Covid-19 News

UK age/death gap is still huge!

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1014926/Technical_Briefing_22_21_09_02.pdf

Briefing 22.

From Delta::

Death among age <50 154 (of 420'689) or about 0.035%

Death among age >50 1644 (of 71'107) Here > 92% are vaccinated !! (only 6700 are unvaccinated !!)

So death age >50 is about 70x more likely despite almost all are vaccinated...

But this report data is not always in line with worldometers UK-death data that shows more deaths. So it looks like there is an error somewhere in one table.

But the delta data seems to be OK as this type did enter the last two months.

COVID-19 Symptoms Involving Pervasive Putrid Smell — University of Utah KOL Discusses Parosmia

COVID-19 Symptoms Involving Pervasive Putrid Smell — University of Utah KOL Discusses Parosmia

The University of Utah recently went on the record with concerns of growing phenomena with COVID-19 infections, that is parosmia. A condition where normal

trialsitenews.com

The University of Utah recently went on the record with concerns of growing phenomena with COVID-19 infections, that is parosmia. A condition where normal smells, from coffee to bananas changes into an unpleasant or even repulsive smell such as rotten meat or garbage. Parosmia wasn’t as common in previous COVID-19 waves but now in Utah and elsewhere the condition becomes ever more commonplace.

Recently Richard Orlandi, MD, ear, nose, and throat physician, and professor in the Department of Surgery at the University of Utah Health shared some insight into this common symptom associated with COVID-19. The reality is that according to the University of Utah Health “Very little is understood about the relationship between COVID-19 and parosmia. It may not seem as urgent as other long-term symptoms of COVID-19 such as heart problems, depression, and respiratory illness. However, physicians say it can be problematic.”

Prof. Orlandi shared “Your sense of smell is important,” Orlandi says. “It’s what helps you enjoy food and sense danger, as in the case of smoke. It’s connected to our memories, such as the way your mom or grandma’s perfume smells. Depending on the severity, this condition can range from an annoyance to a frustrating and anxiety-inducing symptom.”

What follows is a summary of the University of Utah Health overview of COVID-19-based parosmia.

Why does COVID-19 lead to parosmia?

No one knows.

How long does the condition last?

One study out of Iraq suggests up to six months but the average duration is about 3 months.

What about a treatment—any?

There is no known treatment for COVID-19-induced parosmia however some believe “smell therapy” could help. As described by the University of Utah Health this therapy “involves smelling strong scents such as citrus, perfume, ammonia, or eucalyptus each day to re-train the brain to “remember” how to smell. More study is needed to know if this therapy actually works.” The “U” suggests that after that the best thing to do is avoid offending scent triggers.

Prof. Orlandi shared “Right now, so little is known about the long-term effects of COVID-19,” Orlandi says. “This is just one of the many long-term symptoms doctors and researchers are studying. All we really know is that the majority of patients do experience a return of their normal senses of taste and smell, but it’s unclear if and how many patients will get fully back to normal.“

Lead Research/Investigator

Richard Orlandi, MD

Parosmia Due to COVID-19 Disease: A 268 Case Series

Parosmia Due to COVID-19 Disease: A 268 Case Series

Although parosmia is a common problem in the era of the COVID-19 pandemic, few studies assessed the demographic and clinical aspects of this debilitating…

www.ncbi.nlm.nih.gov

Quote from JedRothwell

No, it would be short. Very short. There is no a single point you can make, which is why you will not try. You are not fooling anyone.

What do you have against silk fabric?

Okay, I will grant, the feeling of satin gives me willies, and a satin blanket tends to slide off the bed. But I don't go railing on about it.

I do not argue with anyone

I just suggest other option.

the bad side will likely suggest a last warning.

As I'm not religious, I will stay with satin as the forum frowns on such talk.

you can pronounce Clayton in other languages

but its not your style.

good luck all.

Why Don't Kids Tend To Get as Sick From COVID-19?  The coronavirus seems to be mild in most children, but scientists are not sure why Their immune system is untrained, so it doesn't react violently: immunosuppressives like Hydroxychloroquine or Fluvoxamine have similar effect. My theory is that coronavirus even utilizes violent immune reaction (cytokine storm) for its invading the organism and once it doesn't met with it, then it becomes harmless. It thus hijacks immunity compromised with previous failed vaccinations and widespread viral vectors from GMO food and pollens.

Several studies out of the UK showed extremely low child death rates. Of almost half a million infections, there were 25 deaths, 15 of which were in children with serious underlying illness. The hospitalization rate of coronavirus - while already low for children - dropped to nearly zero for kids at the case of delta variant. Corona has a lower death rate than flu/pneumonia in children. See also:

• Could children have been our secret weapon against coronavirus? They may behave like "walking vaccine" for their families, i.e. reservoir of attenuated virus.
• Having Children Turns Co-Parents Into Immune System Twins ...
• Brooklyn’s Hasidic Jews are acting like they have herd immunity. Also Amish people are known by their good immunity and low tendency for autoimmune diseases.
• Kids and the Delta Variant: Should you Act Differently?
• UNICEF: Schools are not 'main drivers' of Covid among kids, Schools Aren’t Super-Spreaders

Quote from Zephir_AWT

Their immune system is untrained, so it doesn't react violently: immunosuppressives like Hydroxychloroquine or Fluvoxamine have similar effect. My theory is that coronavirus even utilizes violent immune reaction (cytokine storm) for its invading the organism and once it doesn't met with it, then it becomes harmless. It thus hijacks immunity compromised with previous failed vaccinations and widespread viral vectors from GMO food and pollens.

Hi Zephir. I prefer the explanations given in your link than your speculation which AFAIK has no evidence.

On the other hand, most young children do not develop severe complications from the measles and chickenpox, whereas those illnesses can be “disastrous” in adults, Pavia said. (Vaccination is recommended for those illnesses, too, but no vaccine is 100% effective.)

“This is where we really don’t have great answers,” Pavia said.

One theory is that when faced with certain unfamiliar viruses, children can fight them off because they have a robust layer of defense called the “innate” immune system. This consists of white blood cells called macrophages, which can detect and gobble up foreign particles in the bloodstream regardless of their identity.

Older people have an added deficit: The various layers of their immune systems start to become less effective. Many also have underlying conditions, such as heart disease. And increasingly, the bodies of older people suffer from chronic, low levels of age-related inflammation, nicknamed “inflammaging.”

So when older people become infected with a virus, the combination of even more inflammation and a weaker immune system can be deadly, Iwasaki said.

“You have this perfect storm of not having the right antiviral defenses and having elevated inflammaging,” Iwasaki said.

Every year, most flu-related deaths in the U.S. occur in older people. The same pattern appears so far with the new coronavirus, according to the summary of 44,672 confirmed cases from the Chinese Center for Disease Control and Prevention.

The link is not entirely accurate, but here is a nature review: https://www.nature.com/articles/s41591-020-01202-8

Here is a good more recent summary of the nasty things COVID does to the immune system (which in some people persist) https://www.immunology.org/sit…ote_August_2020_FINAL.pdf

The idea that the delta variant is less severe for children has no evidence to back it up - as far as I know. If that graph of your is from the US the falling lines would be due to vaccination - especially vaccination of at risk and older children who represent most of the deaths - since the underlying death rate is very low - and who will be almost certainly vaccinated.

