Portable hand-held proprietary xenon inhaler for rapid reduction of opioid withdrawal symptoms

便携式手持式专有氙气吸入器可快速减少阿片类药物戒断症状

• 批准号: 10390876
• 负责人: Vlad Bogin
• 金额: $ 32万
• 依托单位: NOBILIS THERAPEUTICS, INC.
• 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 2023-05-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390876
• 关键词: Adrenergic Agonists; Adrenergic Receptor; Anesthesia procedures; Antiinflammatory Effect; Anxiety; Attenuated; Blood; Brain; Buprenorphine; Capital; Client; Clinical; Clonidine; Complex; Critical Care; Data; Development; Devices; Diarrhea; Dizziness; Dose; Elements; Gases; Goals; Hand; Helping to End Addiction Long-term; Hepatic; Hospitals; Hour; Human; Hyperactivity; Hypotension; Impairment; Individual; Inflammation; Inhalation; Inhalation Device; Inhalators; Kidney; Lead; Legal patent; Licensing; Maintenance; Medical; Modeling; Morbidity - disease rate; Morphine; Mus; Naltrexone; Nausea; Opiate Addiction; Opioid; Opioid Antagonist; Opioid agonist; Oral; Outcome; Oxidative Stress; Panic Disorder; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Population; Post-Traumatic Stress Disorders; Procedures; Relapse; Rewards; Safety; Schedule; Sedation procedure; Severities; Signal Transduction; Small Business Technology Transfer Research; Societies; Supervision; Sympathetic Nervous System; Symptoms; Syndrome; Testing; Therapeutic; Time; Tissues; Treatment Refusal; United States Food and Drug Administration; United States National Institutes of Health; Vomiting; Withdrawal; Withdrawal Symptom; Xenon; buprenorphine treatment; care providers; cost; drug seeking behavior; experience; handheld equipment; head-to-head comparison; imaging agent; lofexidine; mortality; mu opioid receptors; non-opioid analgesic; noradrenergic; off-label use; opioid tapering; opioid therapy; opioid use; opioid use disorder; opioid withdrawal; patients who use opioids; phase 2 study; portability; pre-clinical; prescription opioid; programs; side effect

Summary/Abstract People with opioid use disorder (OUD) experience aversive opioid withdrawal symptoms (OWS) including nausea, diarrhea, vomiting, and anxiety, which emerge when blood opioid levels wane. These symptoms perpetuate unprescribed opioid use and accompanying morbidity and mortality, costing society nearly $80 billion per year. Withdrawal symptoms also emerge upon initiation of OUD pharmacotherapy with µ opioid receptor antagonists (buprenorphine: partial; naltrexone: full), complicating, and sometimes resulting in patient refusal of, treatment initiation or continuation. Better management of OWS is considered a “gateway to opioid dependence treatment”. The a2-adrenergic receptor agonists clonidine and lofexidine attenuate opioid withdrawal symptoms by inhibiting noradrenergic signaling. However, these agents have shortcomings: they don’t fully suppress withdrawal symptoms or subjective discomfort, they induce problematic side effects (hypotension, sedation, discontinuation syndrome), their dosing must be adjusted for renal or hepatic impairment patients, and, as oral medications, they are slow acting. Thus, there is an urgent unmet need for better and faster-acting treatments. One strategy to reduce OWS severity is to lower opioid-induced inflammation and oxidative stress, which upregulate noradrenergic tone, sympathetic nervous system (SNS) activity, and OWS severity. Inhaled xenon (Xe) gas inhibits inflammation and SNS activity and is hypothesized to attenuate OWS severity. Xe is used at low concentration (28%) as an imaging agent and rarely induces hypotension or dizziness, even in critical care populations. Xe rapidly (within minutes) equilibrates in brain and other tissues and inhibits SNS activity, suggesting that it may be superior to a2-adrenergic agonists for attenuating OWS. Moreover, Xe has no demonstrable abuse liability, making it superior to opioid agonist substitution treatment for relieving OWS. In this Phase I STTR program, we propose to conduct preclinical proof of concept studies in morphine-dependent mice to determine whether 30% Xe, which is non-sedating when given by inhalation, rapidly reduces OWS severity. If Xe is effective, we will file an IND for a human STTR Phase II study to evaluate whether Xe decreases OWS during medically-managed opioid tapering required before buprenorphine initiation. Nobilis Therapeutics developed a proprietary portable hand-held Xe inhalation device and the drug/device combination has been cleared by the US Food and Drug Administration for testing in humans with Posttraumatic-Stress Disorder. This device also could be used in OUD studies, supporting capital efficiency with exit potential. Nobilis holds a patent covering Xe’s anti-inflammatory effects and licenses a patent from McLean Hospital covering Xe’s antianxiety effects. Accordingly, elements are in place to develop and market Xe therapy, if effective, to several potential clients including care providers and companies that sell buprenorphine, naltrexone, and Xe. Thus, commercial viability is high.

摘要/摘要 患有绿然药物使用障碍（OUD）的人经历厌恶的卵虫类戒断症状（OWS） 恶心，腹泻，呕吐和动画，当血液中的水平减弱时会出现。这些符号 使未经规定的阿片类药物使用和参与发病率和死亡率永久化，使社会造成近80美元 每年十亿。戒断症状也出现在用µ oid的OUD药物治疗的启动之后出现 受体拮抗剂（丁丙诺啡：局部；纳曲酮：完整），有时会导致患者 拒绝，治疗计划或延续。更好地管理OWS被认为是“通往阿片类药物的门户” 依赖性处理”。A2-肾上腺素受体激动剂可乐定和洛己烷衰减OOid 通过抑制去甲肾上腺素能信号传导的戒断症状。但是，这些代理有缺点：他们 不要完全抑制戒断症状或主观不适，它们会引起问题副作用 （低血压，镇静，停药综合征），必须调整其剂量 损害患者，作为口服药物，他们的表现缓慢。那是紧迫的未满足的需求 更好，更快的疗法。降低OWS严重程度的一种策略是降低阿片类药物诱导的 炎症和氧化应激，上调赤字肾上腺素，交感神经系统（SNS） 活动和OWS的严重性。吸入氙（XE）气体抑制感染和社交媒体活动，并假设 减轻OWS的严重性。 XE在低浓度（28％）时用作成像剂，很少诱导 低血压或头晕，即使在重症监护群体中也是如此。 XE在大脑和 其他组织并抑制SNS活性，表明它可能优于A2-肾上腺素激动剂 衰减OWS。此外，XE没有明显的虐待责任，使其优于阿片类药物激动剂 替代治疗以缓解OWS。在此阶段I STTR计划中，我们建议进行临床前 吗啡依赖性小鼠的概念证明，以确定30％XE（非隔离）是否 当通过吸入给出时，迅速降低了ORW的严重程度。如果XE有效，我们将为人类提交IND STTR II期研究以评估XE在医学管理的阿片类药物锥度期间是否降低OW 在丁丙诺啡倡议​​之前需要。 Nobilis Therapeutics开发了专有的便携式手持XE 美国食品药品监督管理局已清除吸入装置和药物/装置组合 用于在创伤后压力障碍的人类中进行测试。该设备也可以用于OUD研究， 以退出潜力来支持资本效率。 Nobilis拥有一项涵盖XE的抗炎作用的专利 并获得了麦克莱恩医院的专利，涵盖了XE的抗焦虑作用。根据，元素在 开发和销售XE治疗的场所，如果有效，则可以向包括护理提供者和包括护理提供者和 出售丁丙诺啡，纳曲酮和XE的公司。那是商业生存能力很高。