Thread by @eh_den

#MERCKyBusiness - IS THE CURE WORSE THAN THE DISEASE?

(thread)

Why today's announcement that #molnupiravir cuts risk of #COVID19 hospitalization and death in half IS NOT GOOD NEWS, but a demonstration of #BigPharma murky business, or in the case of #Merck, #MerckyBusiness.

If you believe, for example, @DrEricDing, a senior fellow of the Federation of American Scientists, it is time to open our Champagne bottles. An antiviral drug can cut hospitalization and death in half in a randomized trial. Finally!

#MERCKyBusiness

https://twitter.com/DrEricDing/status/1443880627837734946

It is such great news that the U.S. government already made an advance purchase of 1.7 million doses of the drug at a cost of $1.2 billion.

Great news, we are being told.

LET US LOOK AT THE FACTS.

#MERCKyBusiness

https://twitter.com/DrEricDing/status/1443882061819957249

#molnupiravir (AKA MK-4482/EIDD-2801) is not really a new drug, in the sense that it is a prodrug of N4-hydroxycytidine (NHC), which means it was designed to improve the bioavailability of how it absorb, distributed, metabolized, and excreted.

#MERCKyBusiness

"N4-hydroxycytidine was first described in the literature in 1980 as a potent mutagen of bacteria and phage".

N4-Hydroxycytidine, N(4)-Hydroxycytidine,
Beta-D-N4-hydroxycytidine, and EIDD-1931 are all synonyms.

#MERCKyBusiness
pubchem.ncbi.nlm.nih.gov/compound/N_4_-…

We now know that Molnupiravir works by promoting SARS-CoV-2 mutagenesis, which means that this drug promotes the genetic information of an SARS_CoV_2 to change by the production of a mutation, and by doing so is supposed to disable it.

#MERCKyBusiness

ncbi.nlm.nih.gov/pmc/articles/P…

But what also do we know about the compound which this product is based upon?

Well, quite a number of alarming things.

#MERCKyBusiness

N4-Hydroxycytidine is TOXIC:

N4-Hydroxycytidine (NHC) "exhibits measurable levels of cytotoxicity, with 50% cytotoxic concentration values … in cell lines"

#MERCKyBusiness
pubmed.ncbi.nlm.nih.gov/31767721/

"β-D-N4-hydroxycytidine (rNHC) and its orally bioavailable prodrug, molnupiravir, does inhibits SARS-CoV-2 in vitro BUT IS MUTAGENIC IN MAMALIAN CELLS…resulting in DNA mutation of dividing mammalian cells."

#MERCKyBusiness
pesquisa.bvsalud.org/global-literat…

And also, based on whistleblower charges of cronyism behind the drug, that "some earlier studies suggested EIDD-2801 (#molnupiravir) COULD CAUSE HARMFUL GENETIC MUTATIONS".

#MERCKyBusiness

pulitzercenter.org/stories/emails…

So quick recap - a drug that can cause DNA damage, AND which is a bioavailable version what exhibits measurable levels of 50% toxicity to cells is considered to be good news that #Merck is asking for emergency authorization FOR THE WORLD?

#MERCKyBusiness

https://twitter.com/DrEricDing/status/1443884068219785223

How by looking at 775 adults who had health problems with mild-to-moderate COVID-19, and with a period of trial of 30 days which resulted in 6.8% reduction in hospitalization or death (14.1% vs 7.3%) Merck wants such authorization?

#MERCKyBusiness

https://twitter.com/DrEricDing/status/1443883346170351617

How come @DrEricDing, an Epidemiologist & health economist, Senior Fellow @FAScientists, w/former 16 years @Harvard, a @JohnsHopkins alum is reporting on this drug as if we found the fountain of life?

Doesn't he care about the dangers of this drug?

#MERCKyBusiness

I want to remind everyone that #Merck already in the past has suppressed the clinical trial evidence about the dangers of one product, #VIOXX, that led to the death of many people.

#MERCKyBusiness

hsionline.com/2005/08/25/mer…

The fact a medical product has one desirable effect does not allow us to ignore the other impact of that product on the body. Good example is radiation - it can kill cancer cells, but also is deadly to your body.

#MERCKyBusiness

ncbi.nlm.nih.gov/pmc/articles/P…

A drug that carries zero liability under emergency authorization = goldmine for Merck.

