Note to Readers - A Story about this Story
This Open Letter and Challenge to Rachel Maddow was first published on Medium on August 29. It received 1.99K views before it was removed two days later due to "elevated risk of potential harm to persons or public health.”
I welcome ideas and insights the origins of this policy and any conflicts of interest.
The article was very timely on August 29, and sadly, still is.
I appreciate any initiatives to respectfully engage Rachel Maddow and others in dialogue and to inspire accurate, science-based reporting on Ivermectin in the hopes of raising consciousness, reducing suffering and saving lives.
I am new to Substack, trying to figure it out and still setting it up. I am exceedingly grateful for allowing freedom of expression during these times of shocking censorship.
You may subscribe to CoronaWise free.
“We share the same biology regardless of ideology” from song by Sting, “Russians” on Dream of the Blue Turtles Album
I used to watch your show religiously, having followed you for years. I remember you on Air America and watched your first MSNBC show, I believe on your grandmother’s birthday. You are brilliant, know how to investigate deeply and connect dots. You are an amazing teacher and educate my family members on current events.
I am a psychologist, with a former practice in psychoneuroimmunology, studying exceptional physical healing, and a political psychologist analyzing psychological dynamics in politics, psychological manipulation of fear, nuclear proliferation, demystification, and conflict transformation. I moved to DC to be near think tanks and do more good. We have a mutual friend, Steve Clemons.
A few months ago, I stopped watching cable news because I could no longer tolerate the condescending, contemptuous tone. I had been watching and analyzing, mostly MSNBC, plus some CNN and FOX. I tuned in to your show again on August 20 because my sister told me that your reporting was amazing.
I experience you as a decent, ethical person with integrity, but am troubled by some reporting that succumbs to corporate influenced groupthink. We need smart analysts like you to challenge and demystify seductive, inflammatory, harmful, mindsets.
I debate with friends about whether you indeed have integrity and would revise your opinion upon a deep investigation of independent, accurate scientific information, or whether you are beholden to your Big Pharma sponsors’ conflicts of interests that promote false information which endangers the public. Big Pharma is by far the biggest US lobby, more than double Big Oil.
I was beyond shocked at your August 20 segment with false, misleading information on Ivermectin that discourages the use of this life-saving drug, thus allowing unnecessary suffering and death while falsely attributing its use to a Republican agenda. https://www.yahoo.com/entertainment/rachel-maddow-rips-fox-news-060454042.html
Since completing this article I saw your August 27 segment, https://www.msnbc.com/rachel-maddow/watch/new-facet-of-covid-crisis-misguided-people-taking-ivermectin-anti-parasite-animal-drug-119660101526
Anyone who reads this entire article, follows the links and video testimonies and then listens your segment will get a lesson in pure propaganda. My apologies for this Rachel. I think you believe that what you are saying is true.
On August 20, you suggested that
· Ivermectin (IVM) was only a horse de-wormer
· IVM and Hydroxychloroquine (HCQ) have no studies showing they work
· One IVM study was withdrawn because data was faked and plagiarized
· IVM and HCQ are snake oil, mainly promoted by Fox and Trump, insinuating that people who use them are stupid, crazy, and Republican
· The FDA, NIH, WHO, and Merck advises against IVM. True, but why?
I will fact-check these after presenting irrefutable facts about IVM.
For brevity and flow, there are links throughout and detailed scientific information at the end to establish impeccable credibility and to share. Most people have not seen this highly censored information and are mimicking scripted propaganda to doctors and patients, including several of my loved ones.
· What is Ivermectin (IVM)?
A 5-minute search would reveal that Ivermectin is an inexpensive, extremely safe drug, with over 3.7 billion doses given over 40 years, that won the 2015 Nobel Prize in Physiology of Medicine.
Gratitude to David Otness for sending a comment with links to the Nobel Prize acceptance speeches.
