3083 replies to this topic

[Hebbeh]

It's this Twitter thread:

https://twitter.com/...628906472980482

 

discussing this paper amongst others

https://chemrxiv.org...phyrin/11938173

 

https://archive.is/ONUmi

 

Suffice it to say I'm skeptical if this is correct as extreme symptoms leading to death would be evenly distributed across all age groups rather than targeting predominantly the elderly if this was the case.  And what about the groups that experience just mild symptoms?  This is a computer modeling study that doesn't fit real world observations.

 

This was discussed in this thread starting in post 88 here:

 

https://www.longecit...olutions/page-3

[Kalliste]

Suffice it to say I'm skeptical if this is correct as extreme symptoms leading to death would be evenly distributed across all age groups rather than targeting predominantly the elderly if this was the case.  And what about the groups that experience just mild symptoms?  This is a computer modeling study that doesn't fit real world observations.

 

This was discussed in this thread starting in post 88 here:

 

https://www.longecit...olutions/page-3

 

If, and mark my words, IF there is an iron angle to this you would expect those with the most iron and the worst antioxidation to be hit worst. Who are those? Old men with diabetes would come to mind.

Women have menstruation to keep them in check. They are also not dropping dead.

 

But maybe I'm just iron-sperg posting here. 

 

Will any antioxidant help with this? We don't know, but we know they are already being used. Or is China trolling us with reports of C-vitamin use for instance? 

We now IV-C is good for sepsis. 

We also now that any unpatented substance is impossible to research, even with crowdfunding. 

 

Big companies ready their weapons when somebody even tries to bring an alternative to their patented stuff. 

 

 

Merck made a "hit list" of doctors who criticized Vioxx according to testimony in a Vioxx class action case in Australia. The list, emailed between Merck employees, contained doctors' names with the labels "neutralise," "neutralised" or "discredit" next to them.

https://www.cbsnews....enting-doctors/

Edited by Kalliste, 09 April 2020 - 06:23 AM.

[albedo]

Regarding iron in particular I guess it is a matter of homeostasis.

This is from Dr David Sinclair's blog:

 

"...My advice to a friend was to get in the best physical and mental shape these next couple of months:

Maintain cardio fitness, which will increase capillary and red blood cell counts. Lift weights if possible. Move.

Don’t be low in iron but also don’t overdose.

Keep taking your medicines unless an MD says to stop.

Eat less often during the day. I skip at least one meal, usually breakfast, and eat sensibly at other meals.

Avoid super intense exercise or long-term fasting.

Take 2500 - 5000 IU of vitamin D3 a day, which doctors say keeps your immune system in good shape.

Keep blood sugar levels in check by avoiding sugar and processed grains.

Focus on plants. Meats should include fish, preferably on the low end of the food chain to avoid heavy metals.

Eat colored plants, either fresh or snap-frozen, and don’t overcook them. They contain xenohormetic molecules that activate cell defenses.

Include nuts, avocado, and olive oil in your diet. Oleic acid from these foods will activate SIRT1, the defense enzyme, the same way resveratrol does (fasting also liberates oleic acid from fat stores). 

Keep humidity up in the home to maintain airway health and mucus. If your house isn’t humidified, get a humidifier for the bedroom.

Turn off breaking news channels. Read a book. Listen to a podcast. Make something.

Get sufficient sleep. Consider L-theonine. Avoid screens at night. Avoid big meals and alcohol near bedtime. Download f.lux software to dim the screens. If you use your phone in bed, wear blue-light blocking glasses..."

 

[Kalliste]

A bad study on HCQ from France

https://www.scienced...399077X20300858

 

 

