The most difficult scientific advances become possible when you ask the right question. In the case of COVID-19, I understand that the right question is: why do some people become seriously infected when exposed to low viral load, while others are not sick even when exposed to high viral loads? The situation resembles the film The Andromeda Strain, which I used for many years as an example of scientific research in my Philosophy of Science classes. There is a deathly virus that came in a spaceship, which kills the vast majority of people. However, a baby and a drunk are immune to the action of this virus. A scientist then asks the right question: why are these two people immune? When investigating the physiology of these people, he discovers that both have their PH in certain ranges, the baby alkaline due to excessive crying, and the drunk acid from the ingested drink. In the case of Corona, we have indicators that its action occurs mainly in the mitochondria (see Castalia Francon´s insights below), which has an evolutionary origin due to endosymbiosis (when the eukaryotic cell incorporates bacteria that help it perform certain functions). Mitochondrial DNA is exclusively maternal in origin. Some factors that affect the mitochondria, such as nicotine and metformin, may predispose to the action of the virus. All this indicates that it is necessary to research the affinity of the virus with certain segments of the mitochondrial DNA, to verify if there is a segment present in the mitochondrial DNA of susceptible people, which is not found in the DNA of people not susceptible to the disease. After this discovery CRISPR technology may be used succssfully.
The mechanisms of action of Metformin against Diabetes, boosting mitochondria and reducing the stress caused by excess glucose, may be useful for the fight against the new Coronavirus. I have discussed with experts the action of Metformin and its relation to cancer tumor genesis in another RG question (https://www.researchgate.net/post/Does_the_use_of_metformin_against_type_2_diabetes_increase_or_decrease_the_probability_of_appearance_of_cancer_tumors).
To answer the above question, it is necessary to take into account recent data on the mechanism of action of the virus and empirical statistical (positive or negative) correlation between use of Metformin and the lethality of the virus. Is there any data on this correlation?
According to comments by Castalia Francon, "Neutrophils are known as the core of the 'innate immune systems". They are our 'first responders" to any imminent medical holocaust...NETS, 'Neutrophilic Extracellular Traps" as the battlefield. These powerful products of our neutrophils are essentially a nuclear option against the pathogens. As such they do whatever they can to prevent that explosive death of the neutrophil that will ensnare them...
For bacteria and viruses, their goal of survival entails first avoiding, by whatever means they have, the phagocytosis efforts and then countering the next move of the neutrophils, their death by NETosis.
To attempt this, they seek to manipulate the communications between mitochondria and the cell so as to stall the Neutrophil in a limbo known as "autophagy" while the microbe can continue to reproduce and spread.
The term "autophagy" came into use to denote a systematic, almost "thoughtful" process by means of which the neutrophils, just like macrophages, could move sequentially through a series of considerations pertaining to how to deal with their situation in terms of life and death. But by its very nature as an extremely complex process entailing many dimensional considerations, it is also readily exploitable by pathogens, and in particular by viruses
Many pathogens have been shown to evade or exploit autophagy in macrophages, aiming to establish an intracellular niche for long-term survival and replication Subversion of autophagy by microbes in neutrophils is far less studied but the Corona situation seems to point to it...Our best analogy to it is how when we with to delete", 'our computers ask us, "Are you sure'?" It appears most likely that autophagy is the manifestation of a process that almost always goes on, and eventuates in some adaptive response....unless, of course, the communications between mitochondria and cell are distorted or diminished by pathogen actions.
Viruses and bacteria have evolved over millions of years as each others nemeses, long before we were on the scene, thus the virus is naturally inclined to maniupulate the mitochrondira and by means of that to in turn manipulate the entire cell which is driven by the mitochondria and their needs...
Unfortunately the current 'expert' narrative speaks dichotomously of either "promoting" or 'inhibiting" autophagy instead of coming to terms that there is an ongoing and complex battle going on where any one aspect can shift the nature of the complex decision making.one way or the other. The pathogen, however, is most happy when no clear decisions at all is reached.
The essential treatment for Corona Virus infection is to assure that once the phagocytosis fails....which it often does...that the neutrophils are not stalled from their productive and special death with its Neutrophilic Extracellular Trap creation...which releases the remarkable power of their own DNA to act as a potent immune system weapon against microbes.
We would not be surprised if the CRISPR technology which is now surfacing with so much promise is not an aspect of the manner in which DNA/chromatin sections can be used productively to kill viruses...as they have been used for millennia, apparently, by bacteria.
In summary
• Previous smoking habit is highly associated with the dire effects of Corona Infection....and it also leads to a maladaptive tendency towards' "autophagy" which renders those persons' neutrophils unable to engage in "NETosis " and create "NETS""t
• Smokers neutrophils seem to have phenotypically altered over the course of their previous smoking habit so that they are unable to properly engage in their intense first line of defense, phagocytosis (via NADPH mechanisms).
