On 2021-10-25 17:06:17, user Lucy Carpenter wrote:
My first reaction is, why are you testing Nafamostat - a front-end, early stage antviral meant to block or inhibit TMPRSS-2 at the earliest entry and activation points for the virus - at the back-end, late-stage viral sequence of Covid19 pneumonia? By then, the host is typically so overrun with viral microbials that front-end antivirals will probably not make a measurable difference.
But that is not what the purpose is, for this particular component. Your methodology and assumptions, to me, appear flawed. For two reasons:
- We all know the very high efficacy of children's natural, Innate Immunity against Covid. In the US, and worldwide. 99.7%+ (in the US it is a much higher figure) of all children worldwide easily fight off Covid. Minor symptoms if any; and less than a 1% death rate. In the US, per Hopkins and other figures, as of Oct. 7th, roughly 700 children - out of US population of 73 million children - had died of Covid19. We can all do the math on this. If we could 'bottle' the Innate Immunity function that is keeping almost every single child alive and well for almost two years it would be championed worldwide as a 'miracle cure.'
What makes the child's immunity different than adults or others? We all know this is a complex synergy - aminos, enzymes, different glyco protein structures, etc - but what stands out in immunity research is:<br />
A - children detect Covid much earlier, much earlier, broad-range viral pattern recognition, in the nasal passage (and throat, many children are still mouth breathers); <br />
B - children attack the virus much earlier - at the attachment and activation stage, well before viral replication. They recognize and start attacking the virus as soon as it enters their nose or throats; this limits the 'viral load' on their systems to a manageable level that is easily dispatched. Like stopping a hurricane when it just starts to form, off the coast of Africa; vs waiting for it to hit land in Florida. <br />
--- THIS IS WHY YOUR STUDY WITH NAFAMOSTAT APPEARS FLAWED: YOU ARE NOT MEASURING THE IMPACT OF NAFAMOSTAT ON STOPPING THE ENTRY OF COVID INTO THE HOST, AND LIMITING THE MICROBIAL LOAD BEFORE IT EVEN GETS TO REPLICATION STAGE -- WHAT THE REPURPOSING WAS DESIGNED TO ACHIEVE. <br />
Nafamostat was designed to be one of several elements attempting to emulate a child's Innate Immunity; and the child's very early blocking of ACE2 and TMPRSS-2 expression in the nasal and throat passages.
You are testing instead, the 'wrong' goal for this antiviral; the goal of Nafamostat was never to reduce inflammation or cytokine response -- if you want to test an antiviral for that, test a mega dose of Vitamin D IM or IV; or dexamethasone -- but to INHIBIT THE VIRAL ENTRY INTO THE HOST, BEFORE REPLICATION STAGE. By the time a human as Covid pneumonia, the microbial load is so extreme, it is time to shift gears to another type of antiviral response. (Concentrated D, btw, has excellent efficacy when combined with dexamethasone, against any viral or bacterial lung inflammatory response and infection.)
- Children possess different types of membrane lining in their nasal mucosal for different reasons than what antivirals like Nafamostat would accomplish; but Nafamost is one of the guesses at how to emulate at least part of this upfront difference in immunity function with children: <br />
"SARS-CoV-2 copies, angiotensin-converting enzyme 2, and TMPRSS2 gene expression were similar in children and adults, but children displayed higher expression of genes associated with IFN signaling, NLRP3 inflammasome, and other innate pathways. Higher levels of IFN-?2, IFN-?, IP-10, IL-8, and IL-1? protein were detected in nasal fluid in children versus adults." (https://insight.jci.org/art... "https://insight.jci.org/articles/view/148694)") Other studies from August 2021 on spend more focus on the T cell concentration in children, vs adults, etc.
Bottom line: children have more, and better, general (broad-spectrum, not specialized) immunity and fighter cells in their nasal mucosal and this serves to support very early viral recognition -- broad-range, not specialized, as the vaccines wish to change this Innate Immunity in children - and viral attack mechanisms, from their natural, Innate Immune system, than adults. We cannot yet replicate this different concentration of Immunity cells in a child's nose, into a nose spray for adults. Much of it is genetic: God coded our systems so give children extra protection during their earliest years. *But that would be a good goal.<br />
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So we lack a once-daily nasal spray for adults, which could coat our nasal passages with the same distribution and type of IFN-?2, IFN-?, IP-10, IL-8, and IL-1? protein and T cells and so on, encoded with extra-sensitive, broad-range viral recognition pattern recognition; that our children have. Until we get there, at least up-front, early stage broad-range antiviral components (not a complete pro-drug but a component of a complete antiviral) like nafamostat were intended or designed to 'emulate' specific 'functions' of what we know that children do naturally at the front end: 1 - recognize the virus and 2 - block it BEFORE replication stage by blocking or inhibiting Attraction, Attachment, and Activation.
