Coronavirus: Thread

[grarpamp]

Ivermectin Fans Have a New Champion to Root For - 3CL Protease
Inhibitor Tollovid

http://www.mytollovid.com/
https://todosmedical.com/
https://ivmmeta.com/
https://www.clinicaltrials.gov/ct2/results?cond=COVID-19&term=ivermectin&cntry=&state=&city=&dist=&Search=Search
https://www.nature.com/articles/s42003-020-01577-x
https://www.nature.com/articles/s41593-021-00926-1
https://www.news-medical.net/news/20211027/Study-uncovers-how-novel-coronavirus-disrupts-normal-cell-defenses-to-hijack-human-host-cells.aspx
https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(20)30464-8/fulltext
https://www.nejm.org/doi/10.1056/NEJMc2114907
https://www.biospace.com/article/releases/todos-medical-receives-new-fda-certificate-of-free-sale-for-tollovid-daily-including-3cl-protease-inhibitor-claim/
https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-additional-phase-23-study-results
https://www.provistadx.com/neutralization-antibody-panel?hsLang=en-us
https://www.timesofisrael.com/health-minister-suggests-fourth-vaccine-dose-amid-rising-fears-of-fifth-covid-wave/
https://www.dailywire.com/news/fauci-tells-cnn-its-a-matter-of-when-not-if-definition-of-fully-vaccinated-changes
https://www.dailywire.com/news/cdc-director-threat-of-suicide-drugs-flu-to-youth-far-greater-than-covid
https://www.cnn.com/videos/health/2021/12/14/anthony-fauci-covid-19-omicron-hospitalizations-data-sot-vpx-nr.cnn
https://www.who.int/news-room/feature-stories/detail/who-advises-that-ivermectin-only-be-used-to-treat-covid-19-within-clinical-trials
https://www.fda.gov/consumers/consumer-updates/why-you-should-not-use-ivermectin-treat-or-prevent-covid-19
https://pubmed.ncbi.nlm.nih.gov/31724441/
https://academic.oup.com/ofid/article/8/11/ofab358/6316214
https://www.chemistryworld.com/news/ivermectin-debacle-exposes-flaws-in-meta-analysis-methodology/4014477.article
https://www.otcmarkets.com/stock/TOMDF/news/Todos-Medical-Announces-Positive-Observational-Trial-Results-for-Oral-Antiviral-3CL-Protease-MPro-Inhibitor-Tollovir?id=323148
https://www.acsh.org/news/2021/12/02/how-does-pfizers-pavloxid-compare-ivermectin-15967
https://www.ems1.com/coronavirus-covid-19/articles/understanding-ivermectin-I6HFMGuIN9stMjii/
https://reader.elsevier.com/reader/sd/pii/S1879625721000407?token=F4E7C679A61973D4C6559C8894A1A6A417B5FDF6A886A5CFA061221BC656C4968CBDA0A4B5A0466CFA597405D840DE9A&originRegion=us-east-1&originCreation=20211212021531
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817688/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751445/
https://www.pfizer.com/news/press-release/press-release-detail/pfizer-provide-us-government-10-million-treatment-courses
https://www.acsh.org/news/2021/12/02/how-does-pfizers-paxlovid-compare-ivermectin-15967
https://soseiheptares.com/uploads/Presentation%20and%20Webcast/2021/2021.08%20MPro%20Factsheet.pdf
https://www.science.org/doi/10.1126/science.abl4784
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430524/
https://tollovid.myshopify.com/products/tollovid%E2%84%A2-immune-support-capsules


Early in the pandemic it was pretty obvious to a lot of doctors that
ivermectin seemingly worked. The issue is that there were no well
controlled studies and lack of a solid protocol in clinical
management. In places like Central and South America Doctors didn’t
have time to do controlled studies; they simply prescribed it to all
the patients as a triage to stem the overflowing hospital corridors.
For many it seemingly worked because they got the drug early in the
disease. When there were calls for a clinical trial, there was no
control group that hadn’t already been given ivermectin so it suffered
from its own success. There are over 80 clinical trials for ivermectin
in just the United States right now, but based on the 3CL protease
mechanism of action that is so powerful in treating COVID patients,
ivermectin is unlikely to attain approval. But there is a new and
improved ivermectin called Tollovid and you can buy it TODAY to have
immune support.  Unfortunately for ivermectin, the variants emerged
and they came with a much higher viral load.  This is likely why
studies done later in the pandemic didn't confirm the early efficacy
that the doctors witnessed.
Targeting the 3CL Protease

