This article talks about the mechanisms of action of ivermectin against the SARS-CoV-2 variants.
The topic was inspired by a question from a colleague, Dr. Haruhuani S., regarding the article, Encephalitis may explain the high COVID-19 deaths in China. From the comments section:
Obvious question: how do ivermectin and hydroxychloroquine do against this variant?
Thanks for your work, Dr. Santiano. It is much appreciated.
Initially, I planned on putting ivermectin and hydroxychloroquine together, but ivermectin is quite long already. I will answer the hydroxychloroquine part in a future issue.
Short answer
Ivermectin could work against the new variants. There are several mechanisms for how ivermectin works, but the most essential to me is that ivermectin allows proper antiviral response.
The SARS-CoV-2 can inhibit the immune response to allow for its replication. To make it happen, viral proteins enter the nucleus and decrease the immune response against it, allowing it to replicate.
Caly et al. found that ivermectin prevents viral entry by preventing human proteins from bringing the virus into the nucleus. The consequence is the prevention of viral replication and a cytokine storm. [1]
I talked about it in my updated article – What makes Ivermectin a kick-ass antiviral?
The difference between viral and human responses to antibiotics
If the primary effect of an antiviral is against the virus, the virus can adapt by changing or mutating its amino acid sequences and render the antiviral ineffective. A study showed that’s what happens in Paxlovid.[3]
In contrast, with an antiviral that works using human mechanisms like ivermectin, antiviral resistance does not develop and will continue to be effective no matter what SARS-CoV-2 variants appear.
This is why ivermectin can be used for prevention for a long time, as it was done for river blindness in Africa. I discussed that at – Solved! The Ivermectin African Enigma
Long answer
Ivermectin has other effects on the host’s immune system. Asiya Kamber Zaidi & Puya Dehgani-Mobaraki wrote a review article, The mechanisms of action of ivermectin against SARS-CoV-2—an extensive review.
In it, they included the effects of ivermectin on the SARS-CoV-2 virus. The many mechanisms of ivermectin give it many weapons against SARS-CoV-2.
That means while a mutation in the virus’s genome might affect the effectiveness of another antiviral, ivermectin can pick another mechanism from its toolbox to defeat the virus.
Zaidi and Dehgani-Mubaraki were not kidding when they said it was an extensive review.
I copied and pasted their tabulated findings and retained their references with the links.
The improved immune response against SARS-CoV-2 stems from inhibiting the import proteins described above.
A list of studies demonstrating the probable mechanisms of ivermectin (IVM) against SARS-CoV-2
| The main role of ivermectin against SARS-CoV-2 | Study authors | Study year | References |
|---|---|---|---|
| A. Direct action on SARS-CoV-2 | |||
| Level 1: Action on SARS-CoV-2 cell entry | |||
| IVM docks in the region of leucine 91 of the spike protein and histidine 378 of the ACE-2 receptor | Leher et al. | 2020 | [21] |
| IVM has the highest binding affinity to the predicted active site of the S glycoprotein; Considerable binding affinity to the predicted active site of the SARS-CoV-2 RdRp protein; Highest binding affinity to the predicted active site of nsp14; highest binding affinity to the active site of the TMPRSS2 protein | Eweas et al. | 2021 | [22] |
| IVM utilizes viral spike protein, main protease, replicase, and human TMPRSS2 receptors as the most possible targets for executing its antiviral efficiency by disrupting binding | Choudhury et al. | 2021 | [23] |
| Level 2: Action on importin (IMP) superfamily | |||
| in the presence of a viral infection, IVM targets the IMPα component of the IMP α/β1 heterodimer and binds to it, preventing interaction with IMP β1, subsequently blocking the nuclear transport of viral proteins | Yang et al. | 2020 | [25] |
| Level 3: Action as an ionophore | |||