William Campbell's Nobel Prize acceptance speech, "Ivermectin: A Reflection on Simplicity"
"Satoshi Ōmura - Nobel Lecture: A splendid gift from the Earth: The origins & impact of Avermectin"
Ivermectin is on the WHO’s list of essential medicines. It is sold over-the-counter in many countries. Merck’s patent on IVM expired in 1996, so it can’t make billions for Big Pharma.
Originally approved to treat parasites, IVM was discovered to be a “multifaceted medication” with antiviral, antimicrobial, anticancer, and immune-modulating mechanisms beneficial for many conditions. Doctors repurposed IVM for “off label” uses, a common practice. It has been considered a “miracle drug” by those who study it.
Here is “The Story of Ivermectin,” 24 minutes and very well done. https://rumble.com/vlpecw-the-story-of-ivermectin.html
· Covid Cure Search Leads to IVM
Since the US government refused to explore immediate treatments for Covid, in March 2020, Professor Paul Marik created an expert panel of reputable published treating physicians, the Frontline Covid-19 Critical Care Alliance (FLCCC). They formed a task force to search the medical literature for existing drugs to repurpose for Covid, ASAP.
They discovered Ivermectin to be highly effective for prevention, early treatment, late-stage disease, and long-haul symptoms against coronaviruses and variants. Early treatment prevented cytokine storms, hospitalizations, the use of ventilators, and deaths.
Doctors continuously share data and collaborate on dosage and combinations to make the protocols more effective against the variants. The current protocols, continuously updated, can be found online here.
· The First International Ivermectin for Covid Conference on April 24–25, 2021 held by BIRD, BRITISH IVERMECTIN RECOMMENDATION DEVELOPMENT, convened by Dr. Mobeen Syed.
Dr. Mobeen Syed’s introductory lecture, “What is IVM and how does it work?” described 5 mechanisms of IVM https://bird-group.org/conference-post-event/ See all 5 at the end of this article.
For example, here is Mechanism #2
· Prominent Published, Treating Physicians Testify for Early Treatment of Covid to Prevent Deaths
Dr. Pierre Kory testified before the Senate on December 8, 2020. https://odysee.com/@FrontlineCovid19CriticalCareAlliance:c/Dr.-Pierre-Kory-FLCCC-Alliance-testifies-to-senate-committee-about-I-MASK-incl.-the-following-QA-part-490351508:3 Many sites of the recording were removed.
Dr. Kory and others refer to a study in Argentina in which “0.0% of the 788 workers taking ivermectin vs. 58% of the 407 controls contracted COVID-19.” Dr. Kory has been taking IVM prophylactically, once a week for 8 months and has not gotten sick.
Dr. Peter McCullough, the most published doctor in his field, in the world, in history, editor of two prestigious medical journals, authored the most articles about Covid, including the most downloaded article in the world. He frequently testifies about the importance of early treatment. Here is his testimony to Texas Senate HHS Committee (19 minutes)
Here is a 2-minute video
Dr. Peter McCullough — 5 Things About COVID That They Don’t Want You To Hear
Different forms of evidence from a variety of sources combine to create a coherent, robust picture of the effectiveness of Ivermectin. Isolated studies that may use doses too high, too low, too late, too frequent, too infrequent, or in a different formulation, alone or in combination, funded by fear-mongering parties with conflicts of interest, cannot refute the overwhelming preponderance of effectiveness. Even aspirin is dangerous in high doses.
While double-blind, randomized control studies are considered the gold standard of scientific research, if something is true in reality it will be manifested in many forms and not be contradictable by one or two suspicious, fraudulent studies.
Truth will be supported by
· Basic Science
· Clinical Experience
· Observational Clinical Studies
· Randomized Clinical Studies
· Epidemiologic Studies
· Withholding Treatment
These doctors are practically in tears about the suppression of information, unethical deprivation of early treatment, and censorship of independent doctors who keep their patients out of hospitals. Why is this information unknown in hospitals?
How did almost every US doctor get the same memo? “There is no treatment. Do nothing. Stay home until it gets worse. Then go to the hospital.”
