Ivermectin: an award-winning drug with expected antiviral activity against COVID-19

Formiga, Fabio Rocha; LeBlanc, Roger; Rebouças, Juliana de Souza; Farias, Leonardo P.; Oliveira, Ronaldo N. de; Pena, Lindomar

doi:10.1016/j.jconrel.2020.10.009

Cited by 71 publications

(53 citation statements)

References 39 publications

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“…These difficulties can be overcome by formulating liposomal ivermectin or other ivermectin formulations with improved properties. Furthermore, inhalation therapy of ivermectin can deliver high drug concentration to the lungs and airways to reduce the viral loads in such areas [ 41 ] or else it can be used in combination with other agents that differ in mechanism of action [ 38 ].…”

Section: Future Recommendationsmentioning

confidence: 99%

Ivermectin as a potential drug for treatment of COVID-19: an in-sync review with clinical and computational attributes

et al. 2021

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Introduction COVID-19 cases are on surge; however, there is no efficient treatment or vaccine that can be used for its management. Numerous clinical trials are being reviewed for use of different drugs, biologics, and vaccines in COVID-19. A much empirical approach will be to repurpose existing drugs for which pharmacokinetic and safety data are available, because this will facilitate the process of drug development. The article discusses the evidence available for the use of Ivermectin, an anti-parasitic drug with antiviral properties, in COVID-19. Methods A rational review of the drugs was carried out utilizing their clinically significant attributes. A more thorough understanding was met by virtual embodiment of the drug structure and realizable viral targets using artificial intelligence (AI)-based and molecular dynamics (MD)-simulation-based study. Conclusion Certain studies have highlighted the significance of ivermectin in COVID-19; however, it requires evidences from more Randomised Controlled Trials (RCTs) and dose-response studies to support its use. In silico-based analysis of ivermectin's molecular interaction specificity using AI and classical mechanics simulation-based methods indicates positive interaction of ivermectin with viral protein targets, which is leading for SARS-CoV 2 N-protein NTD (nucleocapsid protein N-terminal domain).

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Section: Future Recommendationsmentioning

confidence: 99%

Ivermectin as a potential drug for treatment of COVID-19: an in-sync review with clinical and computational attributes

et al. 2021

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“…The apparent critical role of this short protein in coronaviruses evading the innate immune response would lead to it being a major target for small interfering RNA (siRNA) degradation delivered in liposomes via a nasal spray after swabbing for testing for SARS‐CoV‐2 (see review of La Fauce and Owens) [30]. Formiga et al [3] outlined other possible delivery systems for micro‐ and nanoparticles. If a longer lasting therapeutic was needed, then short hairpin RNA (shRNA) delivered in a plasmid could be substituted instead [30].…”

Section: Resultsmentioning

confidence: 99%

“…Ivermectin (Figure ) is an essential drug with clinical approval for treating different types of parasitic infections in humans and animals. More recently however, several studies have documented antiviral effects of ivermectin and the potential to repurpose it as a therapeutic agent for viral infections [1–3]. Most scientific investigations in this area have been done in vitro , by infecting mammalian cells and, using this approach, efficacy has been reported against many viruses with most notable effects on enveloped, positive‐sense, single‐stranded flaviviruses including Dengue, West Nile, Yellow fever and Zika [4–8].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the potential for the in vitro antiviral effects of ivermectin to translate into clinically relevant applications against infections in mammals is yet to be determined. Recent reviews of ivermectin as an antiviral [2,3] highlight the need to better understand the pharmacological considerations. Therefore, in this study, we sought to undertake a systematic review of all published work on antiviral effects of ivermectin and our objective was to present an integrative, critical appraisal of the qualitative and quantitative antiviral properties of ivermectin for putative applications in agriculture and medicine with examination of SARS‐CoV‐2.…”

Section: Introductionmentioning

confidence: 99%

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A systematic review of experimental evidence for antiviral effects of ivermectin and an in silico analysis of ivermectin's possible mode of action against SARS‐CoV‐2

