Etimizol for reversal of Xylazine-fentanyl respiratory depression

PROJECT SUMMARY / ABSTRACT Increasing use of xylazine, most often in combination with other drugs such as fentanyl, is a rapidly growing threat to human health in the United States. Patients presenting with xylazine intoxication may have central nervous system depression, hypotension, and bradycardia. Naloxone can reverse opioid-induced respiratory depression but does not reverse the effects of xylazine. There is no xylazine-reversal agent currently approved for use in humans. One may also need to consider that opioid agonists may be combined not only with xylazine but with other drugs that cause respiratory depression alone or in combination. Therefore, there is an urgent need to identify and rapidly introduce into clinical practice respiratory stimulant agents with a non-opioid mechanism of action. Synventa identified an old respiratory stimulant drug, etimizol, that was developed about 60 years ago but was never marketed outside Eastern Europe. Ability of etimizol to reverse opioid-induced respiratory depression was established in rabbits in 1960s and was recently confirmed and extended by the Synventa team using models of morphine-, phenobarbital- and gamma-hydroxybutyrate-induced respiratory depression in laboratory rodents via non-opioid mechanisms. These studies were: i) conducted under exploratory study rigor standards (limited sample size, male animals only, no pre-specified exclusion criteria or analysis), and ii) have not established the ability of etimizol (or its main metabolite) to reverse respiratory suppression induced by xylazine alone or in combination with opioid agonists. In this regard, and in line with RFA-DA-23-021, the current application proposes preclinical proof of concept studies to confirm the ability of ethimizol to reverse respiratory depression induced by opioid-xylazine combination. In Phase 1, we will (Aim 1) characterize the ability of xylazine to cause respiratory depression when given alone or in combination with fentanyl in mice; (Aim 2) deliver confirmatory evidence regarding the ability of etimizol to reverse respiratory depression induced by opioid-xylazine combination; (Aim 3) evaluate the ability of etimizol’s main metabolite to reverse respiratory depression induced by opioid-xylazine combination.