https://academic.oup.com/jid/article/224/3/415/6272009
Mutagenic ribonucleoside analogs must be metabolized through a 5′-diphosphate precursor, which for the normal ribonucleotides is the substrate for ribonucleotide reductase (RNR) in the biosynthetic pathway for the synthesis of 2′-deoxyribonucleotide DNA precursors [12]. As a DNA precursor, dNHC (2’-deoxyribose form of NHC) would have the potential to be a mutagen to host cell DNA. We examined this possibility using a genetic selection system that records loss of gene function. CHO-K1 cells are functionally haploid for the HPRT gene, which when expressed confers sensitivity to the toxic base analog 6-TG, with resistance to 6-TG being conferred by mutations that inactivate the HPRT gene/protein function. We used loss of HPRT gene function in CHO-K1 cells to test for DNA mutagenesis activity of rNHC, FAV, and RBV. To increase the sensitivity of detection of mutagenic activity, we exposed the cells to these analogs for 32 days before selecting for HPRT knockout with 6-TG. As a positive control we briefly exposed cells to UV light. In an initial experiment we found rNHC was mutagenic to the cells in a dose-dependent manner (up to 3 µM), presumably through conversion to dNHC (Figure 2A). In a second experiment we again tested rNHC up to 3 µM and in addition tested FAV and RBV at 10 µM. rNHC again conferred 6-TG resistance in a dose-dependent fashion, while RBV showed little to no activity and FAV at 10 μM exhibited a modest yet significant increase in the number of 6-TG–resistant colonies (Figure 2A). rNHC and FAV did not inhibit cell growth at the concentrations tested for mutagenicity, while RBV inhibited cell growth even at 3 µM as well as the 10 µM tested (Supplementary Figure 4). For this second experiment, we also tested 3 anti-human immunodeficiency virus-1 (HIV-1) nucleoside analogs as an additional control for mutagenic activity. Zidovudine (AZT), lamivudine (3TC), and tenofovir (TDF) showed no mutagenic activity when tested at 10 µM (Figure 2B), a concentration that did not inhibit cell growth (Supplementary Figure 4) even though this concentration was able to inhibit HIV-1 infectivity (with EC50s between 1 and 10 µM) in this cell type, demonstrating uptake and metabolism (Supplementary Figure 5). Thus, rNHC induced 6-TG resistance at concentrations that did not inhibit cellular growth, consistent with rNHC-diphosphate being a substrate both for the synthesis of rNHC-triphosphate for incorporation into RNA and for RNR on the pathway to synthesize dNHC-triphosphate for incorporation into DNA.
We next extracted RNA from individual colonies of cells, then amplified and sequenced most of the HPRT mRNA to document the presence of mutations in 6-TG–resistant colonies. A total of 42 colonies were sequenced and 32 (76%) of them had missense substitutions or frame shifts from deletions within the partial gene region sequenced (Figure 2B). In the 3 µM rNHC culture, 80% of the sequences contained different lesions, with 20% likely representing clones that expanded and resampled before selection. This analysis shows that the HPRT target is capable of recording many different mutations but also that in this format the assay is semiquantitative in that there is a possibility for 1 mutation to give rise to more than 1 resistant colony with the same mutation.
cop paste for a reason so everyone can read it
the retards are the ones who think this drug has the same mechanism of action as ivermectin…
come battle me retard… dare ya
ok, what do you want to know?
This is the key statement within the study..
Due to their mechanism of action,mutagenic ribonucleoside analogs could be metabolized by the host cell to the 2′-deoxyribonucleotide form by ribonucleotide reductase and then incorporated into DNA, leading to mutagenesis of the host
Zerohedge cited the same studies done a few months ago.
These people are fucking reckless playing with human lives and not considering long-term consequences and the need for extended studies.
Two Indian drugmakers to end trials of generic Merck pill for moderate COVID-19
BENGALURU, Oct 8 (Reuters) - Two Indian drugmakers have requested permission to end late-stage trials of their generic versions of Merck & Co's (MRK.N) promising experimental oral antiviral drug molnupiravir to treat moderate COVID-19, a week after Merck said its own trial had succeeded for mild-to-moderate patients.