| Two ivermectin molecules, reacting with each other in a “head-tail” mode, can create a complex suitable to be considered an ionophore. These allow neutralization of the virus at an early stage of the infection before it adheres to the host cells and enters it | Rizzo | 2020 | [27] |
| Ivermectin acts as an ionophore by chloride channel upregulation to generate apoptosis and osmotic cell death. | Dueñas-González et al., Dominguez-Gomez et al. |
2021, 2018 |
[28], [29] |
| B. Action on host targets for viral replication | |||
| Level 4: Action as an antiviral | |||
| IVM has antiviral properties against other viruses, including the RNA viruses such as Zika virus (ZKV), dengue virus, yellow fever virus (YFV), West Nile virus (WNV), Hendra virus (HEV), Newcastle virus, Venezuelan equine encephalitis virus (VEEV), chikungunya virus (CHIKV), Semliki Forest virus (SFV), and Sindbis virus (SINV), Avian influenza A virus, porcine reproductive and respiratory syndrome virus (PRRSV), human immunodeficiency virus type 1 as well as DNA viruses such as equine herpesvirus type 1 (EHV-1) and pseudorabies virus (PRV) | Heidary et al. | 2020 | [30] |
| IVM acts as an inhibitor of HIV-1 nuclear protein transfer | Wagstaff et al. | 2011 | [31] |
| IVM causes a decrease in viral gene expression in BKPyV due to the inhibition of nucleus entry | Bennett et al. | 2015 | [32] |
| IVM demonstrated IMP α/β-dependent nuclear transfer inhibition and reduced virus replication in a dose-dependent manner for BoHV-1 | Raza et al. | 2020 | [33] |
| Level 5: Action on viral replication and assembly | |||
| In Vero/hSLAM cells infected with the SARS-CoV-2 virus, when “exposed” to 5 µM, IVM showed a 5000-fold reduction in viral RNA at 48 h when compared to the control group | Caly et al. | 2020 | [34] |
| Utilizing a modeling approach, predicted lung accumulation of ivermectin over ten times higher than EC 50 | Arshad et al. | 2020 | [35] |
| Best binding interaction between IVM and RNA-dependent RNA polymerase (RdRp) | Swargiary et al.a | 2020 | [37] |
| Highly efficient binding of IVM to nsp14 | Ma et al. | 2015 | [39] |
| Highly efficient binding of IVM to the viral N phosphoprotein and M protein | Eweas et al. | 2021 | [22] |
| Level 6: Action on posttranslational processing of viral polyproteins | |||
| IVM binds to both proteins, Mpro, and to a lesser extent to PLpro of SARS-CoV-2 | Eweas et al. | 2021 | [22] |
| IVM inhibits 3 chymotrypsin-like proteases | Mody et al. | 2021 | [40] |
| Level 7: Action on karyopherin (KPNA/KPNB) receptors | |||
| IVM inhibits the KPNA/KPNB1- mediated nuclear import of viral proteins | Caly et al. | 2020 | [34] |
| C. Action on host targets for inflammation | |||
| Level 8: Action on interferon (INF) levels | |||
| IVM promotes the expression of several IFN-related genes, such as IFIT1, IFIT2, IF144, ISG20, IRF9, and OASL | Seth et al. | 2016 | [45] |
| Level 9: Action on Toll-like receptors (TLRs) | |||
| IVM blocks the activation of the NF-kappa B pathway and inhibition of toll-like receptor 4 (TLR4) signaling | Zhang et al. | 2008 | [47] |
| Level 10: Action on nuclear factor-κB (NF-κB) pathway | |||
| IVM at its very low dose, which did not induce cytotoxicity, drastically reversed the resistance of tumor cells to the chemotherapeutic drugs both in vitro and in vivo by inhibiting the transcriptional factor NF-κB. | Jiang et al. | 2019 | [49] |
| IVM inhibits lipopolysaccharide (LPS)-induced production of inflammatory cytokines by blocking the NF-κB pathway and improving LPS-induced survival in mice | Zhang et al. | 2008 | [47] |
| Level 11: Action on the JAK-STAT pathway, PAI-1 and COVID-19 sequalae | |||
| IVM inhibits STAT-3, SARS-CoV-2-mediated inhibition of IFN and STAT 1, with the subsequent shift to a STAT-3- dominant signaling network that could result in almost all of the clinical features of COVID-19; STAT-3 acts as a “central hub” that mediates the detrimental COVID-19 cascade | Matsuyama et al. | 2020 | [44] |
| STAT-3 induces a C-reactive protein that upregulates PAI-1 levels. Ivermectin inhibits STAT-3 | Matsuyama et al. | 2020 | [44] |
| The PD-L1 receptors present on the endothelial cells are activated by STAT-3, causing T cell lymphopenia. IVM inhibits STAT-3 through direct inhibition | Matsuyama et al. | 2020 | [44] |