Kinobe

Owens

2021

Fundamemntal Clinical Pharma

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Viral infections remain a major cause of economic loss with an unmet need for novel therapeutic agents. Ivermectin is a putative antiviral compound; the proposed mechanism is the inhibition of nuclear translocation of viral proteins, facilitated by mammalian host importins, a necessary process for propagation of infections. We systematically reviewed the evidence for the applicability of ivermectin against viral infections including SARS‐CoV‐2 regarding efficacy, mechanisms and selective toxicity. The SARS‐CoV‐2 genome was mined to determine potential nuclear location signals for ivermectin and meta‐analyses for in vivo studies included all comparators over time, dose range and viral replication in multiple organs. Ivermectin inhibited the replication of many viruses including those in Flaviviridae, Circoviridae and Coronaviridae families in vitro. Real and mock nuclear location signals were identified in SARS‐CoV‐2, a potential target for ivermectin and predicting a sequestration bait for importin β, stopping infected cells from reaching a virus‐resistant state. While pharmacokinetic evaluations indicate that ivermectin could be toxic if applied based on in vitro studies, inhibition of viral replication in vivo was shown for Porcine circovirus in piglets and Suid herpesvirus in mice. Overall standardized mean differences and 95% confidence intervals for ivermectin versus controls were −4.43 (−5.81, −3.04), p < 0.00001. Based on current results, the potential for repurposing ivermectin as an antiviral agent is promising. However, further work is needed to reconcile in vitro studies with clinical efficacy. Developing ivermectin as an additional antiviral agent should be pursued with an emphasis on pre‐clinical trials in validated models of infection.

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“…A single dose of IVM effectively removed SARS-CoV-2 viral RNA in cell culture by 48 h. It was suggested that IVM might be used for the treatment of COVID-19 patients in the early phase with mild to moderate symptoms, PCR positive for SARS-CoV-2 virus, and those without comorbidities such as chronic obstructive pulmonary disease, diabetes, hypertension, obesity, acute or chronic renal failure, and coronary diseases. IVM suggested anti-CoV-2 effects are based on in vitro studies, showing that this compound inhibits the importin alpha/beta-1 nuclear transporter, and thus, in cell cultures, reduces the replication of various viruses including SARS-CoV-2 (Bray et al 2020 ; Caly et al 2020 ; Rizzo 2020 ; Sharun et al 2020 ; Heidary and Gharebaghi 2020 ; Dixit et al 2020 ; Chaccour et al 2020a , b ; Formiga et al 2020 ). In addition, in a silico-based analysis of Ivermectin’s molecular interaction indicates positive interaction of Ivermectin with viral protein targets, which is leading for SARS-CoV 2 N-protein NTD (nucleocapsid protein N-terminal domain) (Kaur et al 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Metabolism and interactions of Ivermectin with human cytochrome P450 enzymes and drug transporters, possible adverse and toxic effects

Rendić¹

2021

Arch Toxicol

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The review presents metabolic properties of Ivermectin (IVM) as substrate and inhibitor of human P450 (P450, CYP) enzymes and drug transporters. IVM is metabolized, both in vivo and in vitro, by C-hydroxylation and O-demethylation reactions catalyzed by P450 3A4 as the major enzyme, with a contribution of P450 3A5 and 2C9. In samples from both in vitro and in vivo metabolism, a number of metabolites were detected and as major identified metabolites were 3″-O-demethylated, C4-methyl hydroxylated, C25 isobutyl-/isopropyl-hydroxylated, and products of oxidation reactions. Ivermectin inhibited P450 2C9, 2C19, 2D6, and CYP3A4 with IC 50 values ranging from 5.3 μM to no inhibition suggesting that it is no or weak inhibitor of the enzymes. It is suggested that P-gp (MDR1) transporter participate in IVM efflux at low drug concentration with a slow transport rate. At the higher, micromolar concentration range, which saturates MDR1 (P-gp), MRP1, and to a lesser extent, MRP2 and MRP3 participate in IVM transport across physiological barriers. IVM exerts a potent inhibition of P-gp (ABCB1), MRP1 (ABCC1), MRP2 (ABCC2), and BCRP1 (ABCG2), and medium to weak inhibition of OATP1B1 (SLC21A6) and OATP1B3 (SLCOB3) transport activity. The metabolic and transport properties of IVM indicate that when IVM is co-administered with other drugs/chemicals that are potent inhibitors/inducers P4503A4 enzyme and of MDR1 (P-gp), BCRP or MRP transporters, or when polymorphisms of the drug transporters and P450 3A4 exist, drug–drug or drug–toxic chemical interactions might result in suboptimal response to the therapy or to toxic effects.

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Ivermectin: an award-winning drug with expected antiviral activity against COVID-19

Cited by 71 publications

References 39 publications

Ivermectin as a potential drug for treatment of COVID-19: an in-sync review with clinical and computational attributes

Ivermectin as a potential drug for treatment of COVID-19: an in-sync review with clinical and computational attributes

A systematic review of experimental evidence for antiviral effects of ivermectin and an in silico analysis of ivermectin's possible mode of action against SARS‐CoV‐2

Metabolism and interactions of Ivermectin with human cytochrome P450 enzymes and drug transporters, possible adverse and toxic effects

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