Trandolapril (RU44570) was orally administered to dogs at a daily dose of 2.5, 25 or 250 mg/kg for 13 weeks. After the administration period, 25 and 250 mg/kg groups were observed for recovery for 4 weeks. The results obtained are as follows: 1. One male in the 250 mg/kg group showed decrease of food consumption and body weight, stomatitis, hematemesis, decumbence, hypothermia, and finally loss of reactivity to stimuli. This animal was killed because of these severe changes on the 39th day of administration. Among the surviving animals, a temporary loss of body weight was observed in a few animals of the 25 and 250 mg/kg groups, and a decreased food consumption was sporadically seen in a few animals of the 250 mg/kg group during the administration period. No abnormal changes were found in the clinical observation and water intake in the surviving animals. 2. The changes attributable to the pharmacological effect of RU44570 were a decreased activity of the angiotensin-converting enzyme, increases in plasma renin activity and urine volume, and decreases in specific gravity and concentrations of Na, K and Cl in the urine of every administration group. A decrease in blood pressure and an increase in the PAS and Bowie positive granules in the juxtaglomerulat cells were also found in the 25 and 250 mg/kg groups. In addition, thickening of the afferent arteriolar wall of the glomeruli, a basophilic change of the renal tubular epithelial cells, and localized atrophy and hypertrophy of the renal tubules were observed in the 25 and 250 mg/kg groups, and increases in BUN, ALP and creatinine, and a slight dilation of the renal tubules were seen in the 250 mg/kg group. These observations indicated that RU44570 affected renal structure at a dose of 25 mg/kg or more renal function at a dose of 250 mg/kg. The animal killed in a moribund state showed nephrosis which consisted mainly of a moderate dilation of the fenal tubules and vacuolation of the renal tubular epithelial tells, stomatitis, severe hemorrhage and necrosis with neutrophil infiltration in the fundus of the glandular stomach, atrophy of the hemopoietic system, and ectopic calcification in the heart, kidneys, stomach, trachea and alveolar wall. Changes in the kidneys similar to those observed in other animals were also detected. These changes suggested that this animal lapsed into a moribund state due to renal dysfunction and the resultant uremia. 3. Decreases in the RBC, Ht and Hb were observed in the 25 and 250 mg/kg groups. Histologically, an increase in Kupffer's cells that ingested hemosiderin in the liver and increased hemosiderin deposition in the red pulp of the spleen were found in these groups. Hence, a hemolytic anemia was surmised in the 25 and 250 mg/kg groups. However, no changes were found in the myelogram or no compensatory reactions such as increased extramedullary hemopoiesis were detected. 4. After the recovery period, 1 female showed decreases in the RBC, Ht and Hb, and another female showed decreased blood pressure in the 250 mg/kg group. In addition, increased granules in the juxtaglomerular cells and thickening of the glomerular afferent arteriolar wall were found in the 25 and 250 mg/kg groups. However, these changes were less intense than those observed after the administration period. Other changes observed at the end of the administration period were no longer detected after the recovery period. In conclusion, the no-adverse-effect level of RU44570 for beagles was 2.5 mg/kg in this 13 week oral toxicity study. At the dose of 25 mg/kg or more, effects on the erythrocyte system and kidneys were observed. However, the effects were reversible and most of the changes disappeared after a 4 week recovery period.
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