Gralla E J, Coleman G L, Osbaldiston W, Sawicki W L, Jonas R M, Bertino J R
Cancer Chemother Rep. 1975 May-Jun;59(3):523-30.
The effects of the intravenous administration of triazinate by single and multiple injections were studied in beagle dogs and rhesus monkeys. In dogs, dose levels ranging from 0.3125 to 40 mg/kg were given either as single doses daily for 5 days, or once weekly for 6 weeks. The 5-day regimen was also studied in monkeys with dose levels from 2.5 to 40 mg/kg/day. Prominent drug-related and drug-dependent effects which appeared in both species were piloerection, muscular weakness, and respiratory difficulty which occurred during and immediately after the administration of dose levels of 10 mg/kg or greater. Gastrointestinal toxicity was severe in dogs but mild in monkeys. Lymphoid tissue toxicity was manifested by a circulating lymphopenia and localized cellular depletion in the germinal centers of lymphoid tissues. In dogs, signs of bone marrow toxicity consisted of a circulating neutropenia and, at necropsy, a reduction in the number of erythroid and myeloid elements plus megaloblastosis. Only the latter change was observed in monkeys. This difference in the hematopoietic toxicity between the beagle dog and the rhesus monkey was corroborated by the findings from in vitro studies with bone marrow. DNA synthesis in beagle bone marrow cells was depressed significantly by triazinate as compared with cells from rhesus marrow. A direct renal toxic effect was observed in monkeys given high doses of triazinate (20 and 40 mg/kg/day or 240-280 mg/m/day) for 5 days.
通过单次和多次注射静脉给予三嗪酸酯的效果在比格犬和恒河猴中进行了研究。在犬中，剂量水平范围为0.3125至40mg/kg，每天单次给药，持续5天，或每周一次，持续6周。在猴子中也研究了5天给药方案，剂量水平为2.5至40mg/kg/天。在两个物种中出现的与药物相关和药物依赖性的显著效应是竖毛、肌肉无力和呼吸困难，这些效应在给予10mg/kg或更高剂量水平期间及给药后立即出现。胃肠道毒性在犬中严重，但在猴子中轻微。淋巴组织毒性表现为循环淋巴细胞减少和淋巴组织生发中心的局部细胞耗竭。在犬中，骨髓毒性的迹象包括循环中性粒细胞减少，尸检时红系和髓系细胞数量减少以及巨幼细胞形成。在猴子中仅观察到后一种变化。比格犬和恒河猴造血毒性的这种差异通过骨髓体外研究的结果得到证实。与恒河猴骨髓细胞相比，三嗪酸酯显著抑制比格犬骨髓细胞中的DNA合成。在给予高剂量三嗪酸酯（20和40mg/kg/天或240 - 280mg/m/天）5天的猴子中观察到直接的肾毒性作用。
