Countermeasures Against Chemical Threats: Countermeasures Against Cyanide

说明（由申请人提供）：平民和军事人员潜在接触氰化物的来源包括含氮材料燃烧、商业事故和故意释放氰化化学品。获取和释放氰化物相对容易，这意味着不应忽视在恐怖袭击中使用氰化物造成大规模伤亡的风险。在氰化物暴露的情况下，快速干预对于有效的医疗干预至关重要：治疗需要“三分钟溶液”。可快速注射的解毒剂应满足这一要求。然而，目前还没有这样的治疗方法——目前的氰化物解毒剂是静脉注射的。由于静脉注射既耗时又需要训练有素的医务人员，大量接触氰化物可能会使许多受害者得不到治疗。由于可通过自动注射器给药，因此可由受过最低限度训练的人员快速完成，因此迫切需要一种速效、可注射IM的解毒剂，用于治疗大量氰化物伤亡。为了满足这一需求，我们正在推进我们的临床前先导药物磺胺根的临床开发。我们之前已经在小鼠、猪和兔的氰化物毒性模型中证明了磺胺素的有效性。在这些模型中，磺胺素通过肌肉注射逆转氰化物毒性是有效的，因此应满足三分钟溶液。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验证来推进这种氰化物拮抗剂的临床应用，证明磺胺素在这些动物模型中的有效性，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人体安全性研究，同时根据动物规则进行NDA提交所需的GLP研究。成功完成该项目的目标应导致一项氰化物中毒的临床对策，适用于个人接触氰化物造成大规模伤亡的所有情况。

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.