Malfatti Michael A, Enright Heather A, McCloy Summer, Ubick Esther A, Kuhn Edward, Subramanian Alagu, Lao Victoria Hio Leong, Lam Doris, Be Nicholas A, Hok Saphon, Lau Edmond Y, Kaseman Derrick C, Mayer Brian P, Valdez Carlos A
Physical and Life Sciences Directorate, Biosciences and Biotechnology Division, Global Security Directorate, Forensic Science Center, and Materials Science Division, Lawrence Livermore National Laboratory, Livermore, California 94550, United States.
ACS Cent Sci. 2024 Oct 23;10(12):2200-2212. doi: 10.1021/acscentsci.4c00682. eCollection 2024 Dec 25.
Subetadex-α-methyl (SBX-Me), a modified, polyanionic cyclodextrin scaffold, has been evaluated for its utilization as a medical countermeasure (MCM) to neutralize the effects of fentanyl and related opioids. Initial toxicity assays demonstrate that SBX-Me has a nontoxic profile, comparable to the FDA-approved cyclodextrin-based drug Sugammadex. Pharmacokinetic analysis showed rapid clearance of SBX-Me with an elimination half-life of ∼7.4 h and little accumulation in major organs. SBX-Me was also evaluated for its ability to counteract the effects of fentanyl, carfentanil, and remifentanil in rats. Recovery times in rats exposed to sublethal fentanyl doses were found to be shorter when treated with SBX-Me after opioid exposure. The recovery times were reduced from ∼35 to ∼17 min for fentanyl, ∼172 to ∼59 min for carfentanil, and ∼18 to ∼12 min for remifentanil. SBX-Me increased the elimination half-life for fentanyl and remifentanil from 5.37 to 6.42 h and 8.24 to 9.74 h, respectively. These data support SBX-Me as a solid platform from which further research can be launched for the development of a MCM against the effects of fentanyl and its analogs. Furthermore, the data suggests that SBX-Me and other analogs are attractive candidates as broad spectrum opioids targeting MCMs.
亚倍他德-α-甲基（SBX-Me）是一种经过修饰的聚阴离子环糊精支架，已被评估用作一种医学应对措施（MCM），以中和芬太尼及相关阿片类药物的作用。初步毒性试验表明，SBX-Me具有无毒特性，与美国食品药品监督管理局（FDA）批准的基于环糊精的药物舒更葡糖相当。药代动力学分析显示，SBX-Me清除迅速，消除半衰期约为7.4小时，在主要器官中几乎没有蓄积。还评估了SBX-Me对抗大鼠体内芬太尼、卡芬太尼和瑞芬太尼作用的能力。发现在阿片类药物暴露后用SBX-Me治疗时，暴露于亚致死剂量芬太尼的大鼠的恢复时间更短。芬太尼的恢复时间从约35分钟减少到约17分钟，卡芬太尼从约172分钟减少到约59分钟，瑞芬太尼从约18分钟减少到约12分钟。SBX-Me使芬太尼和瑞芬太尼的消除半衰期分别从5.37小时增加到6.42小时和从8.24小时增加到9.74小时。这些数据支持SBX-Me作为一个坚实的平台，可在此基础上开展进一步研究，以开发一种对抗芬太尼及其类似物作用的医学应对措施。此外，数据表明SBX-Me和其他类似物作为针对医学应对措施的广谱阿片类药物是有吸引力的候选药物。