Pfizer has proved that blocking the 3CL protease is the best method
for an antiviral, with its clinical results far surpassing efforts by
Merck and others. What we know is that ivermectin is a weak 3CL
protease inhibitor so while it might have worked well in the initial
stage of the pandemic, once Alpha and Delta arrived with their much
higher viral loads, ivermectin simply couldn’t compete once the virus
was established in a person. The reason why is discussed later in the
article. It’s also likely that ivermectin was showing really weak
efficacy that can only be mined through meta analyses since it's such
a weak 3CL protease inhibitor—to the point that its benefits cannot
easily be measured. And some of these studies gathered through the
meta analysis, particularly those showing high efficacy for
ivermectin, were fraudulent or biased.

Ivermectin Doubles as a 3CL Protease Inhibitor

Before COVID-19 hit Ivermectin was viewed as a viral inhibitor.  In
vitro studies showed benefit against HIV, Dengue, West Nile, Yellow
Fever, and the Zika virus. The other mechanism of action was that
Ivermectin facilitated the transport of proteins to the nucleus.
These proteins formed would end up signaling cytokine production to
improve cellular defense and alarm to neighboring cells.  People were
claiming that Pfizer’s drug was a repurposed ivermectin as both drugs
inhibit the 3CL protease. It was found that:

    “ivermectin blocked more than 85% of 3CLpro activity of
SARS-CoV-2. Although the anti-viral activity of ivermectin mediated
through the blocking of α/β1 importin is established, herein we report
the inhibitory effects of ivermectin on 3CLpro enzyme of SARS-CoV-2,
suggesting additional anti-viral mechanism of ivermectin towards
SARS-CoV-2.”

Since the pandemic started scientists have learned much more about the
mechanisms behind inhibiting 3CL protease. There is a belief that the
3CL protease cleaves NEMO and prevents the cellular alarm signal from
making it to the nucleus. In addition to this, the 3CL protease if
left unchecked ends up cleaving Galectin-8 which is responsible for
the cellular defense of xenophagy, which is the process of engulfing
the virion and digesting them.

    “We discovered that the virus attaches to and deactivates an
important sensor protein in the host cell called galectin-8, which
protects the cell against infection. By deactivating galectin-8,
SARS-CoV-2 disarms a cell's antiviral defense system and allows the
virus to take over the host." - Dr. Chris Overall, study's senior
author, Canada Research Chair, and principal investigator, UBC Centre
for Blood Research, Life Sciences Institute and Faculty of Dentistry

Ivermectin the Prophylactic

Many people are using it as a prophylactic and in theory that makes
sense why it would work given the many mechanisms of action, but there
are trade-offs that come in the form of side effects. A report in the
Lancet spelled out clinical benefits very early in the disease
progression and a lessening of side effects and that the results
suggested a larger trial would be needed to confirm that.  Some may
call this New England Journal of Medicine (NEJM) report a propaganda
piece against ivermectin, but the NEJM has an impeccable reputation
that put out a pretty convincing article that demonstrated that
prevention and treatment using ivermectin was not a good idea due to
considerable toxicity and questionable efficacy.  Patient symptoms
included gastrointestinal distress (nausea, vomiting, & diarrhea),
confusion, weakness, hypotension, and seizures.  The most common side
effects for ivermectin include itching and hives, dizziness, headache,
nausea, diarrhea and muscle pain. In order to achieve a large
reduction in viral load to the point that it makes you feel better,
large doses of ivermectin would be needed.  That is clearly not a good
idea because of the potential side effects whereby the cure becomes
worse than the disease.

There is a new 3CL protease inhibitor called Tollovid that earned its
Certificate of Free Sale from the FDA. It's basically ivermectin on
steroids without any side effects.  Ivermectin was invented in 1975
and was so ideal for its use (killing parasitic worms) that no one has
tried to improve it in close to 50 years because it was used for short
periods of time and the safety profile was manageable given the
circumstances.  Much was learned from the recently announced Pfizer
data that showed the 3CL protease is an integral part of the disease.
So all the naysayers that said ivermectin didn’t work were mistaken.
It’s no longer a question of whether it worked or not.  Ivermectin
clearly takes on the 3CL protease, but it has limitations.  The
controversy at the FDA level is whether or not it was taken soon
enough, or whether it is potent enough to see a clinical benefit.  The
answer to these questions could have been quantified with viral load
samples perhaps taken hourly but there is no approved test for this
and the point is moot because there is an upgraded version available
right now.
Ivermectin Officially Defunct for Variants

