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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要隔离和删除口服摄入的处方药存在重大未满足的医疗需求以及来自胃肠道 (GI) 的非法兴奋剂，以预防和治疗用药过量。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十年来，美国有超过 400 万儿童和年轻人服用该药物。用于治疗注意力缺陷多动障碍 (ADHD) 的处方兴奋剂和急诊室预计每年与这些药物相关的就诊人数将超过 200,000 人次，到 2020 年，这一数字将达到 510 万人次。 12 岁及以上的人报告过去一年滥用处方兴奋剂，其中 758,000 人持有处方兴奋剂目前的治疗标准是口服木炭，但疗效有限。非法兴奋剂甲基苯丙胺是美国滥用增长最快的药物，但目前尚无治疗方法类似的化合物可用作“俱乐部”药物，并且可用于治疗冰毒中毒。潜在致命，尤其是与饮酒结合使用。因此，它是一种有效且易于给药的药物。需要解毒剂来快速结合口服兴奋剂并防止吸收进入血液。这种立即治疗将挽救生命。该项目的目标是开发一种广谱口服药物。给予解毒剂以预防和治疗因口服摄入引起的急性危及生命的中毒我们的解毒剂基于一类新型螯合剂，可以紧密结合、灭活并清除有害物质。口服时，它们在胃肠道中发挥作用并减少体内的物质。木炭的治疗标准有许多局限性。相比之下，我们的水溶性螯合剂更有效、见效更快、安全且易于管理。有效的治疗，我们将实现以下目标：目标 1 将完成结合的体外筛选我们将研究多价螯合剂对多种兴奋剂的亲和力，并选择一种候选药物进行体内研究。我们将评估存在和不存在的个体兴奋剂的结合亲和力和选择性。预期结果是体内研究的一种主要口服治疗候选药物。在体内评估主要候选药物对口服兴奋剂的耐受性和功效啮齿动物模型，使用木炭作为对照，我们将主要候选者的功效和时间过程量化为 1)。消除一定浓度的苯丙胺、哌醋甲酯和 3,4-亚甲二氧基甲基苯丙胺足以引起严重中毒，从胃肠道进入粪便，并且 2) 阻止吸收通过血浆和尿液中的定量，将这些化合物进入血液。监测生理参数和行为，这些研究将确定这种口服药物的剂量范围。预期结果是一种能够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。