birth defects, cancer, Clinical trials, COVID-19, Covid-19 pill, Emergency Use Authorization, Emory, fetal death, Merck, Molnupiravir, MSD, mutagenicity, mutations, NHC, Pfizer, pharmaceuticals, rNHC, SARS-CoV-2, US FDA
“FDA Approves Merck COVID-19 Pill”, December 23, 2021 12:20 PM “A day after approving Pfizer’s COVID-19 pill, the U.S. Food and Drug Administration has granted emergency use authority to a similar pill produced by Merck.” https://www.voanews.com/a/fda-approves-merck-covid-19-pill/6366966.html. Merck is called MSD in some countries.
We question the safety of both the Pfizer and Merck pill. So, criticizing the Merck pill isn’t condoning the Pfizer one. And, we certainly don’t condone the mRNA vaccines, either. It simply means we haven’t finished a post on the Pfizer pill yet. Emergency Use means they can’t be sued – beware. It’s been speculated that Molnupiravir could created problematic Covid-19 mutants, along with cancer, birth defects, etc.
Molnupiravir was first developed by Emory, which probably stands to profit from this drug. So, researchers from Emory having written the article entitled “Cancer And Birth Defects: Potential Risks Of Molnupiravir” makes the article all the more compelling. The conclusion is simply common sense, however. From Wikipedia we learn that Monupiravir was original developed for the flu, which means that it’s not specific for Covid-19. If it is non-specific, and related to RNA, it’s easy to deduce that it may cause mutations leading to death or disability of fetuses, as well as the beginnings of cancer. Wikipedia says that “Molnupiravir inhibits viral reproduction by promoting widespread mutations in the replication of viral RNA by RNA-directed RNA polymerase”. https://en.wikipedia.org/wiki/Molnupiravir “RNA polymerase is essential to life, and is found in all living organisms and many viruses…”https://en.wikipedia.org/wiki/RNA_polymerase While there are several types, this should raise the questions examined in the article below. Based on common sense, we found it by typing Monupiravir and cancer. The article “Cancer And Birth Defects: Potential Risks Of Molnupiravir” is Open Access so can be read for free.
The Merck of Monupiravir is US Merck, which is called MSD outside of the US and Canada: https://en.wikipedia.org/wiki/Merck_%26_Co
Note the Clinical Trials exclusions: https://www.clinicaltrials.gov/ct2/show/NCT04575597?term=molnupiravir&draw=2&rank=2
“Cancer And Birth Defects: Potential Risks Of Molnupiravir? By Shuntai Zhou, Collin S Hill, Sanjay Sarkar, Longping V Tse, Blaide M D Woodburn, Raymond F Schinazi, Timothy P Sheahan, Ralph S Baric, Mark T Heise, Ronald Swanstrom, β-D-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells, The Journal of Infectious Diseases, Volume 224, Issue 3, 1 August 2021, Pages 415–419, November 15, 2021
Excerpted from the Abstract:
“Mutagenic ribonucleosides can act as broad-based antiviral agents. They are metabolized to the active ribonucleoside triphosphate form and concentrate in genomes of RNA viruses during viral replication. β-D-N4-hydroxycytidine (NHC, initial metabolite of molnupiravir)… also displays host mutational activity in an animal cell culture assay, consistent with RNA and DNA precursors sharing a common intermediate of a ribonucleoside diphosphate. These results indicate highly active mutagenic ribonucleosides may hold risk for the host”.