I've noticed that people with incorrect ideas about the effectiveness of COVID vaccines (maybe this is you) have to jump through hoops to find other reasons for the reductions in severity of disease caused by vaccination: e.g. thinking that delta is less severe than original (it is about twice as severe).

THH

Quote from Zephir_AWT

. My theory is that coronavirus even utilizes violent immune reaction (cytokine storm) for its invading the organism and once it doesn't met with it, then it becomes harmless.

This is not theory as it is a proven fact. A CoV-19 infection ramps up the expression of ACE-2 receptors that the virus needs for entering the cell. This has been shown already more than a year ago!

Here a study of the non existing Long Covid in children : https://www.medrxiv.org/conten…101/2021.05.16.21257255v2

Of course there are long time symptoms after Covid as there are long time symptoms after flu too. So long flu would be a much greater concern than Long-Cov for children as flu is at least 100x more deadly for them.

Quote from Wyttenbach

This is not theory as it is a proven fact. A CoV-19 infection ramps up the expression of ACE-2 receptors that the virus needs for entering the cell. This has been shown already more than a year ago!

W - you quoted one part of Zephir's post which, I agree, is factual. I did not agree with the non sequitur final conclusion:

It thus hijacks immunity compromised with previous failed vaccinations and widespread viral vectors from GMO food and pollens.

Quote from THHuxleynew

The idea that the delta variant is less severe for children has no evidence to back it up - as far as I know. If that graph of your is from the US the falling lines would be due to vaccination - especially vaccination of at risk and older children who represent most of the deaths - since the underlying death rate is very low - and who will be almost certainly vaccinated.

Sorry - I was careless (and too quick) here. That graph ending in June was before the latest delta wave of infections in the US, and the shape of the graph relates to infections (not shown), so provides pretty well no info about severity.

Not Even Done with 3rd Booster Israel’s Vaccine Czar Already Talking #4 & Implying #5 & More — Madness or Sound Health Policy?

Not Even Done with 3rd Booster Israel’s Vaccine Czar Already Talking #4 & Implying #5 & More — Madness or Sound Health Policy?

The prospect for an endless stream of jabs becomes ever more distinct, one can just sense it in their bones. Yesterday Salman Zakra, Israel’s

trialsitenews.com

The prospect for an endless stream of jabs becomes ever more distinct, one can just sense it in their bones. Yesterday Salman Zakra, Israel’s national coronavirus czar, called out to the “Kan” public that the population needs to start preparing for a fourth COVID-19 vaccine. Not specifying the timing nonetheless not even a year has passed, and Israel is deep into the third booster and with only partial data, these kinds of proclamations are grossly negligent at best and far more nefarious if one opts for a cynical interpretation. Or is the acceptance already at this early stage still in the pandemic that an endless stream of jabs is not only inevitable but also prudent?

The whole situation becomes more bizarre as it turns out the Times of Israel reports that Zakra made similar comments during an interview with the Times of Israel last month declaring not only that we will need to prepare for a fourth, but also a fifth, a sixth and perhaps an ongoing occurrence mentioning “the possibility of subsequent waves.”

A Shot ‘Every Few Months’

In an unbelievable disclosure Zakra, also a medical director for Ziv Medical Center during that interview declared the following:

“And thinking about this and the waning of the vaccines and the antibodies, it seems every few months—it could be once a year or five or six months—we’ll need another shot.” So rather than any questioning of a vaccine-centric only strategy, the waning early-stage vaccine product, and variants such as Delta this novel vaccine marketer suggests all Israeli society simply line up for an ongoing progression of mRNA vaccine jabs.

In fact, Zakra even expects specialized jabs covering the various variants. The monetization potential for pharmaceutical companies boggles the mind. Already Pfizer is projected to generate $33 billion in their first full year of vaccine sales—this staggers the mind as most pharmaceutical companies don’t have that kind of revenue in a year with all of their products.

Priming the Pump

Will the entire society in Israel line up to support such quackery? It’s not responsible at all to declare whether vaccines or therapies are necessary or not until sufficient data is not only generated but fully comprehended.

In the meantime, the “Green Pass” system takes off in Israel—essentially a vaccine passport that gives one a pass into places like public gatherings, eateries, games, or the like. This vaccine passport in Israel expires after the holder receives the second or third dose, reports the Times of Israel indicating that a fourth dose is already in the works.

These responses of course all but guarantee massive demand for these vaccine products, even if they are working only partially well. Yes, they do reduce the probability of severe SARS-Cov-2 infection but as TrialSite has followed in Israel a whole lot of fully vaccinated folks are falling quite ill as well, in many cases requiring hospitalization.

In the meantime, Israel’s population, especially those in their 40s and up are overwhelmingly vaccinated yet the pandemic’s Delta-variant-driven surge rages impacting the entire society.

Pfizer CEO All but Acknowledges Vaccines Won’t be Enough — Here Comes the Antivirals & Billions More

Pfizer CEO All but Acknowledges Vaccines Won’t be Enough — Here Comes the Antivirals & Billions More

Pharmaceutical companies are now publicly acknowledging that a vaccine-centric strategy will not be sufficient to overcome the COVID-19 pandemic as

trialsitenews.com

Pharmaceutical companies are now publicly acknowledging that a vaccine-centric strategy will not be sufficient to overcome the COVID-19 pandemic as TrialSite has reported for over 1.5 years. The most recent declaration wasn’t from some up-and-coming biotech seeking to monetize a novel therapy during the pandemic nor some lightweight but rather the Chief Executive Officer of the world’s most powerful COVID-19 vaccine producer—Pfizer.

That’s right. Pfizer’s CEO Albert Bourla recently tweeted “Success against #COVID19 will likely require both vaccines & treatments. We’re pleased to share that we started a Phase 2/3 study of our oral antiviral candidate—specifically designed to combat SARS-Cov-2 in non-hospitalized, low-risk adults.”

Bourla’s tweet pointed to a recent Pfizer press release announcing the advancement of this targeted antiviral to Phase 2/3 clinical trials.

A Massive Nascent Market

TrialSite had declared for many months now that one reason for the intensified pressure against ivermectin was to clear the market of any low-cost competition for higher-priced, novel therapeutics. After all, Doctor Anthony Fauci and the federal research apparatus already declared over $3 billion will be spent on these companies.

That’s because 90%+ of all worldwide COVID-19 cases are mild-to-moderate in symptom: primary care physicians have pleaded since last spring for a focus on caring for early SARS-CoV-2 infection. They note that this would be key to keeping most infections from progressing to a more severe situation.

That’s why so many independent physicians have embraced off-label drugs to help patients. Early on hydroxychloroquine was used and of late prescriptions for ivermectin have exploded. While the Food and Drug Administration (FDA) and Center for Disease Control and Prevention (CDC) now warn against any use of ivermectin except for clinical trials, partially due to reports of a 3-fold increase in calls to poison control centers.

TrialSite recently accessed the data from the Association of Poison Control Centers and identified that the data is quite different than the government is letting on. In fact, hand sanitizer is considerably more dangerous than ivermectin based on the TrialSite data review.

