The mechanisms of action of Ivermectin against SARS-CoV-2: An evidence-based clinical review article

Journal of Antibiotics ^ | 06/15/2021 | Asiya Kamber Zaidi & Puya Dehgani-Mobaraki

[SeekAndFind]

Abstract

Considering the urgency of the ongoing COVID-19 pandemic, detection of various new mutant strains and future potential re-emergence of novel coronaviruses, repurposing of approved drugs such as Ivermectin could be worthy of attention. This evidence-based review article aims to discuss the mechanism of action of ivermectin against SARS-CoV-2 and summarizing the available literature over the years. A schematic of the key cellular and biomolecular interactions between Ivermectin, host cell, and SARS-CoV-2 in COVID-19 pathogenesis and prevention of complications have been proposed.

[SeekAndFind]

Conclusion

Considering the urgency of the ongoing COVID-19 pandemic, simultaneous detection of various new mutant strains and future potential re-emergence of novel coronaviruses, repurposing of approved drugs such as Ivermectin could be worthy of attention.

[ProtectOurFreedom]

...Ivermectin could be worthy of attention...until Big Pharma decides otherwise.

[SeekAndFind]

Fig. 1: A schematic of the key cellular and biomolecular interactions between Ivermectin, host cell, and SARS-CoV-2 in COVID-19 pathogenesis and prevention of complications.

Ivermectin; IVM (red block) inhibits and disrupts binding of the SARS-CoV-2 S protein at the ACE-2 receptors (green). The green dotted lines depict activation pathways and the red dotted lines depict the inhibition pathways.

The TLR-4 receptors are directly activated by SARS-CoV-2 and also by LPS mediated activation (seen during ICU settings) causing activation of NF-Kb pathway and MAP3 Kinases leading to increased intranuclear gene expression for proinflammatory cytokines and chemokines (responsible for cytokine storm) and NO release (responsible for blood vessel dilatation, fluid leak, low blood pressure, ARDS and sepsis).

The NF-Kb and STAT-3 pathway activation is central to the pathogenesis and sequelae of COVID-19. STAT-3 physically binds to PAK-1 and increases IL-6 transcription. The annexin A2 at the cell surface converts plasminogen; PLG to plasmin under the presence of t-PA. Plasmin triggers activation and nuclear translocation of STAT-3.

An upregulation of STAT-3 stimulates hyaluronan synthase-2 in the lung cells causing hyaluronan deposition leading to diffuse alveolar damage and hypoxia. STAT-3 also directly activates TGF-beta initiating pulmonary fibrosis; a typical characteristic of SARS-COV-2 lung pathology. The damaged type 2 cells express PAI-1 and an already hypoxic state also causes an upregulation of PAI (through Hypoxic inducible factor-1) along with direct stimulation by STAT-3. Simultaneous STAT-3 and PAI-1 activation inhibits t-PA and urokinase-type plasminogen activator leading to thrombi formation.

Also, the SARS-CoV-2 spike protein binds to the CD147 on red blood cells and causes clumping. IVM in turn, binds to SARS-CoV-2 Spike protein and hence prevents clumping. T cell lymphopenia in COVID-19 can also be attributed to the direct activation of PD-L1 receptors on endothelial cells by STAT-3. IVM directly inhibits the NF-kb pathway, STAT-3, and indirectly inhibits PAK-1 by increasing its ubiquitin-mediated degradation.

The natural antiviral response of a cell is through interferon regulatory genes and viral RNA mediated activation of TLR-3 and TLR7/8- Myd88 activation of transcription of interferon-regulator (IRF) family.

For a virus to establish an infection, this antiviral response needs to be inhibited by blocking interferon production. The proteins such as importin and KPNA mediate nuclear transport of viral protein and subsequent IFN signaling. The SARS-CoV-2 proteins (ORF-3a, NSP-1, and ORF-6) directly block IFN signaling causing the surrounding cells to become unsuspecting victims of the infection. IVM inhibits both importin a-b (green) as well as the KPNA-1 receptors (brown) causing natural antiviral IFN release. IVM also inhibits viral RdrP, responsible for viral replication.

