Four Week Oral Toxicity Study of WR242511 in Dogs. Volume 1

Abstract

Abstract : This study evaluated the toxicity of WR242511 tartrate in dogs following four weeks of daily administration by gelatin capsule. Dose levels studied were 0, 0.1, 0.3 and 1.0 mg base/kg/day. The primary toxic effects of WR242511 were seen in the RBCs, lungs and platelets. Although subtle, hemolytic anemia was supported by reticulocytosis, secondary splenic extramedullary hematopoiesis and bone marrow hyperplasia in high dose animals. A slight, statistically insignificant decrease in body weight (-0.6 kg) was also seen in high dose males and females. Methemoglobinemia, the desired pharmacologic effect, accompanied by clinical signs of cyanosis (blue gums, tongue and sclera), and mild to moderate thrombocytopenia were observed in mid and high dose animals. WR242511 treatment induced interstitial pulmonary inflammation in seven out of eight high dose animals. Minimal, but significant increases in serum AST, globulin, and triglyceride levels in high dose males and decreases in albumin levels and A/G ratio in both high dose males and females, not accompanied by corresponding histopathologic changes in the liver, suggests that WR242511 is marginally hepatotoxic. Additionally, increased serum haptoglobin levels, indicative of an acute phase reaction, were observed in mid dose males and high dose animals. Because the aforementioned toxic responses were limited to the mid and high dose levels, the no-observed effect level (NOEL) of WR242511 tartrate was 0.1 mg base/kg/day.