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

项目概要： 根据疾病控制中心（CDC），合成阿片类药物是目前最常见的原因， 过量死亡在美国，而海洛因和处方阿片类药物死亡人数显着下降，因为 2017.尽管纳洛酮广泛可用，但芬太尼和芬太尼类似物（F/FA） 随着纳洛酮F/FA耐药报告的增加，高剂量快速注射 F/FA在2分钟内引起声带闭合（VCC）和严重胸壁僵硬（CWR）导致气道阻塞 分钟，效果持续长达10分钟，似乎对纳洛酮有抗药性。相反，吗啡- 衍生的阿片类药物（如海洛因）引起呼吸抑制和轻度肌肉僵硬， 纳洛酮，但不知道在人类中引起VCC。这表明不同的药理机制 F/FA诱导的VCC与μ阿片介导的吗啡诱导的呼吸抑制相比 受体。为了支持这一假设，我们发表的药理学数据表明F/FA，但不是 吗啡或纳洛酮对可调节这些F/FA诱导的作用的非原位靶点具有亲和力。的in 体外数据包括可能与人类生理相关的F/FA浓度，基于可用的 F/FA的脑脂质浓度模型。此外，我们已经在我们的动物模型中证明， 这些芬太尼诱导的效应对高剂量纳洛酮具有抵抗性， 目标的这一初步数据表明，开发有效的药物过量疗法需要生物学方法， 模型重新概念化F/FA过量死亡的根本原因，以包括VCC，此外， 呼吸抑制因此，第一阶段提案的目标是完成 复制临床上在人类中观察到的快速芬太尼毒性作用的综合动物模型， 解决VCC的制剂的初步鉴定。目前没有联邦药品管理局 针对这些F/FA毒性效应的批准治疗，该项目直接解决了 开发一类新的治疗药物，专门针对F/FA过量。

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.