Developing and Evaluating Countermeasures Against Tetramethylenedisulfotetramine

制定和评估针对四亚甲基二磺四胺的对策

基本信息

批准号：
8934197
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
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8934197
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 Health 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 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 neurons prevent receptor response screening sedative skills subcutaneous tetramethylenedisulfotetramine treatment planning

项目摘要

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）：针对平民的恐怖袭击威胁仍然是民众和负责保护民众的人员的重大关切。四亚甲基二磺四胺 (TMDT) 构成重大威胁。 TMDT 是一种强效神经毒性化学物质，曾在全球范围内作为灭鼠剂使用，直到相关危害导致其停止使用。尽管其生产、销售和使用已被禁止，但它在中华民国广泛存在，并与许多意外和故意中毒事件有关。美国发生的一起严重中毒事件引起了CDC的高度关注。 TMDT 具有许多特性，使其成为治疗大规模中毒的理想化学品。作为一种水溶性、无臭、无味的物质，它非常适合用于食品和水的掺假。它在环境中也很稳定和持久，并且可以由容易获得的起始材料廉价且容易地合成。它具有剧毒，并具有长期影响。目前尚无针对该药剂的已知特异性解毒剂。 TMDT 是一种结构上与印防己毒素相关的笼惊厥药，其作用机制是阻断 GABAA 受体复合物的 Cl-离子载体。我们的初步结果表明，TMDT 会诱发一种综合征，包括急性癫痫发作（阵挛和强直阵挛）和癫痫相关死亡以及具有致命结果的迟发性癫痫发作。与 GABAA 受体增强剂（地西泮）相比，NMDA 受体拮抗剂（氯胺酮）可以更好地预防致命后果。我们的假设是，TMDT 通过与 GABAA 受体-氯离子载体复合物结合来阻断 Cl- 内流，从而导致膜超极化丧失、突触后神经元过度兴奋以及 [Ca2+]i 持续增加。待确定的具体目标：目标 1：建立并应用脑神经元培养筛选来确定 TMDT 对策。 1A。测量原代大脑皮层细胞培养物中 TMDT 诱发的 [Ca++]I 变化，并建立可靠、经过验证的条件，用于体外评估 TMDT 作用的候选对策。 1B.从 FDA 批准的镇静催眠抗惊厥麻醉和 NMDA 受体拮抗剂类别中筛选多种药物，并根据 TMDT 拮抗剂活性对它们进行排名。目标 2：在体内小鼠模型中检查 TMDT 的短期和长期影响，并测试针对 TMDT 作用的潜在对策。 2A。体内筛选 GABAAR 激动剂和 NMDAR 拮抗剂类别的多种药物，并根据 TMDT 拮抗剂活性对它们进行排名。 2B。检查选定的药物以防止延迟 TMDT 毒性。 2C。确定 TMDT 诱发综合征的再次挑战。这项研究将进行简单的体外筛选测试，以揭示对 TMDT 综合征有效的治疗方法。该体外筛选的排名将与体内测试中确定的药物功效排名相关联，以确认有效性。我们的研究结果将在 FDA 批准的药物中找出治疗短期毒性并预防长期毒性的现成疗法。这将增强紧急情况下对 TMDT 暴露的医疗响应能力。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tetramethylenedisulfotetramine neurotoxicity: What have we learned in the past 70 years?

四亚甲基二磺四胺神经毒性：过去 70 年我们学到了什么？

DOI：
10.1016/j.nbd.2019.104491
发表时间：
2020-01-31
期刊：
Neurobiology of Disease
影响因子：
6.1
作者：
M. Lauková;J. Velíšková;L. Velíšek;M. Shakarjian
通讯作者：
M. Shakarjian

Tetramethylenedisulfotetramine: pest control gone awry.

四亚甲基二磺四胺：害虫防治出了问题。

DOI：
发表时间：
2016-08
期刊：
影响因子：
5.2
作者：
Shakarjian, Michael P;Laukova, Marcela;Velíšková, Jana;Stanton, Patric K;Heck, Diane E;Velíšek, Libor
通讯作者：
Velíšek, Libor

Developmental and sex differences in tetramethylenedisulfotetramine (TMDT)-induced syndrome in rats.

四亚甲基二磺四胺（TMDT）诱导的大鼠综合征的发育和性别差异。