We only need to observe that in Italy, where the death rates from Corona are soaring, they differ in the terms of their 'lockdown" from ours. Whereas, in the US, pharmacies and groceries and other vital retailers are excluded, in Italy, stunningly, tobacconists and vapes shops join pharmacies as essential and are exempted from lockdown.
Normally, the generation of the ROS products via phagocytosis is a prerequisite for the subsequent death via NETosis.. This is unsurprising since that a failure to be able to engage in phagocytosis would already connote some abnormality or deficit.
•It has however been found that even when the initial phagocytosis does not occur, that, if system can be induced downstream to generate ROS, then NETosis and the creation of those 'traps' is still possible.
• Chloroquine is known to be an "autophagy preventer" in that it can serve to rescue the neutrophil system and thus precipitate the creation of 'NETS. It seems to achieve a mobilization of the NET trap system even though phagocytosis has not succeeded. Exactly what it does is still not clear.
It appears that it is optimal to administer chloroquine early, but only after the first phagocytosis efforts of the neutrophil system but before the virus has seized the opportunity, by manipulating the communications between mitochondria and the cell, to spread and do maximum damage".
Castalia Francon
Many thanks for your excellent contributions! You have the merit of identifying the place where the war against the coronavirus should be fought!in your second message, you wrote: "excessive autophagy usually contributes to the pathogenesis of a variety of diseases, including cardiac disorders. Up until now, it has been a mystery as to how beneficial autophagy turns into a harmful autophagic cell death".
This comment is closely related to the possible action of metformin. While chloroquine and azythromicin destroy the system together the virus, metformin may be an alternative strategy to improve mitochondrial function. So the question is if metformin helps the system to fight the virus, or if it helps the virus to reproduce itself in the system.
Just FYI the combination of metformin with hydroxychloroquine can be fatal as per:
https://www.biorxiv.org/content/10.1101/2020.03.31.018556v1
Alex Kritov Mny thanks for the paper! This seems to be the first published result about metformin that can be relevant to the treatment of COVID-19. It suggests a halt of metformin during administration of chloroquine in humans. I paste the abstract below:
Fatal toxicity of chloroquine or hydroxychloroquine with metformin in mice
N.V Rajeshkumar, Shinichi Yabuuchi, Shweta G. Pai, Anirban Maitra, Manuel Hidalgo, Chi V. Dang
doi: https://doi.org/10.1101/2020.03.31.018556This article is a preprint and has not been certified by peer review.
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Abstract
Guided by the principle of primum non nocere (first do no harm), we report a cautionary note on the potential fatal toxicity of chloroquine (CQ) or hydroxychloroquine (HCQ) in combination with anti-diabetic drug metformin. We observed that the combination of CQ or HCQ and metformin, which were used in our studies as potential anti-cancer drugs, killed 30-40% of mice. While our observations in mice may not translate to toxicity in humans, the reports that CQ or HCQ has anti-COVID-19 activity, the use of CQ resulting in toxicity and at least one death, and the recent Emergency Use Authorization (EUA) for CQ and HCQ by the US Food and Drug Administration (FDA) prompted our report. Here we report the lethality of CQ or HCQ in combination with metformin as a warning of its potential serious clinical toxicity. We hope that our report will be helpful to stimulate pharmacovigilance and monitoring of adverse drug reactions with the use of CQ or HCQ, particularly in combination with metformin.
Dear, Mr. Pereira,
The metformin do not boost mitochondria. The main effect is to kill the mitochondria of the liver responsible to process and transport the glycogen to the blood stream given the glucagon signal is there. Thus the glucose is confined in the liver and can not be released in the blood and the blood sugar level seems normal. It's very doubtful if this helps with infection, when the need of fast supply of energy is higher.
Linked with quinine group, the metformin is a binary poison. It reacts chemically, and can kill by itself. And if ACE inhibitors or similar are added, their side effects (most of them identical with COVID will pop up), and the chloroquine will just destroy the pancreas due to the excess of glucagon and Alpha cells activation that can not provide energy to the cells due to the O2 deficiency, when mainly anaerobic cycle is available.
Especially in very old males, the metformin deteriorates the energy cell balance and the outcome will be fatal. Preprint Late life metformin treatment limits cell survival and short...
I suppose, it will be better when treating COVID-19 to stop any diabetic medication and use insulins only with continuous blood glucose level tracing, keeping it higher.
