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

摘要/摘要 患有阿片使用障碍(OUD)的人会经历厌恶的阿片戒断症状(OWS)，包括 恶心、腹泻、呕吐和焦虑，当血液中阿片类药物水平下降时会出现这些症状。这些症状 长期使用非处方阿片类药物以及伴随的发病率和死亡率，给社会造成近80美元的损失 每年10亿美元。开始使用阿片类药物治疗时，也会出现戒断症状 受体拮抗剂(丁丙诺啡：部分；纳曲酮：完全)，并发症，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“通往阿片类药物的大门” 依赖治疗“。A2-肾上腺素能受体激动剂可乐定和洛非西定减弱阿片类药物 通过抑制去甲肾上腺素能信号的戒断症状。然而，这些代理人也有缺点：他们 不要完全抑制戒断症状或主观不适，它们会产生有问题的副作用 (低血压、镇静、停药综合征)，其剂量必须针对肾脏或肝脏进行调整 而且，作为口服药物，它们的作用很慢。因此，有一种迫切的、未得到满足的需求 更好、更快的治疗方法。降低OWS严重程度的一个策略是降低阿片类药物诱导的 炎症和氧化应激可上调去甲肾上腺素、交感神经系统(SNS) 活动和OWS严重性。吸入氙气(Xe)抑制炎症和SNS活动，这是假设的 以减轻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，即使在重症监护人群中也是如此。Xe在大脑中迅速(在几分钟内)平衡， 并抑制SNS活性，提示它可能优于α2-肾上腺素能激动剂 弱化OWS。此外，Xe没有明显的滥用责任，使其优于阿片类激动剂 缓解OWS的替代治疗。在这个第一阶段的STTR计划中，我们建议进行临床前 在吗啡依赖小鼠中进行的概念验证研究，以确定30%Xe，这是非镇静剂 当吸入给药时，可以迅速减轻OWS的严重程度。如果XE有效，我们将为人类申请IND 评估Xe在药物管理的阿片类药物逐渐减少期间是否减少OWS的STTRII期研究 在丁丙诺啡开始使用前需要。诺比利斯治疗公司开发了一种专利便携式手持式Xe 吸入器和药物/装置组合已被美国食品和药物管理局批准 用于在患有创伤后应激障碍的人类身上进行测试。该设备还可以用于OUD研究， 以退出潜力支撑资本效率。Nobilis拥有Xe抗炎作用专利 并获得了McLean医院的专利，涵盖Xe的抗焦虑效果。相应地，元素位于 开发和销售Xe疗法的地方，如果有效的话，给几个潜在的客户，包括护理提供者和 销售丁丙诺啡、纳曲酮和Xe的公司。因此，商业可行性很高。

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.