Dear colleagues,
Which factors could influence the outcome of COVID-19 patients, especially when invasive mechanical ventilation is required, and which alternative intervention possibilities could be applied?
N-Acetylcysteine:
The condition of hypoxia in COVID-19 patients leads to an increase of insulin secreation via ROS (reactive oxygen species) and HIF-1a (hypoxia-inducible factor 1 alpha) [1–3]. It is known that insulin is upregulating the genexpression of vascular AT1 receptors (angiotensin II receptors typ1) [4]. An increase of AT1-receptors is related with an higher risk for lung pathologies [5]. AT1-receptor blockers have been shown to be efficient against diaphragm dysfunction, provoked by artifical ventilation [6]. It was demonstrated that AT1-receptors modulates tubular kidney injury [7]. During invasive mechanical ventilation the risk of AKI (acute kidney injury) triples [8]. Besides other factors (insulinresistance, ect.) is the increase of AT-1 receptors involved in the possible development of hyperglycemia during artifical ventilation [9].
In a study, published 2017, it was shown, that 89% of the arifical ventilated patients (n=174) became hyperglycemic and the mortality rate increased significantly (35.1% vs 10.5%, P < .05), when the blood glucose level increased >140 mg/dL [10,11].
Not only AT1-receptor blockers, such as Losartan, wich inter alia increase the insulin sensitivity and therefore improve the glucose homeostasis, but also NAC (N-Acetylcysteine) should be recognized in the prevention and also in the therapy [12].
Especially as NAC functions as a powerful radical scavenger and could have a major impact in the beginning of the cascade, namely by reducing the ROS and thus reducing the further stress of the insulin – renin – angiotensin – aldosterone system. Aldosterone could cause cardiac arrythmias, cardiac arrythmias were seen in COVID-19 patients [13,14].
Up to now NAC is not routinely used in patients with ARDS (acute respiratory distress syndrom), although scientific publication already mentioned it and classify it as medication of particular importance for ARDS, because of it‘s well-established safety profile and promising preliminary clinical data [15]. However, not only the good tolerability and minimal side effects, but also the inexpensiveness and high availability should raise greater awareness towards NAC at this time. Recently, publication 2019, it was shown, that NAC could attenuate AKI in a cisplatin induced AKI mouse model by inhibiting the C5a receptor of the complement system [16]. The high relevance of blocking the signal chain of C5a and therefore suppression of the cytokine storm in ALI (acute lung injury) as a result of influenza A viruses H5N1, H7N9, and severe acute respiratory syndrome (SARS) coronavirus was mentioned in a publication of the year 2015 [17]. Worth mentioning is, that the blockage of C5a could decrease heart injury due to hypertension [18]. Although it seems that COVID-19 patients rather develop a hypotonia [5]. This fact, besides that virus (SARS-CoV-2) binds to ACE2, made the use of ACE-inhibitors and sartans, such as Losartan, questionable as these medications could promote the activity and expression of ACE2.
At this point only one intervention possibility for an multifactorial system is shown, but this could be very promissing as it acts at the beginning of the cascade.
Flavonoids: Rutin/Querectin and other querectin-derivates:
Flavonoids are known for there anti-oxidative, anti-inflammatory and anti-virale mode of action [19]. Rutin, quercetin-3-O-b-rutinosid, could suppress an isoproterenol induced angiotensin II and aldosteron increase and showed a protective effect for lung tissue during ALI [20]. In an experimentell trial kaempferol, a metabolit of rutin, turned out to be helpfull against ALI, probably via MAPK and NF-κB [19,21]. Just as quercetin, a further metabolit of rutin, appeared to be protective against pneumotoxic substances [19,21]. Regarding the oral administration and bioavailibility of rutin by daily intake of 500mg rutin over a period of six weeks evokes an 2,5-fold quercetin, 3-fold kaempferol and 10-fold isorhamnetin plasma level increase [21]. Besides the possible application of rutin, respectively quercetin, against symptomatic problems during a SARS-CoV-2 infection, it also could be a candidat to directly combat the viral load. Recent molecular docking research, not yet peer-reviewed, with Autodock 4.2 showed besides Nelfinavir and Lopinavir, also kaempferol and quercetin as possible inhibitors for the SARS-CoV-2 main protease [22]. And in direct correlation with this study, a study from 2006 should be mentioned, in which quercetin-3-b-galactoside was identified as inhibitor for 3C-like protease of SARS-CoV [23]. Important to mention the further findings of this study: “(1) removal of the 7-hydroxy group of the quercetin moiety decreases the bioactivity of the derivatives; (2) acetoxylation of the sugar moiety abolishes inhibitor action; (3) introduction of a large sugar substituent on 7-hydroxy of quercetin can be tolerated; (4) replacement of the galactose moiety with other sugars does not affect inhibitor potency.“ [23].
