The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 18 , Issue 4
Showing 1-6 articles out of 6 articles from the selected issue
  • Ryuichi KATO, David E. CASE, Hideo HAKUSUI, Kosei NODA, Fumio SAGAMI, ...
    1993 Volume 18 Issue 4 Pages 211-238
    Published: November 25, 1993
    Released: February 21, 2008
    JOURNALS FREE ACCESS
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  • Takako UEDA, Yoshie TOYOSHIMA, Tamio KUSHIHASHI, Toyohiko HISHIDA, Haj ...
    1993 Volume 18 Issue 4 Pages 239-244
    Published: November 25, 1993
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    We investigated the effects of dimethyl sulfoxide (DMSO) on radiation damage in the mouse. DMSO(i.p.0.11g/mouse)administered 30 min before exposure protected the mice from the gamma-whole body irradiation:the 30 days lethality was significantly decreased from 44% to 16%(P<0.55). The contents of thiobarbituric acid reative substances(TBA-RS)in the mouse liver increased linearly between days 2 and 10 after 9 Gy gamma ray irradiation. The TBA-RS contents in the liver on days 2 to 10 after irradiation were reduced by DMSO pretreatment. The irradiation decreased superoxide dismutase(SOD)activity in the liver on day 10. Decrease in SOD activity was prevented by DMSO pretreatment. In the electron microscopic study, the mitochondria in the irradiated mouse liver were swollen, but we could observe no change after DMSO pretreatment. The results suggest that DMSO has radioprotective effects, probably due to inhibition of lipid peroxidation.
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  • Michishige NOGUCHI, Koki TANAKA, Yuki KUWAMURA, Tomiko FUKUSHIMA, Yosh ...
    1993 Volume 18 Issue 4 Pages 245-255
    Published: November 25, 1993
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The toxicokinetic parameters of phenobarbital(PB) were assessed in a female rat model of liver disease. In a preliminary study to determine the optimum dose of DL-ethionine(ET) for creating liver damage, intraperitoneal injection of 250, 500, or 1, 000 mg/kg of ET was done for 4 days. ET treatment caused an increase in serum GOT and GPT activity and a decrease in the serum glucose concentration. In the liver, triglycerides and free fatty acids were increased and glucose and S-adenosyl-methionine(SAM) were decreased. Histologic examination revealed diffuse fatty degeneration of the hepatocytes. These findings accorded with those already reported as characteristic of ET intoxication. The toxicokinetic parameters for PB were determined after oral or intravenous administration of 100 mg/kg of PB to rats with ET (500 mg/kg, i.p.)-induced hepatotoxicity. After oral administration of PB, prolongation of the Tmax, increased AUC0, and decreased ke and CL values were noted in ET-treated rats. When PB was given intravenously, the AUC0 was increased while the values of α, β and CL were decreased. A high level of urinary excretion of PB persisted for 48 hr. Protein binding of PB was unchanged in ET-treated animals, but the extent of bioavailability of PB tended to increase. These results indicate that elimination of PB was impaired in the ET-treated rats.
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  • Toshiyuki FUJII, Yuji OISHI, Shiro FUJIHIRA, Masahiko MATSUO, Masaaki ...
    1993 Volume 18 Issue 4 Pages 257-263
    Published: November 25, 1993
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    In the present study, gastric pH was lowered by hydrochloric acid to investigate whether the cause of enterochromaffin-like(ECL) cell hyperplasia was due to the inhibition of acid secretion by omeprazole or due to the direct action of the drug. Omeprazole was given to female Crj:CD(SD) rats in a daily oral dose of 2 or 8 mg/kg for 13 weeks, and 20 ml/kg of 0.12 N HCl was further given orally to the animals 3 and 6 hours after each dosing. The animals were killed at the end of the dosing period, and the stomach was removed and weighed. The thickness of the gastric wall was measured and ECL cell count and area rate of the cells were calculated with an image analyzer. There were no effects of the treatment with HCl on stomach weight or thickness of the gastric wall, but ECL cell count and area rate of the cells decreased markedly by the treatment with HCl. Therefore, the cause of gastric ECL cell hyperplasia induced by omeprazole was suggested to be sustained high gastric pH levels.
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  • Sachiko UEHARA, Toshihiko HIROMORI, Naohiko ISOBE, Takashi SUZUKI, Ter ...
    1993 Volume 18 Issue 4 Pages 265-275
    Published: November 25, 1993
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The metabolic fate of 2-PAM and its antidotal effect on organophosphorus compound poisoning in rats were studied. When 14C-2-PAM was administered intravenously, the amount of 14C reaching the brain was small. Following administration by intramedullary injection, 14C was present in high concentrations in the brain, and 72-90% of the 14C present in the brain corresponded to the unchanged form of 2-PAM. 2-PAM was rapidly excreted into the urine and feces following either intramedullary or intravenous administration. The half-life of 2-PAM in the brain following intramedullary administration was 1.52 hr. Intramedullary administration of 2-PAM to rats poisoned with fenitrothion or malathion enabled their survival and induced reactivation of brain cholinesterase.
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  • [in Japanese], [in Japanese], [in Japanese]
    1993 Volume 18 Issue 4 Pages App4-App23
    Published: November 25, 1993
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    In the present review, we will present a method for the prediction of a maximal tolerated dose, MTD, of anititumor drugs in humans based on toxicokinetic, pharmacodynamic and toxicodynamic informations obtained from findings in the literature and our previous studies. This method may be useful in conducting a clinical study of a new antitumor drug efficiently and performing a cancer chemotherapy at a proper dosage schedule. Antitumor drugs can be classified into two types, depending on their cytotoxic mechanisms, type 1 drugs, cell cycle phase-nonspeciffc agents, i.e., area under the curve for drug concentration versus time (AUC)-dependent drugs, and type 2 drugs, cell cycle phase-specific agents, i.e., those that are exposure time-dependent. There was an excellent correlation between mouse AUC at LD10 and human AUC at MTD in comparison with that between mouse LD10 and human MTD for type 1 drugs but not for type 2 drugs. For type 1 drugs, the correlation between mouse AUC at LD10 and human AUC at MTD was better for unbound than for total drug. Pharmacokinetically guided dose escalation strategy proposed by Collins et al.is useful for type 1 drugs; species differences in protein binding should, however, be considered.
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