New Approach: Repurposing Ivermectin (IVM) for Treatment of AUDs

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  • 1. Alcohol Brain Research Lab FDA-approved, commonly used anti-parasitic, from Streptomyces avermitilis. The therapeutic potential of IVM is attributed to action on a non-mammalian, glutamate- gated inhibitory chloride channel. IVM potentiates mammalian GABAA and glycine receptors, 7 nicotinic acetylcholine receptors, histamine receptors in vitro and has been shown to act as a weak anticonvulsant in mice. Work in humans suggests additional sites of action. Among P2XRs, IVM specifically modulates P2X4Rs. New Approach Repurposing Ivermectin (IVM) for Treatment of AUDs
  • 2. IVM addresses preclinical characteristics of AUD IVM , member of the avermectin family of macrocyclic lactones Primary activity: Positive modulators P2X4R Secondary: weak potentiation of GABAAR IVM addresses preclinical disease hall marks: Decreases EtOH acquisition and preference in two-bottle choice 24 hr access drinking paradigm (social drinking abuse) Decreases EtOH intake in Drinking in Dark paradigm (Binge Model) 30 day IVM administration reduces Ethanol Intake & Preference in C57BL/6Mice without any signs of tolerance or dependence Weak anxiolytic activity non addictive 2 Yardley MM et al. (2012) Neuropharmacology 63: 190-201. Yardley et al NeuroReport in press. Bortolato et al, Int J Neuropsychopharm 2012 Wyatt LR et al (2014) Neurochemical Research: 39 (6):1127-39. Asatryan L, et al. (2010) J Pharmacol Exp Ther 334:720-728. Asatryan L, et al (2013) Intl. J Neuropsychopharmacology 17 (6) 907-916.
  • 3. Alcohol Brain Research Lab Human Laboratory Trials To be conducted with our clinical partners at UCLA Dr. Lara Ray. Enroll small group of alcohol dependent individuals in a randomized, placebo-controlled, pilot safety trial. Individuals not seeking treatment. Test the combination of IVM with controlled alcohol administration in alcohol dependent individuals. One year to complete. The results from this study will be used to inform a large scale clinical trial of IVM for alcoholism. First in human study for IVM
  • 4. Why Study Alcohol Abuse? 8.5% of US adults suffers from alcohol use disorders (AUDs). In US --Alcohol Related Deaths 100,000 to 200,000 annually Leading Cause of Accidental Death in 15-24 year olds Alcoholism affects over 18 million people in the U.S. Excess alcohol consumption is the third leading cause of preventable death in the US. Alcohol related birth defects (FAS and FASD) Drinking alcohol during pregnancy can cause a baby to be born with life-long disabilities 100% preventable Leading cause of birth defects with mental retardation Annual Economic Impact: ~$235 billion Lost Production Medical Costs Vehicle Accidents Violent Crimes Social Response