Dear Friends,
We are going through some important challenges as Coronavirus (COVID-19) spreads across the world. It seems that many of us may need to deal with Coronavirus at some point so it makes sense for us to be ready and have knowledge on relevant approaches to help our body fight that, in case this will be needed. Since many of us here have good research skills as well as good knowledge and understanding of the cellular mechanisms and drugs & supplements that can modulate those mechanisms, it is a good idea to start applying that knowledge on Coronavirus subject in order to find as many solutions with potential as we can.
If you like that idea, please join me and share here your findings. We will first start creating a list (that will be continuously updated) with supplements and drugs that have potential as stand-alone treatment, and in the second part we can create a list of cocktails of drugs and supplements that can work well together to fight Coronavirus. This doesn’t mean that the scope of this website changes. But it’s a good chance for us to contribute to life by doing this type of work, finding and creating awareness on potential options.
Interestingly, as you will see below, most antiviral drugs and supplements are known as drugs and supplements that stand out in the fight against cancer.
Here is a good overview on the Curent COVID-19 situation: https://www.covidgraph.com/p/coronavirus.html
Drugs and Food Supplements
Hydroxychloroquine (Plaquenil)
Whats is this: Hydroxychloroquine (brand name Plaquenil) is an anti-malaria drug. It is typically used by those travelling to countries with malaria risk. I think in some countries this may even be an over the counter drug. It should be available in most of the countries and cheap. Therefore, it should be accessible for most of the people. This drug has also important potential against cancer and it has been discussed here in more details. Note that Hydroxychloroquine is the name for the active ingredient. Just Google this and you will find various Brand names that may be available in your country or at online pharmacies.
Why it has potential: Recent research indicates it has good potential against Coronavirus:
- Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro – this study was published very recently (February 2020) and indicates that chloroquine functioned at both entry, and at post-entry stages of the 2019-nCoV infection. In addition to this antiviral activity, chloroquine has an immune-modulating activity which may work in synergy with its antiviral activity. “it is postulated that chloroquine works by altering ACE2 glycosylation and endosomal pH. Its anti-inflammatory properties may be beneficial for the treatment of SARS.” (Ref.)
- Coronavirus puts drug repurposing on the fast track – a Nature publication at the end of February 2020 indicates that Chloroquine or hydroxychloroquine has been selected for clinical trials in patients infected with Coronavirus
- In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) – a publication from March 2020 indicating that Hydroxychloroquine was more potent than Chloroquine. The publication further proposes the following treatment schedule: “a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection”. Typically, the pills have 200mg. That means 2 pills 2x/day first day, followed by 2 pills/day during the coming days.
- As discussed many years ago on this website Hydroxychloroquine is a Zinc ionophore (binds Zing and facilitate the entrance of that inside cells). Combining Zinc with Zinc ionophores such as Hydroxychloroquine has been used successfully against tumors (Reference). There are various discussions and suggestions at this point indicating that the major anti-viral action of Hydroxychloroquine against COVID-19 is related to it’s ionophore action. If that is the case we could use other drugs against COVID that have the Zinc ionophore capability, such as Disulfiram and food supplements such as Quercetin (onion extract) and EGCG (green tea extract).
- Update March 18th: since I published this article a few days ago, it becomes more and more clear that Hydroxychloroquine has the potential to save a lot of life. Here is a recent Youtube from a Franch scientist discussing these aspects as well as the increase in bennefits when combining Hydroxychloroquine with the anti-biotic Azithromycin https://www.youtube.com/watch?v=ydcrROJFEU0 In this case, patinets received 600mg Hydroxychloroquine (200mg 3x/day) and azithromycin (500mg on day 1 followed by 250mg per day, the
next four days) to prevent bacterial super-infection (Ref.) A few patients did not responded to Hydroxychloroquine and the authors expect this was because of the way Hydroxychloroquine was metabolised in those patients as two patients were mother and child not responding. - Update July 28: “Hydroxychloroquine+azithromycin has been widely misrepresented in both clinical reports and public media … These medications need to be widely available and promoted immediately for physicians to prescribe.” (Ref.)
How to take: According to the above paper it can work both prior to and also after the virus entered the cell. First day it is taken 400mg 2x/day, and the coming 4-9 days we take 200mg/day.
Note: both Azithromycin and Hydroxychloroquine are associated with QT prolongation, caution is advised if considering use of both drugs in pts at risk for QT prolongation or receiving other drugs associated with arrhythmias and in those with chronic medical conditions.
Vitamin C
What is this: we all know what this is. Vitamin C has also been discussed here as a cancer treatment option.
What is the potential:
- Sepsis was the most frequently observed complication in Coronavirus patients due to a pro-inflammatory responses of the immune system (Ref.)
- When the immune systems acts in a pro-inflammatory way, the immune cells are overactive and for that they need to up-regulate glycolisis (fermentation) (Ref.)
- Vitamin C inhibits glycolisis (fermentation) (Ref.) Here is a longer list of similar inhibitors (Ref.)
- Based on the above, Vitamin C can inhibit fermentation required for the immune cells to be overactive, and as a result inhibit pro-inflammatory activity of the immune cells that can trigger sepsis
- In addition, during the replication, viruses create ER-stress (Ref.)
- ER-stress requires and as a result upregulates glycolsis and lipogenesis (Ref.1, Ref.2)
- And since as discussed above Vitamin C inhibits glycolsis required during viral replication and ER-stress, Vitamin C has an anti-viral activity
- Indeed, here is a clinical study on 463 patients showing that mega-doses of Vitamin C administered orally (6 grams/day) could reduce or inhibit the symptoms caused by viral infection responsible for the common flu (Ref.)
- In addition, Vitamin C improves survival rate in sepsis and acute respiratory distress syndrome (ARDS) (Ref.)
How to take: According to the above paper, I would take 6 grams/day (one every hour) in the first few days when symptoms are apparent and after that reduce the dose as symptoms go away. Note: high dose Vitamin C may induce diarrhoea in some people – if that is the case, I would spread the 6g over more than 6 hours. I would take both normal Vitamin C and if possible liposomal Vitamin C. If possible, from time to time, I would even go for an intravenous high-dose Vitamin C.
Niclosamide
What is this: Niclosamide is an over the counter antihelminthic drug used to treat intestinal worm infections. However, Niclosamide has also been shown to have strong anti-cancer potential and it has been often discussed on this website. It is a drug that is relatively cheap and can be found at online pharmacies or even on eBay. It should be easily accessible.
What is the potential:
- Recently, niclosamide has been identified as an effective antiviral agent against a number of pH-dependent viruses, such as human rhinoviruses and influenza virus, severe acute respiratory syndrome-coronavirus, Chikungunya virus, and flaviviruses (Ref.)
- Niclosamide treatment was observed to completely inhibit viral antigen synthesis. Reduction of virus yield in infected cells was dose dependent (Ref.)
- Inhibition of Severe Acute Respiratory Syndrome Coronavirus Replication by Niclosamide (Ref.)
- “Of particular note, the licensed drug niclosamide, a treatment for tapeworms that had previously been identified as an SKP2 inhibitor, was shown to be capable of drastically reducing the replication of the MERS virus in cell culture.” (Ref.)
- effective against various viral infections with nanomolar to micromolar potency such as SARS-CoV, MERS-CoV, ZIKV, HCV, and human adenovirus (Ref.)
- Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral Effects
How to take: I would probably take 2g/day (maybe even higer dose if the issue is more severe). The capsules available are those type that can be dissolved in the mouth, so they are perfect for addressing the throat infections. The typical bio-availability of this drug is low but this is not an issue since here it can address the throat infections directly as they are dissolved.
Thalidomide
What is this: a FDA approved drug. Please see the story of Thalidomide here (Ref.) This drugs may be a little more challenging to obtain but still possible. It is more expensive in western countries and 10x cheaper in other countries.
What is the potential:
- To my knowledge, Thalidomide has been first proposed as an effective solution against Coronavirus by Dr. Hada on January 31st this year, exactly here in cancertreatmentsresearch.com, and our community is honoured by that (Ref.) Please read his comment here.
- Indeed, on February 26th, nearly one month later Chinese doctors reported that they succeed to save the life of one Coronavirus patinet using Thalidomide: “Thalidomide Combined with Low-dose Glucocorticoid in the Treatment of COVID-19 Pneumonia”
- The above great results are expect to be related to the anti-inflammatory of Thalidomide, by inhibiting the cytokine surge and regulating immune functions.