There are very good scientific explanations why ivermectin worked on
the wild type virus and good reasons why it can work in the early
stages of the disease.  However, just because it worked under these
sheltered conditions doesn’t give people license to claim that it
works now.  It should be clear it doesn't work now and that it has
been replaced by Tollovid.  The higher infectivity and viral load of
these new variants has effectively dramatically diluted the efficacy
of the drug to the point whereby no clinical benefit would be expected
to be observed. It will still block 3CL protease, but the problem is
that it won’t block enough of it.  The level of protease inhibition is
determined by looking at viral load and not even lethal levels of the
drug will even get close to making a dent.
Behind the Rise of Ivermectin

The reason there are so many Ivermectin fans is because people were
sitting there thinking how silly it was to pursue the concept of herd
immunity.  For decades our society has been trying to reach herd
immunity for mutating viruses yet people still contract the flu.
Despite these decades of experience, people that get their flu shots
understand they can still contract it and that there is no herd
immunity.  Herd immunity is like Camelot, a perfect society that just
isn't real. The flu hasn't been stamped out yet, nor will it ever be
using these antiquated methods. There still isn't an answer for HIV,
but politicians and that includes Fauci, assured the American people
that this time with COVID, it was going to be different.  Many saw
through the smokescreen and asked why they weren't more focused on
therapeutics. Luckily, the company that came up with Tollovid, was
very focused.

It's undeniable that vaccines do work and have played a major role in
flattening the curve, but they just weren't used effectively.  Had
they been used with widespread testing and verification of antibody
levels with the cPass test (FDA EUA approved neutralizing antibody
test), the United States may have had a chance to mute the Delta wave.
Instead, this holiday season, many Americans are burdened with the
choice of seeing family and potential infection or sheltering in
place.

As the pandemic rages on this holiday season with the rise of the
Omicron variant, Israel starting to push the 4th dose (second
booster), and Fauci changing his mind once again the pandemic by
suggesting a redefinement of what “fully vaccinated” means, and the
health authorities pushing vaccinations for kids (who if health are at
virtually no risk for COVID-19 symptoms, let alone death) Americans,
especially the anti-vaxxers, are looking for their own solutions to
the pandemic. Many Americans are getting tired of masks and lockdowns
and therefore the only two things these people can do are stay healthy
and look for treatments or prophylactic treatments. This generally
means taking supplements like Vitamin D to support immune function,
and either taking daily or stocking up on oral antivirals to prevent
severe disease if COVID-19 is contracted. With Omicron, even the
vaccinated are at risk of contracting the disease and getting
hospitalized. For those that have the new ivermectin called Tollovid,
there is another option of boosting the immune system while sharing
time with the family.

So many people have turned to ivermectin as an oral antiviral, with
ivermectin prescriptions surging, but the subject of whether it works
or not has been hotly debated. Dissenters citing issues with virtually
all of ivermectin clinical trial designs, including small sample
sizes, dosing with other drugs, heterogeneous populations, a lack of
blinding, and other factors that make it difficult to draw
scientifically valid conclusions from these studies.
Data for Ivermectin

The data for ivermectin is very confusing. There are even entire
websites set up for gathering ivermectin data, whether fraudulent or
not. Consumers hear about doctors prescribing ivermectin to everyone,
doctors refusing to prescribe ivermectin, ivermectin being a miracle
drug, and ivermectin being less than useless in fighting COVID-19.
Which is it?

There’s debates, generally between those who follow regulatory
authorities and those who don’t trust regulatory authorities, as to
what is the truth. The WHO, for instance, advises ivermectin use only
for clinical trials, basically saying that the medical community needs
better run trials to prove the drug’s benefit. On the other hand, the
FDA is totally against it. But a review of actually well run trials
(placebo controlled, randomized, blinded studies) such as this one
suggest a very modest benefit if used early. The trial results suggest
very slight benefits, including a trend to reduction in viral load and
quicker recovery from loss of sense of smell, a far cry from reducing
death.

With Pfizer recently announcing an oral antiviral that proved in one
well designed, randomized, placebo-controlled, blinded study,
consumers of ivermectin must be wondering why it takes a meta analysis
of over 30 studies to even suggest that ivermectin is efficacious for
COVID-19. With a massive sample size, it’s easy to prove a therapeutic
benefit, but studies are conflicting on ivermectin. Pfizer’s pill,
which works by blocking a viral enzyme produced in cells called the
3CL protease, clearly works. This proves the clinical utility of
blocking the 3CL protease and ivermectin fans need to take this new
information into account. In fact, ivermectin has been shown to
inhibit the 3CL protease, but the amount of ivermectin one needs to
sufficiently block the enzyme are unattainable with a normal dose, and
would result in significant toxicity if one took enough ivermectin to
achieve this.

