Testing the Vitamin B12 Analog Cobinamide Against Selected Chemical Threats

测试维生素 B12 类似物椰酰胺对选定化学威胁的影响

基本信息

批准号：
8214958
负责人：
GERRY R BOSS
金额：
$ 38.65万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-26 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8214958
关键词：
Adult Affinity Anabolism Animal Model Animals Antidotes Apoptotic Binding Biological Models Breathing Cell Death Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Charge Chemical Agents Chemicals Clinical Trials Cobalamin Cobalt Cultured Cells Cyanides Development Dose Drosophila melanogaster Drug Kinetics Effectiveness Exposure to Gases Goals Growth Human Human Cell Line Hydrazine Hydrogen Sulfide Hydroxocobalamin Hydroxyl Radical Injection of therapeutic agent Laboratories Larva Lead Left Ligand Binding Mammalian Cell Marketing Modeling Morbidity - disease rate Mus Oral Oryctolagus cuniculus Pathway interactions Peritoneal Pharmaceutical Preparations Phase Phase I Clinical Trials Poison Poisoning Positioning Attribute Rattus Research Research Personnel Resources Ribonucleotides Right-On Security Simulate Sodium Sodium Azide Solutions Structure Testing Toxic effect United States Food and Drug Administration Vitamin B 12 Water Work analog animal rule aqueous cell growth chemical binding clinical toxicology cobinamide corrin effective therapy egg fly in vivo interest meetings mortality mouse model pre-clinical programs randomized placebo controlled trial

项目摘要

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.

描述（由申请人提供）：恐怖袭击中可使用多种有毒化学品，美国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，对于这些化学物质中的许多，目前还没有可以在现场快速施用的特异性解毒剂。我们发现其中三种药剂——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，并且没有好的解毒剂——与钴酰胺（钴胺素的倒数第二个前体）以高亲和力结合。 B12) 生物合成。我们目前正在开发 Cobinamide 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方面非常有效。 Cobinamide 在剂量达 500 mg/kg 时对小鼠和大鼠无毒性，2009 年 6 月，我们与食品和药物管理局举行了新药研究前 (IND) 会议，讨论将 Cobinamide 用作药物的用途。氰化物解毒剂。我们预计在 2012 年冬季开始可滨酰胺的 I 期临床试验和关键动物研究。由于氰化物具有极高的毒性，因此不能用于人类，因此，可滨酰胺需要通过“动物规则途径”获得批准。 “其中在两种动物物种中进行的随机安慰剂对照研究取代了 II 期和 III 期临床试验。因此，可滨酰胺可能很快就会上市。如果它可以用作对抗氰化物之外的其他化学威胁剂的对策，那将非常有用。我们现在建议遵循与可宾酰胺作为氰化物解毒剂的早期开发阶段相同的范例，确定可宾酰胺是否可以用作肼、叠氮化钠和硫化氢的解毒剂。具体来说，我们计划确定可宾酰胺作为培养细胞和黑腹果蝇中这三种化学制剂的解毒剂的功效。如果可宾酰胺在这些模型系统中的一个或两个中均有效，那么我们将研究其在以下模型中的功效：致死小鼠模型。拟议的工作可能会导致针对目前尚无有效疗法的一种或多种化学威胁剂的治疗，从而允许使用一种解毒剂来对抗多种化学威胁。此外，由于大部分临床前毒理学和药代动力学研究以及一期临床试验已经完成，因此可以节省资源。公共健康相关性：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，目前尚无有效的解毒剂。我们已经证明，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、果蝇和小鼠中进行研究，以评估可宾酰胺对抗这三种有毒物质的功效。