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

项目总结/摘要 CDC数据显示，2013年至2020年，芬太尼相关死亡人数增加了10倍，现在是两倍。 涉及海洛因的。芬太尼和芬太尼类似物（F/FA）是常见于兴奋剂的癫痫发作 “俱乐部毒品”。使这一危机更加严重的是F/FA与兴奋剂的同时使用，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， 海洛因、可卡因或甲基苯丙胺（单独或混合）参与了近85%的药物过量 2019年1月至6月期间，24个州和哥伦比亚特区的死亡人数。不幸的是， 了解药物间的相互作用和F/FA共中毒的生理后果， 兴奋剂，而且没有针对性的治疗。共中毒表现为一个复杂的临床连续性 由于不同的作用部位和药物相互作用，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。主要的阿片类药物逆转剂纳洛酮，一种μ-阿片受体 (MOR)拮抗剂，作为一个单独的治疗，可能会引起急性阿片类药物戒断加剧， 兴奋作用;纳洛酮的作用持续时间短也可能导致再麻醉。 了解阿片类兴奋剂合用中的药物相互作用至关重要。此外，单一治疗剂 通过增强药代动力学， 清除会非常有益。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类阿片兴奋剂合并中毒。更好地了解 F/FA-兴奋剂共中毒的体内生理和药理学影响，并提供基础 对于CS-1103及其与纳洛酮联合使用，我们将在啮齿动物研究中进行以下研究： 阿片类药物中毒：目标1将确定芬太尼的生理和药理作用， 清醒的行为大鼠中的甲基苯丙胺共中毒。我们会注射芬太尼， 在各种比例、剂量水平和阿片样物质和兴奋剂给药之间的时间长度下的甲基苯丙胺。我们 将量化对呼吸，新陈代谢，血液动力学，麻醉药代动力学，肌肉僵硬， 和镇静/不动。这些研究将使我们更好地了解 芬太尼和甲基苯丙胺，以指导未来的治疗。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 醒着的老实的老鼠我们将确定CS-1103单独给药（以及与纳洛酮联合给药）的剂量 这是使目标1中确定的麻醉剂诱导效应正常化所必需的。这些研究将阐明安全性， 这些新疗法的疗效、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.