Hi.

Although far from an academic, and being a registered nurse. I have an interest in this based upon my workplace in critical care medicine.

I am trying to seperate two recent competing points of opinion.

1: That ACE inhibition and ARBs as being theoretically both protectorate against covid-19 to ACE2 binding;

https://www.bmj.com/content/368/bmj.m406/rr-2

2) That the same drugs may have the precise opposite effect, as in this piece and a competing bmj piece to to the link above (which theorises the exact opposite);

https://www.bmj.com/content/368/bmj.m810/rr-2

I do understand that competing research proposal is important to arrive at balanced finding, but wondered what the current prevalence of evidence greater suggests.

I'm sorry if this seems a naive question, but believe that my colleagues will find any further opinion (should anyone be able to offer any) of interest when we inevitably receive our first critically ill covid-19 client.

Many thanks.

Thanks Andrei.

So as I see it, both are theorized possibly involved in increased covid19 comorbidity, but arbs may represent the lesser risk?

Bear with me!

I will get there..

Morbidity, I meant.. not comorbidity.

Thanks..

Dear All,

as I recently learned the laboratories examining cells of postively tested individuals showed high count of viral ssRNA, this was the case in individuals showing no signs, mediocre signs and signs of severe and critical illness. There seems to be no connection between intracelluar Virus count and state of the patient!?

Hi Benito.

As stated I am a nurse in critical care and not a doctor, but am interested in this subject.

Can I ask specifically what tissue these samples reflect?

As I believe it, ace2 is present within most organs, although I was under the impression that it proliferated more abundantly within lung parenchyma, meaning the binding of coronavirus to ace2 might be observed to be more prevalent there, resulting theoretically in more devastating inflammatory changes leading to ards and increased morbidity.

Again, I hope that my assessment doesnt come across as naive, although I would be happy to be corrected as long as it doesnt detract from the importance of this thread.

The tissue reflected upper airway tissue.

The bodies inflammation reaction seems to display the biggest issue. This is why a least part of ARDS patients react positively to chloroquine phosphate as it is used in malaria.

Of course. Collected via bronchoscopy of course.

Thankyou Benito. It's interesting, but I guess conclusions are still a long way from being drawn.

I am guessing the most reliable findings in relation to this thread will occur once statistical data amongst covid19 patients is analysed, looking specifically at hypertensive patients across all routes of medicinal management (including acei and arb treatment).

Given the crisis that this coronavirus seems likely to imbue on healthcare systems (especially critical care), it hardly seems a priority.

I did note that arbs are being trialled amongst severely I'll covid clients somewhere, although (I was led to believe) not based upon anything more empirical than the current conjecture.

I am surprised however that there appear to be few historical statistics like this relative to SARS or mers..

Or are there? Surely this data can be amassed in retrospect?

.. and I refer to those progressing into illness who were actively taking these drugs pre illness of course, as they would naturally be rapidly withdrawn once a patient becomes septicaemia heralds vasodilation.

As I have (possibly simplistically) visualized it, surely initial ace2 proliferation (if caused by these drugs) would be seen to worsen outcomes.

Viral load being heavy in all cases of tissue sampling (I am thinking) can't inform in terms of this thread unless collected from medicinal treated hypertensive patients?

Angiotensin converting enzyme (ACE) inhibitors inhibits not only the convention of angiotensin II from angiotensin I, but also the bradykinase that degrades bradykinin. As bradykinin is generally pro-inflammatory or an inflammatory mediator, whether the use of ACEI may worsen the symptoms during Covid-19 infection has to be considered.

Transitioning from acei to arb is argued generally well tolerated amongst those requiring to (having developed associated cough, for example). Acei half life in renally healthy individuals is 12 hours, and so I am guessing early suspension of acei and moving to an arb if necessary may therefore be seen as an appropriate measure given the lack of harm it would seem likely to bring about in the monitored medical environment?

Paul Walker agreed

ACE inhibitors seemingly lead to over-expression of ACE2 within body tissue. However, as stated patients with varying symptoms had similar intracellular viral ssRNA counts. This might implicate, that the ACE2 receptor status is irrelevant in terms of developing symptoms or not, but as stated by Weiguo different adherent processes might be relevant.

Benito Jonas Baldauf good point

Maybe this article is of interest?

https://www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600(20)30116-8.pdf

An important study to be made. Data must exist somewhere?

Related to the topic, how fast would the ACE2-receptors normalize upon withdrawal of ACE-inhibtors and ARBs?

