Ivermectin

Martin, Richard J., et al. Trends in parasitology 37.1 (2021): 48-64.

Ivermectin is a mixture of more than 80% 22,23-dihydroavermectin B1a and B1b, a remarkably potent broad-spectrum anthelmintic and insecticide. At therapeutic doses of 150-200 micrograms/kg, it yields plasma concentrations of 11-54 ng/mL (13-63 nM) and is generally safe with acute toxicity seen only at very high doses. Beyond its classical antiparasitic uses, recent studies have explored repositioning ivermectin for antiviral, antimalarial, antimetabolic, and anticancer applications, though these require concentrations substantially higher than those used for anthelmintic purposes.
Experimental Protocol: This review synthesized the evidence for ivermectin's mechanism of action as an anthelmintic and insecticide, focusing on its role as a selective positive allosteric modulator of glutamate-gated chloride (GluCl) channels found in nematodes and insects. The review also examined ivermectin's effects on other ion channels, including GABA receptors and G-protein-coupled inwardly rectifying potassium (GIRK) channels in mammalian hosts. Recent repositioning studies were evaluated, including in vitro and in vivo experiments exploring ivermectin's antiviral, antimalarial, antimetabolic, and anticancer effects, with particular attention to the concentrations used relative to clinical anthelmintic concentrations.
Performance Evaluation: Ivermectin and its analogs selectively open inhibitory GluCl ion channels in pharyngeal muscles, motor nerves, female reproductive tracts, and excretory/secretory pores of nematodes, leading to inhibition of pharyngeal pumping, motility, reproduction, and host immunosuppression. At higher concentrations, ivermectin also modulates ion channels in host central nervous systems, though the blood-brain barrier normally limits such effects. Preliminary repositioning studies have shown antiviral, antimalarial, antimetabolic, and anticancer effects in tissue culture, but at concentrations significantly higher than anthelmintic concentrations.

Heidary, Fatemeh, et al. The Journal of antibiotics 73.9 (2020): 593-602.

Ivermectin, discovered in the late 1970s and recognized with the 2015 Nobel Prize in Physiology or Medicine, is a broad-spectrum drug with antiparasitic, antiviral, and immunomodulatory actions. Given the COVID-19 pandemic, there has been significant interest in repurposing existing medications. This systematic review comprehensively evaluated ivermectin's antiviral effects based on in vitro and in vivo studies spanning 50 years.
Experimental Protocol: A comprehensive PubMed search was conducted from January 1970 to April 2020, using an extensive MeSH-based syntax incorporating all ivermectin nomenclature combined with antiviral search terms. Articles were reviewed with no language restrictions. The review examined evidence against RNA viruses (Zika, dengue, yellow fever, West Nile, chikungunya, HIV-1, and SARS-CoV-2) and DNA viruses (equine herpes type 1, BK polyomavirus, and pseudorabies virus).
Performance Evaluation: Multiple studies reported antiviral effects of ivermectin against a broad range of RNA and DNA viruses. The proposed mechanism involves inhibition of the importin alpha/beta receptor responsible for transmitting viral proteins into the host cell nucleus. A key in vitro study demonstrated that 5 micromolar ivermectin produced a 5,000-fold reduction in SARS-CoV-2 viral RNA within 48 hours in Vero/hSLAM cells. However, concentrations used in vitro are substantially higher than those achievable with standard oral dosing. In vivo animal studies revealed broad antiviral effects, but clinical trials are necessary to evaluate potential efficacy in clinical settings. The review concludes that ivermectin could serve as a candidate for treating various viral infections, pending clinical validation.