Hospital patients’ families knowledgeable enough to request Ivermectin are refused. Three New York hospitals and their lawyers denied patients IVM despite a prescription from their doctors. “In essence, the argument was that they did not have the right to try a potentially life-saving medication.”
They had to sue to get IVM. The New York State Supreme Court Justices sided with the patients. Lawyer Ralph Lorigo won three court orders forcing New York hospitals to administer Ivermectin to dying patients. Each “made near-miraculous recoveries after the Ivermectin was given. In each case, these patients were in the Intensive Care Unit on ventilators, unable to breathe on their own, and universally, after the drug was given, they rapidly improved and were able to breathe on their own.” Ivermectin Wins in Court Again: For Human Rights By Justus R. Hope, MD
These doctors estimate a high percentage of deaths could have been prevented. Dr. Kory calls this “unforgivable.”
· Censorship, Suppression, Fraudulent Studies
Doctors and scientists promoting inexpensive, unpatentable drugs and combinations with nutraceutical treatments are censored, de-platformed, punished, and suspended. Facebook, Reddit, Change.org, and YouTube remove posts on these, citing violation of “community standards.” I mentioned Ivermectin on a FB post and was immediately flagged.
On July 24, Youtube shut down World Ivermectin Day with 3000 participants.
Here are IVM stories, https://worldivermectinday.org/ivermectin-stories/
· One Example of Propaganda
On your August 27 show, you featured America’s Front Line Doctors and their leader, Dr. Simone Gold who was arrested for entering the Capitol on January 6. A friend of mine pointed out that,
“Rachel focused on America’s Front Line Doctors (AFLD) rather than on The Front Line Covid 19 Critical Care Alliance (FLCCC). The first set of doctors were easy to demonize but it would’ve been impossible to have come up with anything against doctors like Pierre Kory and Paul Marik. They would have demolished any argument that Rachel or her producers had attempted to make against Ivermectin.
I literally don’t know if I could ever watch Rachel again even though I’ve been a semi-regular watcher for so many years. In addition to being a total hit job it was also remarkably tedious as she clearly did not have anything substantive to go on and so it seems all she did was find one farm supply store after another in the South who were selling lots of Ivermectin.
How many lives could be saved if she had an open mind and an open heart and brought on someone like Pierre? I guess we’ll never know but it sure would be a considerable number.”
· Afraid of the Wrong Things: Fear Wins
FLCCC doctors decrying pervasive medical orders to do nothing, passionately warn that doing nothing is dangerous, including not using Ivermectin in the first days is dangerous. It is astonishing how people are afraid of the wrong things.
People are terrified of taking an extremely safe, potentially life-saving, suffering-reducing, Nobel Prize-winning, WHO essential medicine, but are not afraid of allowing the disease to progress to the cytokine storm and beyond. People are also afraid of taking highly recommended supplements like Vitamin C, quercetin, and others but not afraid of doing nothing.
I know people who were given IVM by people who love them who were frightened out of taking it. In my small sample, fear of IVM won.
Loved ones are at the center of a hysterical tug of war with friends, relatives and doctors pulling on each side, increasing immune-suppressing stress and anxiety and delaying or preventing critical early treatment.
In addition to the excruciating frustration of watching people get worse when they can be helped, those of us who recommend IVM to help our loved ones are disbelieved, distrusted, accused of believing silly conspiracy theories and being influenced by Republicans. We lose respect. Our credibility is damaged while provoking new conflicts in our relationships.
Rachel — Fact-Checking Your Reporting
· You reported that Ivermectin was a horse de-wormer.
IVM is one ingredient in animal parasite medications. IVM for humans is safely sold over-the-counter in many countries. Many people procure IVM to prevent Covid or to have handy in their “Just in case Covid kit” of remedies if needed, including IVM, Vitamin D3, Vitamin C, Quercetin, Zinc, Melatonin, Gargle/mouthwash.
· You reported that poison control gets calls from people taking Ivermectin for animals. Somewhat true, likely exaggerated. But why?