No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the Combination of
Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection.
Jean Michel Molina1-3, Constance Delaugerre2-4, Jerome Le Goff2-4, Breno Mela-Lima1, Diane
Ponscarme1, Lauriane Goldwirt5, and Nathalie de Castro1.
1 Infectious Diseases Department, Saint Louis Hospital, 75010 Paris, France
1Université de Paris, 75000 Paris, France.
3U944 INSERM, Université de Paris, 75000 Paris, France
4Virology Department, APHP-Saint Louis Hospital, 75010 Paris, France
5Pharmacology Department, APHP, Saint-Louis Hospital, 75010 Paris, France
Corresponding author: Dr. Jean-michel Molina; Infectious Diseases Department, APHP-Saint
Louis Hospital, 1 avenue Claude Vellefaux, 75010 Paris, France; Tel: +33.1.42.49.90.66;
Email : jean-michel.molina@aphp.fr
The COVID-19 epidemic is the worst worldwide pandemic in a century with more than 500,000 cases and 25,000 deaths so far. In France, more than 30,000 cases have been reported up to March 27, and nearly 2,000 have died. 
Pending the availability of a vaccine, there is a critical need to identify effective treatments and a number of clinical trials have been implemented worldwide. 
Chloroquine analogs have been shown to inhibit the acidification of endosomes and to exhibit in vitro a non specific antiviral activity at high micromolar concentration against a broad range of emerging virus (HIV, dengue, hepatitis C, chikungunya, influenza, Ebola, SARS and MERS viruses) and more recently COVID-19 (1-2). 
In France, following the results of a clinical study in Marseille, there is considerable interest for the use of hydroxychloroquine to treat COVID-19 disease, and the French Ministry of Health recently allowed the use of hydroxychloroquine to treat COVID-19 disease pending the results of ongoing clinical trials (3). 
In their study, Gautret et al. reported a 100% viral clearance in nasopharyngeal swabs in 6 patients after 5 and 6 days of the combination of hydroxychloroquine and azithromycin (3).
Page 2 of 3
Journal Pre-proof
This rate of viral clearance was lower with hydroxychloroquine alone (57.1%) and was only 12.5% in patients who did not receive hydroxychloroquine (p< 0.001).
Such a rapid and full viral clearance was quite unexpected and we wished to assess in a prospective study virologic and clinical outcomes of 11 consecutive patients hospitalized in our department who received hydroxychloroquine (600 mg/d for 10 days) and azithromycin (500 mg Day 1 and 250 mg days 2 to 5) using the same dosing regimen reported by Gautret et al. (3). 
There were 7 men and 4 women with a mean age of 58.7 years (range: 20-77), 8 had significant comorbidities associated with poor outcomes (obesity: 2; solid cancer: 3; hematological cancer: 2; HIV-infection: 1). 
At the time of treatment initiation, 10/11 had fever and received nasal oxygen therapy. Within 5 days, one patient died, two were transferred to the ICU. In one patient, hydroxychloroquine and azithromycin were discontinued after 4 days because of a prolongation of the QT interval from 405 ms before treatment to 460 and 470 ms under the combination. Mean through blood concentration of hydroxychloroquine was 678 ng/mL (range: 381-891) at days 3-7 after treatment initiation.
Repeated nasopharyngeal swabs in 10 patients (not done in the patient who died) using a qualitative PCR assay (nucleic acid extraction using Nuclisens Easy Mag®, Biomerieux and amplification with RealStar SARS CoV-2®, Altona), were still positive for SARS-CoV2 RNA in 8/10 patients (80%, 95% confidence interval: 49-94) at days 5 to 6 after treatment initiation. 
These virologic results stand in contrast with those reported by Gautret et al. and cast doubts about the strong antiviral efficacy of this combination. Furthermore, in their report Gautret et al also reported one death and three transfers to the ICU among the 26 patients who received hydroxychloroquine, also underlining the poor clinical outcome with this combination. 
In addition, a recent study from China in individuals with COVID-19 found no difference in the rate of virologic clearance at 7 days with or without 5 days of hydroxychloroquine, and no difference in clinical outcomes (duration of hospitalization, temperature normalization, radiological progression) (4). These results are consistent with the lack of virologic or clinical benefit of chloroquine in a number of viral infections where it was assessed for treatment or prophylaxis with sometimes a deleterious effect on viral replication (5-8). 
In summary, despite a reported antiviral activity of chloroquine against COVID-19 in vitro, we found no evidence of a strong antiviral activity or clinical benefit of the combination of hydroxychloroquine and azithromycin for the treatment of our hospitalized patients with severe COVID-19. Ongoing randomized clinical trials with hydroxychloroquine should provide a definitive answer regarding the alleged efficacy of this combination and will assess its safety. 
Déclaration de liens d’intérêts : Les auteurs déclarent ne pas avoir de lien d’intérêts

 

 

[Hebbeh]

If, and mark my words, IF there is an iron angle to this you would expect those with the most iron and the worst antioxidation to be hit worst. Who are those? Old men with diabetes would come to mind.
Women have menstruation to keep them in check. They are also not dropping dead.

But maybe I'm just iron-sperg posting here. /[/url]

However, that theory claims COVID-19 kills by destroying your hemoglobin which would be independent of your iron status as an old man or menstrual women. The theory claims you become hypoxic from lack of working hemoglobin and that is what kills you. And if true, then destroyed hemoglobin is independent of iron status and no amount of vitamin C is going to fix the destroyed hemoglobin.

[thompson92]

However, that theory claims COVID-19 kills by destroying your hemoglobin which would be independent of your iron status as an old man or menstrual women. The theory claims you become hypoxic from lack of working hemoglobin and that is what kills you. And if true, then destroyed hemoglobin is independent of iron status and no amount of vitamin C is going to fix the destroyed hemoglobin.

 

Presumably there is a high level of ROS from the iron being removed from the hemoglobin.  It's not really independent, it's another issue for your antioxidant system to deal with because otherwise -- what protein is sequestering the Fe?  It's going to react somewhere.

[Hebbeh]

Presumably there is a high level of ROS from the iron being removed from the hemoglobin. It's not really independent, it's another issue for your antioxidant system to deal with because otherwise -- what protein is sequestering the Fe? It's going to react somewhere.

If you have no working hemoglobin then iron would be the least of your worries.

[Kalliste]

The argument has been made that vitamin C will interact with the virus before the damage to Hemoglobin happens and the Vitamin C (and other antioxidant systems) would be able to prevent at least some of the oxidative insult to the lungs by interfering with the iron (fenton Chemistry?) that produce oxidative damage to lung tissue.

 

Anyway, many antioxidants are fairly harmless in the short run (I don't like long term Vit C it interfers with hormetic effects) so I wonder if we turn it around, do you expect the disease to be even worse in a patient who get <insert=Antioxidant Cocktail>?

[Hebbeh]

The argument has been made that vitamin C will interact with the virus before the damage to Hemoglobin happens and the Vitamin C (and other antioxidant systems) would be able to prevent at least some of the oxidative insult to the lungs by interfering with the iron (fenton Chemistry?) that produce oxidative damage to lung tissue.

Anyway, many antioxidants are fairly harmless in the short run (I don't like long term Vit C it interfers with hormetic effects) so I wonder if we turn it around, do you expect the disease to be even worse in a patient who get <insert=Antioxidant Cocktail>?

In this theory, how would vitamin C prevent the damage to the hemoglobin from occurring? If true, I don't see how vitamin C protects the hemoglobin from damage.

[sciack]

However, that theory claims COVID-19 kills by destroying your hemoglobin which would be independent of your iron status as an old man or menstrual women. The theory claims you become hypoxic from lack of working hemoglobin and that is what kills you. And if true, then destroyed hemoglobin is independent of iron status and no amount of vitamin C is going to fix the destroyed hemoglobin.

