Transcutaneous Phrenic Nerve Stimulation for Treating Opioid Overdose

经皮膈神经刺激治疗阿片类药物过量

• 批准号: 10681111
• 负责人: SANDRA D COMER
• 金额: $ 92.73万
• 依托单位: CORIDEA, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681111
• 关键词: Apnea; Applications Grants; Automated External Defibrillator; Award; Benzodiazepines; Blood gas; Breathing; Businesses; Cardiovascular system; Cause of Death; Cessation of life; Chest; Chest wall structure; Clinical; Clinical Trials; Cocaine; Collaborations; Commercial grade; Communities; Data; Detection; Devices; Diagnosis; Dose; Drug Modelings; Electric Stimulation; Electrodes; Electronics; Emergency response; Environment; Epidemic; Evolution; External Defibrillator; Family suidae; Fentanyl; Functional disorder; Future; Generations; Geometry; Goals; Grant; Home; Homeostasis; Hospitals; Human; Human Volunteers; Hypoventilation; Hypoxic Brain Damage; Illicit Drugs; Impedance Cardiography; Individual; Industrialization; Institutional Review Boards; Intervention; Investigation; Laboratories; Life; Marketing; Mechanics; Mediating; Medical; Methamphetamine; Modeling; Morbidity - disease rate; Muscle Rigidity; Naloxone; Neck; Opioid; Opioid Antagonist; Opioid Receptor; Outpatients; Overdose; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phase; Physiological; Pre-Clinical Model; Preclinical Testing; Preparation; Process; Qualifying; Recording of previous events; Research; Research Project Grants; Respiration; Safety; Small Business Innovation Research Grant; Stimulant; Structure of phrenic nerve; Support System; Symptoms; System; Testing; Time; Training; United States; Update; Ventilatory Depression; Wooden Chest Syndrome; Work; combat; data submission; design; design verification; experience; fentanyl overdose; fentanyl use; healthy volunteer; human model; illicit opioid; innovation; models and simulation; mortality; non-opioid analgesic; noradrenergic; opioid epidemic; opioid overdose; opioid use disorder; opioid user; overdose death; porcine model; portability; pre-clinical; preclinical development; prototype; remifentanil; research clinical testing; respiratory; safety and feasibility; safety testing; synthetic opioid; tool; trial design; usability; ventilation

In the U.S., an exponential increase in opioid-related overdose deaths has occurred over the last decade. The hallmark symptom of an opioid-related overdose is decreased respiration, which can result in permanent hypoxic brain injury within minutes. The purpose of the proposed research is to develop a community-deployable Automated External Respiration System (AERS) device that is capable of maintaining adequate respiration in individuals experiencing opioid-induced respiratory depression - via external stimulation of the phrenic nerve - until other medical interventions (e.g., naloxone) can be administered or the effects of the opioids dissipate naturally over time. The concept of the AERS device is modeled after Automated External Defibrillator devices (AEDs), which are now widely available in medical and public settings for use by both medically trained and untrained individuals. A prototype AERS device was developed under a previous Small Business Innovation Research grant awarded to Coridea and demonstrated to be safe and effective in sustaining breathing in a preclinical model of drug- induced respiratory depression. The proposed research seeks to qualify the prototype system for human use, demonstrate feasibility and safety in human volunteers in a hospital setting, and then develop a commercial system capable of community deployment. The current prototype will be further optimized in miniature pigs (Aim 1a), and then evaluated for safety using rigorous testing in pigs under fentanyl-induced respiratory depression with different levels of chest wall compliance to mimic fentanyl-induced “wooden chest syndrome,” and finally in the setting of naloxone reversal (Aim 1b). Results from Aims 1a and 1b will be used to support an IDE for testing the AERS device in a clinical model of opioid-induced respiratory depression in healthy volunteers without (Aim 2a) and with opioid use disorder (Aim 2b). A commercial-grade, AED-like device will then be designed (Aim 3a) and tested in a human factors study (Aim 3b). The data collected in Aims 1-3 will be submitted to the FDA for approval of a pivotal trial (designed in collaboration with the FDA), which will be supported by a future grant proposal. The AERS device is built on the successful concept for treating cardiovascular dysfunction and can potentially be used in combination with AEDs to treat multi- drug overdoses (e.g., stimulants + opioids), and may offer a critical tool for use by medical and lay persons to reduce the morbidity and mortality associated with opioid overdoses.

在美国，过去十年中，阿片类药物相关的过量死亡人数呈指数增长。这 阿片类药物相关过量的标志性症状减少了呼吸，这可能导致永久性低氧 几分钟之内的脑损伤。拟议的研究的目的是开发一个可动人的人 自动化外部呼吸系统（AERS）设备，能够保持足够的呼吸 经历了OioID诱导的呼吸抑郁症的个体 - 通过外部刺激神经神经 - 直到可以施用其他医疗干预措施（例如纳洛酮）或阿片类药物的影响消散 自然会随着时间的流逝。 AERS设备的概念以自动化外部除颤器设备进行建模 （AED），现在在医疗和公共环境中广泛使用，以供受过医学培训和 未经训练的人。 原型AERS设备是根据先前的小型企业创新研究赠款开发的 在Coridea上，在药物的临床前模型中可以安全有效地维持呼吸 诱发呼吸抑郁症。拟议的研究旨在使原型系统符合人类使用的原型系统， 在医院环境中证明人类志愿者的可行性和安全性，然后开发广告 能够社区部署的系统。当前的原型将在微型猪中进一步优化（AIM 1A），然后在芬太尼诱导的呼吸道抑郁症的猪中使用严格的测试评估安全性 具有不同水平的胸壁符合模仿芬太尼引起的“木制胸部综合症”的依从性，最后 纳洛酮逆转的设置（AIM 1B）。 AIMS 1A和1B的结果将用于支持测试IDE 在没有阿片类药物诱导的呼吸道抑郁症的临床模型中，AERS设备没有任何（AIM） 2a）和卵毒素使用障碍（AIM 2B）。然后将设计一种商用级，类似AED的设备（AIM 3A） 并在人为因素研究中进行了测试（AIM 3B）。 AIMS 1-3中收集的数据将提交给FDA 批准关键试验（与FDA合作设计），该试验将得到未来的赠款的支持 提议。 AERS设备建立在治疗心血管功能障碍的成功概念上，并可能有可能 与AED结合使用，以治疗多药量过量（例如刺激剂 +阿片类药物），并可能提供 医疗和外行人使用的关键工具，以降低与卵子相关的发病率和死亡率 过量服用。