ESH made a statement and noted that it “reflects current evidence at time of release and may need updating according to novel evidence”.

https://www.eshonline.org/spotlights/esh-statement-on-covid-19/

Thank you all. Great input. To sum it up:

- ACE2 expression is increased in patients treated with ACE inhibitors, ARB, ibuprofen or thiazolidinediones

- ACE2 expression could influence the course of COVID19 in 2 different ways: increased expression leads to increased mortality (by promoting viral entry) or increased expression leads to decreased mortality (due to ACE2 anti-inflammatory effects that could prevent ARDS development)

- some data may even suggest that viral load is not related to disease severity, so maybe ACE2 expression isn't the issue here, but rather some other mechanism (such as bradykinase-bradykinin balance)

Once again, thank you all. And good luck fighting this. We are beginning to see a explosion here in Portugal...

Are there drugs which prevent ACE receptors from being expressed completely?

Cristovao, could you kindly recommend papers that investigated this rise of ACE2 expressions in ACE inhibitors, ARB, ibuprofen or thiazolidinediones?

Another paradox is age, increasing age decrease ACE2 expression, while mortality is more in elderly!!

Elderly people take more ACE inhibitors, ARBs and Ibuprofen, might this be an explanation?

I've just asked a similar question, in the initial infection stage ACE II inhibitors could block entry but post infection with increased viral load, could we see a somatic inhibition of vascular constriction and the resultant dilatory effect having a hypovolemic presentation putting greater strain on the cardiac system paired with lowered O2 stats? In other words, is the infection causing hypotension in patients normally presenting with hypertension? Are there parallels to heparin overdoses?

Thank you, Jason, this is an additional aspect worth considering.

I thought more of the over-expression of ACE2 receptors in the lung cell membranes as a cellular reaction to the ACE inhibitors, ARBs and Ibuprofen, which was described in literature.

www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600(20)30116-8.pdf

As these are the gates for the virus, more gates per cell should result in more viruses entering the lung cells in patients with these medications, which are usually the old ones.

Relative to a previous reply, I believe most acei has a half life of 12 hours, resultant in trace blood levels in 3.5 days, whilst most arbs have a slightly lesser half life, meaning trace in 2 to 3 days.

Whether there is a delay leading to the cessation of further negative/positive effects in terms of Covid19 infection via other relativeinternal processes, I am not sure?

Another facet that would result in blood levels of these drugs remaining high despite withdrawal is of course the renal failure likely to occur in difficult to manage septicaemic individuals.

This would appear to me to be a highly likely outcome given my direct experience of ards patients in the critical care environment.

On that basis, and the weighting of the above discussion, the only possible pre research recommendation unlikely to result in negativity (but more likely positivity) is to withdraw acei and introduce arbs therapy in hypertensive patients as soon as viral diagnosis is attained.

Maintaining a septicaemic (likely hypotensive) critically ill patient on even a low dose of arb (should any benefit be perceived) might however prove a controversial care decision as goes critical care medicine prior to good clinical evidence.

Hi Paul, thanks that's very insightful. I'm not sure doseage levels would matter much if the virus is competitively binding to the receptors with as an antagonistic affect and messing up blood pressure homeostasis.

Maximilian, I was on a similar thought pathway on ingress but then started thinking about the possibility of the limited co-morbidity data being a sequelae effect on the burden load on the cardiovascular system, despite being antithetical, hypotension could pose an acute burden in the CV patients compared to chronic hypertension.

Maximilian Moser

First of all, a scientifically relevant discussion that suffers

from the mixing of very complicated pathophysiological

arguments and corona hype. Every reasonably thoughtful doctor

has certainly listened up to the identification of the ACE2

receptor and realized that a simple harmful or perhaps also

protective presumption of activity is just impossible.

Stating connections between the (very sensible but not

proven) RAS blocker prescription among elderly and patients in

northern Italy and the mortality rate uncritically is simply

adventurous. I would favor the more reasonable approach,

practiced by Paul Walker during a critical respiratory

deterioration, usually with sepsis

(and concomitant hypotension), to discontinue ACE inhibitors

like any other antihypertensive agent (according to respective

half-lives). Every clinician would know about the sometimes

allergy pretending symptom (rarely up to pulmonary edema) of

the ACE inhibitors, arising suspicion in this context.

However, no circumstances should urge us to remove this proven

therapy in its clearly proven setting amongst patients with

hypertension for some HOAX cruising the media.

