The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 20 , Issue SupplementII
Showing 1-13 articles out of 13 articles from the selected issue
  • Mikito KIKUMORI, Ikuo NISHIDA, Takayoshi NISHIMURA, Kimio YASUHIRA, No ...
    1995 Volume 20 Issue SupplementII Pages 153-163
    Published: December 25, 1995
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The single dose toxicity studies of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, were conducted in Slc : ddY mice, Slt : SD rats, and beagle dogs of both sexes. The drug was administered intravenously (i.v.) to mice, rats and dogs, and intramuscularly (i.m.) to mice and rats. The animals were observed for 14 days after administration. LD50 values were more than 500 mg/kg and 200 mg/kg in mice and rats, respectively, by the i.v. route, and more than 20 mg/kg in both animal species by the i.m. route. In dogs, the minimum lethal dose was more than 200 mg/kg by the i.v. route. Mice that received more than 125 mg/kg by the i.v. route showed tremor and a decrease in locomotor activity during administration and for 30 min thereafter. Mice that received more than 5 mg/kg by the i.m. route showed tremor 5 min after administration and for 2 hr thereafter. Rats that received more than 50 mg/kg by the i.v. route showed tremor, and those that received 200 mg/kg by the same route showed a decrease in locomotor activity and ataxic gait, during and immediately after administration. Rats that received more than 5 mg/kg by the i.m. route showed tremor, and those that received 20 mg/kg by the same route showed salivation 5 min after administration and for 30 min thereafter. Dogs that received more than 12.5 mg/kg by the i.v. route revealed excitement, biting, vocalization, mydriasis, salivation, urination, defecation, licking chops, vomiting, increase in heart rate, panting, hyperthermia, tremor and conjunctival injection during administration and for 6 hr thereafter. The body weight, food consumption and water consumption, and pathological findings showed no changes attributable to the dosing of montirelin hydrate in any animal.
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  • Yasuyuki NISHIGUCHI, Motokuni NAKAZAWA, Takaaki OKA, Yoshimi HAGIDAI, ...
    1995 Volume 20 Issue SupplementII Pages 165-169
    Published: December 25, 1995
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Montirelin hydrate (NS-3) is a new drug for the treatment of disturbance of consciousness. The single dose toxicity studies of its degradation product and impurity (CNK-603) and its metabolite (CNK-6004) were conducted in Slc: ddY mice. The Compounds Were administered intravenously to male and female mice. Deaths occurred in both sexes of mice receiving more than 125 mg/kg of CNK-603. There were no treatment-related effects on survival in both sexes of mice receiving doses up to 2, 000 mg/kg of CNK-6004. Approximate lethal dose of CNK-603 was 125 mg/kg and lethal dose of CNK-6004 was more than 2, 000 mg/kg. Decrease in locomotor activity was observed in mice receiving the two compounds. Tremor, prone position and dyspnea were seen in mice receiving CNK-603. The body weight showed no changes attributable to the dosing of the two compounds in mice. In autopsies, congestion and hemorrhage in the lung were observed in dead mice given CNK-603. There were no remarkable changes in mice given CNK-6004. These results show that the lethal dose of CNK-603 is over 4 times lower than that of montirelin hydrate, and that CNK-6004 is less toxic than montirelin hydrate.
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  • Mikito KIKUMORI, Ikuo NISHIDA, Motoyoshi KOJIMA, Yuzou TANIGUCHI, Kimi ...
    1995 Volume 20 Issue SupplementII Pages 171-189
    Published: December 25, 1995
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A repeated dose toxicity study of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in Sprague-Dawley rats. Male and female rats were given the drug intravenously for 5 weeks at doses of 0 (control), 0.05, 0.5, 5 and 50 mg/kg. After discontinuation of the treatment, a 4-week recovery test was also conducted in the 0, 0.5 and 50 mg/kg groups. No deaths related to the treatment were observed. Tremor was seen in the 50 mg/kg group. Polyuria was observed in the 5 and 50 mg/kg groups. There were decreases in body weight gain in the 0.5 ma/kg group and over of males, and in food consumption in all male dose groups and increase in water consumption in the 5 and 50 mg/kg groups. In blood chemical examination, decrease in triglyceride was observed in the 5 and 50 mg/kg groups of males. Urinalysis Showed increase in urine volume in the 0.5 ma/kg group and over. Ophthalmoscopic and hematologic examinations failed to show any abnormalities attributable to the treatment. Pathological examination disclosed serous cell hypertrophy of the submandibular gland in all dose groups and increase in its organ weight in the 0.5 ma/kg group and over. The changes mentioned above were satisfactorily reversible except for the serous cell hypertrophy of the submandibular gland in the 50 mg/kg group. The decrease in food consumption and serous cell hypertrophy of the submandibular gland in the 0.05 mg/kg group were considered to be of no toxicological significance. These results show that the NOAEL of montirelin hydrate is 0.05 mg/kg for 5-week repeated dose toxicity in rats.