How to take: In positive case report above, the Chinese doctors gave 100mg Thalidomide every 24 hours, combined with with low-dose glucocorticoid. The patient started to immediately improved, already with the day 1 after administration of Thalidomide.
Quercetin
What is this: Quercetin is an extract found in many fruits, vegetables, leaves, seeds, and grains and in high amounts in onions. It can be found at online shops as food supplement in capsules such as e.g. 500mg/capsule, and is relatively cheap. Next to extracts such as Curcumin, Green tea extract, Berberine, Quercetin is one of the most relevant natural extracts in the fight against cancer (Ref.) as well as auto-immune disease and allergic reactions (Ref.).
What is the potential:
- Quercetin has important anti-viral (Ref.1, Ref.2, Ref.3, etc.) activities as well as anti-inflammatory (Ref.), both of which aspects are very important in prevention and/or treatment to reduce potential lethal mechanisms in Coronavirus infected patients.
- Quercetin has already proven successful at treating Ebola and Zika viruses and researchers in Québec believe it could prove effective against COVID-19 (Ref.). The Foundation of the Montreal Clinical Research Institute (IRCM) anounced a $1 million contribution from the Lazaridis Family Foundation to support research led by the researchers in Québec on the antiviral drug isoquercetin (Ref.)
- Quercetin makes very much sense to use as is a MCT (1-4) inhibitor which as a result inhibits fermentation and in turn inhibits viral replication, due to similar mechanisms as discussed in the Vitamin C section above
- Quercetin is also a Zinc ionophore (please see the discussion on ionophore in the Hydroxychloroquine section)
How to take: In the preventive phase, I would take 1g/day and for active disease I would take 3g/day. If possible, such dose as 3g/day should be increased step by step. On this line, eating (not cocked) onion should also have some preventive role due to the high Quercetin content.
Scutellaria baicalensis
What is this: Scutellaria baicalensis, also called Chinese skullcap, has been widely used as a medicinal plant in China for thousands of years. This plant is available online as a food supplements and is relatively cheap. This is one of my favourite plants in fighting cancer (Ref.) and it is known to exhibiting many biological activities, including antibacterial, antiviral, and/or anti-inflammatory properties (Ref.).
What is the potential:
- Scutellaria baicalensis extracts are known to have antiviral activity (Ref.) and specifically against SARS coronavirus (Ref.)
- For some viral infections, Scutellaria baicalensis exerted more potent antiviral effects compared with ribavirin in a clinical trial (Ref.)
- Baicalin from Scutellaria Baicalensis blocks viral infection and reduces inflammatory cell infiltration and lung injury (Ref.)
How to take: I would take 3g/day Scutellaria baicalensis. Capsules of 500mg Scutellaria baicalensis are available as food supplement online.
N-acetylcysteine (NAC)
What is this: over the counter food supplements used to treat acetaminophen poisoning. Cheap and available everywhere. It is also used as a mucus thinner to help reduce bronchitis exacerbations.
What is the potential:
- It has antiviral action: In a clinical study enrolling 262 patients, those receiving NAC experienced significantly fewer influenza-like episodes and days of bed confinement – only 25% of the virus-infected subjects in the NAC group developed symptoms, as contrasted to 79% of those of placebo (Ref.)
- Due to the anti viral and anti-inflammatory action of NAC, it has been recently proposed that this should be used as a part of a strategy to help provide relief in those infected with COVID-19 (Ref.)
How to take: I would take 600mg 2x/day. Available as food supplement online.
Arbidol (Umifenovir)
What is this: a Russian drug no used (in Russia and China) to treat influenza A and B, acute respiratory viral infections, severe acute respiratory syndrome (including complicated by bronchitis, pneumonia); secondary immunodeficiency states; complex therapy of chronic bronchitis, pneumonia and recurrent herpetic infection.
What is the potential:
- Several in vitro studies indicate that Arbidol possesses inhibitory effect on coronavirus (Ref.)
- A retrospective case-control study from China indicating that Arbidol could reduce the infection risk of the novel coronavirus in hospital and family settings (Ref.)
- Clinical trials on the efficacy of Arbidol on COVID-19 are ongoing
How to take: the positive case report cited above states that the typically used 200mg, three times a day, 5-10 days. The cost/box in Russia seems to be at about 25USD for a box of 10x200mg capsules.
Glycyrrhizinate (Licorice)
What is this: Glycyrrhizinate is the major active component of licorice root extract, an ancient medicinal plant sometimes also used as alternative cancer treatment. Licorice can be found as a food supplement at shops on-line.
What is the potential:
- Has been employed against coughs and colds for long time in traditional Chinese medicine as well as to settle disturbed digestion and has anti-inflammatory activity
- It is well recognised as an extract that has antiviral activity (Ref.1, Ref.2, Ref.3 )
- One German study reports in 2003: “Of all the compounds, glycyrrhizin was the most active in inhibiting replication of the SARS-associated virus. Our findings suggest that glycyrrhizin should be assessed for treatment of SARS” (Ref.)
- Professor Hong Ding of Wuhan University has proposed a combination of diammonium glycyrrhizinate and vitamin C as a COVID-19 therapy and a clinical trial is running on this now (Ref.1, Ref.2)
How to take: The clinical trials gives Diammonium Glycyrrhizinate Enteric-coated Capsules (oral, 150mg, Tid), Vitamin C tablets (oral, 0.5g, QD). That means 450mg Glycyrrhizinate/day and 2g Vitamin C/day. Glycyrrhizinate capsules are available in China only. As an alternative to that, I would use licorice root extract supplements since they contain high amount of Glycyrrhizinate. Glycyrrhizin, glycyrrhizic acid, and glycyrrhizinate amount to 10% to 25% of the root extract (Ref.). Assuming 10% Glycyrrhizinate, in order to achive the dose used in the clinical trial we would need to use about 5g Licorice root extract/day. This seems safe, given that Licorice root has been used in daily doses from 760 mg to 15 g for ulcer and gastritis (Ref.).
Melatonin
What is this: a hormone that regulates the sleep-wake cycle. Can be found as food supplement online and it is currently used by many as an anti-cancer and anti-inflammatory treatment.
What is the potential:
- has been found to be effective in fighting viral infections in a variety of experimental animal and in vitro studies (Ref.) and has been proposed even as an anti sepsis treatment (Ref.)
- suppresses TLR9-triggered proinflammatory cytokine production, inhibiting the of upregulation of TNF-α, IL-6, IL-12 p35, IL-12 p40 and IL-10 mRNA expressions, thus regulating TLR9-mediated innate immune responses (Ref.) TLR9-mediated innate immunity and inflammation plays important roles in infectious diseases, autoimmune diseases and cancer (Ref.)
- a very recent scientific study (March 2020) suggesting Melatonin as a potential anti-COVID-19 drug (Ref.)
How to take: available online as capsules of 1,3,5,10,20mg. In some countries it is not allowed to be sold in capsules >5mg as it is seen as a hormone. Nevertheless cancer patients are using even 200mg/day (of course they do not start with this but they move up step by step to this dose). Nevertheless, I would use probably 5mg before sleep as a prevention and 20mg/day or more before sleep when fighting corona. Our body, also produces Melatonin. Better quality sleep promotes the secretion of Melatonin. To improve this quality and have higher levels of Melatonin produced, I would block out all distracting noise and eliminate as much light as possible, including the stand-by light from electronic devices.
Coconut (Lauric acid/Monolaurin & Capric acid/Monocaprin)
What this is: Lauric acid is a medium-chain fatty acid which makes up about 50% of coconut oil, and Monolaurin is a metabolite that is naturally produced by the body’s own enzymes upon ingestion of coconut oil and is also available in pure form as a supplement. Capric acid amkes up about 5%-10% of coconut oil.
What is the potential:
- Lauric acid/Monolaurin & Capric acid/Monocaprin have anti viral action (Ref.1), anti-bacterial (Ref.1, Ref.2), and anti-cancer (Ref.) action. The anti-viral action is addressing the following:
- Lauric acid and Monolaurin have been recently proposed by a scientist and a MD from Philippines and US as a treatment against COVID (Ref.1, Ref.2)
How to take: The clinical trial proposal: 3 three tablespoons of Virgin Coconut Oil, daily or higher and/or Monolaurin (95% purity, 800 mg daily) and/or Monocaprin (95% purity, 800 mg daily) (Ref.). Even better, if infected, I would eat one coconut/day, or at least half of it.
Camostat and Nafamostat
What is this: Japanese drugs approved for the treatment used for e.g. treatment of chronic pancreatitis or postoperative reflux esophagitis. Camostat (brand name Foipan) is an oral drug and Nafamostat (brand name Fusan) is an intravenous one.
