Acute and subchronic toxicology of LY-195115 in rats and dogs

Abstract

LY-195115 is a new (investigational) inotropic agent. When given orally to either young adult rats or mice, single doses of 2500 or 5000 mg/kg were tolerated with minimal lethality. Clinical signs included muscle weakness, hypoactivity, and evidence of hemorrhage. Dogs and monkeys survived a single oral dose of 10 and 5 mg/kg, respectively; however, there was sinus tachycardia for 6–8 h post dose in both species. Rats (207/sex/group) were fed diets containing LY-195115 in concentrations of 0, 0.005, 0.025, or 0.1% for 3 months. The average daily intake of the compound was approximately 0, 3.5, 17, or 70 mg/kg in both sexes. Deaths occurred only in the high-dose group. Body weight gain, food consumption, and efficiency of food utilization were significantly reduced in males in the 0.1 % dose group and animals of both sexes in this group had changes in hematology, clinical chemistry, and urinalysis parameters indicative of renal damage. Crystals containing LY-195115 were present in the urine of animals from the 0.025% and 0.1 % treatment groups. Secondary hydronephrosis due to kidney stone formation was observed on gross and microscopic pathologic evaluation in the males of the 0.025% group and animals of both sexes in the 0.1% group. In addition, periarteritis was present in the adventitia and muscularis of small and medium-sized arteries in the pancreas, lymph node, kidney, and stomach of some animals in all LY-195115 treatment groups. No overt signs of toxicity were produced in beagle dogs (4/sex/group) given daily oral doses of 0.03, 0.12, or 0.5 mg/kg of LY-195115 for 3 months. The only adverse effect was the occurrence of focal subendocardial fibroplasia in the heart in 2 high-dose male dogs. Thus, subchronic exposure of rats to doses of LY-195115 as high as 70 mg/kg produced minimal mortality, renal toxicity, and mild, limited vascular changes, while dogs tolerated doses up to 0.5 mg/kg with no evidence of any effect of treatment except minimal histological changes in the heart consequent to the expected cardiotonic action of the compound.