molnupiravir, mutagenicity, NHC, SARS-CoV-2
Topic: cell culture techniques antiviral agents dna mammals mutagenesis ribonucleosides rna sars-cov-2
Excerpts from pp. 417 and 419:
“Cancer therapies often rely on genotoxic agents that disproportionately impact the dividing cells in the tumor, although such treatments can contribute to subsequent tumors . SARS-CoV2 infection results in an age-related acute respiratory disease spectrum that can be life-threatening, especially in the elderly and individuals with select underlying comorbidies . rNHC has the potential to have therapeutic benefit in this setting. However, 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. This risk can be inferred based on the common intermediate of the ribonucleoside diphosphate shared in the synthesis of both ribonucleoside triphosphates and 2′-deoxyribonucleoside tri-phosphates. The concern would be 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. To test this inference, we used an HPRT gene knockout assay to assess mutagenesis of host DNA and readily demonstrated this activity for rNHC, presumably through a dNHC metabolite. We take this as evidence that in exposing the viral population to mutagenesis in its RNA form, the host is likely to be exposed in its DNA form. It seems unlikely that a short course of therapy would spare the host from this exposure because both RNA precursors that affect the virus and DNA precursors that would affect the host pass through the common ribonucleoside diphosphate intermediate. Many mutagens damage DNA in dividing or resting cells ; in contrast, the mutagenic activity of rNHC in vivo would be limited to dividing cells where the synthesis of DNA pre-cursors is ongoing, conditions analogous to the cell culture assay used here. Thus, an assessment of mutagenic potential to the host in vivo should focus on tissues rich in dividing cells and use sufficiently sensitive assays to detect single nucleotide substitutions. rNHC has powerful in vitro and in vivo activity against a large number of highly pathogenic emerging RNA viruses and represents a potentially important drug for use in the current and future pandemics. However, the risks for the host may not be zero and these risks need to be carefully evaluated in under-taking therapies that are by their nature designed to change the coding capacity of a virus’ genetic material. Evaluating the utility of this drug should be done in those likely to receive the greatest benefit with monitoring provided to assess potential long-term genotoxic side effects. In addition, developing strategies to limit the potential for genotoxicity should be an important goal.”
1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA, 2Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA, 3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA, 4Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA, 5Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, Georgia, USA, 6Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA, and 7 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA https://doi.org/10.1093/infdis/jiab247
The vaccine may also allow cancer to grow by a different mechanism – immune suppression (at least for a few months): https://miningawareness.wordpress.com/2021/10/02/is-there-a-covid-vaccine-cancer-connection-apparent-immuno-suppressive-impacts-of-vaccine/
While mRNA vaccines are unlikely to alter DNA, they can alter it, though this certainly isn’t the only problem with them: https://miningawareness.wordpress.com/2021/08/09/reverse-transcribed-sars-cov-2-rna-can-integrate-into-the-genome-of-cultured-human-cells/
A letter to the BMJ (formerly named British Medical Journal):
“Letters Covid-19: Molnupiravir effects
Buyer beware: molnupiravir may damage DNA
BMJ 2021; 375 doi: https://doi.org/10.1136/bmj.n2663 (Published 04 November 2021) Cite this as: BMJ 2021;375:n2663
by Johan M van Schalkwyk, perioperative physician
Although the Ingelfinger rule seems to have dissolved into dust with the coming of covid-19,1 I was a little disappointed that your journal seems to have mirrored Merck’s press release about molnupiravir without substantial critical comment.2
Molnupiravir clearly induces intense mutagenesis in SARS-CoV-2,3 and this accounts for its efficacy. But β-d-N4-hydroxycytidine, the active metabolite of molnupiravir, is not only cytotoxic but also mutagenic in mammalian cells.4 The drug may damage DNA.
There is a certain irony that vaccine shy people who have believed the untruth that vaccines against SARS-CoV-2 alter DNA seem poised to reach for a perceived “alternative” that may actually alter their DNA adversely. This worry is supported by the rise in Merck’s share price and Moderna’s corresponding drop, as reported by Reuters.5
Footnotes to BMJ letter
Competing interests: None declared.
This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.
* Badrinath P, Gupta A. Have we abandoned the Inglefinger rule in the COVID era? [electronic response to Wise J. Data transparency: “Nothing has changed since Tamiflu”]. BMJ 2020. https://www.bmj.com/content/369/bmj.m2279/rr-1.