What is the potential:
- In order to enter the cell Coronavirus first attaches itself to ACE2 receptors. However, for this to happen, another element is required called TMPRSS2
- In 2016, a Japanese team discovered that Nafamostat effectively inhibits SARS-CoV effective connection with the cell membrane by inhibiting TMPRSS2 (Ref.)
- On March 3 2020, German scientists reported that by inhibiting TMPRSS2, Camostat (a drug similar to Nafamostat) blocks the entry of SARS-CoV-2 virus into the cells (Ref.)
- Even more recently, during March 2020, it has been reported that Japanese scientists tested Nafamostat in SARS-CoV-2 and that it may inhibit the infection of cells by COVID-19 at a doses that is less than one-tenth that needed for Camostat to achieve the same (Ref.). Nevertheless, the advantage of Camostat is that is an oral drug.
- Therefore, Camostat or Nafamostat could be two different drugs that can be used for the prevention and spread of the viral infection alone or in combo with other drugs such as Hydroxycgloroquine.
How to take: The typical dose of Camostat for chronic pancreatitis is 600 mg daily, for postoperative reflux esophagitis 300 mg are taken. The daily dose is split in 3 doses and taken after each meal. (Ref.)
Ivermectin
What is this: this is a drug used both in humans and animals with an established safety profile for human use, approved by FDA for various parasitic infections (as a side note, this drug is known to have broad anti-cancer activity (Ref.)). This is a cheap and easy to access drug.
What is it’s potential:given
- shown to have anti-viral activity against a broad range of viruses (Ref.1, Ref.2, Ref.3)
- On April 3rd 2020, Australian researchers reported that (Ref.):
- Ivermectin is an inhibitor of the COVID-19 causative virus (SARS-CoV-2) in vitro
- A single treatment able to effect ∼5000-fold reduction in virus at 48h in cell culture.
How to take:
- a recent systematic review, including a meta-analysis, has shown that adverse effects following single-dose treatment with up to 0.8 mg/kg of Ivermectin occur without significant differences of frequency or intensity to those at regular currently approved doses (Ref.)
- here is a paper published in The Lancet in 1994, where patients have been treated with Ivermectin doses up to 1.6mg/kg given as subsequent injections at weekly or biweekly intervals. ” No clinical adverse effects were noted in any of the patients, including the one who received ivermectin for 12 weeks. In fact, many reported improved sleep, less depression, and better bowel and bladder function during the trial.” (Ref.)
- based on the above, taking a single dose of up to 56mg for a person of 70kg (i.e. 0.8 mg/kg) is expected to be safe and may be effective against COVID
- however, note that this is still a high dose – this is why I would start with a lower dose to test the reactions, and I would increase the dose towards the target 56mg if no adverse reactions are experienced. A dose that is typically used is 0.2mg/kg and this should be safe to start with (Ref.).
Update April 22nd:
- Usefulness of Ivermectin in COVID-19 Illness: The administration of ivermectin during COVID-19 illness in hospitalized patients is associated with a lower mortality and hospital length of stay. These findings require confirmation in randomized controlled trials.
- Local Doctor Tries New Coronavirus Drug Treatment
Update July 29th:
- a planned clinical trial in Italy and Spain considering Ivermectin doses at 0.6mg/kg and 1.2mg/kg for 5 days in a raw https://clinicaltrials.gov/ct2/show/NCT04438850
- A retrospective study of 173 COVID-19 patients treated with IVM in four Florida hospitals at a dose of 200 µg/kg yielded a 40% reduction in mortality https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3636557
- Effectiveness of Ivermectin as add-on Therapy in COVID-19 Management (Pilot Trial) https://www.x-mol.com/paper/1281102007506747392
- A recent study conducted from May 2 to June 5, 2020 at the First Affiliated Hospital Xi’an Jiaotong University involving 116 patients who tested positive for COVID-19 has concluded that concerning treatment outcome, adverse effects, and safety, although both treatments regimes were effective in this study, the combination of Ivermectin with Doxycycline was superior to that of Hydroxychloroquine and Azithromycin therapy for the use in cases of mild to moderate infections. https://www.worldhealth.net/news/ivermectin-displaying-promising-results/
Nitazoxanide
What is this: an antihelminthic drug used to treat intestinal worm infections, structurally similar to Niclosamide. This is a cheap and easy to access drug.
What is it’s potential:
- inhibits the replication of a broad range of other RNA and DNA viruses including respiratory syncytial virus, parainfluenza, coronavirus, rotavirus, norovirus, hepatitis B, hepatitis C, dengue, yellow fever, Japanese encephalitis virus and human immunodeficiency virus in cell culture assays (Ref.)
- Proposed to have activity against SARS-CoV-2 (Ref.1, Ref.2)
- Suppresses production of proinflammatory cytokines – suppresses IL6 in mice (Ref.)
How to take: Dosages investigated for treatment of influenza and influenza-like illness or being investigated for other viral infections: Adults and adolescents: 500 or 600 mg orally twice daily for 5 days (Ref.).
Dipyridamole
What is this: an FDA approved drug that inhibits blood clot formation and causes blood vessel dilation when given at high doses over a short time. Its a safe drug with favorable and broad pharmacological properties. The relevance of this against COVID-19 was brought to my attention in a private discussion with Jane McLelland who specifically likes this drug for it’s anti cancer activity. This is a cheap and easy to access drug.
What is it’s potential:
- antiviral activity was previously demonstrated against Herpes simplex virus, Mengovirus RNA replication, human immunodeficiency virus (HIV) and prevented Epstein-Barr virus reactivation (Ref.)
- it has been used successfully in several COVID19 patients in China: “Two weeks after initiation of dipyridamole treatment, 3 of the 6 severe cases (60%) and all 4 of the mild cases (100%) were discharged from the hospital. One critically ill patient with extremely high levels of D-dimer and lymphopenia at the time of receiving DIP passed away. All other patients were in clinical remission.” (Ref.)
- in April this year another (preprint) paper indicated that “molecular docking reveals the potential of dipyridamole to inhibit COVID-19 virus main protease (Ref.)
How to take: in the above case report The daily treatment protocol comprised of 150 mg in 3x/day for seven consecutive days, next to the typical anti-viral treatment including Ribavirin, corticoids and oxygen therapy (Ref.)
Vitamin D
What is this: Vitamin D, also found as a food supplement, is a hormone precursor produced by our own body with the help of sunlight which has an important role on adaptive immunity and cellular differentiation, maturation and proliferation of several immune cells.
What is it’s potential:
- there is a large amount of evidence that patients with respiratory disease are frequently deficient in vitamin D, and that Vitamin D supplementation may be important in protection against respiratory infections (Ref.1, Ref.2)
- vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data (Ref.)
- the decreased vitamin D status in calves had been reported to cause the infection of bovine coronavirus – supplementation during an acute infection diminishes disease severity and duration in the young animal (Ref.)
- Adults have deficiency in Vitamin D3. As an example in Ireland:
- One in eight older adults are always deficient
- One in five older adults are deficient in winter
- One in two over 85 are deficient in winter
- One in four over 70 are likely to be deficient during the “stay in home” time during COVID19 challenges
- Reference: https://tilda.tcd.ie/publications/reports/pdf/Report_Covid19VitaminD.pdf
- vitamin D deficiency among populations of the southern Mediterranean regions (Italy, Spain, France, Cyprus, Turkey and Israel) is widespread (Ref.1, Ref.2) – these are some of the country that saw the hardest COVID19 hit
- vitamin D has been suggested as a treatment option in COVID19 patinets (Ref.)
- a clinical trial on Vitamin D in COVID19 patients to be done in Spain: https://www.
clinicaltrials.gov/ct2/show/ NCT04334005 - Update September 2020: great results of the clinical trial in Spain indicating that https://www.sciencedirect.com/science/article/pii/S0960076020302764
- The vitamin D endocrine system may have a variety of actions on cells and tissues involved in COVID-19 progression.
- Administration of calcifediol or 25-hydroxyvitamin D to hospitalized COVID-19 patients significantly reduced their need for Intensive Care United admission.
- Calcifediol seems to be able to reduce severity of the disease.
How to take: In the above clinical trial, they are going to use 25000 UI of vitamin D/day. Vitamin D supplementation will be taken in the morning together with a toast with olive oil to facilitate its absorption.
