An oral therapeutic to treat intoxication by prescription and illicit stimulants

一种治疗处方药和非法兴奋剂中毒的口服疗法

• 批准号: 10602918
• 负责人: Xinhua Li
• 金额: $ 31.99万
• 依托单位: CLEAR SCIENTIFIC, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602918
• 关键词: Acute; Adult; Affinity; Age; Alcohol consumption; Alcohols; Amphetamines; Animals; Antidotes; Area Under Curve; Attention deficit hyperactivity disorder; Behavior; Behavioral; Binding; Blood; Blood Circulation; Brain; Buffers; Cessation of life; Charcoal; Child; Complex; Cyclic GMP; Dose; Emergency department visit; Feces; Gastrointestinal tract structure; Goals; In Vitro; Individual; Ingestion; Injectable; Intestinal Absorption; Intoxication; Lead; Life; Liquid substance; Medical; Methamphetamine; Molecular; National Institute of Drug Abuse; Oral; Oral Administration; Oral Ingestion; Outcome; Overdose; Perception; Persons; Pharmaceutical Preparations; Physiologic Monitoring; Physiological; Plasma; Powder dose form; Reporting; Ritalin; Rodent; Rodent Model; Sensory; Specificity; Stimulant; Stomach; Therapeutic; Time; Toxic effect; Unconscious State; Urine; Water; Work; absorption; acute toxicity; aged; analog; base; capsule; club drug; drug of abuse; ecstasy; in vivo; lead candidate; methamphetamine effect; microcalorimetry; misuse of prescription only drugs; mortality; novel; prescription stimulants; prevent; programs; screening; standard of care; stimulant use disorder; therapeutic candidate; young adult

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.

项目摘要/摘要 有很大的未满足的医疗需求，需要隔离和删除口腔摄入的处方 和胃肠道（GI）的非法兴奋剂，以预防和治疗过量。这 在过去 从儿童到成年人的所有年龄段的十年。美国超过400万儿童和年轻人服用 用于治疗注意力缺陷多动症（ADHD）和急诊室的处方刺激物 （ER）与这些药物相关的访问估计每年超过200,000。 2020年，有510万人 12岁及以上的年龄较大 刺激性使用障碍。当前的护理标准，口服木炭，效率有限。这 非法刺激甲基苯丙胺是美国增长最快的滥用药物，但目前尚无治疗 可用于治疗甲基含量。类似的化合物被广泛用作“俱乐部”药物，并且是 潜在的致命，特别是与饮酒结合使用。因此，潜力，易于管理的人 需要解毒剂来快速结合，并防止口服刺激剂滥用血液。 这样的立即治疗将挽救生命。该项目的目的是开发一个宽阔的口头 施用解毒剂，以预防和治疗由口服摄取引起的急性威胁生命的醉酒 我们的解毒剂基于一种新型的隔离物，它们紧密结合，灭活和明显有害 具有高特异性的物质。口服时，它们在胃肠道中工作并减少 吸收血液和大脑的靶标。护理标准，木炭有许多局限性。在 对比，我们的水溶性隔离物具有更大的潜力，更快的作用，安全且易于管理。选择一个 潜在理论，我们将实现以下目的：AIM 1将完成绑定的视频筛查 螯合剂与各种兴奋剂的亲和力，并选择用于体内研究的候选者。我们将 屏幕结合亲和力和选择性。我们将在有和不存在的情况下评估单个兴奋剂 酒精。预期结果是用于体内研究的口头治疗候选者之一。 AIM 2意志 评估铅候选者在体内的耐受性和效率 啮齿动物模型，使用木炭作为对照。我们将将主要候选人的效率和时间课程量化为1） 以浓度消除苯丙胺，甲基苯甲酸酯和3,4-甲基二甲基甲基甲基苯丙胺 足以从胃肠道变成粪便，并引起明显的肠毒性，2）防止滥用 这些化合物通过血浆和尿液的定量进入血液。此外，我们将 监测生理参数和行为。这些研究将确定该口腔的剂量范围 治疗。预期结果是候选人，可快速清除体内的兴奋剂， 毒性的物理和行为迹象的逆转，准备进行大型动物研究。