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  • Shigenori FURUKAWA, Ikuo NISHIDA, Mikito KIKUMORI, Yuzou TANIGUCHI, Ts ...
    1995 Volume 20 Issue SupplementII Pages 191-213
    Published: December 25, 1995
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A repeated dose toxicity study of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in Sprague-Dawley rats. Male and female rats were given the drug intravenously for 26 weeks at doses of 0 (control), 0.0004, 0.02, 1 and 50 mg/kg. After discontinuation of the treatment, a 9-week recovery test was also conducted in the 0, 1 and 50 mg/kg groups. No deaths related to the treatment were observed. Tremor and polyuria were seen in the 50 mg/kg group. There were decrease in body weight gain, and increase in water consumption in the 1 and 50 mg/kg groups. In those dose groups of males, decrease in food consumption was observed. Ophthalmoscopic examination failed to show any abnormalities attributable to the treatment. Blood chemical examination disclosed decrease in total cholesterol in the 50 mg/kg group. There were also decreases in phospholipid in the 50 mg/kg group of females, and in triglyceride in the 1 and 50 ma/kg groups of males. Urinalysis and hematologic examination failed to show any abnormalities attributable to the treatment. In pathological examination, serous cell hypertrophy and increase in organ weight of the submandibular gland were observed in the 1 and 50 mg/kg groups, and increase in organ weight of thyroid was revealed in the 0.02 ma/kg group and over. The changes mentioned above were satisfactorily reversible except for the decrease in food consumption in the 50 mg/kg group of males. Increased thyroid weight in the 0.02 mg/kg group was considered to be of no toxicological significance. These results show that the NOAEL of montirelin hydrate is 0.02 mg/kg for 26-week repeated dose toxicity in rats.
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  • Robert J. HARLING, Chirukandath GOPINATH, Theodor MATTHIESEN, Seitaro ...
    1995 Volume 20 Issue SupplementII Pages 215-236
    Published: December 25, 1995
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A repeated dose toxicity study of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in beagle dogs. The dogs were given the drug intravenously for 4 weeks at doses of 0 (control), 0.0002, 0.002, 0.02, 0.2, 2 and 20 mg/kg in males and 0, 0.2, 2 and 20 mg/kg in females. After discontinuation of the treatment, a 4-week recovery test was also conducted in the 0 and 20 mg/kg groups. No deaths related to the treatment were observed. There were no changes in body weight gain, and food and water consumptions. Nasal discharge was seen in all dose groups. Salivation, emesis and hypoactivity were observed in the 0.2 mg/kg group and over. Licking chops were seen in the 2 and 20 mg/kg groups. Trembling and agitated/restless behavior were seen in the 20 mg/kg group. Electrocardiographic examination revealed elevated heart rate in the 0.2 mg/kg group and over. Ophthalmoscopic and hematologic examinations, and urinalysis failed to show any abnormalities attributable to the treatment. Blood chemical examination disclosed increases in T3 level in the 2 and 20 mg/kg groups of males and in T4 level in the 0.2 mg/kg group and over of males. There were no pathological findings attributable to the treatment. The changes mentioned above were satisfactorily reversible. The nasal discharge seen in the 0.02 mg/kg group and below was considered to be of no toxicological significance. These results show that the NOAEL of montirelin hydrate is 0.02 mg/kg for 4-week repeated dose toxicity in dogs.
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  • Seitaro ISHIBASHI, Yoshihito NISHIZAWA, Yuzou TANIGUCHI, Mikito KIKUMO ...
    1995 Volume 20 Issue SupplementII Pages 237-257
    Published: December 25, 1995
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A repeated dose toxicity study of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in beagle dogs. Male and female dogs were given the drug intravenously for 26 weeks at doses of 0 (control), 0.02, 0.2, 2 and 20 mg/kg. After discontinuation of the treatment, a 9-week recovery test was also conducted. No deaths related to the treatment were observed. Nasal discharge in all dose groups, and tremor, salivation and emesis in the 0.2 mg/kg group and over were seen. Decrease in body weight gain was observed in the 2 and 20 mg/kg groups. There were no abnormalities in body temperature, and food and water consumptions. Urinalysis and electrocardiographic, ophthalmoscopic and hematologic examinations failed to show any abnormalities attributable to the treatment. In blood chemical examination, increase in T3 level was observed in the 2 and 20 mg/kg groups of females. There were no pathological findings attributable to the treatment. The changes mentioned above were satisfactorily reversible. The nasal discharge seen in the 0.02 mg/kg group was considered to be of no toxicological significance. These results show that the NOAEL of montirelin hydrate is 0.02 mg/kg for 26-week repeated dose toxicity in dogs.