But the stakes to clear out any generic competition are too great. TrialSite estimates that at a minimum this antiviral early-onset market for mild-to-moderate COVID-19 could hit a few billion per year and that number could grow to several billion a year with market access around the world.

Given COVID-19 more than likely will hang around for at least a couple more years, if not permanently a vaccine will not probably be the answer to eradication but rather one of a handful of medical tools used to control and manage the virus so humans can seamlessly coexist.

The Pharma-Gov. Complex

So, the $3+ billion Fauci has already mentioned represents a key target for the pharmaceutical companies that seek to socialize or externalize as many costs as possible under the guise of pandemic and the PREP Act explained by TrialSite recently. The Act ensures the companies and the entire health delivery value-chain have no liability and that rather, all liability goes to the government providing a very limited pool of funds for consumers—and that’s all they wrote. America’s visionary politicians can be thanked for that gift.

TrialSite chronicled the NIH, ACTIV, and U.S. HHS and BARDA spend all last year which led to a literal cash trough for select pharmaceutical companies. Demonstrating the intense bias toward novel pharmaceuticals, the pandemic revealed just how connected the NIH and pharmaceutical companies are at the hip. While many physicians hoped to test ivermectin last year, for example, tens of billions were spent on just a few companies as TrialSite reported.

Yes, the NIH completely failed to not only embrace antivirals (other than ensuring Gilead’s remdesivir—rejected by the World Health Organization—was accelerated through the emergency use authorization (EUA) and then approval process). But numerous repurposed compounds were identified that could have been acted upon, however, the NIH opted to spend what TrialSite suspects is not of $20 billion on a few vaccines and monoclonal antibody products.

Again, under cover of no liability due to the PREP Act, the U.S. taxpayer continued their subsidization of pharma most recently with Merck, the New Jersey pharmaceutical company that received $356 million in taxpayer funding at the end of 2020 while recently under the current POTUS secured a $1.2 billion guaranteed contract should the investigational candidate be authorized on an emergency use basis or formally approved. Merck has been actively crisscrossing the globe ensuring their own ivermectin, used to treat billions of people against River Blindness, never sees approval.

TrialSite did recently reported on preclinical research at Texas A&M which revealed that the investigational MP18 destroyed Merck’s molnupiravir in a head-to-head lab test.

The early-stage investigational product worked so well that San Diego-based Sorrento Therapeutics has licensed the investigational product and will aggressively seek an IND by the end of the year.

Roche is also working on a COVID-19 antiviral known as AT-527 in partnership with Atea Pharmaceuticals. The two have a Phase 3 clinical trial (NCT04889040) at over 204 trial sites all over the world, not including America. The study should be done soon.

Pfizer First Patient First Dose

Pfizer announced an important milestone in the world of clinical trials, that is the first patient first dosage—including the first dosing using PF-07321332—an investigational orally administered protease inhibitor antiviral therapy designed specifically to combat COVID-19 in non-hospitalized, symptomatic adult participants who have confirmed diagnoses of COVID-19 and aren’t at risk for severe illness which could lead to hospitalization or death.

While Pfizer has led all COVID-19 vaccine sales approaching the tens of billions, that isn’t enough for investors’ appetite for pandemic monetization. As mentioned previously the stakes are too big for them to ignore hence why CEO Albert Bourla’s tweets telling the world the truth—those vaccines likely won’t be sufficient to overcome the pandemic. He is a smart man. After all, at the helm, his company will generate over $30 billion from the one vaccine product.

Global Pfizer Program

The PF-07321332 study is part of a global clinical development program, consisting of multiple ongoing and planned clinical trials to evaluate this early-intervention, outpatient therapeutic candidate for potential use in a broad population of patients. The first registrational trial in this program, a pivotal Phase 2/3 study of PF07321332/ritonavir in non-hospitalized, symptomatic adult participants who have been diagnosed with SARS-CoV-2 infection and are at increased risk of progressing to severe illness, began enrolment in July 2021.

Final Competitive Thoughts

While Roche seems furthest along, they don’t appear to focus, at least not yet, on the lucrative U.S. market. While Merck indirectly via Indian sub-licensees is backing a real-world care program using molnupiravir in Vietnam even though the drug is not authorized on an emergency basis or approved anywhere. This caught TrialSite’s attention yet received no press whatsoever. While physician societies yell and scream about licensed physicians treating consenting patients with ivermectin in America Merck actually uses an experimental drug on a population in a pilot even though the drug isn’t approved, and the clinical trials continue. That accounting can be read here. Well, at least some elites in the rich countries might just say behind closed doors—“it’s only Vietnam.”

In the meantime, the FDA and CDC will continue to collaborate with medical societies and industry to keep non-profitable options such as ivermectin as far away from the American public as they can.

Pfizer’s CEO doesn’t go on and send out a tweet such as this one without being very serious. The vaccine-centric strategy isn’t sufficient to overcome COVID-19 and the American public will soon enough be subjected to not only the third booster (and possibly another one after that—a version 2.0) but also an antiviral regiment key to inhibit the vast, overwhelming number of COVID-19 cases. Critical care physicians knew this was needed last spring.

Brazilian Snake Venom Could Help Fight COVID-19, Study Says

Brazilian Snake Venom Could Help Fight COVID-19, Study Says

Brazilian researchers have found a molecule in snake venom that could fight COVID-19. The discovery might be the first step toward a medication to fight the virus.

Scientists found that the molecule produced by the jararacussu snake prevented the virus' ability to spread in monkey cells by 75 percent. The study was published in the scientific publication Molecules this month.

Rafael Guido is a professor with the University of Sao Paulo and an author of the study. He said the molecule in the venom “was able to inhibit a very important protein from the virus."

The molecule is called a peptide, or a group of amino acids. The molecule is able to connect to an enzyme of the coronavirus called PLPro without harming other cells. PLPro is an important part of how the virus reproduces.

The peptide is already known to scientists for its ability to fight bacteria. Guido said the peptide can be made in a laboratory, so jararacussu snakes do not need to be caught.

"We're wary about people going out to hunt the jararacussu around Brazil, thinking they're going to save the world,” said zoologist Giuseppe Puorto with the Butantan Institute in Sao Paulo. "It's not the venom itself that will cure the coronavirus,” he added.

The jararacussu is one of the largest snakes in Brazil, and can be up to 2 meters long. It lives in Brazil’s Atlantic Forest and is also found in Bolivia, Paraguay and Argentina.

Researchers will test different amounts of the molecule and see if it is able to prevent the virus from entering cells at all.

They hope to test the molecule in human cells one day, but there are currently no plans to start.

Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors

The COVID-19 outbreak has rapidly spread on a global scale, affecting the economy and public health systems throughout the world. In recent years,…

www.mdpi.com

Quote from Fm1

Roche is also working on a COVID-19 antiviral known as AT-527 in partnership with Atea Pharmaceuticals.

So vaccines are here to just fill the earning gap until expensive new antivirals are available.....

Luckily we will no longer need them as almost everybody will have natural protection soon.

The only problem that will remain is vaccinated that never got a natural infection.

See Figur 12 : https://assets.publishing.serv…Technical_Briefing_20.pdf

Double vaccinated have a lower CT value than single vaccinated !!! This means higher virus load with delta what is a clear sign of ADE, that could become much worse with new variants.

