Harumi UEDA

Tsumura & Co., Edo, Tōkyō, Japan

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Publications (6)8.48 Total impact

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    ABSTRACT: We examined the mechanism of the protective effect of sodium malate on cis-diamminedichloroplatinum(II) (cisplatin, CDDP)-induced nephrotoxicity in mice and obtained the following findings: 1: Sodium malate showed a maximum reduction of toxicity when it was administered at the same time as CDDP or at 30 min before the administration of CDDP; the reduction was significantly decreased when sodium malate was given after the administration of CDDP. 2: It is thought that diamminoplatinum(II) malate (DPM) is produced in the body following the administration of a combination of CDDP and sodium malate. DPM showed the same antitumor effect as CDDP and produced little nephrotoxicity. 3: When CDDP was combined with sodium malate, the time necessary for the elimination of platinum from the blood was prolonged, showing a intermediate value between the times for the elimination of CDDP and DPM from the blood. When the drug clearance was calculated based on this result, it was found that about 40% of the CDDP administered is converted to DPM in the blood. 4: In an experiment using L-[14C] malic acid, it was shown that sodium malate is distributed in the liver and the kidney at high concentrations, but in the tumor at only a low concentration. 5: When sodium malate was administered in combination with CDDP, the amount of platinum which accumulated in the kidney after 24 h was decreased by about 55% compared with the uncombined group, but there was no change in the amount of platinum which accumulated in the tumor. These results suggest that the sodium malate administered may be distributed rapidly in the blood and the tissue, and about 40% is bound to CDDP and converted to DPM, thus reducing the nephrotoxicity of CDDP.
    No preview · Article · Feb 1998 · Biological & Pharmaceutical Bulletin
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    ABSTRACT: The effects of oral treatment with sodium malate, an active ingredient of Juzen-taiho-to, on the nephrotoxicity, bone marrow toxicity, hepatotoxicity and gastrointestinal toxicity caused by i.p. administration of 9 doses of 3.0 mg/kg/d cisplatin (CDDP) (on days 3, 4, 5, 6, 7, 8, 10, 11 and 12) were examined in ddY mice inoculated with sarcoma 180 (S-180) cells on day 1 of the study. The CDDP-induced increases in blood urea nitrogen, serum creatinine, serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminases and relative stomach weight and the decreases in food intake and body weight were inhibited nearly to the control levels without reducing the antitumor activity of CDDP against S-180 by the oral treatment with sodium malate of 12 doses of more than the equimolar amount of CDDP (on days 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14 and 15). However, the CDDP-induced decreases in white blood cell and platelet counts and relative spleen and thymus weight could not be inhibited completely by combination with sodium malate, even at a dose of twice the equimolar amount of CDDP. The sodium malate-induced reduction of CDDP-induced nephrotoxicity and hepatotoxicity was observed after oral administration, as well as with i.p., s.c. and i.v. administration, and the effect was almost the same for each route of administration. Sodium malate also reduced the toxicity induced by high doses of CDDP (4.5, 6.0, 7.5, 9.0 and 12.0 mg/kg/d) at doses of twice the equimolar amount of CDDP. Sodium malate at a dose of 10.68 mg/kg/d (twice as high as carboplatin, CBDCA) did not reduce the nephrotoxicity, bone marrow toxicity, hepatotoxicity and gastrointestinal toxicity caused by i.p. administration of 9 doses of 15.0 mg/kg/d CBDCA on days 3, 4, 5, 6, 7, 8, 10, 11 and 12 in ddY mice inoculated with sarcoma 180 (S-180) cells on day 1 of the study. From this study, it was suggested that sodium malate could become a useful agent for the reduction of CDDP-induced toxicity, particularly nephrotoxicity and hepatotoxicity.
    No preview · Article · Feb 1998 · Biological & Pharmaceutical Bulletin
  • Kiyoshi SUGIYAMA · Harumi UEDA · Yoshimasa ICHIO