Ivermectin’s inability to sufficiently block the 3CL protease could
explain why various studies fail to conclusively prove its clinical
benefits, and so ivermectin users should be looking for more powerful
and proven 3CL protease inhibitors. As of now, there are only two
pills available: Paxlovid (Pfizer’s prescription drug) and Tollovid,
which is a 3CL protease inhibitor nutraceutical. These products are
much more potent at blocking the 3CL protease and users should expect
a much more robust clinical effect.
Why Ivermectin Can’t Block 3CL Protease Like Pfizer’s Drug

It’s easy to Google search a list of compounds that might block the
3CL protease. In fact, various flavonoids found in one’s normal diet
can block the enzyme. However, to sufficiently block the viral
replication process, there must be enough of these compounds in the
body and so the question becomes: how much of the compound does one
need? Unfortunately, these compounds are likely unable to sufficiently
block viral replication in achievable quantities. The same goes for
ivermectin. It comes down to the amount needed in the body and how
much one can absorb into the body. There are various metrics to
measure this but the main measurement is IC50 (inhibitory
concentration required to reduce the target’s maximum activity by
50%). For translating how much of an oral compound one must take, the
bioavailability and pharmacokinetics of the drug are what is
important: i.e. how well the drug is absorbed and then how slowly it
is eliminated from the body. Ivermectin falls short in both of these
categories, and consumers need to find a 3CL protease that can
deliver.
A Comparison of 3CL Protease Inhibitors

Different 3CL protease inhibitors such as Paxlovid, Tollovid, and
ivermectin have differing levels of clinical activity. First, Pfizer
recently confirmed a 88-89% hospitalization or death reduction in its
phase 2/3 trial for at-risk patients and a 70% benefit for those at
normal risk, as well as confirmed activity against Omicron.

Ivermectin, on the other hand, was suggested to have a mortality
benefit of 56% in a meta-analysis of dozens of clinical trials using
the drug. However, the authors later removed various clinical trials
from the analysis based on risk of bias or fraud. According to Andrew
Hill,

    “When we take out the trials at risk of bias or fraud, we don’t
see any effects of ivermectin on survival and don’t see any effects on
clinical recovery”

An article discussing Hill’s meta analysis concluded:

    “He estimates that of the 18 randomised control trials about a
third are either fake or not conducted as described. ‘There’s not a
single randomised control trial which reliably says ivermectin saves
lives,’ says Sheldrick. A key conclusion for him is that ‘trust is
toxic in research’ and that starting from a position of trust ‘is one
of the biggest things that needs to change’.

    [...]

    ‘The thing that really shocked me and my co-authors is how much of
it is deliberate fraud,’ says Sheldrick. ‘Things like the same 11
patients copied and pasted, over and over.’ In another example,
hundreds of patients were supposedly recruited using complicated
protocols in incredibly short time scales with a team of three.”

There is a lack of any one high-quality trial that shows ivermectin
works in treating COVID-19, and the studies that suggest robust
benefit have clear evidence of fraud. This doesn’t mean that
ivermectin has no benefit that will ever be proven but it makes sense
given ivermectin’s properties why the benefit has not been observed;
when it comes to blocking the 3CL protease, Ivermectin pales in
comparison to Paxlovid and Tollovid.

Ivermectin debacle exposes flaws in meta-analysis methodology

Tollovid on the other hand is a newly developed all-natural
nutraceutical that blocks the 3CL protease. There’s not a ton of data
available on it besides the fact that it has been safely given to over
5000 people and that the company producing it is ramping up their
manufacturing capacity due to demand for the product.

When looking for clinical evidence, the nutraceutical has a cousin in
a phase 2 clinical trial—a drug, called Tollovir, being developed by
Todos Medical that has the same active pharmaceutical ingredient (API)
extracted from natural sources. The phase 1/2 exploratory,
observational study in hospitalized patients (as opposed to Pfizer’s
study that tested people with symptoms, not those already
hospitalized) showed a 100% mortality benefit as well as reductions in
inflammatory biomarkers and shortened hospital stays with the treated
group versus untreated.

