Pre-Clinical and Clinical Studies of Cobinamide, A New Cyanide Detoxifying Agent

描述(申请人提供)：美国每年生产超过20亿磅的氰化物，用于各种行业，因此平民意外或故意接触氰化物是一个真正令人担忧的问题。目前对氰化物中毒的治疗必须静脉注射，限制了其在大规模伤亡情况下的使用。在对抗计划的支持下，我们一直在开发维生素B12类似物椰子酰胺作为氰化物解毒剂，并发现它在几个动物物种中是一种非常有效的氰化物解毒剂。由于它的高效力，以及高度的水溶性，可以通过肌肉注射给予足够量的氰化物，以从两倍于LD100的氰化物中拯救动物。钴胺在溶液中是稳定的，我们正在与一家公司就在自动注射器中包装钴胺进行认真的谈判。我们预计在2011年12月之前完成所有临床前化学和动物研究，并准备在2012年1月开始第一阶段临床试验。我们将有足够的资金通过免费延长目前的ACCECT拨款来完成临床前研究。作为一种氰化物解毒剂，椰子酰胺需要得到美国食品和药物管理局(FDA)的批准，通过“动物规则路径”，当疗效研究不能在人类身上进行伦理研究时使用。严格的动物实验是在良好的实验室操作规范(GLP)条件下进行的，取代了第二阶段和第三阶段临床试验。因此，第一阶段研究必须相应地扩大，并包括La剂量递增和Ib扩展安全性研究。我们现在建议对可比胺进行1a和1b期研究，首先在健康的成年人中进行，然后在三个可能在平民灾难中暴露于氰化物的特殊人群中进行：儿童、老年人和肾脏受损的受试者。后者被包括在内，因为可比酰胺是由肾脏排泄的。在儿童研究之前，幼年动物的毒理学和药代动力学研究将在加利福尼亚州门洛帕克的SRI国际进行。作为拟议工作的一部分，我们计划在俄亥俄州辛辛那提的巴特尔纪念研究所进行GLP疗效研究，并向FDA提交新药申请(NDA)。为了证明椰子酰胺的疗效并确定其在人体内的相对效力，我们计划研究椰子酰胺对吸烟者血液氰化物和硫氰酸盐浓度的影响。在拟议的工作完成后，可比胺将可用于治疗大量接触氰化物的平民。 与公共卫生相关：氰化物是一种作用迅速的毒物，需要立即治疗。目前的氰化物疗法无法很好地治疗大量中毒者。我们建议进行一种新的氰化物解毒剂的I期临床试验，这种解毒剂可以通过肌肉注射迅速给许多接触氰化物的受害者使用。

DESCRIPTION (provided by applicant): Over two billion pounds of cyanide are produced annually in the United States for use in a variety of industries, and thus accidental or intentional exposure of civilians to cyanide is a real concern. Current treatments of cyanide poisoning must be given intravenously, limiting their use in a setting of mass casualties. Under support of the CounterACT Program, we have been developing the vitamin B12 analog cobinamide as a cyanide antidote, and have found it to be an extremely potent cyanide countermeasure in several animal species. Because of its high potency, and, additionally, high degree of water solubility, sufficient amounts can be given by intramuscular injection to rescue animals from two times the LD100 of cyanide. Cobinamide is stable in solution, and we are in serious negotiations with a company to package cobinamide in an autoinjector. We expect to have all preclinical chemical and animal studies completed by December, 2011, and be ready to embark on Phase I Clinical Trials in January, 2012. We will have sufficient funds to complete the preclinical studies through a no-cost extension of the current CounterACT grant. As a cyanide antidote, cobinamide will need to be approved by the Food and Drug Administration (FDA) through the "Animal Rule Pathway," which is used when efficacy studies cannot ethically be performed in humans. Rigorous animal studies conducted under Good Laboratory Practice (GLP) conditions substitute for Phase II and III clinical trials. Phase I studies must, therefore, be correspondingly larger, and include la dose escalation and Ib extended safety studies. We now propose to conduct Phase la and Ib studies of cobinamide, first in healthy adults, and then in three special populations that would likely be exposed to cyanide in a civilian disaster: children, the aged, and renal-impaired subjects. The latter subjects are included, because cobinamide is excreted by the kidneys. Prior to the studies in children, toxicology and pharmacokinetic studies in juvenile animals will be performed at SRI International, Menlo Park, CA. As part of the proposed work, we plan to conduct GLP efficacy studies in one animal species at Battelle Memorial Institute, Cincinnati, OH, and to submit a New Drug Application (NDA) to the FDA. To document cobinamide's efficacy and determine its relative potency in humans, we plan to study cobinamide's effects on blood cyanide and thiocyanate concentrations in cigarette smokers. At the completion of the proposed work, cobinamide would be available to treat a large number of civilians exposed to cyanide. Public Health Relevance: Cyanide is a rapidly acting poison that requires immediate treatment. Current cyanide therapies do not lend themselves well to treating a large number of poisoned persons. We propose to conduct Phase I clinical trials of a new cyanide antidote that could be given rapidly by intramuscular injection to many cyanide-exposed victims.