Reversal of ventilatory depression by drug mixtures

药物混合物逆转通气抑制

• 批准号: 10606301
• 负责人: Shawn Michael Flynn
• 金额: $ 3.7万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-15 至 2025-01-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606301
• 关键词: Accounting; Address; Agonist; Allosteric Site; Binding; Cessation of life; Characteristics; Clinical; Dangerousness; Data; Development; Diprenorphine; Dose; Drug Interactions; Drug Kinetics; Effectiveness; Exposure to; FDA approved; Fentanyl; Heroin; Human; In Vitro; Knowledge; Laboratories; Mediating; Metabolic Pathway; Methocinnamox; Methods; Morphinans; Naloxone; Naltrexone; Nature; Opioid; Opioid Antagonist; Opioid agonist; Overdose; Overdose reversal; Pharmaceutical Preparations; Pharmacology; Phase; Primates; Procedures; Property; Public Health; Rattus; Reporting; Research; Research Personnel; Risk; Rodent; Role; Site; Testing; Time; Training; United States; Ventilatory Depression; Whole Body Plethysmography; analog; antagonist; career; carfentanil; depressive symptoms; design; exposed human population; fentanyl analog; improved; lipophilicity; mu opioid receptors; novel; opioid mortality; opioid overdose; overdose death; overdose risk; pre-clinical research; preclinical study; prescription opioid; skills; synthetic opioid; trend; ventilation

ABSTRACT For the first time, over 100,000 deaths were caused by drug overdose in a 12-month period (April 2020 - April 2021) in the United States. Synthetic opioids, primarily fentanyl, accounted for over 60% of all overdose deaths during this span (87% of opioid overdose deaths). Over the past decade, the number of overdose deaths involving synthetic opioids has risen 20-fold, approaching 60,000 in 2020. The emergence of fentanyl analogs, some of which are much more potent than fentanyl (e.g., carfentanil, reported to be ~100 times more potent than fentanyl), pose serious risk to public health. Another dangerous characteristic of exposure to these drugs is that they are predominantly taken unknowingly which, combined with their potency, increases the risk of overdose. The opioid receptor antagonist naloxone is the only FDA-approved treatment for opioid overdose. While naloxone has saved countless lives, its effectiveness is limited by its short duration of action and that its antagonism is competitive – that is, that the effects of naloxone can be surmounted by taking more of an opioid agonist. Clinical reports suggest that larger or more frequent doses of naloxone are required to reverse opioid overdose involving carfentanil or other fentanyl analogs, and preclinical studies show reduced effectiveness of opioid antagonists to antagonize the effects of carfentanil relative to other opioid agonists. The novel opioid receptor antagonist methocinnamox (MCAM) binds non-competitively at the mu opioid receptor and has extremely long-lasting effects. A recent study demonstrated that some effects of MCAM are mediated through binding an allosteric site on the mu opioid receptor. This finding warrants further study and provides rationale for evaluating the potential of using mixtures of antagonists to reverse opioid-induced ventilatory depression. The proposed studies use whole-body plethysmography in rats to address current trends in opioid overdose death and the need for development of new treatment options for opioid overdose, testing the hypotheses that the effects of mixtures of opioid agonists will be greater than each drug when given alone, and that mixtures of the opioid antagonists naloxone and MCAM will be more potent than naloxone alone at reversing the effects of opioid agonists on ventilation. Aim 1 will determine the nature of the interaction between the effects of heroin, fentanyl, and carfentanil on ventilation. Aim 2 will determine the nature of the interactions between naloxone, MCAM, and diprenorphine for reversing the ventilatory depressive effects of heroin, fentanyl, and carfentanil, and begin to assess the mechanism of this interaction. The proposed studies will determine the nature of interactions between opioid agonists commonly involved in opioid overdose and evaluate whether mixtures of opioid antagonists might be more effective alternatives to naloxone for reversing opioid overdose. Results from these studies will provide valuable information related to recent trends in opioid overdose death and possible improvements in the treatment of opioid overdose. The proposed training plan will develop my skills at designing, conducting, and disseminating my independent research, paving the way to becoming a successful independent investigator.

抽象的 在12个月（2020年4月至4月）中，药物过量导致了超过100,000人死亡。 2021年）在美国。合成阿片类药物（原发性芬太尼）占所有过量死亡的60％以上 在此跨度（占阿片类药物过量死亡的87％）。在过去的十年中，过量死亡人数 涉及合成阿片类药物的增长20倍，在2020年接近60,000。芬太尼类似物的出现， 其中一些比芬太尼高得多（例如，据报道，据报道， 芬太尼），对公共卫生构成严重风险。接触这些药物的另一个危险特征是 它们主要是未知的，加上它们的效力，增加了过量的风险。 阿片受体拮抗剂纳洛酮是唯一用于阿片类药物过量的FDA批准治疗方法。尽管 纳洛酮挽救了无数的生命，其有效性受到其短期行动的限制，并且 对抗具有竞争力 - 也就是说，可以通过服用更多阿片类药物来克服纳洛酮的影响 激动剂。临床报道表明，需要更大或更频繁的纳洛酮来逆转OID 涉及carfentanil或其他芬太尼类似物的过量药物，临床前研究表明， 卵巢拮抗剂可拮抗Carfentanil相对于其他卵动物拮抗剂的作用。小说的opioid 受体拮抗剂甲激素（MCAM）在MU阿片受体上非竞争性结合，并具有 极度持久的效果。最近的一项研究表明，MCAM的某些影响是通过 在MU阿片类接收器上绑定变构位点。这一发现值得进一步研究，并为 评估使用拮抗剂混合物来逆转阿片类药物诱导的通气抑郁症的潜力。这 拟议的研究使用大鼠的全身庞大描绘来解决阿片类药物过量死亡的当前趋势 以及为阿片类药物过量开发新的治疗选择的需求，证实了假设 单独给出时，阿片类激动剂混合的影响将大于每种药物，并且混合的混合 卵毒剂纳洛酮和MCAM比单独的纳洛酮更有潜力 通风的激动剂。 AIM 1将确定海洛因芬太尼效应之间相互作用的性质， 和carfentanil进行通风。 AIM 2将确定纳洛酮，MCAM和 二肾上振用于逆转海洛因，芬太尼和carfentanil的通气性抑郁作用，并开始 评估这种相互作用的机制。提出的研究将确定相互作用的性质 卵虫类激动剂通常参与卵毒素过量，并评估opioid angonists的混合物是否可能 对于逆转阿片类药物过量的纳洛酮的替代品是更有效的替代方法。这些研究的结果将提供 有价值的信息与阿片类药物过量死亡的最新趋势有关，并可能改善 治疗阿片类药物过量。拟议的培训计划将培养我在设计，进行，进行和 传播我的独立研究，从而成为成功的独立研究者的道路。