And where this theory comes from? From what I read high hemoglobin for example is a higher risk to develop a severe Covid

[osris]

Yes it is bad, because the binders and fillers will add up to many grams too. Not negligible at all. Having to modulate the negative effects of so much junk, you better would go without vitamin C pills or capsules in the many grams range.

 

Wikipedia is sponsored by the pharmaceutical industry, therefore don't expect anything evidence based in their natural medicine reviews.

 

Where you're from? Though vitamin C might run short in local shops, it can still be bought by the tons online. Like 3.8 tons of 1kg bags at https://purebulk.com...=14294918037553 (only down half a ton from a month ago).
 

 

I'm in the UK. Here, the powder is very expensive for quite a small bottle - not even a tub - of it at any physical health shops that are still open. I haven't looked online for better deals yet.

 

About the buffers etc. You are probably right. It was just that Linus Pauling suggested mega-dosing with vitamin tablets, and so I assumed it was ok, if he said it.

[BlueCloud]

Trump just said that they need to add zinc to the hydroxy. 

 

So if you need to buy some zinc you better buy now before a shortage.

 

 

And we all know how much of a great virologist and epidemiologist expert he is  .... Politicians should just shut their mouths and do what scientists advise them. Any politician who is trying to instrumentalize science to advance their politics is despicable ( and I'm not just talking about Trump here ). And yes , zinc is definitely key in this epidemic.

 

 

Didier Raoult saying he doubts many vaccines and that the sun is good? (not for Covid maybe but in general if my translation is ok) Is somebody better at french than me. 

 

https://www.francetv...lat_894481.html

 

 

 

It's this Twitter thread:

https://twitter.com/...628906472980482

 

discussing this paper amongst others

https://chemrxiv.org...phyrin/11938173

 

https://archive.is/ONUmi

 

 

So how about Pauling levels of vitamin C and intravenous vitamin C 

 

 

The article is commenting on a book written by Dr raoult sometimes ago. The thing is, Dr Raoult has been a very controversial figure for a while, and has probably done as much damage to the popularity of HCQ as he has helped its popularity. He enjoys going against most established theories, and plays a lot on his "renegade" persona. Many of his extremely abundant publications have been so sloppy he was banned for a year in 2006 from the journals of the American Society of Microbiology. The French government who funded his Institute in Marseille, took away his INSERM label ( a sort of quality label for government funded entities ) after once again some accusations of falsifications of various papers he cowrote ( many of them published in a Journal he co-owns). He once said "Nothing amuses me more than destroying established theories". While that could be amusing indeed, the problem with such attitude is that it is not motivated by reason but by an irrational contrarian attitude that just hurts the advancement of science.

He also called climate change a hoax, and even more ironically : the same person who is now touted as this epidemic hero ( mostly by himself) has published various papers and Youtube videos in January and early March calling the Covid19 a crazy hysteria about an insignificant virus that will never even spread to the rest of the world. he quickly changed his tune of course once he saw how wrong he was, then proceeded to release another sloppy study on HCQ.

 

In the article you link to , he is basically saying in his book that half of the vaccination recommended are completely useledd and not needed, that protecting yourself from the sun is not needed and bad except for young kids with fair skin, and that the more you expose yourself to the sun , the less dangerous the melanoma you might catch will be  ( the article comments that this actually goes against what most studies have found ). he also says that antibiotics should be prescribed to anyone that gets flu symptoms  for more than 3 days because the risk of surinfection is more dangerous than overuse of antibiotics ( there again, the article comments that this goes against most established medical practices )

 

When he released that famous first study on HCQ, he publicly blamed the government health authorities for not jumping immediately on recommending its use in a widespread manner, calling it it a "cabale" against him because he is not part of "the establishment". This immediately fueled the immense popularity of HCQ on social networks in France, with huge threads on Twitter, Facebook, young gamers forums etc with people commenting on the "conspiracy" of the Government not immediately using this molecule because they are sold to Big Pharma. This quickly became instrumentalized by political opposition parties , who then all  became suddenly virology experts and the biggest proponents  of HCQ in France. Raoult of course seemed to enjoy his new cult-like popularity status in France , and fueled it by various trolling Twitter messages and videos.

The government never rejected actually HCQ, but because of Raoult's controversial reputation, said that they need a bit more time to look into it before recommending its use. Ironically again , Raoult IS part of the 12 experts commitee appointed by the government to advise them on the pandemic, while acting as if he was some outsider rebel genius. The health authorities later on recommended HCQ as a treatment because of the urgency of the situation, while starting a much bigger ( 3000 patients) , better quality study on HCQ to get to the bottom of the situation.

 

Sadly, Raoult may very well have stumbled on something important with HCQ , but simultaneously slowed down and hurt its adoption because he made various scientists and governments skeptical about it with his sloppiness and irrational attitude.

Edited by BlueCloud, 09 April 2020 - 11:59 AM.

[pamojja]

And we all know how much of a great virologist and epidemiologist expert he is  .... Politicians should just shut their mouths and do what scientists advise athem. Any politician who is trying to instrumentalize science to advance their politics is despicable ( and I'm not just talking about Trump here ). And yes , zinc is definitely key in this epidemic.

 

The opinion here of the Robert Koch institute (similar to the CDC in Germany) doesn't agree. Experts can only advise. Politcians are voted in for listening not only to virologists, but experts of all other fields too (ie. epidemiology) - and for making political decisions. Only because one disagrees with one particular president shouldn't be a reason for abolishing democracy. Nobody should shut their mouth (not to talk about the widespread censorship going on at present..) Everyone should vote.
 

I'm in the UK. Here, the powder is very expensive for quite a small bottle - not even a tub - of it at any physical health shops that are still open. I haven't looked online for better deals yet.