This drug might lead to DNA damage and cytotoxicity yet "scientists", media & regulators don't care. We are in a post-modernism era: science is dead, long live scientism!

#MERCKyBusiness

Take a close look at who is hailing this drug (media, "scientists", "journalists"), and realize that THEY DO NOT CARE ABOUT YOUR HEALTH, THEY DO NOT CARE ABOUT YOU.

Notice how these are the same people who have been "selling" you facemasks, lockdowns & vaccines.

#MERCKyBusiness

Where else you can find me, in case twitter will decide to suspend me:

Telegram: T.ME/EH_DEN
GAB: gab.com/ehden
Substack: ehden.substack.com
Blog: SenseOfAwareness.com

Deep love,
Ehden

#MERCKyBusiness

"similar experimental drugs in this class had been shown to cause reproductive toxicity in animals, and OFFSPRING FROM TREATED ANIMALS HAD BEEN BORN WITHOUT TEETH AND WITHOUT PARTS OF THEIR SKULLS"

PLEASE READ HERE:
pulitzercenter.org/stories/emails…

Thank you @TigerBosco!
#MERCKyBusiness

Read the article (Pulitzer Center), and ask yourself - how can a bioavailable version of what has such bad safety history suddenly being "sold" as a miracle drug?

Why is the whistleblower testimony (safety, cronyism) suddenly not relevant?
#MERCKyBusiness
pulitzercenter.org/stories/emails…

TIP!
IF you wish to translate the text of this thread to other languages, please go to DeepL.com, and use it to translate the text of the thread, which is located at:
t.me/eh_den/144. THANK YOU!

To the claims that genotoxicity was disproven …

Wait for it 😉

#MERCKyBusiness

https://twitter.com/eh_den/status/1444246027503026177

#MERCKyBusiness - disproved² thread
1/x
In this part I will address the claims that Merck has already addressed the genotoxicity concerns, because obviously, the minute you make a claim against #BigPharma you are assured to get "fact checkers" demanding to cancel you.
👇👇👇

2/x
The whole saga started with a research I've mentioned its results above, entitled "β-D-N 4-hydroxycytidine (NHC) inhibits SARS-CoV-2 through lethal mutagenesis but is also mutagenic to mammalian cells.".

#MERCKyBusiness
doi.org/10.1093/infdis…

3/x
Zhou et al claimed that "rNHC (or molnupiravir) Is Mutagenic in a Mammalian Cell Assay" and that "there are risks for the host in that the same mutagenic activity that impacts viral replication has the potential for incorporation and mutagenesis of host DNA."
#MERCKyBusiness

4/x
They also stated that "mutations in host DNA COULD CONTRIBUTE TO THE DEVELOPMENT OF CANCER, , OR CAUSE BIRTH DEFECTS EITHER IN A DEVELOPING FETUS OR THROUGH INCORPORATION INTO SPERM PRECURSOR CELLS".

#MERCKyBusiness

5/x
What was even more worrying is that a short therapy would not prevent the host from exposure "because both RNA precursors that affect the virus and DNA precursors that would affect the host pass through the common ribonucleoside diphosphate intermediate."

#MERCKyBusiness

6/x
This started disproved² saga. Let us look at "Developing a direct acting, orally available antiviral agent in a pandemic: the evolution of molnupiravir as a potential treatment for COVID-19" ("Current Opinion in Virology", Oct 2021)

#MERCKyBusiness
doi.org/10.1016/j.covi…

7/x
This article (AFAIU) is an editorial by the researchers who developed/worked on molnupiravir, telling the story of their work. It is useful to start with it, even though it is retrospective, as it gives good context.

#MERCKyBusiness

8/x
First, the predecessor of molnupiravir (EIDD-2801) was EIDD-1931, which has the capacity to cross the blood–brain barrier, as it was developed to treat VEEV (Venezuelan equine encephalitis virus).
AFAIU, It means molnupiravir can cross the brain barrier.
#MERCKyBusiness

9/x
"EIDD-1931 was orally bioavailable, widely distributed to organs including the lungs and appeared to be actively transported into the CNS where it was quickly anabolized to the active 5'-triphosphate"

MERCKyBusiness

10/x
EIDD-1931 inhibits replication of multiple RNA viruses of influenza, various coronaviruses, respiratory syncytial virus (RSV), VEEV), Chikungunya and Ebola (in animal models). HOWEVER, it metabolized quickly in non-human primates.

