TY - JOUR
T1 - Oral delivery of ivermectin using a fast dissolving oral film
T2 - Implications for repurposing ivermectin as a pharmacotherapy for alcohol use disorder
AU - Yardley, Megan M.
AU - Huynh, Nhat
AU - Rodgers, Kathleen E.
AU - Alkana, Ronald L.
AU - Davies, Daryl L.
N1 - Funding Information:
DLD is an inventor on a patent for the use of IVM for the treatment of alcohol-use disorders. The authors have no other conflict of interest and are entirely responsible for the scientific content of the paper. This work was supported in part by research grants SC CTSI NIH/NCRR/NCATS – TL1TR000132 (M.M.Y.) and UL1TR000130 (D.L.D.), AA022448 (D.L.D.), and the USC School of Pharmacy.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - 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.
AB - 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.
KW - Alcoholism therapy
KW - Drug delivery
KW - Drug repositioning
KW - Medications development
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U2 - 10.1016/j.alcohol.2015.03.006
DO - 10.1016/j.alcohol.2015.03.006
M3 - Article
C2 - 26095588
AN - SCOPUS:84940448630
SN - 0741-8329
VL - 49
SP - 553
EP - 559
JO - Alcohol
JF - Alcohol
IS - 6
ER -