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More Therapeutic Ideas for the Coronavirus: Too Much Inflammation?

So today I’d like to talk about some of the other anti-coronativirus possibilities that I haven’t gone into yet – these posts will never make a comprehensive list, but at least I can cover some of the more interesting ideas, I hope.

Interleukin-6 is an interesting story. This preprint from German researchers presents some evidence that IL-6 levels correlate with the likelihood of severe respiratory symptoms in coronavirus-infected patients: the more IL-6, the worse the outlook. That makes sense, because the protein is already well-established as a big player in immune and inflammation pathways. The question is whether in some patients the immune response gets out of hand; there’s a very real chance that many of the worst outcomes are as much a problem with a patient’s reaction to the viral infection rather than the infection per se. There were early indications of this in the epidemic; this is the “cytokine storm” that you hear about so much these days, and the remedy for such a situation is to try to turn the immune signaling back down.

Anti-IL-6 antibody therapies have been developed for just that purpose, for patients with autoimmune disorders who need to turn the dial down in just that manner. Rheumatoid arthritis patients generally have elevated IL-6, for example, and tocilizumab (brand name Actemra) was approved by the FDA in 2010 as a therapy. It’s since picked up other indications, such as use in “cytokine release syndrome”, a similar over-stimulation that can show up as a complication in the new CAR-T engineered T-cell therapies for cancer. So its use in the current epidemic seems like a reasonable idea. It’s been approved for that purpose in China, there are anecdotal reports from there, from Italy and from other areas, and there are trials underway or planned in China, Switzerland, the US, Belgium, Greece, and Denmark at the very least. There’s another anti IL-6 antibody that was approved in 2017 (sarilumab, brand name Kevzara), and that one is also going into coronavirus trials.

Update: via the comments, there also siltuximab (brand name Sylvant), an antibody which targets the IL-6 protein itself rather than receptor, as the two above do. It’s also being looked at in the clinic, and it’ll be interesting to see if there are different effects, since some of these proteins have functions beyond those mediated by their receptors.

A similar possibility is anakinra (brand name Kineret), which targets the IL-1 system. Interleukin-1 is also a big player in the immune response, and unraveling its complexities is an ongoing project, since there are 11 related interleukins in that family (isn’t immunology great?) But they generally work through a limited set of IL receptors, and there’s even a natural antagonist protein (IL-1R) that blocks one of them. Anakinra is a modified version of that antagonist, and it’s also in trials (in fact, it’s an arm of some of the same trials investigating the IL-6 antibody). And there are other ways to target the response. Here’s a proposal to use antagonists of the alpha-1 adrenergic receptor such as prazosin, and here’s one to try low-molecular weight heparin. Sphingosine kinase 2 is involved in inflammation signaling, and an investigational inhibitor of the enzyme (opaganib) is being tried in Italy. Ruxolitinib (brand name Jakavi) is a Janus kinase inhibitor that also affects these pathways and is being looked at as well. There’s even a technique to filter out such signaling molecules from the blood that’s getting a look.

Obviously turning down the inflammation response if there aren’t signs of overstimulatory trouble would (you’d think) be a bad idea. Many of these drugs carry warning labels on them already about not using them during acute infections or noting that they can increase the risk of one. But if overstimulation of the immune response really is the problem, this approach could be just what’s needed. Picking out the patients that will benefit will be the tricky part!

72 comments on “More Therapeutic Ideas for the Coronavirus: Too Much Inflammation?”

  1. Robert R. Fenichel says:

    “Prazosin” is so spelled

    1. Derek Lowe says:

      So the link should have told me! Fixed. . .

  2. DoesitMatter says:

    Wonder if Indomethacin’s known anti-inflammatory activity would complement its obscure, but known, effect against Coronaviruses?

    https://www.ncbi.nlm.nih.gov/pubmed/17302372

    1. Kaleberg says:

      I was prescribed indomethacin once, for pain. It cranked up my blood pressure big time. I switched back to ibuprofen. I gather indomethacin has many happy users, but I’d keep an eye on blood pressure when using it for COVID.