Thank you, Paul, these are important aspects for a possible handling of patients!

I repeat what I understood:

ACEi half life: 12 hours ; only traces left after 3,5 days

ARBs half life: 9 hours (?) ; only traces left after 2-3 days

Renal failure patients: longer drug activity expected

Is is there any time delay after the drug washout until the receptor count goes back to normal level?

Sorry, Benito, this was not a HOAX but a correspondence in Lancet Resp. Med. which argues on sound scientific grounds. And the authors are not suggesting a removal of therapy but rather a replacement by therapies that do not open the gates of ACE 2 receptors.

If there is any doubt that an otherwise proven therapy could be dangerous or even fatal under certain circumstances, would you not try to rule out this possibility before exposing your patients to a possible danger?

I hope a study will be started soon to check, if there is any connection between the fatal outcomes and the patient's medication. Please correct me, but to my knowledge no such study exists that disproved the suspicion?

• Maximilian Moser thank you so much and like to reiterate your good question earlier in a slightly different way: Once the administration of ACEIs is stopped/withdrawn in patients (or other relevant experimental paradigms), how long does it take for the receptors, which are knowingly up-regulated after ACEIs, to return to the level without ACEIs intervention?

We obviously know that the data exists in terms of hypertensive patient outcomes relative to the hypertension management route they are treated with, even if up to the point that its treatment is withdrawn due to the hypotensive effects of intubation/ mechanical ventilatory sedation and/or sepsis.

Historical respiratory outcomes post intubation could be compared amongst those receiving aceis/arbs versus calcium channel blockers (for example)?

Not purely scientific given all of the variables, although it could well offer reasonably compelling data that adds credence to either a withdrawal of a drug at early diagnosis or further thinking?

Given the complexity of proving the exact pathways that aceis/arbs exert in relation to the virus, that might seem a more costly approach in both time and lives lost.

I have just opened a thread discussing the possibility of vagal modulation of COVID -19 inflammatory reactions, which might offer a chance to influence the outcome: https://www.researchgate.net/post/Children_have_a_high_chance_to_survive_COVID-19_infections-might_strong_vagal_activity_in_childhood_prevent_too_strong_immune_responses

Maximilian Moser I concur with your perception to rule out any potential harm to patients. However, the manuscript you mention is not arguing on sound scientific ground but on retrospective data analysis. Therefore they hypothesize rather than state. This hypothesis has not entered (SO FAR) consensus statements by ESCardio or ESH or any other "expert group" as linked to this discussion and clearly stated by Weiguo Zhang (please see above).

I want to emphasize, that in these critical times hypothesis can lead to misunderstanding, leading to WhattsApp messages going "viral", leading to premature conclusions.

A good friend of mine has one of the biggest invitro fertilisation clinics in Europe. Due to the message coming from Vienna University (later proving "fake news") that the course of COVID-19 could be agravated by using NSARs he changed the algorithm.

I am glad we live in times of evidence based medicine, and I urge every healthcare professional to adhere to evidence rather than eminence.

The viral load itself will have an (exponentially increasing) anti-hypertensive affect so removal of a low dose is unlikely to make a difference, re-normalisation of cardiovascular homeostasis is unlikely to be resolved via pharmacologic intervention (unless I've missed out a whole class of agonists). This could mimic issues with high altitude/high-G flights which the air force uses pressure suits to mechanically load a pressure function to peripherals to increase venous return.

Benito Jonas Baldauf , the only fake news concerning the matter we discuss was, that Medical University of Vienna has performed a study. This seems to have circulated in Whatsapp. From this, obviously wrong information, suddenly the conclusion was drawn by some doctors, that ALL news concerning ARBs, ACEIs and Ibuprofen and their possible connection to COVID-19 infection complication is ALSO fake news, which is really NOT the case.

So let us take serious the concerns of responsible scientist as long as no study is available, as their arguments are comprehensible. In most of the patients, a transient change in medication might be much less dangerous than a severe pneumonia.

I agree with you that at the same time a study which investigates data from COVID -19 patients that had or had not fatalities during the recent past would be really helpful.

If anyone has access to such data or to other scientists that have, please urge them to start such a study!

Maximilian Moser I consent in terms of a possible connection of ACE2 relevant medication and outcome in COVID should further be evaluated.