#MERCKyBusiness

11/x
EIDD-2801 (molnupiravir) is a prodrug of EIDD-1931, which "facilitated movement across the gut lining and EFFICIENTLY DELIVERED EIDD-1931 to the circulating volume of all species tested, including non-human primates"

#MERCKyBusiness

12/x
*BREAK*
Notice - molnupiravir is in fact a drug that was designed to deliver EIDD-1931 in an efficient way.

Now comes the interested section - the genotoxicity tests:

#MERCKyBusiness

13/x
"Because of a positive Ames test, the potential for genotoxicity has been thoroughly evaluated for molnupiravir both in vitro and in vivo."

Ames test use a bacteria to test if a given chemical can cause mutations in the DNA of an organism being tested.

#MERCKyBusiness

14/x
(JUST A REMINDR)
In vitro ("in the glass" in Latin) - test performed on living tissue.
In vivo ("in the living" in Latin) - test on an organism, such as a rodent, or human beings.

#MERCKyBusiness

15/x
According to the article, they performed two
in vivo rodent mutagenicity assays: the Pig-a
mutagenicity assay, and the Big Blue1 (cII Locus) transgenic rodent assay.

MERCKyBusiness.

16/x
According to the authors, "in both assays…the impact of molnupiravir treatment on mutation rates was not differentiable from mutation rates observed in untreated historical control animals."

#MERCKyBusiness

17/x
Even better, "molnupiravir was negative for induction of chromosomal damage in in vitro micronucleus (with and without metabolic activation) and in vivo rat micronucleus assays."
#MERCKyBusiness

18/x
Which led the authors to conclude "based on the totality of genotoxicity data molnupiravir is not considered to pose an increased risk of genotoxicity in clinical use."

Problem solved, right?

Not so quick.
Let's dig in a little bit.

#MERCKyBusiness

19/x
IN OUR UPCOMING SECTION, I will look at a more detailed of the actual tests, ask if it was really disproved, and … well, perhaps even reach the disproved² phase.
#MERCKyBusiness
As always, don't forget to check the SHOW REPLIES because there is more to come, soon!
👇👇👇👇

#MERCKyBusiness - disproved² thread - PART 2
20/x

Digging deeper into the saga.

To learn more about what was actually done, let's head to "Letter to the Editor in Response to Zhou et al" ("The Journal of Infectious Diseases", Troth et al., Jul 2021)
doi.org/10.1093/infdis…

21/x
This letter describes the actual disprove activities that were done as a response to the letter I've mentioned above.

#MERCKyBusiness

https://twitter.com/eh_den/status/1444453940511248388

22/x
As mentioned above, the authors state that they "have conducted a more comprehensive series of in vitro and in vivo genotoxicity studies, which, based on the totality of the data, demonstrate a low risk for genotoxicity with MOV in clinical use."

#MERCKyBusiness

23/x
The authors confess/agree that rNHC (or molnupiravir) is mutagenic in vitro, but claim that this is not relevance in vivo.

#MERCKyBusiness

24/x
And, as was mentioned above, they conducted 2 experiments in 2 distinct rodent mutagenicity in vivo models. (Pig-a mutagenicity assay and Big Blue [cII locus] transgenic rodent assay.

#MERCKyBusiness

25/x
According to the authors, "The impact of MOV (molnupiravir) treatment on mutation rates was not differentiable from mutation rates observed in untreated historical control animals."

Let's zoom in.

#MERCKyBusiness

26/x
The two experiments referenced have not been published nor peer reviewed, and were conducted on rats.

Pig-a was done by Charles River Laboratories
criver.com/research-phase…

And Big Blue was done by BioReliance:
bioreliance.com/us

#MERCKyBusiness

27/x

The scientists used Pig-a assay. Let's learn more about this method, from "The Pig-a Gene Mutation Assay in Mice and Human Cells: A Review" (Olsen et al, 2017).

#MERCKyBusiness
doi.org/10.1111/bcpt.1…

28/x
Even though the work summarized in this paper largely avoids rat-based studies, it does raise important points.
Pig-a uses only minute blood volumes, so it is a fast test (rather than killing the rat and doing an analysis of the organs.