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  • Tagahiko MORINAGA, Shigenori FURUKAWA, Shigenobu FUJII, Mikito KIKUMOR ...
    1995 Volume 20 Issue SupplementII Pages 259-275
    Published: December 25, 1995
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A study of fertility and early embryonic development to implantation of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in Sprague-Dawley rats. Male rats were given the drug intravenously from 63 days before mating to the end of mating period and female rats from 14 days before mating to day 7 of pregnancy ; the dose levels for both males and females were 0 (control), 0.02, 1 and 50 mg/kg. The females were sacrificed on day 20 of pregnancy for examination of their fetuses. In the 50 mg/kg group, tremor, disappeared within some minutes, was observed during administration period in all animals. Food and water consumptions increased in the females and body weight gain was suppressed in the males. Moreover prolonged estrus cycle was observed at early period of the administration in the females, but it recovered at late period of the administration. However, there were no toxicities in the males and females in the 1 mg/kg or less groups. The drug had no adverse effects on reproductive function of the parent animals, or on development of fetuses. These results show that the NOAEL of montirelin hydrate are 1 mg/kg for general toxicity in parent animals, and 50 mg/kg for reproductive function of the parent animals and for development of fetuses.
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  • Masataka WATANABE, Isao TOTENO, Tagahiko MORINAGA, Shigenori FURUKAWA, ...
    1995 Volume 20 Issue SupplementII Pages 277-296
    Published: December 25, 1995
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A study of the effect of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, during the period of organogenesis was conducted in Sprague-Dawley rats. Female rats were given the drug intravenously at dose levels of 0 (control), 0.02, 1 and 50 ma/kg from day 7 to day 17 of pregnancy. Twenty-three or twenty-five female rats per dose level were sacrificed on day 20 of pregnancy for examination of their fetuses, and the pregnant rats (13-15 per dose levels) were allowed to deliver naturally for postnatal examination of their offspring. In the 1 or 50 mg/kg group, water consumption and the weights of adrenals of the dams increased and the weights of the thymus of the dams decreased. In addition, tremor, disappeared within some minutes, was observed from day 7 to day 16 of pregnancy in all dams given 50 mg/kg. Moreover, food consumption increased and the weights of the submaxillary glands of the dams given 50 mg/kg increased. The drug had no effect on the number of corpora lutea and implantations, on fetal mortality, on fetal body weights, on sex ratio, or on external, visceral and skeletal development of the fetuses. The drug also did not affect delivery. The drug did not have any adverse effected on the newborn such as the number of live newborns, birth index and body weights of live newborn, or on the postnatal development of the first generation offspring (F1) such as differentiation, functional development, emotionality, motor ability, learning ability or reproductive performance. The drug also had no adverse effects of the second generation offspring (F2). These results show that the NOAEL of montirelin hydrate are 0.02 mg/kg for general toxicity in mother animals, 50 mg/kg for pregnancy and delivery of mother animals and 50 mg/kg for development of their offspring.
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  • Tagahiko MORINAGA, Shigenori FURUKAWA, Shigenobu FUJII, Kimio YASUHIRA ...
    1995 Volume 20 Issue SupplementII Pages 297-307
    Published: December 25, 1995
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A study of the effect of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, during the period of organogenesis was conducted in New Zealand white rabbits. Female rabbits were given the drug intravenously at dose levels of 0 (control), 0.01, 0.1 and 1 ma/kg from day 6 to day 18 of pregnancy. Female rabbits were sacrificed on day 29 of pregnancy for examination of their fetuses. In the 0.1 mg/kg group, food consumption decreased slightly. In the 1 mg/kg group, tachypnea, salivation and rhinorrhea were observed, and body weight and food consumption decreased and water consumption increased. The drug had no effect on the number of corpora lutea and implantations, or on fetal mortality, on fetal body weights, on placental weight, on sex ratio, or on external, visceral and skeletal development of the fetuses. These results show that the NOAEL of montirelin hydrate are 0.1 mg/kg for general toxicity in mother animals, and 1 mg/kg for pregnancy of mother animals and for development of fetuses.
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  • Tagahiko MORINAGA, Shigenobu FUJII, Mikito KIKUMORI, Tsukao NISHIMORI, ...
