Developing and Evaluating Countermeasures Against Tetramethylenedisulfotetramine

制定和评估针对四亚甲基二磺四胺的对策

• 批准号: 8796530
• 负责人: Michael Peter Shakarjian
• 金额: $ 40.25万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8796530
• 关键词: Acute; Affect; Agonist; Anesthetics; Anticonvulsants; Antidotes; Appearance; Attention; Binding; Biological Assay; Cell Culture Techniques; Cellular biology; Centers for Disease Control and Prevention (U.S.); Cerebrum; Cessation of life; Characteristics; Charge; Chemicals; China; Chloride Ion; Chlorides; Clonic Seizure; Complex; Convulsants; Data; Detection; Diazepam; Dose; Drug Combinations; Electroencephalography; Emergency Situation; Environment; Evaluation; FDA approved; Food Adulterations; Goals; Human; In Vitro; Individual; Intervention; Ionophores; Ketamine; Knowledge; Long-Term Effects; Measures; Medical; Membrane; Methods; Morbidity - disease rate; Mus; NMDA receptor antagonist; Nerve Degeneration; Neurons; New York City; Odors; Outcome; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology and Toxicology; Picrotoxin; Poison; Poisoning; Population; Predisposition; Production; Qualifying; Recommendation; Recurrence; Refractory; Research; Rodenticides; Sales; Seizures; Staining method; Stains; Status Epilepticus; Synapses; Syndrome; Taiwan; Taste Perception; Terrorism; Testing; Therapeutic; Time; Toddler; Tonic - clonic seizures; Toxic effect; Video Recording; Water; chemical threat; drug efficacy; effective therapy; fluoro jade; hazard; hypnotic; in vivo; mortality; mouse model; neurotoxic; postsynaptic; prevent; public health relevance; receptor; response; screening; sedative; skills; subcutaneous; tetramethylenedisulfotetramine; treatment planning

DESCRIPTION (provided by applicant): The threat of terrorist attacks on civilians remains a significant concern for the populace and for those charged with their protection. Tetramethylenedisulfotetramine (TMDT) constitutes a significant threat. TMDT is a potent neurotoxic chemical that was available worldwide as a rodenticide until associated hazards led to discontinuance of its use. Although its production, sale, and use have been banned, it is widely available in the Peoples' Republic of China, and has been associated with numerous accidental and intentional poisonings. A severe poisoning in the U.S. was a subject of great attention by the CDC. TMDT has many characteristics that make it a desirable chemical for mass poisoning. Being a water soluble, odorless, and tasteless substance, it is ideally suited to use in adulteration of food and water. It is also stable and persistent in the environment, and can be cheaply and easily synthesized from readily available starting materials. It is acutely toxic, and has long-term effects. There is no known specific antidote to this agent. TMDT is a cage convulsant structurally related to picrotoxin and blocks the Cl- ionophore of the GABAA receptor complex as a mechanism of action. Our preliminary results indicate that TMDT induces a syndrome consisting of acute seizures (clonic and tonic- clonic) and seizure-related death and delayed seizures with lethal outcome. NMDA receptor antagonists (ketamine) better prevented lethal outcome compared to GABAA receptor potentiators (diazepam). Our hypothesis is that TMDT by binding to GABAA Receptor-Chloride Ionophore Complex blocks Cl- influx with consequent loss of membrane hyperpolarization, hyperexcitability of post-synaptic neurons, and sustained increases in [Ca2+]i. Specific Aims to be determined: Aim 1: Establish and apply a cerebral neuronal culture screen to identify TMDT countermeasures. 1A. Measure TMDT-evoked changes in [Ca++]I in primary cerebral cortical cell cultures, and establish reliable, validated conditions for in vitro evaluation of candidate countermeasures for TMDT actions. 1B. Screen multiple agents from FDA-approved sedative- hypnotic-anticonvulsant-anesthetic and NMDA receptor antagonist classes, ranking them for their TMDT- antagonist activity. Aim 2: Examine short- and long-term effects of TMDT in an in vivo mouse model and test potential countermeasures against TMDT actions. 2A. Screen multiple agents from GABAAR agonist and NMDAR antagonist classes in vivo, ranking them for their TMDT-antagonist activity. 2B. Examine selected agents for protection against delayed TMDT toxicity. 2C. Determine re-challenge in the TMDT-induced syndrome. This research will result in straightforward in vitro screen test to reveal treatments effective against the TMDT syndrome. Ranking of this in vitro screen will be correlated to the ranking of efficacy of the drugs determined in the in vivo tests t confirm the validity. Results of our research will identify readily available therapies that treat short-term and prevent long-term toxicity, out of FDA-approved drugs. This will enhance medical response capabilities to TMDT exposure during an emergency.

描述（由申请人提供）：恐怖袭击对平民的威胁仍然是民众和被指控保护的人的重要关注点。四甲基二硫胺（TMDT）构成了重大威胁。 TMDT是一种有效的神经毒性化学物质，在全球范围内可作为啮齿动物，直到相关的危害导致停用其使用。尽管已禁止其生产，销售和使用，但在中华民国已广泛使用，并且与许多意外和故意中毒有关。美国疾病预防控制中心（CDC）引起了极大关注的严重中毒。 TMDT具有许多特征，使其成为质量中毒的理想化学化学物质。作为水溶性，无味和无味的物质，它非常适合掺假食物和水。它在环境中也是稳定且持续的，并且可以 便宜，很容易从可用的起始材料中合成。它具有急性毒性，并具有长期影响。该药物没有已知的特异性解毒剂。 TMDT是一种与picrototoxin相关的笼子抽搐，并阻止了GABAA受体复合物的cl离子机作为一种作用机理。我们的初步结果表明，TMDT诱导了一种由急性癫痫发作（clonic and tonic-Clonic）组成的综合征，与癫痫发作相关的死亡和癫痫发作延迟癫痫发作。与GABAA受体增强剂（地西eepam）相比，NMDA受体拮抗剂（氯胺酮）更好地预防了致命的结果。我们的假设是，通过与GABAA受体 - 氯离子载体复合物结合TMDT会阻止Clux，从而导致膜超极化，突触后神经元的过度兴奋性，并持续增加[CA2+] i。要确定的具体目标：目标1：建立和应用脑神经元培养筛查以识别TMDT对策。 1a。测量原发性脑皮质细胞培养中[Ca ++] I的诱发变化，并为TMDT作用的候选对策进行体外评估，建立可靠的，经过验证的条件。 1B。筛选来自FDA批准的镇静剂 - 催眠 - 抗癌 - 动理和NMDA受体拮抗剂类别的多个药物，对它们的TMDT-拮抗剂活性进行了排名。 AIM 2：检查TMDT在体内小鼠模型中的短期和长期影响，并测试针对TMDT动作的潜在对策。 2a。筛选来自Gabaar激动剂和NMDAR拮抗剂类别的多种代理，并将其对TMDT-Antagonist活性进行排名。 2b。检查选定的药物以防止TMDT毒性延迟。 2C。确定TMDT诱导综合征中的重新挑战。这项研究将导致直接的体外筛查测试，以揭示针对TMDT综合征的有效治疗方法。该体外筛查的排名将与体内测试中确定的药物疗效的排名相关。我们的研究结果将确定可用的疗法，这些疗法可以通过FDA批准的药物来治疗短期并防止长期毒性。这将增强紧急情况下TMDT暴露的医疗响应能力。