IVM Ivermectin, ACE-2 angiotensin-converting-enzyme 2, LPS Lipopolysaccharide, TLR Toll-like receptor, t-PA tissue-like plasminogen activator, PLG Plasminogen, IMPab Importin alpha-beta, Rdrp RNA dependant RNA polymerase, KPNA-1 Karyopherin Subunit Alpha 1, NF-kB nuclear factor kappa-light-chain-enhancer of activated B cells, Map3Kinases Mitogen-activated Kinases, PAK-1 P21 Activated Kinase 1, STAT-3 Signal transducer and activator of transcription 3, PAI-1 Plasminogen activator inhibitor-1, HIF-1 Hypoxia-Inducible Factor

[BobL]

India got sick of the explosion of cases there last spring, so they went back to Ivermectin. The Czech Republic was having a bad time also, so they went to Ivermectin and basically wiped out the virus.

Even though the vaccines are unproven, I also think they should be available to the public...they may help, in some cases, in addition to Ivermectin, of course.

[ProtectOurFreedom]

However, the use of ivermectin orally in an outpatient setting also requires strict and well defined guidelines to avoid any form of overdosing that could lead to toxicity. A study by Baudou, E et. al described two human ABCB1 nonsense mutations associated with a loss of function in a patient who had an adverse reaction to ivermectin after the administration of a usual dose. This finding warrants caution regarding medical prescriptions of ivermectin and other ABCB1 substrates.

Tens of billions of doses administered (maybe hundreds of billions?) and they find ONE CASE of "loss of function" in a patient given the usual dose and that warrants caution?

OK, that's it. Shut down Ivermectin. It is unsafe. Just way too dangerous.

[Titus-Maximus]

If Moses carried down tablets that were Ivermectin tablets from Mount Sinai, Big Pharma and their paid countless whores in Congress and the media would still be trying to destroy it, dismiss it, ridicule it, lie about it, and bury it because it’s going to take billions out of their pockets. Romney tried to block Ivermectin, because he is a scumbag.

[SeekAndFind]

Results

Ivermectin as an anti-helminth

Ivermectin has been approved as an anti-helminthic [15]. It is a selective positive allosteric modulator at the glutamate-gated chloride channels found in nematodes and insects and acts by binding to these channels leading to chloride ion influx causing hyperpolarization of the cell and hence, dysfunction [16 ]

However, at higher concentrations, Ivermectin can also bind to host GABA receptors only when the blood-brain barrier (BBB) is “leaky”. This is not the case in healthy human beings with an intact BBB as the drug is “excluded” by a p-glycoprotein drug pump (MDR-1). Chandler et al. considered Ivermectin to be free of potential neurological adverse drug reactions, except in situations of overdose[17]

[SeekAndFind]

Ping for your interest

[catnipman]

thanks for posting this ... mechanism of action described here is consistent with all other scholarly articles i’ve read, and has nothing at all to do with “opening” ionophores to “let zinc in”, which morons keep posting here over and over again ...

[SeekAndFind]

RE: nothing at all to do with “opening” ionophores to “let zinc in”

They’re confusing Ivermectin with Hydroxychloroquine. The above mechanism is the theory proposed by Dr. Zev Zelenko, who has treated and cured over a thousand Covid-19 patients with Hydroxychloroquine.

However, Dr. Zelenko’s latest treatment protocol INCLUDES BOTH Hydroxychloroquine *AND* Ivermectin ( in fact he will prescribe both in his practice ).

[Bob434]

But then so e ‘study’ In India should it ‘isn’t effective and this is what doctors all jump on despite the vast anecdotal evidences that it does work. They just came out with a finding and decided to not use ivermectin anymore I. India for some. Unknown reason, yet everything points the fact that kvermectin is very effective. The msm jumped on the story and now that is all you hear fro them, that ivermectin has ‘been proven to be innefective’

There is something very dirty going on I. The medical wor,d righ g now

[Bob434]

That’s what they did with hcq too. It POSSIBLY CAUSED heart prob,problems, In a few people (although no direct link w a ever estab,ished as far as I know), and I’m ediztely countries that were using it successfully, dropped it like a hot potatoe. All because they hated Trump, and apparently were in bed with vaccine and other expensive drug manufacturers. Hcq has been sued for 60 plus years with a very safe record whe. Given u Der supervision, but by golly all of a sudden it became ‘too dangerous to administer’ for covid.