So in the near future we will only see CoV-19 deaths among once double, triple, quadruple vaccinated due to ADE to new mutations.

Low Socioeconomic Status Mediates Vaccine Hesitancy and COVID-19 Hospitalizations

Low Socioeconomic Status Mediates Vaccine Hesitancy and COVID-19 Hospitalizations

As media headlines continue to attribute the overwhelming majority of hospitalized COVID-19 cases to unvaccinated people, little attention is focused on

trialsitenews.com

As media headlines continue to attribute the overwhelming majority of hospitalized COVID-19 cases to unvaccinated people, little attention is focused on the interaction of social, biological, and nutritional determinants underlying hospitalizations. Visit the emergency department of most hospitals at any time, and you are likely to find patients with low socioeconomic status (SES). These patients are also more likely to be obese and overweight, have chronic health conditions like diabetes, chronic kidney disease, hypertension, and cardiovascular diseases, and they are more likely to have lower nutritional status from ingesting highly processed foods containing excessive calories, fat, sugar, and salt. How do all these factors potentially interact to affect COVID-19 hospitalizations, and where does vaccine hesitancy stand in relation to these factors?

The word “syndemic” refers to compromised health and deprived social conditions that interact and synergistically increase a population’s vulnerability to epidemics and pandemics. The high prevalence of chronic diseases in our society increases the population’s vulnerability to infection during the COVID-19 pandemic, evidenced by the fact that many chronic conditions are comorbid with COVID-19.

Moreover, vulnerability to infection is further increased in segments of the population with low SES within whom chronic conditions have the highest prevalence.

Obesity and Nutrition

Centers for Disease Control and Prevention (CDC) previously reported that 78% of people hospitalized with COVID-19 are either obese (50.2%) or overweight (27.8%). A diet of ultra-processed foods high in additives is associated with obesity and being overweight. Furthermore, social conditions that contribute to obesity in low SES communities include food deserts with poor availability of fresh healthy foods.

Nutritional status also is an important factor in immunity that is relevant to COVID-19. Sodium toxicity from dietary salt has been potentially implicated as a cause of COVID-19 and SARS-CoV-2 infection.

Hospitalizations versus Ambulatory Care

People with lower SES prefer acute care services provided in hospitals, which they find are more affordable, easier to access and have greater quality than ambulatory care located in private offices of primary healthcare providers.

People with lower SES who show up at the hospital also may be more inclined to delay seeking care until their illness is more serious.

Vaccine Hesitancy and SES

Obviously, vaccines do not address the many underlying and interacting social, biological, and nutritional causes in syndemics. Yet, the media continues to blame vaccine hesitancy for COVID-19 hospitalizations.

In the figure below, people with low SES have more vaccine hesitancy (Letter A in the figure), such as in Black and Hispanic communities. Vaccine hesitancy is also associated with increased hospitalization (C in the figure). However, the association of vaccine hesitancy and increased hospitalization appears to be mediated by poor health and adverse social conditions in low SES segments of the population (Letter B), not by lack of vaccination!

Furthermore, COVID-19 mRNA vaccines have ultralow absolute risk reductions of approximately 1%, and they are unlikely to have any impact at all on reducing hospitalizations. Just because healthy people in the vaccine clinical trials did not have an increased risk of hospitalization doesn’t mean the vaccines prevented hospitalizations.

Rather than attempting to contain and manage pandemic infections with vaccines, masks, social distancing, and lockdowns, directly addressing the underlying causes of syndemics is a more promising public health strategy to reduce epidemics, pandemics, and hospitalizations.

This is how provxx mafia communication works: Japan::

Over 80% recovered from Moderna COVID vaccine side effects within 3 days: Japan univ. study - The Mainichi

SASEBO, Nagasaki -- Among those who received Moderna vaccine shots during workplace coronavirus inoculations conducted at a university in southwestern

mainichi.jp

However, even in cases where side effects occurred, they subsided within three days for over 80% of respondents, for both the first and second rounds of vaccinations.

Real bad news:: About 20% have long lasting Symptoms > 3 days!!

Really very rare side effects just for Moderna.

Quote from Fm1

TrialSite had declared for many months now that one reason for the intensified pressure against ivermectin was to clear the market of any low-cost competition for higher-priced, novel therapeutics. After all, Doctor Anthony Fauci and the federal research apparatus already declared over $3 billion will be spent on these companies.

It is only the non-science ivermectin pressure groups that claim there is this intensified pressure. They do that because:

• They do not evaluate the science as an objective scientist would - they conclude that it is obvious ivermectin is highly effective based on clearly flawed meta-analysis of variable data from trials and just wrong ecological arguments
• They ignore the expensive government-funded trials in US and UK that continue to evaluate ivermectin and will lead to immediate usage of these drugs if they work.

Given these trials (US ACTIV-6, UK PRINCIPLE) exist, will generate definitive results shortly, and any competing drugs will not be cleared for a long time, there is obviously no attempt to suppress ivermectin for financial reasons.

Quote from THHuxleynew

there is obviously no attempt to suppress ivermectin for financial reasons.

Why then e.g. (among others) did Merck get 1.2 Billion for an already failed drug to make it work for early treatment like Tamiflu that is of no use too???

You should stop your Big Pharma FUD. It simply is childish and silly.

Quote from THHuxleynew

It is only the non-science ivermectin pressure groups that claim there is this intensified pressure. They do that because:

• They do not evaluate the science as an objective scientist would - they conclude that it is obvious ivermectin is highly effective based on clearly flawed meta-analysis of variable data from trials and just wrong ecological arguments
• They ignore the expensive government-funded trials in US and UK that continue to evaluate ivermectin and will lead to immediate usage of these drugs if they work.

Given these trials (US ACTIV-6, UK PRINCIPLE) exist, will generate definitive results shortly, and any competing drugs will not be cleared for a long time, there is obviously no attempt to suppress ivermectin for financial reasons.

You couldn't explain India, data sucks coming out of India is your usual excuse but tell me Thomas, how do you explain the southern hemisphere where ivermectin is used. Vaccination rates are about 29% for the southern hemisphere and that's at the top end, probably closer to 20%

Quote from Wyttenbach

Why then e.g. (among others) did Merck get 1.2 Billion for an already failed drug to make it work for early treatment like Tamiflu that is of no use too???

You should stop your Big Pharma FUD. It simply is childish and silly.

1. Merck have not been payed 1.2 billion. They will be paid this if the drug is shown effective in upcoming Phase 3 trials and approved

2. molnupiravir is in Phase III trials https://www.clinicaltrialsaren…eback-molnupiravir-trial/

The trial is backed by Merck and its inventors. No public money spent unless phase III (high quality, large) is positive. This is the same standard as ivermectin is currently being tested for at public expense.

Merck and Ridgeback Biotherapeutics have reported preliminary results from a Phase IIa trial of investigational oral antiviral agent molnupiravir EIDD-2801/MK-4482 for Covid-19.

An orally-bioavailable form of a potent ribonucleoside analogue, molnupiravir hinders multiple RNA virus replication, including SARS-CoV-2.