    2. Nathan says:

      New paper:
      “Indomethacin has a potent antiviral activity against SARS CoV-2 in vitro and canine coronavirus in vivo” (2020)

  3. Andy II says:

    I’m sure that everyone is already aware of this: BCG vaccination vs. Coronavirus infections. Not sure if this topic had been already covered by Derek but just in case.

    My friend forwarded me this: Fewer coronavirus deaths seen in countries that mandate tuberculosis vaccine https://www.japantimes.co.jp/news/2020/04/09/world/science-health-world/fewer-coronavirus-deaths-seen-countries-mandate-tuberculosis-vaccine/#.Xo9ZiZkpB4E

    Can an Old Vaccine Stop the New Coronavirus? https://www.nytimes.com/2020/04/03/health/coronavirus-bcg-vaccine.html

    The preliminary study posted on medRxiv, a site for unpublished medical research, finds a correlation between countries that require citizens to get the bacillus Calmette-Guerin (BCG) vaccine and those showing fewer number of confirmed cases and deaths from COVID-19. Though only a correlation, clinicians in at least six countries are running trials that involve giving front-line health workers and elderly people the BCG vaccine to see whether it can indeed provide some level of protection against the new coronavirus.

    1. MagickChicken says:

      I feel like all nurses should already be vaccinated against TB, given its transmissibility.

      1. Barry says:

        and they would be if there were an efficacious Tuberculosis vaccine. People are still working on that 100yrs later. The BCG vaccine doesn’t protect adults against TB

        1. Thomas Lumley says:

          At least as important, the vaccine means you can’t be usefully tested for exposure

        2. OC says:

          Clinical trial in rhesus macaques showed significantly improved efficacy of BCG vaccine vs pulmonary tuberculosis infection when given intravenously vs intradermally.

          https://www.jwatch.org/na50641/2020/01/30/intravenous-bcg-prevents-tuberculosis-animal-model

          Obviously you’d need to run trials to assess safety in humans but would note vaccine is 100 years old and no adverse events were noted in the animal model.

    2. Marlene Beier says:

      As we may all know, the human immune system remains the vital key to our survival. Over the years, many people tend to naturally develop higher immune strength to certain infections. Therefore, since the symptoms of COVID-19 are very alike that of Tuberculosis (TB), maybe a closer look at the antibodies of individuals that may have had active TB and are now healthy might lead Researchers on to something! Assuming those individuals do actually show certain resilience because they had been exposed to similar infections like COVID-19, such higher defense mechanism can be passed on to COVID-19 patients, hence help save lives. This can be done in line with the current Blood Plasma trails instead of just relying and rushing for limited convalescence plasma from recovered COVID-19 patients. This might also help to alleviate challenges at the moment in relation to getting correct antibody titre for Blood plasma trials. I reckon each country would hopefully have records of past active TB patients who are now healthy and willing to donate blood to help out! You never know, hopefully further research into the findings might lead Researchers to develop a vaccine for COVID-19. BCG vaccine trials is a good hopeful preventive measure but may not necessarily help people who are already infected with COVID-19.

  4. Aleksei Besogonov says:

    Have you seen the invermectin study: https://www.sciencedirect.com/science/article/pii/S0166354220302011 ?

    1. Derek Lowe says:

      Yep, that’s coming up in another post shortly! Thanks. . .

      1. Sam says:

        Derek, can I flag the first 25 minutes of this podcast for you? Doris Cully worked on ivermectin for Merck and she talks about that research in detail. My lay understanding is, the approved dosing does not inhibit SARS-CoV2 and the inhibitory doses have never really been given in humans. Thanks again!

        https://www.microbe.tv/twiv/twiv-599/

        1. Renee says:

          Yeah, the title to that study seems misleading when you look at the dosing.