Others to be discussed:
Colloidal silver, Zinc, Sambucol, Omega‐3 (Ref.), Selenium (Ref.), Berberine, Aspirin (Ref.), Metformin, Oregano Oil, Description
Indometacin (Ref.), Artemisia Annua, Olive Leaf Extract, Probiotics (Ref.), Alpha Lipoic Acid (Ref.), 2DG – all have potential in the fight against COVID.
How I would use the drugs and supplements listed above
(Assuming there is no medical assistance available)
As prevention, I would use
- 500mg Quercetin/day,
- 1g Scutellaria baicalensis,
- 3g Vitamin C (spread across the day),
- NAC 600mg 1x/day
- Good sleep and if required 5mg Melatonin before sleep
- Selenium supplement (not discussed above yet)
- Zinc supplements (not discussed above yet)
- high dose Vitamin C from time to time if possible
- I am still thinking of it makes sense to use Hydoxychloroquine as a prevention methoth (200 up to 400mg/day)
If flu-like symptoms, I would use the following:
- 500mg Quercetin/day,
- 3g Scutellaria baicalensis,
- 6g or more Vitamin C (spread across the day),
- NAC 600mg 2x/day
- Good sleep and 5mg Melatonin before sleep
- 5g/day licorice root as a food supplement
- Selenium supplement (not discussed above yet)
- Increase Zinc supplements (lozenges) (not discussed above yet)
- high dose Vitamin C if possible, at least one time/week
- Hydoxychloroquine 200mg/day
If Coronavirus infection confirmed:
- 3g/day Quercetin,
- 3-5g Scutellaria baicalensis,
- 6g or more Vitamin C (spread across the day),
- 5g/day licorice root as a food supplement
- Selenium supplement (not discussed above yet)
- Good sleep and 20mg or more Melatonin before sleep
- Increase Zinc supplements (lozenges) (not discussed above yet)
- high dose Vitamin C if possible, at least one time/week
- Niclosamide 2g/day
- Hydoxychloroquine 400mg 2x/day, and the coming 4-9 days we take 200mg/day
- If symptoms increasing I would start Thalidomide 100mg/day
Cocktails of Drugs and Supplements
- One cocktail has been discussed here.
- Another cocktail of drugs and supplements has been discussed here.
- According to French scientists: combining Hydroxychloroquine with the anti-biotic Azithromycin https://www.youtube.com/watch?v=ydcrROJFEU0 is very effective. In this case, patients received 600mg Hydroxychloroquine (200mg 3x/day) and Azithromycin (500mg on day 1 followed by 250mg per day, the next four days) to prevent bacterial super-infection (Ref.)
- According to Dr Vladimir Zelenko (Ref.) combining the following would be more effective:
- Hydroxychloroquine 200mg twice a day for 5 days
- Azithromycin 500mg once a day for 5 days
- Zinc sulfate 220mg once a day for 5 days
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Important Notes
I would consider to hold or lower the use of ACE inhibitor drugs: A recent paper indicates that “ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19@ (Ref.) (Thank you Johan for heads up on this one.)
ACE inhibitors are a class of medication used primarily for the treatment of high blood pressure and heart failure. Frequently prescribed ACE inhibitors include benazepril, zofenopril, perindopril, trandolapril, captopril, enalapril, lisinopril, and ramipril. Here is a more extensive list of ACE inhibitors (Ref.)
The same paper (Ref.) states that there is no “evidence to suggest that antihypertensive calcium channel blockers increased ACE2 expression or activity, therefore these could be a suitable alternative treatment in these patients.”. So doctors can switch their patients from ACE2-inhibitors to calcium-channel-inhibitors to address their heart-related challenges.
Keep yourself worm: cooler temperatures can enable replication of the common cold virus, at least in part, by diminishing antiviral immune responses. (Ref.) Drink hot tea often.
(This idea was “stolen” from Dr. Pavia Milfeldt Lumholt (Ref.))
Take Paracetamol (Acetaminophen) instead of Ibuprofen: Taking anti-inflammatory drugs such as ibuprofen and cortisone can worsen the infection in people who have become ill with the new coronavirus. That has been tweeted by the French Minister and the reason for that seems to be the fact that these drugs increase the ACE receptors on the uninfected cells, which in turn allows the COVID virus to get into the cells. (Ref.) The advise is a result of the information reported in this scientific publication (Ref.).
More Relevant Options
- Actemra (tocilizumab) from Roche, an inhibitor of Interleukin 6 (IL-6) used in the treatment of rheumatoid arthritis, was reported recently as showing positive results when used to treat Covid-19 patients in Italy and China (Ref.). Because it inhibits Interleukin 6 (IL-6), it can now be used to treat coronavirus patients with severe lung damage.
.
This can work because the immune system in Covid-19 patients responds to the infection by overproducing inflammatory cytokines such as IL-6 in the phenomenon called cytokine storm. This in turn induces severe lung damage. Inhibiting this inflammatory response of the immune system may often help patients survive.
.
Note that EGCG, a natural extract from green (Ref.1, Ref.2) found online as a food supplement may also inhibit IL-6. Loratadine may also lower that (Ref.).
. - Tetrandrine – a drug mainly found in China is in clinical trail to treat COVID patients https://clinicaltrials.gov/ct2/show/NCT04308317?cond=covid&draw=2&rank=9
.
It is given 60mg 4x/day for a course of 1 week(Take 6 days, stop using for 1 day).
.
Tetrandrine is used because it is an antagonist of calmodulin, has anti-tumor, anti-inflammatory effects, and can effectively inhibit fibroblasts, thereby inhibiting pulmonary fibrosis. The study is expected to treat patients with mild and severe neo-coronary pneumonia through standard treatment regimens in combination with tetrandrine tablets, thereby reducing the clinical progress of some patients, improving prognosis, reducing the incidence of pulmonary fibrosis during rehabilitation, and improving patients’ quality of life.
. - Cardiac glycosides – a recent study from Korea reported that cardiac glycosides could be a solution against COVID-19: “Consistent with these previous studies, our data indicate that the cardiac glycosides, ouabain, digitoxin, and digoxin, efficiently inhibit MERS-CoV infection. Ouabain, in particular, has been found to block the entry stage of coronaviruses, such as MERS-CoV, through Src kinase signaling.” (Ref.) Gardiac Glycosides are some of my preferred weapons against cancer and Ouabain one that stands out in that group. This has been used in the past to address heart disease but it was taken out of the market and replaced by drugs from pharmaceutical industry. Some are calling Ouabain, “the insulin of the heart”. Ouabain is a a plant extract that African warriors and hunters traditionally used as a heart-stopping poison on their arrows. There are still ways to obtain Ouabain from sources in Brasil or Switzerland (made by compounding pharmacy).
. - Favipiravir – a drug used in Japan to treat influenza seems to be effective at treating the novel coronavirus that causes COVID-19 (Ref.) However, the drug seems less effective in patients with severe symptoms.
. - “A joint research team of the Shanghai Institute of Materia Medica and Shanghai Tech University performed drug screening in silicon and an enzyme activity test, and they reported 30 agents with potential antiviral activity against SARS-CoV-2 on January 25, 2020. These agents are indinavir, saquinavir, lopinavir, carfilzomib, ritonavir, remdesivir, atazanavir, darunavir, tipranavir, fosamprenavir, enzaplatovir, presatovir, abacavir, bortezomib, elvitegravir, maribavir, raltegravir, montelukast, deoxyrhapontin, polydatin, chalcone, disulfiram, carmofur, shikonin, ebselen, tideglusib, PX12, TDZD-8, cyclosporin A, and cinanserin. The same study also found that Chinese herbal medicines such as Rhizoma Polygoni Cuspidati and Radix Sophorae Tonkinensis may contain active ingredients against SARS-COV-2.” (Ref.) Again, next to the typical anti-viral drugs, repurposed drugs in oncology such as Disulfiram and food supplements known to fight cancer, are found to be possibly effective against COVID-19.
. - Sea buckthorn berry – Korean researchers found substance inhibiting COVID-19 (Ref.)
