An oral therapeutic to treat intoxication by prescription and illicit stimulants

项目总结/摘要 有一个显著的未满足的医疗需求，以隔离和删除口服摄入的处方 和非法兴奋剂从胃肠道（GI）道，以防止和治疗过量。的 过去，处方药和非法兴奋剂的供应、使用、误用和滥用急剧增加 从儿童到成人的所有年龄段。在美国，超过400万儿童和年轻人服用 用于治疗注意缺陷多动障碍（ADHD）的处方兴奋剂，以及急诊室 (ER)与这些药物有关的就诊估计每年超过20万人次。2020年，510万人 12岁及以上的人报告在过去一年中滥用处方兴奋剂， 兴奋剂使用障碍目前的标准治疗，即口服活性炭，疗效有限。的 非法兴奋剂甲基苯丙胺是美国增长最快的滥用药物，目前还没有治疗方法 可以用来治疗冰毒中毒类似的化合物被广泛用作“俱乐部”药物， 可能致命，特别是与酒精消费相结合。因此，一种有效的，易于管理的 需要解毒剂来快速结合口服摄入的兴奋剂并防止其吸收到血流中。 这种即时治疗将挽救生命。该项目的目标是开发一种广谱的口服 用于预防和治疗由口服摄入引起的急性危及生命的中毒的解毒剂 兴奋剂我们的解毒剂是基于一种新型的螯合剂， 具有高度特异性的物质。口服时，它们在胃肠道中起作用， 目标被吸收到血液和大脑中。护理标准，木炭，有一些限制。在 相比之下，我们的水溶性螯合剂更有效、作用更快、安全且易于施用。选择 为了获得有效的治疗药物，我们将进行以下目标：目标1将完成体外结合筛选 本发明的目的是评估螯合剂对广谱刺激剂的亲和力，并选择用于体内研究的候选物。我们将 筛选结合亲和力和选择性。我们将评估个别兴奋剂的存在和不存在 酒精预期结果是一种用于体内研究的口服给药治疗候选药物。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， 啮齿类动物模型，使用木炭作为对照。我们将量化主要候选人的有效性和时间进程，以1） 消除安非他明，哌醋甲酯，和3，4-亚甲二氧基甲基安非他明，在浓度 足以引起严重中毒，从胃肠道进入粪便，和2）阻止吸收 这些化合物进入血液，通过它们在血浆和尿液中的定量。此外，我们将 监测生理参数和行为。这些研究将确定这种口服给药的剂量范围。 治疗预期结果是提供快速清除体内兴奋剂的候选药物， 逆转毒性的生理和行为迹象，为大型动物研究做好准备。

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.