* Mahase E. Covid-19: Molnupiravir reduces risk of hospital admission or death by 50% in patients at risk, MSD reports. BMJ2021;375:n2422. doi:10.1136/bmj.n2422 pmid:34607801FREE Full TextGoogle Scholar
* Kabinger F, Stiller C, Schmitzová J, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol2021;28:740-6. . doi:10.1038/s41594-021-00651-0 pmid:34381216CrossRefPubMedGoogle Scholar
* Zhou S, Hill CS, Sarkar S, et al. β-d-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells. J Infect Dis2021;224:415-9. . doi:10.1093/infdis/jiab247 pmid:33961695CrossRefPubMedGoogle Scholar
* Krauskopf L, Maddipatla M. Merck COVID-19 pill success slams Moderna shares, shakes up healthcare sector. https://www.reuters.com/business/healthcare-pharmaceuticals/merck-covid-19-pill-success-slams-moderna-shares-shakes-up-healthcare-sector-2021-10-01/“https://www.bmj.com/content/375/bmj.n2663
Another article, “Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis” states: “Molnupiravir is an orally available antiviral drug candidate currently in phase III trials for the treatment of patients with COVID-19. Molnupiravir increases the frequency of viral RNA mutations and impairs SARS-CoV-2 replication in animal models and in humans. Here, we establish the molecular mechanisms underlying molnupiravir-induced RNA mutagenesis by the viral RNA-dependent RNA polymerase (RdRp). Biochemical assays show that the RdRp uses the active form of molnupiravir, β-D-N4-hydroxycytidine (NHC) triphosphate, as a substrate instead of cytidine triphosphate or uridine triphosphate….
Beside the high antiviral potency of NHC, potential risks have to be considered. Host RNA polymerases may use MTP as substrate, and indeed the mitochondrial DNA-dependent RNA polymerase can use EIDD-1931 and incorporate NHC monophosphate into RNA in vitro52. In addition, possible mutagenic effects of NHC were recently described in mammalian cells53. Therefore, it will be important to characterize the effects of molnupiravir and NHC on cellular polymerase function in future studies.” Kabinger, F., Stiller, C., Schmitzová, J. et al. “Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis”. Nat Struct Mol Biol 28, 740–746 (2021). https://doi.org/10.1038/s41594-021-00651-0 Most, or all, of the above authors are affiliated with the Max Planck Institute.
Here’s one example of Merck working with the Max Planck Institute:
“A team comprising investigators from the Max Planck Institute of Biochemistry, the University of Dundee, GlaxoSmithKline and MSD, known as Merck & Co., Inc., in the United States and Canada…” See: “Identifying Another Piece in the Parkinson’s Disease Pathology Puzzle”, January 28, 2016: https://www.biochem.mpg.de/5250695/20160128_Steger_Mann
Max Planck is connected to the Pfizer-BioNTech-Comirnaty vaccine through the BioNTech investors, the Strüngmann twins’ Ernst Strüngmann Institute: https://en.wikipedia.org/wiki/Ernst_Strüngmann_Institute There’s also this weird, indirect, connection: Tobias Bonhoeffer of the Max Planck Institute served on the Wellcome Trust Board until August 2021 or later: https://miningawareness.wordpress.com/2021/11/30/omicron-points-to-minions-of-fauci-us-cdc-gates-wellcome-british-intel-rockefeller-in-south-africa/ See too: https://miningawareness.wordpress.com/2021/10/09/is-nazi-war-criminal-friedrich-wilhelm-kruger-the-grandfather-of-the-biontech-vaccine-pfizer-multi-billionaire-strungmann-twins-why-is-no-one-asking-investigating/
“In its triphosphate form, molnupirivar is a substrate for the mitochondrial RNA polymerase, which can also incorporate MTP as a U or C analog. Reassuringly, the same study noted that mitochondrial function over 14 days was not significantly inhibited 15, and Sheahan et al. did not observe mutagenesis of host mRNA8. However, it has been suggested that exposure to molnupiravir can be mutagenic to host DNA during host DNA replication 16. Therefore, the potential off-target effects will require further investigation.” Malone, B., Campbell, E.A. “Molnupiravir: coding for catastrophe”. Nat Struct Mol Biol 28, 706–708 (2021). The authors are affiliated with the Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY, USA. https://doi.org/10.1038/s41594-021-00657-8
Formal Inclusion and Exclusion Criteria for the Molnupiravir Clinical Trials:
“Efficacy and Safety of Molnupiravir (MK-4482) in Non-Hospitalized Adult Participants With COVID-19 (MK-4482-002)
Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
* Has documentation of laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with sample collection ≤5 days prior to the day of randomization. PCR is the preferred method; however with evolving approaches to laboratory confirmation of SARS-CoV-2 infection, other molecular or antigen tests that detect viral ribonucleic acid (RNA) or protein are allowed if authorized for use in the country. Serological tests that detect host antibodies generated in response to recent or prior infection are not allowed.
