Clear Scientific, LLC

A Novel Therapeutic Approach for Treatment of Acute Intoxication by Co-use of Opioids and Stimulants - Project Summary/abstract This Effort Addresses the Urgent Need for a Therapeutic Agent That Effectively and Rapidly Reverses the Toxic Effects Caused by Co-use of Multiple Substances. Opioid Use in the Context of Polysubstance Use Is Common and Further Exacerbates the Problem of Treating Acute Opioid Overdose; Up to 60% of Overdose Cases Presenting for Emergency Treatment Involve Two or More Substances. Alcohol Is Frequently Also Present in Patients Presenting for Treatment of Acute Drug Overdose. While Naloxone Is an Effective Treatment for Respiratory Depression and Apnea Caused by Opioid Overdose, There Is No Approved Treatment for Potentially Life- Threatening Intoxication by Co-use of Opioids and Stimulants. the Long-term Goal of This Program Is to Develop a Broad-spectrum Antidote to Treat Acute Life-threatening Intoxication Caused by Co-use of Multiple Substances of Abuse, Both Stimulants and Opioids, Based on a Novel Class of Sequestrants. Sequestrants Use a Novel Mechanism to Treat Symptoms of Acute Intoxication. in Contrast to a Receptor Antagonist Such as Naloxone, Sequestrants Rapidly and Tightly Bind Target Substances in the Plasma, Thereby Inactivating Their Effects and Reversing the Acute Toxicity; Ultimately the Substances Complexed With Sequestrants Are Eliminated From the Body in the Urine. in This R43 Program We Will Synthesize and Select a Therapeutic Compound That Has Broad Spectrum Activity Against Opioids, Synthetic Opioids, Stimulants, and Their Active Metabolites. We Will Focus on Substances Most Commonly Found in Combination in Patients Presenting for Emergency Care, as These Are Most Likely to Be Life-threatening: Fentanils, 6-ACETYLMORPHINE and Morphine (heroin Metabolites), Methamphetamine, Amphetamine, and Cocaine. to Select a Potent Compound With Broad Spectrum Activity, We Will Undertake the Following Aims: Aim 1 Will Synthesize and Screen Candidate Sequestrants to Identify a Compound Active Against Multiple Substances of Abuse. We Will Synthesize Candidate Sequestrants at the 1 G Scale, and Screen for Binding Affinity and Selectivity. We Will Evaluate Three Scenarios: Individual Substances and Their Active Metabolites, Combinations of Substances And/or Active Metabolites, and Binding in the Presence of Alcohol. Expected Outcome Is One Lead Therapeutic for Treatment of Intoxication With Multiple Substances. Aim 2 Will Evaluate the Lead Therapeutic Candidate In-vivo for Both Tolerability and Efficacy Against Selected High-priority Substance of Abuse Combinations in a Rodent Model. We Will Quantify the Efficacy and Time Course of the Lead Compound to Eliminate Multiple Substances From Blood and Into Urine. We Will Administer Intravenously Substance Mixtures Sufficient to Cause Significant Intoxication. We Will Then Administer the Lead Compound and Quantify Plasma and Urine Concentration of Substances. Expected Outcome Is a Therapeutic Candidate That Shows Rapid Clearance From Blood of Multiple Substances and the Reversal of Physiological and Behavioral Signs of Toxicity. We Anticipate That Successful Completion of Aims 1 and 2 Will Yield a Therapeutic Candidate Ready for Further Dose Ranging Studies in Rodent and Canine.