So far the facts are:

• upregulation of ACE2 in heart cells by ACE inhibitors and angiotensin-1 receptor blockers could be shown in animal experiments with rats
• there is no evidence that these drugs exacerbate the COVID-19 course. In the case of ACE inhibitors and sartans, the opposite could also be the case

Tadeusz Osadnik I tried to point this out in the following question thread. One possible reason is that children have a high vagal activity which is known to reduce inflammation: https://www.researchgate.net/post/Children_have_a_high_chance_to_survive_COVID-19_infections-might_strong_vagal_activity_in_childhood_prevent_too_strong_immune_responses

With the large amount of data data that is (unfortunately) collected during this current COVID-19 pandemy ist should be possible model linkage between prescription of ACEIs /ARBs and severity of COVID-19. Daily defined dosage per 1000 inhabitants (DID) varies considerably between countries: Italy (Campania) 2016 (Malo S 2019): 220, Spain (Aragon) 2016 (Malo S 2019): 160; Lithuania 2012 (Lisauskienė I 2017): 190; Sweden 2012 (Lisauskienė I 2017): 145; Norway 2012 (Lisauskienė I 2017): 120; Australia 2006 (Huang LY 2013): 120, Taiwan 2006 (Huang LY 2013): 42.

Multivariate modeling of influence of DID of ACEIs/ARBs on mortality of CIVID-19 would be an option.

Here is a new paper related to the virus https://pubmed.ncbi.nlm.nih.gov/32064853/ the mortality part may be more relevant to the group discussion, though the uses of anti-hypertensive drugs or cardiovascular drugs were not specified. The original is in Chinese, I have the following with the help of Google translator. “Deaths, crude case fatality rate and case fatality rate: Among the 44 672 confirmed cases, there were a total of 1023 deaths, with a crude case fatality rate of 2.3% and a case fatality rate of 0.015 / 10 person-days, which means that the average risk of death per patient observed for 10 days was 0.015. The highest crude case fatality rate in the age group ≥80 years was 14.8%. The crude case fatality rate was 2.8% for men and 1.7% for women. By occupation, the highest crude case fatality rate for retirees is 5.1%. The crude case fatality rate (2.9%) in Hubei Province was 7.3 times higher than in other provinces (0.4%). The crude case fatality rate for patients with no comorbidities is approximately 0.9%, and the case fatality rate is much higher for patients with comorbidities, 10.5% for cardiovascular disease patients, 7.3% for diabetes, 6.3% for chronic respiratory disease, and 6.0%, cancer was 5.6%. Severe cases accounted for 13.8%, and critical cases accounted for 4.7%. The crude case fatality rate of critical cases was 49%, and the case fatality rate was 0.325, which means that the average risk of death for every 10 days observed in each case was 0.325. See Table 1.”

Thankyou Je Do.

That is very helpful. As stated I am a registered nurse in ICU and am learning all the time, but do not have a medical education.

Given the premise that at1 may exacerbate acute lung injury, and that at2 will protect against it, as I see it that lends credence to the argument that ARB's may protect whereas ACEi's may exacerbate.

I base this upon the modality of ARB's, which (and apologies if I have been railroaded in my understanding) are argued to block angiotensin 1 receptors.

ACEi's conversely inhibit the formation of angiotensin ii.

I am very probably guilty of under thinking the complexity of the various chemical availabilties in different drug scenarios versus receptor status, but would be happy for clarification if even possible.

Ie. Is this further argument that arbs are a safer modality of treatment than ACEi , if not even a protective influence?

I hope that doesnt come across as naive and having missed some basic principles.

Much of the controversy about the positive or negative effect of ARB/ACEI is based on a time confusion. The positive effect of ACE2 would only occur AFTER the SARS-CoV-2 entered into the target cells. On the opposite, BEFORE its entry, the ACE2 availability may potently increase the number of receptors for the virus spike proteins and leads to an enhanced severity of the infection. What we urgently need now is the ratio of death according to the use or not of ARB/ACEI among the patients with comorbidities (hypertension, diabetes, CVD). It's a great stress to ignore whether we do or do not reduce the risks of patients with such a meaningfull mechanism in mind.