The agent was invented by Emory University’s not-for-profit biotechnology company, Drug Innovations at Emory (DRIVE). All funds used for developing EIDD-2801 after it was licenced by Ridgeback were provided by Wayne and Wendy Holman and Merck.

Quote from Fm1

You couldn't explain India, data sucks coming out of India is your usual excuse but tell me Thomas, how do you explain the southern hemisphere where ivermectin is used. Vaccination rates are about 29% for the southern hemisphere and that's at the top end, probably closer to 20%

FM1. I have noticed that I post long detailed explanations of things like - why do India COVID rates look low. Summary only below:

• Demographics (average 15 years younger than developed countries => 6X fewer COVID deaths just from age)
• Government suppression (applies variably but particularly in Uttar pradesh where independent on the ground newspaper investigation reporting is showing 10X more excess deaths in mortuaries than govt COVID figures)
• COVID cases and deaths not counted in country areas. Where there is no healthcare and no tests COVID cases, and deaths, are written off as fevers
• In some places COVID was allowed to run through the population in previous waves (less bad results because it is younger) who now have pretty good immunity.

You could not explain is incorrect when i referenced specific reporting proving what i was saying, and in any case it should surprise no-one.

Summary (there are exceptions, but this is mostly true):

Developed richer countries with good health systems, access to vaccines, and regulators not influenced by politics

• Do not allow ivermectin, hydroxychloroquine
• Have old populations and therefore high COVID death rates (until at risk population are fukly vaccinated, which in some countries has not yet happened)
• Have accurate reporting of cases and deaths (though in some countries testing may be limited and therefore cases may be not that accurate).

Poorer less developed countries, with less access to vaccines and regulators more influenced by politics:

• Do allow HCQ, ivermectin
• Have younger populations so much lower death rates and IFR anyway
• Many have under-reporting of cases and deaths (not enough tests or local healthcare in rural locations)
• A few have under-reporting of deaths (political interference)

These things are not rocket science, and they exaplin all the ecological data. Whereas, if ivermectin works well (rather than just marginally), you cannot explain the negative high quality trial data.

I've even suggested (this is my idea, and may be rubbish) how ivermectin might seem to work well by reducing symptoms (it has some known effect as an anti-inflammatory). That might make it a bit effective in treating early or late-stage COVID, ut it could equally mean it does harm. Reducing symptoms from mild infection is not the same as working in terms of reducing serious infection, but would be obvious to doctors prescribing it. Because COVID in these low population age countries has such a low severe disease rate that can explain why many people believe it works (and the fact that doctors notoriously go on believing treatments they give work, even when they don't).

I cannot believe, if you have paid attention to my posts on this, that you think this is no explanation.

If you give me a specific S hemisphere country we will look at the data in detail: but those same factors might apply - or there might be other country-specific reasons - or both.

I criticise your overall evaluation of this stuff because you are not paying attention to the details. They matter a lot.

Best wishes, THH

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

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

www.nature.com

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.

Introduction

A relatively recent surge in zoonotic diseases has been noted over the past few decades. Several reasons could be responsible for this “spill-over” of disease-causing agents from animals to humans. These include an exponential rise in the global population causing man to encroach new ecological habitats in search of space, food, and resources as well as improved opportunities for rampant wildlife trade causing inter-species pathogen jumps. The 1980s was known for HIV/AIDS crisis that originated from the great apes, while the Avian flu pandemic in 2004-07 came from the birds. The pigs lead to the Swine flu pandemic in 2009 and bats were the original hosts of Ebola, Severe Acute Respiratory Syndrome (SARS), Middle Eastern respiratory syndrome (MERS), and probably Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) outbreak as well.

COVID-19 has already caused millions of deaths worldwide and has paralyzed not only the world’s healthcare system but also the political and economic relations between countries [1]. The fact that the SARS-CoV-2 virus has been thought to have originated from wildlife and may have “jumped” into humans, not only highlights future risks from animal-borne diseases but also provides an important clue to its resolution. In such a scenario, where this “jump” has been made from animal to human, it seems only logical to review a drug that has worked efficiently against a disease-causing agent and is available in a form that is safe for human consumption since the early 1980 s.

Ivermectin belongs to a group of avermectins (AVM), which is a group of 16 membered macrocyclic lactone compounds discovered at the Japanese Kitasato institute in 1967 during actinomycetes cultures with the fungus Streptomyces avermitilis [2]. This drug radically lowered the incidence of river blindness and lymphatic filariasis and was discovered and developed by William C. Campbell and Satoshi Ōmura for which they received the Nobel Prize in Physiology or Medicine in 2015 [3, 4]. Ivermectin is enlisted in the World Health Organization’s Model List of Essential Medicines [5].

Drug repurposing, drug redirecting, or drug reprofiling is defined as the identification of novel usages for existing drugs. The development risks, costs as well as safety-related failure, are reduced with this approach since these drugs have a well-established formulation development, in vitro and in vivo screening, as well as pharmacokinetic and pharmacodynamic profiles. Moreover, the first clinical trial phases of many such drugs have been completed and can be bypassed to reduce several years of development. Therefore, drug repurposing has the potential to reduce the time frame for the whole process by up to 3–12 years and carries great potential [6].

Although several drugs received Emergency Use Authorization for COVID-19 treatment with unsatisfactory supportive data, Ivermectin, on the other hand, has been sidelined irrespective of sufficient convincing data supporting its use. Nevertheless, many countries adopted ivermectin as one of the first-line treatment options for COVID-19.

With the ongoing vaccine roll-out programs in full swing across the globe, the longevity of the immunity offered by these vaccines or their role in offering protection against new mutant strains is still a matter of debate. The adoption of Ivermectin as a “safety bridge” by some sections of the population that are still waiting for their turn for vaccination could be considered as a “logical” option.

Several doctor-initiated clinical trial protocols that aimed to evaluate outcomes, such as reduction in mortality figures, shortened length of intensive care unit stay and/or hospital stay and elimination of the virus with ivermectin use have been registered at the US ClinicalTrials.gov [7]. Real-time data is also available with a meta-analysis of 55 studies to date. As per data available on 16 May 2021, 100% of 36 early treatment and prophylaxis studies report positive effects (96% of all 55 studies). Of these, 26 studies show statistically significant improvements in isolation. Random effects meta-analysis with pooled effects using the most serious outcome reported 79% and 85% improvement for early treatment and prophylaxis respectively (RR 0.21 [0.11–0.37] and 0.15 [0.09–0.25]). The results were similar after exclusion based sensitivity analysis: 81% and 87% (RR 0.19 [0.14–0.26] and 0.13 [0.07–0.25]), and after restriction to 29 peer-reviewed studies: 82% and 88% (RR 0.18 [0.11–0.31] and 0.12 [0.05–0.30]). Statistically significant improvements were seen for mortality, ventilation, hospitalization, cases, and viral clearance. 100% of the 17 Randomized Controlled Trials (RCTs) for early treatment and prophylaxis report positive effects, with an estimated improvement of 73% and 83% respectively (RR 0.27 [0.18–0.41] and 0.17 [0.05–0.61]), and 93% of all 28 RCTs. These studies are tabulated in Table 1. The probability that an ineffective treatment generated results as positive for the 55 studies to date is estimated to be 1 in 23 trillion (p = 0.000000000000043). The consistency of positive results across a wide variety of cases has been remarkable. It is extremely unlikely that the observed results could have occurred by chance [8].