Since propagandized, disinformed doctors admonish patients against using IVM, it is hard to get. Some resort to available medications for animals. Antibiotics, antivirals, and many medications are commonly used for humans and other mammals.
Carlos Chaccour, of the Barcelona Institute for Global Health, receives texts from people with infected family members searching for any form of ivermectin. “They send me a photo of a veterinary formulation and ask me, ‘Would you mind telling me what dose we should use? It is broadly available and people are broadly desperate and this could lead to misuse.” (High-profile coronavirus retractions raise concerns about data oversight)
“The FLCCC has a long-held position that people should never use medications formulated for animals. Moreover, you should never self-dose or use a prescription medication without the guidance of a healthcare professional. You can read our full statement here.”
FLCCC, https://covid19criticalcare.com, https://myfreedoctor.com offer telemedicine with doctors who prescribe IVM. BIRD has an Ivermectin Buyers Club
· You said no studies showed IVM worked and one faked study was withdrawn
In a review of 51 studies, 50 showed benefits. One claiming a neutral effect was criticized in an open letter signed by 120 physicians, “Open Letter by U.S. Doctors: JAMA Ivermectin Study Is Fatally Flawed.”
IVM is most potent in the first days of the virus. Studies can be manipulated to administer IVM too late and too little and claim it is less effective.
“Ivermectin has already been adopted by 25 percent of the world’s countries to prevent and treat COVID-19. Bangladesh, where Ivermectin is broadly used in almost every home, enjoys a 99% lower per capita death rate from COVID-19 than the US.” https://covid19criticalcare.com/webinars-lectures/
“There is a blackout on any conversation about how Ivermectin beat COVID-19 in India. When I discussed the dire straits that India found itself in early this year with 414,000 cases per day, and over 4,000 deaths per day, and how that evaporated within five weeks of the addition of Ivermectin, I am often asked, "But why is there no mention of that in the news?"
· You accused FOX News of pushing dangerous, ineffective “snake oil”
You showed clips of Laura Ingraham and Sean Hannity claiming that Ivermectin was effective. Actually, it is, even though it was they who said it.
I am not a Republican and no fan of FOX News, but I am not so mindless that I refuse to discern any validity in their reporting. I do not have a compulsion to automatically reject 100% of their content just because it’s on FOX.
MSNBC, CNN, and FOX are gripped in a pathological dance of compulsory mutual disparagement. You all incite contempt and disdain. It hurts individuals and the country. It fuels a collective cognitive disorder, characterized by black-and-white, all-or-nothing, concrete thinking, splitting everything into opposites. People mindlessly identify in opposition to the other without conscious thought or discernment. “Poor reality testing” is when the perception of objective reality is colored by emotions.
People are suffering and dying because of the politicization of health. Can you help us rise above this?
There is a terrible reason why doctors and scientists appear on FOX News to report on Ivermectin, HCQ, vitamin D, preventive measures, early treatments, and immune boosters.
It is not because they are Republicans or Trump lovers. It is because they are blacklisted from MSNBC, CNN, NPR, and Big Pharma-sponsored mainstream media. They would love to be on your show but are censored and ostracized while you tout life-saving treatments as poison.
Rachel, you are too intelligent to be sucked into this drama. I expect more from you. We need you to help us to think more clearly and transcend the opposites. Why don’t you invite them on your show? Why don’t you report on their censorship and the disinformation about disinformation?
· You lumped Hydroxychloroquine HCQ with IVM as harmful drugs promoted by FOX News
You played a clip of Trump saying that HCQ is working. You said there were no studies showing that HCQ worked. Actually, there are.
In Covid’s early days, Dr. Vladimir Zelenko figured out a protocol combining HCQ, zinc and azithromycin, used around the world. He successfully treated over 6000 patients and evolved his protocols to include Ivermectin and “nutraceutical bundles,” potent nutritional supplements which were new to him. Here is an interview with him
Here are his latest protocols.
A propaganda campaign against HCQ sponsored by competitive special interests manipulated research methodology by giving lethal doses to older, ill subjects to claim it increased mortality.