Furthermore quercetin, as well as Chloroquin, has a zinc ionophore activity [24]. Zinc has an inhibiting effect on the RNA-polymerase of corona-virus and blocks replication in cell culture [25].
At the moment the Canadian researchers Michel Chrétien and Majambu Mbikay explore in Wuhan the antiviral competence of isoquercetin in relation to SARS-CoV-2.
Dietary supplements are freely available. It could be of global significance, in the area discussed here.
Kind regards,
Rosita Dangmann
Contact: [email protected]; Phone: 0049 172 2314785
For the bibliography please open the pdf.
I worked on ROS and NAC. I think the following references can be interesting
N-acetyl-L-cysteine (NAC) Inhibits Virus Replication and Expression of Pro-Inflammatory Molecules in A549 Cells Infected With Highly Pathogenic H5N1 Influenza A Virus. DOI: 10.1016/j.bcp.2009.08.025
and
Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. https://erj.ersjournals.com/content/10/7/1535
and
N-acetylcysteine improves oxidative stress and inflammatory response in patients with community acquired pneumonia. A randomized controlled trial
https://journals.lww.com/md-journal/FullText/2018/11090/N_acetylcysteine_improves_oxidative_stress_and.35.aspx
Will be happy to discuss
Scientists and medical experts don't have a good understanding of what virus characteristics and environmental factors control virus persistence in the environment -- for example, in aerosols and droplets, on surfaces including skin and in water including seawater, according to Boehm and Wigginton. "When a new virus emerges and poses a risk to human health, we don't have a good way of predicting how it will behave in the environment
https://www.sciencedaily.com/releases/2020/03/200326160759.htm
Dear Manash K Paul ,
thank you for your response. The references you mentioned are very interesting. Those information putting NAC, not only as symptomatic therapy, but also as a kind of causative, antiviral, and protectiv treatment in the center of interest. As most of the references are dealing with influenza, I tried to find some information about corona virus pathology in the context of NAC.
“Redox Biology of Respiratory Viral Infections” Olga A. Khomich, Sergey N. Kochetkov, Birke Bartosch and Alexander V. Ivanov https://www.mdpi.com/1999-4915/10/8/392/pdf
“The effect of inhibition of PP1 and TNFα signaling on pathogenesis of SARS coronavirus” Jason E. McDermott, Hugh D. Mitchell, Lisa E. Gralinski, Amie J. Eisfeld, Laurence Josset, Armand Bankhead, Gabriele Neumann, Susan C. Tilton, Alexandra Schäfer, Chengjun Li, Shufang Fan, Shannon McWeeney, Ralph S. Baric, Michael G. Katze and Katrina M. Waters https://europepmc.org/article/pmc/pmc5035469
It was shown, that TNFα promotes pathogenesis of SARS coronavirus, instead of reducing it via activation of the immune system. As TNFα generates mitochondrially ROS, NAC could interrupt the following cascade. Clinical tests should review, if this is applicable to SARS-CoV-2.
This information taken together with the results of the study “Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment” S. De Flora, C. Grassi, L. Carati, you mentioned, makes NAC a promising candidate in the prevention of severe outcomes of SARS-CoV-2. What I found interesting is the fact, that high doses of 1200mg NAC per person per day over 6month did not show side effects and the overall severity of influenza-like symptoms were significant decreased. It would be interesting, if NAC influences the level of antibody titre. I found an article (“Effect of N-acetylcysteine on mucosal immunity of respiratory tract” O.V. KALYUZHIN) in russian language, which I am unfortunately not able to read (and understand), but the author stated in the abstract, that “There was no convincing evidence that NAC is able to suppress any component of mucosal immunity”.
What is your opinion about NAC regarding COVID-19?
Greetings,
Rosita
https://www.ecdc.europa.eu/sites/default/files/documents/RRA-seventh-update-Outbreak-of-coronavirus-disease-COVID-19.pdf
In reply to Rosita Dangmann’s request, PLEASE read the following article, towards the end as to the time-line I can address this in detail. Meantime, I would like to finish on what I started about the “Cytokine Storm” a few days ago...
WHEN to Intervene in the “Cytokine Storm?”
BEFORE we begin, some “light relief”:
Quotable Quotes
These few “gems” by Gov.Andrew Cuomo:
“DON’T be reactive; you NEED to be pro-active”!
(A few days after my Pt.1 newsletter in which I said “The Best form of Defence is...Offence” a Shaolin kung fu tenet). Cuomo said: “Don’t be on the Defence (Defense – American spelling).....BE on the Offence”.