Table 1 All 55 ivermectin COVID-19 trials (As per data available on 16 May 2021) divided based on stage of treatment (Early Vs Late) and the type of study

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However, a controlled outpatient trial by López-Medina et al. demonstrated that, in mild COVID-19, Ivermectin showed no improvement [9]. Misinterpretation of results were noted due to possible gaps in regards to the study quality (study design, the methodology adopted, statistical analysis, and hence the conclusion).

Ivermectin has rapid oral absorption, high liposolubility, is widely distributed in the body, metabolized in the liver (cytochrome P450 system) and excreted almost exclusively in feces [4]. Following a standard oral dose in healthy humans, it reaches peak plasma levels at 3.4 to 5 h; and plasma half-life has been reported to be 12 to 66 h [10]. Despite its widespread use, there are relatively few studies on the pharmacokinetics of Ivermectin in humans [11]. Ivermectin binds strongly to plasma proteins in healthy subjects (93.2%) [12]. Such an “avid binding” can be beneficial when administered in countries where malnutrition and hypoalbuminemia are common, leading to an increased availability of “free fraction” of ivermectin [4]. Hypoalbuminemia is a frequent finding in patients with COVID‐19 and it also appears to be linked to the severity of lung injury [13]. Therefore, Ivermectin might be useful when used in such a setting.

There is evidence supporting the use of Ivermectin in decreasing mortality figures in patients with SARS-CoV-2 infection. 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 [14].

This article aims to discuss the mechanism of action by summarizing the in vitro and in vivo evidence demonstrating the role of Ivermectin in COVID-19 as per the available literature over the years. [Table 2] 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 has been proposed. [Fig. 1]

Table 2 A list of studies demonstrating the role of Ivermectin (IVM) on SARS-CoV-2

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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.

figure1

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

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Methods

A comprehensive search of the PubMed database was conducted from January 1, 2008 up to January 30, 2021 using syntax constructed using MeSH Database as follows: (stromectol OR Ivermectin OR “dihydroavermectin”) OR (22 AND 23-dihydroavermectin B) AND (antiviral OR virus OR COVID-19 OR SARS-CoV-2). All the results obtained were manually reviewed for content, relevance and included when considered appropriate. The papers cited in the references were also reviewed and included when considered appropriate. The articles were retrieved manually to exclude any duplicates.

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].

SARS-CoV-2 virus structure

SARS-CoV-2 is a sarbecovirus with structural similarity to SARS-CoV-1. Out of the four structural proteins of the SARS-CoV-2 beta coronavirus, namely: Spike (S) protein, membrane (M) protein, envelope (E) protein, and nucleocapsid (N) protein, the S protein is responsible for eliciting potent neutralizing antibody responses. The entry of SARS-CoV-2 into the host cell is mediated by the binding of the S1 subunit of its S protein (receptor binding domain) to the Angiotensin-converting enzyme 2 (ACE-2) receptors present on the host cell surface [18]. The S2 subunit is associated with a fusion protein that binds with the cell membrane after priming with Transmembrane protease, serine 2 (TMPRSS-2) and is responsible for fusion with the host cell.

The SARS-CoV-2 genome consists of ∼29.8 kb nucleotides; it possesses 14 open reading frames (ORFs) encoding 27 proteins [19]. The 5′ two-thirds of the viral genome encodes the replicase gene. It contains two ORFs: ORF1a and ORF1b. ORF1a/b encodes two polyproteins by polymerase frameshifting; these are then post-translationally cleaved into 15 non-structural proteins (nsps): nsp1–10 and nsp12–16. The rest of the genome encodes for the four structural proteins [(S protein, E protein, M protein, N protein], in addition to eight accessory proteins (3a/3b, p6, 7a/7b, 8b, 9b, and ORF14) [19]. The replicase also encodes the papain-like protease (PLpro) and the serine-type protease or main protease (Mpro) [20].

In principle, a molecule can act as an anti-viral drug if it “inhibits some stage of the virus replication cycle, without being too toxic to the body’s cells [21].”

The possible modes of action of anti-viral agents would include the following:

1.

Inactivate extracellular virus particles.

2.

Prevent viral attachment and/or entry.

3.

Prevent replication of the viral genome.

4.

Prevent synthesis of specific viral protein(s).

5.

Prevent assembly or release of new infectious virions

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.

Direct action of Ivermectin on SARS-CoV-2

Level 1: Action on SARS-CoV-2 cell entry

A study by Lehrer S et al observed that Ivermectin docked in the region of leucine 91 of the SARS-CoV-2 spike protein and histidine 378 of the host cell ACE-2 receptor blocking its entry into the host cell [22]. In yet another study by Eweas et al., potential repurposed drugs such as Ivermectin, chloroquine, hydroxychloroquine, remdesivir, and favipiravir were screened and molecular docking with different SARS-CoV-2 target proteins including S and M proteins, RNA-dependent RNA polymerase (RdRp), nucleoproteins, viral proteases, and nsp14, was performed. Ivermectin showed the following 5 important docking properties [23]:

1.

Highest binding affinity to the predicted active site of the S glycoprotein (Mol Dock score −140.584) and protein–ligand interactions (MolDock score−139.371).

2.

Considerable binding affinity to the predicted active site of the SARS-CoV-2 RdRp protein (MolDock score −149.9900) and protein–ligand interactions (MolDock score −147.608), it formed H-bonds with only two amino acids: Cys622 and Asp760.

3.

Highest binding affinity (MolDock score −212.265) to the predicted active site of nsp14.

4.

The highest binding affinity to the active site of the TMPRSS2 protein (MolDock score −174.971) and protein–ligand interactions (MolDock score −180.548). Moreover, it formed five H-bonds with Cys297, Glu299, Gln438, Gly462, and Gly464 amino acid residues present at the predicted active site of the TMPRSS protein

5.

The free binding energy of the spike protein (open) was higher in Ivermectin (−398.536 kJ/mol) than remdesivir (−232.973 kJ/mol).

An In-silico data analysis conducted by Choudhury et al. demonstrated that Ivermectin efficiently utilizes viral spike protein, main protease, replicase, and human TMPRSS2 receptors as the most possible targets for executing its “antiviral efficiency” by disrupting binding. Since Ivermectin exploits protein targets from both, the virus and human, this could be the behind its excellent in vitro efficacy against SARS-CoV-2 [24].

The development of vaccines for SARS-CoV-2 is centered around spike protein biology (virus targeted) and the recently documented “vaccine escape strains” have been a cause of worry. In such a situation, Ivermectin, is both, virus as well as host targeted and hence could act as a potential therapeutic against these new strains that could “escape” immunity offered by the vaccine.

