 - 11.3 kg (females) at dosing initiation. In the present investigation, the primary toxic effects of WR242511 tartrate were seen in the lungs, RBCs and platelets. Mild reductions in body weight gain were seen in mid and high dose animals. Methemoglobin, the desired pharmacologic effect, was produced in a dose-dependent fashion and was accompanied by clinical signs of cyanosis (blue gums, tongue and sclera). Mild anemia as supported by reticulocytosis, secondary splenic hematopoiesis and bone marrow hyperplasia occurred primarily in high dose animals. Significant thrombocytopenia was seen during the treatment period in the mid and high dose animals, presumably in response to the anemic state. Administration of WR242511 resulted in pulmonary lesions in mid and high dose animals consisting of alveolar macrophage accumulation, chronic perivascular inflammation, chronic interstitial inflammation, and basophilic granular material in the alveoli. Minimal, but statistically significant changes in clinical chemistry parameters suggestive of liver injury were seen. However, histopathologic evidence of liver injury was not observed, suggesting that WR242511 is marginally hepatotoxic.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 07, 1996
- Accession Number
- ADA640613
Entities
People
- Barry S. Levine
Organizations
- University of Illinois at Chicago