According to the Centers for Disease Control (CDC), synthetic opioids are currently the most common cause of overdose death in the U.S, while heroin and prescription opioid deaths have decreased significantly since 2017. Despite the widespread availability of naloxone, deaths from fentanyl and fentanyl analogues (F/FA) continue to rise in parallel with increasing reports of F/FA resistance to naloxone. High doses of rapidly injected F/FA cause airway obstruction from vocal cord closure (VCC) and severe chest wall rigidity (CWR) within 2 minutes, effects that persist for up to 10 minutes and appear to be resistant to naloxone. In contrast, morphine- derived opiates (e.g. heroin) cause respiratory depression and mild muscle rigidity that is responsive to naloxone, but are not known to cause VCC in humans. This suggests distinct pharmacological mechanisms underlying F/FA-induced VCC, compared to morphine-induced respiratory depression mediated by mu opioid receptors. In support of this hypothesis, our published pharmacological data demonstrate F/FA, but not morphine or naloxone, have affinity for off-site targets that may regulate these F/FA-induced effects. The in vitro data include F/FA concentrations that may be physiologically relevant to humans, based on available models of brain lipid concentrations for F/FA. Additionally, we have demonstrated in our animal model that these fentanyl-induced effects are resistant to high dose naloxone and may involve these off-site receptor targets. This preliminary data suggests the development of effective therapies for overdose require a biological model that re-conceptualizes the underlying causes of F/FA overdose deaths to include VCC, in addition to respiratory depression. Therefore, the goal of this Phase I proposal is to complete the validation of a comprehensive animal model replicating the rapid fentanyl toxicity effects seen clinically in humans and the preliminary identification of formulations that address VCC. There are currently no Federal Drug Administration approved treatments that target these F/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 deaths in the U.S., underscoring the critical need for more effective overdose treatments in the ongoing opioid crisis. Torralva Medical Therapeutics, LLC is developing an animal model that replicates the unique effects of fentanyl toxicity seen in humans 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 clinical need to treat naloxone-resistant effects of F/FA overdose, have the advantage they can be used for conventional morphine-derived drug overdose (e.g. heroin) and/or combinations of F/FA with morphine-derived drugs, and have the potential to dominate the overall U.S. market for opioid overdose treatment recently estimated at $290 million.
Project Terms: alpha-1 adrenergic receptors ; airway obstruction ; airflow limitation ; airflow obstruction ; airway limitation ; obstructed airflow ; obstructed airway ; Breathing ; Respiratory Aspiration ; Respiratory Inspiration ; inspiration ; Autopsy ; necropsy ; postmortem ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Brain ; Brain Nervous System ; Encephalon ; Centers for Disease Control and Prevention (U.S.) ; CDC ; Centers for Disease Control ; Centers for Disease Control and Prevention ; United States Centers for Disease Control ; United States Centers for Disease Control and Prevention ; Central Nervous System Agents ; CNS agent ; Central Nervous System Drugs ; centrally acting drug ; Statistical Data Interpretation ; Statistical Data Analyses ; Statistical Data Analysis ; statistical analysis ; Cessation of life ; Death ; Heroin ; Diacetylmorphine ; Diamorphine ; Drug Combinations ; Pharmacotherapy ; Drug Therapy ; drug treatment ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Fentanyl ; Actiq ; Duragesic ; Fentanest ; Fentyl ; Phentanyl ; Goals ; Human ; Modern Man ; In Vitro ; Intubation ; Laryngismus ; Laryngospasm ; Laryngoscopy ; Lipids ; Methamphetamine ; Crystal Meth ; Deoxyephedrine ; Desoxyephedrine ; Methylamphetamine ; N-Methylamphetamine ; Methods ; Biological Models ; Biologic Models ; Model System ; Morphine ; Infumorph ; Kadian ; MS Contin ; MSir ; Morphia ; Oramorph ; Oramorph SR ; Roxanol ; Statex SR ; Muscle Rigidity ; Muscular Rigidity ; Naloxone ; United States National Institutes of Health ; NIH ; National Institutes of Health ; Overdose ; Pharmacology ; Plethysmography ; Prazosin ; Furazosin ; Drug Prescriptions ; Drug Prescribing ; medication prescription ; prescribed medication ; Production ; Public Health ; Publishing ; Sprague-Dawley Rats ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Adrenergic Receptor ; Adrenoceptors ; Epinephrine Receptors ; adenoreceptor ; Research ; Technology ; Testing ; Time ; Transducers ; vocal cord ; Vocal Fold ; carfentanil ; 4-methoxycarbonyl fentanyl ; 4-methoxycarbonylfentanyl ; carfentanyl ; mu opioid receptors ; μ opioid receptors ; μ-OR ; μOR ; Measures ; Drug Delivery Systems ; Drug Delivery ; Illicit Drugs ; Mediating ; base ; Chest wall structure ; Chest Wall ; Thoracic Wall ; Site ; Acute ; Clinical ; Phase ; Physiological ; Physiologic ; Medical ; Chemicals ; Ventilatory Depression ; Respiratory Depression ; depressed breathing ; depression of breathing ; Opioid ; Opiates ; Adrenergic Antagonists ; Adrenergic Blockaders ; Adrenergic Blockers ; Adrenergic Receptor Antagonists ; Adrenergic Receptor Blockaders ; Adrenergic-Blocking Agents ; Adrenolytic Agents ; Adrenolytic Drugs ; Adrenolytics ; Anti-Adrenergics ; Anti-adrenergic Agents ; Antiadrenergic Agents ; Antiadrenergics ; non-opioid analgesic ; non-narcotic analgesic ; non-opiate analgesic ; non-opioid ; non-opioid therapeutics ; nonnarcotic analgesics ; nonopiate analgesic ; nonopioid ; nonopioid analgesics ; analog ; tamsulosin ; Therapeutic ; System ; diamorphine overdose ; heroin overdose ; Receptor Protein ; receptor ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Toxicities ; Toxic effect ; novel ; Reporting ; Modeling ; response ; CNS Nervous System ; Central Nervous System ; Neuraxis ; preventing ; prevent ; Address ; Dose ; Affinity ; Data ; in vivo ; Validation ; Characteristics ; Intravenous Bolus ; IV bolus ; Development ; developmental ; cost effective ; Resistance ; resistant ; drug testing ; drug detection ; commercialization ; therapeutic development ; therapeutic agent development ; community setting ; FDA approved ; effective therapy ; effective treatment ; preclinical efficacy ; pre-clinical efficacy ; efficacy testing ; overdose death ; overdose fatalities ; prescription opioid ; licit opioid ; opiate medication ; opioid medication ; prescribed opiate ; prescribed opioid ; prescription opiate ; health data ; Formulation ; Treatment-related toxicity ; therapeutic toxicity ; therapy toxicity ; treatment toxicity ; Opioid Antagonist ; Opiate Antagonist ; Opiate receptor antagonist ; Opioid receptor antagonist ; opioid epidemic ; opiate crisis ; opioid crisis ; opioid overdose ; opiate overdose ; opiate related overdose ; opioid drug overdose ; opioid induced overdose ; opioid intoxication ; opioid medication overdose ; opioid poisoning ; opioid related overdose ; opioid toxicity ; opioid mortality ; opiate deaths ; opiate mortality ; opioid deaths ; opioid overdose death ; opioid related death ; Injections ; Drug Screening ; synthetic opioid ; synthetic opiate ; off-target site ; fentanyl overdose ; Helping to End Addiction Long-term ; HEAL Initiative ; Helping End Addiction Long-term ; Helping End Addiction Longterm ; Helping to End Addiction Longterm ;
