New Approach: Repurposing Ivermectin (IVM) for Treatment of AUDs
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Transcript of New Approach: Repurposing Ivermectin (IVM) for Treatment of AUDs
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, α7 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
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
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Yardley MM et al. (2012) Neuropharmacology 63: 190-201.Yardley et al NeuroReport – in press.Bortolato et al, Int J Neuropsychopharm 2012Wyatt 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.
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
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