. - A drug screening based on computational methods indicating a long list of re-purposed drugs that may help against COVID-19: Ribavirin, Valganciclovir, β-Thymidine, Aspartame, Oxprenolol, Doxycycline, Acetophenazine, Iopromide, Riboflavin, Reproterol, 2,2′-Cyclocytidine, Chloramphenicol, Chlorphenesin carbamate, Levodropropizine, Cefamandole, Floxuridine, Tigecycline, Pemetrexed, L(+)-Ascorbic acid, Glutathione, Hesperetin, Ademetionine, Masoprocol, Isotretinoin, Dantrolene, Sulfasalazine, Silybin, Nicardipine, Sildenafil, Platycodin D, Chrysin, Neohesperidin, Baicalin, Sugetriol-3,9-diacetate, (–)-Epigallocatechin gallate, Phaitanthrin D, Piceatannol, Rosmarinic acid, Magnolol, Lymecycline, Chlorhexidine, Alfuzosin, Cilastatin, Famotidine, Almitrine, Progabide, Nepafenac, Carvedilol, Amprenavir, Tigecycline, Demeclocycline, Montelukast, Carminic acid, Mimosine, Flavin mononucleotid, Lutein, Cefpiramide, Phenethicillin, Candoxatril, Nicardipine, Estradiol valerate, Pioglitazone, Conivaptan, Telmisartan, Doxycycline, Oxytetracycline, and more (Ref.) . Some of those in the list that draw my attention as they are also very relevant in cancer are the re-purposed drugs Doxycicline, Sulfasalazine and Atorvaquone and the food supplements Glutathione, Silybin, Rosmarinic acid, Magnolol, (–)-Epigallocatechin gallate, Lutein, Oleanolic acid.
. - Colchicine, a drug used to treat gout and Behçet’s disease was proposed by the Canadian researchers to be used for inhibition of the pro-inflammatory reaction of the immune system killing people infected with COVID-19 (Ref.1, Ref.2). As a results a trial was stated on Colchicine.
. - Ozone – A Plausible “Penny” Costing Effective Treatment for Corona Virus – Ozone Therapy
. - Mefloquine – re-purposed drug, in trials in Russia against COVID19 – https://www.plenglish.com/index.php?o=rn&id=53950&SEO=russia-presents-trial-to-fight-against-covid-19
. - Mega dose of Vitamin D3: http://www.askdrray.com/coping-with-covid-19-coronavirus/
. - Nitazoxanide (Ref.1, Ref.2)
. - Reserpine (Ref.1, Ref.2)
. - EPA fatty acid + Artemisia Annua extract in clinical trials for COVID19 https://www.nutritioninsight.com/news/fatty-acid-and-sweet-wormwood-on-road-to-clinical-trials-for-covid-19.html
Other Important References
A new treatment strategy against MERS – Autophagy-inducing substances – including licensed drugs – were shown to be capable of reducing the viral replication rate. (Ref.)
Potential antivirals and antiviral strategies against SARS coronavirus infections
Repurposing host-based therapeutics to control coronavirus and influenza virus
Biopharma products in development for COVID-19
Tranexamic acid: A potential treatment option for coronavirus disease 2019
Disclaimer
This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.
Please read an extended version of the Disclaimer here: https://www.cancertreatmentsresearch.com/?page_id=1794
Beside Pubmed, a good source of information on Covid-19 is:
https://www.reddit.com/r/COVID19/
Thank you Ovidiu for the link and thank you for being the first to pay specific attention to what dr. Hada had to say about Thalidoimide and its potential to treat Coronavirus infected patients.
Kind regards,
Daniel
@Daniel: could you please contact Dr. Hada, and ask him to share his opinion on Cepharantine, which is used in Japan for about 40 years? The reason is this:
Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus (2019-nCoV) related coronavirus model. PMID: 32149769
I’d also like to add something about risk factors (basal, pre-infection), you could add something about improving those:
– low lymphocytes, high neutrophils;
– high C-reactive protein;
Thank you all for the contributions. The situation is getting bad in Madrid, I am very sorry to have to deal with this virus together with the fight against cancer.
These are hard times
Kind regards
thanks!
Shanghai Government Officially Recommends Vitamin C for COVID-19
http://orthomolecular.org/resources/omns/v16n16.shtml
http://www.orthomolecular.org/resources/omns/v16n17.shtml
Thank you Johan! Very useful references on Vit C for COVID-19
Kind regards,
Daniel
– Spirulina extract inhibits influenza virus replication: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828654/
– Beta-glucans: https://www.researchgate.net/publication/8669962_Antiviral_Effect_of_Saccharomyces_cerevisiaeb-glucan_to_Swine_Influenza_Virus_by_Increased_Production_of_Interferon-g_and_Nitric_Oxide
– N-acetyl-L-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules: https://www.ncbi.nlm.nih.gov/pubmed/19732754 (NAC should be avoided in most cases if cancer is present!!!)
Thanks a lot Carl. I will go through these.
Kind regards,
Daniel
Plitidepsin:
https://www.lavanguardia.com/vida/20200313/474107869086/pharmamar-contactara-autoridades-posibles-estudios-pacientes-coronavirus.html
Many thanks to Daniel and all contributors!
ANTIVIRAL EFFECTS OF SAIKOSAPONINS ON HUMAN CORONAVIRUS 229E IN VITRO:
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1440-1681.2006.04415.x
Identification of natural compounds with antiviral activities against SARS-associated coronavirus:
https://www.ncbi.nlm.nih.gov/pubmed/15885816/
Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds:
https://www.ncbi.nlm.nih.gov/pubmed/16115693/
Biflavonoids from Torreya nucifera displaying SARS-CoV 3CL(pro) inhibition:
https://www.ncbi.nlm.nih.gov/pubmed/20934345/
Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13.:
https://www.ncbi.nlm.nih.gov/pubmed/22578462/
Immunomodulatory and anti-SARS activities of Houttuynia cordata.
https://www.cancertreatmentsresearch.com/a-list-of-drugs-and-supplement-to-fight-coronavirus/
http://nutrition.merschat.com/foods-by-nutrient.cgi?Nutr_No=788&Measure=&page=1
“this is page 1 of 4 displaying 29 foods ordered by their concentration of Myricetin per 100 grams.”
“Myricetin is structurally similar to fisetin, luteolin, and quercetin and is reported to have many of the same functions as these other members of the flavonol class of flavonoids” wikipedia
Great post D and great contributions everyone! Here is Life Extension’s Corona Virus Protocol, which is being regularly updated, and has many of the things already mentioned: https://www.lifeextension.com/protocols/infections/2019-novel-coronavirus-sars-cov2-covid-19.
Thanks to everything we learned on this site, we already have Chloroquine, lots of zinc, and IV vitamin C and ozone in-house. Hopefully, we won’t need it for corona purposes. Wishing everyone good health.
-Shanti
Thanks a lot dear Shanti! And it’s very nice to see that Life Extension put a list together that may help to minimise getting Coronavirus. Thank you for sharing the link.
(Unfortunately, I annoyed some people with this post because due to an error (a WordPress plugin error) it was send multiple times to the e-mail box of all subscribers).
Like many, I am thinking that once someone has Corona, we should stop some of the immune-activating supplements and focus on anti-inflammation. What do you think about this approach?
It’s amazing to see how once again, that most drugs and supplements with anti-viral properties are the same that stand out in the fight against cancer. (we often discussed the fact that many signs point towards cancer as an infection disease that may have a viral trigger AND driver behind, for more cancers than we think today)
Kind regards,
Daniel
Hi D-
What a great question to ask! I’m sure others may have their take, but here is mine. Unlike H1N1 which took its toll on those who were younger with robust immune systems who easily went into cytokine storm, COVID 19 seems to go for the elderly and those with comorbidities and I think the cytokine storm is a last rally by the immune system. While cytokines do seem to be involved in the lung damage, even in early stages of COVID, they may also be involved in helping the immune system to fend off the virus. Johan’s post abut anti-inflammatories potentially worsening the course of disease has admittedly influenced my thought on this: https://www.connexionfrance.com/French-news/Covid-19-Ibuprofen-can-worsen-infection. For me the question comes down to, at what point in the course of the illness do you discontinue immune support? Before exposure, when it is asymptomatic, when it is mild, or when severe symptoms begin to manifest? To be on the safe side, I would probably discontinue stimulating immune support in the mild phase. I’m thinking things like AHCC, mushrooms and echinacea might fall in this category. Immune modulators like Melatonin may both inhibit cytokine storm and support the immune system. I think vitamin D, bidens and some other herbs might fall here. Then there are things that have direct antiviral properties, like zinc, IVC, and garlic that I would also continue. Interesting that EGCG has some research as an antiviral, but it also has research on calming cytokine storm (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3945414/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711683/). Anyhow, I would be interested in your thoughts. Your comment about antiviral and anticancer approaches being so similar was spot on, we are amazed to find we already have the top meds and nutrients for COVID in our medicine cabinet!
Best,
Shanti
Hi Shanti,
And what a nice and clean response.
