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

项目摘要/摘要 美国疾病控制与预防中心的数据显示，2013至2020年间，与芬太尼有关的死亡人数增加了10倍，现在是现在的两倍 涉及海洛因的案件。芬太尼和芬太尼类似物(F/FA)在兴奋剂发作中常见 还有“夜总会毒品”使这一危机雪上加霜的是同时使用F/FA和兴奋剂，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。非法制造的芬太尼， 海洛因、可卡因或甲基苯丙胺(单独或联合使用)与近85%的药物过量有关 2019年1月至6月，24个州和哥伦比亚特区的死亡人数。不幸的是，有有限的 F/FA联合中毒的药物-药物相互作用和生理后果的理解 兴奋剂，而且没有针对性的治疗方法。联合中毒表现为一系列复杂的临床症状 由于不同的作用部位和药物与药物的相互作用而产生的症状，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。主要的阿片反转剂--微阿片受体纳洛酮 (MOR)拮抗剂作为一种单独治疗药物，可引起急性阿片类药物戒断，而非拮抗剂则加剧了这一现象 刺激性作用；纳洛酮的作用时间短也可能导致再麻醉。 了解阿片类兴奋剂联合使用中药物与药物的相互作用是至关重要的。此外，单一的治疗方法 这通过增强药代动力学，同时逆转了两种共中毒药物的不良影响 放行将是非常有益的。我们的候选药物CS-1103目前正在作为逆转药物进行研究 甲基苯丙胺也有望治疗阿片类兴奋剂联合中毒。为了更好地理解 F/FA刺激剂联合中毒对体内生理和药理的影响并提供依据 对于CS-1103，以及它与纳洛酮的联合使用，我们将在啮齿动物研究中承担以下目标 阿片中毒：目标1将确定芬太尼的生理和药理作用- 清醒、行为正常的大鼠甲基苯丙胺共中毒。我们会给你芬太尼和 甲基苯丙胺在不同的比例、剂量水平和阿片类药物和兴奋剂剂量之间的时间长度。我们 将量化对呼吸、新陈代谢、血流动力学、醉人药代动力学、肌肉僵硬、 和镇静/静止。这些研究将提供一个更好的理解之间复杂的相互作用 芬太尼和甲基苯丙胺，以指导未来的治疗。目标2将决定生理学和 CS-1103逆转芬太尼-甲基苯丙胺联合中毒的药理作用 醒着，行为不端的老鼠。我们将单独确定CS-1103的剂量(也将与纳洛酮联合使用) 需要将目标1中确定的醉酒诱导效应正常化。这些研究将澄清安全性， 这些新疗法的有效性、最佳剂量和治疗潜力，并将提供指导 未来的大型动物和人类研究。

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.