| Level 12: Action on P21 activated kinase 1 (PAK1) | |||
| IVM suppresses the Akt/mTOR signaling and promotes ubiquitin-mediated degradation of PAK1 hence compromising STAT-3 activity and decreasing IL-6 production | Dou et al. | 2016 | [59] |
| Level 13: Action on Interleukin-6 (IL-6) levels | |||
| IVM suppressed IL-6 and TNFα production | Zhang et al. | 2008 | [47] |
| IVM “dramatically reduced” IL-6/IL-10 ratio modulating infection outcomes | De Melo et al. | 2020 | [60] |
| Level 14: Action on allosteric modulation of P2X4 receptor | |||
| Positive allosteric modulation of P2X4 by IVM enhances ATP-mediated secretion of CXCL5 | Layhadi et al. | 2018 | [63] |
| Level 15: Action on high mobility group box 1 (HMGB1) | |||
| Ivermectin inhibits HMGB1 | Juarez et al. | 2018 | [65] |
| Level 16: Action as an immunomodulator on lung tissue and olfaction | |||
| No olfactory deficit was observed in IVM-treated females; IVM dramatically reduced the IL-6/IL-10 ratio in lung | De Melo et al. | 2020 | [60] |
| Level 17: Action as an anti-inflammatory | |||
| Anti-inflammatory action of IVM was explained as inhibition of cytokine production by lipopolysaccharide challenged macrophages, blockade of activation of NF-kB, and the stress-activated MAP kinases JNK and p38, and inhibition of TLR4 signaling | Zhang et al. | 2008 | [47] |
| Ci et al. | 2009 | [67] | |
| Yan et al. | 2011 | [68] | |
| Immune cell recruitment, cytokine production in bronchoalveolar lavage fluid, IgE, and IgG1 secretion in serum as well as hyper-secretion of mucus by goblet cells was reduced significantly by IVM | Yan et al. | 2011 | [68] |
| D. Action on other host targets | |||
| Level 18: Action on plasmin and annexin A2 | |||
| Annexin acts as a coreceptor for the conversion of plasminogen to plasmin in the presence of t-PA. increased levels of plasmin leads to direct activation of STAT-3 | Zaidi et al. | 2020 | [69] |
| IVM directly inhibits STAT-3 and could play a role in the inhibition of COVID-19 complications | Matsuyama et al. | 2020 | [44] |
| Level 19: Action on CD147 on the RBC | |||
| The SARS-CoV-2 does not internalize into the red blood cells but such attachments can lead to clumping. IVM binds to the S protein of the SARS-CoV-2 virus making it unavailable to bind with CD147 |
Scheim et al. | 2020 | [70] |
| Level 20: Action on mitochondrial ATP under hypoxia on cardiac function | |||
| IVM increased mitochondrial ATP production by inducing Cox6a2 expression and maintains mitochondrial ATP under hypoxic conditions. This prevents pathological hypertrophy and improves cardiac function | Nagai et al. | 2017 | [72] |
Agendas and Retractions
If you click on the work of Zaidi & Dehgani-Mobaraki, you will see that it has been retracted. But if you look at why it was retracted, you will read, (emphasis added)
Postpublication review confirmed that while the review article appropriately describes the mechanism of action of ivermectin, the cited sources do not appear to show that there is clear clinical evidence of the effect of ivermectin for the treatment of SARS-CoV-2.
When the editor-in-chief said that “cited sources do not appear to show that there is clear clinical evidence of the effect of ivermectin for the treatment of SARS-CoV-2,” they must have missed the 95 studies in https://c19ivm.org/meta.html that showed that ivermectin is effective in the most meaningful clinical outcomes like reducing mortality, ventilation, ICU admission, and hospitalization.
This shows that politics instead of scientific evidence was used to retract the article and discredit an effective drug.
In a USA Watchdog interview, Dr. Pierre Kory, said that the attack on ivermectin is responsible for the deaths of at least 800,000 people.
Enough of the rant.
The figure below is a summary of c191vm.org’s findings.
Some studies showing ivermectin’s effectiveness were conducted in 2022 when the Omicron variant was dominant. An example is a study by Delandre et al. that showed ivermectin’s efficacy against 30 clinical SARS-CoV-2 strains belonging to 14 variants.
I hope I answered your question, Dr. Spruce H.
