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

描述（由申请人提供）：美国每年生产超过20亿磅氰化物，用于各种行业，因此平民意外或故意暴露于氰化物是一个真实的问题。目前氰化物中毒的治疗必须通过静脉注射，这限制了它们在大规模伤亡情况下的使用。在CounterACT计划的支持下，我们一直在开发维生素B12类似物cobinamide作为氰化物解毒剂，并发现它在几种动物中是一种非常有效的氰化物对策。由于其高效力，以及另外的高水溶性，可以通过肌内注射给予足够的量以将动物从两倍于LD 100的氰化物中拯救出来。Cobinamide在溶液中是稳定的，我们正在与一家公司进行认真的谈判，以将Cobinamide包装在自动注射器中。我们预计在2011年12月完成所有临床前化学和动物研究，并准备在2012年1月开始I期临床试验。我们将有足够的资金来完成临床前研究，通过免费延长目前的CounterACT赠款。作为一种氰化物解毒剂，可宾胺需要通过“动物规则途径”获得美国食品和药物管理局（FDA）的批准，该途径用于无法在人类中进行伦理上的疗效研究。在良好实验室规范（GLP）条件下进行的严格动物研究取代了II期和III期临床试验。因此，I期研究必须相应地更大，并包括la剂量递增和Ib扩展安全性研究。我们现在建议进行cobinamide的Ia期和Ib期研究，首先在健康成人中进行，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，老年人和肾功能受损的受试者。包括后一种受试者，因为可宾胺由肾脏排泄。在儿童研究之前，将在SRI International，门洛帕克，CA进行幼龄动物的毒理学和药代动力学研究。作为拟定工作的一部分，我们计划在Battelle Memorial Institute（辛辛那提，OH）对一种动物种属进行GLP疗效研究，并向FDA提交新药申请（NDA）。为了证明氯苯氨酰胺的疗效并确定其在人体中的相对效力，我们计划研究氯苯氨酰胺对吸烟者血液中氰化物和硫氰酸盐浓度的影响。在拟议的工作完成后，将可获得可宾酰胺，用于治疗大量接触氰化物的平民。 公共卫生相关性：氰化物是一种快速作用的毒药，需要立即治疗。目前的氰化物疗法不适合治疗大量中毒者。我们建议对一种新的氰化物解毒剂进行第一阶段临床试验，这种解毒剂可以通过肌肉注射迅速给予许多氰化物暴露的受害者。

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.