 

About the buffers etc. You are probably right. It was just that Linus Pauling suggested mega-dosing with vitamin tablets, and so I assumed it was ok, if he said it.

 

A viral pneumonia in the experience of Carthart may need up to 200 g of ascorbic acid a day. Which is substancially more than the mega-doses talked about for maintaining general health by Pauling, ie. 6-18 g per day. Also the fillers at the time of Pauling might have been more harmless.

 

This is a US source: https://purebulk.com...=14294918037553 (not adviseable if from Germany, since could get confiscated by customs)

 

And here one in the EU, which ships internationally: https://shop-breinba...0/Products/1011
 

Edited by pamojja, 09 April 2020 - 12:00 PM.

[BlueCloud]

The opinion here of the Robert Koch institute (similar to the CDC in Germany) doesn't agree. Experts can only advise. Politcians are voted in for listening not only to virologists, but experts of all other fields too (ie. epidemiology) - and for making political decisions. Only because one disagrees with one particular president shouldn't be a reason for abolishing democracy. Nobody should shut their mouth (not to talk about the widespread censorship going on at present..) Everyone should vote.
 

 

I was exagerating of course, we know politicians won't shut it, but instrumentalzing science politically will always hurt it, not advance it. The biggest pushers for HCQ in France were the extreme-right wing parties, because this was a golden opportunity to hit on the government, not because of their suddenly acquired microbiology knowledge. The exact same political parties that were criticizing the same government just a month ago for taking the the coronavirus seriously, were  against the confinement, and calling it hysteria from the government put in place for the only sake of extending control over the population ( while critisizing the same government now for not starting the confinement earlier ). Many politicians work by contrarian attitudes ( if A says X is good, then we must say that X is bad ). This pollutes the way serious research and scientific knowledge spreads among the population. This is why I say that the word of scientists should be put over the word of politicians.

Edited by BlueCloud, 09 April 2020 - 12:15 PM.

[Hebbeh]

And where this theory comes from? From what I read high hemoglobin for example is a higher risk to develop a severe Covid

 

Did you not read Kalliste links that the exchange was discussing regarding "COVID-19 is causing prolonged & progressive hypoxia (starving your body of oxygen) by binding to the heme groups in hemoglobin in your red blood cells. Patients are progressively desaturating (losing o2 in their blood), & as a result, it’s leading to organ failures"? And no, I don't buy into the theory.

 

Kalliste, on 08 Apr 2020 - 10:17 PM, said:

It's this Twitter thread:

https://twitter.com/...628906472980482

 

discussing this paper amongst others

https://chemrxiv.org...phyrin/11938173

 

https://archive.is/ONUmi

 

[Mr Serendipity]

I have beta thalassemia minor, so I create less hemoglobin. My doctor (new at the time) once thought I was anaemic after blood test results, before I informed him I had B thalassemia minor (which I’m not allowed to take iron for), so I’m probably mildly anaemic all of the time. So I wonder how corona is effecting me differently if any.

Edited by Jesus is King, 09 April 2020 - 01:55 PM.

[sciack]

I have beta thalassemia minor, so I create less hemoglobin. My doctor (new at the time) once thought I was anaemic after blood test results, before I informed him I had B thalassemia minor (which I’m not allowed to take iron for), so I’m probably mildly anaemic all of the time. So I wonder how corona is effecting me differently if any.

yeah me too on the same boat... we have lower haemoglobin but more red blood cells and higher ferritin.... I think it is not ideal but who knows...

[Florin]

Breathing technique for removing COVID-19 lung mucus:

• Take a deep breath in.
• At the end of it, hold your breath for five seconds, then release.
• Do this five times — five breaths total.
• Next, take a sixth deep breath in, then at the end of it cough strongly — covering your mouth when you do so.
• The six breaths plus cough at the end represent once cycle. Repeat this cycle twice.
• Lie on your stomach on a bed, taking slightly deeper breaths than normal for the next 10 minutes.

https://www.today.co...-better-t177870

 

Edited by Florin, 09 April 2020 - 07:17 PM.

[xEva]

I think the porphyrin/heme theory was discarded too quickly:

 

Shawn Evans, attending emergency physician and director of resuscitation at Scripps Memorial Hospital La Jolla, said ... the vast majority of young people who contract the disease fare well and recover. But for a minority, it appears to cause a unique change in the blood’s oxygen-carrying hemoglobin cells.

“Young people who are otherwise fit can tolerate this longer, but at the expense of their heart and their pulmonary functions,” said Evans, who likened some of the symptoms in younger people to prolonged carbon monoxide exposure.

 

https://www.washingt...omments-wrapper

 

Here  Dr. Seheult discusses the paper that claims that covid-19 attacks 1-beta chain if hemoglobin and captured the prophyrin to inhibit heme metabolism, at 20:21

 

One thing he does not address is the bilateral uniformity of the ground-glass opacities seen with this virus, which has been commented on by numerous drs (i.e. how unusual it is). I think this frequently shared observation supports the notion that inflammation and the acute respiratory distress syndrome that follows may be the consequence of  "inability to exchange carbon dioxide and oxygen frequently" -- rather than the other way around (i.e. hypoxia being the consequence of inflammation and ARDS).

 

Many people complain of weakness and headaches, which are the early symptoms of hypoxia.

 

Edited by xEva, 09 April 2020 - 08:22 PM.

[BlueCloud]

Article behind a paywall , but basically says that this aternoon, Dr Raoult gave the president of France the premiere of the results of a new study that  he  conducted on 1061 patients, with a complete remission in 10 days, claiming a 91% rate of success.

 

 

Edited by BlueCloud, 09 April 2020 - 08:27 PM.