Merck earlier this year suspended its own development of molnupiravir as a treatment for hospitalized COVID-19 patients since many of them have reached a phase of the disease that is too late for an antiviral drug to provide much help.
The Indian companies - Aurobindo Pharma Ltd (ARBN.NS) and MSN Laboratories - did not exclude hospitalized patients in designing their moderate COVID-19 trials, according to study documents, although it was not known if the trials ultimately included people in the hospital.
Merck spokesperson Melissa Moody said Merck and the Indian companies had defined “moderate” disease differently.
Merck's trials are based on U.S. Food and Drug Administration definitions, which for moderate COVID-19 describe blood oxygen levels as no lower than 93%. It defines blood oxygen levels for severe COVID-19 as 93% or lower.
The trials in India define moderate COVID-19 blood oxygen levels as 90% to 93%, according to the trial documents for the two companies.
Aurobindo and MSN are continuing to conduct studies of molnupiravir in patients with mild COVID-19 who have not been hospitalized, according to trial documents and the website of the Indian drug regulator's internal expert committee.
Merck and partner Ridgeback Biotherapeutics last week said molnupiravir had nearly halved the risk of hospitalization or death in at-risk non-hospitalized patients with mild-to-moderate COVID-19, results hailed by experts as potentially a major advance in fight against the illness.
The Indian drug regulator's committee also disclosed on its website that Aurobindo and MSN had presented interim clinical trial data for moderate COVID-19 patients and asked to end the trials.
A source with the Drug Controller General of India said the pill has not shown "significant efficacy" against moderate COVID-19, though it was having success against mild cases.
An Aurobindo spokesperson did not comment on the effectiveness of the drug in its trial. The spokesperson said the company had "faced challenges in patient recruitment at this juncture" for its trial in moderate COVID-19 patients, adding "we are evaluating the further course of action."
Aurobindo started the planned 100-patient trial of its generic version of the Merck pill against moderate COVID-19 in August, and is also running a trial that hopes to include 1,200 patients testing the pill against mild disease.
MSN did not respond to a request for comment.
INDIA TRIALS
Merck, whose shares closed down 1.6% at $80.63, has entered into voluntary licensing agreements with at least eight Indian drugmakers for molnupiravir, with an aim to turn the South Asian nation into a manufacturing hub for the drug to supply low- and middle-income nations. read more
Five of the eight Indian companies - Dr Reddy's Laboratories (REDY.NS), Cipla (CIPL.NS), Sun Pharma (SUN.NS), Torrent Pharmaceuticals (TORP.NS) and Emcure Pharmaceuticals - are conducting a joint trial for the antiviral drug only in mild COVID-19 patients in an outpatient setting.
The other licensed company, Hetero, in early July announced interim data from its own late-stage trial of generic molnupiravir in mild COVID-19 patients and submitted an application to regulators for its emergency use.
Hetero is separately conducting a study on moderate COVID-19 patients and has said those results will be presented at a future date.
https://www.reuters.com/business/healthcare-pharmaceuticals/aurobindo-pharma-stop-molnupiravir-trial-moderate-covid-19-patients-2021-10-08/
https://www.the-scientist.com/news-opinion/plenty-of-evidence-for-recombination-in-sars-cov-2-69156
Some researchers have pointed out that, if the virus were prevented from recombining, mutations might accumulate to the point that it becomes hampered or even unable to replicate and spread. That could mean that drugs that interfere with recombination specifically could help end the pandemic.
The pandemic will end easily.
It techinically already has.
A well tested inactivated vaccine might be the way to go. Make sure if spike is part of it, the dose won't get into blood and all tissues causing same array of issues.
mutationaly escape still a concern and all vaccine associated disease enhancments, etc still possible
I agree. I agree. Even with natural immunity, the virus will eventually evade, until of course… it can't… natural immunity is the best way to go….
With monoclonal antibodies, I was wondering if it would hinder natural immunity?
I need to see research and not just theory.
It inactivated vaccines could also pose dangers with reasoning i mentioned weeks ago, especially in elderly.
White House seeks $65B to prepare for future pandemics in 'Apollo'-like effort
https://endpts.com/white-house-seeks-65b-to-prepare-for-future-pandemics-in-apollo-like-effort/