On March 31, he said: “We’ve been behind it on Day 1 since it got here. And we’ve been playing “catch up”. You DON’T win by playing “catch up”. We have to get ahead of it”.
“The 2nd Rule is: NEVER underestimate your opponent....and we under-estimated the Virus...It has proven to be much more powerful & dangerous than we expected....And the 3rd. point is: PLAN forward, get AHEAD of it! Anticipate the next “BATTLE” and plan for it (exactly my Modus Operandi”!)
“This Virus spreads like a fire thro’ dry gras, with strong wind behind it....”
When New York city had its first 600-death day, he said: “This spreading like a bullet train!”
I would say it like this: ”This “Thing” is NO longer a “Freight Train” irreverently ploughing its way thro’ populations any which way; it is NOW a “bullet train” smashing its way thro ANY population ANYWHERE”....
This was from 1 of the Media people at a White House Press Briefing: “We’re at War without ANY ammo!”
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OK, this is my quick preliminary Reply to Rosita Dangmann of this Forum who said: “Which factors could influence the outcome of COVID-19 patients and which alternative intervention possibilities could be applied?”
We're headed there in probably a week’s time or more....As I mentioned a few days ago, we started a BIG Newsletter Series (of 12 or more long, detailed postings) several weeks back. & NEXT, I will be drilling down to the 4 main forms of the Immune System, of which 3 are major [ Intrinsic (eg. Inteferons, Autophagy, micro-RNA, etc.), Innate, & Acquired/Adaptive)] & 1 somewhat "Experimental" form [Convalescent Plasma Therapy (aka Passive Antibody Therapy), something un-proven against this virus]. And after that, we’ll get down to some advanced Nutritional Medicine [ALL with their respective published Clinical Evidence]
For the antecedents to this, please read the start ('The PRELIMINARY') of our Series [COVID-19: The EQUALIZER Series] & the 3 that followed that (I have uploaded them here in our new RG membership). We're building this up in a logical sequence; The next to come out (hopefully in the next day or two) will be this close look at our Immune systems.
One more word about my expose` the other day on the "Cytokine Storm". I gave you all a glimpse of the Inflammatory dynamics at work. The thing I forgot to mention is that these Inflammatory cytokines are not ALL "bad" – in ‘Inflammation Dynamics, there is NO such thing as such thing as ‘something being TOTALLY & ALL bad. It starts out “good” to serve a purpose, but when that “purpose” is not attained (for whatever reasons, and there are lots of that!), then its continued influence is bad (it CAN be real bad!). In infections [as in most, if not all, other Acute-Phase situations], the Inflammatory enzymes & Chemokines are pumped out in an attempt to deal with the microbial invader(s) - they marshal all the leucocyte members (of the various Immune Systems ) to "do battle". IN a realistic time-frame, IF successful, this phase should last from 1 - 3 weeks. IF by the end of 2 weeks, the temporary upward-exponential curve doesn't flatten and the symptomatology keeps getting worse, you KNOW the "Fight" is NOT going to be successful. By the end of the 3rd. week, IF the sero-IgM is still high (OR, worse, still rising) you should know the "Fight" is almost ....LOST.
WHAT would then be happening with the so-called "Cytokine Storm"?
Well, via the body's -ve 'Feedback' loops [eg. DCs, B-cells, TOLL-like receptors (TLRs), etc.], the body WILL know what's going on.... One example: the surface-borne TLR10 can "sense" the exosomal presence of the flu-type virus at the point of its “docking” operation (for COVID-19, it is ACE2 – see our Pt.1 article) with the host cell. There are many other sensing cytokines that can “tell” the body that the Virus is STILL there, undefeated [THAT is WHY it ramps up the “Storm”...]. BUT it doesn’t know whatelse to do except keep driving the “Storm”....In fact, if anything, it WILL ramp up the “Storm”, in a vain & futile attempt to drive more neutrophils & other Leucocytes into battle [NK, DCs, monocytes (to generate more macrophages & other phagocytes), T-cells, Defensins, etc, etc.] to the “sites of battle”. Clinically, IF the Neutrophil count:Total Lymphocyte sero-count ratio is > 10, the Px is going to be in a REAL rough, tough time.... (IF the ratio is around 6, the Px prognosis will be ....much better)
The increasing tide of Inflammatory cytokines WILL inflict MORE damage for sure on those body parts I previously mentioned. Not to mention the direct damage inflicted by this type of Virus....DON’T forget: THIS Corona-Virus is much larger, physically, than ALL previous corona-viruses (it IS the BIGGEST “bully-boy” of ALL the Corona-viruses we’ve ever known before....). The damage inflicted by it is vicious, resolute, pathologically morbid..... it’s like millions/billions of very tiny razor-blades cutting up your insides - THIS is downright scary!
