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

4
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 GABA A 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. New Approach – Repurposing Ivermectin (IVM) for Treatment of AUDs

description

 

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

Page 1: 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

Page 2: 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

2

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.

Page 3: New Approach: Repurposing Ivermectin (IVM) for Treatment of AUDs

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

Page 4: New Approach: Repurposing Ivermectin (IVM) for Treatment of AUDs

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