* Had initial onset of signs/symptoms attributable to COVID-19 for ≤5 days prior to the day of randomization and at least 1 of the following sign/symptom attributable to COVID-19 on the day of randomization.
* Has mild or moderate COVID-19.
* Has at least 1 characteristic or underlying medical condition associated with an increased risk of severe illness from COVID-19.
* Males agree to the following during the intervention period and for at least 4 days after the last dose of study intervention: Either abstain from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; or must agree to use contraception.
* Females are not pregnant or breastfeeding, and at least one of the following conditions applies: Is not a woman of child bearing potential (WOCBP); or is a WOCBP and using a contraceptive method that is highly effective (a low user dependency method OR a user dependent method in combination with barrier method), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) for at least 4 days after the last dose of study intervention; a WOCBP must have a negative highly sensitive pregnancy test (urine or serum test is required) within 24 hours before the first dose of study intervention.
* Is currently hospitalized or is expected to need hospitalization for COVID-19 within 48 hours of randomization.
* Is on dialysis or has reduced estimated glomerular filtration rate (eGFR) 50 copies/mL (regardless of CD4 count) or an AIDS-defining illness in the past 6 months, participants with HIV may only be enrolled if on a stable antiretroviral therapy regimen; a neutrophilic granulocyte absolute count 3X upper limit of normal at screening.
* Has a platelet count <100,000/μL or received a platelet transfusion in the 5 days prior to randomization.
* Is taking or is anticipated to require any prohibited therapies.
* Is unwilling to abstain from participating in another interventional clinical study through Day 29 with an investigational compound or device, including those for COVID-19 therapeutics.
* Has hypersensitivity or other contraindication to any of the components of the study interventions as determined by the investigator.
* Has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant or that could prevent, limit, or confound the protocol-specified assessments including but not limited to: participants who are not expected to survive longer than 48 hours after randomization, or participants with a recent history of mechanical ventilation, or participants with conditions that could limit gastrointestinal absorption of capsule contents.”
The above version was saved ca end November/1 December 2021 from:
An archived version: http://web.archive.org/web/20211118033548/https://clinicaltrials.gov/ct2/show/NCT04575584?term=Molnupiravir&draw=2&rank=1
Link to Procedure for clinical trials document -https://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
We guess that the hamsters, in the following study, were killed for the histopathological examination of their lungs and thus didn’t live long enough to test for cancer:
Rana Abdelnabi, Caroline S Foo, Steven De Jonghe, Piet Maes, Birgit Weynand, Johan Neyts, “Molnupiravir Inhibits Replication of the Emerging SARS-CoV-2 Variants of Concern in a Hamster Infection Model“, The Journal of Infectious Diseases, Volume 224, Issue 5, 1 September 2021, Pages 749–753, ….
Financial support. This work was supported by the Katholieke Universiteit Leuven/Universitair Ziekenhuis Leuven COVID-19 fund; the Fonds Wetenschappelijk Onderzoek COVID-19 call (grant number G0G4820N); the European Union Horizon 2020 Research and Innovation Program SCORE Project (grant number 101003627); and the Bill and Melinda Gates Foundation (grant number INV-00636). https://doi.org/10.1093/infdis/jiab361
Disclaimer: This post doesn’t constitute medical advice. Nor does any other post. Only you can decide what’s right for you. Hopefully you are lucky enough to have found a trustworthy intelligent doctor to help you make decisions. Remember, you are unique and only you are responsible for your health.