A New Orally Active, Aminothiol Radioprotector-Free of Nausea and Hypotension Side Effects at Its Highest Radioprotective Doses
A New Orally Active, Aminothiol Radioprotector-Free of Nausea and Hypotension Side Effects at Its Highest Radioprotective Doses
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DOI：
10.1016/j.ijrobp.2011.11.038
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发表时间：
2012-04-01
影响因子：
7
通讯作者：
Fahl, William E.
中科院分区：
文献类型：
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作者：
Soref, Cheryl M.;Hacker, Timothy A.;Fahl, William E.
目的：对一种新的氨基硫醇PrC-210进行了口服放射防护试验（大鼠，小鼠; 9.0戈伊全身，否则对100%的动物是致命的）和存在使人衰弱的副作用（恶心/呕吐，低血压/昏厥），限制使用目前的氨基硫醇，氨磷汀（Ethyol，WR-2721）。方法和材料：在照射前的时间将PrC-210水溶液给予大鼠和小鼠，并记录60天的存活率。将皮下（SC）氨磷汀（阳性对照）或SC PrC-210施用于雪貂（Mustela putorius furo），并记录干呕/呕吐反应。向动脉插管大鼠腹腔内注射氨磷汀（阳性对照）或PrC-210，以对药物诱导的低血压进行评分。结果：口服PrC-210使大鼠和小鼠模型在100%致死的全身辐射剂量（9.0戈伊）下获得100%的存活率。在照射前30 - 90 min经口灌胃给予PrC-210，可提供较宽的辐射防护窗口。PrC-210和氨磷汀副作用的比较是惊人的，因为在用PrC-210处理的10只雪貂中没有干呕或呕吐，并且在用PrC-210处理的动脉插管大鼠中没有诱导性低血压。测试的PrC-210剂量是小鼠中0.5最大耐受剂量（MTD）PrC-210剂量的雪貂和大鼠等效剂量。该小鼠0.5 MTD PrC-210剂量的人体等效剂量可能是用于人体的最高PrC-210剂量。通过比较，小鼠0.5 MTD氨磷汀剂量，400 mg/g体重（相当于人氨磷汀剂量910 mg/m2），当在上述模型中以相同的雪貂和大鼠剂量进行测试时，雪貂100%出现干呕/呕吐，大鼠100%发生显著的进行性低血压。PrC-210氨基硫醇在这些临床前模型中没有可检测到的恶心/呕吐或低血压副作用，是人类药物开发的合理候选药物，可用于各种辐射防护环境中的健康人体，包括医疗辐射，太空旅行和核事故。(C)2012 Elsevier Inc.
Purpose: A new aminothiol, PrC-210, was tested for orally conferred radioprotection (rats, mice; 9.0 Gy whole-body, which was otherwise lethal to 100% of the animals) and presence of the debilitating side effects (nausea/vomiting, hypotension/fainting) that restrict use of the current aminothiol, amifostine (Ethyol, WR-2721).Methods and Materials: PrC-210 in water was administered to rats and mice at times before irradiation, and percent-survival was recorded for 60 days. Subcutaneous (SC) amifostine (positive control) or SC PrC-210 was administered to ferrets (Mustela putorius furo) and retching/emesis responses were recorded. Intraperitoneal amifostine (positive control) or PrC-210 was administered to arterial cannulated rats to score drug-induced hypotension.Results: Oral PrC-210 conferred 100% survival in rat and mouse models against an otherwise 100% lethal whole-body radiation dose (9.0 Gy). Oral PrC-210, administered by gavage 30 -90 min before irradiation, conferred a broad window of radioprotection. The comparison of PrC-210 and amifostine side effects was striking because there was no retching or emesis in 10 ferrets treated with PrC-210 and no induced hypotension in arterial cannulated rats treated with PrC-210. The tested PrC-210 doses were the ferret and rat equivalent doses of the 0.5 maximum tolerated dose (MTD) PrC-210 dose in mice. The human equivalent of this mouse 0.5 MTD PrC-210 dose would likely be the highest PrC-210 dose used in humans. By comparison, the mouse 0.5 MTD amifostine dose, 400 mg/g body weight (equivalent to the human amifostine dose of 910 mg/m(2)), when tested at equivalent ferret and rat doses in the above models produced 100% retching/vomiting in ferrets and 100% incidence of significant, progressive hypotension in rats.Conclusions: The PrC-210 aminothiol, with no detectable nausea/vomiting or hypotension side effects in these preclinical models, is a logical candidate for human drug development to use in healthy humans in a wide variety of radioprotection settings, including medical radiation, space travel, and nuclear accidents. (C) 2012 Elsevier Inc.