Again, there is something dirty afoot. Hcq and ivermectin are safe, far saver infwct than. MAny over the counter meds on shelves that anyone can buy, and at worst, it might give I testing upset, And do nothing for the covid, BUT, IF it does help, being that they are so safe, one would think it would be totally worth it to try everything,possible, to help save 1000’s of lives. B

But nope, doctors are innexplicably vehemently against them.

[Battle Axe]

Check out a Belgian virologist Geert Vander Bossche.

https://www.youtube.com/watch?v=fkSZj-rzBWI

[BobL]

“There is something very dirty going on I. The medical wor,d righ g now”

You might want to check to see if Ivermectin also works for Tourettes.

[Bob434]

Bahahahaha ohhhh thats so funny!

[ProtectOurFreedom]

My own doctor would not discuss the use of HCQ, Ivermectin or monoclonal antibodies in advance of me getting sick. I got a telemedicine prescription for HCQ, Ivermectin, and Doxycycline. The Walgreens pharmacist filled the Ivermectin and Doxy scrip, but would not fill HCQ unless I was proven to have COVID.

It's just nuts.

The WHO got to India and they reversed their decision on Ivermectin a couple weeks ago.

WHO Celebrates As Indian Health Regulator Removes Ivermectin from Its Covid-19 Protocol

June 8, 2021 by Nick Corbishley

After India finally gets somewhat of a grip on its deadly second wave, one of its health regulators just took away one of its main lines of defense.

[Texas Fossil]

Also a peer reviewed study article just released.

American journal of Therapeutics
Ivermectin for Prevention and Treatment of COVID-19 Infection

https://journals.lww.com/americantherapeutics/Abstract/9000/Ivermectin_for_Prevention_and_Treatment_of.98040.aspx

-

FR Comments: https://freerepublic.com/focus/f-chat/3969678/posts

Note: 27 page .pdf of the study is downloadabled at the link.

[Bob434]

Yeah I saw that reversal by India, pretty sad when it’s been nearly proven that hcq is saving lives In certain situations.

States that banned hcq and ivermectin are directly responsible for 1000’s upon 1000’s of deaths.

Our state wouldn’t even fill it if I did get a prescription. The gov banned pharmacies from filling it.i had to bet ivermectin from tractor supply, which I didn’t like doing, but if worse came to worse, I had something besides ‘wait and take aspirin if you feel bad approach that doctors were prescribing. At least I would have tried everything I could to TRY to have a positive outcome if I got it, due to health issues.

I can not understand the profession that preaches ‘do no harm’ would not want to try to use perfectly safe drugs with a boatload of anecdotal evidence to show it works, along with, regular covid protocols if one gets hospitalized. It just makes no sense to me. If the hcq and iver doesn’t work, well at least I tried, if it does, then it’s quite possibly a life saved, or even health issues preventative since covid can cause lasting problems In some folks.

[iontheball]

thanks for posting this ... mechanism of action described here is consistent with all other scholarly articles i’ve read, and has nothing at all to do with “opening” ionophores to “let zinc in”, which morons keep posting here over and over again ...
_____________________
Geez, you are commenting on the wrong drug. Those comments were made in the context of HCQ, not Ivermectin. Furthermore, Ivermectin has similar ionophore qualities, which suggest taking zinc with Ivermectin may not be a bad idea also. Here’s what the instant article says about the ionophore qualities of Ivermectin.

“Level 3: Action as an Ionophore

Ionophores are molecules that typically have a hydrophilic pocket which constitutes a specific binding site for one or more ions (usually cations), while its external surface is hydrophobic, allowing the complex thus formed to cross the cell membranes, affecting the hydro-electrolyte balance [27]. It can be hypothesized that two ivermectin molecules, reacting with each other in a “head-tail” mode, can create a complex suitable to be considered such [28]. These ionophores allow neutralizing the virus at an early stage of the infection before it can adhere to the host cells and enter it to exploit their biochemical machinery for the production of other viral particles.