[BlueCloud]

Ok, Raoult has put a preliminary preprint of the study mentionned in my previous post on his website now https://www.mediterr...pre-prints-ihu/

 

it’s the last one : covid ihu-6

Edited by BlueCloud, 09 April 2020 - 10:04 PM.

[xEva]

Logically, you would want all the receptors blocked all the time. So I would take the maximum dose that I could safely tolerate, broken as evenly as possible throughout the day (probably delivered IV at a measured rate). I have no insights as to which particular drug would be ideal.

 

I suspect that studies which find them to be harmful involve patients on the drugs who, upon admission, quit taking them (because they usually need to be consumed orally, which isn't viable on a ventilator, or because they forgot them in the rush to the hospital), resulting in an explosion in viral load above and beyond their previous growth rate. And all else being equal, they're a proxy for cardiovascular age, so there's some degree of sample bias at work.

 

in the end data wins:

 

both poor clinical and virological outcomes were associated to the use of selective beta-blocking agents and angiotensin II receptor blockers (P<0.05)

 

https://www.mediterr...042020_vD1v.pdf
 

So far only the abstract is available. Would be interesting to see the details when the full text is published.

[lancebr]

in the end data wins:

 

both poor clinical and virological outcomes were associated to the use of selective beta-blocking agents and angiotensin II receptor blockers (P<0.05)

 

https://www.mediterr...042020_vD1v.pdf
 

So far only the abstract is available. Would be interesting to see the details when the full text is published.

 

So is the mortality rate of 0.5% in elderly a good thing or bad thing based upon this study?

 

 

[Dorian Grey]

I think the porphyrin/heme theory was discarded too quickly:

 

Shawn Evans, attending emergency physician and director of resuscitation at Scripps Memorial Hospital La Jolla, said ... the vast majority of young people who contract the disease fare well and recover. But for a minority, it appears to cause a unique change in the blood’s oxygen-carrying hemoglobin cells.

“Young people who are otherwise fit can tolerate this longer, but at the expense of their heart and their pulmonary functions,” said Evans, who likened some of the symptoms in younger people to prolonged carbon monoxide exposure.

 

https://www.washingt...omments-wrapper

 

Here  Dr. Seheult discusses the paper that claims that covid-19 attacks 1-beta chain if hemoglobin and captured the prophyrin to inhibit heme metabolism, at 20:21

 

One thing he does not address is the bilateral uniformity of the ground-glass opacities seen with this virus, which has been commented on by numerous drs (i.e. how unusual it is). I think this frequently shared observation supports the notion that inflammation and the acute respiratory distress syndrome that follows may be the consequence of  "inability to exchange carbon dioxide and oxygen frequently" -- rather than the other way around (i.e. hypoxia being the consequence of inflammation and ARDS).

 

Many people complain of weakness and headaches, which are the early symptoms of hypoxia.

 

Ahh!  I've read the iron displaced in the damaged hemoglobin becomes free/labile iron, which is the ultimate pro-oxidant causing inflammation & resulting pulmonary fibrosis ground-glass opacities (thanks Kalliste for pointing me in the right direction!).  If this is so, a chelator (quercetin, curcumin, apolactoferrin) might be protective?  I got spooked about IP6 a couple weeks back...  Sorry I can't find the link, but it was on one of the earlier pages of this thread.  Something about the virus possibly utilizing IP6 to enhance its membrane stability?  

 

I'm really excited about recent findings of ventilation damage. UK PM Boris Johnson was put on oxygen rather than vent, & I recently saw hyperbaric oxygen rather than vent might be the new big thing for COVID.  More on this here:

 

 

I'll try to followup with a proper post tomorrow.  

Edited by Dorian Grey, 10 April 2020 - 05:15 AM.

[Kalliste]

There is a debate on the possibility of inhibiting NLRP3 / inflammasome as a method of dealing with Covid

 

 

Prof. Akiko Iwasaki

@VirusesImmunity

·

Apr 5

Several studies are coming out saying that blood LDH (lactate dehydrogenase) levels early in #COVID19 disease correlates with severe disease progression. This is a clue that #pyroptosis may be a the core of this disease (1/n). https://medrxiv.org/content/10.1101/2020.03.24.20040162v1

https://jci.org/articles/view/137244

Lactate dehydrogenase, a Risk Factor of Severe COVID-19 Patients

BACKGROUND The World Health Organization (WHO) has recently declared coronavirus disease 2019 (COVID-19) a public health emergency of global concern. Updated analysis of cases might help identify the...

 

medrxiv.org

 

Prof. Akiko Iwasaki

@VirusesImmunity

·

Apr 5

What is LDH? It is an enzyme found within the cytosol of nearly all cells. Ed Miao's group showed that LDH release is a reliable way to monitor #pyroptosis, a form of cell death that depends on inflammasomes leading to plasma membrane rupture. (2/n) https://ncbi.nlm.nih.gov/pubmed/23852598

 

Prof. Akiko Iwasaki

@VirusesImmunity

·

Apr 5

LDH is not released by apoptosis or even hyperactivation of macrophages. It requires pyroptosis and membrane rupture shown by

@jkagan1

's group. (3/n) https://sciencedirect.com/science/article/pii/S1074761317305149

 

 

P Apr 5

How might #SARSCoV2 induce pyroptosis? A study showed that #SARSCoV1's Orf8 triggers NLRP3 inflammasome activation and pyroptosis in macrophages. Whether #SARSCoV2 Orf8 also activate pyroptosis is unknown. (4/n) https://ncbi.nlm.nih.gov/pubmed/31231549

 

