A cytokine storm is suggestive of severe COVID-19 cases. Clinical trials for IL-1, 6 blocker or JAK1 inhibitor are underway to treat this devastating conditions. INFa is reported to associate with disease severity, although the sample size is limited ( Article Viral Invasion and Type I Interferon Response Characterize t...
). IFN blocker might also be a clinical candidate to treat severe pneumonia such as Anifrolumab, which is in clinical trial for lupus. Any idea?
SARS-CoV-2. COVID-19. - Cytokine Storm. Proinflammatory cytokines. Cholinergic anti-inflammatory pathway
https://en.wikipedia.org/wiki/Cholinergic_anti-inflammatory_pathway
(see: https://www.researchgate.net/post/What_is_a_new_idea_How_are_new_ideas_born_in_science_art_and_politics )
SARS-CoV-2. COVID-19. - Cytokine Storm. Proinflammatory cytokines. Cholinergic anti-inflammatory pathway https://en.wikipedia.org/wiki/Cytokine_release_syndrome
https://www.researchgate.net/profile/PF_Zabrodskii/research
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Cytokine release syndrome (CRS) or cytokine storm syndrome (CSS) is a form of systemic inflammatory response syndrome (SIRS) that can be triggered by a variety of factors such as infections and certain drugs.[3] It occurs when large numbers of white blood cells are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. CRS is also an adverse effect of some monoclonal antibody drugs, as well as adoptive T-cell therapies.[4][5] Severe cases have been called cytokine storms.[2] When occurring as a result of drug administration, it is also known as an infusion reaction.[1]
https://en.wikipedia.org/wiki/Cytokine_release_syndrome
I wrote a thesis on here about Elderberry (Sambucus nigra) being anti-bacterial and anti-viral. It is free to read on researchgate.It is being used by Public Health England. but I am in an at risk group due to having autoimmune diseases and I caught Covid-19. I self treated at home even though I had it quite badly. I have had pneumonia before and I felt it start again. Then what was unmistakably a cytokine storm. I drank a lot of elderberry cordial (made to my own recipe at the back of my thesis).-about 3 litres diluted with hot water over a few days and have recovered. I am trying now to get proper clinical trials on this now. Elderberry has been used in medicine for thousands of years and is still in the pharmacopoeia of some countries still. It has bioactive molecules which attach to and inhibit many viruses including other envelope viruses two of which are other coronaviruses. I think this works and saved my life. Obviously only one case and we need proper clinical trials as we say in England "one swallow does not make a summer".However Sambucus grows over much of the world and can be a cheap medicine for the poor. But I think elderberry doesn't just inhibit the virus, I think it modulates the cytokine storm. I felt fluids going into my lungs but was able to stop it very quickly.I gave an account in comments under my thesis just after I began to recover.Please someone do the trials if I can't.
Dear , researches in line of cytokines interpaly in patients with COVID-19 could proffer solution in the treatment and recovery of the patients and reduce the rate deaths worldwide.
Yes, I know> I am trying to get one of the Oxford professors who is running other clinical trials to run one on elderberry (Sambucus). I have been asking more important people to get interested.I have also been begging Public health England to include it in the trials they are running.The other good thing about elderberry is that it grows almost world wide (including sub Saharan Africa ) so it has potential to be a cheap medicine for the poor.Please someone trial it.
Thank you very much for a valuable info, Julia. COVID-19 should be treated with agent, which has antiinflammmatory as well as antiviral activity. Elderberry is very likely to be one of the candidate, but I wounder if this agent can prevent respiratory failure. As you indicated, the therapeutics should be inexpensive, because the patients throughout the world have to be medicated to escape from the nightmare. I have noticed that this agent has been tested for IVA and IVB ( Article Randomized Study of the Efficacy and Safety of Oral Elderber...
).
