Countermeasures Against Chemical Threats: Countermeasures Against Cyanide

化学威胁对策：氰化物对策

• 批准号: 8551737
• 负责人: STEVEN E PATTERSON
• 金额: $ 65.84万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8551737
• 关键词: Accidents; Address; Adverse event; Analytical Chemistry; Animal Model; Antidotes; Blood; Canis familiaris; Chemicals; Clinic; Clinical; Clinical Trials; Cyanides; Development; Dose; Dose-Limiting; Drug Formulations; Drug Kinetics; Evaluation; Exposure to; Family suidae; Goals; Goat; Grant; Guidelines; Health Personnel; Human; Human Resources; Human Volunteers; Individual; Injectable; Intervention; Intramuscular Injections; Kidney; Lead; Left; Liver; Macaca; Medical; Military Personnel; Modeling; Mus; Names; New Zealand; Organ; Oryctolagus cuniculus; Persons; Phase; Pilot Projects; Poisoning; Prodrugs; Rattus; Relative (related person); Research; Research Personnel; Risk; Safety; Series; Sheep; Sodium Chloride; Solutions; Source; Time; Toxic effect; Training; Translating; Validation; Water; animal rule; bench to bedside; genotoxicity; intravenous administration; mass casualty; meetings; novel; pre-clinical; programs; reproductive; safety study; volunteer

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.

描述（由申请人提供）：平民和军事人员可能接触氰化物的来源包括含氮材料的燃烧、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。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“三分钟解决方案”。“一种快速、IM注射解毒剂的可用性应该满足这一要求。然而，没有这样的治疗方法-目前的氰化物解毒剂是静脉注射。由于静脉注射很耗时，需要训练有素的医务人员，大量接触氰化物可能会使许多受害者得不到治疗。由于IM给药可以通过自动注射器进行，因此可以由受过最低限度培训的人员快速完成，因此迫切需要一种速效的IM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领导，磺胺药的临床开发。我们先前已经证明了磺胺原在氰化物毒性的小鼠、猪和兔模型中的功效。在这些模型中，磺胺原通过肌肉注射可有效逆转氰化物毒性，因此应满足3分钟溶液的要求。我们最近与FDA举行了一次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，证明磺胺在这些动物模型中的疗效，并进行临床试验所需的GLP药代动力学和安全性评价。然后，我们将开始1期人体安全性研究，同时根据动物规则进行NDA提交所需的GLP研究。成功完成本项目的目标应导致氰化物毒性的临床对策，将适用于从个人到大规模伤亡环境的所有氰化物暴露情况。 公共卫生相关性：我们发现了一种新的氰化物解毒剂，我们命名为sulfanegen，并证明它比现有的氰化物毒性模型中的解毒剂更有效。我们将进行必要的研究，将这种解毒剂从实验室转移到床边。因此，成功完成这一项目的目标将产生一种临床解毒剂，在涉及氰化物的恐怖袭击中可能有用。

项目成果

Determination of 3-mercaptopyruvate in rabbit plasma by high performance liquid chromatography tandem mass spectrometry.

• DOI: 10.1016/j.jchromb.2014.01.006
• 发表时间: 2014-02-15
• 期刊: JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
• 影响因子: 3
• 作者: Stutelberg, Michael W.;Vinnakota, Chakravarthy V.;Mitchell, Brendan L.;Monteil, Alexandre R.;Patterson, Steven E.;Logue, Brian A.
• 通讯作者: Logue, Brian A.

In-vitro mercaptopyruvate sulfurtransferase species comparison in humans and common laboratory animals.

人类和常见实验动物的体外巯基丙酮酸硫转移酶种类比较。

• DOI: 10.1016/j.toxlet.2017.04.005
• 发表时间: 2017
• 期刊: Toxicology letters
• 影响因子: 3.5
• 作者: Moeller,BryantM;Crankshaw,DauneL;Briggs,Jacquie;Nagasawa,HerbertT;Patterson,StevenE
• 通讯作者: Patterson,StevenE

Cyanide toxicity in juvenile pigs and its reversal by a new prodrug, sulfanegen sodium.

• DOI: 10.1213/ane.0b013e31824c4eb5
• 发表时间: 2012-05
• 期刊: Anesthesia and analgesia
• 影响因子: 5.7
• 作者: Belani KG;Singh H;Beebe DS;George P;Patterson SE;Nagasawa HT;Vince R
• 通讯作者: Vince R

Sodium nitroprusside in 2014: A clinical concepts review.

• DOI: 10.4103/0970-9185.142799
• 发表时间: 2014-10
• 期刊: Journal of anaesthesiology, clinical pharmacology
• 作者: Hottinger DG;Beebe DS;Kozhimannil T;Prielipp RC;Belani KG
• 通讯作者: Belani KG

Development of sulfanegen for mass cyanide casualties.

• DOI: 10.1111/nyas.13114
• 发表时间: 2016-06
• 期刊: Annals of the New York Academy of Sciences
• 影响因子: 5.2
• 作者: Patterson SE;Moeller B;Nagasawa HT;Vince R;Crankshaw DL;Briggs J;Stutelberg MW;Vinnakota CV;Logue BA
• 通讯作者: Logue BA