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Evaluation of the drug-drug interactions of fentanyl with stimulants in the context of overdose

过量服用芬太尼与兴奋剂之间药物相互作用的评估

基本信息

批准号：
10433799
负责人：
Xinhua Li
金额：
$ 11.49万
依托单位：
CLEAR SCIENTIFIC, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10433799
关键词：
Acute Adverse effects Animals Automobile Driving Behavioral Binding Blood Pressure Blood gas Breathing Centers for Disease Control and Prevention (U.S.)Cessation of life Clinical Cocaine Collaborations Complex Data District of Columbia Doctor of Philosophy Dose Drug Evaluation Drug Interactions Drug Kinetics Effectiveness Electrocardiogram Fentanyl Foundations Future General Hospitals Half-Life Heart Rate Heroin Human In Vitro Individual Injections Intoxication Intravenous Length Link Masks Massachusetts Metabolism Methamphetamine Muscle Rigidity Naloxone Neuraxis Opioid Overdose Pharmaceutical Preparations Pharmacology Physiological Plasma Rattus Reflex action Renal clearance function Respiratory Muscles Rodent Safety Sedation procedure Seizures Site Symptoms Therapeutic Tidal Volume Time Translating Urine Ventilatory Depression analog awake base club drug drug candidate emergency settings hemodynamics in vivo mu opioid receptors novel novel therapeutic intervention novel therapeutics opioid epidemic opioid overdose opioid withdrawal overdose death respiratory synthetic opioid targeted treatment ventilation

项目摘要

Project Summary/Abstract CDC data show that between 2013 and 2020 fentanyl-linked deaths have increased 10-fold and are now twice those involving heroin. Fentanyl and fentanyl analogues (F/FA) are commonly found in seizure of stimulants and “club drugs.” Compounding this crisis is the concurrent use of F/FA with stimulants, particularly methamphetamine and cocaine, driving the so-called 4th wave of the opioid crisis. Illicitly manufactured fentanyl, heroin, cocaine, or methamphetamine (alone or in combination) were involved in nearly 85% of drug overdose deaths in 24 states and the District of Columbia during January-June 2019. Unfortunately, there is limited understanding of the drug-drug interactions and physiological consequences of F/FA co-intoxication with a stimulant, and there are no targeted therapies. Co-intoxication manifests in a complex continuum of clinical presentation due to different effect sites and drug-drug interactions, which can intensify or mask symptoms. Some symptoms include opioid-induced respiratory depression and muscle rigidity, and stimulant-induced increases in blood pressure and heart rate. The primary opioid reversal agent, naloxone, a µ-opioid receptor (MOR) antagonist, as a solo therapeutic, may provoke acute opioid withdrawal exacerbated by unopposed stimulant effects; naloxone's short duration of action may also result in re-narcotization. It is crucial to understand the drug-drug interactions in opioid-stimulant co-use. In addition, a single therapeutic that reverses the adverse effects of both co-intoxicants, simultaneously, through enhanced pharmacokinetic clearance would be highly beneficial. Our drug candidate, CS-1103, currently being studied as reversal agent for methamphetamine, also holds promise for treatment of opioid-stimulant co-intoxication. To better understand the in vivo physiologic and pharmacologic impact of F/FA-stimulant co-intoxication and to provide a foundation for CS-1103, and its use in conjunction with naloxone, we will undertake the following Aims in rodent studies of opioid intoxication: Aim 1 will determine the physiological and pharmacological effects of fentanyl- methamphetamine co-intoxication in awake, behaving rats. We will administer fentanyl and methamphetamine at various ratios, dose levels, and length of time between opioid and stimulant dosing. We will quantify effects on breathing, metabolism, hemodynamics, intoxicant pharmacokinetics, muscle rigidity, and sedation/immobility. These studies will provide a better understanding of the complex interaction between fentanyl and methamphetamine, to guide future therapies. Aim 2 will determine the physiological and pharmacological effects of fentanyl-methamphetamine co-intoxication reversal by CS-1103 in awake, behaving rats. We will identify doses of CS-1103 alone (and also in conjunction with naloxone) required to normalize intoxicant-induced effects identified in Aim 1. These studies will clarify the safety, efficacy, optimum dosing, and therapeutic potential of these novel therapeutics and will provide data that guides future large animal and human studies.

项目概要/摘要 CDC数据显示，2013年至2020年间，与芬太尼相关的死亡人数增加了10倍，目前是两倍涉及海洛因的。芬太尼和芬太尼类似物 (F/FA) 常见于兴奋剂癫痫发作和“俱乐部毒品”。 F/FA 与兴奋剂的同时使用使这场危机更加复杂化，特别是甲基苯丙胺和可卡因，推动了所谓的第四波阿片类药物危机。非法制造芬太尼，近 85% 的药物过量涉及海洛因、可卡因或甲基苯丙胺（单独或组合） 2019 年 1 月至 6 月期间，24 个州和哥伦比亚特区出现死亡病例。不幸的是，死亡人数有限了解药物间相互作用以及 F/FA 共中毒的生理后果兴奋剂，并且没有靶向治疗。共中毒表现在一系列复杂的临床过程中由于不同的作用位点和药物间相互作用而导致的表现，可能会加剧或掩盖症状。一些症状包括阿片类药物引起的呼吸抑制和肌肉僵硬，以及兴奋剂引起的血压和心率增加。主要阿片类药物逆转剂纳洛酮，μ-阿片类受体 (MOR) 拮抗剂作为单独治疗可能会引起急性阿片类药物戒断，而无对抗则加剧这种戒断兴奋作用；纳洛酮的作用持续时间短也可能导致再次麻醉。了解阿片类兴奋剂共同使用中的药物相互作用至关重要。此外，单一治疗通过增强药代动力学，同时逆转两种共毒物的不利影响清关将是非常有益的。我们的候选药物 CS-1103 目前正在研究作为逆转剂甲基苯丙胺也有望用于治疗阿片类兴奋剂合并中毒。为了更好地理解 F/FA 刺激物共中毒的体内生理和药理学影响并提供基础对于 CS-1103 及其与纳洛酮的联合使用，我们将在啮齿动物研究中实现以下目标阿片类药物中毒：目标 1 将确定芬太尼的生理和药理作用清醒、行为正常的大鼠中甲基苯丙胺共中毒。我们将给予芬太尼和不同比例、剂量水平以及阿片类药物和兴奋剂给药之间的时间长度的甲基苯丙胺。我们将量化对呼吸、新陈代谢、血流动力学、麻醉药代动力学、肌肉僵硬、和镇静/不动。这些研究将有助于更好地理解两者之间复杂的相互作用。芬太尼和甲基苯丙胺，指导未来的治疗。目标 2 将确定生理和 CS-1103 逆转芬太尼-甲基苯丙胺共中毒的药理作用醒着，表现得像老鼠。我们将确定单独使用 CS-1103 的剂量（以及与纳洛酮联合使用的剂量）需要使目标 1 中确定的麻醉剂引起的影响正常化。这些研究将阐明安全性、这些新型疗法的功效、最佳剂量和治疗潜力，并将提供指导数据未来的大型动物和人类研究。