Dear Colleagues,
Cytokine release syndrome (CSR) is well described and know in the world of oncology, typically we see it when use CAR-T cell therapies in leukemias/lymphomas. It starts usually with fever and develops into clinically meaningful and life threatening disorder within ~72 hours, i.e. it is no acute condition. So, as soon as u see first signs of CRS (fever, flue like symptoms) u start IL-6 inhibitors like tocilizumab. IFN-gamma, TNF-alpha blockers are not really working well in CRS compared to toci.
In COVID as per these days experiences it is about the same: do not wait when pts will drive into ARDS (acute respiratory distress syndrome), start toci or any other IL-6 blocker early, my colleagues and me discussed starting it at the first signs of pneumonia or when you see pO2 going down. That will prevent ARDS and need to put pt on vent. The problem is the lack of IL-6 blockers and that is why often they are used late when pt is on vent or close to ARDS. In that cases efficacy of the therapy is much lower since basically ARDS is the end of the game. I strongly suggest to accompany IL-6 blockers with early anticoag agents like fraxiparin in prophylactic doses at early stages and in higher doses at coagulogramm controll in later stages to prevent or treat DIC which looks like a potential trigger for SRC. My personal opinion is also that use of therapeutic doses of different membrane stabilizers like anti-histamines or anti-leukotriens at early stages will do nothing bad.
Stay safe and healthy
I had had pneumonia before and I felt it starting again.When I used lots of elderberry it brought an end to that. I am doing all I can to get doctors at Oxford to include it in their clinical trials. One, Professor Horby whom I have never met seems to have a CV which suggests he would be extra inclined towards medicine which might help the poor. I think elderberry stopped me getting to the stage of respiratory failure.Poor Prof Horby. I keep sending him begging emails, phone messages and letters. I am not giving him any peace until he includes elderberry in his trials.I am stuck 150 miles away from Oxford so I can't actually see him, but he is the one at Oxford organizing clinical trials on likely treatments. But if anyone anywhere else wants to try, PLEASE do. You need about 3 litres elderberry juice made into cordial with sugar (to make it keep)u,nless it is for a diabetic of course.I see several scientist at Harvard have been reading my thesis. Go on harvad and beat Oxford to a trial. Sambucus canadensis grows in USA and Sambucus nigra is naturalized there.. I just want anyone to do trials. It grows In lots of poorer contries. pakistan for instance . Peru. PLEASE please anyone try it.
I'm very happy that you were able to fight through a difficult bout with Covid-19 (confirmed case?) and hope others will fare as well and hopefully better should they partake of elderberry cordials. Your use of it may have been key and if so what do you suppose the elderberry extract provided? Your interesting masters thesis provides possibilities but I was unable to find mention of zinc, especially zinc ionophores as one of them.
The Covid-19 epidemic has kindled renewed interest in zinc homeostasis and zinc ionophores (hydroxychloroquine is one). Some bioflavonoids are zinc ionophores and one, quercetin (1), is found in the flowers and berry clusters of Sambucus species (2). Have you considered that the medical benefit ascribed to Elderberry may be in part derived from bioflavonoids in the elderberry drink that may have ionophoric capacity in concert with zinc (perhaps Kaempferol is one [3])?
(1) Dabbagh-Bazarbachi, H, et al. Zinc ionophore activity of quercetin and epigallocatechin-gallate: from Hepa 1-6 cells to a liposome model. J Agric Food Chem. 2014 Aug 13;62(32):8085-93. doi: 10.1021/jf5014633. Epub 2014 Jul 31.
(2). Sidor, A, et al. in your thesis refs.
(3) Isaac, AO, et al. Ameliorative Effects of Kaempferol and Zinc Gluconate on Erythrocyte Osmotic Fragility and Haematological Parameters in Wistar Rats Exposed to Noise Stress
https://biomedicine.imedpub.com/ameliorative-effects-of-kaempferol-and-zinc-gluconate-on-erythrocyte-osmotic-fragility-and-haematological-parameters-in-wistar-rat.php?aid=20403
Sergey, thank you for your valuable info. As you noted, availability of anti-IL-6 Ab is an issue in spite of the promising effect of the series. Apparently, small molecule alternatives should be explored to solve cost/distribution problem. With regard to IL-6 blockade, for example, NF-kB can be targeted by small molecules, and several marketed drugs are reported to inhibit this pathway (refer to Article Identification of Known Drugs that Act as Inhibitors of NF-κ...