Some studies tested HCQ without zinc, essential to the protocol, to claim it doesn’t work, to manufacture falsehoods, fears and politicization. The purpose of HCQ, a zinc ionophore, is to get the zinc inside the cells where it prevents viral replication. Thus, people are misled to believe myths about HCQ, including you.
Why don’t you know that the Lancet retracted their fraudulent articles about HCQ?
“This whole event is catastrophic — it is problematic for the journals involved, it is problematic for the integrity of science, it is problematic for medicine, and it is problematic for the notion of clinical trials and evidence generation.” Ian Kerridge, bioethicist, University of Sydney, Australia. High-profile coronavirus retractions raise concerns about data oversight
From a personal note from Dana Ullman, MPH, CCH, author of ten books on homeopathic medicine –
“Further, the fact that the Lancet published this study even if there was FULL transparency ignores the fact that THIS study was set-up to FAIL and set-up to “disprove” HCQ because the experimenters purposefully left out the inclusion of ZINC. Once again, these are FACTS, not theories.
We cannot assume that the editors at the Lancet or at Nature were ignorant of the importance of zinc because it is a part of EVERY protocol throughout the world with HCQ for people with Covid-19.
Then, whenever the studies found “toxic” and dangerous effects of HCQ, the experimenters just “happened” to use 4 to 6 times its usual doses.
The fact that the media ignores these facts is an important part of the problem we are all facing.
The power of science is being replaced on the power of economics on science. Sad…and true.
— Dana Ullman, MPH, CCH
Dr. Meryl Nass describes 53 strategies used to block HCQ in How a false hydroxychloroquine narrative was created, and more which “produced a unified message about hydroxychloroquine (HCQ), and produced similar policies about the drug in the US, Canada, Australia, NZ and western Europe. The message is that generic, inexpensive hydroxychloroquine(costing only $1.00 to produce a full course) is dangerous and should not be used to treat a potentially fatal disease, Covid-19, for which there are no (other) reliable treatments.”
“Hydroxychloroquine has been used safely for 65 years in many millions of patients. And so the message was crafted that the drug is safe for its other uses, but dangerous when used for Covid-19. It doesn’t make sense, but it seems to have worked.”
· You asserted that the FDA NIH, and WHO advise against Ivermectin. True, but why?
These agencies are captured by Big Pharma and Big Insurance. With numerous patents, royalties, hidden sources of profit and international connections, a campaign to get shots into 7.5 billion arms, they make fortunes from the “vaccines” and are positioned to capture the entire world market with endless boosters for fading efficacy and infinitely mutating variants. In addition, they use fear to promote vaccine passports, surveillance, and control of personal data and social control.
While suppressing cheap IVM and HCQ, the FDA encourages the use of Gilead’s patented Remdesivir, granted Emergency Use Authorization, at the cost of $3200 per person. Remdesivir has very little benefit and serious side effects.
On your August 27 show you reported that IVM caused liver and kidney damage. It does not. Remdesivir does. See “Renal and liver injury following the treatment of COVID-19 by remdesivir” in the Journal of Nephtopathology and elsewhere. Also see See Remdesivir Fails to Prevent Covid-19 Deaths in Huge Trial
IVM is approved by the FDA but not for Covid.
Emergency Use Authorization can only be granted if no other effective treatments exist. If every doctor used IVM to prevent or treat early Covid, or if everyone could buy it over the counter and people were kept out of hospitals, there would be no legitimate need for new drugs and “vaccines.”
Doctors in the FLCCC, BIRD and others are exploring plausible ways to end the pandemic in a short time, with IVM as a significant part of the solution, based on data where it has widespread use.
BIRD (BRITISH IVERMECTIN RECOMMENDATION DEVELOPMENT) is campaigning for UK approval to help it beat Covid https://bird-group.org
Questions for Rachel
· Am I right in my debate with my friends in believing that you would be willing to revise your reporting based on investigation of suppressed facts and independent science?
