The Place of Ivermectin in the Management of Covid-19: State of the Evidence
Main Article Content
Abstract
Background and aims.
The covid 19 pandemic necessitated the use of old, repurposed, and new drugs, in addition to vaccines and public health measures. There are still many controversies about the efficacy and impact of some of the medications used, which need further elucidation.
We review the pharmacological properties and the place of the repurposed drug, Ivermectin (IVM) in the prophylaxis and treatment of SARS - CoV- 2 (severe acute respiratory syndrome coronavirus 2.) infection or Covid 19 disease.
Major findings: in-vitro, in-vivo, and human studies
In vitro studies in Vero/hSlam cells caused a 99.98 % inhibition of SARS - Cov-2 (5000-fold) within 48 hours. The IC50 (half maximal inhibitory concentration) for this virucidal action was 2.8μM, which was thought unattainable in humans in-vivo. Thus, there was initial skepticism on pharmacokinetic grounds as to possible efficacy of IVM in humans with Covid 19. There are, however, a multiplicity of anti-covid 19 mechanisms, beyond mere anti-viral effects, such as blockade of ACE2 receptor viral entry, and the anti-cytokine and anti-inflammatory effects of IVM. IVM has a long half-life of 18 - 24 hours, Mean Residence Time (MRT) of 3.4 days and a preferential site of lung accumulation.
In-vivo studies in Syrian Golden hamsters confirmed the symptomatic, anti-inflammatory, anti-cytokine, histopathological and survival benefit of IVM, which was more manifest in female animals.
In a January 2023 meta-analysis of studies (s) in total number of patients (n) for various parameters (p), the reduction in risk relative to placebo or controls were as follows:
- Overall improvement (s= 95) (n= 134,554) was 62% [95%CI 54-69].
- Mortality (s=48) (n=120,000) there was 51% reduction [95%CI 37-62].
- Hospitalization (s=29) (n = 44, 784), there was 34% reduction [ 95% CI 20-45].
- Viral clearance (s=20) (n= 3945) there was 45% reduction [95%CI 31-55].
- Prophylaxis (s=17) (n=19,764) showed 82% reduction [95%CI 73-88]
6 Randomised Control Trial (RCT) studies (s= 45) (n=2173) showed a 54 % mortality reduction [95% CI 39-65]
In addition, IVM has been shown in studies to cause a rapid reversal of hypoxemia (SPO2 < 94%) and a rapid increase in SPO2, an effect exhibiting a gender dichotomy. (SPO2 is the percentage of the maximum carrying capacity of the blood). This effect on SPO2 has been attributed to IVM’s reversal and prevention of SARS-CoV-2 virus induced hemagglutination. The dosage used for treatment of covid 19 varied widely within studies, but doses of 200-400 μg/kg twice weekly or daily for 5 consecutive days, caused significant viral clearance and clinical improvement, with minimal safety concerns. For prophylaxis, a dose of 200μg/kg for two consecutive days every 15 days was found effective in studies.
Conclusion: This review provides powerful evidence that IVM is efficacious singly or as a part of a regimen for covid 19. IVM could potentially be combined with newer oral anti-covid 19 agents, such as Paxlovid, for effective and life-saving regimen in patients infected with covid-19. The anti-viral properties of these drugs can synergize with the anti-inflammatory and anti-cytokine properties of Ivermectin. Ivermectin is also useful prophylactically, especially where vaccines are unavailable or undesirable.
Article Details
How to Cite
O.E., Babalola; A.A ., Ajayi.
The Place of Ivermectin in the Management of Covid-19: State of the Evidence.
Medical Research Archives, [S.l.], v. 11, n. 4, apr. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3778>. Date accessed: 18 apr. 2024.
doi: https://doi.org/10.18103/mra.v11i4.3778.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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11. Suputtamongkol Y, Avirutnan P, Mairiang D, Angkasekwinai N, Niwattayakul K, Yamasmith E, Saleh-Arong FA, Songjaeng A, Prommool T, Tangthawornchaikul N, Puttikhunt C, Hunnangkul S, Komoltri C, Thammapalo S, Malasit P. Ivermectin Accelerates Circulating Nonstructural Protein 1 (NS1) Clearance in Adult Dengue Patients: A Combined Phase 2/3 Randomized Double-blinded Placebo Controlled Trial. Clin Infect Dis. 2021 May 18;72(10):e586-e593. doi: 10.1093/cid/ciaa1332. PMID: 33462580.
12. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Jun;178:104787. doi: 10.1016/j.antiviral.2020.104787. Epub 2020 Apr 3. PMID: 32251768; PMCID:
13. Georgi Momekov & Denitsa Momekova(2020)Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view: antiviral levels are not likely attainable with known dosing regimens,Biotechnology & Biotechnological Equipment,34:1,469-474,DOI:10.1080/13102818.2020.1775118ref.
14. Lehrer S, Rheinstein PH. Ivermectin Docks to the SARS-CoV-2 Spike Receptor-binding Domain Attached to ACE2. Vivo 2020;34:3023–6. https://doi.org/10.21873/invivo.12134. PMID: 32871846; PMCID: PMC7652439
15. Yang SNY, Atkinson SC, Wang C, Lee A, Bogoyevitch MA, Borg NA, et al. The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer. Antivir Res. 2020;177:104760.
16. Arshad U, Pertinez H, Box H, et al. Prioritization of Anti-SARS- Cov-2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human pharmacokinetics. Clin Pharmacol Ther (2020), https://doi.org/10. 1002/cpt.1909
17. Seth C, Mas C, Conod A, Mueller J, Siems K, Kuciak M, et al. LongLasting WNT-TCF response blocking and epigenetic modifying activities of withanolide f in human cancer cells. PLoS One. 2016;11:e0168170.
18. Zhang X, Song Y, Ci X, et al. Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice. Inflamm Res. 2008;57:524–9. https://doi.org/10. 1007/s00011-008-8007-8. [PMID: 19109745]
19. Matsuyama T, Kubli SP, Yoshinaga SK, et al. An aberrant STAT pathway is central to COVID-19. Cell Death Differ. 2020;27:3209–25. https://doi.org/10.1038/s41418-020-00633-7
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