title: Oral delivery of ivermectin using a fast dissolving oral film: Implications for repurposing ivermectin as a pharmacotherapy for alcohol use disorder.
abstract: Individuals suffering from an alcohol-use disorder (AUD) constitute a major health concern. Preclinical studies in our laboratory show that acute and chronic intraperitoneal (i.p.) administration of ivermectin (IVM) reduces alcohol intake and preference in mice. To enable clinical investigation to use IVM for the treatment of an AUD, development of an oral formulation that can be used in animals as well as long-term preclinical toxicology studies are required. The present work explores the use of a promising alternative dosage form of IVM, fast-dissolving oral films (Cure Pharmaceutical®), to test the efficacy and safety of oral IVM in conjunction with alcohol exposure. We tested the effect of IVM (0.21 mg) using a fast-dissolving oral film delivery method on reducing 10% v/v alcohol (10E) intake in female C57BL/6 mice using a 24-h access two-bottle choice paradigm for 6 weeks (5 days per week). Differences in ethanol intake, preference for ethanol, water intake, fluid intake, food intake, changes in mouse and organ weights, as well as histological changes to kidney, liver, and brain were analyzed. The IVM group drank significantly less ethanol over the 30-day period compared to the placebo (blank strip) and the no-treatment groups. Organ weights did not differ between the groups. Histological evaluation showed no differences in the brain and kidney between groups. In the liver, there was a slight increase in the incidence of microvesicular fatty and degenerative changes of the animals receiving the thin strips. No overt hepatocellular necrosis or perivascular inflammation was noted. Overall, these data support the use of this novel method of oral drug delivery for longer-term studies and should facilitate FDA required preclinical testing that is necessary to repurpose IVM for treatment of an AUD.
authors.affiliation: Department of Psychology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Yardley
authors.affiliation: Titus Family Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USA.
authors.forename: Nhat
authors.initials: N
authors.lastname: Huynh
authors.affiliation: Titus Family Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USA.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Rodgers
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USA.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Alkana
authors.affiliation: Titus Family Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USA. Electronic address: ddavies@usc.edu.
authors.forename: Daryl L
authors.initials: DL
authors.lastname: Davies
mesh_terms: D000284:Administration, Oral; D000428:Alcohol Drinking / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D019973:Alcohol-Related Disorders / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D058492:Drug Repositioning / Q000379:methods*; D005260:Female; D007559:Ivermectin / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D012995:Solubility
chemical_list: D007559:Ivermectin
keywords: Alcoholism therapy; Drug delivery; Drug repositioning; Medications development