Level 2: Action on Importin (IMP) superfamily

Inside the cell, the nuclear transport of proteins into and out of the nucleus is signal-dependent and mediated by the Importin (IMP) superfamily of proteins that exist in α and β forms. This IMPα/β1 exists as a heterodimer with a “IBB” (IMP β-binding) site present over IMP α that binds to IMP β1 on “cargo recognition” by IMPα. The SARS-CoV-2 virus upon host cell entry tends to “load” its proteins over the host protein IMP α/β1 heterodimer (importin) to enter the nucleus through the nuclear pore complex. Once inside, the importin molecule detaches while the viral protein from the SARS-CoV-2 virus hijacks the host cell machinery and inhibits the natural cell “anti-viral” response by blocking the release of interferon (an antiviral substance released by an infected cell to alert the surrounding cells of an ongoing viral attack). As a result, the surrounding cells become “unsuspecting victims” of the virus and the infection continues with the virus escaping recognition by the immune cells [25]. Ivermectin, in presence of a viral infection, 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. This allows the cell to carry out its normal antiviral response [26]. In such a case, it should be noted that the activity of Ivermectin here is viro-static, that is, it neutralizes the virus by competing for the same receptor.

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.

Action on host targets for viral replication

Level 4: Action as an antiviral

A systematic review article by Heidary, F. discussed the “anti-viral” properties of Ivermectin against other viruses including the RNA viruses such as Zika Virus (ZKV), Dengue virus, yellow fever virus (YFV), and 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) [29].

Level 5: Action on viral replication and assembly

An in-vitro study by Caly L et al. demonstrated that the Vero/hSLAM cells infected with the SARS-CoV-2 virus when “exposed” to 5 µM Ivermectin showed a 5000-fold reduction in viral RNA at 48 h when compared to the control group [30]. This study attracted opinions regarding the inability of Ivermectin to achieve the therapeutic effect of COVID-19 through routine dosage. Contrary to this, Arshad et al, by utilizing modeling approach, predicted lung accumulation of Ivermectin over 10 times higher than EC 50. This likelihood of attainment of higher lung tissue concentrations of Ivermectin leaves the door open for further research especially for respiratory infections [31].

An explanation for the study by Caly et al was provided in a review article: Global trends in clinical studies of ivermectin in COVID-19 by Yagisawa et al., co-authored by Prof. Satoshi Ōmura, regarding the “setting of the sensitivity for experimental systems in vitro”. As per the authors, using Vero/hSLAM cells, the antiviral activity of the test drug was reliably measured and the sensitivity of the IC50 = 2 μM set by them was appropriate as neither false positives nor false negatives occurred. Therefore, the study by Caly et al. merely indicated that ivermectin was found to have anti-SARS-CoV-2 activity in vitro—no more, no less. Also, the fact that there are in vivo infection experiments that could be used to connect in vitro experiments to clinical studies [32].

Another in-silico study by Swargiary et al. demonstrated the best binding interaction of −9.7 kcal/mol between Ivermectin and RdRp suggesting inhibition of viral replication [33]. The RdRP residing in nsp12 is the centerpiece of the coronavirus replication and transcription complex and has been suggested as a promising drug target as it is a crucial enzyme in the virus life cycle both for replication of the viral genome but also for transcription of subgenomic mRNAs (sgRNAs) [34]. Ivermectin binds to the viral rdrp and disrupts it. The highly efficient binding of ivermectin to nsp14 confirms its role in inhibiting viral replication and assembly. It is well known that nsp14 is essential in transcription and replication. It acts as a proofreading exoribonuclease and plays a role in viral RNA capping by its methyltransferase activity [35]. Moreover, highly efficient binding of ivermectin to the viral N phosphoprotein and M protein is suggestive of its role in inhibiting viral replication and assembly [23].

Level 6: Action on post-translational processing of viral polyproteins

Once gaining entry into the host cell, the viral RNA is translated by the host ribosome into a large “polyprotein”. Some enzymes break away through autoproteolysis from this polyprotein and further help other proteins to break off and carry out their function for replication. One such enzyme, 3 chymotrypsin-like proteases (3’cl pro/ Mpro) is responsible for working on this polyprotein causing other proteins to “librate” and carry out viral replication. Ivermectin binds to this enzyme and disrupts it. It also efficiently binds to both proteins, Mpro, and to a lesser extent to PLpro of SARS-CoV-2; therefore, it has a role in preventing the post-translational processing of viral polyproteins [23].

Level 7: Action on Karyopherin (KPNA/KPNB) receptors

Karyopherin-α1 (KPNA1) is essential for the nuclear transport of signal transducers and activators of transcription 1 (STAT1) [36], and the interaction between STAT1 and KPNA1 (STAT1/KPNA1) involves a nonclassical nuclear localization signal (NLS). Ivermectin inhibits the KPNA/KPNB1- mediated nuclear import of viral proteins allowing the cell to carry out its normal antiviral response [30].

Action on host targets for inflammation

Level 8: Action on Interferon (INF) levels

These virus-infected cells release interferons that bind to the IFN receptors present on neighboring cells alerting them of a viral attack. The IFN-I and IFN-III receptors then further activate members of the JAK-STAT family. The virus after gaining entry into the host cell hijacks the host cell machinery and works towards antagonizing the normal interferon-mediated host cell antiviral response. SARS-CoV-2 proteins such as ORF3a, NSP1, and ORF6 inhibit IFN-I signaling [37, 38]. As a result, the cells surrounding the SARS-CoV-2 virus-infected cell “fail” to receive “critical and protective IFN signals” causing this SARS-CoV-2 virus to replicate and spread without any hindrance. This is one of the main reasons that, at this stage, COVID-19 infection is “hard to detect” clinically [39].

Ivermectin has been shown to promote the expression of several IFN-related genes, such as IFIT1, IFIT2, IF144, ISG20, IRF9, and OASL [40].

Level 9: Action on Toll- like-Receptors (TLRs)

Upon virus entry, the intracellular pattern recognition receptors (PRRs) present on the host cells are responsible for detecting the viral attack. The virus activates one such PRR named the Toll-like receptors (TLRs). These receptors are present on various immune system cells that help them locate and bind with the pathogen. The activation of TLRs, causes oligomerization, further activating downstream interferon regulatory factors (IRFs) and nuclear factor-kappa B (NF-kB) transcription factors inducing INF production [41]. Ivermectin plays a role in the blockade of activation of NF-kB pathway and inhibition of TLR4 signaling [42].

Level 10: Action on Nuclear Factor-κB (NF-κB) pathway

Activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway induces the expression of various pro-inflammatory genes, including those encoding cytokines and chemokines [43]. Jiang et al. demonstrated that Ivermectin 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 inhibition of the transcriptional factor NF-κB [44]. Also, Zhang et al., suggested that Ivermectin inhibits lipopolysaccharide (LPS)-induced production of inflammatory cytokines by blocking the NF-κB pathway and improving LPS-induced survival in mice [42]. Therefore, using Ivermectin would be helpful in ICU settings where there are increased chances of bacterial infections (LPS mediated).

Level 11: Action on the JAK-STAT pathway, PAI-1 and COVID-19 sequalae

A strong correlation exists between SARS-CoV-2 viral load, disease severity, and progression [45]. COVID-19 not only causes flu-like symptoms such as fever, dry cough but could also lead to widespread thrombosis with microangiopathy in pulmonary vessels [46], raise D-dimer levels [47], cause lymphopenia [48], raise proinflammatory cytokine and chemokine production [49] as well as lead to a significant elevation of CRP levels [50]. SARS-CoV-2 has structural similarity with SARS-CoV-1. Several SARS-CoV-1 proteins antagonize the antiviral activities of IFNs and the downstream JAK (Janus kinase)-STAT signaling pathways they activate. JAK family kinases display a wide range of functions in ontogeny, immunity, chronic inflammation, fibrosis, and cancer [51].

