By Daryl L. Davies
Alcohol use disorder (AUD) has a major national health impact in the United States, affecting over 17 million people, causing more than 100,000 deaths, and costing over $200 billion annually. Presently there are only three Food and Drug Administration (FDA)-approved treatments on the market for AUD, all of which have led to limited success even when combined with psychosocial support. As such, novel approaches that allow for rapid development of new and effective medications for the treatment and/or prevention of AUD represents an important public health goal.
The Davies laboratory has been testing the feasibility of repurposing ivermectin (IVM), an FDA-approved drug for the treatment of onchocerciasis (river blindness), as a novel pharmacotherapy for AUD. Notably, the use of a repurposing strategy allows for a drug discovery pathway to be completed at a lower cost and shorter time frame than for development of an entirely new chemical entity. In support of repurposing IVM as a pharmacotherapy for AUD, the Davies laboratory has developed a large body of evidence showing that IVM can significantly reduce ethanol intake acutely and chronically in both male and female mice where a significant degree of the anti-alcohol effect has been linked to activity on purinergic, P2X4 receptors (P2X4Rs). Importantly, the safety of combining IVM (30 mg QD) with an intoxicating dose of intravenous alcohol (0.08 g/dl) was recently tested in 11 alcoholic patients where no safety events were reported.
Despite some promise, IVM’s poor blood brain barrier (BBB) penetration may limit its utility as a treatment for AUD. To this end, the Davies group has recently begun to investigate the utility of moxidectin (MOX), an IVM analogue, as an alternative to IVM for the treatment and/or prevention of AUD. Notably, in animals and in vitro models, MOX is reported to have superior BBB penetration and higher brain concentration when compared to IVM, which is in part due to MOX lower affinity for P-glycoproteins.
Initial preclinical work in the Davies laboratory found that administration of MOX significantly reduced ethanol intake across multiple drinking paradigms possibly by modulating mesolimbic dopamine activity in the central nervous system (CNS). Moreover, a portion of the anti-alcohol effects of MOX appeared to be linked to positive modulation of P2X4Rs. Using a validated liquid-chromatography in tandem with mass-spectrometry method, they found that MOX levels in the CNS were higher (compared to IVM) and that maximum CNS levels were achieved in a shorter period of time. Taken that MOX is currently in clinical development as an alternative to IVM for treating onchocerciasis, coupled with the MOX/ethanol findings from the Davies laboratory sets the stage for the rapid development (repurposing) of MOX as a novel therapy for AUD.
To find out about what the Davies laboratory concluded from their studies, visit this poster (#R6340) on Thursday, October 29, 2015, from 8:00 am–11:30 am ET in Exhibit Hall WA3 at the 2015 AAPS Annual Meeting and Exposition!