Tollovir Phase 1/2 Data

There isn’t a huge number of patients tested in the clinical trial,
but hospitalized patients are much more difficult to treat than
outpatients and the data looks excellent with nobody taking Tollovir
dying. This bodes well for consumers looking to boost their immune
function with the nutraceutical, Tollovid, and these initial results
look much better than anything ivermectin had to offer.

The question most are facing is: If all the drugs block the 3CL
protease, why would Paxlovid and Tollovid perform so much better than
ivermectin? As mentioned before, it comes down to how well the 3CL
protease is blocked.

A short answer is that ivermectin, while blocking the 3CL protease
effectively in vitro (in a petri dish), needs to be present in the
body at absurd levels to block the virus. Below is a table which can
be used as a rough, descriptive guide of a range of potencies and the
probability of whether a compound of a given potency has a reasonable
chance of being "strong" enough to be a useful drug. Values are
approximate:



Comparative IC50 Values for 3CL Protease Inhibitors (adapted)

The key thing here is that these rule-of-thumb charts assume some sort
of drug toxicity. That’s why the “potential utility as a drug”
assumptions rule out drugs like ivermectin with such a poor IC50 as
impossible to make into a COVID-19 drug via 3CL protease inhibition.
As seen in the clinic and as noted by the New England Journal of
Medicine, many patients experience toxicity and significant side
effects when trying to take enough ivermectin to block COVID-19
replication.

In vitro 85% inhibition of 3CL pro may sound amazing to those who
don’t study drug development, but it isn’t. This is because, to block
the enzyme’s activity by 85%, a concentration of 50 µM ivermectin is
required. This is an extremely high concentration for a typical drug.

At the approved ivermectin dose, 12 mg for the typical 60kg human, the
maximum plasma concentration (cmax) of ivermectin is 47 ng/mL. When
compared to the IC50 of ivermectin (21.5 µM, or 18,815 ng/mL) the cmax
1/400th of what would be required to block the enzyme. There is
nowhere near enough ivermectin in a normal dose to block SARS-CoV-2
viral replication.

With poison control centers reporting 2 mg/kg doses being toxic
(typically that’s 120mg in tablet form), any attempt to truly make
ivermectin block the 3CL protease would likely result in a trip to the
emergency room. Tollovid and Paxlovid, on the other hand, appear to be
doing their job at biologically tolerated levels with fantastic
clinical trial data. One might ask the question of whether
Tollovid/Tollovir can truly reach reasonable blood levels, but the
answer is that it has a much higher dose and the natural product is so
well tolerated that this plasma concentration can be achieved. Pfizer
also reported low bioavailability of its other screened compounds
before selecting Paxlovid as a preclinical candidate, so it's possible
Tollovid has better solubility/bioavailability too.

3CL Protease Inhibitor Chart

Treatment
	

Ivermectin
	

Paxlovid
	

Tollovid

Oral Dose
	

12mg/day

[source]
	

300mg +100mg ritonavir

(2x/day)

[source]
	

900mg/day

[source]

IC50
	

21.5µM

[source]
	

6nM-18nM

[source 1, source 2, source 3]
	

1.2µM

Binding Affinity
	

−32 kJ/mol

[source]
	

−102 kJ/mol

[source]
	

Cmax (ng/ml)
	

23.5-50

[source]
	

~3,000

(EC90 = 292ng/ml)

[source]
	

tmax (h)
	

3.4-10.3

[source]
	

~1.5
	

t1/2 (elimination, h)
	

11.1-12.6

[source]
	 	

Dose Limiting Toxicity Observed
	

Yes
	

Suspected
	

No

Natural Product
	

No
	

No
	

Yes


Time to Stock up on Tollovid

The ivermectin and anti-big pharma crowds need to look into stocking
up on Tollovid as an alternative to COVID-19 treatment as a
replacement for ivermectin. Alternatively, for those who are convinced
that ivermectin still works, Tollovid could be used as a backup in
case it doesn’t do enough. After all, Tollovir was tested in the
hospitalized setting successfully. Further, consumers who oppose drugs
in general can buy Tollovid knowing it comes from a plant. There’s
really no downside to keeping an open mind about these things,
especially when visiting with at-risk family and friends during the
holiday season. Nobody wants to be the one that got their beloved
friend or family member sick and that person gets hospitalized or dies
from COVID, but only a few options like Tollovid offer immune support.
And there comes some peace of mind knowing Pfizer isn’t trying to rip
everyone off by selling “Pfizermectin,” since Ivermectin can’t do what
Paxlovid does. Regardless of vaccination status, everyone has the
opportunity to protect their friends and family this holiday season.