Lawrence Livermore National Laboratory (LLNL) researchers have unveiled a promising new treatment, subetadex, to combat the life-threatening effects of fentanyl and related opioids. This breakthrough could provide a significant advantage for medical professionals grappling with the ongoing opioid crisis, which has claimed over 210,000 American lives in the past three years.
The treatment, developed under a three-year grant from the Defense Threat Reduction Agency (DTRA), is detailed in a paper published in the American Chemical Society (ACS) journal, ACS Central Science. Audrey Williams, director of LLNL's Forensic Science Center, emphasized the importance of this advancement, stating, "The development of a medical countermeasure candidate for the treatment of exposure to a variety of opioids is a really exciting advancement in the fight to counter the opioid epidemic."
Subetadex: A Novel Approach to Opioid Overdose
Currently, naloxone (Narcan) is the primary drug used to reverse fentanyl overdoses. However, its short half-life (30-80 minutes) often necessitates repeated administrations. Subetadex offers a potential solution with its longer half-life of approximately 7.5 hours. According to LLNL biologist Mike Malfatti, subetadex works by encapsulating the opioid, preventing it from binding to opioid receptors in the body.
In vivo studies conducted by the LLNL team demonstrated that subetadex significantly accelerated recovery times in models exposed to sub-lethal doses of fentanyl. Specifically, recovery times were reduced from approximately 35 minutes to 17 minutes for fentanyl, from 172 minutes to 59 minutes for carfentanil, and from 18 minutes to 12 minutes for remifentanil.
The Science Behind Subetadex
Subetadex, like sugammadex, is a cyclodextrin. Project principal investigator Carlos Valdez, a chemist in the Lab's Forensic Science Center, explained that the team initially explored sugammadex due to its ability to bind the anesthetic rocuronium. However, sugammadex proved ineffective against fentanyl due to its large cavity. Further testing revealed that subetadex, a smaller version of sugammadex, exhibited strong binding affinity for fentanyl.
Nuclear magnetic resonance (NMR) experiments confirmed that subetadex binds effectively to fentanyl and does not readily release it. Valdez noted, "We found by NMR that the subetadex was binding to fentanyl quite well and that it was not letting go of it. That was a big moment."
Future Directions
Initial in vitro toxicity assessments indicate that subetadex has a non-toxic profile, comparable to the FDA-approved drug sugammadex. A pharmacokinetic study, using a carbon-radiolabeled version of subetadex, showed rapid clearance of the compound from major organs.
The LLNL team plans to focus on increasing the half-life of subetadex to enable its use as a prophylactic measure for first responders and military personnel. They also aim to broaden its applicability as a broad-spectrum treatment against a wider range of opioids.