As addressed below in the discussion with Milen, it’s important to point out that only one small category of anti-inflammatory should be avoided. That is not because of their anti-inflammatory action which is very helpful in Corona-patients, but because those specific ones (such as Ibuprofen, ACE inhibitors and angiotensin II type-I receptor blockers) lead to an up-regulation of ACE2 receptors that are also used by the Coronavirus to connect to the normal cells. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30116-8/fulltext
I totally resonate with your thoughts on phasing in and out the strong immune-modulators while constantly maintaining and if needed increase the anti-viral ones. The only major question I have now, is if it makes sense to use Hydroxychloroquine as a preventive measure, specifically during the coming few months when people may be more susceptible. Some of my friends, doctors, are considering to use for their parents as a preventive measure. I also think your point on EGCG is a very good one. So I would go for a lot of Green tea these days, as I do feel some flu-like symptoms.
Kind regards,
Daniel
@Daniel: I asked the question about Hydroxychloroquine as prophylactic on Quora on Thursday, but got no answer yet.
https://www.quora.com/unanswered/Should-hydroxychloroquine-be-given-as-a-prophylactic-against-the-community-spread-of-COVID-19
Hi D-
My thought with the Chloroquine / Hydroxychloroquine is that they would be good to use prophylactically because of their action as zinc ionophores (Hydroxychloroquine hasn’t been studied as a zinc ionophore, but it is so closely related to Chloroquine, it probably is). Some have proposed that one of the anti-viral mechanisms of these two meds is increasing intracellular zinc, which then inhibits viral replication in the cell. If that is the case, their use as a preventative makes sense. Also, since it can take up to 2 weeks to develop symptoms, it seems you would want the meds in the system for that entire time period where you may not know you have been infected.
Thank you for the clarification with the anti-inflammatory, now that I pulled up the link, I see that it is more about the ACE2.
I hope you are feeling ok D, do you have many cases where you are. Please take care.
Warmly,
Shanti
Hi Shanti
Still dosing for preventive use isn’t clear yet because of prolonged use of chloroquine may lead to blindness
But as its half-life time is quite long (few weeks) can it be administered in on/off cycles to avoid complications?
Kind Regards
Hi Asafsh-
I agree that neither medication is free from side effects, so that has to be balanced with risk of exposure and complications from an infection. It is my understanding that Chloroquine retinopathy occurs after years of daily use, usually greater than 5-10, could you elaborate on your concern? People could also use hydroxychloroquine instead, which has lower toxicity. Or, instead of the treatment dose of 200mg Chloroquine bid, they could use 200mg once a day for prevention, which seems to be an established safe dose for years, as least as far as the retina is concerned. I’m not a proponent of people who are not high-risk taking these prophylactically, but it could be a consideration for those with known exposure or working in a high-risk environment.
Hi Shanti
the https://www.webmd.com/drugs/2/drug-8633/chloroquine-oral/details says that
“This medication may cause serious eye/vision problems. The risk for these side effects is increased with long-term use of this medication (over weeks to years) and with taking this medication in high doses.”
The duration isn’t well defined (at least according to this site).
Seems there are not stats on elder patients, or at least i didn’t see such.
I don’t question this drug usage, just interested to know if due to chloroquine long half-time we have a chance to reduce the dose when administering it for prevention purposes.
Kind Regards
Hi Asaf,
It’s important to make the distinction between Chloroquine and Hydroxychloroquine https://pubmed.ncbi.nlm.nih.gov/4057189-comparison-of-hydroxychloroquine-and-chloroquine-use-and-the-development-of-retinal-toxicity/
The second is safer.
Also, I just discussed with some friends who often use Hydoxy for their patients and the seem confident enough to suggest to their parents as a (potentially) preventive measure.
Kind regards,
Daniel
Hi Shanti,
Thank you. I totally agree, the ionophor activity may bring an extra anti-viral mechanism of action C/H.
I am OK indeed. It’s funny that most of the fiends around (or > half of them) have some form of flu (coincidence?). I also felt some irritation on the throat but pushed a lot of Vitamin C, Zinc lozenges, Sambucol, Nac, hot tea and a few others and things seem to stay at a low level. I never used so much Vitamin C before and its clear it helps a lot. For every flu from now on I will use this method which was put together by one outstanding man (not sure if he agrees with sharing his name here 🙂 and which seems to be very effective.
Kind regards,
Daniel
Hi Asaf,
Understood, and always to be safer when there is a concern. These two pages below help define the toxicity of Chloroquine and Hydroxychloroquine a little better in regards to dose and duration.
https://emedicine.medscape.com/article/1229016-overview#a4
https://emedicine.medscape.com/article/1229016-overview#a5
As D points out better to go with hydroxychloroquine if available, we only have chloroquine on hand here, but hopefully won’t have to use it.
Hi D- I have my suspicions on the identity of this outstanding man and his effective protocol! I am glad you are keeping it at bay :-).
Hi Shanti and Daniel
Thank you for clarification!
Kind Regards
“ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19”
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30116-8/fulltext
advice from french authorities is to use paracetamol but NOT ibuprofen in case of fever and pain.
Extremly helpful!
Here is a list of ACE inhibitors (many but not all) from Wikipedia:
ACE inhibitors are easily identifiable by their common suffix, ‘-pril’. ACE inhibitors can be divided into three groups based on their molecular structure:
Sulfhydryl-containing agents
Captopril (trade name Capoten), the first ACE inhibitor
Zefnopril
Dicarboxylate-containing agents
This is the largest group, including:
Enalapril (Vasotec/Renitec/Berlipril/Enap/Enalapril Profarma)
Ramipril (Altace/Prilace/Ramace/Ramiwin/Triatec/Tritace/Ramitac)
Quinapril (Accupril)
Perindopril (Coversyl/Aceon/Perindo)
Lisinopril (Listril/Lopril/Novatec/Prinivil/Zestril, Lisidigal)
Benazepril (Lotensin)
Imidapril (Tanatril)
Trandolapril (Mavik/Odrik/Gopten)
Cilazapril (Inhibace)
Phosphonate-containing agents
Fosinopril (Fositen/Monopril) is the only member of this group
Naturally occurring
A comprehensive resource on anti-hypertensive peptides is available in form of a database. It contains around 1700 unique antihypertensive peptides[38]
Arfalasin (HOE 409) is angiotensin antagonist. U.S. Patent 4,013,791
Dairy products
Casokinins and lactokinins, breakdown products of casein and whey, occur naturally after ingestion of milk products, especially cultured milk. Their role in blood pressure control is uncertain.[39]
The lactotripeptides Val-Pro-Pro and Ile-Pro-Pro produced by the probiotic Lactobacillus helveticus or derived from casein have been shown to have ACE-inhibiting and antihypertensive functions.[40][41] In one study, L. helveticus PR4 was isolated from Italian cheeses.[42]
https://en.wikipedia.org/wiki/ACE_inhibitor
many thanks, Daniel!!
Therapeutic Drugs Targeting 2019-nCoV Main Protease by High-Throughput Screening
https://www.biorxiv.org/content/10.1101/2020.01.28.922922v2.full
D, camostat mesilate; already approved in Japan.
Corona virus could completely overwhelm our health care system; perhaps a drug such as the above could be rapidly deployed so that an ICU crisis could be avoided. If people never became very sick, then there would be no reason to worry about rationing of scarce medical resources.
https://www.cell.com/cell/fulltext/S0092-8674(20)30229-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420302294%3Fshowall%3Dtrue
There is a warning from French minister of health that anti-inflametory medicine can worsen the condition in covid-19:
https://www.theguardian.com/world/2020/mar/14/anti-inflammatory-drugs-may-aggravate-coronavirus-infection?fbclid=IwAR0RZ-rMtoBgv9V4hY6IS7veip-0y4momrlvfaLWhZ4AYCdmxhLl1EtzDb4
Hi Milen,
Thank you for addressing this point.
That warning is about Ibuprofen (and several other drugs), not all anti-inflammatory according to this publication in The Lancet https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30116-8/fulltext noted above by Johan.
Anti-inflammatory in general are actually very good specifically when a patient deals with Corona.
The issue with Ibuprofen is that it may increase ACE2 receptor expression, as stated in the above paper.
This in turn cold increase the chance of virus to access the uninfected cells, so it’s best to avoid it at these times and replace it’s use with other anti-inflammatory or anti-pain medication such as Paracetamol, Diclofenac, Celecoxib. Diclofenac, for example, should actually even help reduce the viral replication as well over reactions of the immune system as it is a fermentation inhibitor.
Kind regards,
Daniel
Seems Israel uses Remdesevir and Chloroquine for treatment.