Another recent article “Should anti-diabetic medications be reconsidered amid COVID-19 pandemic” mentioned metformin. It stresses that “apparent association between COVID-19 and DM include impaired innate immune system in people with DM. In addition, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin- receptor blockers (ARBs), used so widely in people with DM have been implicated as a connecting link between COVID-19 and DM”. https://www.diabetesresearchclinicalpractice.com/action/showPdf?pii=S0168-8227%2820%2930396-X
The question obviously remains if healthy individuals may have benefit from metformin supplementation during Covid-19..
Alex Kritov Better change to insulin even for diabates type 2, according to Kostadin Koroutchev ´s suggestion!
The comment by Castalia is also pertinent...Metformin may induce autophagy, which is good for severely infected cells, but not good for healthy cells...
Well, some metformin effects.
Old style article:
Article Mechanism by Which Metformin Reduces Glucose Production in T...
Whatever the mechanism the metformine impedes the blood glucose to rise when the glucose is needed in the blood as energy source (table 1 ctrl/diabetic+metformin).
New style article:
Article Metformin pathways: Pharmacokinetics and pharmacodynamics
The metformine suppress the mitochondria Complex I and having that path blocked, what is not used is not reproduced, in the cells the specialized mitochondria diminish at least as function. In all the cases the blood sugar level remains low even when it should rise to combat infection that diminish O2 supply to the cells.
One can measure this even in the gym. Metformin and weight lifting achievements and especially HIIT do not fit well (ref. ask the trainer). Both activities are anaerobic.
Actually there is some observation about the energy need and infections, very fresh one. DOI: 10.2196/preprints.18912
I think that even B12 and Ca+ is indicator not to use metformin in that viral infection.
Kostadin Koroutchev In (relatively) healthy type 2 diabetic persons using metformin for a long time to lower blood glucose, does the blockage of mitochondria kill liver cells, or just prevent them from raising blood glucose levels?
Another question is if high levels of glucose in the blood could be good to fight the covid-19 - in this case, could not taking metformin during the crisis have a beneficial effect?
I think so. Nobody will die with blood sugar 150 for 3 weeks, but the glucose is better not to be artificially confined. The liver cells are not killed. The mitochondiria that can provide glucose to the blood effectively are inhibited and probably are less as number, well effectively the mitochondia are killed.
The interaction of the metformine and some of the drugs used can be dangerous.
Castalia Francon
The big picture seems clearer now, but a mathematical model of all this complexity is probably not possible. Often mathematical modelers simplify the system to fit into the variables they choose... I have had a hard time fighting these reductionist approaches. However, today there are some new approaches to "Big Data", I am skeptical, but it is possible that a new tool emerges to find patterns of organization in complex dynamical systems.
We should not forget that Metformin also has broad-ranging effects that extend far beyond blood sugar control. It increases the production of longevity-promoting signaling molecules in cells, such as mTOR and AMPK—all of which reduce fat and sugar storage and increase youthful functioning at the cellular level. There is ongoing clinical trial for Metformin supplementation for longevity:
https://clinicaltrials.gov/ct2/show/NCT02432287
And:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772077/pdf/cshperspectmed-AGE-a025932.pdf
Alex Kritov My concern in the other thread on metformin was if long-term usage could cause stress and facilitate the inactivation of calcium-induced apoptosis, leading to more risk of cancer tumor formation. In spite of this risk, the doctors and researchers recommnded me to continue the treatment. Vera Maura Fernandes de Lima suggested a combination with curcumin, which seems to be very healthy for me (on the basis of one week of usage).
Metformin secondary effect could be utilized in spite its tumor predisposing effect .But posological considerations are important and its combination with an orchestra of antioxidants . Permutation of various nutriceutical with different doses of metformin might be promising it is worthy experimenting upon
Castalia,
when I begun to teach myself immunology, about 2,5 years ago, the analogy I used was two orchestras, one called metabolism, the other immune system, two conductors, liver and thym. they must play two symphonies that are perfect matches to play toghether, they are entrained. the music is right, we have health. then something is wrong, a conductor got drunk, or a chord in violin snaps.
you see, no math and yet complexity .
Castalia Francon
Your diagram(s) is(are) very useful. Fortunately we can understand it(them), or a part, without the maths. Of course, if you intend to publish the findings in an impact journal, a mathematical model and computer simulation of complex systems is required, but there is a cost - excessive simplification, otherwise you build a system with too many variables and non-functional relations, which is non-computable!
Castalia Francon
What is the main mechanism of apoptosis? Inactivation of mitochondria seems to be not sufficient to kill the cell. What more is required? Poisoning by means of excessive calcium release in the cytosol? Rupture of membranes? Binding of viruses with the nuclear DNA?
Castalia Francon
The issue is if the "cell decision" is quantitative or qualitative. When you talk of a computational mechanism, do you imply that the decision is quantitative, IOW, more signaling or stronger signaling wins the game? Or is it possible that weaker signaling of a special kind wins the game?
