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.

摘要 在12个月期间（2020年4月至2022年4月），首次有超过10万人死于药物过量 2021年）在美国。合成阿片类药物，主要是芬太尼，占所有过量死亡的60%以上 在此期间（87%的阿片类药物过量死亡）。在过去的十年里，吸毒过量死亡的人数 涉及合成阿片类药物的案件增加了20倍，2020年接近6万起。芬太尼类似物的出现， 其中一些比芬太尼更有效（例如，据报道，卡芬太尼的效力比 芬太尼），对公众健康构成严重威胁。接触这些药物的另一个危险特征是， 这些药物主要是在不知情的情况下服用的，加上其效力，增加了过量服用的风险。 阿片受体拮抗剂纳洛酮是FDA批准的唯一治疗阿片类药物过量的药物。而 纳洛酮挽救了无数生命，其有效性受到其作用时间短的限制， 拮抗作用是竞争性的，也就是说，纳洛酮的作用可以通过服用更多的阿片类药物来克服 激动剂临床报告表明，需要更大或更频繁剂量的纳洛酮来逆转阿片类药物 涉及卡芬太尼或其他芬太尼类似物的过量，临床前研究显示卡芬太尼或其他芬太尼类似物的有效性降低。 阿片样物质拮抗剂相对于其它阿片样物质激动剂拮抗卡芬太尼的作用。新型阿片类药物 受体拮抗剂甲氧肉桂酸（MCAM）与μ阿片受体非竞争性结合， 极其持久的影响。最近的一项研究表明，MCAM的一些作用是通过以下途径介导的： 结合μ阿片受体上的变构位点。这一发现值得进一步研究，并提供了理由， 评价使用拮抗剂混合物逆转阿片样物质诱导的抑郁症的潜力。的 拟议的研究使用大鼠全身体积描记术来解决阿片类药物过量死亡的当前趋势 以及需要为阿片类药物过量开发新的治疗选择，测试假设， 阿片样物质激动剂的混合物的作用将大于单独给予时的每种药物，并且阿片样物质激动剂的混合物的作用将大于单独给予时的每种药物的作用。 阿片类拮抗剂纳洛酮和MCAM在逆转阿片类药物的作用方面将比单独的纳洛酮更有效 激动剂通气。目标1将确定海洛因，芬太尼， 卡芬太尼进行通气目的2将确定纳洛酮、MCAM和 二丙诺啡用于逆转海洛因、芬太尼和卡芬太尼的镇静抑郁作用，并开始 评估这种相互作用的机制。拟议中的研究将确定 阿片激动剂通常涉及阿片类药物过量，并评估阿片拮抗剂的混合物是否可能 更有效的替代纳洛酮逆转阿片类药物过量。这些研究的结果将提供 关于阿片类药物过量死亡的最新趋势和 阿片类药物过量的治疗拟议的培训计划将发展我的技能，在设计，进行， 传播我的独立研究，为成为一名成功的独立调查员铺平道路。