烷化剂的penclomedine诱发大鼠小脑浦肯野细胞的退化。
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O ' reilly年代,奥赫恩E,射频,Rowinsky EK, Molliver我
烷化剂的penclomedine诱发大鼠小脑浦肯野细胞的退化。
新药投资。2003年8月,21 (3):269 - 79。
- PubMed ID
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14578677 (在PubMed]
- 文摘
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目的:Penclomedine(笔),multichlorinated alpha-picoline导数代谢高活性烷基化的物种,被选为临床开发由于其突出的活动与多种人类肿瘤异种移植时管理像双亲地或口服。其主要毒性dose-limiting neurocerebellar毒性在临床前和临床研究,已与等离子体的钢笔浓度峰值的大小,而不是等离子体浓度的主要假定的烷基化代谢物,4,o-demethylpenclomedine (DMPEN)。这些观察,以及笔的毒素的药物,和组织分布资料,表明母体化合物主要负责小脑毒性。在这个报告中描述的研究进行描述的神经病理学笔神经毒性,长期目标的发展战略,以最大化其治疗指数。设计:男性Sprague-Dawley老鼠接受相关治疗剂量的笔,口服和腹腔内(i.p),在各种管理计划,和DMPEN i.p管理。神经毒性的动物被监控,和大脑部分神经病理学检查,特别是浦肯野细胞损失和神经损伤。大脑部分是使用标准的组织化学染色技术和应用OX-42检测小胶质细胞被激活后神经元损伤,和calbindin D (28 k),钙结合蛋白表达的小脑浦肯野细胞。结果:剂量neurocerebellar毒性与旁矢状面的乐队的浦肯野细胞变性和在大鼠小胶质激活在小脑蚓部明显处理笔100 - 400毫克/公斤ip单剂量。神经损伤大脑的其他地区没有被观察到。此外,临床和组织病理学的证据在大鼠小脑毒性是明显处理类似的总剂量笔管理ip dailyx5-day剂量的时间表。相似的组织学研究,在一个相同的神经解剖学的分布,观察大鼠笔口头处理; however, the magnitude of the neuronal toxicity was much less than in animals treated with equivalent doses of PEN administered i.p. Although acute lethality occurred in some rats treated with equimolar doses of DMPEN as a single i.p. treatment, surviving animals exhibited neither signs nor histopathological evidence of neurocerebellar toxicity. CONCLUSIONS: PEN produces selective dose- and schedule-dependent Purkinje cell degeneration in the cerebellar vermis of rats, whereas therapeutically relevant doses of PEN administered orally are better tolerated and produce less neurocerebellar toxicity. In addition, roughly equivalent, albeit intolerable, doses of the major active metabolite DMPEN, which was lethal to some animals, produced neither clinical manifestations of neurocerebellar toxicity nor Purkinje cell loss. These results support a rationale for investigating whether PEN administered orally, which may undergo significant first-pass metabolism to DMPEN and other less toxic intermediates, or treatment with DMPEN, itself, may result in less neurocerebellar toxicity and superior therapeutic indices than PEN administered parenterally.
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- 药物