Castalia Francon your ideas are novel but survival of cells is cellular physiology and sometimes its not predictable and I agree with you but you have to broaden you foresight as it regards to nuclear role and ting-tang of protein dynamics. Since you know that the mitochondrion plays in cell death and energetics ......the nucleus is the principal controller .So I suggest all your mathematical inferences about signalling should towards greater likelihood of cell survival and maintenance of homeostasis. Some of the molecules play a key role this should be overemphasized
Castalia Madam am really impressed but in line with your hypothesis we should protect the other cellular components from the invasion of the virus in the same vein we can ameliorate mitochondrial dysfunction in early invaded cells then destroy the commandeered cells. Also it is important to note that the cause of death through intubation could be an idiosyncrasy and at the late phase of the disease this measures would not be useful.I suggest we work on the mitochondrion for the the stability of the cellular respiration which would enhance longevity to the patients........
Castalia, your model does not and cannot explain the obvious entrainement between metabolism and immune response.
the simple John Carew Eccles simple model os synapse, based on computers, is simply wrong; bette,r an artifact of the use of barbiturate.
Castalia Francon
Sorry, but I agree with Vera Maura Fernandes de Lima that 0 or 1 switches are not the essence of life. This is a controversial issue, and my view is that life and consciousness depend on frequency, amplitude and phase-modulated hydro-ionic waves. The information is the waveform. The binary model used by Eccles is a derivation from MCullough and Pitts´"logical calculus", which was good for artificial computers, but does not capture what happens in living tissue. Otherwise, computers could be alive and conscious...
New finding suggest that the virus causes blood clotting. In this case good old Aspirin could be a treatment in the final phases?
https://nymag.com/intelligencer/2020/04/we-still-dont-know-how-the-coronavirus-is-killing-us.html
Castalia, when you answer a direct question withou a complaint, and sending tons of reading, maybe people can understand you.
We conclude that TNT-mediated transfer of functional mitochondria reverse stressed cells in the early stages of apoptosis.
You can interpret any result in many ways. Define why the cited one is the best and only interpretation. This is discussion group not a literary society.
Castalia Francon
you wrote: ´´mitochondria utilize Tunneling nanotubes (TNTs) which are F-actin-based membrane tubes that form between cells in culture and in tissues. They mediate intercellular communication ranging from electrical signalling to the transfer of organelles. They play a the role via TNTs in the interaction between apoptotic and healthy cells...We conclude that TNT-mediated transfer of functional mitochondria reverse stressed cells in the early stages of apoptosis. This provides new insights into the survival mechanisms of damaged cells in a multicellular context.´´Alfredo: This is important information, thank you. However, it is not clear how these finding apply to COVID-19 infection and treatment. For this reason, we began to discuss if there are binary switches in living tissue to ´decide´ if the cell will die with the virus, or if the cell will survive and let the virus infect other cells. In this context, the usage of metformin may help to propagate the virus within the tissues. How to make progress from this agreed basis?
Castalia Francon
Giving press to mitochondria is good, but denying apoptosis is not, unless you know something the world doesn´t know yet.
I just inserted ´calcium apoptosis´ in PubMed and found 18200 results. One example:
Biochem Biophys Res Commun. 2015 Apr 24;460(1):72-81. doi:
10.1016/j.bbrc.2015.01.137.
Calcium and mitochondria in the regulation of cell death.
Orrenius S, Gogvadze V, Zhivotovsky B.
The calcium ion has long been known to play an important role in cell death
regulation. Hence, necrotic cell death was early associated with intracellular
Ca(2+) overload, leading to mitochondrial permeability transition and functional
collapse. Subsequent characterization of the signaling pathways in apoptosis
revealed that Ca(2+)/calpain was critically involved in the processing of the
mitochondrially localized, Apoptosis Inducing Factor. More recently, the calcium
ion has been demonstrated to play important regulatory roles also in other cell
death modalities, notably autophagic cell death and anoikis. In this review, we
summarize current knowledge about the mechanisms involved in Ca(2+) regulation of these various modes of cell death with a focus on the importance of the mitochondria.
...and my paper with Pregnolato and Damiani:
Article Patterns of calcium signaling: A link between chronic emotio...
The hidden part of the post:
I just inserted ´calcium apoptosis´ in PubMed and found 18200 results. One example:
Biochem Biophys Res Commun. 2015 Apr 24;460(1):72-81. doi:
10.1016/j.bbrc.2015.01.137.
Calcium and mitochondria in the regulation of cell death.
Orrenius S, Gogvadze V, Zhivotovsky B.
