This study evaluated the toxicity of WR238605 Succinate in rats following six months of daily oral (gavage) administration. WR238605 Succinate is an 8- aminoquinoline derivative which has demonstrated antimalarial potential in preclinical studies. Dose levels studied were 0 (vehicle control), 0.5, 2.0 and 9.0 mg base/kg/day, and were based on a three month toxicity study with a three month recovery period in rats (UIC/TRL Study No. 098) in which anemia and lung lesions were seen at 6 and 18 mg base/kg/day whereas 0.5 mg base/kg/day was the no-observed effect level. In the present study, the animals were = 7 weeks old, and weighed 216 - 289 g (males) and 160 - 204 g (females) upon initiation of drug treatment. The primary toxicities of WR238605 Succinate were to RBCs, the lungs and the liver. Mortality occurred in one high dose male rat. Treatment-related clinical signs in high dose animals included rough coat, hunched posture, labored breathing (males), and piloerection (females). Body weight gains were significantly reduced in high dose animals and mid dose males. Also, food consumption was decreased in high dose animals. High dose males, and mid and high dose females had decreased RBC counts, HCT and HGB concentration, suggestive of mild anemia. The anemia may have been hemolytic in origin due to the presence of Heinz bodies and increased methemoglobin levels. Microscopic lesions observed in the spleen, bone marrow, kidneys and adrenal glands may have been secondary to anemia and/or hemolysis. High dose animals had elevations in mature neutrophil and lymphocyte numbers. Mild thrombocytopenia was seen in mid and high dose males. Pulmonary lesions in male and female rats in the mid and high dose groups consisted of foamy macrophage accumulation, chronic interstitial inflammation, and hemorrhage (high dose groups only).
