Optimization of Bile Sequestrants to Treat Superwarfarin Poisoning

超级华法林，也称为长效抗凝血杀鼠剂（LAAR），是本发明化合物的修饰形式。 抗凝剂华法令，在20世纪70年代啮齿动物发展时开发为强效灭鼠剂 对华法林的抵抗LAAR的效力是华法林的100倍， 半衰期（20天或更长）;最常用的一种是溴鼠灵（BDF）。增加使用 LAAR导致意外中毒增加，主要是幼儿。这些中毒事件， 含有少量的BDF，通常通过提供含有凝血因子的血浆来治疗， 补充维生素K1几天。然而，由于以下原因， 非故意（例如意外溢出）和故意（例如自杀和杀人企图）原因;以及 LAAR已被用于恐怖主义和军事企图，造成平民伤亡， 最近的一次是由于合成大麻素的污染，造成多达400人住院治疗。 还有几起死亡虽然VK 1用于预防出血死亡，但它不能清除BDF， 因此，治疗可能需要长达一年的时间，费用极高，也不会减少VK 1- 独立的LAAR毒性作用，可导致神经病理学和肾损伤。前几 我们的研究表明，用消胆胺（CSA）治疗BDF中毒的家兔， 批准的胆汁螯合剂，防止肠肝再循环，将存活率从33%提高到 百分之九十本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，以迅速消除体内的LAAR。将进行研究， 优化CSA的量和时间，以增加成年兔的消除，使用不同的 BDF以及其他LAAR的量;以及预防肾毒性诱导所需的量。 损伤和神经病理学。将进行研究以确认CSA导致两种患者的LAAR清除 雄性和雌性兔子，并能够防止任何后果，新生儿由于产前 怀孕的兔子。阳性结果将为CSA的最终临床测试提供基础 中毒的病人。

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.