The calcium ion has long been known to play an important role in cell death
regulation. Hence, necrotic cell death was early associated with intracellular
Ca(2+) overload, leading to mitochondrial permeability transition and functional
collapse. Subsequent characterization of the signaling pathways in apoptosis
revealed that Ca(2+)/calpain was critically involved in the processing of the
mitochondrially localized, Apoptosis Inducing Factor. More recently, the calcium
ion has been demonstrated to play important regulatory roles also in other cell
death modalities, notably autophagic cell death and anoikis. In this review, we
summarize current knowledge about the mechanisms involved in Ca(2+) regulation of these various modes of cell death with a focus on the importance of the mitochondria.
...and my paper with Pregnolato and Damiani:
Article Patterns of calcium signaling: A link between chronic emotio...
Castalia Francon
How can the electromegnetic transmission of mitochondria happen between two or more cells? An extracellular EM wave is needed. Could NETs be the medium for it?
Castalia,
John Eccles won the Nobel prrize in 1963 with his synapse mobel base on the logic neuron, as Alfredo said here. and you apparently extended to all cells this logic gates. I do not think is usefull for people to pontificate and sell ideas without willing to disscuss them.
The actual model has metabolism and immune system entrained because it is obvious, fever is an example. The actual model has the vagus as the causal organ and therapies to cut the vagus are old or destroy the ganglia are being propposed. The drag is this do not finnishes entrainment. I took you attribute to microarrays all kind of functions. They will explain physiology and pathophysiology.
Castalia Francon
and ALL - I included the paragraph below in the description of the questionThe most difficult scientific advances become possible when you ask the right question. In the case of COVID-19, I understand that the right question is: why do some people become seriously infected when exposed to low viral load, while others are not sick even when exposed to high viral loads? The situation resembles the film The Andromeda Strain, which I used for many years as an example of scientific research in my Philosophy of Science classes. There is a motal virus that came in a spaceship, which kills the vast majority of people. However, a baby and a drunk are immune to the action of this virus. A scientist then asks the right question: why are these two people immune? When investigating the physiology of these people, he discovers that both have their PH in certain ranges, the baby alkaline due to excessive crying, and the drunk acid from the ingested drink. In the case of Corona, we have indicators that its action occurs mainly in the mitochondria, which has an evolutionary origin due to endosymbiosis (when the eukaryotic cell incorporates bacteria that help it perform certain functions). Mitochondrial DNA is exclusively maternal in origin. Some factors that affect the mitochondria, such as nicotine and metformin, may predispose to the action of the virus. All this indicates that it is necessary to research the affinity of the virus with certain segments of the mitochondrial DNA, to verify if there is a segment present in the mitochondrial DNA of susceptible people, which is not found in the DNA of people not susceptible to the disease. After this discovery CRISPR technology may be used succssfully.
lfredo, what kills is the cytokine storm. The beguining of it happens at the venules pos cappilaries, there eosinophis degranulate and their giant cationic protein is released. it as huge protein, with several functional segments.
Within the cell, the package includes calcium (there you are) and very low pH. 2-3.
Upon release, this protein unfolds, (it is a glycoprotein) has polyarginine segment that makes hetero polymer with the basement membrane heparan sulfate of the venule.
specifically with heparan sulfate of the charged gel. Tha´s is the anchor. now, the protein finnishes the unfolds, and the angiotensinogen segment acts, vessels responds.
venules let plasma out and this attracts other leucocytes, among which macrophagues and more eosinophils. positive feedback beguins...
Coceptually, one can cut this at start with protamine, polyarginine avid for heparan sulfate. It will replace the cationic protein, but never via endovenous, the pathway must be nose to brain or brain and lung pathway.
Castalia, there are hundreds of people preconizin heparin as therapy, all of them talk heme.
you are talking about Alexander Wunsh , a physiscian in Heidelber with his
holistic medicinne and photobiology.
https://selfhack.com/blog/dr-alexander-wunsch-on-the-sun-circadian-rhythms-and-light-therapies/
Castalia Francon
and Vera Maura Fernandes de LimaThank you for bringing complex information to the debate. I confess that now you are moving beyond my capacity of understanding, but I hope the RG experts will be able to comment on your hypotheses. The goal of this question is to bring light to the issues, I am just the person making the question for the RG community to answer.
I wish they'd tested all the people who were either asymptomatic, or had very mild symptoms, for having previously had the anti-flu vaccine administered. Since it kicks the immune system into action against over 70 different viruses, maybe it helps in the production of antibodies similar to those needed to fight COVID-19?
I guess we'll never know.
The answer to this question lies in the genes
Genomic medicine, by looking at the genomic structure of an individual, has the answer why a certain person responds differently to different infections, and also respond differently to different treatment.
