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20亿磅的氰化物用于各种工业，因此平民意外或故意暴露于氰化物是一个真正令人担忧的问题。目前氰化物中毒的治疗必须通过静脉注射，限制了其在大规模伤亡情况下的使用。在抵消计划的支持下，我们一直在研发维他命B12类似物cobinamide作为氰化物解毒剂，并发现它对几种动物具有极强的氰化物对抗作用。由于其效力高，而且水溶性高，通过肌肉注射给予足量的氰化物，可以使动物从LD100的两倍中获救。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，将Cobinamide包装在自动注射器中。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I期临床试验。我们将有足够的资金完成临床前研究，通过免费延长目前的抵消补助金。作为一种氰化物解毒剂，cobinamide将需要通过“动物规则途径”（Animal Rule Pathway）获得美国食品和药物管理局（FDA）的批准，这是在伦理上不能在人类身上进行功效研究时使用的。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。我们现在建议对cobinamide进行la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。后一种受试者也包括在内，因为复方甲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Battelle纪念研究所对一种动物进行GLP功效研究，并向FDA提交新药申请（NDA）。为了证明cobinamide的功效并确定其在人体中的相对效力，我们计划研究cobinamide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，将有可宾酰胺用于治疗大量接触氰化物的平民。

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.