Superwarfarins are modified forms of warfarin (Coumadin) with greater toxicity and longer duration of action. They potently reduce vitamin K levels throughout the body by inhibiting its recycling leading to loss of activity of Vitamin K dependent proteins including prothrombin. Loss of prothrombin leads to systemic anticoagulation, hence the basis for the widespread use of superwarfarins as rodenticides and to reduced embolisms in stroke patients. Superwarfarins were developed following reports of warfarin resistant rodent strains and are now commonly used throughout the world. Reported clinical occurrences of superwarfarin poisoning have reached over 16,000 per year in the USA, with >90% in children under age 6. Although superwarfarin poisoning can be treated it requires long term supplementation with Vitamin K, and any interruption in treatment can lead to recurrence of symptoms. Other VKDPs play important roles in brain development; and reductions in those proteins is associated with increased inflammation, neuronal damage, loss of myelin, and cognitive deficits. In addition, in utero exposure to warfarin has adverse effects on embryonic development, suggesting the in utero exposure to superwarfarins could have disastrous outcomes. The superwarfarin most commonly used today as a rodenticide is brodifacoum (BDF). The estimated fatal oral dose for humans is very low (15 mg), and because it is highly lipophilic, it accumulates in tissues with a biological half-life of over 20 days. Thu, even though there is an existing cure BDF poisoning (chronic Vitamin K treatment), its toxicity, exceptionally long half-life, the relative ease of obtaining it, and the array of potential methods for its harmful distribution (contamination by aerosol dispersal or direct application on plants sol, or food), make BDF a serious potential chemical threat. In this proposal, we will test the therapeutic potential of an already approved FDA treatment, Lipid Emulsion (LE), as a countermeasure against BDF poisoning. The infusion of LE is already used to treat certain toxic drug overdoses, and is thought to act in part by scavenging toxins and movement to the liver where they are metabolized. Acute LE infusion should offer rapid removal of BDF from the body, thereby preventing life threatening reductions in clotting, protect against long-term debilitating CNS sequelae of poisoning; and prevention of in utero exposure. In addition, since intravenous administration of a counter measure may be impractical in a scenario involving mass casualties, we have developed an alternative method of administration, namely intraosseous (IO) which infuses LE into bone where it can rapidly enter the blood stream. In this program, we will optimize the ability of IO LE to eliminate BDF from adult rat tissues. If levels are not sufficienty reduced by a single IO bolus, we will add follow up IV infusions of LE. We will characterize the consequences of in utero exposure to BDF, and optimize treatment of pregnant rats with LE to minimize those later consequences. A major goal of this project is to submit an IND for the use of LE to treat BDF poisoning; since testing in humans is not feasible, in year 4 of this project we will carry out similar studies in rabbits to match the FDA requirements under the animal rule for a new drug. We anticipate that LE will be proven to be an effective treatment for BDF poisoning, thereby providing a mechanism to address the potential damage due to a large scale release of BDF by either intentional or accidental causes.
There are no established protocols to deal with a mass casualty disaster following exposure to a superwarfarin such as brodifacoum; our studies will provide the necessary data to propose an IND to use intra osseous administration of a lipid emulsion as a first line method to exposed victims, thereby reducing mortality, subsequent neurological problems, and in utero abnormalities.
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|Hauck, Zane Z; Feinstein, Douglas L; van Breemen, Richard B (2016) LC-MS-MS Analysis of Brodifacoum Isomers in Rat Tissue. J Anal Toxicol 40:304-9|
|Ayee, Manuela Aseye Ayele; Roth, Charles William; Akpa, Belinda Sena (2016) Structural perturbation of a dipalmitoylphosphatidylcholine (DPPC) bilayer by warfarin and its bolaamphiphilic analogue: A molecular dynamics study. J Colloid Interface Sci 468:227-237|
|Feinstein, Douglas L; Akpa, Belinda S; Ayee, Manuela A et al. (2016) The emerging threat of superwarfarins: history, detection, mechanisms, and countermeasures. Ann N Y Acad Sci 1374:111-22|
|Marangoni, M Natalia; Martynowycz, Michael W; Kuzmenko, Ivan et al. (2016) Membrane Cholesterol Modulates Superwarfarin Toxicity. Biophys J 110:1777-1788|
|Fettiplace, Michael R; Kowal, Katarzyna; Ripper, Richard et al. (2016) Insulin Signaling in Bupivacaine-induced Cardiac Toxicity: Sensitization during Recovery and Potentiation by Lipid Emulsion. Anesthesiology 124:428-42|
|Ware, Kyle M; Feinstein, Douglas L; Rubinstein, Israel et al. (2015) Brodifacoum induces early hemoglobinuria and late hematuria in rats: novel rapid biomarkers of poisoning. Am J Nephrol 41:392-9|
|Fettiplace, Michael R; Lis, Kinga; Ripper, Richard et al. (2015) Multi-modal contributions to detoxification of acute pharmacotoxicity by a triglyceride micro-emulsion. J Control Release 198:62-70|
|Fettiplace, Michael R; Pichurko, Adrian; Ripper, Richard et al. (2015) Cardiac depression induced by cocaine or cocaethylene is alleviated by lipid emulsion more effectively than by sulfobutylether-?-cyclodextrin. Acad Emerg Med 22:508-17|
|Fettiplace, Michael R; Akpa, Belinda S; Rubinstein, Israel et al. (2015) Confusion About Infusion: Rational Volume Limits for Intravenous Lipid Emulsion During Treatment of Oral Overdoses. Ann Emerg Med 66:185-8|
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