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Related:
- SARS-CoV-2 Spike Protein Cause Red Blood cell Clumping, and Ivermectin Prevents it
- The NFL is giving their players IVERMECTIN as a prophylactic AND to prevent “positive” Covid tests
- A new study shows a 100% decreased hospitalization rate with regular ivermectin use
- Ivermectin prevents binding to human cells by blocking the spike protein
- The many problems of the Ivermectin study in the NEJM
- Japanese company announces Ivermectin has antiviral properties
- City-wide use of Ivermectin lowered COVID-19 cases, hospitalizations and deaths in Itajaí, Brazil
- What makes Ivermectin a kick-ass antiviral?
- Where to Get Ivermectin
- How to get Ivermectin
- Bayes Theorem Confirms Meta-analysis of Ivermectin’s Effectivity against COVID-19
- News that ivermectin overdose is clogging up hospitals is not true
- Ivermectin vs Remdesivir for COVID-19
- Solved! The Ivermectin African Enigma
- IVMMETA.COM: A website of studies on Ivermectin’s efficacy
- Ivermectin is effective against Influenza and Cold Virus In Vitro
References:
- 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: PMC7129059.
- Zaidi, A.K., Dehgani-Mobaraki, P. The mechanisms of action of Ivermectin against SARS-CoV-2: An evidence-based clinical review article. J Antibiot 75, 122 (2022). https://doi.org/10.1038/s41429-021-00430-5
- Zhou Y, Gammeltoft KA, Ryberg LA, Pham LV, Tjørnelund HD, Binderup A, Duarte Hernandez CR, Fernandez-Antunez C, Offersgaard A, Fahnøe U, Peters GHJ, Ramirez S, Bukh J, Gottwein JM. Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system. Sci Adv. 2022 Dec 21;8(51):eadd7197. doi: 10.1126/sciadv.add7197. Epub 2022 Dec 21. PMID: 36542720; PMCID: PMC9770952.
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This is great. Thank you! I was first attracted to your site by your article indicating that ivm is likely effective against influenza and RSV. I see you have other posts along this line and I plan to peruse them. Wonderful!
I have amassed a stash of 5-day course ivm plus vitamins which have been shared informally among a dozen or so of people in our community, over the past couple of years, who were on the verge of going to the ER with Covid. Every single one recovered rapidly with this treatment. (Horse paste works great, and one pkg. of Durvet apple-flavored is easily divided into five approx. 22. 5 mg doses, fine for most adults in the community. Take inside a tablespoon or so of unsweetened applesauce.)
I considered hydroxychloroquine but decided against it because there are a few heart conditions, possibly undiagnosed in community members, which contraindicate use. But! I think it was through your article (?) I found a pharmacist reference to chinchona tea, which I have ordered.
I want to amass a kit of things that are cheap which are likely to be of help in future community threats like this, whether a new virulent Covid strain or other viral infection. The many mechanisms of action of ivm, both on the human and on the virus, make me feel more confident that stocking up on ivm is a good choice as well as stocking up on the other vitamins recommended by FLCCC. Horse paste price has come down since the scare has diminished, but might go up again so I have purchased online while it is cheap.
Makes one wonder how many old cheap drugs are useful for very many things I think of how pharma-funded research zeroes in on one novel use enableing them to produce high-priced treatments which are then recommended to everyone rather than the cheap old things. Oh, I am glad I am no longer in the business
Anyway, I appreciate your work very much! and I am glad that you are out there
In case you did not see it yet, here is a nice summary letter I saw today from some Swedish professionals.
https://dailysceptic.org/2023/01/13/covid-vaccines-are-obviously-dangerous-and-should-be-halted-immediately-say-senior-swedish-doctors/
Best wishes!
Thank you for the lovely letter. I was a proponent of HCQ before ivermectin came along. Thank goodness that horse paste was available, and there must be thousands who survived COVID secondary to that. Regarding effective OTC products, I discovered NAC, peptobismol, Bromelain, and bromhexine. The combination of peptobismol and NAC can potentially cure many hard-to-treat bacterial infections like MRSA and C diff. Yesterday I posted over-the-counter antioxidants that can prevent ionizing radiation injury.
Thank you for this excellent review. It is great to see all the mechanisms of ivermectin in one place. I understand that ivermectin does not readily cross the blood brain barrier. Is there enough inflammation from Covid or other viruses to make this less of a problem in clinical treatment?
You are welcome, and thank you for the kind words. This is how I understand your question, Does ivermectin play a role in brain inflammation due to COVID or other viruses? I would be happy to answer your question. Please correct my interpretation if needed.
I wrote an article about your question. I hope I answered it. https://drjessesantiano.com/ivermectins-role-in-preventing-the-neurologic-effects-of-sars-cov-2/