Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota (C.A.B., M.M.W., M.P.); Department of Veterinary Population Medicine, University of Minnesota, Minneapolis, Minnesota (M.M.W.); Reno School of Medicine, University of Nevada, Reno, Nevada (S.G.P., J.A.-U., D.A.); University of Minnesota Center for Immunology, Minneapolis, Minnesota (M.P.); and Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington (M.P.)
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota (C.A.B., M.M.W., M.P.); Department of Veterinary Population Medicine, University of Minnesota, Minneapolis, Minnesota (M.M.W.); Reno School of Medicine, University of Nevada, Reno, Nevada (S.G.P., J.A.-U., D.A.); University of Minnesota Center for Immunology, Minneapolis, Minnesota (M.P.); and Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington (M.P.).
J Pharmacol Exp Ther. 2022 May;381(2):129-136. doi: 10.1124/jpet.121.001048. Epub 2022 Feb 13.
The incidence of fatal drug overdoses in the United States is an alarming public health threat that has been exacerbated by the COVID-19 pandemic, resulting in over 100,000 deaths between April 2020 and April 2021. A significant portion of this is attributable to widespread access to fentanyl and other synthetic opioids, alone or in combination with heroin or psychostimulants, such as cocaine or methamphetamine. Monoclonal antibodies (mAb) offer prophylactic and therapeutic interventions against opioid overdose by binding opioids in serum, reducing distribution of drug to the brain and other organs. Here, we investigated the efficacy of a leading antifentanyl mAb, clone HY6-F9, in reversal and prevention of fentanyl-induced toxicity compared with the opioid receptor antagonist naloxone (NLX) in rats. In postexposure models, rats were challenged with fentanyl, followed by HY6-F9, NLX, or both. HY6-F9 reversed fentanyl-induced antinociception, respiratory depression, and bradycardia, and rats retained protection against additional challenges for at least 1 week. Although intravenous NLX reversed fentanyl-induced respiratory depression more rapidly than mAb alone, kinetics of reversal by intravenous mAb were similar to subcutaneous NLX. Coadministration of mAb and NLX provided greater protection than individual treatments against high doses of fentanyl. Prophylactic administration of mAb reduced the ED of NLX approximately twofold against 2.25 mg/kg of fentanyl. Finally, mAb sequestered fentanyl and its metabolite norfentanyl in serum and reduced brain concentrations of fentanyl. These results support the translation of mAb as medical interventions alone or in combination with NLX to prevent and reverse fentanyl-related overdose. SIGNIFICANCE STATEMENT: Fentanyl-related overdoses have increased dramatically in the US and worldwide. Currently, approved pharmacotherapies for treatment of opioid use disorder and reversal of overdose are not sufficient to curb the incidence of opioid-related deaths. Additionally, fentanyl and its potent analogs present a potential risk from use in deliberate poisoning or chemical attacks. This study demonstrates the use of monoclonal antibodies as a countermeasure to fentanyl-induced toxicity in pre- and postexposure scenarios, supporting their use in combination with the opioid antagonist naloxone.
美国致命药物过量的发生率是一个令人震惊的公共卫生威胁，而 COVID-19 大流行加剧了这一威胁，导致 2020 年 4 月至 2021 年 4 月期间有超过 10 万人死亡。其中很大一部分是由于广泛获得芬太尼和其他合成阿片类药物所致，这些药物单独或与海洛因或苯丙胺类兴奋剂（如可卡因或甲基苯丙胺）联合使用。单克隆抗体（mAb）通过与血清中的阿片类结合，减少药物向大脑和其他器官的分布，从而提供针对阿片类药物过量的预防和治疗干预。在这里，我们研究了一种领先的抗芬太尼 mAb（克隆 HY6-F9）在逆转和预防芬太尼诱导的毒性方面与阿片受体拮抗剂纳洛酮（NLX）相比的疗效，在暴露后模型中，大鼠接受芬太尼后，再接受 HY6-F9、NLX 或两者的组合。HY6-F9 逆转了芬太尼引起的镇痛、呼吸抑制和心动过缓，并且大鼠至少在 1 周内保持对额外挑战的保护。尽管静脉内 NLX 比单独使用 mAb 更快地逆转芬太尼引起的呼吸抑制，但静脉内 mAb 的逆转动力学与皮下 NLX 相似。mAb 和 NLX 的联合给药比单独治疗对高剂量芬太尼提供更大的保护。预防性给予 mAb 可使 NLX 对 2.25 毫克/千克芬太尼的 ED 值降低约两倍。最后，mAb 将芬太尼及其代谢物去甲芬太尼结合到血清中，并降低了脑中的芬太尼浓度。这些结果支持将 mAb 作为单独或与 NLX 联合使用的医疗干预措施，以预防和逆转与芬太尼相关的过量用药。
与阿片类药物相关的过量用药在美国和全球范围内急剧增加。目前，用于治疗阿片类药物使用障碍和逆转过量用药的批准药物疗法不足以遏制阿片类药物相关死亡的发生率。此外，芬太尼及其强效类似物在故意中毒或化学袭击中使用时存在潜在风险。本研究在暴露前和暴露后情况下证明了单克隆抗体作为对抗芬太尼诱导毒性的一种对策，支持将其与阿片受体拮抗剂纳洛酮联合使用。