      2. George Stanchev says:

        Please take a look at the following calculations

        https://twitter.com/__ice9/status/1246716095614070784?s=20

        Quote

        Oral bioavailability is about 25% but that varies. IC50 is 2.5µM. Molar mass is 875.1g/mol. Assuming uniform tissue distribution, best guess human equivalent might be ~440mg.

        This is likely to be fatal.

        Typical human dose is only 200 mcg/kg = ~14mg.

        1. OC says:

          https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133431/

          Cites studies showing plenty of evidence doses up to 2,000mcg/kg safe and well tolerated.

          Still suspect may struggle to get lung tissue levels up to effective IC50 value though.

  5. PK Matters says:

    Effective in vitro at ~2 micromolar = 1.75 micrograms/ml. Observed Cmax in circulation = 50 ng/ml (Canga et al, AAPS J. 2008 Mar; 10(1): 42–46).

    1. Sharif says:

      Certara has simulated plasma and lung ivermectin steady-state concentration following a 3-fold higher than approved dose. At this high dose, lung concentrations are approximately 20-fold lower than the IC50 of 2uM. Take a look at Certara’s webinar at 46 min https://www.youtube.com/watch?v=aXpBjfemexQ

  6. Mitch Berkson says:

    Any connection between IL-6 (if it suppresses hair growth) and “…investigating whether the genetic cause of hair loss could help to explain greater severity and more fatalities among male COVID-19 patients.”

    https://www.brown.edu/news/2020-04-07/androgen
    https://onlinelibrary.wiley.com/doi/10.1111/dth.13365

      1. JimM says:

        Really interesting. From the abstract of the article you link, Derek:

        Taken together, our data strongly suggest that DHT-inducible IL-6 inhibits hair growth as a paracrine mediator from the DP.[Dermal Papilla]

        So men taking Finasteride, which inhibits production of DHT, could suffer less inflammation, perhaps.

        But adipocytes produce il-6, and obese people show higher levels; even more worryingly, pregnant women also have higher levels of il-6 — and mortality rates from the 1918 pandemic flu were apparently far higher among pregnant women than the general population.

        1. Luke says:

          I’m a 62 year old man and I’ve been on testosterone replacement therapy for about 5 years since my natural production packed up. It’s clear that I have always been on the low side. I suspect klinefelter though the only time I took a test the hospital messed up and the test failed to produce a result one way or another.

          I take Nebido, which is a long duration injection lasting (for me) 11 weeks. My next shot is due in 3 weeks and I am seriously wondering whether I should skip it. Apart from the difficulty of finding a primary care nurse to give it, I am internally debating whether I am better going to a low T state for now, unpleasant as that will be.

        2. charlie says:

          and I’ve got to wonder what role the il-6 myokine plays in this.

      2. Ben says:

        Kinda reluctant to mention this but, “In all of the hair loss patients, the mean serum zinc was 84.33±22.88, significantly lower than the control group (97.94±21.05 µg/dl) (p=0.002)”
        .
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870206/

  7. Andy II says:

    This might be a duplicate but is very intriguing. And it looks like very hot now.

    Fewer coronavirus deaths seen in countries that mandate tuberculosis vaccine:
    The preliminary study posted on medRxiv, a site for unpublished medical research, finds a correlation between countries that require citizens to get the bacillus Calmette-Guerin (BCG) vaccine and those showing fewer number of confirmed cases and deaths from COVID-19. Though only a correlation, clinicians in at least six countries are running trials that involve giving front-line health workers and elderly people the BCG vaccine to see whether it can indeed provide some level of protection against the new coronavirus.

    https://www.japantimes.co.jp/news/2020/04/09/world/science-health-world/fewer-coronavirus-deaths-seen-countries-mandate-tuberculosis-vaccine/#.Xo9mfZkpB4E

    https://www.sciencemag.org/news/2020/03/can-century-old-tb-vaccine-steel-immune-system-against-new-coronavirus

    https://www.cnn.com/2020/04/09/health/tuberculosis-bcg-vaccine-coronavirus/index.html

    1. Jonathan says:

      The UK is on course to have one of the highest mortality rates in Europe, if not the world. We have had compulsory BCG immunisations for a very long time, I’m 55 and it wasn’t new when I had mine at age 13. So at least in one high profile country I would argue that this is not the case.

