Abstract
The chronic toxicity of (-)-(2S, 3aR, 7aS)-1-[(S)-N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]alanyl]hexahydro-2-indolinecarboxylic acid (trandolapril: RU44570), a novel angiotensin-converting enzyme blocking antihypertensive drug, was assessed in rats by oral administration for 12 months at dosage levels of 0.05, 0.25, 2.50 and 25.00 mg/kg/day, comparing with the control animals received 0.5% methylcellulose solution. Reversibility of the drug-induced changes was also examined by 3 months' withdrawal following the administration period. 2) There was no death or general symptom that was thought to be attributable to the administration of RU44570. 3) The body weight gain was significantly suppressed from 1st week to the end of administration period in male animals of the dosage groups of 2.50 mg/kg or more and from week 1 to 15 of administration in female animals of the 25.00 mg/kg dosage group. During the withdrawal period, the difference of the body weights between these groups and control was reduced and that was never statistically significant. 4) The food consumption generally tended to be lowered in male animals of the dosage groups of 2.50 mg/kg or more throughout the administration period. The values were significantly different from that of control group on almost all measurement points from week 2 to 34 of administration. The difference of the food consumption of these groups from control group tended to be smaller thereafter, although significant difference was seen sporadically. Male animals of the 0.05 and 0.25 mg/kg dosage groups also showed the tendency of decreased food consumption infrequently. There was no constant tendency of fluctuation in the food consumption among the each RU44570 treated group during the withdrawal period. 5) The water consumption increased significantly in male animals of the 25.00 mg/kg dosage group from 1st week to the end of administration period. Male animals of the 2.50 mg/kg dosage group showed similar high value of the water consumption but the degree was lesser than that of 25.00 mg/kg dosage group. Although female animals of the 25.00 mg/kg dosage group showed significantly increased water consumption from week 3 to 4 of administration, they began to show decreasing tendency from approximately week 10 of administration conversely. From week 26 of administration, the water consumption of this group significantly decreased frequently comparing with that of control group. Female animals of the 2.50 mg/kg dosage group showed similar decrease in water consumption from approximately week 26 of administration. The value of water consumption was still high in male animals of the 25.00 mg/kg dosage group during the withdrawal period, however, reached to the level of control at week 13 of withdrawal after gradual remission. Female animals of the 0.05 mg/kg dosage group showed significant and remarkable high value in water consumption at week 1 of withdrawal. The water consumption of this group tended to increase thereafter, but the difference from that of control group was not significant. The fluctuations of water consumption in other treated groups was not observed during the withdrawal period. 6) No significant change that was thought to be attributable to the administration of RU44570 was detected by the ophthalmological examination. 7) Urinalysis revealed increased urine volume, high value of pH and the changes associated with diluted urine in male animals of the dosage groups of 0.05 mg/kg or more, i. e., lower content or value in electrolytes, bilirubine, ketone body, protein, urobilinogen, occult blood, specific gravity and number of cells in the sediment. These changes were not observed at the end of withdrawal period. 8) No drug-induced changes in kidney function were detected by PSP (Phenolsulfonphthalein) test. 9) Hematological examinations revealed significant decrease in erythrocytes counts and packed cell volume with dose dependency in male animals of the dosage groups of 2.50 m
