United States: Amidst the deadly opioid epidemic, which could claim millions of lives by 2029, a recent breakthrough in overdose treatments offers hope for mitigating this public health emergency. Researchers from Stanford University and Washington University in St. Louis have introduced a novel drug, called compound 368, which significantly enhances the effectiveness of naloxone (Narcan) in treating opioid overdoses.
Naloxone, a common and effective opioid overdose treatment available without a prescription in the US, works by deactivating opioid receptors in the brain, spinal cord, and peripheral nervous system. However, its effects last only about 2 hours, whereas potent opioids like fentanyl can remain in the bloodstream for up to 8 hours.
Compound 368 appears to be the solution scientists have been searching for. In lab studies with human cells, compound 368 enhanced naloxone’s deactivation of opioid receptors by 7.6 times and kept naloxone bound to these receptors 10 times longer.
The researchers found compound 368 in a library of 4.5 billion molecules while looking for compounds that can bind to alternative sites on opioid receptors already occupied by naloxone. Using a special electron microscope, they showed that compound 368 binds to a receptor site next to naloxone, stabilizing and inactivating the opioid receptor.
The study, led by biochemist Evan O’Brien at Stanford, demonstrated that compound 368, in combination with low doses of naloxone, both reverses and blocks the deadly effects of opioids like morphine and fentanyl. In living mice administered high doses of morphine, compound 368 alone had no significant impact. However, when combined with naloxone, it modestly reduced morphine-induced respiratory depression.
For fentanyl, the combination treatment proved even more effective. The study concluded that regardless of the naloxone dose, treatment with compound 368 significantly enhanced naloxone’s ability to reverse fentanyl-induced effects.
While the study results are promising, the efficacy of compound 368 against mixed opioids, commonly found in street drugs, remains unclear. These drugs often contain combinations of fentanyl, heroin, and non-opioid substances like the horse tranquilizer xylazine, significantly raising the risk of overdose.
Although compound 368 still needs to be tested in humans, neuropharmacologist Catherine Cahill from the University of California, Los Angeles, who was not involved in the study, praised the findings. In a Nature review, she called it “a considerable advance… opening up fresh avenues of investigation in the search for solutions to the opioid crisis.”
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