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

摘要/摘要 阿片类药物使用障碍（OUD）患者会出现令人厌恶的阿片类药物戒断症状（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就会出现。这些症状 使非处方阿片类药物使用及其伴随的发病率和死亡率永久化，使社会损失近80美元， 每年10亿。戒断症状也出现在使用µ阿片类药物开始OUD药物治疗后 受体拮抗剂（丁丙诺啡：部分;纳洛酮：完全），并发症，有时导致患者 拒绝、开始或继续治疗。更好地管理OWS被认为是“通往阿片类药物的大门” 依赖治疗”。α 2-肾上腺素能受体激动剂可乐定和洛非西定减弱阿片样物质 戒断症状通过抑制去甲肾上腺素能信号传导。然而，这些代理人有缺点：他们 不能完全抑制戒断症状或主观不适，它们会引起严重的副作用 （低血压、镇静、停药综合征），必须根据肾或肝的情况调整剂量。 作为口服药物，它们是缓慢作用的。因此，迫切需要 更好更快的治疗方法降低OWS严重程度的一种策略是降低阿片类药物诱导的 炎症和氧化应激，上调去甲肾上腺素能紧张，交感神经系统（SNS） 活动和OWS严重性。吸入氙气（氙气）抑制炎症和SNS活动，并假设 减轻OWS的严重程度。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。快速（几分钟内）在大脑中平衡， 并抑制SNS活性，这表明它可能上级α 2-肾上腺素能激动剂， 衰减OWS。此外，阿托伐他汀没有明显的滥用倾向，使其优于阿片类激动剂上级 替代治疗缓解OWS。在这个I期STTR项目中，我们建议进行临床前研究， 在吗啡依赖小鼠中进行的概念验证研究，以确定30%的吗啡是否具有镇静作用， 当吸入时，迅速降低OWS的严重程度。如果药物治疗有效，我们将为人类提交IND STTR II期研究，以评估在药物管理的阿片类药物减量期间，OWS是否减少 在开始丁丙诺啡治疗前需要。Nobilis Therapeutics开发了一种专有的便携式手持治疗仪， 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 在患有创伤后应激障碍的人身上进行测试。该装置也可用于OUD研究， 支持具有退出潜力的资本效率。Nobilis拥有一项专利， 并从姆克林医院获得了一项专利，该专利涵盖了抗焦虑作用。因此，元素在 开发和销售抗抑郁疗法的地方，如果有效的话，向几个潜在的客户，包括护理提供者， 销售丁丙诺啡、纳洛酮和丁丙诺啡的公司。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.