Optimization of Bile Sequestrants to Treat Superwarfarin Poisoning

治疗超级华法林中毒的胆汁螯合剂的优化

• 批准号: 10707127
• 负责人: Douglas L. Feinstein
• 金额: $ 64.39万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707127
• 关键词: Acceleration; Accidents; Acute; Adult; Anticoagulants; Appearance; Bile fluid; Blood Coagulation Factor; Cephalic; Cessation of life; Child; Cholestyramine; Circulation; Coagulation Process; Cognitive deficits; Data; Development; Dose; Emulsions; Enterohepatic Circulation; Exposure to; Extravasation; FDA approved; Fat emulsion; Female; Funding; Goals; Hemorrhage; Homicide; Hospitalization; Human; Hydrophobicity; Inhalation; Injury; Laboratories; Lethal Dose 50; Liver; Midwestern United States; Military Personnel; Modeling; Mus; Nervous System Trauma; Oryctolagus cuniculus; Patients; Persons; Pharmaceutical Preparations; Plasma; Poison; Poisoning; Population; Pruritus; Rattus; Resistance development; Risk; Rodent; Rodenticides; Soybeans; Suicide; Symptoms; Testing; Toxic Actions; Toxic effect; United States National Institutes of Health; Vitamin K 1; Warfarin; cost; dosage; fetal anticoagulant syndrome; hypercholesterolemia; male; mortality; neonate; neuroinflammation; neuropathology; pre-Investigational New Drug meeting; pregnant; prenatal; prenatal exposure; prevent; pup; rapid technique; renal damage; research clinical testing; synthetic cannabinoid; young woman

Superwarfarins, also called long acting anticoagulant rodenticides (LAARs) are modified forms of the anti-coagulant warfarin, developed as potent rodenticides in the 1970's when rodents developed resistance to warfarin. LAARs are up to 100-fold more potent than warfarin and have extremely long half-lives (20 days or longer); one of the most commonly used is Brodifacoum (BDF). Increased use of LAARs led to an increase in accidental poisonings, mainly in young children. Those poisonings, which contain low amounts of BDF, are typically treated by providing plasma that contains clotting factors, and giving Vitamin K1 supplements for a few days. However, larger exposures occur due to unintentional (e.g. accidental spills) and intentional (e.g. suicide and homicide attempts) reasons; and LAARs have been used in terroristic and military attempts to cause injury and death on civilians and military, most recently by contamination of synthetic cannabinoids causing up to 400 hospitalizations and several deaths. While VK1 is used to prevent mortality from bleeding, it does not clear BDF from the body, so treatment can require up to a year at extremely high cost, nor does it reduce VK1- independent LAAR toxic actions which can lead to neuropathology and kidney damage. In previous studies we showed that treatment of BDF poisoned rabbits with cholestyramine (CSA), an FDA approved bile sequestrant which prevents enterohepatic recirculation, increased survival from 33% to 90%. This proposal expands upon those studies, with the overall goal to develop CSA as a countermeasure for LAAR poisoning to rapidly eliminate LAARs from the body. Studies will be done to optimize the amount and timing of CSA needed to increase elimination in adult rabbits, using different amounts of BDF as well as other LAARs; and the amounts needed to prevent the induction of kidney damage and neuropathology. Studies will be done to confirm CSA causes LAAR clearance in both male and female rabbits, and is able to prevent any consequences to neonates due to prenatal exposure of pregnant rabbits. Positive findings will provide the basis for eventual clinical testing of CSA in poisoned patients.

超级战毒素，也称为长作用抗凝剂啮齿动物（LAARS）是修改的形式 抗凝蛋白华法林，在1970年代发展为有效的啮齿动物 抵抗华法林。 Laars比华法林高出100倍，并且非常长 半衰期（20天或更长时间）；最常用的是Brodifacoum（BDF）。增加的使用 Laars导致意外中毒的增加，主要是在幼儿中。那些中毒 包含低量的BDF，通常通过提供包含凝血因子的等离子体来治疗 并提供几天的维生素K1补充剂。但是，由于 无意（例如意外溢出）和故意（例如自杀和杀人企图）原因；和 LAAR已用于恐怖和军事企图，以造成平民伤害和死亡， 军事，最近受到的合成大麻素污染，最多可导致400种住院治疗 和几次死亡。虽然使用VK1来防止死亡率出血，但它无法从中清除BDF 身体，因此治疗最多需要一年的成本，也不会减少VK1- 独立的LAAR有毒作用可能导致神经病理学和肾脏损害。在上一个 我们的研究表明，用胆碱胺（CSA）（FDA）治疗BDF中毒的兔子 批准的胆汁螯合剂可防止肠肝循环，将生存率从33％增加到 90％。该提案扩大了这些研究，其总体目标是将CSA作为一个 LAAR中毒的对策可以快速消除体内的LAARS。研究将进行 优化使用不同 BDF和其他LAAR的数量；以及防止肾脏诱导所需的金额 损害和神经病理学。将进行研究以确认CSA导致两者的LAAR清除率 雄性和女性兔子，能够防止产前对新生儿的任何后果 孕妇兔子的暴露。积极的发现将为CSA最终的临床测试提供基础 在中毒患者中。