ContraPest-an oral bait for fertility management of rodent pests

描述(申请人提供)：几千年来，啮齿动物一直吃我们的食物，并将疾病传播给我们。据估计，每年有3亿只挪威褐鼠被引入美国，造成270亿美元的经济损失。从历史上看，灭鼠策略一直是通过各种方法来消灭鼠害，但主要是使用毒饵，这种毒饵是抗凝血的灭鼠剂。除了与使用毒饵相关的所有问题外，例如毒杀非目标动物/宠物、6岁以下儿童和污染环境，毒药并不能解决问题。在控制鼠害数量方面有很大潜力的一种非致命性战略是生育控制。但到目前为止，对自由活动的野生动物，如夜间活动的小型啮齿动物，还没有实现有效的控制，因为给老鼠注射的药物必须通过口服途径分配。工业化学品4-乙烯基环己烯二环氧化物(VCD)加速闭锁的自然过程，导致大鼠卵巢卵泡枯竭，导致卵巢衰竭和永久性不孕。当每天重复给予VCD时，卵泡耗尽，平均而言，在开始给药后第58天，原始/初级卵泡完全消除和卵巢早衰，并在小鼠中导致不孕。到目前为止，VCD诱导的卵泡耗竭是通过腹膜腔给药实现的。然而，为了开发和商业化一种导致野鼠不育的产品，必须以诱饵形式口服。这个第一阶段的应用程序旨在测试以下三个特定目标的假设。大鼠口服VCD将导致卵泡数量完全耗尽，导致不孕不育，证明了研制一种大鼠生育控制诱饵的可行性。目的1.确定大鼠口服VCD耗竭原始卵泡所需的剂量。目的2.确定VCD完全耗尽卵泡数量的时间进程。目的3.测定VCD排泄物的药代动力学。第一阶段实验的结果将确定VCD暴露所需的剂量和持续时间，以导致卵巢卵泡完全枯竭。这些结果将使我们能够获得足够的信息，以进行第二阶段的应用，以开发一种口头诱饵和诱饵协议来管理野生动物啮齿动物种群。大鼠是这些研究的目标，他们知道大鼠比小鼠对VCD更具抵抗力。因此，在老鼠身上取得成功，很容易转化为老鼠。此外，老鼠是主要的目标害虫物种，因为它们污染和破坏我们的食物供应，以及目前用于管理老鼠种群的危险灭鼠剂控制方法，构成了巨大的经济和重大公共卫生风险。PHS 398/2590(11/07版)页面续格式页面 公共卫生相关性：对野鼠的管理对于最大限度地减少农业和财产损失以及传染病的传播至关重要。致命的方法将有毒物质引入环境，因此成为柜台上可用药物清除的目标。该项目的目标是提供数据，支持使用工业化学品4-乙烯基环己烯二环氧化物(VCD)最终开发一种环境中性的永久性啮齿动物生育控制诱饵来管理野生鼠种群的可行性。

DESCRIPTION (provided by applicant): Rodent pests have eaten our food and transmitted diseases to us for millennia. There are an estimated 300 million introduced Norway or brown rats in the U.S. that cause $27 billion of economic losses annually. Historically the strategy has been to kill rat pests through a variety of methods but primarily by using poison baits that are anticoagulant rodenticides. In addition to all of the problems associated with using poison bait, e.g. poisoning nontarget animals/pets, children under the age of 6, and contaminating the environment, poison does not address the problem. A non-lethal strategy that has significant potential to manage rodent pest number is fertility control. But thus far effective control of free-ranging wildlife, such as small, nocturnal rodents, has not been achieved because distribution to dose rats must be via an oral route. The industrial chemical 4-vinylcyclohexene diepoxide (VCD) accelerates the natural process of atresia leading to depletion of rat ovarian follicles causing ovarian failure and permanent sterility. Follicle depletion occurs when VCD is given in repeated intraperitoneal daily doses and on average, complete elimination of primordial/primary follicles and premature ovarian failure occur by day 58 following the onset of dosing and in mice causes infertility. To date VCD induced follicle depletion has been achieved by intraperitoneal administration. However to develop and commercialize a product to cause wild rat infertility it must be given orally in a bait. This Phase I application aims to test the following hypothesis in three specific aims. Oral administration of VCD to rats will lead to complete depletion of ovarian follicle populations, resulting in infertility demonstrating feasibility for development of a fertility control bait for rats. Aim 1. Determine the dose needed to deplete primordial ovarian follicles in rats by oral exposures to VCD. Aim 2. Determine the time course over which VCD completely depletes ovarian follicle populations. Aim 3. Determine the pharmacokinetics of VCD excretion. Results from Phase I experiments will define the dose and duration of VCD exposure necessary to cause complete ovarian follicle depletion. These results will enable us to obtain sufficient information to progress to a Phase II application to develop an oral bait and baiting protocol to manage wildlife rodent populations. Rats are being targeted in these studies, with the understanding that rats are more resistant to VCD than mice. Thus, success with rats, can easily be translated to mice. Furthermore, rats are the primary target pest species based on the enormous economic and significant public health risks they pose both by their contamination and destruction of our food supplies and the dangerous rodenticide control approaches currently being used to manage rat populations. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: Management of wild rats is critical to minimize agriculture and property damage and the spread of infectious diseases. Lethal approaches introduce poison into the environment and consequently are being targeted for removal from over the counter availability. The goal of this project is to provide data to support the feasibility of using the industrial chemical 4-vinylcyclohexene diepoxide (VCD) to ultimately develop an environmentally neutral permanent rodent fertility control bait to manage wild rat populations