Intralipid: A novel frontline countermeasure for brodifacoum poisoning

描述（由申请人提供）：超级华法林是华法林（香豆素）的改性形式，具有更大的毒性和更长的作用时间。它们通过抑制维生素K的再循环，导致维生素K依赖蛋白（包括凝血酶原）的活性丧失，从而有效地降低了整个身体的维生素K水平。凝血酶原的丧失导致全身性抗凝，因此是广泛使用超华法林作为灭鼠剂和减少中风患者栓塞的基础。超级华法林是在对华法林耐药的啮齿动物菌株的报道之后开发的，现在在世界各地普遍使用。据报道，在美国，超级华法林中毒的临床病例每年超过16000例，其中90%为6岁以下儿童。虽然超级华法林中毒可以治疗，但需要长期补充维生素K，任何治疗中断都可能导致症状复发。其他vkdp在大脑发育中发挥重要作用；这些蛋白质的减少与炎症增加、神经元损伤、髓磷脂丧失和认知缺陷有关。此外，子宫内接触华法林对胚胎发育有不利影响，这表明子宫内接触超级华法林可能会产生灾难性的后果。目前最常用的超级华法林是杀鼠剂溴法（BDF）。估计人类口服致死剂量非常低（15毫克），由于它具有高度亲脂性，在组织中积累的生物半衰期超过20天。然而，尽管目前有一种治疗BDF中毒的方法（慢性维生素K治疗），但它的毒性、异常长的半衰期、相对容易获得，以及一系列潜在的方法

DESCRIPTION (provided by applicant): 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.