·

Apr 5

While LDH correlates well with disease severity, this may not be the reason for severe disease. However, pyroptotic (pyro=fire, ptosis=falling) death is very immunogenic, releasing intracellular contents and can lead to blood clotting. (5/n) https://ncbi.nlm.nih.gov/pubmed/31076358

 

·

Apr 5

Blood clotting is also associated with poor prognosis in #COVID19. (6/n) https://ncbi.nlm.nih.gov/pubmed/32073213

 

·

Apr 5

There are other reasons why inflammasome inhibitors might be a promising approach - to increase host disease tolerance. Please see a nice thread by

@padminipillai

explaining this concept. (7/n)

Quote Tweet

 

Padmini Pillai

@padminipillai

· Mar 26

As the elderly are more susceptible to #COVID19 w/ signs of lung #inflammation, here's a thread about our @virusesimmunity 2016 flu paper on #antiviral resistance, excessive lung #inflammation, & a strategy to boost disease tolerance! https://science.sciencemag.org/content/352/6284/463.long

Show this thread

I believe inflammasome inhibitors should be tested for #COVID19 treatment. I've said this before but I believe it is worth repeating here. I hope pharma companies working on developing such inhibitors for other disease indications can help

 

(end)

 

 

There are other reasons why inflammasome inhibitors might be a promising approach - to increase host disease tolerance. Please see a nice thread by

@padminipillai

explaining this concept. (7/n)

https://twitter.com/...165595740385285

 

 

 

Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease

Science  22 Apr 2016:
Vol. 352, Issue 6284, pp. 463-466
DOI: 10.1126/science.aaf3926

Flu immunity shows its age

As we age, our immune systems change; in many ways not for the better. For instance, the elderly account for 90% of influenza deaths annually. Pillai et al. now report that influenza-infected human monocytes, a type of immune cell, exhibit reduced antiviral activity. In influenza-infected mice, two innate immune sensing pathways work together to promote antiviral immunity to influenza. Mice lacking antiviral immunity (similar to the situation in elderly people) had elevated bacterial burdens in their lungs and increased inflammatory responses, which both contributed to their increased susceptibility to influenza.

Science, this issue p. 463

Abstract

Influenza A virus (IAV) causes up to half a million deaths worldwide annually, 90% of which occur in older adults. We show that IAV-infected monocytes from older humans have impaired antiviral interferon production but retain intact inflammasome responses. To understand the in vivo consequence, we used mice expressing a functional Mx gene encoding a major interferon-induced effector against IAV in humans. In Mx1-intact mice with weakened resistance due to deficiencies in Mavs and Tlr7, we found an elevated respiratory bacterial burden. Notably, mortality in the absence of Mavs and Tlr7 was independent of viral load or MyD88-dependent signaling but dependent on bacterial burden, caspase-1/11, and neutrophil-dependent tissue damage. Therefore, in the context of weakened antiviral resistance, vulnerability to IAV disease is a function of caspase-dependent pathology.

https://science.scie...2/6284/463.long

 

5. NLRP3 Inflammasome and the Xenohormesis Hypothesis

As it was described in detail above, polyphenols like resveratrol, curcumin, EGCG, and quercetin are potent inhibitors of NLRP3 inflammasome-mediated IL-1β production, typically acting at more than one element of the involved pathways (Figure 3). However, it should be noted that these polyphenols have an even much broader biological effect, as they influence a variety of pathways [119], though not all are directly connected to the function of the NLRP3 inflammasome. Importantly, more than 8000 natural polyphenols have been described [120], providing a large library of compounds as potential inflammasome inhibitors. Many of these polyphenols (such as resveratrol and curcumin) are overproduced by stressed plants, triggering pathways mimicking the effect of caloric restriction. It has been proposed that organisms, from yeast to humans, consuming stressed plants could interpret the stress signal carried by such polyphenols as a potential risk of future limitation of food availability, and, in turn, adapting for the pursuit of longevity, a theory termed as Xenohormesis [121–123]. Interestingly, the structurally unrelated resveratrol and curcumin can achieve this caloric restriction mimicking effect by activating AMPK and Sirt1 [124]. However, polyphenols are also known to have an antioxidant effect, activate glutathione S-transferases, and inhibit COX enzymes among many other effects [125, 126]. Interestingly, one of the most frequently used COX inhibitor is aspirin, a derivative of another stress-induced phytochemical, salicylic acid.

A major concern of polyphenol use in therapy is the bioavailability of these compounds. Nevertheless, typical dietary polyphenol intake is about 14 mg/kg/day, which is within the range of providing biologically active doses [127].

6. Concluding Remarks

Most of the time, inflammasome-mediated IL-1β production or caspase-mediated pyroptosis is beneficial for the host, as it protects from infection or prevents further damage. However, prolonged cytokine production, as in the case of sterile inflammation caused by endogenous danger signals, may lead to the development of autoinflammatory or metabolic diseases. Chronic inflammation compromises the host’s life quality and requires sustained pharmacological and surgical treatments. The paradigm of drug discovery in Western medicine is to develop highly selective compounds against individual druggable targets. Currently, the main treatment methods for these patients are targeting IL-1β. However, prolonged usage of drugs may induce different side effects; furthermore, some form of medications are very expensive, which limits their widespread use.

Besides the high expenses, another drawback of traditional drug design is that many of the promising compounds fail in the early or later stages of drug development. Traditional medicine uses many plant products to treat diseases; however, the exact mechanisms behind their use is still mostly lacking, partially as a consequence of the pleiotropic effect of the active compounds, as detailed in this review. Nevertheless, clarification of the molecular mechanism of action of such natural compounds, already used in traditional medicine for quite some time, will undoubtedly aid in the production of safe and cheap candidate medications to be used in the treatment of diseases, including those appearing as a consequence of NLRP3 inflammasome-mediated IL-1β overproduction.

https://www.hindawi....i/2016/5460302/

Curcumin...

