Testing the Vitamin B12 Analog Cobinamide Against Selected Chemical Threats

摘要 与疾病控制中心合作，恐怖袭击中可能会使用多种有毒化学物质 国土安全部列出了80多种潜在的化学威胁物质。不幸的是， 可在现场快速给药的特定解毒剂对其中许多没有 化学制品。我们发现其中三种试剂--肼、叠氮化钠和硫化氢， 所有这些都被认为是高度优先的化学威胁，而且没有好的解毒剂--与 对钴胺的高亲和力，这是钴胺(维生素B12)生物合成的倒数第二个前体。我们是 目前正在开发椰子酰胺作为氰化物解毒剂，并发现它在 中和培养的哺乳动物细胞、果蝇、小鼠和兔子中的氰化物。 考宾胺对小鼠和大鼠无毒，剂量不超过500毫克/公斤，2009年6月，我们进行了一次预- 调查人员新药(IND)与美国食品和药物管理局(FDA)就使用 作为氰化物解毒剂的椰子酰胺。我们期待启动I期临床试验和关键动物 2012年冬季之前的可比胺研究。由于氰化物的极端毒性，它不能被给予 人类，因此，可比胺将需要通过“动物规则路径”获得批准，在该路径中 两种动物的随机安慰剂对照研究取代了II期和III期临床试验。 因此，可比酰胺可能很快就会上市。它将是非常有用的如果它 除氰化物外，还可用作对抗其他化学威胁剂。我们现在 建议确定可比酰胺是否可用作联氨、叠氮化钠和 硫化氢，遵循与可比酰胺早期开发阶段相同的范例 作为氰化物解毒剂。具体地说，我们计划确定可比酰胺作为对抗疾病的解毒剂的有效性。 这三种化学药剂在培养细胞和黑腹盘藻中均有存在。如果可比胺对或有效 这两个模型系统，然后我们将研究其在一个致命的小鼠模型的效果。拟议中的工作 可能导致治疗一种或多种目前尚无有效治疗方法的化学威胁剂 存在，允许一种解毒剂用于对抗多种化学威胁。此外，资源将 因为大多数临床前毒理学和药代动力学研究，以及I期 临床试验，将已经完成。

SUMMARY A wide variety of toxic chemicals could be used in a terrorist attack, with the Centers for Disease Control and the Department of Homeland Security listing over 80 potential chemical threat agents. Unfortunately, specific antidotes that can be administered quickly in the field are not available for many of these chemicals. We have found that three of these agents-hydrazine, sodium azide, and hydrogen sulfide, all of which are considered high priority chemical threats and for which no good antidote exists--bind with high affinity to cobinamide, the penultimate precursor in cobalamin (vitamin B12) biosynthesis. We are currently developing cobinamide as a cyanide antidote, and have found it to be extremely effective at neutralizing cyanide in cultured mammalian cells, Drosophila melanogaster, and mice and rabbits. Cobinamide is non-toxic to mice and rats up to doses of 500 mg/kg, and, in June, 2009, we had a pre- Investigators New Drug (IND) meeting with the Food and Drug Administration concerning the use of cobinamide as a cyanide antidote. We anticipate starting Phase I Clinical Trials and pivotal animal studies of cobinamide by Winter, 2012. Because of the extreme toxicity of cyanide, it cannot be given to humans, and, thus, cobinamide will need to be approved through the "Animal Rule Pathway, " in which randomized placebo-controlled studies in two animal species replace Phase II and III Clinical Trials. Thus, cobinamide could become available on the market relatively soon. It would be extremely useful if it could be used as a countermeasure against other chemical threat agents in addition to cyanide. We now propose to determine if cobinamide can be used as an antidote against hydrazine, sodium azide, and hydrogen sulfide by following the same paradigm as during the early development phase of cobinamide as a cyanide antidote. Specifically, we plan to determine cobinamide's efficacy as an antidote against these three chemical agents in cultured cells and D. melanogaster. If cobinamide is effective in either or both these model systems, we will then study its efficacy in a lethal mouse model. The proposed work could lead to a treatment for one or more chemical threat agent for which no effective therapy currently exists, allowing one antidote to be used against more than one chemical threat. Moreover, resources will be saved because most of the pre-clinical toxicology and pharmacokinetic studies, and the Phase I Clinical Trials, will have already been done.