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    ABSTRACT: The effect of an oral treatment with the Kampo formulation Juzen-taiho-to on the toxicity caused by the intraperitoneal administration of 15 mg/kg carboplatin (CBDCA) 9 times (on days 3, 4, 5, 6, 7, 8, 10, 11 and 12) was examined in ddY mice, which were subcutaneously inoculated with sarcoma 180 (S-180) cells on day 1. White blood cell counts, platelet counts, bone marrow cell counts, relative spleen and thymus weight, food intake and body weight decreased significantly, to about 29%, 13%, 14%, 59%, 36%, 42% and 72% of the control levels, respectively, and serum glutamic-oxaloacetatic transaminase, serum glutamic-pyruvic transaminase and relative stomach weight increased significantly, to about 4, 6 and 3 times the control levels, respectively, by the treatment with CBDCA. However, the blood urea nitrogen and serum creatinine were only slightly increased compared to the control value. Co-treatment with 1.7 g/kg of a lyophilized water extract of Juzen-taiho-to once a day 12 times (on days 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14 and 15) prevented both the decreases and increases caused by CBDCA to near the control levels without reducing the antitumor activity of CBDCA against S-180. The inhibitory effect of Juzen-taiho-to against CBDCA-induced myelosuppression was similar to that against 3.0 mg/kg cisplatin (CDDP) 9 times, while CBDCA-induced myelosuppression was more serious in comparison with CDDP. Therefore, these findings indicate that Juzen-taiho-to could be an effective drug for protecting against the side effects induced by CBDCA in the clinic as well as by CDDP.
    No preview · Article · May 1995 · Biological & Pharmaceutical Bulletin
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    ABSTRACT: The effects of oral treatment with 1-, 5-, 10- and 20-fold the usual daily dose of Juzen-taiho-to on the nephrotoxicity, immunosuppression, hepatic toxicity and gastrointestinal toxicity caused by i.p. administration of 3.0 mg/kg cisplatin (CDDP) 9 times (on days 3, 4, 5, 6, 7, 8, 10, 11, and 12) were examined in ddY mice inoculated with sarcoma 180 (S-180) cells on day 1. The increase in blood urea nitrogen, serum creatinine, serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminases and relative stomach weight and decrease in white blood cell count, platelet count, relative spleen and thymus weight, food intake and body weight caused by CDDP were inhibited to nearly the control levels without reducing the antitumor activity of CDDP against S-180 by the oral treatment with either 10-fold (1.7 g/kg) or 20-fold (3.4 g/kg) the usual daily dose of Juzen-taiho-to 12 times (on days 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, and 15). All the mice receiving 4.5, 6.0, 7.5, 9.0, and 12.0 mg/kg CDDP died by day 12, while treatment with 3.4 g/kg Juzen-taiho-to efficiently prolonged the survival time. These findings indicate that Juzen-taiho-to may provide protection against most clinical toxicity caused by CDDP, and Juzen-taiho-to may allow us to administer a much higher dose of CDDP in clinical therapy.
    No preview · Article · Feb 1995 · Biological & Pharmaceutical Bulletin
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    ABSTRACT: The effects of ingredients of Shi-Quan-Da-Bu-Tang (Juzen-taiho-to) on the nephrotoxicity and bone marrow toxicity caused by i.p. administration of 3 mg/kg cis-diamminedichloroplatinum (II) (CDDP) 9 times (on days 3, 4, 5, 6, 7, 8, 10, 11, 12) were examined in ddY mice s.c. inoculated with sarcoma 180 (S-180) cells on day 1. Angelicae Radix showed the strongest protective effect against the toxicity among the ingredients. The ED50 of a water extract of Angelicae Radix was 17.8 mg/kg for nephrotoxicity (indicated by an increase in blood urea nitrogen) and 59.4 mg/kg for bone marrow toxicity (indicated by a decrease in white blood cell count), when it was administered perorally (p.o.) on days, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15. The water extract did not exert any significant effect on the antitumor activity of CDDP. Bioassay-directed fractionation of the water extract resulted in isolation of a constituent having protective effects against the toxicity: sodium L-malate, C4H4Na2O5, was found to exhibit protective effects against both nephrotoxicity (ED50: 0.4 mg/kg, p.o.) and bone marrow toxicity (ED50: 1.8 mg/kg, p.o.), without reducing the antitumor activity of CDDP. These findings indicate that Angelicae Radix and its constituent sodium L-malate could provide significant protection against CDDP-induced nephrotoxicity and bone marrow toxicity without reducing the antitumor activity.
    No preview · Article · Jan 1995 · CHEMICAL & PHARMACEUTICAL BULLETIN

  • No preview · Article · Dec 1991 · International Journal of Immunopharmacology