· Are you free to speak the truth or are you beholden to your Big Pharma sponsors to promote falsehoods for their profit?
· Might you evolve your rhetoric and help soften the intolerable disparagement and help us transcend the hostile right/left split? Might you create a space for amicable dialogue and enlightenment?
Challenges for Rachel
I challenge you to
· Invite Drs. Pierre Kory and Peter McCullough on your show to explain Ivermectin, prevention and early treatment.
· Invite Dr. Meryl Nass on your show to explain the anatomy of conducting fraudulent studies to create false narratives, and about IVM and other aspects of Covid.
· Do a story on censorship of IVM and doctors who use it and what is behind it.
· Do a segment on the relationship between vitamin D levels and Covid survival and natural protocols that boost immunity, perhaps a story like this, New initiative to deliver immune support You can help empower people to take some control of their own health instead of remaining passive and helpless.
· Review your show’s policies, staff and process of vetting information for scientific accuracy and conflicts of interest.
TRUTH OR CONSEQUENCES
I am very sorry for the Covid trauma that you went through with your partner, Susan. I am grateful that she survived. I hope she is well. Imagine if she had been given IVM in the first days and if you could have taken it prophylactically to be with her during a brief, untraumatic recovery.
Rachel, you have a huge, loyal following, a brilliant mind and are an awesome teacher. You are in a position to raise consciousness, badly needed, and to do nothing less than reduce suffering and save lives by speaking the truth about IVM.
This is not about right and left, but about life and death.
You have literally before you a choice between life and death, health and sickness, truth and lies, integrity and complicity.
“I call heaven and earth as witnesses against you today that I have set before you life and death, blessing and cursing. Therefore, choose life, so that you and your descendants may live”. DEUTERONOMY 30:19
We all need you to choose life.
Sincerely, Diane Perlman
Information and Resources for a Deeper Dive into Covid
Below are some credible links for more information. Do your own exploration. Always consider the source and conflicts of interest. As Woodward and Bernstein of Watergate fame, in “All the President’s Men” were advised, “Follow the money.”
BRITISH IVERMECTIN RECOMMENDATION DEVELOPMENT BIRD https://bird-group.org
Frontline Covid Critical Care Alliance FLCCC Studies and reviews on IVM
· The Expert Review Report, “Medical Safety of Ivermectin” can be downloaded here
Dr. Dan Stock’s 6 minute presentation to the Mt. Vernon School Board in Indiana
This is a DO NOT MISS video! We are extremely excited to debut this video for you all. We interviewed pioneer and ground-breaking researcher Dr. Hector Carvallo. He is the investigator and author of the IDEA Trial and IVERCAR Trial, two ground-breaking studies on Ivermectin for the prevention and treatment of COVID-19. He has done substantial work on Ivermectin, Iota Carrageenan, Bromhexine, and more for both prophylaxis and treatment of COVID-19! He was one of the first researchers to do significant work on treating and preventing COVID-19 with Ivermectin. He not only will help us in understanding the science and evidence behind these therapies, but will also give us a glimpse into the challenges they have faced in getting this cheap, broadly available therapeutic approved on a larger scale! Do not miss this tremendously interesting discussion! *IDEA Trial — Ivermectin, Dexamethasone, Enoxaparin, Aspirin for COVID-19 *IVERCAR Trial — Ivermectin and Iota Carrageenan Prophylaxis for COVID-19
The evidence base for ivermectin against COVID-19
To date, the efficacy of ivermectin in COVID-19 has been supported by the following:
1. Since 2012, multiple in vitro studies have demonstrated that Ivermectin inhibits the replication of many viruses, including influenza, Zika, Dengue, and others.9–17
2. Ivermectin inhibits SARS-CoV-2 replication and binding to host tissue through several observed and proposed mechanisms.18
3. Ivermectin has potent anti-inflammatory properties with in vitro data demonstrating profound inhibition of both cytokine production and transcription of nuclear factor-κB (NF-κB), the most potent mediator of inflammation.37–39
4. Ivermectin significantly diminishes viral load and protects against organ damage in multiple animal models when infected with SARS-CoV-2 or similar coronaviruses.31,32
5. Ivermectin prevents transmission and development of COVID-19 disease in those exposed to infected patients.40–45
6. Ivermectin hastens recovery and prevents deterioration in patients with mild to moderate disease treated early after symptoms.45,49–52,61,62
7. Ivermectin hastens recovery and avoidance of ICU admission and death in hospitalized patients.45,51,53,63–66
8. Ivermectin reduces mortality in critically ill patients with COVID-19.45,53,63
9. Ivermectin leads to temporally associated reductions in case fatality rates in regions after ivermectin distribution campaigns.48
10. The safety, availability, and cost of ivermectin are nearly unparalleled given its low incidence of important drug interactions along with only mild and rare side effects observed in almost 40 years of use and billions of doses administered.75
