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，也被称为长效抗凝剂灭鼠剂（LAARs），是一种改性的