Optimization of Bile Sequestrants to Treat Superwarfarin Poisoning

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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.