Based on epidemiologic studies performed on SARS-COV infected cells which utilize the same ACE2 cell entry mechanism, found down-regulation of ACE2 after viral cell entry as well as increase cytokine expression, considered a possible explanation for pulmonary destabilization in SARS. I believe extrapolating this information in the setting of SARS-COV-2 is not unreasonable.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1829448/

Also I believe it essential to consider the rates of ACEi/ARB withdrawal in the ICU setting of COVID-19 patients: upregulation of ACE2 in these patients due to drug use prior to infection potentially increase the virulence of SARS-COV-2, inherit down-regulation of ACE2 upon intracellular infection with COV-2, potential withdrawal of ACE2-inducing medication pushes patient to sub-normal ACE2 levels, precipitating dis-regulated immune response (potentially cytokine overproduction), resulting in the worsened pulmonary/ cardiac prognosis in these patients.

I am a PharmD. by the way.

How about the antiviral properties of NSAIDs?

Several NSAIDs have found to have antiviral properties.

Indomethacin has a potent antiviral activity against SARS coronavirus.

Source: https://www.intmedpress.com/servefile.cfm?suid=35d8dc5e-70f4-491f-acad-e35f99be9211

Ibuprofen-https://www.discovermagazine.com/health/new-drug-inspired-by-ibuprofen-protects-against-flu

Indomethacin and Naproxen

https://www.pharmacists.ca/cpha-ca/assets/File/cpha-on-the-issues/Use-of-NSAIDs-in-patients-with-COVID-19-FINAL-EN.pdf

Antiviral

Source: Article Non-Steroidal Anti-Inflammatory Drugs Increase the Antiretro...

https://www.ncbi.nlm.nih.gov/pubmed/20032540

Seen incase of CoV (2002), CCoV, Inflenza A&B

Source: https://www.youtube.com/watch?v=dT6mHi_8V5E&t=79s

NSAIDs and Coronavirus: https://www.researchgate.net/post/NSAIDs_and_Coronavirus

Maybe it's just coincidence, but I've found this data from Japan and South Korea. ACEis are not prescribed there as in the rest of the world.

Article Korea hypertension fact sheet 2018

Article Current prescription status of antihypertensive drugs in Jap...

Gustavo Campos It was reported many years ago that the tolerance to ACEIs was lower than to other classes of antihypertensive drug therapy in patients of the East Asia, i.e. Korea, Japan and China

https://pubmed.ncbi.nlm.nih.gov/10826395/

https://pubmed.ncbi.nlm.nih.gov/11338920/

https://pubmed.ncbi.nlm.nih.gov/10694829/

There can be a couple of reasons, e.g.

1. Higher dietary salt intake in the region, which increases blood volume and lowers renin activity, thereby the blood pressure-lowering effect of ACEIs seen in others is less.  

2. Genetic polymorphisms of angiotensin-converting enzyme (I/D) - the I carriers are more in east Asia and sensitive to ACEs-induced cough.

Results between ACE-I-induced cough and ACE insertion/deletion polymorphisms and BDKRB2 gene polymorphism have been reported in studies. The majority of the populations in these studies are of East Asian origin. This might be the reason for less prescription in this context within South Korea and Japan.

Unfortunately Big Pharm is attempting to mitigate potential damage by focusing attention ONLY on the immunomodulatory/ pulmonary-protective aspect of ACE2. I was worried about this:

https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaa235/5810479

Article Host susceptibility to severe COVID-19 and establishment of ...

It seems Hypertension is correlated with severe cases.

I think that Patients using ACE2 inhibitors and ARB inhibitors, are more protected from COVID-19 than patients do not use them. Why? Exactly because of ACE2 inhibitors and ARB inhibitors are blocking ACE2 AND ARB receptors. So, is impossible for retrovirus to enter in to the human pulmonary cells through these receptors. So, grave conditions that cause ARDS do not come from entering of retrovirus through ACE2 or ARB pathways, but are maybe from secondary bacterial infection.

Pirro Prifti , ACEI are blocking the angiotensine converting enzyme thus reducing the conversion of less active angiotensine I to the more active angiotensine II, a vasopressin. This is the reason why they are lowering blood pressure. The reduction of angiotensine II by this inhibition in turn lead to an upregulation of ACE2 receptors in some animal studies, as the organism tried to balance the lack of a stimulus by more receptors.

These receptors are, at the same time, thedocking stations for viruses like SARS and MERS, and also COVID-19.

There is a summary of recommendations for differentiated action, depending on the history and state of the patients here: https://www.cebm.net/angiotensin-converting-enzyme-ace-inhibitors-and-angiotensin-receptor-blockers-in-covid-19/

if are you right then patients must to be taken more and more inhibitors to block ACE2 receptors. Or not? But is not true in reality. Patients continue to take the same doses of inhibitors of ACEi . So problem is not entering of retroviruses through ACE2 or ARB receptors but is another reason why retroviruses entering to the interstitial stroma of alveols. Retrovirusesare to say 'big ' viruses and can not enter through ACE receptors but maybe they activate inflamator enzymes and so create path to enter into the cells.

