The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 23 , Issue SupplementIII
Showing 1-11 articles out of 11 articles from the selected issue
  • Hiroyuki YANAGI, Kojiro YAMAGUCHI, Kiyoshi SHIMIZU, Yutaka SHICHINO, K ...
    1998 Volume 23 Issue SupplementIII Pages 409-413
    Published: July 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Single-dose toxicity studies of sodium N-[2-[4-(2, 2-dimethylpropionyloxy)phenylsulfonylamino]benzoyl]aminoacetate tetrahydrate(ONO-5046·Na), a novel neutrophil elastase inhibitor, were conducted in Sprague-Dawley(SD)rats and beagle dogs. The rats of both sexes were administered ONO-5046·Na intravenously at a single dose of 150, 300 or 450 mg/kg. The male dogs were also given ONO-5046·Na at a single dose of 75 or 150 mg/kg. In the rat study, hypoactivity, bradypnea and paleness of limbs and pinna were observed at doses of 300mg/kg and above. In particular, one of six female rats in the 450 mg/kg group showed clonic convulsion and died. In surviving animals, those signs disappeared within 3 hr after administration. No effect on body weight gain was seen in either group. Necropsy findings showed a slight foamy fluid in the bronchus, hemorrhage at the right knee joint muscle, tendon and lung in a dead animal. In the dog study, no effects on clinical signs, body weight, food consumption and blood biochemistry were seen in any animals of the 75 and 150 mg/kg groups. It is concluded that the approximate lethal doses are 450 mg/kg in rats and 150 mg/kg and above in dogs.
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  • Hiroyuki YANAGI, Kojiro YAMAGUCHI, Kiyoshi SHIMIZU, Yutaka SHICHINO, K ...
    1998 Volume 23 Issue SupplementIII Pages 415-434
    Published: July 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A 4-week repeated dose toxicity study with 4-week recovery test of sodium N-[2-[4-(2, 2-dimethylpropionyloxy)phenylsulfonylamino]benzoyl]aminoacetate tetrahydrate(ONO-5046·Na), a novel neutriphil elastase inhibitor, was conducted in Sprague-Dawley(SD)rats.The rats of both sexes were administered ONO-5046·Na intravenously at a daily dose of 0(vehiclr control and saline control), 18.75, 37.5, 75 or 150 mg/kg. ONO-5046·Na did not affect clinical signs, body weight, food consumption, ophthalmology, urinalysis, hematology, blood chemistry, organ weights, necropsy or histopathology at any dose. These results indicate that the NOAEL of ONO-5046·Na in rats is 150 mg/kg/day for both sexes in this study.
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  • Kojiro YAMAGUCHI, Hiroyuki YANAGI, Kiyoshi SHIMIZU, Yutaka SHICHINO, K ...
    1998 Volume 23 Issue SupplementIII Pages 435-455
    Published: July 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    4-week repeated dose toxicity study with 4-week recovery test of sodium N-[2-[4-(2, 2-dimethylpropionyloxy)phenylsulfonylamino]benzoyl]aminoacetate tetrahydrate(ONO-5046·Na), a novel neutrophil elastase inhibitor, was conducted in beagle dogs. The dogs of both sexes were administered ONO-5046·Na intravenously at a daily dose of 0(vehicle control), 7.5, 15 or 30 mg/kg. In the 15 mg/kg female group and the 30 mg/kg male and female groups, transient hypoactivity and ataxic gait were observed. It is considered that these symptoms were attributed to the pharmacological effect of ONO-5046·Na. Also, in the 30 mg/kg male and female groups, erythrocyte, hematocrit and hemoglobin were decreased.In the 30 mg/kg male group, lung weight was increased. However, histopathological examination revealed there were no changes in any organs including the lungs. There were no treatment-related changes in body weights, food consumption, opthalmology, occult blood in feces, urinalysis, blood chemistry, electrocardiography, blood pressure, temperature, pulse rate, hepatic and renal function or necropsy. These results indicate that the NOAEL of ONO-5046·Na in dogs is 15 mg/kg/day for both sexes in this study.
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  • Kojiro YAMAGUCHI, Yoshiya AZE, Kiyoshi SHIMIZU, Yutaka SHICHINO, Harut ...
    1998 Volume 23 Issue SupplementIII Pages 457-482
    Published: July 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A 6-month repeated dose toxicity syudy with 1-month recovery test of sodium N-[2-[4-(2, 2-dimethylpropionyloxy)phenylsulfonylamino]benzoyl]aminoacetate tetrahydrate(ONO-5046·Na), a novel neutrophil elastase inhibitor, was conducted in Sprague-Dawley(SD)rats. The rats of both sexes were administered ONO-5046·Na intravenously at a daily dose of 0(vehicle control), 18.75, 37.5 or 75 mg/kg. ONO-5046·Na did not affect clinical signs, body weight, food consumption, opthalmology, urinalysis, hematology, blood chemistry, organ weight, necropsy or histopathology at any dose. These results indicate that the NOAEL of ONO-5046·Na in rats is 75 mg/kg/day for both sexes in this study.
