The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 6 , Issue SupplementII
Showing 1-4 articles out of 4 articles from the selected issue
  • Kiyoshi IMAI, Yuzo HAYASHI, Koroku HASHIMOTO
    1981 Volume 6 Issue SupplementII Pages 179-188
    Published: December 25, 1981
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The acute toxicity of captopril, a potential inhibitor of angiotensin converting enzyme, was studied in Sprague-Dawley rats and ICR mice. In the oral administration, a decrease of spontaneous motor activity, lacrimation, salivation and decline of body temperature was noted in the rats and mice. In the mice, tarry stool was also noted. The LD50 was estimated as : 4249 mg/kg in male mice, 5050 mg/kg in female mice, 4336 mg/kg in male rats and 4245 mg/kg in female rats. In the dead animals, a hemorrhagic erosion or ulcer was recognized in the glandular stomach. An intravenous captopril in mice, caused immediate death by dyspnea in some animals within 3 minutes, but delayed death was also occurred within 24 hours showing a decrease of spontaneous motor activity and decline of body temperature. The LD50 was estimated as 3154 mg/kg in male mice and 3225 mg/kg in female mice. A single intravenous administration of captopril in dose of 1600 mg/kg did not cause any death in the rats of both sexes. The mice of both sexes well tolerated a single subcutaneous administration of captopril in a dose of 2400 mg/kg. No death occurred in rats of both sexes received subcutaneously captopril in a dose of 1200 mg/kg. At an injection site, a necrotic ulcer was noted in the skin of rats and mice which received subcutaneously captopril in a dose of 1600 mg/kg or more and 1200 mg/kg, respectively.
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  • Kiyoshi IMAI, Shinsuke YOSHIMURA, Tsuneo OHTAKI, Koroku HASHIMOTO
    1981 Volume 6 Issue SupplementII Pages 189-214
    Published: December 25, 1981
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Subacute toxicity of captopril by daily oral administration at dose levels of 10 mg/kg, 30 mg/kg, 100 mg/kg, 300 mg/kg, 900 mg/kg and 2700 mg/kg for one month was studied in Sprague-Dawley rats. In the 2700 mg/kg group, 13 of 18 males and 17 of 18 females died with marked emaciation and abdominal distension. In the 900mg/kg group, 1 of 18 males and 3 of 18 females died also during the administration period. In dead animals, a marked dilatation of gastrointestinal tract was noted showing multiple hemorrhagic erosions and/or ulcers in the glandular stomach. The remainder of these groups exhibited polydipsia and polyuria during the dosage period. In the 300mg/kg and 100 mg/kg groups, all animals survived throughout the entire experimental period showing polydipsia and polyuria. In the 30 mg/kg and 10 mg/kg groups, all animals survived also throughout the entire dosage period without showing any toxic sign. Regarding plasma analysis, the BUN and creatinine concentration was significantly elevated in the group of 100 mg/kg or more. In the hematological examination, there was a decrease of erythrocyte counts, hemoglobin contents and hematocrit values in the group of 300 mg/kg or more. Pathological examinations revealed a marked thickening of the wall in afferent arterioles and interlobular arteries of the kidney in association with hypertrophy and hyperplasia of juxtaglomerular cells in 100 mg/kg, 300 mg/kg, 900 mg/kg and 2700 mg/kg groups. In these groups, multiple hemorrhagic erosions with or without ulcer were also noted in the glandular stomach. In the spleen, a slight increase of extramedullary hematopoiesis and hemosiderosis was noted in the 100 mg/kg, 300 mg/kg, 900 mg/kg and 2700 mg/kg groups, in which an increase of erythropoietic elements was also noted in the bone marrow. From these results, the maximum nontoxic dose was estimated as about 30 mg/kg/day by oral administration of captoprilin the rats.
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  • Koroku HASHIMOTO, Kiyoshi IMAI, Shinsuke YOSHIMURA, Tsuneo OHTAKI
    1981 Volume 6 Issue SupplementII Pages 215-246
    Published: December 25, 1981
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The chronic administration of captopril to Sprague-Dawley rats was performed under the barrier system by feeding ad libitum with mixed diet in various concentrations of captopril with 3 months recovery period. The number of animals was 180 female and 180 male including 5 groups of control, 30, 100, 300 and 900 mg/kg/day. The maximum nontoxic dose was estimated as about 30 mg/kg/day for male but a little more than this for female rats. Body weight increase was significantly reduced in male but for the first 3 months in female rats. No death was ascribed to the toxic effect of captopril. Polydipsia and polyuria in male, and the significant increase in values of BUN and inorganic phosphate in both sexes were observed. The reduction in erythrocyte count, values of hemoglobin and hematocrit, hemosiderosis in reticulum cells of the spleen and Kupffer cells in the liver and the increase of erythropoieses indicated hemolytic anemia. Heart weight reduced while kidney weight increased. Pathological examination revealed hypertrophia and hyperplasia of JG cells and thickening of walls of afferent arterioles with hyperplasia of vascular smooth muscle cel1s and increase of collagen fibers. Thickening of walls extended to walls of the interlobular arteries which remained after withdrawal of captopril for 3 months though JG granules attenuated. The age-related increases of incidences of proteinuria and myocardial fibrosis were attenuated dose-dependently which are probably due to hypotension induced by captopril.
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  • Tsuneo OHTAKI, Kiyoshi IMAI, Shinsuke YOSHIMURA, Koroku HASHIMOTO
    1981 Volume 6 Issue SupplementII Pages 247-270
    Published: December 25, 1981
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Thirty four beagle dogs, male and female were orally given 10, 30, 100 and 200mg/kg/day of captopril, an angiotensin converting enzyme inhibitor, for 3 months followed by a recovery test for 4 weeks. One of 4 female dogs which were treated with the highest dose of 200mg/kg/day throughout the experimental period died of bronchial pneumonia. Hypersalivation and occasionally vomiting was observed in dogs treated with 100 and 200mg/kg/day. Skin eruption such as erythema and papules was observed mostly at the ventral surface of the neck, chest and upper abdomen in dogs in these two experimental groups. Histological examination of the lesion revealed cellular infiltration with edema and expansion in the dermis and slight hyperkeratosis with parakeratosis and acanthosis. Changes. in erythrocyte counts, hematocrit values and hemoglobin contents during the course of administration were variable among dogs but these were more obvious in animals treated with higher doses. An increase in erythropoiesis of the bone marrow, extramedullary hematopoiesis and slight hemosiderosis in liver and spleen were revealed by histological examination. Above histological observations suggest that captopril may cause hemolysis. Hypertrophy and hyperplasia of juxtaglomeruiar cells with increased number of JG granules were shown in the highest dosage group even 4 weeks after suspension of captopril administration. A distinct plasma renin activity supported the morphological changes. From the results of three months administration of captopril to beagle dogs, the maximum non-toxic dose may be around 10 mg/kg/day and toxic dose 100 mg/kg/day.
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