      1. A Nonny Mouse says:

        Protection, it seems, only lasts 20 years.

        I refused it given the state of my sister’s and cousins’ arms after the jab even several months later!

        1. dm says:

          Some anecdotal information suggests it is the specific strain of vaccination used. The older/earlier strains are suggested by correlation to be more effective. UK, Australia used newer strains. East Germany, Japan, Portugal used older strains.

          1. milkshake says:

            I got mine BCG in the former Czechoslovakia as a kid, and my positive reaction to TB (tuberculin skin test) lasted into my 40s when I was last tested (Johns Hopkins requires all employees, even non-medical, to take the test). Had to have blood test and chest X-ray to prove I really don’t have TB. It was even worse when applying for Green Card – the doctors at the clinic in the poor suburb of Tucson,really wanted to put me on 3 month drug regiment to cure my live vaccination

      2. Anonymous says:

        Those born after 1992 (ie people 27 years old and below) won’t be immunised, as BCG vaccination in the teens stopped in the mid–late noughties. Not that it detracts from your overall point, because we still have a big chunk of the population who’ve had it, but thought I’d make a (non-judgemental) comment for the sake of correctness.

    2. Simon Auclair the Great and Terrible says:

      Interesting, thought to boost cellular immunity. I bet cell. Imm. Is why some survivors don’t show ab response.

      I first read and posted an article about this last week and been seeing a number since. Heres another. https://asiatimes.com/2020/04/tb-vaccine-offers-hope-in-covid-19-war/

  8. CAR-T guy says:

    Siltuxumab is an IL-6-targeting antibody, whereas tocilicumab and sarilumab target the IL-6 receptor – this might affect the clinical efficacy (e.g. actually increase serum levels of IL-6 if the receptor is blocked by toci/sari).
    Google just told me that there is an Italien single-arm trial on siltuxumab use in COVID-19 pre-published: https://www.medrxiv.org/content/10.1101/2020.04.01.20048561v1

    1. Derek Lowe says:

      I’ll add that to the post – thanks!

  9. Calvin says:

    I’ll add in my 2 cents. So I think the general feeling in the virology community is that what we see if virus replication and once peak viral load is reached we start to see the full effect on the immune system kicking in. I’d bet that disease severity is roughly correlated with higher viral loads. Why some people have a higher viral load than others is interesting. Most likely a combination of initial inoculum and some host genetics/immune response. The virus is very good a hiding from the immune system so that part will be complicated. The question becomes what kicks off the severe immune response. Again I suspect it’s not straightforward and there will be some cell death but also some cell rupture caused by sheer volume of virus. We do know in some other respiratory viruses, disease severity is correlated with viral load, and that one of the big issues is all those cells exploding releasing huge amounts of debris. That’s often felt to the cause of spontaneous apnea in some patients.

    So I suspect that some dampening of the immune system would help, but it’s going to be ferociously hard to figure out what to dampen and my how much. And it’s likely to vary patient to patient.

    All in all I think this is worth trying, but at the end of the day viruses exist to replicate, and if you can stop them replicating (before it gets to peak viral load) that always works.

  10. Marko says:

    No mention of hydroxychloroquine in an article about IL-6 suppression ? How strange.

    Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology
    https://www.nature.com/articles/s41584-020-0372-x

    “In vitro, hydroxychloroquine and chloroquine inhibit the production of IL-1, IL-6, TNF and IFNγ by mononuclear cells (Fig. 4). Furthermore, treatment with hydroxychloroquine inhibits the production of TNF, IFNα, IL-6 and CCL4 (also known as MIP1β) in pDC and natural killer cell co-cultures stimulated with RNA-containing immune complexes…..”