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  • Masami OKAMOTO, Makoto IDE, Hiromi SUZUKI, Takahiro ISHII, Kazutoshi T ...
    1998 Volume 23 Issue SupplementIII Pages 483-501
    Published: July 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A 6-month repeated dose toxicity study with 1-month recovery test of sodium N-[2-[4-(2, 2-dimethylpropionyloxy)phenylsulfonylamino]benzoyl]aminoacetate tetrahydrate(ONO-5046·Na), a novel neutrophil elastase inhibitor, was conducted in beagle dogs. The dogs of both sexes were administered ONO-5046·Na intravenously at a daily dose of 0(vehicle control), 7.5, 15 or 30 mg/kg. In the 15 mg/kg and above groups, transient ataxic gait was observed. It is considered that this symptom could be attributed to the pharmacological effect of ONO-5046·Na. Macro-and micro-scopic hemorrhage at the injection site was observed in the ONO-5046·Na treated groups. However, it is considered that these findings could be attributed to the long-term repeated dosing procedure, and were not toxic changes. There were no treatment-related changes in body weight, food consumption, opthalmology, urinalysis, hematology, blood chemistry, electrocardiography and organ weights. These results indicate that the NOAEL of ONO-5046·Na in dogs is 30 mg/kg/day for both sexes in this study.
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  • Noboru CHIHARA, yoshiya AZE, Tatsuya NISHIMURA, Ryugen SHIRAKAWA, Taka ...
    1998 Volume 23 Issue SupplementIII Pages 503-514
    Published: July 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Fertility study of sodium N-[2-[4-(2, 2-dimethylpropionyloxy)phenylsulfonylamino]benzoyl]aminoacetate tetrahydrate(ONO-5046·Na), a novel neutrophil elastase inhibitor, was conducted in Sprague-Dawley(SD)rats. ONO-5046·Na was administered intravenously at doses of 18.75, 37.5 and 75 mg/kg/day to male rats from 64 days prior to mating, through the mating period and until necropsy, and to female rats from 15 days prior to mating until Day 7 of gestation, in order to examine its effects on fertility and reproductive performance of males and females and the development of their fetuses. There were no changes attributable to ONO-5046·Na in general signs, body weight, food consumption or autopsy findings in males and females. No drug-related changes were observed in estrous cycles, copulation and fertility indices in males and females. Pituitary wiegth of dams was decreased in each of the ONO-5046·Na treated groups, but no histopathological changes were observed in the pituitary. In the cesarean section findings in dams, ONO-5046·Na had no effects on the number of corpola lutea, the number of live fetuses, the implantation ratio, the resorbed and dead fetus ratio, fetal or placental weight or the incidences of external, skeletal or visceral anomalies of the fetuses. From these results, it is considered that the NOAEL of ONO-5046·Na is 75 mg/kg/day for general and reproductive toxicity in males and females and for developmental toxicity in their fetuses.
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  • Tatsuya NISHIMURA, Noboru CHIHARA, Satoshi SUGAI, Takahiko SAKAMOTO, R ...
    1998 Volume 23 Issue SupplementIII Pages 515-529
    Published: July 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Prenatal and postnatal toxicity of sodium N-[2-[4-(2, 2-dimethylpropionyloxy)phenylsulfonylamino]benzoyl]aminoacetate tetrahydrate(ONO-5046·Na), a novel inhibitor of human neutrophil elastase, was studied in Sprague-Dawley(SD)rats. ONO-5046·Na was injected intravenously at doses of 0, 18.75, 37.5 and 75 mg/kg/day to pregnant rats from day 7 of pregnancy to day 20 after delivery. All pregnant rats were allowed to deliver naturally for postnatal examination of their offspring. No adverse effects on dams were observed in clinical signs, body weigth change, food consumption, pregnant, delivery or lactating performances. ONO-5046·Na did not'affect the postnatal development of offspring, including birth index, survival index, physical and functional development, motor activity, emotionality, learning ability and reproductive performance. From these, results, it is considered that the NOAEL of ONO-5046·Na is 75 mg/kg/day for dams and their offspring.
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  • Tatsuya NISHIMURA, Yutaka NAKAGAWA, Masaki SAKAI, Satoshi SUGAI, Nobor ...
