According to the Centers for Disease Control (CDC), synthetic opioids are currently the most common cause ofoverdose death in the U.S., and have increased opioid deaths by >500% from 2015- 2020. In 2020 alone, over 80% of the69,700 opioid deaths were attributed to these synthetics (fentanyl). Despite the widespread availability of naloxone, theonly FDA approved treatment for opioid overdose, deaths from fentanyl and fentanyl analogues (F/FA) continue to rise inparallel with increasing reports and pharmacological evidence of F/FA resistance to naloxone. High doses of rapidlyinjected F/FA cause airway obstruction from vocal cord closure (VCC) and severe chest wall rigidity (CWR) within 60-90seconds, lethal effects that can persist for up to 10 minutes and appear to be resistant to naloxone. In contrast, morphinederived opiates (e.g. heroin) cause respiratory depression and mild muscle rigidity that is responsive to naloxone, but arenot known to cause VCC in humans. The rapidly lethal phenomenon of VCC suggests unique pharmacologicalmechanisms underlying F/FA effects and may be a factor driving the dramatic increase in community overdose deaths. Insupport of this hypothesis, our published pharmacological data demonstrate F/FA, but not morphine or naloxone, haveaffinity for off-site targets that regulate these F/FA-induced effects. These in vitro data include F/FA concentrations thatmay be physiologically relevant to humans, based on available models of brain lipid concentrations for F/FA and bycomparison with plasma levels in decedents of fentanyl overdose. Additionally, we have demonstrated in our publishedanimal model that intravenous fentanyl induces VCC in <10 seconds, is not reversed by high dose naloxone and involvesthese off-site receptor targets. These data suggest that the development of effective therapies for overdose requires abiological model that replicates clinical effects of F/FA toxicity and a re-conceptualization of the underlying causes ofF/FA overdose deaths to include VCC, in addition to respiratory depression. Therefore, the goal of this Fast-trackproposal is to use an animal model of fentanyl toxicity, to identify specific drug classes that address F/FA induced VCCand respiratory depression. There are currently no Federal Drug Administration approved treatments that target theseF/FA toxicity effects, and this project directly addresses the need for the development of a new class of therapeutics,specific to F/FA overdose.
Public Health Relevance Statement: Project narrative: Data from the Centers for Disease Control (CDC) indicate that fentanyl and fentanyl analogues (F/FA) are the most common cause of overdose death in the U.S., underscoring the critical need for more effective overdose treatments in the ongoing opioid crisis. Torralva Medical Therapeutics, LLC has developed an animal model that replicates the unique effects of fentanyl toxicity seen in humans (vocal cord closure) and has begun target validation and development of novel formulations to effectively antagonize fentanyl doses that are routinely fatal. These formulations will solve the unmet critical need to treat naloxone-resistant effects of F/FA overdose, have the advantage they can be used for morphine- derived drug overdose (e.g. heroin) or combinations of F/FA with morphine-derived drugs, and have the potential to dominate the U.S. market for opioid overdose treatment currently estimated to be over $300 million.
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