Paxlovid use becomes dangerous, HCQ works

And NAC reduces inflammasome activation

Fate has an ironic side to it. Hours after publishing my last substack, the following paper was published online. Paxlovid goes from useless to dangerous as I suspected long ago, and rebound isn’t harmless from a molecular perspective.

Nirmatrelvir treatment blunts the development of antiviral adaptive immune responses in SARS-CoV-2 infected mice

Here, by using a mouse model of SARS-CoV-2 infection, we show that nirmatrelvir administration early after infection blunts the development of SARS-CoV-2-specific antibody and T cell responses. Accordingly, upon secondary challenge, nirmatrelvir-treated mice recruited significantly fewer memory T and B cells to the infected lungs and to mediastinal lymph nodes, respectively. Together, the data highlight a potential negative impact of nirmatrelvir treatment with important implications for clinical management and might help explain the virological and/or symptomatic relapse after treatment completion reported in some individuals.

In line with clinical evidence and prior observations and different models, we now have mouse model evidence to be able to observe and deduce what is exactly happening inside people taking Paxlovid, how/why rebounding isn’t harmless and even the possible long-term problems the indiscriminate use of this drug can entail.

Using this transgenic humanized mouse model, and testing re-challenge especially (akin to a human being re-infected) the mice had a weaker immune response when they faced the virus again.

Additionally, large lymphocytic aggregates consisting of proliferating B cells were detected in the lungs of vehicle- but not nirmatrelvir-treated mice, 4 days after re-challenge

SARS-CoV-2-specific CD8+ and CD4+ T cells recovered from lung homogenates were assessed for intracellular IFN-gamma and TNF-alpha expression upon in vitro stimulation with a 15 pool of SARS-CoV-2 peptides covering the complete nucleocapsid, matrix, and spike proteins). In line with the results obtained for the humoral response, we found that the frequency and absolute number of IFN-gamma + and IFN-gamma + TNF-alpha + SARS-CoV-2-specific CD8+ and CD4+ T cells were significantly lower in the lungs of nirmatrelvir-treated mice compared to vehicle-treated mice, 4 days after homologous re-challenge. Humoral and cellular responses to SARS-CoV-2 were also reduced when nirmatrelvir treatment was initiated later (24 or 48 hours after infection) and when infection was performed with different SARS-CoV-2 variants

Mice treated with nirmatrelvir had weaker CD8 and CD4 responses and weaker expression of Interferon gamma and Tumor Necrosis Factor alpha. Interferon gamma is necessary at the early stages of infection (especially CD8+) to properly clear it, without its proper “release”, you don’t clear infections as well as others, and you can suffer from fluctuations of its levels, sometimes being overwhelmed by a pathogen and your body flooding itself, and in this specific state, problems arise from a dysfunctional, excessive immune response. Authors argue that this effect could be “due to insufficient antigen exposure (quantity and/or duration) of naïve B and T cells.”

Taken together with yesterday’s substack, we now have a better mechanistic perspective on why Paxlovid is actually dangerous, and I am once again vindicated in an observation that many disagreed with. That Paxlovid wasn’t actually rebounding, it was creating persistent infections. Also, it is a possible explanation for something many observed on social media, the untold amounts of vaccinated, who got infected, followed by treatment with Paxlovid, rebounded, then took longer to properly clear the infection, followed by finally getting reinfected and experiencing “the worse covid infection so far, thanks for the booster or it could be worse”.

A suspension of using this dangerous drug would be a good public health measure, but I doubt anyone will even cogitate this. Now, this is the “scratching my head wtf” section of the paper.

However, nirmatrelvir treatment of mice infected with unrelated viruses (i.e., vesicular stomatitis virus [VSV] and lymphocytic choriomeningitis virus [LCMV]) did not inhibit the development of antiviral adaptive immune responses, indicating that nirmatrelvir is not per se an immune suppressive drug.

This was an effect observed solely with SARS-CoV-2, and not other viruses, and also worth of note, other viruses do not experience the same dynamics when treated with antivirals, or certain pathogens treated with antimicrobials, the body still acquires immunity against it.

