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.

超级华法林，也称为长效抗凝灭鼠剂 (LAAR) 是超级华法林的改良形式 抗凝血剂华法林，在 20 世纪 70 年代啮齿动物发达时被开发为强效杀鼠剂 对华法林产生耐药性。 LAAR 的效力比华法林强 100 倍，并且具有极长的药效 半衰期（20 天或更长）；最常用的一种是溴鼠灵 (BDF)。增加使用 LAAR 导致意外中毒事件增加，尤其是幼儿中毒事件。那些中毒事件， 含有少量 BDF，通常通过提供含有凝血因子的血浆进行治疗， 并补充维生素 K1 几天。然而，更大的暴露发生是由于 非故意（例如意外泄漏）和故意（例如自杀和杀人未遂）原因；和 LAAR 已被用于恐怖主义和军事企图造成平民伤亡 军队，最近因合成大麻素污染导致多达 400 人住院 以及数人死亡。虽然 VK1 用于预防出血引起的死亡，但它并不能清除 BDF 因此，治疗可能需要长达一年的时间，且费用极高，而且也不会减少 VK1- 独立的 LAAR 毒性作用可能导致神经病理学和肾脏损伤。在之前的 我们的研究表明，用考来烯胺 (CSA)（FDA 的一种药物）治疗 BDF 中毒的兔子 经批准的胆汁螯合剂，可防止肠肝再循环，将生存率从 33% 提高到 90%。该提案扩展了这些研究，总体目标是将 CSA 发展为 LAAR中毒的对策是迅速消除体内的LAAR。将进行研究 使用不同的方法优化成年兔增加消除所需的 CSA 量和时间 BDF 以及其他 LAAR 的数量；以及防止肾诱导所需的量 损伤和神经病理学。将进行研究以确认 CSA 导致 LAAR 清除 公兔和母兔，能够防止产前对新生儿造成的任何后果 暴露怀孕的兔子。阳性结果将为 CSA 最终的临床测试提供基础 在中毒患者中。