    “….in patients with RA, long-term treatment with hydroxychloroquine (200–400 mg/day) can reduce circulating levels of IL-1 and IL-6 and is associated with improvement in erythrocyte sedimentation rate….”.

  11. Philip says:

    I was listening to the TWiV podcast (#598) and Dr. Daniel Griffin was talking about tocilizumab. He was hopeful and had a warning. Before I go on, I am in IT, so if this is wrong, bet on it being my interpretation. The warning is that when tocilizumab is stopped there can be a very bad rebound because the IL-6 is there, just blocked.

    If the rebound is real, would that mean that siltuximab is a better candidate?

    Here is a question that may show my IT roots, there are drugs that sequester immune cells in the lymph nodes (S1P receptor modulators, Fingolimod, Ozanimod, Siponimod, Ponesimod, Laquinimod or Etrasimod). Would one of those be worth trying?

    1. Jessie says:

      Philip,
      I am not a scientist either, but I listen to TWiV. Here’s what I got out of it (over several episodes):
      In the second week of illness, Dr. Griffin and team are treating people who have signs of cytokine storm (high IL-6, high neutrophil/lymphocyte ratio) with steroids first. He emphasizes that steroids should only be given in the right patient, at the right time and dose.

      Those who continue to progress with a maladaptive immune response get one dose tocilizumab, an IL-6 receptor inhibitor. If tocilizumab is given without first calming the immune system with the steroid, the body will ramp up production of IL-6 to even higher levels. These patients will start to do better while their IL-6 receptors are blocked, but when the tocilizumab wears off, their extra IL-6 will flood the receptors and they will get much worse. If IL-6 production is lowered first with the steroid, the tocilizumab will work, and when it wears off, many patients continue to do very well. Those who don’t may need another dose of tocilizumab, or something else is going on.

      I hope that’s helpful. TWiV is coming out with multiple episodes per week. The MicrobeTV podcast Immune discusses Covid-19 from an immunologist’s perspective and it’s also fascinating.

  12. Curious says:

    From a simplistic point of view opaganib doesn’t seem to have the potency (cell IC50 10-50 uM) or PK (50 mpk oral, Cmax 19 uM, t0.5 4.5h) to do what it says on the side of the bottle, how does it work?

    1. George Stanchev says:

      Can you comment on this article

      https://www.nature.com/articles/s41598-019-55199-3

      (I realize in this community, any mention of natural mollecules is frowned upon – I have been on the receiving end of “please stop!” comments) but Q has IC50 of 2.8uM on SphK1 (of course I am not sure on how inhibiting SphK1 relates to SphK2). i realize, Q has a low bioavailability (though isoQ, gluco-group attached Q, G3C etc can improve this) and very low citotoxicity (in one paper i have seen the number of 3.80 mM but they didn’t attach the data).

      It would be interesting to hear what you think

      1. mary says:

        Citrus and bioflavanoids such as hesperidin act as Protease inhibitors to halt the virus life cycle
        (Qamar et al., 2020; Haider et al., 2020). Beta coronavirus utilizes protease to cleave the structural protein needed during viral formation in the host cells.

        https://www.researchgate.net/publication/339908017_Revealing_the_Potency_of_Citrus_and_Galangal_Constituents_to_Halt_SARS-CoV-2_Infection

        https://www.preprints.org/manuscript/202003.0333/v1

  13. Athena says:

    Colchicine is also tested at the Institut de cardiologie de Montréal (Montreal Heart Institute). It is cheap, non-patented in many countries, but quite toxic. Currently used mainly for gout and Behçet’s disease.
    https://www.colcorona.org/index.php?lang=en

  14. a says:

    What is the skinny from testing scalability/accuracy experts on this high-throughput tech (not antibody testing, but massivley scalable rna tests)?

    https://www.billiontoone.com/covid-19

  15. Toni says:

    The CC chemokines CCL5 (RANTES) is a natural ligand of the CC-chemokine receptor CCR5. The CCL/CCR5 axis is known to be linked with IL-6.
    An anti-CCR5 Antibody (as well as some small compounds like Maraviroc) is used (or investigated?) to treat HIV.
    There is a company (Cytodyne) which has submitted an IND application to conduct a Phase 2 clinical trial with leronlimab (anti-CCR5) as a therapy for COVID-19.
    …but I’m not sure about the proposed mechanism of action.

