An oral therapeutic to treat intoxication by prescription and illicit stimulants

项目摘要/摘要 有一个重大的未得到满足的医疗需求，即隔离和移除口服服用的处方 以及来自胃肠道的非法兴奋剂，以预防和治疗过量用药。这个 处方和非法兴奋剂的可获得性、使用、误用和滥用在过去大幅增加 十年，所有年龄段的人，从儿童到成年人。在美国，超过400万儿童和年轻人 治疗注意力缺陷多动障碍(ADHD)的处方兴奋剂和急诊室 (Er)与这些药物有关的就诊人数估计每年超过20万人次。2020年，510万人 12岁及以上儿童报告在过去一年中滥用处方兴奋剂，75.8万人有处方 兴奋剂使用障碍。目前的护理标准，即口服木炭，疗效有限。这个 非法兴奋剂甲基苯丙胺是美国增长最快的滥用药物，但目前还没有治疗方法 可用于治疗冰毒中毒。类似的化合物被广泛用作“俱乐部”药物，并 具有潜在的致命性，尤其是在饮酒的情况下。因此，一个强有力的、易于管理的 需要解毒剂来迅速结合并防止口服兴奋剂吸收到血液中。 这样的即时治疗将拯救生命。这个项目的目标是开发一种广谱的口述 口服解毒剂防治急性危及生命的中毒 兴奋剂。我们的解毒剂是基于一种新型的隔离剂，它能紧密结合、灭活和清除有害物质 来自体内的物质具有很高的特异性。当口服时，它们在胃肠道工作，并减少 靶向血液和大脑的吸收。护理的标准，木炭，有一些限制。在……里面 相比之下，我们的水溶性隔离剂更有效、更快、更安全、更容易管理。要选择一个 有效的治疗，我们将承担以下目标：AIM 1将完成体外结合筛选 研究隔离剂对广谱兴奋剂的亲和力，并选择一种候选药物进行体内研究。我们会 筛选结合亲和力和选择性。我们将评估有无在场的单独刺激物 一杯酒。预期结果是体内研究的一种铅口服治疗候选方案。目标2将 在体内评估主要候选药物对口服兴奋剂的耐受性和有效性 啮齿动物模型，以木炭为对照。我们将把领先候选人的效力和时间进程量化为1) 消除苯丙胺、哌醋甲酯和3，4-亚甲基二氧基甲基苯丙胺 足以引起严重的中毒，从胃肠道进入粪便，以及2)阻止吸收 通过它们在血浆和尿液中的定量，这些化合物进入血液。此外，我们还将 监测生理参数和行为。这些研究将确定这种口服的剂量范围。 治疗。预期结果是提供从体内快速清除兴奋剂的候选药物，并且 逆转毒性的生理和行为迹象，准备进行大型动物研究。

Project Summary/Abstract There is a significant unmet medical need to sequester and remove orally ingested prescription and illicit stimulants from the gastrointestinal (GI) tract, to prevent and treat overdose. The availability, use, misuse, and abuse of prescription and illicit stimulants has increased dramatically over the past decade across all ages ranging from children to adults. Over 4M children and young adults in the U.S. take prescription stimulants for treatment of attention deficit hyperactivity disorder (ADHD), and emergency room (ER) visits associated with these medications are estimated at over 200,000 annually. In 2020, 5.1 million people aged 12 and older reported the misuse of prescription stimulants in the past year and 758,000 had a prescription stimulant use disorder. The current standard of care, oral administration of charcoal, has limited efficacy. The illicit stimulant methamphetamine is the fastest growing drug of abuse in the U.S., yet no current therapeutics are available for treating meth intoxication. Similar compounds are widely used as “Club” drugs, and are potentially lethal, especially in combination with alcohol consumption. Therefore, a potent, easy-to-administer antidote is needed to rapidly bind, and prevent absorption of, orally ingested stimulants to the bloodstream. Such an immediate treatment will save lives. The goal of this project is to develop a broad-spectrum orally administered antidote to prevent and treat acute life-threatening intoxication caused by orally ingested stimulants. Our antidote is based on a novel class of sequestrants that tightly bind, inactivate, and clear harmful substances from the body with high specificity. When taken orally, they work in the GI tract and reduce absorption of targets to the blood and brain. The standard of care, charcoal, has a number of limitations. In contrast, our water-soluble sequestrants are more potent, faster-acting, safe, and easy to administer. To select a potent therapeutic, we will undertake the following Aims: Aim 1 will complete in-vitro screening for binding affinity of sequestrants against a broad spectrum of stimulants and select a candidate for in-vivo study. We will screen for binding affinity and selectivity. We will evaluate individual stimulants with and without the presence of alcohol. Expected outcome is one lead orally administered therapeutic candidate for in-vivo study. Aim 2 will evaluate the lead candidate in-vivo for both tolerability and efficacy against orally administered stimulants in a rodent model, using charcoal as control. We will quantify the efficacy and time course of the lead candidate to 1) eliminate amphetamine, methylphenidate, and 3,4-methylenedioxymethamphetamine, at concentrations sufficient to cause significant intoxication, from the gastrointestinal tract into feces, and 2) prevent absorption of these compounds into the bloodstream, via their quantification in plasma and urine. In addition, we will monitor physiological parameters and behavior. These studies will establish the dose range for this oral treatment. Expected outcome is a candidate that provides rapid clearance of stimulants from the body and reversal of physiological and behavioral signs of toxicity, ready for large animal studies.