LETHAL NEPHROTOXICITY AND HEMATOLOGIC TOXICITY OF CIS-DIAMMINEDICHLOROPLATINUM AMELIORATED BY OPTIMAL CIRCADIAN TIMING AND HYDRATION
LETHAL NEPHROTOXICITY AND HEMATOLOGIC TOXICITY OF CIS-DIAMMINEDICHLOROPLATINUM AMELIORATED BY OPTIMAL CIRCADIAN TIMING AND HYDRATION
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DOI：
10.1016/0277-5379(82)90116-x
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发表时间：
1982-01-01
期刊：
影响因子：
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通讯作者：
KENNEDY, BJ
中科院分区：
文献类型：
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作者：
LEVI, FA;HRUSHESKY, WJM;KENNEDY, BJ
雌性F344（Fischer）大鼠（n = 341）在光照下保持8 h，黑暗交替保持16 h;在单次腹膜内注射11 mg/kg顺式二氨二氯铂（cis-DDP）后，观察一些大鼠存活21天，而另一些大鼠在4.5天后处死采集血样。在6个等节奏昼夜节律阶段中的一个阶段，在伴随或不伴随腹膜内生理盐水负荷的情况下施用顺式DDP。这种高剂量的顺式DDP导致显著的致死性和肾毒性，但在中度骨髓抑制。血尿素氮（BUN）、循环总白色细胞计数（WBC）和生存时间显示药物毒性的昼夜节律性（P < 0.03）。通过这3个变量衡量的顺式DDP的最佳耐受性来自暗期后半期的给药。通过适当的给药时机，以BUN为指标的顺式DDP肾耐受性提高了2倍。如果在最佳昼夜节律阶段给予水合和顺式DDP，则单独药物时机的益处进一步提高2倍。水化诱导的顺式DDP肾毒性减轻需要水化和顺式DDP的时间确认。
Female F344 (Fischer) rats (n = 341) were kept in light for 8 h alternating with darkness for 16 h; some were observed for survival for 21 days while others were killed for blood sampling 4.5 days after a single i.p. injection of 11mg/kg cis-diamminedichloroplatinum (cis-DDP). cis-DDP was administered with or without concomitant i.p. saline load at one of 6 equispaced circadian stages. This high dose of cis-DDP resulted in marked lethal and renal toxicity, but in a moderate bone marrow suppression. Blood urea nitrogen (BUN), circulating total white blood cell counts (WBC) and survival times revealed statistically significant circadian rhythms of drug toxicity (P < 0.03). Optimal tolerance for cis-DDP gauged by these 3 variables resulted from drug administration in the 2nd half of the dark span. Renal tolerance for cis-DDP gauged by BUN was improved 2-fold by appropriate drug timing. This benefit from drug timing alone was further improved 2-fold if hydration and cis-DDP were given at the optimal circadian stage. Hydration-induced ameloriation of cis-DDP nephrotoxicity requires time qualification of both hydration and cis-DDP.