I-Corps Project plan for:STTR Phase I Development of therapeutics to treat fentanyl overdose using a validated animal model

I-Corps 项目计划：STTR 第一阶段 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: 10541304
• 负责人: Phillip Randolph Torralva
• 金额: $ 5.5万
• 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 2022-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541304
• 关键词: Affinity; Animal Model; Biological Models; Brain; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chest wall structure; Clinical; Data; Development; Dose; Fentanyl; Formulation; Heroin; Human; In Vitro; Innovation Corps; Lipids; Mediating; Medical; Modeling; Morphine; Muscle Rigidity; Naloxone; Opioid; Overdose; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Publishing; Reporting; Resistance; Site; Small Business Technology Transfer Research; Testing; Therapeutic; Toxic effect; Validation; Ventilatory Depression; airway obstruction; analog; base; effective therapy; fentanyl overdose; mu opioid receptors; novel; off-target site; opioid epidemic; opioid mortality; overdose death; prescription opioid; receptor; synthetic opioid; 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, off-site targets our published pharmacological data demonstrate F/FA, but not morphine or naloxone, have affinity for models of brain lipid concentrations for F/FA. Additionally, we have demonstrated in our animal model that 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 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 to include VCC, in addition to respiratory depression. There is currently no Federal Drug Administration development of a new class of therapeutics, specific to F/FA overdose. Under the I-Corp project, the team will seek to validate or modify its hypotheses regarding the market, target customers, and critical market need.

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最多的 在美国过量死亡的常见原因，而海洛因和处方阿片类药物死亡 自2017年以来大幅下降。尽管纳洛酮广泛可用， 芬太尼和芬太尼类似物（F/FA）继续上升，与此同时， F/FA对纳洛酮耐药。快速注射高剂量F/FA会导致气道阻塞， 声带闭合（VCC）和严重的胸壁僵硬（CWR）在2分钟内， 持续时间长达10分钟，似乎对纳洛酮耐药。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， 对纳洛酮有反应，但不知道会引起人体VCC。这表明 与吗啡诱导的VCC相比，F/FA诱导的VCC的药理机制 μ阿片受体介导的呼吸抑制。为了支持这一假设， 我们已发表的药理学数据表明，F/FA，而不是吗啡或 纳洛酮对F/FA的脑脂质浓度模型具有亲和力。此外，我们还有 在我们的动物模型中证明，这可能会调节这些F/FA诱导的效应。的in 体外数据包括可能与人类生理相关的F/FA浓度， 这些芬太尼诱导的效应对高剂量纳洛酮具有抗性， 这些受体靶点。这些初步数据表明， 药物过量的治疗需要一种生物学模型， 除呼吸抑制外，F/FA还包括VCC。目前没有任何联邦 药物管理局开发了一类新的治疗药物，专门针对F/FA过量。 在I-Corp项目下，该小组将寻求验证或修改其关于 市场、目标客户和关键市场需求。