 

Curcumin inhibited the NLRP3 inflammasome by preventing K⁺ efflux and disturbing the downstream events, including the efficient spatial arrangement of mitochondria, ASC oligomerization, and speckle formation.15 apr. 2018

 

Curcumin/Turmeric is also a blood thinner if memory serves me right. I have a vague memory of Inositol showing up in NLRP3 relations too but Inositol is very common in biochemical reserach so the searches for it are very jumbled.

Edited by Kalliste, 10 April 2020 - 06:47 AM.

[Kalliste]

 

Vitamin C inhibits the activation of the NLRP3 inflammasome by scavenging mitochondrial ROS

https://www.research...tochondrial_ROS

 

 

BMC Med. 2013 Aug 6;11:178. doi: 10.1186/1741-7015-11-178.

Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines.

Dashdorj A¹, Jyothi KR, Lim S, Jo A, Nguyen MN, Ha J, Yoon KS, Kim HJ, Park JH, Murphy MP, Kim SS.

Author information

Abstract

BACKGROUND:

MitoQ is a mitochondria-targeted derivative of the antioxidant ubiquinone, with antioxidant and anti-apoptotic functions. Reactive oxygen species are involved in many inflammatory diseases including inflammatory bowel disease. In this study, we assessed the therapeutic effects of MitoQ in a mouse model of experimental colitis and investigated the possible mechanisms underlying its effects on intestinal inflammation.

METHODS:

Reactive oxygen species levels and mitochondrial function were measured in blood mononuclear cells of patients with inflammatory bowel disease. The effects of MitoQ were evaluated in a dextran sulfate sodium-induced colitis mouse model. Clinical and pathological markers of disease severity and oxidative injury, and levels of inflammatory cytokines in mouse colonic tissue were measured. The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed.

RESULTS:

Cellular and mitochondrial reactive oxygen species levels in mononuclear cells were significantly higher in patients with inflammatory bowel disease (P <0.003, cellular reactive oxygen species; P <0.001, mitochondrial reactive oxygen species). MitoQ significantly ameliorated colitis in the dextran sulfate sodium-induced mouse model in vivo, reduced the increased oxidative stress response (malondialdehyde and 3-nitrotyrosine formation), and suppressed mitochondrial and histopathological injury by decreasing levels of inflammatory cytokines IL-1 beta and IL-18 (P <0.001 and P <0.01 respectively). By decreasing mitochondrial reactive oxygen species, MitoQ also suppressed activation of the NLRP3 inflammasome that was responsible for maturation of IL-1 beta and IL-18. In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells.

CONCLUSION:

Taken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease.

https://www.ncbi.nlm...pubmed/23915129

 

I'm sure C60 olive oil has some problem, I took some recently. But who knows

 

Nanomedicine. 2017 Aug; 13(6): 2049–2059.

Published online 2017 Apr 9. doi: 10.1016/j.nano.2017.03.015

PMCID: PMC5549014

NIHMSID: NIHMS886776

PMID: 28404518

Nanoparticle fullerol alleviates radiculopathy via NLRP3 inflammasome and neuropeptides

Li Jin,^a Mengmeng Ding,^a Azra Oklopcic,^b Bayan Aghdasi,^a Li Xiao,^a Ziyi Li,^a Vesna Jevtovic-Todorovic,^b,c,* and Xudong Li^a,*

Author information Copyright and License information Disclaimer

The publisher's final edited version of this article is available at Nanomedicine

See other articles in PMC that cite the published article.

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Abstract

The present study aimed to evaluate the analgesic effect of the antioxidant nanoparticle fullerol in a mouse radiculopathy and a dorsal root ganglion (DRG) culture models. Intervertebral disc degeneration causes significant hyperalgesia and nerve inflammation. Pain sensitization and inflammatory reaction were counteracted by fullerol when disc material was bathed in 10 or 100µM of fullerol prior to implantation. Immunohistochemistry showed similar massive IBA1 positive macrophage infiltration surrounding implanted disc material among groups, but IL-1β and IL-6 expression was decreased in fullerol treated group. In the DRG explant culture, after treatment with TNF-α, the expression of IL-1β, NLRP3, and caspase 1 was significantly increased but this was reversed by the addition of fullerol. In addition, fullerol also decreased the expression of substance P and CGRP in the cultured DRGs. Nanoparticle fullerol effectively counteracts pain sensitization and the inflammatory cascade caused by disc degeneration.

 

 

 

Int J Mol Sci. 2019 Jul 15;20(14). pii: E3466. doi: 10.3390/ijms20143466.

NLRP3 Inflammasome Modulation by Melatonin Supplementation in Chronic Pristane-Induced Lupus Nephritis.

Bonomini F^1,2, Dos Santos M³, Veronese FV³, Rezzani R^4,5.

Author information

Abstract

Lupus nephritis (LN) is a kidney inflammatory disease caused by systemic lupus erythematosus (SLE). NLRP3 inflammasome activation is implicated in LN pathogenesis, suggesting its potential targets for LN treatment. Melatonin, an endogenous indoleamine, is considered an important multitasking molecule that has been reported to have anti-inflammatory effects by inhibiting nuclear factor-kappa B (NF-κB)-mediated inflammatory responses in vivo. This molecule has also protective effects against the activation of the inflammasomes and, in particular, the NLRP3 inflammasome. Thus, this work evaluated the effect of melatonin on morphological alteration and NLRP3 inflammasome activation in LN pristane mouse models. To evaluate the melatonin effects in these mice, we studied the renal cytoarchitecture by means of morphological analyses and immunohistochemical expression of specific markers related to oxidative stress, inflammation and inflammasome activation. Our results showed that melatonin attenuates pristane-induced LN through restoring of morphology and attenuation of oxidative stress and inflammation through a pathway that inhibited activation of NLRP3 inflammasome signaling. Our data clearly demonstrate that melatonin has protective activity on lupus nephritis in these mice that is highly associated with its effect on enhancing the Nrf2 antioxidant signaling pathway and decreasing renal NLRP3 inflammasome activation.

https://www.ncbi.nlm...pubmed/31311094

 

 

Food Res Int. 2020 Jan;127:108628. doi: 10.1016/j.foodres.2019.108628. Epub 2019 Aug 19.