That is the reason why vitamin C in big doses to 24 gr i/v has good effects in treatment of ARDS complication.

I think this minireview explains your question, Pirro Prifti, well: https://www.cebm.net/angiotensin-converting-enzyme-ace-inhibitors-and-angiotensin-receptor-blockers-in-covid-19/

Vitamin C is an antioxidant reducing oxidative stress. Oxidative stress is proinflammatory and therefore less wanted in such conditions.

Allthings are unclear but is known that GeneHancer (GH) Regulatory Elements for ACE2 Gene (6 genes together) are ~14.1kb, but one coronavirus is 27-35 kb.

Dear Maximillian, You are for two reasons:

First vit C has anti inflamatory action; look the article-

Results

In the experimental group, vitamin C significantly reduced the levels of high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), fasting blood glucose (FBG), and triglyceride (TG) after 8 weeks of treatment (overall: P

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492638/

C-reactive protein (hs-CRP) increased in Humans by Fluoride

Article Increased Plasma Neopterin and hs-CRP Levels in Patients wit...

Thank you Pirro, for the interesting link!

The US Government Comparative Toxicogenomics Database has over 100 entries for Fluoride impacting IL-6 in numerous diseases.

Fluoride increasing IL-6 in Human Lung cells

Article Fluoride-induced interleukin-6 and interleukin-8 synthesis i...

It is absolutely important that the intakes of nutrients (inc. vitamin C) should be optimized for general health and well-being. However, it’s not determined yet whether 24 grams per day of ascorbic acid i.v. is empirically-proved beneficial or not. It seems that a dose-response relationship cure is unavailable beyond the circulating level of 70-80 micro mol per litter, which is an achievable plasma plateau known thus far.

An empirical basis for all things is essential, surely?

I am long enough in the tooth clinically to well remember activated protein C (Zigris) used as blanket therapy based upon (biased?) research. Near $7000 per 3 vial course (1 week) for all septic patients in the UK at a then cost of billions of pounds. Years later more balanced research suggested no benefit whatsoever.

Oh.. really???

Can I also say with any confidence that IV selenium, zinc and ascorbic acid (vitamin c) therapy had a positive effect overall over many years of similar application in the critical care clinical environment? Erm...

Certainly not a scientific standpoint, but I can say that despite wishing to note distinct cursory benefits, nothing dictated anything particularly outstanding about any of these treatments to me.

The anti inflammatory properties have been noted and discussed relative to vitamin C in high dosage for many years now, so despite it having definite validation in most peoples minds, the mass of evidence is still unable to dictate emphatic courses of action.

Im not trying to decry any said therapy (excepting the disastrous Zigris...), although the focal point of this thread was supposedly exploring the existing data in relation to covid19, arbs and ace1 was it not?

It's out there (the truth of this) and it shouldn't be too hard to collate hard data as long as sources are prepared to divulge it (it would be surprising were they not given what we are collectively up against).

Is anyone interested in exploring it?

It's a feather for someone's cap..

Just saying....

Dear Zhang, please read your acompanions what they said about high doses of vit c i/v for treatment of covid-19 complication 's ARDS.

https://clinicaltrials.gov/ct2/show/NCT04264533

Dear Paul, I agree with You.

Maximilian Moser

https://www.nejm.org/doi/full/10.1056/NEJMsr2005760?query=RP

Key Points Related to the Interplay between Covid-19 and the Renin–Angiotensin–Aldosterone System

• ACE2, an enzyme that physiologically counters RAAS activation, is the functional receptor to SARS-CoV-2, the virus responsible for the Covid-19 pandemic
• Select preclinical studies have suggested that RAAS inhibitors may increase ACE2 expression, raising concerns regarding their safety in patients with Covid-19
• Insufficient data are available to determine whether these observations readily translate to humans, and no studies have evaluated the effects of RAAS inhibitors in Covid-19
• Clinical trials are under way to test the safety and efficacy of RAAS modulators, including recombinant human ACE2 and the ARB losartan in Covid-19
• Abrupt withdrawal of RAAS inhibitors in high-risk patients, including those who have heart failure or have had myocardial infarction, may result in clinical instability and adverse health outcomes
• Until further data are available, we think that RAAS inhibitors should be continued in patients in otherwise stable condition who are at risk for, being evaluated for, or with Covid-19

Benito Jonas Baldauf

you should also mention the interconnections of the authors of this study to a multitude of pharmaceutical companies:

https://www.nejm.org/doi/suppl/10.1056/NEJMsr2005760/suppl_file/nejmsr2005760_disclosures.pdf

I hope that the clinical retrospective studies on the way will bring more light into the issue.

