Testing the Vitamin B12 Analog Cobinamide Against Selected Chemical Threats

描述（由申请人提供）：各种各样的有毒化学品可用于恐怖袭击，疾病控制中心和国土安全部列出了80多种潜在的化学威胁剂。不幸的是，许多这些化学品没有可以在现场快速施用的特定解毒剂。我们已经发现，三个这些代理商肼，叠氮化钠，硫化氢，所有这些都被认为是高度优先的化学威胁，并没有很好的解毒剂存在-结合高亲和力的钴胺，在钴胺素（维生素B12）生物合成的倒数第二个前体。我们目前正在开发可宾酰胺作为氰化物解毒剂，并发现它在培养的哺乳动物细胞、黑腹果蝇、小鼠和兔子中对中和氰化物非常有效。高达500 mg/kg剂量的Cobinamide对小鼠和大鼠无毒，并且在2009年6月，我们与美国食品药品监督管理局举行了关于使用Cobinamide作为氰化物解毒剂的新药（IND）研究前会议。我们预计将在2012年冬季开始考宾酰胺的I期临床试验和关键动物研究。由于氰化物的极端毒性，它不能用于人类，因此，cobinamide将需要通过“动物规则途径”获得批准，其中两种动物物种的随机安慰剂对照研究取代II期和III期临床试验。因此，可宾酰胺可以相对较快地在市场上获得。如果它能被用来对抗除氰化物之外的其他化学威胁剂，那将是非常有用的。我们现在建议，以确定是否可以使用cobinamide作为解毒剂对肼，叠氮化钠，硫化氢通过以下相同的范例，在早期开发阶段的cobinamide作为氰化物解毒剂。具体而言，我们计划确定cobinamide作为培养细胞和D.黑腹菌如果可宾酰胺在这两种模型系统中的任一种或两种中有效，我们将研究其在 致死小鼠模型。拟议的工作可能导致治疗一种或多种化学威胁剂，目前还没有有效的治疗方法，允许使用一种解毒剂来对抗一种以上的化学威胁。此外，由于大部分临床前毒理学和药代动力学研究以及I期临床试验已经完成，因此将节省资源。 公共卫生相关性：肼、叠氮化钠和硫化氢没有有效的解毒剂，这三种有毒化学物质是国土安全部和疾病控制中心定义的高优先级威胁剂。我们已经表明，这三种化学物质与维生素B12类似物cobinamide具有高亲和力，这表明cobinamide可以作为这些药物的解毒剂;我们现在建议在培养细胞，苍蝇和小鼠中进行研究，以评估cobinamide对这三种有毒药物的疗效。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: No effective antidotes are available for hydrazine, sodium azide, and hydrogen sulfide, three toxic chemicals that are high priority threat agents as defined by the Department of Homeland Security and the Center for Disease Control. We have shown that that these three chemicals bind with high affinity to cobinamide, a vitamin B12 analog, suggesting that cobinamide could serve as an antidote for these agents; we now propose to conduct studies in cultured cells, flies, and mice to evaluate cobinamide's efficacy against these three toxic agents.