#MERCKyBusiness

29/x
HOWEVER, this test "depend on the fact that the compound, or metabolite, of interest is present in the bone marrow in levels reflecting those of target tissues…moreover, understanding the timing of mutation induction…is vital for correct detection"

#MERCKyBusiness

30/x
Another disadvantage to the pig-a method of mutagenic investigation is that unlike alkaline comet assay it does not detect pre-mutagenic DNA lesions.
(Chromosomal aberrations in the form of broken fragments of chromosomes can lead to pre-mutagenic lesions).

#MERCKyBusiness

31/x
The researchers did look at chromosomal
damage in micronucleus assays

"The advantages and disadvantages of the cytokinesis-blockmicronucleus method" describes the limitation of this investigation:

doi.org/10.1016/S0165-…

#MERCKyBusiness

32/x
"This method does not distinguish between dividing and non-dividing cells … it is unable to provide a measure of more subtle changes, such as balanced translocations."

#MERCKyBusiness

33/x

"IT IS, therefore, WRONG TO ASSUME THAT A MICRONUCLEUS ASSAY CAN REPLACE THE DETAILED ANALYSIS OF CHROMOSOME DAMAGE AFFORDED BY METAPHASE ANALYSIS"

#MERCKyBusiness

34/x
More limitations: "Perhaps the major concern with the use of (this method) is that its use may prevent the detection of chemicals that are also inhibitors of cytokinesis or microfilament polymerisation."

#MERCKyBusiness

35/x
"The prospect of using long-term cultured human lymphocytes in in-vitro testing is likely to be more relevant in predicting human risk than using non-human cell".

#MERCKyBusiness

36/x
Which brings us back to molnupiravir and the Big Blue [cII locus] transgenic rodent assay.

Remember I've mentioned pig-a does not identify pre-mutagenic DNA lesions? The other test that was done was a transgenic rodent mutation assay.

#MERCKyBusiness

37/x
Limitation of the method:

"The transgenic mice models respond to mutagens in a similar manner to endogenous genes and are suitable for the detection of point mutations, insertions and small deletions but not large deletions"

#MERCKyBusiness
efsa.onlinelibrary.wiley.com/doi/pdf/10.290…

38/x
Also, Transgenic Rodent (TGR) mutation assays does not seems to detect pre-mutagenic lesions - at least it is my understanding from the wording of this OECD document.

If I'm wrong, please correct me.

doi.org/10.1787/207457…

#MERCKyBusiness

39/x
I believe that the claims that genotoxicity has been disproved are weak, due to the limitations of the methods used, plus the lack of visibility to the details of the in vivo mutagenicity tests and the in vitro micronucleus chromosomal damage tests.

#MERCKyBusiness

40/x
#MERCKyBusiness - disproved² thread - END OF PART 2!

Stay tuned to PART 3, where I will look into more claims the molnupiravir researchers made to disprove the genotoxicity claims, and the response that came as a result …

#MERCKyBusiness

#MERCKyBusiness - IS THE CURE WORSE THAN THE DISEASE? disproved² thread - PART 3!
(41/)

In this segment I am going to continue and disprove the claims of disprove the researchers behind molnupiravir has made, or in other words - did the researchers proved it is safe?

First of all, a FAST recap:
42/x
After Zhou et al has suggested that molnupiravir is neurotoxic, Troth et al replied claiming the tests they conducted showed the product is not neurotoxic. They have done 2 in vivo tests, one using Pig-a.

#MERCKyBusiness

doi.org/10.1093/infdis…

43/x
A possible explanation why they decided on pig-a can be found in the pre-print ed. of "Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity against SARS-CoV-2".

#MERCKyBusiness
doi.org/10.1101/2020.1…

44/x
In it, we find out that "the dose-limiting toxicity in one Investigational New Drug-enabling study … was bone marrow toxicity and included reversible reductions in platelet counts" (this statement disappeared in the final edition).
doi.org/10.1128/AAC.02…

#MERCKyBusiness

45/x
Pig-a is supposed to be good in detecting bone-marrow related neurotoxicity.

However, I've already written in the past about the limitations of the Pig-a test:

https://twitter.com/eh_den/status/1444632808157286409

https://twitter.com/eh_den/status/1444632812800421891

#MERCKyBusiness

46/x
The molnupiravir Pig-a tested peripheral red blood cells, RBCs (according to Troth et al).