If we can know why in COVID-19 some people remain asymptomatic, while others progress rapidly to need ICU care and die, depends on the genetic make -up of the individual human being.
Remember
"Rain falls at all the places but it is the landscape which decides where the water is going to collect"
Please go through the link..
Article Metformin in COVID-19: A possible role beyond diabetes
dear Muhammad Yousuf
if you assertion were true, in the 1970´s we already we would have solved the problem of all ills. And yet here we are with guys like you rpromising paradise is just around the corner just give us a few billions for research etc.
I remember well the joke about garbage DNA, when people could not figure out for what so many basis were there
Probably be very strict with the protection measures, as well as a strict glucometric control. Something that seems fundamental to me is that, in that COVID-19 positive patient, be aware of the possible pharmacological interactions that could occur between the antidiabetics received with the treatments offered for coronavirus. Take a look for this paper
Article Prescription patterns and costs of antidiabetic medications ...
Jorge Andrés Sánchez-Duque Please give me the link to the paper or attach it. Thank you!
Article Prognostic factors in patients with diabetes hospitalized fo...
Dear All, what do you think of this new proposal by Andrey Ponomarenko and colleague?
Presentation Possible mechanism of Immune Response utilizing molecular pr...
Not impressed. Bellow is a copy I made from Ruppert Sheldrake comentary i found inetresting:
Thea Newman, provides an interesting new approach. She suggests that with respiratory diseases, such as COVID-19, there may be particles of viral debris in the air that are not infectious since they are not the complete virus, but they may help to stimulate resistance to the virus through being breathed in in small doses, like a kind of air-borne vaccine. This hypothesis would help to explain why when there have been severe outbreaks, there seems to be an enhanced immunity in broad geographical areas around them, where dust particles can be carried by the wind. In more remote parts of the world, beyond the range of this viral debris, the epidemic will start again with full vigour when introduced by air travellers.
Mayana Zatz is proposing a genetic approach (article in Portuguese):
https://noticias.r7.com/saude/mayana-zatz-vai-mapear-genes-de-risco-e-de-resistencia-para-covid-19-18062020
References about treatment with corticoids (from the Portuguese article below):
https://pebmed.com.br/o-uso-da-corticoterapia-na-covid-19-resultados-do-ensaio-clinico-com-dexametasona/
O uso da corticoterapia na Covid-19: resultados do ensaio clínico com dexametasona
Rafael Duarte
A nova e atual pandemia mundial denominada Covid-19, síndrome respiratória associada ao novo coronavírus SARS-CoV-2, tem desafiado profundamente pesquisadores e profissionais de saúde quanto à decisão sobre o melhor esquema terapêutico para limitar ou prevenir a evolução a temida “tempestade de citocinas” (“cytokine storm”), que pode conduzir à síndrome da angústia respiratória aguda (SARA), com consequente hipoxemia silenciosa, insuficiência respiratória e ao óbito dos pacientes infectados.
A heterogeneidade da resposta imune pró-inflamatória na Covid-19 entre os indivíduos infectados com SARS-CoV-2, associada a prognósticos distintos, geralmente pior em idosos (“inflame-aging”) e em indivíduos com comorbidades, tem profundamente intrigado a comunidade científica. Os imunotipos descritos tem sido alvo de estudos moleculares diversos no intuito de compreender a fisiopatologia e possivelmente prever quais indivíduos tem a maior probabilidade de progredir para SARA, sepse, disfunção orgânica, consequentemente com pior evolução clínica (Mathew et al., 2020, Meftahi et al. 2020).
As suposições iniciais sobre o uso de anti-inflamatórios não esteroidais (AINES) ou corticoides para o tratamento surgiram ainda durante o início da epidemia na China, e foram baseadas inicialmente na literatura científica relacionada às epidemias anteriores por outros coronavírus, SARS-CoV e MERS-Cov (Severe acute respiratory syndrome – SARS, e Middle East respiratory syndrome – MERS), que ocorreram em 2002-2003 e 2012, respectivamente. As publicações sugeriram que o uso precoce desses medicamentos poderiam favorecer a replicação viral e resultar em pior prognóstico.
Corticoterapia na Covid-19
Os primeiros artigos sobre o assunto, publicados até fevereiro de 2020 em revistas científicas internacionais, divulgaram resultados que contraindicavam o uso de AINES ou corticoides para o tratamento precoce de Covid-19 de forma a impedir a evolução da doença para quadros respiratórios de maior gravidade. E tais contraindicações foram prontamente adotadas pela Organização Mundial de Saúde (OMS) em guideline divulgado em 28 de janeiro de 2020.
