Development of therapeutics to treat fentanyl overdose using a validated animal model

项目总结： 根据疾病控制中心(CDC)的数据，合成阿片类药物目前是导致 在美国，过量死亡，而海洛因和处方阿片类药物死亡自那以来显著减少 2017年。尽管纳洛酮广泛可用，芬太尼和芬太尼类似物导致的死亡(F/FA) 在F/FA对纳洛酮耐药的报道不断增加的同时，这一数字继续上升。大剂量快速注射 F/FA导致声带闭合(VCC)和严重胸壁僵硬(CWR)在2 几分钟，持续10分钟的效果，似乎对纳洛酮有抵抗力。相比之下，吗啡- 衍生鸦片类药物(如海洛因)会导致呼吸抑制和轻微的肌肉僵硬，对 纳洛酮，但尚不知道会在人类体内引起VCC。这表明了不同的药理机制。 F/FA诱导的VCC与Mu阿片类药物介导的吗啡诱导的呼吸抑制的比较 感受器。为了支持这一假说，我们发表的药理学数据显示F/FA，但不是 吗啡或纳洛酮对可能调节F/FA诱导的这些效应的异地靶点具有亲和力。入内 根据可用的数据，体外数据包括可能与人体生理相关的F/FA浓度 F/FA的脑脂浓度模型。此外，我们已经在动物模型中证明了 这些芬太尼诱导的效应对大剂量纳洛酮具有抵抗力，并可能涉及这些非现场受体 目标。这一初步数据表明，开发有效的过量用药疗法需要生物学上的 模型重新概念化F/FA过量死亡的根本原因，以包括VCC，除了 呼吸抑制。因此，此第一阶段提案的目标是完成对 复制临床上出现的芬太尼快速毒性效应的综合动物模型 针对VCC的配方的初步鉴定。目前没有联邦药品管理局 已批准的针对这些F/FA毒性影响的治疗方法，该项目直接满足了对 开发一种针对F/FA过量的新疗法。

PROJECT SUMMARY: According to the Centers for Disease Control (CDC), synthetic opioids are currently the most common cause of overdose death in the U.S, while heroin and prescription opioid deaths have decreased significantly since 2017. Despite the widespread availability of naloxone, deaths from fentanyl and fentanyl analogues (F/FA) continue to rise in parallel with increasing reports of F/FA resistance to naloxone. High doses of rapidly injected F/FA cause airway obstruction from vocal cord closure (VCC) and severe chest wall rigidity (CWR) within 2 minutes, effects that persist for up to 10 minutes and appear to be resistant to naloxone. In contrast, morphine- derived opiates (e.g. heroin) cause respiratory depression and mild muscle rigidity that is responsive to naloxone, but are not known to cause VCC in humans. This suggests distinct pharmacological mechanisms underlying F/FA-induced VCC, compared to morphine-induced respiratory depression mediated by mu opioid receptors. In support of this hypothesis, our published pharmacological data demonstrate F/FA, but not morphine or naloxone, have affinity for off-site targets that may regulate these F/FA-induced effects. The in vitro data include F/FA concentrations that may be physiologically relevant to humans, based on available models of brain lipid concentrations for F/FA. Additionally, we have demonstrated in our animal model that these fentanyl-induced effects are resistant to high dose naloxone and may involve these off-site receptor targets. This preliminary data suggests the development of effective therapies for overdose require a biological model that re-conceptualizes the underlying causes of F/FA overdose deaths to include VCC, in addition to respiratory depression. Therefore, the goal of this Phase I proposal is to complete the validation of a comprehensive animal model replicating the rapid fentanyl toxicity effects seen clinically in humans and the preliminary identification of formulations that address VCC. There are currently no Federal Drug Administration approved treatments that target these F/FA toxicity effects, and this project directly addresses the need for the development of a new class of therapeutics, specific to F/FA overdose.