    1998 Volume 23 Issue SupplementIII Pages 531-538
    Published: July 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Teratogenicity of sodium N-[2-[4-(2, 2-dimethylpropionyloxy)phenylsulfonylamino]benzoyl]aminoacetate tetrahydrate(ONO-5046·Na), a novel inhibitor of human neutrophil elastase, was studied. ONO-5046·Na was injected intravenously at doses of 0, 7.5, 15 and 30 mg/kg/day to pregnant Kbl:NZW rabbits from day 6 to day 18 of pregnancy. All female rabbits were sacrificed on day 29 of pregnancy and their fetuses were examined. There were no clinical signs or death attributable to ONO-5046·Na. One dam in the control group and 3 dams in the 30 mg/kg/day group aborted. Body weight gain in the 15 and 30 mg/kg/day groups and food intake in the 30 mg/kg/day group were decreased during the administration period. These changes had recovered by the end of the study. Kidney weight was increased in the 30 mg/kg/day group. There were no effects of ONO-5046·Na in necropsy findings at cesarean section in dams at any dose levels. Developmental toxicity of ONO-5046·Na was not found at any dose levels. From these results, it is considered that the NOAEL of ONO-5046·Na is 7.5 mg/kg/day for pregnant animals and 30 mg/kg/day for fetuses.
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  • Yasuhiko HIROUCHI, Susumu KAKAMU, Akinori SHOJI, Katsumi KOBAYASHI, Ma ...
    1998 Volume 23 Issue SupplementIII Pages 539-552
    Published: July 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A two-stage carcinogenesis promotion test using phenobarbital(PB)as a positive control was performed on mesalazine in rats (F344, male). Pathological and immunohistological examinations were performed to examine the cell damage and proliferation in the liver and kidneys. As the initiation treatment, groups 1, 2, 3 and 5 were administered 200 mg/kg diethylnitrosamine(DEN)dissolved in 0.9% physiological saline, and group 4 was administered 5 ml/kg 0.9% physiological saline once intraperitoneally. Then group 1 was orally administered a water solution(5ml/kg)containing 0.5% CMC-Na, and groups 2, 3 and 4 a similar water solution but containing 150, 300 and 300 mg/kg mesalazine, respectively. Group 5 was administered 0.05% PB mixed in feed from weeks 2 to 8. Partial(2/3)hepatectomy was performed in all 5 groups at week 3 after DEN administration. No clear differences between the groups were observed in general conditions, body weight or amount of food consumption. The number or area-size of hepatic GST-P-positive altered cell foci revealed no significant differences between groups 1, 2 and 3, but a significant increase in number and area-size was observed in group 5. No GST-P positive cell foci were detected in group 4. The number of altered cell foci(H.E.staining)in the DNE groups administered mesalazine was the same as that in group 1. Thus, mesalazine did not promote hepatocarcinogenesis in the present experimental system. Statistically insignificant appearances of basophilic and acidophilic changes were observed in the renal tubular epithelium and mineral deposits in the renal papillary region and cortical margin region. The PCNA labeling rate was significantly lower in group 4, corresponding with the histological finding showing no proliferation of the renal tubular epithelium. judging from the above test results, mesalazine was likely to show neither a promotion effect on the initiation induced by DEN nor cell proliferative activity on the kidneys by administration for this experimental period.
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  • Sakae OBARA, Kazumasa MARUYAMA, Naoto ICHIKAWA, Osamu TANAKA, Michio O ...
    1998 Volume 23 Issue SupplementIII Pages 553-560
    Published: July 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Skin sensitization and photosensituzation tests of hydrophobically modified hydroxypropyl methylcellulose(HM-HPMC), a new cellulose derivative used as a thickener for topical pharmaceuticals, were conducted using guinea pigs. An aqueous dispersion of HM-HPMC(3 w/v %)was applied in the tests. Skin reaction was not observed in any animal in the HM-HPMC-treated group or control group. In the photosensitization test, no skin reaction was found in any animal in the test-preparation group or the control group. It was concluded that the HM-HPMC dispersion does not exhibit skin sensitizing or photosensitizing activity under the condition of this test.
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  • Toshimasa JINDO, Yuri GENDA, Koji KAKIHATA, Hiroshi OHNO, Yoshihiro Ak ...
    1998 Volume 23 Issue SupplementIII Pages 561-574
    Published: July 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Thirteen-week oral repeated dose toxicity of ecabapide, a gastroprokinetic drug, wasinvestigated in dogs at dosage levels of 50, 175 or 600 mg/kg, and in rats at dosage levels of 25, 100, 400 or 1600 mg/kg. In dogs, vomiting, aqueous salivation, body weight gain inhibition, and hemolytic anemia, together with an increase in Heinz body formation, were observed at 175 and/or 600 mg/kg. Histological examination revealed enhanced hemosiderin deposition in the liver and spleen, retention of erythrocytes in the splenic sinus and enhanced erythropoiesis in bone marrow at 175 and/or 600 mg/kg. In the rat study, although increases in serum total protein, albumin and calcium, as well as increased liver and kidney weights, were observed at 400 and/or 1600 mg/kg, no obvious morphological changes were seen. The hemolytic anemia and an increased Heinz body formation were not observed in rats, indicating a species difference. On the basis of these results, the non-toxic dose of ecabapide was considered to be 50 mg/kg in dogs and 100 mg/kg in rats.
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