    1995 Volume 20 Issue SupplementII Pages 309-323
    Published: December 25, 1995
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A study of the effect of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, during the perinatal and lactation periods was conducted in Sprague-Dawley rats. Female rats were given the drug intravenously at dose levels of 0 (control), 0.02, 1 and 50 ma/kg from day 17 of pregnancy to day 21 after delivery. All pregnant rats were allowed to deliver naturally for postnatal examination of their offspring. In the 1 and 50 mg/kg groups, food and water consumptions decreased after delivery and the weights of adrenals of the dams increased. In addition, tremor, disappeared within some minutes, was observed during administration period in all dams given 50 mg/kg. Moreover, body weight gain was suppressed after delivery, and the weights of submaxillary glands increased, and the weights of thymus and liver decreased in the dams given 50 mg/kg. The drug did not affect delivery. The drug did not have any adverse effects on the newborn including the number of live newborns, birth index and body weights of live newborn. In the 1 or 50 mg/kg group, body weight gains were suppressed and food consumption decreased in the offspring. The drug did not have any adverse effects on the postnatal development of the offspring such as differentiation, functional development, emotionality, motor ability, learning ability or reproductive performance. These results show that the NOAEL of montirelin hydrate are 0.02 mg/kg for general toxicity in mother animals, 50 mg/kg for reproductive function in mother animals and 0.02 mg/kg for their offspring.
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  • Keiko IWAKURA, Hironobu TAMURA, Yasuhiro YAMASHITA, Eita KITAYAMA, Yas ...
    1995 Volume 20 Issue SupplementII Pages 325-334
    Published: December 25, 1995
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was examined for mutagenicity in the reverse mutation test, the chromosome aberration test in vitro, and the micronucleus test in mice. The reverse mutation test was performed at dose range of 156.25-5, 000 μg/plate using Salmonella typhimurium strains, TA1535, TA100, TA1537, and TA98, and Escherichia coli WP2uvrA. The drug did not increase reverent colonies significantly in any of the test strains with or without metabolic activation system (S-9mix). The chromosome aberration test was carried out at dose range of 300-4, 800 μg/ml using cultured Chinese hamster lung cells (CHL/IU). No significant increases of the frequencies of cells with chromosomal aberrations were observed with or without metabolic activations. The micronucleus test was conducted in the bone marrow cells of Slc : ddY male mice. Mice were given the drug by a single intraperitoneal administration at doses of 0, 250, 500, 1, 000, and 2, 000 mg/kg. There were no significant increases in the frequencies of micronucleated polychromatic erythrocytes at any dose levels. These results show that montirelin hydrate has no mutagenic activity in vitro or in vivo.
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  • Ryoji SHIBATA, Tatsuya ISHII, Yasuyuki NISHIGUCHI, Keiko IWAKURA, Nobu ...
    1995 Volume 20 Issue SupplementII Pages 335-340
    Published: December 25, 1995
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A vascular irritability study of montirelin hydrate (NS-3) injection, a new drug for the treatment of disturbance of consciousness, was conducted in Japanese white rabbits. The concentration of montirelin hydrate was 4 mg/ml. Saline and 0.75% acetic acid were used as negative and positive control, respectively. In a part of the ear vein, 0.05 ml of each compound was allowed to remain for 3 min after intravenous injections once a day for 8 days. Inflammation in peri-venous region and thrombus were macroscopically observed in injection sites of rabbits with the montirelin hydrate injection group. However, no changes were seen with the negative control group. Histopathological examination revealed periphlebitis, desquamation of endothelial cells and thrombus in rabbits given montirelin hydrate injection or saline. But incidence and degree of periphlebitis caused by montirelin hydrate injection were higher than those caused by saline. On the other hand, the irritating changes caused by 0.75% acetic acid were severer than those by montirelin hydrate injection. These results show that montirelin hydrate injection has a very weak vascular irritability in the ear of rabbits.
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  • Hiroshi FUJISAWA, Takeshi NISHIMURA, Kiyoshi KIMURA
    1995 Volume 20 Issue SupplementII Pages 341-348
    Published: December 25, 1995
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    An antigenicity study of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in Hartley guinea pigs. Animals were sensitized twice by subcutaneous injections of montirelin hydrate in combination with Freund's complete adjuvant and twice by intramuscular injections of montirelin hydrate alone. Montirelin hydrate was found to be negative in the homologous passive cutaneous anaphylaxis test carried out with sera from the sensitized guinea pigs. Negative results were also obtained in the active cutaneous anaphylaxis test and the active systemic anaphylaxis test in guinea pigs sensitized with montilerin hydrate. These results show that montirelin hydrate has no antigenicity under the present experimental conditions.
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