MERCKyBusiness - IS THE CURE WORSE THAN THE DISEASE?

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! 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.
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.

"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.

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.

But what also do we know about the compound which this product is based upon?
Well, quite a number of alarming things. N4-Hydroxycytidine is TOXIC:
N4-Hydroxycytidine (NHC) "exhibits measurable levels of cytotoxicity, with 50% cytotoxic concentration values … in cell lines"
Also, "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."

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

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?

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? 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?

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. 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.

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!

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.

Yours
Ehden

https://twitter.com/eh_den/status/1443971976586989570
https://threadreaderapp.com/thread/1443971976586989570.html

#MERCKyBusiness - disproved² thread

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.

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.".

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."

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".

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."

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)

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.

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.

"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"

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.

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"

*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:

"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.

(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.

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.
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."

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."

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.

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

https://twitter.com/eh_den/status/1444453938007363587
https://threadreaderapp.com/thread/1443971976586989570?refresh=1633219718