Captopril and losartan for mitigation of renal injury caused by single-dose total-body irradiation.
Captopril and losartan for mitigation of renal injury caused by single-dose total-body irradiation.
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DOI：
10.1667/rr2400.1
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发表时间：
2011-01
影响因子：
3.4
通讯作者：
Fish BL
中科院分区：
文献类型：
--
作者：
Moulder JE;Cohen EP;Fish BL
众所周知，血管紧张素转换酶抑制剂（ACEIs）和血管紧张素II型1受体阻滞剂（ARBs）可用于减轻辐射引起的肾损伤。然而，由于各种原因，这些先前的结果不能直接适用于开发减轻与恐怖主义有关的辐射照射所造成伤害的药剂。作为开发符合美国食品和药物管理局（FDA）“动物功效规则”要求的动物模型的一部分，我们设计了新的研究，使用FDA批准的ACEI（卡托普利）或FDA批准的ARB（氯沙坦，Cozaar®）在单次全身照射（TBI）后10天开始，药物剂量相当于（以g/m2/天为基础）规定给人的剂量。卡托普利和氯沙坦作为缓缓剂同样有效，延迟肾功能衰竭的dmf分别为1.23和1.21。这些研究表明，在现实的啮齿动物模型中，放射性肾病可以通过相关剂量的fda批准的药物得到缓解。这为FDA动物功效规则下的关键啮齿动物研究奠定了必要的基础，并提供了如何设计FDA要求的大型动物研究的大纲。
It is known that angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) can be used to mitigate radiation-induced renal injury. However, for a variety of reasons, these previous results are not directly applicable to the development of agents for the mitigation of injuries caused by terrorism-related radiation exposure. As part of an effort to develop an animal model that would fit the requirements of the U.S. Food and Drug Administration (FDA) “Animal Efficacy Rule”, we designed new studies which used an FDA-approved ACEI (captopril) or an FDA-approved ARB (losartan, Cozaar®) started 10 days after a single total-body irradiation (TBI) at drug doses that are equivalent (on a g/m2/day basis) to the doses prescribed to humans. Captopril and losartan were equally effective as mitigators, with DMFs of 1.23 and 1.21, respectively, for delaying renal failure. These studies show that radiation nephropathy in a realistic rodent model can be mitigated with relevant doses of FDA-approved agents. This lays the necessary groundwork for pivotal rodent studies under the FDA Animal Efficacy Rule and provides an outline of how the FDA-required large-animal studies could be designed.