Methocinnamox (MCAM): A novel õ-opioid receptor antagonist for opioid use disorders

Methocinnamox (MCAM)：一种新型 α-阿片受体拮抗剂，用于治疗阿片类药物使用障碍

• 批准号: 10477526
• 负责人: CHARLES P FRANCE
• 金额: $ 14.8万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477526
• 关键词: Address; Administrative Supplement; Agonist; COVID-19 pandemic; Cessation of life; Clinical; Clinical Trials; Dose; FDA approved; Female; Fentanyl; Grant; Heroin; Individual; Laboratories; Literature; Methamphetamine; Methocinnamox; Morphinans; Naloxone; Naltrexone; Opioid; Opioid Antagonist; Opioid agonist; Overdose; Overdose reversal; Parents; Pharmaceutical Preparations; Rattus; Reporting; Research; Sex Differences; Stimulant; Testing; Toxic effect; U-Series Cooperative Agreements; United States National Institutes of Health; Ventilatory Depression; analog; antagonist; carfentanil; experimental study; fentanyl overdose; interest; lipophilicity; male; mu opioid receptors; novel; opioid epidemic; opioid overdose; opioid use disorder; overdose death; parent grant; prevent; response

ABSTRACT/SUMMARY This application for a supplement to parent grant UG3DA048387 is in response to Notice of Special Interest NOT-DA-21-032 “Administrative Supplements for research on fentanyl and derivatives.” The opioid crisis has worsened significantly during the COVID-19 pandemic, in part because of increasing availability of fentanyl and potent fentanyl analogs. Many overdoses involve more than one drug, often an opioid and a stimulant drug, although it is unclear whether stimulants alter the toxic effects of opioids and reversal of those effects by naloxone. The value of naloxone is limited by its short duration of action and that its antagonism can be surmounted by taking more agonist. After rescue from overdose, protection by naloxone often wanes before the effects of the opioid receptor agonist decrease, resulting in the reemergence of ventilatory depression possibly leading to death. Fatal ventilatory depression can occur in the presence of naloxone if an individual continues taking opioids, and there are reports of the need for larger doses and/or more frequent administration of naloxone to reverse and protect against overdose from fentanyl, compared with reversal of overdose from other opioids. Methocinnamox (MCAM) is a long-acting µ opioid receptor antagonist that reverses and prevents the ventilatory-depressant effects of fentanyl. It is not known whether MCAM is equally effective (potent) in reversing ventilatory depression by different opioids. Some studies suggest that opioid receptor antagonists, such as naloxone and naltrexone, do not block effects of different opioids equally and that mixtures of antagonists might be more effective than antagonists alone. Studies in this proposal will address the following: 1) investigate reversal of and protection from ventilatory depression by heroin and by fentanyl and related analogs; 2) compare the novel opioid receptor antagonist MCAM with naloxone and MCAM/naloxone mixtures; 3) characterize the ventilatory-depressant effects of heroin/methamphetamine and fentanyl/methamphetamine mixtures and reversal of those effects by naloxone and MCAM, alone and together; and 4) test for sex differences in the ventilatory-depressant effects of opioids and reversal of those effects by naloxone and MCAM, alone and together. Two specific aims will test the following hypotheses: 1) naloxone is less potent at reversing ventilatory depression by fentanyl and related analogs compared with reversal of ventilatory depression by heroin; 2) MCAM has similar potency at reversing ventilatory depression by all four opioids; 3) methamphetamine does not alter the ventilatory-depressant effects of fentanyl or heroin nor reversal of those effects by antagonists; 4) mixtures of MCAM and naloxone are more effective than either antagonist alone at reversing and protecting against ventilatory depression; and 5) there are no sex differences in the effects of drugs in this study. By characterizing reversal of ventilatory depression of different opioids alone and with methamphetamine, these studies will help guide the treatment of overdose, perhaps including novel opioid receptor antagonists like MCAM or mixtures of antagonists.

摘要/总结 本申请补充家长补助金 UG3DA048387 是为了回应特别兴趣通知 NOT-DA-21-032“芬太尼及其衍生物研究的行政补充。”阿片类药物危机。 在 COVID-19 大流行期间，情况显着恶化，部分原因是芬太尼的供应量增加 许多过量服用涉及不止一种药物，通常是阿片类药物和兴奋剂药物， 尽管尚不清楚兴奋剂是否会改变阿片类药物的毒性作用以及通过以下方式逆转这些作用 纳洛酮的价值受到其作用持续时间短及其拮抗作用的限制。 通过服用更多的激动剂来克服过量服用后，纳洛酮的保护作用通常会在发生之前减弱。 阿片受体激动剂的作用减弱，可能导致通气抑制重新出现 如果个体继续使用纳洛酮，可能会导致致命的通气抑制。 服用阿片类药物，有报告称需要更大剂量和/或更频繁地服用阿片类药物 与逆转其他药物过量相比，纳洛酮可逆转并防止芬太尼过量 阿片类药物 Methocinnamox (MCAM) 是一种长效 µ 阿片受体拮抗剂，可逆转和预防阿片类药物。 尚不清楚芬太尼的通气抑制作用是否同样有效（有效）。 一些研究表明，阿片受体拮抗剂可以逆转通气抑制。 与纳洛酮和纳曲酮一样，不能同等地阻断不同阿片类药物的作用，并且拮抗剂的混合物 该提案中的研究将解决以下问题：1）调查。 海洛因和芬太尼及相关类似物对通气抑制的逆转和保护作用；2) 比较 新型阿片受体拮抗剂 MCAM 与纳洛酮和 MCAM/纳洛酮混合物 3) 的特征； 海洛因/甲基苯丙胺和芬太尼/甲基苯丙胺混合物的通气抑制作用， 纳洛酮和 MCAM 单独或一起逆转这些作用；4) 测试性别差异 阿片类药物的通气抑制作用以及纳洛酮和 MCAM 单独使用和逆转这些作用 两个具体目标将检验以下假设：1）纳洛酮逆转通气的效力较弱。 芬太尼及相关类似物的抑制作用与海洛因逆转通气抑制作用的比较2) MCAM 在逆转所有四种阿片类药物的通气抑制方面具有相似的功效；3) 甲基苯丙胺确实如此； 不改变芬太尼或海洛因的通气抑制作用，也不通过拮抗剂逆转这些作用； 4) MCAM 和纳洛酮的混合物在逆转和保护方面比单独使用任一拮抗剂更有效 对抗通气抑制；5) 本研究中药物的作用没有性别差异。 这些研究描述了单独使用不同阿片类药物和甲基苯丙胺联合使用不同阿片类药物对通气抑制的逆转作用， 研究将有助于指导药物过量的治疗，也许包括新型阿片受体拮抗剂，例如 MCAM 或拮抗剂的混合物。