Countermeasures against cyanide

氰化物对策

基本信息

批准号：
7918865
负责人：
STEVEN E PATTERSON
金额：
$ 30.26万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7918865
关键词：
19p 3-Mercaptopyruvate sulfurtransferase Acetaminophen Acute Adverse effects Affect Affinity Amino Acids Amyl Nitrite Anabolism Animal Model Antidotes Antioxidants Binding Bioavailable Biological Availability Biological Factors Bioshield Burn injury Chemical Warfare Agents Chemicals Chemistry Clinical Clinical Drug Development Cobalamin Combined Modality Therapy Communicable Diseases Complex Cyanides Cysteine Cytoplasm Development Dicarboxylic Acids Disease Disodium Salt Nitroprusside Disulfides Dose Drug Combinations Drug Formulations Drug Kinetics Drug Metabolic Detoxication Emergency Situation Environment Enzymes Erythrocytes Event Explosion Exposure to Fire - disasters Funding Generations Glutathione Goals Hepatic Housing Human Hydrogen Cyanide Hypertension Infusion procedures Injury Institutes International Intervention Intoxication Kidney Left Lethal Dose 50 Life Liver Long-Term Survivors Mammalian Cell Methods Military Personnel Mitochondria Mitochondrial Matrix Modality Modeling Mole the mammal Molecular Structure Mus Neuraxis Neurologic Oxidative Stress Panic Pharmaceutical Chemistry Pharmacotherapy Plants Poisoning Population Prodrugs Property Publications Reflex action Relative (related person)Request for Applications Resistance development Risk Factors Security Series Site Sodium Nitrite Solubility Solutions Sulfur Survivors Testing Therapeutic Therapeutic Effect Therapeutic Index Therapeutic Intervention Therapeutic Uses Thiocyanates Thiosulfate Sulfurtransferase Time Tissues Toxic effect Toxicogenetics Treatment Protocols United States National Institutes of Health Validation Vasodilator Agents War Water World War II analog base beta-mercaptopyruvate cobinamide design disulfide bond reduction dithiane dosage emergency service responder enzyme substrate functional group good laboratory practice hazard improved in vivo method development mouse model multiple drug use nerve agent physical property pre-clinical preclinical study preference prophylactic prototype research study response sodium thiosulfate sulfurtransferase synergism transamination water solubility

项目摘要

Although different nations have variable preferences for specific antidotes against cyanide poisoning, the antidotes of choice in the U.S. for over 30 years have been the combination of sodium nitrite and sodium thiosulfate, both administered intravenously in timely sequence. In recent years, this has been supplemented with the volatile amyl nitrite given nasally for its vasodilatory effect. However, these agents are generally not only slow acting, but have potential for toxicity and serious complications if not used properly. A recent perspective article on cyanide, authored by experts at the USAMRICD, pointed out that in severe cyanide poisonings, rapid intervention is the key, and treatments require a "three minute solution", akin to the nerve agent antidote kit.3 The availability of non-toxic agents that could be taken prophylactically by military personnel on threatened exposure or by first responders to a cyanide emergency, also represents an ideal requirement. These goals have not yet been achieved to date, and the present treatment modalities are unsuitable in a military setting, or in the event of actual use of cyanide as a threat agent on a large scale against the civilian population. We have recently developed (unpublished) a series of prototype cyanide antidotes that release the substrate for the enzyme, 3-mercaptopyruvate sulfurtransferase (3-MPST) in vivo, thereby providing a viable alternative method for detoxifying cyanide by utilizing this ubiquitous cellular enzyme to convert cyanide to the non-toxic thiocyanate. The rationale here is to provide this enzyme with its natural substrate directly, thereby by-passing the necessity for generating it endogenously from the transamination of L-cysteine, a sulfhydryl amino acid known to be less abundant in tissues. We have also developed a unique mouse model-that minimizes the use of large numbers of animals~for assessing the toxicity of sub-lethal doses of cyanide, which is highly amenable for evaluating the antidotal efficacy of our compounds. Having already established "proof of concept" that our prototype compounds protect against cyanide toxicity in mice, we will simultaneously a) expand the prototype series, and design and synthesize analogs around these series to improve antidotal efficacy, bioavailability, and physical properties of these compounds, b) superimpose the endogenous antioxidant glutathione (as its bioavailable form) in the above regimen to evaluate whether such antioxidant co-treatment would improve survivability and protect against the neurological deficits seen in long term survivors of acute cyanide intoxication, and c) accelerate preclinical studies (acute and long term toxicity, ADME, other animal models, etc.) for those compounds already demonstrated to be protective, with the goal of filing an IND application to the FDA. Although most of the compounds of our series are rapid acting, at least one prototype (perhaps more) is slower acting (by design), but fully protective when administered orally; hence, it may be advanced as a candidate for prophylactic use.

尽管不同国家对针对氰化物中毒的特异性解毒剂具有可变的偏好，但美国选择的解毒剂已有30多年了，是亚硝酸钠和钠的组合硫代硫酸盐，均按及时静脉内给药。近年来，这已经补充了挥发性氨基亚硝酸盐的血管舒张作用。但是，这些代理通常不仅很慢表演，但如果不正确使用，则具有毒性和严重并发症的潜力。最近的观点文章由USAMRICD的专家撰写的关于氰化物，指出，在严重的氰化物中毒中干预是关键，治疗需要“三分钟的溶液”，类似于神经剂毒药套件。3 军事人员可能会在威胁暴露的情况下预言的无毒药物的可用性或者是急救人员的紧急情况，也代表了理想的要求。这些目标还没有已经达到了迄今为止，目前的治疗方式在军事环境中不适合实际使用氰化物作为对平民的大规模威胁代理。我们最近开发了（未发表的）一系列氰化物解毒剂，释放底物对于酶，体内3-丙型丙酮酸硫酸盐硫酸盐转移酶（3-MPST），从而提供可行的替代品通过利用这种无处不在的细胞酶将氰化物转化为无毒的方法来排毒氰化物的方法硫氰酸盐。这里的基本原理是直接提供该酶的天然底物，从而通过从L-半胱氨酸的转移，已知的硫酰氨基酸的l-半胱氨酸的跨跨内源性产生它的必要性在组织中少丰富。我们还开发了独特的鼠标模型 - 可以最大程度地减少大型的使用动物的数量〜用于评估亚致死剂量的氰化物的毒性，这是高度适合的评估我们化合物的抗原功效。已经建立了“概念证明”，我们的原型化合物可以预防氰化物的毒性小鼠，我们将同时a）扩展原型系列，并设计和综合这些类似物提高这些化合物的解毒疗效，生物利用度和物理特性的系列，b）叠加上述方案中的内源性抗氧化剂（作为其生物利用形式），以评估是否存在抗氧化剂共同治疗将提高生存能力并预防长期看到的神经缺陷急性氰化物中毒的幸存者，c）加速临床前研究（急性和长期毒性，ADME，其他动物模型等）对于已经证明具有保护性的那些化合物，目的是提出 IND应用于FDA。尽管我们系列的大多数化合物都是迅速作用，但至少一个原型（也许更多）表现较慢（按设计），但口服时完全保护性；因此，可能是作为预防性使用的候选者。