[Twelve-month oral toxicity study of trandolapril (RU44570) in rats].
1) 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.(ABSTRACT TRUNCATED AT 400 WORDS)
Narama
I
I
Research Institute of Drug Safety, Setsunan University, Osaka, Japan.
Nakajima
H
H
Fujishima
H
H
Kurio
W
W
Maeda
H
H
Ozaki
K
K
Kumagai
Y
Y
Hiramatsu
Y
Y
Takabatake
E
E
D000284:Administration, Oral; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001774:Blood Chemical Analysis; D004334:Drug Administration Schedule; D005260:Female; D006403:Hematologic Tests; D007211:Indoles / Q000008:administration & dosage / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects; D007677:Kidney Function Tests; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects; D016482:Urinalysis
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; C052035:trandolapril