Very interesting these discussions about coronavirus. I am in a total risk focus, I am using high doses of vitamin C 4g plus liposomes, zinc, garlic and curcumin + piperine. I am considering using hydroxychloroquine 200mg for 1 week. If things get ugly I would use what I have in my mother’s medicine cabinet: hydroxychloroquine, atorvastatin, liposomal fenofibrate, metformin and rivabirin.
Daniel take care of yourself! 😉
Thanks a lot dear Manuel! Those you mention sound like a good prevention approach. Always check if there is any relation between the drug you use and ACE2 expression, and avoid using those that lead to an increase of ACE2 expression. If hydroxychloroquine that we have available is too little, we can also take one every few or several days (even every week) take one 200mg capsule. This makes sense because the half life of the drug is very long, i.e. 22 days. Take care of you!
Kind regards,
Daniel
What do you think of using Artemisia Annua if you don´t have access to hydroxychloroquine? And how about dosing? 2*500mg a day?
Dear Zdenek,
Thank you. Very good question. I feel Artemisia Annua should be helpful, however, if that is the case the mechanism will be most probably different compared to HydroxyChloroquine. I will check the literature and let you know what are my findings on this.
However, regardless of the literature, knowing how broad-spectrum anti viral, anti cancer, anti parasites this plant is, I would have some Artemisia Annua hot tea cycles done. One expert was recommending one cup of tea as prevention and 3-5 to treat active disease. For Corona, I think tea is best compared to capsules since the virus replicates more in the upper respiratory tract, which includes the nose, mouth, larynx and bronchi. To answer your question regarding the capsules, in cancer treatment, some are using 3x500mg capsules/day. However, for references on safe dose (which could be higher) please check my post on Artemisia Annua.
Kind regards,
Daniel
Hi,
“Lycoris radiata, Artemisia annua, Pyrrosia
lingua, and Lindera aggregata exhibited significant inhibition effects on virus-induced CPE when SARS-CoV strain
BJ001 was used in screening.”
Reference
Interactive map for covid from Microsoft:
https://www.bing.com/covid
seems, countries that are in summer are least affected.
Thank you asafsh. Only now I saw the map.
Kind regards,
Daniel
That’s a great observation, Asafsh. I think vitamin D levels are an important factor in the outcome of the covid-19 infections.
Answering Maxim on this comment https://www.cancertreatmentsresearch.com/contact/#comment-10301
and trying to direct the discussion on the COVID page.
Hi Maxim,
Thank you for your comments!
You are right in that Thalidomide may be more effective in inhibiting the cytokine storm.
However, Thalidomide and Chloroquine, inhibit key components of the coronavirus infection at different points lifecycle.
Both of them have immune modulation properties but in addition to that Chloroquine is addressing and inhibits the process related to the virus entering the cell.
So I think both of them are very valuable tools, and when used together they may represent a much stronger potential solution.
As a note, and I think as a result of the suggestions of Dr. Hada, there are clinical trials in COVID not only with Hydroxychloroquine but also using Thalidomide and Thalidomide+Celecoxib: NCT04273529 and NCT04273581 https://www.guidetopharmacology.org/coronavirus.jsp
Very intresting to hear that you made your own Thalidomide, as you stated here https://www.cancertreatmentsresearch.com/contact/#comment-10290
Can you please share here what was the method you use to synthesise that? Thank you!
Kind regards,
Daniel
For thalidomide synthesis i used as a base this method A FACILE SYNTHESIS OF THALIDOMIDE (https://pubs.acs.org/doi/abs/10.1021/acs.oprd.9b00122)
Only a bit optimized it. I used as a solvent propionic acid and the whole reaction (without isolation and purification of phtaloyl glutamic acid) took place in it.
1) boiled 3 hours phthalic anhydride (50 gr) and glutamic acid (50 gr) in 350 ml of propionic acid.
2) distilled off 150 ml of propionic acid
3) added 100 gram of ammonium acetate
4) slowly raised themperature to 160 C (distilling off acid and water)
5) then slowly in 2 hours (distilling off acid and water) raised temperature to 180 C
6) and completed the reaction at 180 C for 30- 40 minutes (distilling off acid and water)
7) then dissolved residue by boiling in 250 ml DMSO and 25 ml methanol
8) the solution was dumped into 600 ml isopropanol and left to crystallize
9) filtered, washed with water acidified a bit with propionic acid, then with isopropanol and then with acetone
10) dried, in the end at 70 C
11) further can be purifed by dissolving 20 gramms of thalidomide in 100 ml. DMSO at 90 C and dumping it into 200 ml of ethanol
Hi Maxim
Impressive.
Curious, have you checked result against standard by spectrometer or by other means?
Kind Regards
Hi asafsh
No, i did not check. But judging by its very high melting point 271 C and a chinese patent where they purified it only with acetone, and a number of other patents on thalidomide purification in DMSO and DMF – phthalimide and other impurities are very more soluble in these solvents and removed if present.
It is easy to check with TLC, but i did not. I have no lab, because i’m a chemist only by education (studied in biotechnology ).
I checked its melting point only.
Hi Maxim
Thank you for sharing details.
Kind Regards
Did Anybody give it a thought?
That many people (80%) clear it out without any problems, and some even have little symptoms.
If a body can clear it by itself, then what’s the purpose in antivirals?
So, maybe by stimulating the immune system (or modulating its response) patients in the risk group could cope with the disease with their own immune system without developing pneumonia at all.
It needs to be checked if thalidomide could stimulate the immune system and prevent pneumonia from developing. Or at least to quench it from the beginning.
It would be a tremendous cost effective way to treat the covid-19 infection without using expensive medical care units.
Great contribution Maxim! are you chemist?
I do not know at what point to position myself in prevention through prophylaxis, through the immune system or perhaps think about the most effective measures to treat it. Because of course I would not feel safe with 3 g of paracetamol a day as prescribed.
The evidence may be limited for some actions, but I think there is no time to take and try actions like those proposed here. In this Spanish blog by my friend Alfonso F. other measures are contemplated, ranging from fasting, diet, exercise, supplementation with magnesium, ashwagandha, glycine, garlic, vitamin C, oregano oil, taurine … etc.
Speaking of taurine, its derivative “taurolidine” interests me a lot for cancer and surely I add it early to my cocktail, it seems promising compared to COVID-19 on the other hand. This article seems interesting, although it is more focused on bacteria, it can offer antiviral options:
https://journals.plos.org/plosntds/article/file?rev=2&id=10.1371/journal.pntd.0006422&type=printable
Kind regards
Hey Manuel,
Totally agree. Very nice contribution by Maxim.
Have a look at this that I just added to the above post (I think you will like it):
Tetrandrine – a drug mainly found in China is in clinical trail to treat COVID patients https://clinicaltrials.gov/ct2/show/NCT04308317?cond=covid&draw=2&rank=9
It is given 60mg 4x/day for a course of 1 week(Take 6 days, stop using for 1 day).
Tetrandrine is used because it is an antagonist of calmodulin, has anti-tumor, anti-inflammatory effects, and can effectively inhibit fibroblasts, thereby inhibiting pulmonary fibrosis. The study is expected to treat patients with mild and severe neo-coronary pneumonia through standard treatment regimens in combination with tetrandrine tablets, thereby reducing the clinical progress of some patients, improving prognosis, reducing the incidence of pulmonary fibrosis during rehabilitation, and improving patients’ quality of life.
Kind regards,
Daniel
https://www.clinicaltrialsarena.com/analysis/coronavirus-mers-cov-drugs/
“Favilavir, the first approved coronavirus drug in China
The National Medical Products Administration of China has approved the use of Favilavir, an anti-viral drug, as a treatment for coronavirus. The drug has reportedly shown efficacy in treating the disease with minimal side effects in a clinical trial involving 70 patients. The clinical trial is being conducted in Shenzhen, Guangdong province.”
Aplidin (melanoma) also seems to have shown to be promising apparently.(in vitro) https://www.diariodesevilla.es/sociedad/Aplidin-farmaco-Pharmamar-lucha-coronavirus_0_1446155538.html
thanks a lot for your effort dear D. awesome compilation as always.
that’s because it stops cells proliferation which is caused by COVID 19 virus.
Other anti melanoma drugs would work too – as pomalidomide
that explains why children are less prone to this diseases. Their immune system can prevent cell proliferation by itself.