So, did you test this singular component of a true, end-to-end broad-range antiviral therapeutic or cure, for Covid, at the right phase? Because Nafamostat again, is meant to inhibit the 3rd phase in viral development (activation); not to fight high microbial loads at the back end.
- Did you measure the microbial loads in your patients, before and after administration of Nafamosta? Did you then compare these microbial loads A - to each other, time phase; B - to microbial loads found in asymptomatic Covid patients, or children's nasal cells?
- Because Nafamostat is meant to be the most effective at the lowest microbial load point, which is what a child's immunity does; to prevent infection. It was never a contender for a strong infection status, pneumonia anti-inflammatory. There are antibiotics that assume an antirival function, that are very good choices for such a need. But Nafamostat is not one of them. It is like the difference in asthma inhalers: you would never use an Advair maintenance inhaler or leukotrine inhibitor, which limit inflammatory response by removing the conditions for such response, for an accute asthma attack. For that function, you would use a rescue inhaler like Albuterol. <br />
*Does that mean that Advair or leukotrine inhibitors do not work? They work very well. But if you tested Advair against an accute asthma attack, what would your results be? IN SUCH INSTANCE, YOU WOULD HAVE TESTED THE RIGHT DRUG AT THE WRONG PHASE IN A DISEASE LIFECYCLE. AND MEASURED THE WRONG THINGS. AND DONE DIS-SERVICE TO PATIENTS BY RULING OUT CAPABILILITES THEY DO NEED, BY CONCLUDING INCORRECTLY THEY DO NOT WORK. <br />
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The only thing to test with Nafamostat, would have been efficacy against TMPRSS-2 expression: measurement of microbial loads before and after in patients not yet ill. Because that is what the real 'test' and question is: from the cathespan or ace 2 attachment phase, does Nafamostat reduce, and if so by what %, the activation phase of Covid19. <br />
Eg. X amount microbial load was presented for activation; <br />
Y amount exited activation successfully without Nafamostat<br />
Z amount exited activation or was measured, with Nafamostat
Conclusion: Nafamostat inhibited viral 'activation" and reduced microbial load by Nth %. <br />
If you do not fully understand the full life-cycle approach of the Innate Immune system against Covid, what is often termed the "molecular Covid-Host architecture," you will not be testing responses in the right way, at the right time, measuring the right results, etc.
And then you can go into all of your variants, temp differences (significant in the mutations of viral cells from corona to covid), ph, pre-existing conditions, by age, etc. *And, presumably this was all in silico and not human experimentation with very ill real people..<br />
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It is still not fully understood HOW children block these 3 critical phases of the Covid 19 lifecycle. And easily destroy it. (Other elements of the Innate Immunity, that my company has focused on, include destruction of the viral envelope - so that one is actually killing the virus, again before reproduction stage, not just 'fooling' it or sabotaging RNA, which opens the door to more and more deadly viral mutation or new strain development.) <br />
No one should have expected Nafamostat to have an 'anti-inflammatory' response anyway: what does cytokine or the proteins and genes expressed for that response, have to do with tmprss-2?
But it is so CRITICALLY IMPORTANT that researchers NOT DISCARD OR DISCREDIT VALUABLE ANTIVIRAL COMPONENTS, IN FAVOR OF THE VACCINES. OR FROM A PRO-VACCINE POINT OF VIEW. BECAUSE WE NEED FAST, AFFORDABLE TREATMENTS AND A CURE. You said that very well. And we need that new, fast, methodology in place for the next pathogen. But in my view, that methodology will mean embracing a component-based antiviral approach, and plug-and-play elements that tackle the sequential or concurrent viral lifecycle steps, either independently or in a cohesive therapeutic package. Much like we treat cancer. There are many drugs taken at once, typically. They each have different goals. We don't want to test for the wrong thing, and lose a valuable potential ally.