The host proteins, such as the members of the signal transducers and activators of transcription (STATs) and NF-κB, enter the nucleus through nuclear envelope-embedded nuclear pores mediated by the IMPα/β1 heterodimer and play a role in COVID-19 pathogenesis. Frieman et al. demonstrated that accessory SARS ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane [52]. A review article by Matsuyama et al, hinted at 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 [39].

Before discussing further, it is important to understand the link between STAT-3 upregulation and COVID-19 sequelae and the role of Ivermectin in inhibiting STAT-3. STAT-3 acts as a “central hub” that mediates the detrimental COVID-19 cascade. In the lungs, STAT-3 activates Hyaluronan synthase-2 leading to deposition of hyaluronan causing diffuse alveolar damage. The damaged type 2 alveolar cells express PAI-1 (plasminogen activator inhibitor-1). Additionally, hypoxia due to diffuse alveolar damage causes an upregulation of PAI-1 through HIF-1a. STAT-3 also directly activates PAI-1. The simultaneous activation of PAI-1 and STAT-3 inhibits t-PA and urokinase-type plasminogen activator leading to thrombi formation in the capillaries. PAI-1 also binds to TLR-4 receptors on macrophages further activating the NF-kB pathway.

The “cytokine storm” typical of severe COVID-19 involves STAT-3 mediated upregulation of proinflammatory cytokines, TNFα, and IL-6 in macrophages. Additionally, STAT-3 induces a C-reactive protein that upregulates PAI-1 levels. STAT-3 is directly responsible for activating IL-6 gene transcription which further leads to an increase in TGF-β causing pulmonary fibrosis. The PD-L1 receptors present on the endothelial cells are activated by STAT-3 causing T cell lymphopenia. Ivermectin inhibits STAT-3 through direct inhibition preventing COVID-19 sequalae [39].

Level 12: Action on P21 activated Kinase 1 (PAK-1)

The p21 activated kinase 1 (PAK1) physically binds to both JAK1 and STAT3, and the resultant PAK1/STAT3 complex activates IL-6 gene transcription responsible for cytokine storm in COVID-19 [53]. Ivermectin suppresses the Akt/mTOR signaling and promotes ubiquitin-mediated degradation of PAK-1 hence compromising STAT-3 activity and decreasing IL-6 production [54].

Level 13: Action on Interleukin-6 (IL-6) levels

A study by Zhang et al. demonstrated that Ivermectin suppressed IL-6 and TNFα production, two major components of the detrimental cytokine storm induced by SARS-CoV-2 and “dramatically reduced” IL-6/IL-10 ratio modulating infection outcomes [42, 55].

Level 14: Action on allosteric modulation of P2X4 receptor

P2X receptors are the channels selective to cation, are gated by extracellular ATP [56] and mediate several functions in health and disease [57]. From the seven subunits of P2X receptors, P2X4 is most sensitive to Ivermectin. Positive allosteric modulation of P2X4 by Ivermectin enhances ATP-mediated secretion of CXCL5 (pro-inflammatory chemokine). CXCL5 is a chemo-attractant molecule expressed in inflammatory cells in different tissues and modulates neutrophil chemotaxis and chemokine scavenging [58].

Level 15: Action on high mobility group box 1 (HMGB1)

The damage-associated molecular pattern high mobility group box 1 (HMGB1), is released by damaged cells acting as an agonist for the TLR4 receptor and hence mediating lung inflammation associated with COVID-19 [59]. Ivermectin inhibits HMGB1 [60].

Level 16: Action as an immunomodulator on Lung tissue and olfaction

In a study by DeMelo et al., the effects of Ivermectin were investigated on SARS-CoV-2 infection using the golden Syrian hamster as a model for COVID-19. Both, male and female adult golden Syrian hamsters were intranasally inoculated with 6 × 104 PFU of SARS-CoV-2. At the time of infection, animals received a single subcutaneous injection of Ivermectin (antiparasitic dose of 400 μg/kg) classically used in a clinical setting and were monitored over four days. Mock-infected animals received the physiological solution only. Interestingly, Ivermectin had a sex-dependent and compartmentalized immunomodulatory effect, preventing clinical deterioration and reducing the olfactory deficit in infected animals. This effect was sex-dependent: infected males presented a reduction in the clinical score whereas a complete absence of signs was noticed in the infected females. Regarding the olfactory performance, 83.3% (10/12) of the saline-treated males presented with hyposmia/anosmia, in contrast to only 33.3% (4/12) of IVM-treated males (Fisher’s exact test p = 0.036). No olfactory deficit was observed in IVM-treated females (0/6), while 33.3% (2/6) of saline-treated females presented with hyposmia/anosmia (Fisher’s exact test p = 0.455). Ivermectin dramatically reduced the IL-6/IL-10 ratio in lung tissue, which likely accounts for the more favorable clinical presentation in treated animals [55]. Loss of smell has been reported as one of the common symptoms in COVID-19 [61]. Interestingly, majority of patients in India regained their sense of smell after a brief anosmic period during their clinical course. Ivermectin is being used in India as one of the first-line drugs for COVID-19 treatment. It could be hypothesized that Ivermectin might have a role to play in reducing SARS-CoV-2 induced olfactory deficit.

Level 17: Action as an anti-inflammatory

The mechanism for anti-inflammatory action of Ivermectin 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 [42, 61, 62]. Moreover, 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 Ivermectin [63].

Action on other host targets

Level 18: Action on Plasmin and Annexin A2

As per study by Kamber Zaidi et al, annexin A2 may be linked to COVID-19 pathophysiology. Annexin A2 acts as a co-receptor for the conversion of plasminogen to plasmin in the presence of t-PA. Increased plasmin levels are found in co-morbid states and is also responsible for early stages of viral infection. Plasmin leads to direct activation of STAT-3 inducing detrimental COVID-19 sequelae. Ivermectin directly inhibits STAT-3 and could play a role in the inhibition of COVID-19 complications.

Level 19: Action on CD147 on the RBC

The transmembrane receptor CD147, present on the red blood cell (RBC) along with ACE-2 has been recognized as a key binding site for SARS-CoV-2 spike protein. The SARS-CoV-2 does not internalize into the RBC but such attachments can lead to clumping [65]. Ivermectin binds to the S protein of the virus making it unavailable to bind with CD147. This action might also be beneficial in advanced stages of COVID-19 presenting with clotting/thrombotic phenomena.

Level 20: Action on mitochondrial ATP under hypoxia on cardiac function

SARS-CoV-2 has been a well-known cause for acute myocardial injury and chronic damage to the cardiovascular system in active infection as well as in long haulers [66]. Nagai et al. demonstrated that Ivermectin increased mitochondrial ATP production by inducing Cox6a2 expression and maintains mitochondrial ATP under hypoxic conditions preventing pathological hypertrophy and improving cardiac function [67].

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.

Change history

22 June 2021Editor’s Note: Readers are alerted that the conclusions of this paper are subject to criticisms that are being considered by the editors and the publisher. A further editorial response will follow the resolution of these issues