New Ventures in the Genotoxic and Cytotoxic Effects of Macrocyclic Lactones, Abamectin and Ivermectin

Molinari, Gabriela; Soloneski, Sonia; Larramendy, Marcelo L.

doi:10.1159/000293923

Cited by 35 publications

(20 citation statements)

References 45 publications

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“…IVM is a broad-spectrum antiparasitic avermectin (Geary, 2005; Molinari, Soloneski, & Larramendy, 2010; Richard-Lenoble, Chandenier, & Gaxotte, 2003). The current therapeutic potential of IVM is attributed to action on a non-mammalian, glutamate-gated inhibitory chloride channel (Cully et al, 1994; Dent, Davis, & Avery, 1997; Vassilatis et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Oral delivery of ivermectin using a fast dissolving oral film: Implications for repurposing ivermectin as a pharmacotherapy for alcohol use disorder

Yardley

Huynh

Rodgers

et al. 2015

Alcohol

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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.

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Section: Introductionmentioning

confidence: 99%

Oral delivery of ivermectin using a fast dissolving oral film: Implications for repurposing ivermectin as a pharmacotherapy for alcohol use disorder

Yardley

Huynh

Rodgers

et al. 2015

Alcohol

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“…We propose that ivermectin (IVM), a drug used by millions of humans for treatment of parasites [9, 10] can be repositioned as a novel pharmacotherapy to treat and/or prevent excess alcohol consumption and abuse. In P2×4 receptors (P2×4Rs), IVM is used to selectively identify the participation of P2×4Rs from other P2× family members in adenosine 5’-triphosphate (ATP)-mediated processes (Jelinkova et al, 2006; Khakh et al, 1999; Silberberg et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Multiday administration of ivermectin is effective in reducing alcohol intake in mice at doses shown to be safe in humans

Yardley¹,

Neely

Huynh³

et al. 2014

NeuroReport

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Ivermectin (IVM), an FDA approved anthelmintic agent, can significantly reduce ethanol intake in mice following acute administration. The current study evaluates the sustainability and safety of multi-day IVM administration in reducing 10E intake in mice at a dose shown to be safe in humans. We tested the effect of 10-day administration of IVM (3.0 mg/kg/day; i.p.) on reducing 10% v/v alcohol (10E) intake in C57BL/6J mice using a 24-h, two-bottle choice paradigm. On the 10th day of IVM administration, mice were sacrificed at 0, 0.5, 2, 8, 32, 48 and 72 hours post-injection. Brain tissue and plasma samples were collected and analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Analysis of variance (ANOVA) was used to assess the effect of 10-day IVM administration on 10E intake, 10E preference, water intake and total fluid intake with Dunnett’s Multiple Comparison post-hoc test. Individual student’s t-tests were also used to further quantify changes in these dependent variables. IVM significantly decreased 10E intake over a 9-day period (p<0.01). Pre IVM 10E intake was 9.1 ± 3.2 g/kg/24-h. Following the 9th day of IVM injections, intake dropped by almost 30% (p<0.05). IVM had no effect on total water intake or mouse weight throughout the study; however, there was a significant decrease in both preference for 10E (p<0.01) and total fluid intake (p<0.05). Multi-day administration of IVM significantly reduces 10E intake and preference in animals without causing any apparent adverse effects at a dose shown to be safe in humans.

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“…While no selective agonists of P2X4Rs have been developed to date, rich evidence has shown that ivermectin (IVM), a broad-spectrum antiparasitic dihydro avermectin derivative used worldwide in humans and animals (Geary, 2005; Molinari et al, 2010; Richard-Lenoble et al, 2003), acts as a potent and selective positive allosteric modulator of P2X4Rs. IVM’s selectivity affinity (between P2XR subtypes) provides the basis for it to be routinely employed to determine the contribution of P2X4Rs in ATP-mediated processes (Khakh et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Ivermectin reduces alcohol intake and preference in mice

et al. 2012

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The high rate of therapeutic failure in the management of alcohol use disorders (AUDs) underscores the urgent need for novel and effective strategies that can deter ethanol consumption. Recent findings from our group showed that ivermectin (IVM), a broad-spectrum anthelmintic with high tolerability and optimal safety profile in humans and animals, antagonized ethanol-mediated inhibition of P2X4 receptors (P2X4Rs) expressed in Xenopus oocytes. This finding prompted us to hypothesize that IVM may reduce alcohol consumption; thus, in the present study we investigated the effects of this agent on several models of alcohol self-administration in male and female C57BL/6 mice. Overall, IVM (1.25–10 mg/kg, intraperitoneal) significantly reduced 24-h alcohol consumption and intermittent limited access (4-h) binge drinking, and operant alcohol self-administration (1-h). The effects on alcohol intake were dose-dependent with the significant reduction in intake at 9 h after administration corresponding to peak IVM concentrations (Cmax) in the brain. IVM also produced a significant reduction in 24-h saccharin consumption, but did not alter operant sucrose self-administration. Taken together, the findings indicate that IVM reduces alcohol intake across several different models of self-administration and suggest that IVM may be useful in the treatment of AUDs.

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New Ventures in the Genotoxic and Cytotoxic Effects of Macrocyclic Lactones, Abamectin and Ivermectin

Cited by 35 publications

References 45 publications

Oral delivery of ivermectin using a fast dissolving oral film: Implications for repurposing ivermectin as a pharmacotherapy for alcohol use disorder

Oral delivery of ivermectin using a fast dissolving oral film: Implications for repurposing ivermectin as a pharmacotherapy for alcohol use disorder

Multiday administration of ivermectin is effective in reducing alcohol intake in mice at doses shown to be safe in humans

Ivermectin reduces alcohol intake and preference in mice

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