Thank You Dear Benito

@ Cristóvão Figueiredo, a relevant discussion adequately summed up.

There was a phase II study administering recombinant soluble human Angiotensin Converting Enzyme 2 intravenously in healthy volunteers https://clinicaltrials.gov/ct2/results?cond=&term=Ace2+&cntry=CH&state=&city=&dist= Does anyone know whether the results were published?

https://www.quora.com/q/evolutionary-biology-1/Blood-Pressure-Meds-Point-the-Way-to-Possible-COVID-19-Treatment?ch=3&share=0368c627&srid=SyPwe

Weiguo Zhang

Angiotensin‑converting enzyme 2 (ACE2) as a SARS‑CoV‑2 receptor: molecular mechanisms and potential therapeutic target.

Zhang et al. Intensive Care Med (2020) 46:586–590; https://doi.org/10.1007/s00134-020-05985-9.

Dear Jeronimo,

I think is better to make a study about mortality from COVID-19.

In this study must be compared cases of individuals death but that have taken ACEi drugs as treatment of Hipertension , with individuals death that did not have take ACEi drugs. Aim of this study is to understand how ACi drugs can protect or hurt individuals infected with COVID-19.

Second is better to make a comparision study between individuals death from COVID-19 but that have taken ACEi drugs and individuals death from COVID-19 that have taken ARB drugs (losartan, valsartan ibersartan etc).

Dear Paul ,

chronic uses of ACEIs and ARBs lead to upregulation of protective ACE2 receptors, which are protective against COVID-19. however, ACE2 is deem as entry-point for SARS-CoV2 . high risk of mortality of patients with T2DM or hypertension in COVID-19 is related to the augmented plasminogen pathway in those patients, as plasmin is regarded as novel entry-point for SARS-CoV2

with regards

Dear Hayder,

do you know about studies mentioning a protective role for ACE2 receptors against COVID-19 ? If yes, would you please share them with us. Thank you.

Marc P Kaltner

both statements rather than studies, at this time early into the pandemic

Article Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 ...

https://www.news-medical.net/news/20200408/Trial-assesses-tissue-plasminogen-activator-as-a-treatment-for-COVID-19-related-respiratory-failure.aspx

Cristóvão Figueiredo

this is

Benito Jonas Baldauf

Thank you for clarifying !

Frontiers is now calling for papers in the field https://www.frontiersin.org/research-topics/13713/what-do-we-know-about-covid-19-implications-for-cardiovascular-disease?utm_source=fweb&utm_medium=fmain&utm_campaign=sub-rt-fpubh-covid-19?utm_source=em&utm_medium=f-nlt&utm_campaign=sub_cov-rt__call-for-papers

Has two theories that explain virulency of COVID-19:

There’s a G6PD theory:

https://t.co/o2P8g3Bujm

BCG-immunity theory https://t.co/3Rs9RckQLJ

(https://www.medrxiv.org/content/10.1101/2020.04.07.20053272v1)

There is a strong correlation between circulating ACE2 activity (not membrane bound) and pathology/treatment associated with increased risk of developing SARS-CoV-2. See my report.Technical Report Correlation of circulating ACE2 activity with severe acute r...

The rational of this weird association is described in:

Preprint The Rational for Administration of ACE2 Pathway Inhibitors i...

Eh, partially true.

Must be done a comparision data between death persons that were treated with ACEi and ARB medicaments- with death person that were not treated with these kind of medicaments.

Sure! But the problem I see now is clinical trials with ARBs and ACEi administered to normotensive COVID-19 patients, they cannot be protective! And what about the clinical trials with recombinant ACE2 that will further increase circulating and functional ACE2, I think it is not a smart idea!

Thank You.

.........

How does COVID-19 happen?

