One Year Oral Toxicity Study of WR238605 Succinate in Dogs. Volume 1
Abstract
The purpose of this study was to determine specific target organ toxicity, dose-response relationships, and a no observed adverse effect level of WR238605 succinate in Beagle dogs following one year of daily oral administration. WR238605 succinate is being developed as an antimalarial agent Dose levels studied were 0,0.1, 1.0 and 4.0 mg base/kg/day. The dogs were = 7-8 months old and weighed 9.9 - 13.1 kg (males) and 8.0 - 11.4 kg (females) at dosing initiation. The primary toxicities of WR2386XJ5 succinate following one year of oral administration were to the lungs and red blood cells. No mortalities occurred in the study. Body weight gains were decreased in the males in a dose-dependent fashion, but were unaffected in females. Clinical signs were primarily seen in the mid and high dose groups and included diarrhea, emesis and blue tongue. Increased respiratory rate was observed in one high dose male. Methemoglobinemia was produced throughout the study in the mid and high dose groups. Chronic, low level intravascular hemolysis occurred in the mid and high dose groups, as evidenced by the presence of tissue pigmentation changes in Kupffer cells, renal cortex epithelium and in macrophages in spleen, gall bladder, tonsil and lymph nodes (mesenteric, mandibular, bronchial and mediastinal). Furthermore, increased reticuloctye counts, Heinz bodies and serum haptoglobin levels were seen. Thrombocytopenia was seen in the high dose group in week 4, but resolved thereafter. Pulmonary lesions were observed in all animals in the mid and high dose groups, and consisted of foamy macrophage accumulation and chronic interstitial inflammation. Bone marrow hyperplasia occurred in the mid and high dose groups. Lung, liver and splenic weights were increased at the high dose level. Although subtle ECG changes were seen and appear to be treatment-related, they may not represent significant toxicologic effects.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 18, 1997
- Accession Number
- ADA640544
Entities
People
- A. P. Brown
- Barry S. Levine
- R. L. Morrissey
Organizations
- University of Illinois Urbana–Champaign