Russell, Millar & Baillie (2020), por exemplo, publicaram na revista Lancet uma revisão baseada nos estudos prévios com influenza, vírus sincicial respiratório, SARS-CoV e MERS-CoV com diversas conclusões negativas sobre o uso de corticoides, incluindo complicações endócrinas, psicose, aumento da mortalidade e outros. A mesma publicação reforçava que mesmo na vigência de SARA ou mesmo no choque séptico, haveria evidências insuficientes para recomendar o uso de corticoterapia para pacientes críticos.
Também na Lancet, em semanas posteriores, Shang et al. (2020) questionaram a forma de revisão realizada pela publicação anterior e suas conclusões não adequada, e contribuiu para manter a questão do uso de corticoterapia como controversa, a ser esclarecida por novos ensaios clínicos. Os mesmos definiram o uso de corticosteroides como uma possível “faca de dois gumes” para o tratamento Covid-19, descrevendo os possíveis prós e contras (Lu et al., 2020), já que indivíduos com imunodeficiências específicas podem apresentar melhor prognóstico).
Com a progressão dos estudos clínicos sobre os esquemas terapêuticos para a Covid-19, divulgados entre março e abril de 2020, surgiram maiores evidências que favoreceram os benefícios da corticoterapia para doentes críticos graves com SARA em ventilação mecânica, sendo sustentado por Yang et al. (2020), pela Surviving Sepsis Campaign (2020) e outros protocolos institucionais.
Em março, por exemplo, Russell et al (2020) criticaram as conclusões premeditadas adotadas pela OMS sobre a exclusão do uso de AINES e de corticoterapia baseadas em estudos prévios com abordagens questionáveis. Tais autores inclusive sugerem o uso de corticoides em indivíduos não submetidos à intubação orotraqueal-ventilação mecânica.
Esta semana, foram divulgados os resultados preliminares de um ensaio clínico randomizado importante, realizado pelo grupo RECOVERY (Randomised Evaluation of Covid-19 Therapy). O estudo comparou os efeitos do uso de doses baixas de dexametasona (6 mg por via oral ou parenteral) por dez dias por 2.104 pacientes com Covid-19 em múltiplos centros hospitalares (n 0 175) no Reino Unido, com 4.321 pacientes submetidos ao tratamento usual adotado até o momento no país.
Leia também: Combinação de interferon, lopinavir/ritonavir e ribavirina para o tratamento de Covid-19
O uso de dexametasona diminuiu a mortalidade em 1/3 dos doentes sob ventilação mecânica, e 1/5 entre pacientes sob oxigenioterapia não invasiva. Não houve diferença entre os pacientes que não necessitaram de suporte ventilatório. Baseado nesses resultados, uma morte seria prevenida a cada oito doentes com Covid-19 grave sob ventilação mecânica ou em 25 pacientes com necessidade de oxigenioterapia.
O pesquisador Dr. Peter Horby, um dos líderes do estudo, ressalta que que a dexametasona consiste na primeira droga que apresenta efeito benéfico à sobrevida de pacientes com Covid-19 que necessitam de suporte complementar de oxigênio. Há efeito direto na redução da mortalidade, o que clareia as possibilidades de aperfeiçoamento dos esquemas terapêuticos para prevenir complicações pela infecção viral.
Conclusões
Ainda permanece sob investigação o uso precoce ambulatorial de corticoide em doses não elevadas para pacientes infectados com SARS-CoV-2, como sugerido por Kronbichler et al. (2020), para prevenir a tempestade de citocinas, a progressão para necessidade de oxigenioterapia e progressivamente para a SARA. Assim como continuam os estudos sobre o verdadeiro papel das citocinas, incluindo interferon tipo I, interleucina-7, -1β, -6, e TNF-α na fisiopatologia inflamatória da Covid-19, como possíveis alvos específicos para a melhor terapêutica com cloroquina ou inibidores da JAK ou outros fármacos.
Outros detalhes sobre a controversa discussão sobre os esquemas terapêuticos com melhores efeitos para combater as complicações da Covid-19 podem ser consultados nas referências abaixo.
Autor:
Rafael Duarte
M.D., PhD. ⦁ Médico ⦁ Microbiólogo ⦁ Professor Associado / Lab. Micobactérias, Depto. Microbiologia Médica, Instituto de Microbiologia Paulo de Góes, Centro de Ciências da Saúde – Universidade Federal do Rio de Janeiro
Referências bibliográficas:
- RECOVERY Trial (Randomised Evaluation of COVID-19 Therapy ) – Reg. ISRCTN50189673 – Disponível em: https://www.recoverytrial.net/
- Alhazzani W, Møller MH, Arabi YM, et al. Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19). Crit Care Med. 2020;48(6):e440-e469. doi:10.1097/CCM.0000000000004363
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Dear all,
The ethics of double blnd studies in a pandemic situation is for me baffling, many immunomodulators will help some patients, the medical ethics of apllying placebo in half I cannot accept.