Roger Paredes, Head of the Infectious Diseases Section at Germans Trias i Pujol Hospital, near Barcelona, tells Euronews that there are three different stages of the infection for people developing COVID-19 symptoms:

• The viral phase: when the virus replicates very quickly within the respiratory system. Symptoms are similar to common flu and disappear spontaneously after 6 to 10 days (roughly). It is the case for about 80% of the patients.
• The pulmonary phase: The other 20% of the patients might develop a pneumonia. It’s a very specific type of pneumonia, attacking both lungs and causing respiratory distress.
• Severe phase: around 10% of the patients develop a “cytokine storm” an uncontrolled inflammatory response of the immune system which is causing most of the critical conditions and eventually, fatalities.

( https://www.euronews.com/2020/04/09/understanding-covid-19-the-unknown-disease-with-multiple-faces )

Other than drug therapy, angiotensin-converting enzyme (ACE) activity can be suppressed by non-pharmacological approaches. For instance, in a meta-analysis published in 2013, we found a blood pressure-lowering effect of Isoleucine-Proline-Proline and Valine-Proline-Proline ( IPP and VPP, derived from milk or dairy products) Article Lactotripeptides intake and blood pressure management: A met...

A personal observation is that of glutathione deficiency in all underlying conditions seen in COVID-19 mortality, which is true in relation to the elderly. I am not an expert in the field, but given the crisis I have been trying to find a link among those who have succumbed to the disease in the hope to add to the existing body of knowledge.

There is evidence to suggest that glutathione depletion results in H2O2 accumulation and resulting 'cytokine storm', inflammation of lung parenchyma, lung fibrosis, microcirculatory dysfunction, progression to refractory hypotension and fatal septic shock.

Could more efficient cellular viral entry through increased ACE2 receptors in COVID-19 patients on ARBs and ACEi, mean more rapid depletion of already deficient glutathione reserves? Could the morbidity of COVID-19 in addition to atypical RAS signalling, be the accummulation of H2O2 and xenobiotic stress as a result of glutathione depletion? Could environmental conditions, lifestyle and dietary choices add to xenobiotic stress in symptomatic COVID-19 patients. Some of which could include carbon-monoxide exposure, cigarette smoking (low glutathione), narcotic abuse, excessive use of acetaminophen (? Tylenol), ibubrophen use, asbestos exposure, mercury exposure, mycotoxin exposure (black mould), aflatoxin contaminated food and milk (endemic in certain areas of the globe).

Symptoms of Glutathione depletion:

- Shortness of breath

- Cough

- Sepsis

- Nitric oxide deficiency

- Refractory hypotension

- Lung injury

- Fibrosis

Perhaps simple substances that boost glutathione reserves like N-acetylcysteine (mucolytic, reduces fibrosis and pneumonia); alpha lipoic acid, L-glutamine; L-glutathione etc. could improve outcomes of symptomatic patients and prevent adverse reactions in high-risk population.

I may have gone off on a tangent or perhaps this theory has substance.

Thanks.

https://www.google.com/search?sxsrf=ALeKk000z8n5aE8kuPYA84RmIifvI3LN8A%3A1587409196883&ei=LPGdXpSvNYvergSa4564Cw&q=who+are+specific+immuno+globulian+that+are+risen+after+a+COVID-19+infection%3F&oq=who+are+specific+immuno+globulian+that+are+risen+after+a+COVID-19+infection%3F&gs_lcp=ChNtb2JpbGUtZ3dzLXdpei1zZXJwEAMyBAgeEAo6BAgAEEdQgyNYjXdgtIgBaABwAXgBgAHvBogBqS2SAQsyLTYuMS4zLjMuMZgBAKABAQ&sclient=mobile-gws-wiz-serp

does ARBs are more safer than ACEIs in COVID-19

While ESH COVID-19 Task Force published a review last week, it seems largely inconclusive still on the use anti-hypertensive therapy with AECI based on data currently available in the field: Hypertension, the renin–angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-19: European Society of Hypertension COVID-19 Task Force Review of Evidence. https://academic.oup.com/cardiovascres/article/doi/10.1093/cvr/cvaa097/5819836?searchresult=1

Check this site: http://www.nephjc.com/news/covidace2

contains EBM question/answers

If one has been on ARB for many years, will stopping or changing the medication reverse the changes in the receptors caused by the long term use of the medication? If yes, how long does it take for the reversal? If that is not going to happen at a sufficiently fast rate, there would be no point in stopping the medication!

https://www.thegreenjournal.com/article/S0167-8140(20)30185-7/fulltext)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848110/