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

使用经过验证的动物模型开发治疗芬太尼过量的疗法

• 批准号: 10390135
• 负责人: Phillip Randolph Torralva
• 金额: $ 31.97万
• 依托单位: TORRALVA MEDICAL THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390135
• 关键词: Acute; Address; Adrenergic Antagonists; Adrenergic Receptor; Affinity; Animal Model; Autopsy; Biological Assay; Biological Models; Brain; Breathing; Centers for Disease Control and Prevention (U.S.); Central Nervous System Agents; Cessation of life; Characteristics; Chemicals; Chest wall structure; Clinical; Data; Development; Dose; Drug Combinations; Drug Delivery Systems; Drug Prescriptions; Drug Screening; FDA approved; Fentanyl; Formulation; Goals; Helping to End Addiction Long-term; Heroin; Human; Illicit Drugs; In Vitro; Injections; Intravenous Bolus; Intubation; Laryngismus; Laryngoscopy; Lipids; Measures; Mediating; Medical; Methamphetamine; Methods; Modeling; Morphine; Muscle Rigidity; Naloxone; Neuraxis; Opioid; Opioid Antagonist; Overdose; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Physiological; Plethysmography; Prazosin; Production; Public Health; Publishing; Rattus; Reporting; Research; Resistance; Site; Sprague-Dawley Rats; Statistical Data Interpretation; System; Technology; Testing; Therapeutic; Time; Toxic effect; Transducers; Treatment-related toxicity; United States National Institutes of Health; Validation; Ventilatory Depression; airway obstruction; alpha-1 adrenergic receptors; analog; base; carfentanil; commercialization; community setting; cost effective; drug testing; effective therapy; efficacy testing; fentanyl overdose; health data; heroin overdose; in vivo; mu opioid receptors; non-opioid analgesic; novel; off-target site; opioid epidemic; opioid mortality; opioid overdose; overdose death; preclinical efficacy; prescription opioid; prevent; receptor; response; synthetic opioid; tamsulosin; therapeutic development; vocal cord

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.

项目概要： 根据疾病控制中心 (CDC) 的数据，合成阿片类药物是目前最常见的原因 美国因吸毒过量死亡，而海洛因和处方阿片类药物死亡人数自此以来显着下降 2017 年。尽管纳洛酮广泛使用，但芬太尼和芬太尼类似物导致的死亡 (F/FA) 随着 F/FA 对纳洛酮耐药性的报道不断增加，这一数字继续上升。高剂量快速注射 F/FA 在 2 天内因声带闭合 (VCC) 和严重胸壁强直 (CWR) 导致气道阻塞 分钟，效果可持续长达 10 分钟，并且似乎对纳洛酮具有抵抗力。相比之下，吗啡—— 衍生的阿片类药物（例如海洛因）会导致呼吸抑制和轻度肌肉僵硬，从而对 纳洛酮，但尚不清楚是否会导致人类 VCC。这表明不同的药理学机制 与 mu 阿片类药物介导的吗啡诱导的呼吸抑制相比，潜在的 F/FA 诱导的 VCC 受体。为了支持这一假设，我们发表的药理学数据证明了 F/FA，但不是 吗啡或纳洛酮对异位靶标具有亲和力，可调节这些 F/FA 诱导的效应。在 体外数据包括可能与人类生理相关的 F/FA 浓度（基于现有数据） F/FA 的脑脂质浓度模型。此外，我们在动物模型中证明了 这些芬太尼引起的作用对高剂量纳洛酮具有抵抗力，并且可能涉及这些异位受体 目标。这一初步数据表明，开发有效的药物过量疗法需要生物制剂 该模型重新概念化 F/FA 过量死亡的根本原因，除了 VCC 之外，还包括 VCC 呼吸抑制。因此，第一阶段提案的目标是完成对 综合动物模型复制了临床上在人类和动物身上看到的快速芬太尼毒性作用 初步确定解决 VCC 问题的配方。目前没有联邦药物管理局 已批准针对这些 F/FA 毒性作用的治疗方法，该项目直接解决了以下需求： 开发针对 F/FA 过量的新型疗法。