Intralipid: A novel frontline countermeasure for brodifacoum poisoning

说明(申请人提供)：超级华法林是华法林(香豆素)的改良形式，毒性更大，作用时间更长。它们通过抑制维生素K的循环而有效地降低体内的维生素K水平，导致包括凝血酶原在内的维生素K依赖蛋白的活性丧失。凝血酶原的丧失会导致全身抗凝，因此超级华法令被广泛用作灭鼠剂并减少中风患者的血栓形成的基础。超级华法林是在报道对华法林有抗药性的啮齿动物品系后开发出来的，目前在世界各地普遍使用。据报道，美国每年有超过16,000例超级华法林中毒的临床病例，其中90%发生在6岁以下的儿童中。虽然超级华法林中毒是可以治疗的，但它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VKDPs在大脑发育中起着重要作用；这些蛋白的减少与炎症增加、神经元损伤、髓鞘丢失和认知障碍有关。此外，宫内接触华法林对胚胎发育有不利影响，这表明宫内接触超级华法林可能会产生灾难性的后果。当今最常用的杀鼠剂是溴氰菊酯(BDF)。据估计，对人类的致命口服剂量非常低(15毫克)，由于它具有高度亲脂性，它在生物半衰期超过20天的组织中积累。清华，尽管有一种现有的治愈BDF中毒(慢性维生素K疗法)，但它的毒性、异常长的半衰期、相对容易获得它，以及一系列潜在的方法 由于其有害分布(通过气雾剂扩散或直接应用于植物溶胶或食物上的污染)，使BDF成为严重的潜在化学威胁。在这项提案中，我们将测试FDA已经批准的治疗方法--脂肪乳剂(LE)作为对抗BDF中毒的治疗潜力。LE的输注已经被用于治疗某些有毒药物过量，人们认为它的部分作用是通过清除毒素并转移到肝脏进行代谢。急性LE输注应能迅速将BDF从体内清除出去，从而防止危及生命的凝血减少，防止中毒的长期衰弱的中枢神经系统后遗症，并防止宫内暴露。此外，由于在涉及大量伤亡的情况下，静脉注射对抗措施可能是不切实际的，我们开发了另一种给药方法，即骨内注射(IO)，它将LE注入骨骼中，在那里LE可以迅速进入血流。在这个项目中，我们将优化IO LE从成年大鼠组织中清除BDF的能力。如果单次输注量不足以降低血药浓度，我们将增加LE的后续静脉输注。我们将描述子宫内暴露于BDF的后果，并优化LE对怀孕大鼠的治疗，以最大限度地减少这些后续后果。这个项目的一个主要目标是提交一份使用LE治疗BDF中毒的IND；由于在人体上进行测试是不可行的，在这个项目的第四年，我们 将在兔子身上进行类似的研究，以符合FDA对新药的动物规则要求。我们预计LE将被证明是一种有效的治疗BDF中毒的方法，从而提供一种机制来解决由于故意或意外原因导致的BDF的大量释放所造成的潜在损害。

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.