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 患有阿片类药物使用障碍 (OUD) 的人会经历厌恶性阿片类药物戒断症状 (OWS)，包括 当血液中阿片类药物水平下降时，就会出现恶心、腹泻、呕吐和焦虑。这些症状 使非处方阿片类药物使用长期存在，并导致发病率和死亡率增加，给社会造成近 80 美元的损失 每年十亿。开始使用 µ 阿片类药物进行 OUD 药物治疗时也会出现戒断症状 受体拮抗剂（丁丙诺啡：部分；纳曲酮：全部），使情况复杂化，有时会导致患者 拒绝、开始或继续治疗。更好的 OWS 管理被认为是“阿片类药物的门户” 依赖性治疗”。α2-肾上腺素受体激动剂可乐定和洛非西定可减弱阿片类药物的作用 通过抑制去甲肾上腺素能信号传导来缓解戒断症状。然而，这些代理也有缺点： 不能完全抑制戒断症状或主观不适，它们会引起有问题的副作用 （低血压、镇静、停药综合征），必须根据肾脏或肝脏的情况调整其剂量 功能障碍患者，并且作为口服药物，它们起效缓慢。因此，迫切需要未得到满足的 更好更快起效的治疗方法。降低 OWS 严重程度的一种策略是降低阿片类药物引起的 炎症和氧化应激，上调去甲肾上腺素能张力、交感神经系统 (SNS) 活动和 OWS 严重程度。假设吸入氙 (Xe) 气体可抑制炎症和 SNS 活性 减轻 OWS 的严重性。 Xe 在低浓度 (28%) 下用作显像剂，很少诱导 低血压或头晕，甚至在重症监护人群中也是如此。 Xe 在大脑中迅速（几分钟内）达到平衡， 其他组织并抑制 SNS 活性，表明它可能优于 α2-肾上腺素能激动剂 减弱OWS。此外，Xe 没有明显的滥用倾向，使其优于阿片类激动剂 缓解 OWS 的替代治疗。在这一阶段的 STTR 计划中，我们建议进行临床前研究 在吗啡依赖小鼠中进行概念验证研究，以确定 30% Xe（非镇静剂）是否有效 当通过吸入给药时，可迅速降低 OWS 的严重程度。如果 Xe 有效，我们将为人类提交 IND STTR II 期研究旨在评估 Xe 是否会在医疗管理的阿片类药物逐渐减少期间降低 OWS 在开始丁丙诺啡之前需要。 Nobilis Therapeutics 开发了一种专有的便携式手持式 Xe 吸入装置和药物/装置组合已获得美国食品和药物管理局的批准 用于对患有创伤后应激障碍的人类进行测试。该设备也可用于 OUD 研究， 通过退出潜力支持资本效率。 Nobilis 拥有 Xe 抗炎作用的专利 并获得麦克莱恩医院的一项专利许可，涵盖 Xe 的抗焦虑作用。因此，元素位于 开发 Xe 疗法并向包括护理提供者和其他潜在客户（如果有效）进行营销的地方 销售丁丙诺啡、纳曲酮和 Xe 的公司。因此，商业可行性很高。