Big pharma lobby is powerfull indeed.
"It's not that there's going to be one 'Andromeda Strain' that will wipe everybody out on the planet.There are going to be a lot of localized outbreaks putting pressure on medical and veterinary health systems. It will be the death of a thousand cuts."
~ Daniel Brooks (University of Nebraska-Lincoln)
https://www.sciencedaily.com/releases/2015/02/150216064931.htm
I am aphysician and a scientist, I have ethics, so do many colleagues. Do not generilize Castalia.
Agree about FDA and WHO, their purpose now is to maintain the power of its beaureucracies. WHO sinned in delaying the alarm, no question.
Castalia, medicine is the art of healing, it is not science. The doctrine out of molecular biology and statistics- here I include the insurance companies interest of profit at any price- created the actual culture in medicine. It will pass.
I do, however, take issue with your enthusiasm for destruction of universities and learning institutions. before replacement can be clear, to destroy anything is far easy than the construction.
I am not at your league as polemicist, and my energy is far from decades ago, but could not resist
Vera Maura Fernandes de Lima I agree with you. The academic establishment has well known problems, but we cannot claim for destruction without having something better to put in its place.
The same applies to democratic mechanisms in politics. Parliaments have many problems, as corruption, but this is not an argument for the end of democratic representation and imposition of a dictatorial regimen.
Just a question: there are studies showing that nicotine blocks the ACE2 pathway that is necessary for the virus. Thus tobacco use may actually prevent infection. How does that go with the statements that nicotine use may be linked to more cases?
I am also curious about the metformin links, but other people have answered that.
Dear Christer,
Yes you are right , the nicotinic pathway is called the anti-inflammatory pathway. I disscuss it at length in this paper:
- DOI: 10.2174/1570159X12666140630190800
- This viewe
- of protective effect of nicotine is not popular among physicians and other do gooders that want to "save" people because they know better whats is good for everyone.
What is the mechanism of action of this new Coronavir drug??
Russian pharmaceutical company R-Pharm has secured regulatory approval for the use of its antiviral drug Coronavir, to treat patients suffering from Covid-19.
The approval comes after a clinical trial in mild to moderate Covid-19 patients showed that the drug is highly effective in blocking replication of SARS-CoV-2, the novel coronavirus that causes the disease.
R-Pharm was quoted by Reuters as saying: “Coronavir is one of the first drugs in Russia and in the world that does not tackle the complications caused by SARS-CoV-2, but battles the virus itself.”
Study data revealed improvement in 55% of outpatients on day seven of treatment with the drug, compared to 20% of those on standard etiotropic therapy, which targets disease cause instead of symptoms.
In addition, a significant difference was observed at 14 days, added the company. The virus was found to be eliminated in 77.5% of Covid-19 patients by day five of treatment with Coronavir.
In a statement, R-Pharm medical director Mikhail Samsonov said: “Global clinical practice and the clinical study we conducted have confirmed that Coronavir puts a much more rapid stop to the infection as a result of its effective obstruction of the virus’s replication.”
According to Russia’s Central Research Institute of Epidemiology clinical trials head Tatyana Ryzhentsova, the drug entered clinical testing in May and has been used to treat more than 110 outpatients so far.
real good question Alfredo, what is the mechanism the supposed mechnism of coronavir? Where are the russian pharmacologists?
Vera Maura Fernandes de Lima , Christer Johansson and Castalia Francon
Please see this excellent special issue of the journal Brain, Behavior and Immunity, including treatment with cannabis and ayahuasca, psychoimmunological studies, etc.
I wonder why Castalia thinks this is all junk science made by people with low IQ... She prefers to trust compulsive liers like Trump and Bolsonaro...
https://www.sciencedirect.com/journal/brain-behavior-and-immunity/vol/87/suppl/C
67 Articles from the Special Issue on Immunopsychiatry of COVID-19 pandemic; Guest Edited by Carmine Pariante and Kuan-Pin Su
This result is not related to COVID-19, but brings some trouble to metformin users who want to become a father: https://www.the-scientist.com/news-opinion/metformin-prescriptions-linked-to-sons-birth-defects-69849
Metformin: Mechanism of protection against SARS-CoV-2 and effect on the severity and mortality of COVID-19
The articles below indicate the mechanism of metformin on the SARS-CoV-2 and the impact of its use in reducing the severity and mortality from COVID-19 (1-3)
1. Article The Efficacy and Potential Mechanisms of Metformin in the Tr...
2. Article Metformin to decrease COVID-19 severity and mortality: Molec...
3. Article Metformin therapy and severity and mortality of SARS-CoV-2 i...