HOWEVER, measuring Pig-a gene mutation in RBCs seems to be less accurate than measuring gene mutations in reticulocytes (RET) (immune red blood cells).

#MERCKyBusiness

47/x
In a paper published on the topic, out of 24 chemicals, only 3 produced positive response in RBCs vs 13 in RET, and only 3 showed (after a week) Pig-a mutant frequency in RBC vs 12 in RET.

sciencedirect.com/science/articl…

#MERCKyBusiness

48/x
Examples to Pig-a limitations:
1) both tests were unable to identify many chemicals neurotoxicity, including AZT.
2) The RBCs results are time sensitive (better accuracy at week 4 vs week week 1)…

For how long did the Molnupiravir test run? we have NO IDEA!
#MERCKyBusiness

49/x
Now that we put that aside, let us look at the response of Troth et al to Zhou et al paper, where they claimed that Zhou et al's results were incorrect due to multiple reasons.

#MERCKyBusiness

50/x
Troth et al claims against Zhou et al paper:
1) Exposure was too long
2) Historical data was missing
3) cytotoxicity was not assessed at low dosage for 32 days
4) Zhou et al measured mutant colonies rather than mutant frequency.

#MerckyBusiness

51/x
SIDE NOTE: funny to see such claims in a letter that contains within it reference to two researches that are supposed to disprove safety concerns... but were privately conducted and did not disclose any information on practically anything.

#DualStandards?

#MERCKyBusiness

52/x
Zhou et al replied to Troth et al, claiming it should not be a question of whether molnupiravir is mutagenic or not, but how much.

#MERCKyBusiness
doi.org/10.1093/infdis…

53/x
In the following posts I will breakdown the reply of (and counter concerns raised by) Zhou et al:

Do the in-vivo assays focus on dividing cells, and what is the limit of detection of new mutations when dividing cells are assessed?

#MERCKyBusiness

54/x
Because mutagenesis is revealed over a long period in cancer rates and germline mutations, how can Troth et al scale these negative results to a human lifespan?

#MERCKyBusiness

55/x
They explain the 32 days exposure was because a 3-to-6-hour exposure is not enough time for molnupiravir to be taken into the cell then metabolized to become a DNA precursor, and such a short timeframe experiment is not suited for metabolic precursors.

#MERCKyBusiness

56/x
They defended not testing for cytotoxicity at low dosage for 32 days, and stated they "did not notice a difference in growth rate in the presence of 3 µM rNHC during the multiple rounds of cell passage".

#MERCKyBusiness

57/x
Because of the "multiple rounds of cell replication and drug incorporation", "it is difficult to establish a mutation rate", which is "is less relevant than the long term consequences of exposure to a mutagen during treatment."

#MERCKyBusiness

58/x
They closed with:
"It is hard to argue that (molnupiravir) a ribonucleoside precursor to both RNA and DNA goes into one but not the other… TREATMENT WITH MOLNUPIRAVIR WILL LEAD TO MUTATIONS IN HOST DNA IN DIVIDING CELLS".

#MERCKyBusiness

59/x
and that "using negative results to justify this risk as being unimportant is to create a blind spot for potential long-term harm", and that because of that molnupiravir must only be given to people with cofactor risks bigger than mutagenic risks.

#MERCKyBusiness

60/x
With this, I finalized the disproved² sub-thread.

Few more questions, before we end.

#MERCKyBusiness

61/x
Why would regulators rely on assurances provided by private labs which were paid by the manufacturer, using study information that is unavailable to the academic community (and public) to review and scrutinize?

#MERCKyBusiness

62/x
Why no one is raising questions whether or not the methods being used to provide these assurances (e.g. using pig-a assay) are fit-for-purpose and can truly measure with high accuracy the mutagenetic risks related to molnupiravir?

#MERCKyBusiness

63/x
The safety information provided for molnupiravir raises more questions than answers.

WHERE ARE THE JOURNALISTS? WHERE ARE THE RESEARCHERS? WHERE ARE THE REGULATORS?

#MERCKyBusiness

64/64
WE REACHED THE END of this thread which looked at molnupiravir safety.

AGAIN we see an attempt to push aside long-term concerns, AGAIN we see science being ignored, AGAIN we see how profit comes before our safety.

THIS IS IMMORAL. THIS IS WRONG. #RESIST!

#MERCKyBusiness

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