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.

项目摘要： 根据疾病控制中心（CDC）的数据，合成阿片类药物目前是目前的最常见原因 从起来，美国的服用过量死亡，而海洛因和处方阿片类药物死亡自此显着下降 2017年。尽管纳洛酮广泛可用，但芬太尼和芬太尼类似物的死亡（f/fa） 与增加纳洛酮的F/FA耐药性的报告越来越多。高剂量快速注射 F/FA导致声带闭合（VCC）和严重的胸壁刚度（CWR）的气道阻塞2 分钟，效果持续长达10分钟，并且似乎对纳洛酮具有抵抗力。相反，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，这对 纳洛酮，但尚不知道会导致人类VCC。这表明了不同的药理机制 与吗啡诱导的呼吸道抑郁症相比，基本的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，但没有 吗啡或纳洛酮对可能调节这些F/FA诱导效应的现场靶标具有亲和力。 in 体外数据包括可能与人类相关的F/FA浓度，基于可用的 F/FA的脑脂质浓度的模型。此外，我们在动物模型中证明了 这些芬太尼诱导的作用对高剂量纳洛酮具有抗性，可能涉及这些异地受体 目标。该初步数据表明开发过量的有效疗法需要生物学 重新概念化了F/FA过量死亡的根本原因以包括VCC，此外 呼吸抑郁。因此，该阶段I建议的目的是完成验证 综合动物模型复制人类和 对解决VCC的配方的初步识别。目前没有联邦药物管理局 针对这些F/FA毒性效应的批准治疗方法，该项目直接解决了对 开发一种新的治疗剂，特定于F/FA过量。