Green tea polyphenols and epigallocatechin-3-gallate protect against perfluorodecanoic acid induced liver damage and inflammation in mice by inhibiting NLRP3 inflammasome activation.

Wang D¹, Gao Q¹, Wang T², Kan Z¹, Li X¹, Hu L¹, Peng CY¹, Qian F³, Wang Y⁴, Granato D⁵.

Author information

Abstract

Perfluorodecanoic acid (PFDA) is a highly toxic food contaminant that is extensively used in food applications as surface antifouling agent. In this present study, we aimed to assess whether green tea polyphenols (GTPs) and epigallocatechin-3-gallate (EGCG) exert protective effects against PFDA-induced liver damage and inflammation in mice. A mouse model to evaluate liver toxicity was established by giving mice drinking water containing different concentrations of PFDA. GTPs or EGCG (0.32%, w/v) were co-administered to mice exposed to PFDA in drinking water. Overall, GTPs and EGCG extended the survival time and inhibited weight loss among mice who received a lower dose of PFDA. Moreover, GTPs and EGCG ameliorated hepatic oxidative stress, cell apoptosis, necrosis, steatosis, edema, and degeneration, reduced hepatic inflammation and NLRP3 inflammasome activation caused by a moderate dose of PFDA. Taken together, these results show that GTPs or EGCG (or green tea intake) supplements can be beneficial for people exposed to PFDA.

https://www.ncbi.nlm...pubmed/31882076

 

 

[albedo]

Previously also posted on increasing ventilation and protection from aerosol. There is lot of debate as this article in Nature emphasizes. Personally think public recommendations to bring masks should be made quickly but as in the article:  "masks should be recommended for the public only after supplies have been secured for health-care workers, people with symptoms, and vulnerable populations such as the elderly" and that is a problem.

Is the coronavirus airborne? Experts can’t agree

[xEva]

re covid-19's affinity for porphyrins (which then affects heme metabolism) there is another angle to it, and that is that attacks of porphyria are treated with chloroquine and hydroxychloroquine (porphyrias are disorders when too much porphyrins are produced). And! some forms of chronic porphyria are treated with low daily doses of methylene blue. 
 
And interesting in this context is that methylene blue is also considered as antimalarial drug. So what about methylene blue? Anybody thinks it could be helpful?
 
(I'm posting it here, since the covid MB thread is lost to discussion on statistics and estimates)

 

 

@Jesus is King: in the other thread you said your wife turned rather pale with infection. I wonder if you have methylene blue and if a very weak solution of it (in water) would bring some color to her cheeks and make her feel better. Or! better yet, you can add a tinny drop to the drinking bowl of your sneezing cat -- how about that?

 

 

 

Edited by xEva, 10 April 2020 - 11:53 AM.

[resveratrol_guy]

Thanks, Dorian! That was a 2-hour journalistic tour de force.

I dig this guy (Del Bigtree). He fits the stereotype of an intellectually lazy rightwing conspiracy wonk (and uses all the right conspiratorial buzzwords), but he's actually an iconoclastic rationalist who's willing to discuss fringe theories which are grounded in science and math. I just love sociological oddballs. But more to the point, this is well worth your time if you want to know more about the poorly illuminated corners of COVID19, and above all what the appropriate medical and policy responses should be.

It frankly raises more questions than answers.

Edited by resveratrol_guy, 10 April 2020 - 03:37 PM.

[Iporuru]

The Role of Vitamin D in Suppressing Cytokine Storm in COVID-19 Patients and Associated Mortality

Findings: Age-specific CFR in Italy, Spain, and France (70 yo ≤ age < 80 yo) was substantially higher (>1.9 times) than other countries (Germany, South Korea, China); for the elderly (age ≥70 yo), Italy and Spain present the highest CFR (>1.7 times that of other countries). The age-specific ratio of confirmed cases in Italy, Spain, and France has also been substantially higher than in other countries. A more severe deficiency of Vit D (mean 25-hydroxyvitamin D (25OHD) concentration <0.25 ng/L) is reported in Italy and Spain compared to other countries. Our analysis of the reported clinical data (25OHD, CRP) from multiple studies suggests that elimination of severe Vit D deficiency reduces the risk of high CRP levels (odds ratio of 2) which may be used as a surrogate marker of cytokine storm which was estimated to a potential reduction in severe COVID-19 cases of up to 15%. Interpretation: The substantially higher age-specific CFR and the age-specific ratio of confirmed cases in Italy and Spain (countries with low mean 25OHD level) suggest a potential link between severe Vit D deficiency and severe COVID-19, which can lead to a higher CFR. No direct link between the performance of health care systems, the age distribution of the nation, or Vitamin A deficiency and the CFR of COVID-19 were observed. Our analysis of the published data on the status of Vit D and CRP levels (in the US) and laboratory data (CRP levels) reported from 792 patients in China suggests that a proper supplementation of Vit D across populations may reduce the number of severe COVID-19 cases by up to 15 percentage points by lowering the risk factors related to cytokine storm. Our analysis did not eliminate the possibility of the circulation of different sub-genera of COVID-19 across the globe or other factors.