Testing the Vitamin B12 Analog Cobinamide Against Selected Chemical Threats

描述(申请人提供)：各种各样的有毒化学物质可用于恐怖袭击，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物质。不幸的是，可以在现场快速给药的特定解毒剂对这些化学物质中的许多都没有。我们发现，其中三种试剂--肼、叠氮钠和硫化氢--都被认为是高度优先的化学威胁，并且没有好的解毒剂--与钴胺(钴(维生素B12)生物合成的倒数第二个前体)有很高的亲和力。我们目前正在开发椰子酰胺作为氰化物解毒剂，并发现它在培养的哺乳动物细胞、黑腹果蝇以及小鼠和兔子中和氰化物非常有效。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，我们与美国食品和药物管理局(FDA)就使用考宾胺作为氰化物解毒剂举行了新药预调查会议。我们预计在2012年冬季之前开始可比胺的I期临床试验和关键的动物实验。由于氰化物的极端毒性，它不能用于人类，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，在两个动物物种上进行的随机安慰剂对照研究取代了第二阶段和第三阶段临床试验。因此，可比酰胺可能很快就会上市。如果它能被用作对抗氰化物以外的其他化学威胁物质的对策，那将是非常有用的。我们现在建议通过遵循与早期开发阶段作为氰化物解毒剂的可比酰胺相同的范例来确定可比酰胺是否可以用作联氨、叠氮钠和硫化氢的解毒剂。具体地说，我们计划在培养细胞和黑腹葡萄球菌中确定椰子酰胺作为这三种化学制剂的解毒剂的有效性。如果可比酰胺在这两个模型系统中的一个或两个中都有效，那么我们将在一个 致命的小鼠模型。这项拟议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，使一种解毒剂能够用于对抗多种化学威胁。此外，由于大多数临床前毒理学和药代动力学研究以及第一阶段临床试验都已经完成，因此将节省资源。 与公共健康相关：肼、叠氮化钠和硫化氢这三种有毒化学物质被国土安全部和疾病控制中心定义为高度优先的威胁物质，目前还没有有效的解毒剂可用。我们已经证明这三种化学物质与维生素B12类似物可比酰胺具有高亲和力，这表明可比酰胺可以作为这些毒剂的解毒剂；我们现在建议在培养细胞、苍蝇和小鼠中进行研究，以评估可比酰胺对这三种有毒物质的疗效。

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.