).Among them, digitoxin is reported to inhibit a cytokine storm by IVA and implicated for potential COVID-19 therapy ( Preprint Classical drug digitoxin inhibits influenza cytokine storm, ...
). The compound is likely to show antiviral activity to some virus (Article Anti-HSV activity of digitoxin and its possible mechanisms
, https://jvi.asm.org/content/92/6/e01861-17.short). It might better to look into other molecules as well on IL-6 pathway.
As per Leonard's excellent suggestion, one should refer to the following paper: Article Zinc and respiratory tract infections: Perspectives for COVI...
According to the report, Zn is likely to decrease ACE2 activity, which is known as COVID-19 receptor, and more interestingly, inhibit NF-kB signaling. If this is true, Zn chelators plus Zn should be tested as Zn supplement. Other than quercetin, epigallocatechin, kaempferol, Zn-clioquinol might also be a potential candidate for COVID-19 therapy.
Article On Facing the SARS-CoV-2 (COVID-19) with Combination of Nano...
Thank you for your question.
Results of the second phase-III trial of anifrolumab in systemic lupus erythematosus (TULIP-2) were published in last january ( N Engl J Med 2020;382:211-21), and showed an increased prevalence of herpes zoster in the anifrolumab treated group compared to placebo, raising the issue that anifrolumab may suppress IFNI-induced antiviral immunity. Therefore, its use in patients with systemic lupus erythematosus is mitigated during this pandemic of COVID-19, since it remains unknown how it could affect the course of COVID-19 in affected patients. Conversely, its use as treatment of COVID-19 is also mitigated.
The use of JAkis as treatment of COVID-19 is also mitigated since baricitinb has been associated with an increased risk of herpes zoster in patients with rheumatoid arthritis, which could also predict a suppression of antiviral immunity.
This is NOT a medical advice and must be used for educational purpose and clinical studies development only.
Letter to: Cytokine release syndrome in severe COVID-19
Repurposing of bazedoxifene to prevent cytokine storm in COVID-19 patients
Prof. Jan Brábek, PhD, Daniel Rosel, PhD, Michael Fernandes MD
We congratulate John B. Moore and Carl H. June on the recent article 1, describing cytokine release syndrome (CRS) in severe COVID-19 and the role IL6 signaling inhibition with humanized IL6 receptor antibodies in prevention of CRS. 1 The authors may have missed that bazedoxifene acetate (Conbriza, Pfizer) inhibits IL-6 signaling at therapeutic doses.2 The approved daily dose of bazedoxifene, indicated for osteoporosis, should effectively inhibit IL-6 signaling and this way potentially prevent or mitigate Acute Respiratory Distress Syndrome (ARDS) COVID-19 patients. Compared to the monoclonal antibodies, tocilizumab, sarilumab, and siltuxizumab, bazedoxifene has additional advantages related to possible effectiveness against COVID-19 entry and replication 3, as well as scale-up, delivery and cost. At this time, and as implied by Moore and June 1, addressing ARDS, the proximate cause of mortality, with available agents, takes precedence over the development of antiviral antibiotics and vaccines.
We declare no competing interests.
*Jan Brábek, Daniel Rosel, Michael Fernandes [email protected] Charles University, Prague, Czech Republic (JB, DR); and Biotechnology and Biomedicine Center of the Academy of Sciences (BIOCEV) (JB, DR) and Charles University, Vestec, Czech Republic (JB, DR), Medbase, Chapel Hill, NC 27514, USA (MF)
References
1. Moore JB and June CH. Cytokine release syndrome in severe COVID-19. Science 2020; 10.1126/science.abb8925
2. Thilakasiri P, Huynh J, Poh AR, et al. Repurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth. EMBO Mol Med. 2019; 11: e9539.