People in Lombardy (northern Italy) & Spain had reported severe pains in their lungs, hearts, kidneys and small & large intestines....Many had coughed up blood AND seen blood in their stools; several others just fell into a coma & never woke up....
The thing I wanted to emphasize here was the TIMING of the anti-Inflammatory intervention - THIS IS critical. Understanding as we do that pro-Inflammatory cytokines are modulators – they’re NOT “bad” all the time (THAT’S why they’re modulators). You do NOT institute an anti-Inflammatory strategy at the very beginning of experiencing the symptoms or (in the case of the asymptomatic people) when a proper test (a RT-PCR one) shows up +ve and then impose a “selective blockade” on the COX2 members (see my last & very 1st posting here, on RG, just a few days ago) or even the “Pope” right at the top of the Inflammation ”tree”, NF-KappaB; even NF-KB himself HAS a modulatory role to play at this early stage.... You give the “Storm” a short-term leeway to do its thing, ie. you DON’T “interfere” with it right from the word “go!”.
SO, HOW long have you got to play with?? Remember, this IS a “novel” Corona-Virus & NOT too much is known or predictable of its “time-line”.... We can only learn from Wuhan, Lombardy Province, Milan, Madrid, and now New York, the places where the Virus has “played its strong hand”.....
IF by the end of the 2nd. week, & Px looks bad, you know his “fight” with the Virus most likely CANNOT win, and you NOW have to seriously consider “culling” the “Storm”, if not shutting it down completely (which would be TOTALLY impossible, NOT if the Virus is still around in the body). It IS the case of the lesser of the 2 “evils”: the Px either dying OR still alive, but in terrible pain.... At that point, you have NO choice but to move in AND limit the contributary damage from the terribly high levels of he “Storm”. You DON’T have much “room to move” here.... At this point, you MUST try to limit further combined damage (from BOTH the Virus AND the Inflammatory cascades) to the Px’s upper airways, lower airways (including the lungs), the heart, kidneys, & intestines... You have to move in NOW & start, IMMEDIATELY, the TOTAL anti-Inflammatory strategy – inhibit ALL the drivers of COX2 and 5- & 12-LOX Catalysis (especially the latter generating the Leucotrienes which are like “permanent residents” in ALL the airways!). From this highly “critical point” onwards (the hs-CRP would be “mile-high” at THIS point!) and the Inflammation alone can “finish” him off....(remember what I said of the “Lesser” of the 2 “evils”?? It COULD turn out to be the “game-changer” in the Final analysis....)
What about the “quintessential good-guys” (as how I described them before): the COX1 Pathway, leading us to THE most powerful anti-Inflammatory enzyme, PGE1, in the human body ? WHEN do we ramp him up??:
At the beginning (as defined above) OR 2 – 2 ½ weeks later (when it looks obvious the Px
won’t win the fight against the Virus)??
Prostaglandin E1 works independently of ALL the COX2 products (even PGE2) & ALL the Leucotriene products [even LTB4 – the MOST damaging enzyme to the airways (upper & lower) & the lungs....]
SO, you deploy the COX1 drivers right at the beginning....Matter of fact, if you’re smart & want to be “pro-active” right at the beginning (whether you have a COVID +ve test or not), you would start driving up the COX1 straight away....
Our next Newsletter (mapping out the extremely intricate human Immune systems) posting might actually take 2 parts, considering the subject is so terribly complex.....When I’m thro’ with that, THEN we can get down to the “business end” of dealing with the subject of “Defence AND Offence”... Remember, they’re one (read my Pt.1).
One last word here: I just DON’T get it that “they” (Doctors in America) DON’T get it OR “haven’t gotten it” by now! One of the articles in the latest edition (April 6, 2020 – 5 days ago) of “Scientifc American”:
Heart Damage in COVID-19 Patients Puzzles Doctors
Up to one in five hospitalized patients have signs of heart injury. Cardiologists are trying to learn whether the virus attacks the organ
Here, read this article: This "PUZZLE": https://www.scientificamerican.com/article/heart-damage-in-covid-19-patients-puzzles-doctors/?utm_source=newsletter&utm_medium=email&utm_campaign=week-in-science&utm_content=link&utm_term=2020-04-10_featured-this-week&spMailingID=64511835&spUserID=NDY1NTg5Nzc4NTM3S0&spJobID=1861224900&spReportId=MTg2MTIyNDkwMAS2
WHAT is it that they (these Doctors) DON’T get?? THIS is HOW America got “caught with its pants down” – “playing catch-up”, a lingo used by Gov.Cuomo. Guys, DO your “home work”, read the Research....
Dr.L.S. Macloud, Ph.D. (Cambridge Univ.)
