Ivermectin: Potential Role as Repurposed Drug for COVID-19

Dixit, Aparna Banerjee; Yadav, Ramakant; Singh, Amit

doi:10.21315/mjms2020.27.4.15

Cited by 12 publications

(7 citation statements)

References 19 publications

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“…Ivermectin is a semisynthetic anthelmintic agent that selectively binds to glutamate-gated chloride ion channels found in nerve and muscle cells of invertebrates (3). However, an antiviral activity in RNA and DNA viruses has also been reported (4).…”

Section: Introductionmentioning

confidence: 99%

Outcomes of Ivermectin in the treatment of COVID-19: a systematic review and meta-analysis

Castañeda-Sabogal

Chambergo‐Michilot

Toro-Huamanchumo

et al. 2021

Preprint

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BackgroundTo assess the outcomes of ivermectin in ambulatory and hospitalized patients with COVID-19.MethodsFive databases and websites for preprints were searched until January 2021 for randomized controlled trials (RCTs) and retrospective cohorts assessing ivermectin versus control in ambulatory and hospitalized participants. The primary outcome was overall mortality. Secondary outcome was recovered patients. For meta-analysis, random-effects and inverse variance meta-analyses with logarithmic transformation were performed. ROBINS-I for cohort studies, and the Cochrane Risk of Bias 2.0 tool for trials were used. The strength of evidence was assessed using GRADE.ResultsAfter the selection, twelve studies (five retrospective cohort studies, six randomized clinical trials and one case series), were included. In total, 7412 participants were reported, the mean age was 47.5 (SD 9.5) years, and 4283 (58%) were male. Ivermectin was not associated with reduced mortality (logRR: 0.89, 95% CI 0.09 to 1.70, p = 0.04, I2= 84.7%), or reduced patient recovery (logRR 5.52, 95% CI -24.36 to 35.4, p = 0.51, I2 = 92.6%). All studies had a high risk of bias, and showed a very low certainty of the evidence.ConclusionsThere insufficient certainty and quality of evidence to recommend the use of ivermectin to prevent or treat ambulatory or hospitalized patients with COVID-19.

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Section: Introductionmentioning

confidence: 99%

Outcomes of Ivermectin in the treatment of COVID-19: a systematic review and meta-analysis

Castañeda-Sabogal

Chambergo‐Michilot

Toro-Huamanchumo

et al. 2021

Preprint

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“…The antiviral activity of IVM had been reported previously, wherein IVM was found to have in-vitro activity against both RNA and DNA viruses including human immunodeficiency virus type 1, influenza virus, Venezuelan equine encephalitis virus, dengue virus, yellow fever virus and Zika virus [ 7 , 8 ]. In April 2020, the in-vitro activity of IVM against SARS-CoV-2 was reported: a single dose of the drug administered after 2 h of infecting cultured Vero/hSLAM cells reduced the viral load up to 5000 times within 48 h [ 9 ].…”

Section: Introductionmentioning

confidence: 88%

Safety and Efficacy of Ivermectin and Doxycycline Monotherapy and in Combination in the Treatment of COVID-19: A Scoping Review

Bhowmick

Dang²,

Vallish³

et al. 2021

Drug Saf

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Introduction and Objective Ivermectin (IVM) and doxycycline (DOXY) have demonstrated in-vitro activity against SARS-CoV-2, and have a reasonable safety profile. The objective of this systematic review was to explore the evidence in the literature on the safety and efficacy of their use as monotherapy and combination therapy in COVID-19 management. Methods After prospectively registering the study protocol with the Open Science Framework, we searched PubMed, Google Scholar, clinicaltrials.gov, various pre-print servers and reference lists for relevant records published until 16 February, 2021 using appropriate search strategies. Baseline features and data pertaining to efficacy and safety outcomes were extracted separately for IVM monotherapy, DOXY monotherapy, and IVM + DOXY combination therapy. Methodological quality was assessed based on the study design. Results Out of 200 articles screened, 19 studies (six retrospective cohort studies, seven randomised controlled trials, five non-randomised trials, one case series) with 8754 unique patients with multiple stages of COVID-19 were included; four were pre-prints and one was an unpublished clinicaltrials.gov document. The comparator was standard care and ‘hydroxychloroquine + azithromycin’ in seven and three studies respectively, and two studies were placebo controlled; six studies did not have a comparator. IVM monotherapy, DOXY monotherapy and IVM + DOXY were explored in eight, five and five studies, respectively; one study compared IVM monotherapy and IVM + DOXY with placebo. While all studies described efficacy, the safety profile was described in only six studies. Efficacy outcomes were mixed with some studies concluding in favour of the intervention and some studies displaying no significant benefit; barring one study that described 9/183 patients with erosive esophagitis and non-ulcer dyspepsia with IVM + DOXY (without causality assessment details), there were no new safety signals of concern with any of the three interventions considered. The quality of studies varied widely, with five studies having a ‘good’ methodological quality. Conclusions Evidence is not sufficiently strong to either promote or refute the efficacy of IVM, DOXY, or their combination in COVID-19 management. Systematic Review Protocol Registration Details Open Science Framework: https://osf.io/n7r2j . Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01066-y.

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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: Potential Role as Repurposed Drug for COVID-19

Cited by 12 publications

References 19 publications

Outcomes of Ivermectin in the treatment of COVID-19: a systematic review and meta-analysis

Outcomes of Ivermectin in the treatment of COVID-19: a systematic review and meta-analysis

Safety and Efficacy of Ivermectin and Doxycycline Monotherapy and in Combination in the Treatment of COVID-19: A Scoping Review

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

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