3. Zhou Y, Hou Y, Shen J, et al. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discovery. 2020; 6:14.
This is NOT a medical advice and must be used for educational purpose and clinical studies development only.
Letter to: Cytokine release syndrome in severe COVID-19
Repurposing of bazedoxifene to prevent cytokine storm in COVID-19 patients
Prof. Jan Brábek, PhD, Daniel Rosel, PhD, Michael Fernandes MD
We congratulate John B. Moore and Carl H. June on the recent article 1, describing cytokine release syndrome (CRS) in severe COVID-19 and the role IL6 signaling inhibition with humanized IL6 receptor antibodies in prevention of CRS. 1 The authors may have missed that bazedoxifene acetate (Conbriza, Pfizer) inhibits IL-6 signaling at therapeutic doses.2 The approved daily dose of bazedoxifene, indicated for osteoporosis, should effectively inhibit IL-6 signaling and this way potentially prevent or mitigate Acute Respiratory Distress Syndrome (ARDS) COVID-19 patients. Compared to the monoclonal antibodies, tocilizumab, sarilumab, and siltuxizumab, bazedoxifene has additional advantages related to possible effectiveness against COVID-19 entry and replication 3, as well as scale-up, delivery and cost. At this time, and as implied by Moore and June 1, addressing ARDS, the proximate cause of mortality, with available agents, takes precedence over the development of antiviral antibiotics and vaccines.
We declare no competing interests.
*Jan Brábek, Daniel Rosel, Michael Fernandes [email protected] Charles University, Prague, Czech Republic (JB, DR); and Biotechnology and Biomedicine Center of the Academy of Sciences (BIOCEV) (JB, DR) and Charles University, Vestec, Czech Republic (JB, DR), Medbase, Chapel Hill, NC 27514, USA (MF)
References
1. Moore JB and June CH. Cytokine release syndrome in severe COVID-19. Science 2020; 10.1126/science.abb8925
2. Thilakasiri P, Huynh J, Poh AR, et al. Repurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth. EMBO Mol Med. 2019; 11: e9539.
3. Zhou Y, Hou Y, Shen J, et al. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discovery. 2020; 6:14.
In order to explain the cytokine storm we are working on the hypothesis: Nicotinic Cholinergic System and COVID-19. In brief, Spike has obtained a toxin-like sequence which seems to interact with the, neighboring to ACE2, alpha7 nAChRs and by this way is causing hyper-inflammation, angiitis, anosmia etc.
Please have a look at the following:
1. Farsalinos K, Niaura R, Le Houezec J, Barbouni A, Tsatsakis A, Kouretas D, Vantarakis A, Poulas K. Nicotine and SARS-CoV-2: COVID-19 may be a disease of the nicotinic cholinergic system. Toxicol Rep. 2020 Apr 30. doi: 10.1016/j.toxrep.2020.04.012.
2. Farsalinos K, Angelopoulou A, Alexandris N, Poulas K. COVID-19 and the nicotinic cholinergic system. Eur Respir J 2020. doi. 1183/13993003.01589-2020
3. Farsalinos K, Eliopoulos E, Leonidas D, Papadopoulos G, Tzartos S, Poulas K. Molecular Modelling and Docking Experiments Examining the Interaction between SARS-CoV-2 Spike Glycoprotein and Neuronal Nicotinic Acetylcholine Receptors. Preprints 2020;2020050365. doi: 20944/preprints202005.0365.v1.
4. Farsalinos K, Eliopoulos E, Tzartos S, Poulas K. Nicotinic Cholinergic System and COVID-19: Identification of a Potentially Crucial Snake Toxin-Like Sequence in the SARS-CoV-2 Spike Glycoprotein. Preprints 2020, 2020050301 (doi: 10.20944/preprints202005.0301.v1). Version 1 : Received: 17 May 2020 / Approved: 18 May 2020 / Online: 18 May 2020 (11:51:44 CEST)
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