11. The World Health Organization has long included ivermectin on its “List of Essential Medicines.”
Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID-19 have found large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance. Furthermore, results from numerous controlled prophylaxis trials report significantly reduced risks of contracting COVID-19 with the regular use of ivermectin. Finally, the many examples of ivermectin distribution campaigns leading to rapid population-wide decreases in morbidity and mortality indicate that an oral agent effective in all phases of COVID-19 has been identified.
The Panel found the certainty of evidence for ivermectin’s effects on survival to be strong and they recommended unconditional adoption for use in the prophylaxis and treatment of COVID-19.
In summary, based on the totality of the trials and epidemiologic evidence presented in this review along with the preliminary findings of the Unitaid/WHO meta-analysis of treatment RCTs and the guideline recommendation from the international BIRD conference, ivermectin should be globally and systematically deployed in the prevention and treatment of COVID-19.
FLCCC ALLIANCE Front Line Covid-19 Critical Care Alliance Prophylaxis & Treatment Protocols for Covid-19. Power Point Presentation
BIRD First International Ivermectin for Covid Conference April 24–25 Convened by Dr. Mobeen Syed. https://bird-group.org/conference-post-event/
The mechanisms of action of Ivermectin against SARS-CoV-2: An evidence-based clinical review article Asiya Kamber Zaidi1,2 and Puya Dehgani-Mobaraki3 J Antibiot (Tokyo). 2021 Jun 15 : 1–13. doi: 10.1038/s41429-021-00430-5 [Epub ahead of print]
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.
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
The role of Ivermectin against the SARS-CoV-2 virus
The targets of activity of Ivermectin can be divided into the following four groups:
· A. Direct action on SARS-CoV-2
Level 1: Action on SARS-CoV-2 cell entry
Level 2: Action on Importin (IMP) superfamily
Level 3: Action as an Ionophore
· B. Action on host targets important for viral replication
Level 4: Action as an antiviral
Level 5: Action on viral replication and assembly
Level 6: Action on post-translational processing of viral polyproteins
Level 7: Action on Karyopherin (KPNA/KPNB) receptors
· C. Action on host targets important for inflammation
Level 8: Action on Interferon (INF) levels
Level 9: Action on Toll- like-Receptors (TLRs)
Level 10: Action on Nuclear Factor-κB (NF-κB) pathway
Level 11: Action on the JAK-STAT pathway, PAI-1 and COVID-19 sequalae
Level 12: Action on P21 activated Kinase 1 (PAK-1)
Level 13: Action on Interleukin-6 (IL-6) levels
Level 14: Action on allosteric modulation of P2X4 receptor
Level 15: Action on high mobility group box 1 (HMGB1),
Level 16: Action as an immunomodulator on Lung tissue and olfaction
Level 17: Action as an anti-inflammatory
· D. Action on other host targets
Level 18: Action on Plasmin and Annexin A2
Level 19: Action on CD147 on the RBC
Level 20: Action on mitochondrial ATP under hypoxia on cardiac function
The direct “antiviral targets” may be useful in the early stages while the anti-inflammatory targets might be addressed in the later stages of the disease.