Developing and Evaluating Countermeasures Against Tetramethylenedisulfotetramine

描述（由申请人提供）：恐怖分子袭击平民的威胁仍然是民众和负责保护他们的人关注的重大问题。四亚甲基二硫四胺（TMDT）构成重大威胁。TMDT是一种强效神经毒性化学物质，在世界范围内作为灭鼠剂使用，直到相关危害导致其停止使用。虽然它的生产、销售和使用已被禁止，但它在中华人民共和国广泛存在，并与许多意外和故意中毒有关。美国的一起严重中毒事件引起了疾病控制与预防中心的高度关注。TMDT具有许多特性，使其成为大规模中毒的理想化学品。它是一种水溶性、无臭、无味的物质，非常适合用于食品和水的掺假。它在环境中也是稳定和持久的，并且可以

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.