Subchronic toxicity and reversibility of WR6026 dihydrochloride, an 8-aminoquinoline antileishmanial drug, in rats and dogs
✍ Scribed by Barry S. Levine; E. Marianna Furedi-Machacek; Alan P. Brown; Michael J. Tomlinson
- Book ID
- 101265537
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- English
- Weight
- 125 KB
- Volume
- 40
- Category
- Article
- ISSN
- 0272-4391
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✦ Synopsis
WR6026 is an 8-aminoquinoline analog of primaquine that is being developed for the treatment of visceral leishmaniasis and Pneumocystis carinii pneumonia. These studies examined the oral toxicity in Sprague-Dawley rats and Beagle dogs when administered daily for 13 weeks. A 13 week recovery period was included for all dose groups except for the low dose animals. Dose levels studied were 0, 3, 6, and 12 mg base/kg/day (0, 8.7, 17.5, and 35 µmoles base/kg/day) for rats and 0, 0.2, 2, and 3 mg base/kg/ day (0, 0.58, 5.8, and 8.7 µmoles base/kg/day) for dogs. The primary toxic effects of WR6026 in both species included hemolytic anemia, methemoglobinemia clinically manifested by cyanosis, and transient thrombocytopenia. Mild hepatotoxicity was seen in dogs and was manifested by serum chemistry changes, hepatocellular necrosis, and periportal cellular infiltrates. Leukocytosis was seen in both species during the treatment period. Secondary responses to hemolytic anemia included splenic extramedullary hematopoiesis and hemosiderosis in liver, spleen, and kidney. Renal changes included proteinic droplets in the renal proximal convoluted tubules of female rats. Although toxicity was generally confined to the mid-and highdose levels in both species, some indices of toxicity were seen in the low dose groups and subsequently a no effect level was not determined. The toxic effects of WR6026 had essentially resolved by the end of the 13 week recovery period in both species except for anemia in male dogs.