    1. drsnowboard says:

      A case of if you only own a hammer, everything looks like a nail to you..?

    2. Jose says:

      This company is not reputable and no one should take them seriously. Let alone their army of know nothing lunatics in it. Claim the drug does all sort of miraculous things and shows no data to support it. Never seen such sloppy claims despite a long line of drugs with same MOA from reputable companies that failed pretty definitively.

    3. Dennis says:

      A lot has happened with respect to Leronlimab since this article was posted. E-IND performance against 50+ patients, albeit uncontrolled, shows statistical significance of Leronlimab as effective treatment for cytokine storm. Blinded, placebo controlled studies (P2 and P2/3) are underway with results expected in a few weeks. Seminal analysis currently under peer review. Pre-print available here: https://www.researchsquare.com/article/rs-26517/v1

      Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19

      Addressing RANTES and others in the cytokine inflammation cascade proves to be the most effective therapy at this point.

  16. Andy II says:

    I don’t know if this had been discussed already. Several people pointed out this pub to COVID-19. So, we knew something would come out soon.

    A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence.
    Nat Med. 2015 Dec;21(12):1508-13. (you can download a PDF free here: https://www.nature.com/articles/nm.3985).

    The authors (US, China, Switzerland) generated a chimeric virus expressing the spike of bat coronavirus SHC014 in a mouse-adapted SARS-CoV backbone. It can efficiently use multiple orthologs of the SARS receptor human angiotensin converting enzyme II (ACE2), replicate efficiently in primary human airway cells. Additionally, in vivo experiments demonstrate replication of the chimeric virus in mouse lung with notable pathogenesis. Evaluation of available SARS-based immune-therapeutic and prophylactic modalities revealed poor efficacy; both monoclonal antibody and vaccine approaches failed to neutralize and protect from infection with CoVs. Our work suggests a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations.

  17. KRL says:

    Your point of view is not simplistic, Curious. The evidence that opaganib (ABC294640) is a selective SphK2 inhibitor is thin. SphK2 null mice have significantly higher levels of blood S1P than wild type mice and bona fide SphK2 inhibitors drive upward excursions in circulating S1P levels (in mice and rats) in a dose dependent manner. Low potency SphK2 inhibitors such as opaganib lack this property. Should opaganib prove efficacious as an anti-viral medicine, it will be interesting to learn its MOA.

  18. Simon C says:

    I’ve been looking at this scenario from the viewpoint of nutritional supplements.

    We’ve all heard about vitamin c and its apparent usage in mega doses in some cases of covid19. Sure enough, it reduces il-6.

    Panax ginseng has some interesting positive studies of it up against influenza. It reduces il-6 and seems to have a synergistic relationship with vitamin c.

    Vitamin d in certain situations has been shown to lower il-6.

    You’d think that reducing cytokines in advance of infection might not be a good thing but there is no evidence that doing so hurts, at least if its done by such supplements. In fact, quite the contrary. It seems to improve outcomes.

    And yet pharmacological interventions that reduce il-6 in the form of NSAIDs have been shown to give worse outcomes in patients with pneumonia.

