SUBCHRONIC TOXICITY AND REVERSIBILITY OF WR6026 DIHYDROCHLORIDE, AN 8-AMINOQUINOLINE ANTILEISHMANIAL DRUG, IN RATS AND DOGS

WR6026 is an 8-aminoquinoline analog of primaquine that is being devel oped for the treatment of visceral leishmaniasis and Pneumocystis cari nii pneumonia. These studies examined the oral toxicity in Sprague-Daw ley rats and Beagle dogs when administered daily for 13 weeks. A 13 we ek 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 mu moles base/kg/day) for rats and 0, 0.2, 2, a nd 3 mg base/kg/day (0, 0.58, 5.8, and 8.7 mu moles base/kg/day) for d ogs. The primary toxic effects of WR6026 in both species included hemo lytic anemia, methemoglobinemia clinically manifested by cyanosis, and transient thrombocytopenia. Mild hepatotoxicity was seen in dogs and was manifested by serum chemistry changes, hepatocellular necrosis, an d periportal cellular infiltrates. Leukocytosis was seen in both speci es during the treatment period. Secondary responses to hemolytic anemi a included splenic extramedullary hematopoiesis and hemosiderosis in l iver, spleen, and kidney. Renal changes included proteinic droplets in the renal proximal convoluted tubules of female rats. Although toxici ty was generally confined to the mid- and high-dose levels in both spe cies, some indices of toxicity were seen in the low dose groups and su bsequently a no effect level was not determined. The toxic effects of WR6026 had essentially resolved by the end of the 13 week recovery per iod in both species except for anemia in male dogs. (C) 1997 Wiley-Lis s, Inc.