Countermeasures Against Chemical Threats: Countermeasures Against Cyanide

说明(申请人提供)：平民和军事人员可能接触氰化物的来源包括燃烧含氮材料、商业事故和故意释放含氰化学品。获取和释放氰化物相对容易，这意味着在恐怖袭击中使用氰化物造成大规模伤亡的风险不应被忽视。对于氰化物暴露的情况，快速干预对于有效的医疗干预至关重要：治疗需要“三分钟解决方案”。一种快速的IM可注射解毒剂的可用性应该满足这一要求。然而，目前还没有这样的治疗方法--目前的氰化物解毒剂是通过静脉注射的。因为静脉注射很耗时，需要训练有素的医务人员，大量接触氰化物很可能会让许多受害者得不到治疗。由于IM管理可以通过自动注射器执行，因此可以由受过最低程度培训的人员快速完成，因此迫切需要一种快速有效的IM可注射解毒剂来治疗大规模氰化物伤亡。为了满足这一需求，我们正在推进我们的临床前先导磺胺类药物的临床开发。我们之前已经在小鼠、猪和兔的氰化物中毒模型中证明了磺胺的有效性。在这些模型中，磺胺根在肌肉注射逆转氰化物毒性方面是有效的，因此应该满足三分钟的溶液。我们最近与FDA举行了IND前会议，我们的目标是通过动物模型的验证将这种氰化物拮抗剂推向临床，在这些动物模型中证明磺胺类药物的有效性，并进行临床试验所需的GLP药代动力学和安全性评估。然后，我们将开始第一阶段的人类安全研究，同时根据动物规则进行所需的GLP研究，以提交NDA。本项目目标的圆满完成将导致针对氰化物毒性的临床对策，该对策将适用于从个人到大规模伤亡环境的所有氰化物接触案例。 公众健康：我们发现了一种新的氰化物解毒剂，我们将其命名为磺胺根，并证明在氰化物中毒模型中，它比现有的解毒剂更有效。我们将进行必要的研究，将这种解毒剂从替补席上转移到床边。因此，成功完成这一项目的目标将产生一种临床解毒剂，在发生涉及氰化物的恐怖袭击时可能有用。

DESCRIPTION (provided by applicant): Sources for potential exposure to cyanide of both civilians and military personnel include combustion of nitrogenous materials, commercial accidents and the deliberate release of a cyanogenic chemical. The relative ease in obtaining and releasing cyanide means that the risk of cyanide use in a terrorist attack resulting in a mass casualty situation should not be ignored. Rapid intervention is critical for effective medical intervention in cases of cyanide exposure: treatments require a "three minute solution." The availability of a rapid, IM injectable antidote should meet this requirement. However, there are no such available treatments - the current cyanide antidotes are administered intravenously. Because intravenous administration is time consuming and requires well trained medical personnel mass exposure to cyanide would likely leave many victims untreated. Because IM administration can be performed via an autoinjector and can therefore be done rapidly by minimally trained personnel there is a critical need for a rapid-acting, IM-injectable antidote for the treatment of mass cyanide casualties. In order to address this need we are advancing our preclinical lead, sulfanegen to clinical development. We have previously demonstrated efficacy of sulfanegen in murine, swine and rabbit models of cyanide toxicity. In these models sulfanegen is effective in reversal of cyanide toxicity by intramuscular injection and therefore should meet the three minute solution. We have recently held a pre-IND meeting with the FDA and our goal is to advance this cyanide antagonist to the clinic by validation of animal models, demonstrate efficacy of sulfanegen in these animal models and perform the required GLP pharmacokinetic and safety evaluation required for clinical trials. We will then commence a Phase 1 human safety study while simultaneously performing the required GLP studies for NDA submission under the animal rule. Successful completion of the aims of this project should lead to a clinical countermeasure for cyanide toxicity that will be applicable in all cases of cyanide exposure from individuals to mass casualty settings. PUBLIC HEALTHRELEVANCE: We have discovered a novel cyanide antidote that we have named sulfanegen and demonstrated that it is more effective than existing antidotes in models of cyanide toxicity. We will perform the necessary studies to translate this antidote from the bench to the bedside. Successful completion of the goals of this project will therefore result in a clinical antidote that could be useful in the case of a terrorist attack involving cyanide.