    1. Lane Simonian says:

      Panax ginseng is a particularly interesting potential therapeutic because it maintains beneficial immune responses while tamping down too great an inflammatory response.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659612/

      https://www.jkms.org/Synapse/Data/PDFData/0063JKMS/jkms-27-1472.pdf

  19. tw says:

    What about the effect of Doxycycline reducing IL-6? As observed here in Dengue patients http://downloads.hindawi.com/journals/cdi/2011/370872.pdf, with Dengue potentially having some similarities to Covid 19 https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30158-4/fulltext

  20. good morning! says:

    My arthritis drug Flurbiprofen is slowing Cytokines down too. Small molecure, readily available, widely used.

    1. George Stanchev says:

      Ciclesonide has shown a lot of promise in Asia

      1. ToXDoX says:

        I think that this is one medication if we were able to mass produce has huge upside as it’s a corticosteroid without some of the negatives, particularly increased susceptibility to infections. South Korea has been looking at it and looks like has planned a couple of studies. They are also claiming along with it’s steroidal effects that it possibly may have antiviral activity as well. Only problem is that I do believe at its current dosing regimen, it’s not going to be effect for more than mild symptoms.

        Also in regards to Simon C and his post on NSAIDs, one cofounder there with NSAIDs and worsening outcome is that those patients may be late presenters. If the patients are trying to just self medicate and decrease fever, they may be presenting on day 5, 6+ of the infection. Usually when they wait this long, they can worsen quickly very suddenly. That and these are the patients that are being reported into the registry as well.

        1. Simon C says:

          This is the study I’d seen regarding nsaids and pneumonia…

          https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617416/#!po=1.13636

        2. Simon C says:

          “It is a remarkable fact that a compound like melatonin, which has the potential of acting in a proinflammatory way, can also efficiently suppress inflammatory responses, especially when these are strong and, in the extreme, life‐threatening.”

          “Suppression of NLRP3 activation by melatonin has been observed under various conditions. This was shown in radiation‐induced damage by radiotherapy of oral mucositis,89 and small intestine toxicity,90 in the septic heart,91-93 pyroptosis induction in adipose tissue,94 subarachnoid hemorrhage,95, 96 **acute lung injury,97**”

          https://onlinelibrary.wiley.com/doi/full/10.1111/jpi.12525

          NLRP3 Inflammasomes: Pandora’s box for sepsis

          https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294171/

          ” Recent studies have demonstrated that betaine treatment can significantly inhibit NLRP3 inflammasome-related proteins, such as NLRP3″

          https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976740/

          1. Holmsteinn Jonasson says:

            The company Acellera uses computer modeling to check for drugs that can bind to COVID-19 and discovers that MELATONIN actually binds to SARS-COV-2 main protease. This essentially means it is able to disrupt the virus ability to bind to our cells. Now it’s apparent that Melatonin has both a direct effect on both the virus and in managing the humans inflammatory immune response. https://www.acellera.com/covid19?fbclid=IwAR2gQ2SBlNvMakA2WROx-fDNb62jU6o0h2KBdEpTHe2eWEgmIML2rBmJL6c

            See also here table 3. https://arxiv.org/abs/2004.00979

  21. Birone says:

    “Anti-IL-6 antibody therapies have been developed for just that purpose, for patients with autoimmune disorders who need to turn the dial down in just that manner.”

    It looks like olmesartan reduces IL-6 levels:
    “olmesartan medoxomil significantly reduced serum levels of high-sensitivity C-reactive protein, high-sensitivity TNFalpha, IL-6, and MCP-1”
    https://www.ncbi.nlm.nih.gov/pubmed/17192125

    “OM treatment significantly reduced IL-6 levels in the aorta-ligated rats”
    https://www.europeanreview.org/article/6178

    “Treatment with olmesartan significantly reduced a panel of inflammation markers currently used to characterize vascular inflammation such as hsCRP, hsTNF-α, and IL-6.”
    https://www.ahajournals.org/doi/10.1161/01.cir.0000140265.21608.8e

    “At study entry, valsartan was changed to olmesartan (20 mg/day) or telmisartan (40 mg/day) and administered for 8 weeks… the decreases in serum interleukin-6 and highly sensitive C-reactive protein were more significant by olmesartan treatment.”
    https://www.nature.com/articles/hr2008303