Now to some… remarkable findings… to say the least. First, this paper published a couple of months back

Followed by this recently published systematic review and meta-analysis.

COVID-19 Infection in Rheumatic Patients on Chronic Antimalarial Drugs: A Systematic Review and Meta-Analysis

HCQ always work ever since the very first day. In fact, from the many pathways HCQ acts upon, one of the most remarkable I found was the fact that it is a potent inhibitor of Th17 cells. Perhaps a good time to dig up this forgotten substack I published ages ago.

HCQ and evils of Pfizer

Very early on, Pfizer ran a clinical trial using azithromycin and hydroxychloroquine to treat Covid-19, achieving good success. And for the most part of 2021, and many months of 2022, I tried very hard to find one of the little booklets Pfizer sent with the first few batches of its mRNA vaccine, but this one was scrubbed in such a way I could not find.

Pfizer advised the use of HCQ to treat any moderate to severe adverse reaction from its mRNA vaccine. In case you don’t read the substack linked above, Pfizer also owns what could be regarded as the number 1 company in HCQ research, especially the synthetic (more potent) forms.

And now more uses for my favorite amino acid (and supplement).

N-acetylcysteine Reduces Inflammasome Activation Induced by SARS-CoV-2 Proteins In Vitro

The present work shows novel evidence of the effects of SARS-CoV-2 on airway inflammasome activation in critically ill COVID-19 patients, as well as the correlation between the increased inflammasome activation and COVID-19 severity and mortality. In vitro, we showed that the combination of recombinant S, E, and M SARS-CoV-2 proteins were able to activate the inflammasome in macrophages and bronchial epithelial cells, increasing the release of pro-inflammatory mediators through a mechanism that includes TLR2/MyD88/NfκB/ERK1/2 activation. In addition, we showed that large exposures of low in vitro concentrations of NAC of 16 µM and 35 µM, corresponding with plasma levels achieved by oral 600 mg and 1200 mg administrations [30,31], were able to inhibit inflammasome activation and inflammation, which may be of potential value as adding scientific knowledge to support the chronic use of NAC in COVID-19 patients.

Here the authors studied live critically ill patients to find if there was activation of inflammasome in the airways, and if there was an association between airway inflammation, systemic inflammation, and hospital, and 28-day mortality (when people are discharged and die elsewhere and not in the hospital).

The model used to test the blood of the critically ill patients here using Spike Envelope and Membrane protein (a mosaic protein, made up of different parts of the virus), and they found no increase in ROS (the increase in ROS is usually found solely upon Spike use, or obviously the natural infection), so here NAC had solely anti-inflammatory effects, independent of its other effects on cells and the redox system.

The combination of those proteins (S-E-M) starts another important signaling pathway upon TLR2, increasing NF-kB, and therefore activating inflammasomes, one of the leading causes for a lot of the changes we observe both from the infection and the Spike protein.

Worth noting for those unaware that TLR2 is also activated, intracellularly by LPS, and this pathway (TLR2-ERK) can also regulate the expression of Galectin-3, worth to note because, by “default”, NAC will also help tackle this important pathway, a pathway not being researched in the context of SARS-CoV-2 infection at this moment, and mRNA-Spike exposure.

The dosage used here is equivalent to the human dosage I recommend to most people on a “daily basis”, only recommending higher dosage if the person's unique situation/status demand it, it took me years to accept that some people (me especially) can’t minimal dose everything and improve, but I still prefer minimal dosing for the most part.

Alas, one “bad news”, one revolting but the good news (anyone can import HCQ if they want to, it is not restricted, nor expensive if I am not mistaken), and one “good news”, with another promising use and new pathway NAC acts upon and alleviates damage and inflammation. I have written extensively on the uses of NAC and how it fits in the SARS-CoV-2 dynamics, so while this might “read light”, you can go digging (use the search bar here on substack) and find copious amounts of previous research.

I wish everyone a wonderful night/Thursday.

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