Ueda H, Sugiyama K, Yokota M, Matsuno K, Ezaki T
Institute of Traditional Chinese Medicines, School of Pharmaceutical Sciences, University of Shizuoka, Yada, Japan.
Biol Pharm Bull. 1998 Jan;21(1):34-43. doi: 10.1248/bpb.21.34.
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.
在研究第1天接种肉瘤180（S-180）细胞的ddY小鼠中，研究了十全大补汤的活性成分苹果酸钠口服给药对腹腔注射9剂3.0mg/kg/d顺铂（CDDP）（第3、4、5、6、7、8、10、11和12天）所致肾毒性、骨髓毒性、肝毒性和胃肠道毒性的影响。口服12剂超过等摩尔量CDDP（第3、4、5、6、7、8、10、11、12、13、14和15天）的苹果酸钠，可将CDDP诱导的血尿素氮、血清肌酐、血清谷草转氨酶、血清谷丙转氨酶升高以及相对胃重量增加和食物摄入量及体重下降抑制至接近对照水平，且不降低CDDP对S-180的抗肿瘤活性。然而，即使苹果酸钠剂量为等摩尔量CDDP的两倍，联合使用也不能完全抑制CDDP诱导的白细胞和血小板计数以及相对脾脏和胸腺重量的下降。口服、腹腔注射、皮下注射和静脉注射苹果酸钠后，均观察到其对CDDP诱导的肾毒性和肝毒性的减轻作用，且各给药途径的效果几乎相同。苹果酸钠还能减轻高剂量CDDP（4.5、6.0、7.5、9.0和12.0mg/kg/d）诱导的毒性，剂量为等摩尔量CDDP的两倍。在研究第1天接种肉瘤180（S-180）细胞的ddY小鼠中，第3、4、5、6、7、8、10、11和12天腹腔注射9剂15.0mg/kg/d卡铂（CBDCA），剂量为10.68mg/kg/d（是卡铂的两倍）的苹果酸钠不能减轻其所致的肾毒性、骨髓毒性、肝毒性和胃肠道毒性。从本研究结果提示，苹果酸钠可能成为减轻CDDP诱导毒性，特别是肾毒性和肝毒性的有用药物。