    AND may block the downstream inflammatory effects of IL-6, eg in this study where exogenous IL-6 was supplied:
    “costimulation with ANG II and IL-6 significantly increased AGT mRNA and protein expressions (1.26 +/- 0.10 and 1.16 +/- 0.13 over control, respectively). Olmesartan, an ANG II type 1 receptor blocker, and an IL-6 receptor antibody individually inhibited this synergistic effect. ”
    https://www.researchgate.net/publication/5388954_Costimulation_with_angiotensin_II_and_interleukin_6_augments_angiotensinogen_expression_in_cultured_human_renal_proximal_tubular_cells

  22. Daniel Jones says:

    Back during the Gulf war, as I recall, one defense against the threat of chemical warfare involved the prompt injection of a counter-agent. It couldn’t be done in advance because the counter-agent was toxic in its own right unless the chemical warfare agent was present. A poison to cancel a poison, the exact reverse of a binary agent with relatively harmless components.

    It’s a risky business, this.

    I must say an agent to target the offending protein and another that targets the receptor activity makes for interesting studies as well. I really want to know how that works out.

  23. Tourettes of Chemistry says:

    Cytokine storm review:

    https://www.knowablemagazine.org/article/health-disease/2020/what-cytokine-storm

    The diagnostics of a balanced immune system vs the indicators of a ‘strong’ or weak immune system would appear as a significant need – ratios of IL-x’s along with ferritin and ‘C-reactive’ protein would be useful over intuitive diagnosis.

    Anyone with deeper knowledge?

  24. Derek- why do you not mention targeting the NLRP3 protein? Increasingly SARS2-CoV is viewed as a IL-1beta driven disease. Better to stop the cytokine storm further upstream. See results in Phase 2b gout results in The Lancet:
    https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30065-5/fulltext
    Follow Dr Charles Dinarello!
    Olatec Therapeutics
    Director

    1. Simon C says:

      Obviously I can’t get hold of dapansutrile, but I’ve got extra melatonin and trimethylglycine in the house in readiness.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678949/

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976740/

  25. moco safadi says:

    Derek.
    Why not using Clarithromycin instead of Azithromycin, taking in account the plenty of data available showing the higher anti-inflammatory effects especially against IL-6?

  26. mary says:

    Fresgh ginger reduces IL1 and IL6
    https://www.ncbi.nlm.nih.gov/pubmed/22884532

    It also stimulates interferon b
    https://www.ncbi.nlm.nih.gov/pubmed/23123794

  27. mary says:

    Would Metformin have a positive effect?
    Has there been any analysis of increased susceptibility in diabetics who take metformin only compared to those that take other possibly ACE/ACE2 affecting medications ?

    Metformin ameliorates IL-6-induced hepatic insulin resistance via induction of orphan nuclear receptor small heterodimer partner (SHP) in mouse models.
    https://www.ncbi.nlm.nih.gov/pubmed/22349108

  28. JP Leonard says:

    Re: More Therapeutic Ideas for the Coronavirus https://www.newsmax.com/us/exercise-aerobics-running-weight-lifting/2020/04/17/id/963484/
    Study: Exercise Proven to Help Avoid Serious COVID-19 Cases
    “Exercise releases an increasing amount of “extracellular superoxide dismutase” (EcSOD) into muscles, which helps prevent disease, Yan’s study found.”
    How much exercise are people getting in nursing homes.
    Recent report, 40% of fatalities in NJ were in nursing homes. Of course that is also where the elderly with chronic conditions are who account for 99% of deaths.
    Most people are getting LESS exercise now because of the shut downs.
    Why not focus on protecting those at risk instead of making the healthy majority sick and impoverished?

  29. Trevor says:

    I wonder if people that have already had the flu virus jab have been checked to see if they have caught the coronvirus?,if not maybe this pre virus might stop you from developing the coronvirus???.only an idea or theory???.

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