Elders are more prone to it (cancer usually comes in the old age too)
although they can carry virus, it does not cause much of cell proliferation in them.
anti melanoma drugs must be an effective cure for it. People will carry viruses, but as for children it would not do much harm
By the way you should look at the early stages of COVID 19 in the lungs ( https://www.jto.org/article/S1556-0864(20)30132-5/fulltext )
There was diffuse thickening of alveolar walls (Fig. 3B), consisting of proliferating interstitial fibroblasts and type II pneumocyte hyperplasia. Focal fibroblast plug (arrow) and multinucleated giant cells (arrowheads) were seen in the airspaces (Fig. 3C), indicating varying degrees of proliferative phase of diffuse alveolar damage. Some areas had abundant alveolar macrophages along with type II pneumocyte hyperplasia (Fig. 3D).
It seems that the time for the early lung lesions or COVID-19 to become severe enough to cause clinical symptoms is rather long.
********
My thoughts: As one virusologist said, these damage in the lungs opens the doors to the secondary infections (viral and bacterial). After that there’s a rapid deterioration of lungs (more powerful reaction, in a matter of hours) and the patient needs breathe oxygen to stay alive.
IMHO: The best treatment is to prevent this reaction, even better to prevent lesions in the lungs from the early stage (doors for infections).
Antivirals won’t help when this reaction will have occurred.
Hydroxychloroquine probably helps at this final stage as it helped in lepra reactions (antiinflammation, not because it inhibits virus replications). It could better help in early stages as prevention of this secondary reaction and could also inhibit the virus replication.
Thalidomide would help to prevent lesions and inflammations too, and it would work better for the secondary reaction (a lepra reaction analogue).
To prove my point that it is very like lepra reaction type 2 successfully treated with thalidomide, look at histological examination of ENL ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795734/ )
Cytological examination of swelling in both the cases showed neutrophils, lymphoid cells, clusters of foamy macrophages, histiocytes, and giant cells. Fite stain was positive, which confirmed the cytological diagnosis of ENL.
in each case (ENL – lepra reaction, SARS, COVID -19) there’s an epithelian proliferation, macrophages, giant cells
and look at this Leprosy as a Model of Immunity ( https://www.medscape.com/viewarticle/818739_5 )
These data indicate that the body needs a long time to get rid of a heavy load of even dead bacilli within the macrophages.
P.S. antivirals in the last stage of COVID 19 won’t help because there will be already a lot of macrophages and for their cleaning time is needed.
you can only prevent this build up in the early stages of the disease, but nobody would give you intravenous remdesivir at that stage and in the last stage it will be ineffective, because you won’t have time and the macrophages is already in place.
COVID 19 works as in previous SARS infections ( https://www.thelancet.com/pb-assets/Lancet/extras/03art4347web.pdf )
Coronavirus infection in the early stages seems to stimulate epithelial cells and results in cellularproliferation and squamous metaplasia in the lung. This type-2 pneumocyte hyperplasia and hypertrophy has also been identified with porcine reproductive and respiratory syndrome virus (an arterivirus tentatively classified under the Coronaviridae) as well as porcine respiratorycoronavirus (previously known as transmissiblegastroenteritis virus, respiratory variant). In thoseinfections mild type-2 pneumocyte proliferation isassociated with squamous metaplasia. In SARS, macrophage proliferation is more prominent in theconsolidated areas of the lung; this distribution is also seen with porcine respiratory coronavirus.
In contrast to typical diffuse alveolar damage in which neutrophils and fibroblasts are the main cellular agents and macrophages have a lesser role,9in patients with fatal SARS macrophages are the prominent leucocyte in the alveoli, even in the early stages of the disease. The finding of haemophagocytosis in the lung and white-pulp atrophy of the spleen identified in SARS is reminiscent of that reported in fatal influenza subtype H5N1 disease in 1997. Haemophagocytosis has been attributed to cytokine dysregulation. Lymphopenia is another feature common to both SARS-CoV and H5N1 influenzapneumonia. Both viruses have crossed to human beings from animals or birds. Experimental studies in which macrophages are infected in vitro suggest that, compared with conventional human influenza viruses, the subtype H5N1 influenza A viruses isolated in 1997 are hyperinducers of proinflammatory cytokines.
with the word “cellular proliferation” cancer treatment comes to mind, drugs that inhibit cells proliferation. May be antiangiogenic drugs would work to stop it too
https://www.medrxiv.org/content/10.1101/2020.03.11.20031096v1
“People with blood group A have a significantly higher risk for acquiring COVID-19 compared with non-A blood groups, whereas blood group O has a significantly lower risk for the infection compared with non-O blood groups.”
https://www.eturbonews.com/542533/coronavirus-risk-for-asians-africans-caucasians-revealed/?fbclid=IwAR3F9ixB-9PoVmkAenjapwU3aD-lJB6Wc59oHbyKoNv2evj_fZanS7GVcTI
basically not a good time to be an eastern asian male with blood group A.
https://www.thailandmedical.news/news/breaking-new-coronavirus-research-shows-that-the-sars-cov-2-coronavirus-has-a-fourth-route-of-attacking-human-host-cells-making-it-a-real-super-virus
“Initial studies have showed that the SARs-CoV-2 attacks human host cells through the ACE-2 receptors, then furin targets and lately GRP78 receptors.
…
The latest study shows that SARS-CoV-2can invade human host cells via a novel route of CD147-spike protein (SP). SP bound to CD147, a receptor on the host cells, thereby mediating the viral invasion.”
Should ACE2 based risk statement need re-evaluation from cd147 perspective?
For South Korea – is that coronavirus they experienced in 2015 helped them (immune system) to adapt better to the new covid-19? majority of patients during latest covid-19 in South Korea are young…
https://en.wikipedia.org/wiki/Angiotensin-converting_enzyme_2#cite_note-20
Shouldn´t vitamin D3 be added into the antiviral mix in the light of these info?
– Potential Inhibitor of COVID-19 Main Protease (Mpro) From Several Medicinal Plant Compounds by Molecular Docking Study: https://www.preprints.org/manuscript/202003.0226/v1
“The binding energies obtained from the docking of 6LU7 with native ligand, nelfinavir, lopinavir, kaempferol, quercetin, luteolin-7-glucoside, demethoxycurcumin, naringenin, apigenin-7-glucoside, oleuropein, curcumin, catechin, epicatechin-gallate, zingerol, gingerol, and allicin were -8.37, -10.72, -9.41, -8.58, -8.47, -8.17, -7.99, -7.89, -7.83, -7.31, -7.05, -7.24, -6.67, -5.40, -5.38, and -4.03 kcal/mol, respectively. Therefore, nelfinavir and lopinavir may represent potential treatment options, and kaempferol, quercetin, luteolin-7-glucoside, demethoxycurcumin, naringenin, apigenin-7-glucoside, oleuropein, curcumin, catechin, and epicatechin-gallate appeared to have the best potential to act as COVID-19 Mpro inhibitors. ”
– Disinfectants for Use Against SARS-CoV-2: https://www.epa.gov/pesticide-registration/list-n-disinfectants-use-against-sars-cov-2
A video by a French doctor, who treated Covid-19 patients with Hydroxychloroquine at 600 mg / day, alone or combined with Azithromycin. Interesting, the combination cleared the virus faster (but I worry about interactions). In this video he speaks French, there is another video, where he does his best to speak English, but I prefer the original one.
https://www.youtube.com/watch?v=SfiUlVpqHfE
Azithromicin as some macrolide antibiotics has antiinflammation properties
Comparative anti-inflammatory effects of roxithromycin, azithromycin and clarithromycin.
https://www.ncbi.nlm.nih.gov/pubmed/9579712
it is all in line with quenching lung’s inflammation.
Macrolides are the most benign antibiotics in terms of side effects.
Roxithromycin has more powerful anti inflammation effects.
So, he could try it next time, too
Thank you Ovidiu. Here is the same in English as you indicated https://www.youtube.com/watch?v=ydcrROJFEU0
Don’t know if it helps to French, but it does not to Italians. They officially use Hydroxychloroquine but today is 475 new deaths.
Sadly, stat figure in Italy is devastating.
Comparing South Korea and Italy, where both life expectancy is around 82 years, there is huge diffs in covid fatality. ~0.1 to 10%.
Looks like South Korea was prepared better to SARS (as they experienced similar disease in the past).
Yet, gender and age profiles are different too.
BTW, Daily Mail today published article where Chinese doctor who successfully treated 9 covid elder patients with UC-MCS steam cells.
I’ve seen somewhere as study showing the difference between this infected in Italy and S. Korea – a breakdown by age Those in S Korea were much younger. Probably Europe will be more strongly affected as the population is older here. At least this is a dimension to be considered.
Kind regards,
Daniel
read this article, today. mentioned there – women experienced more infection in S.K., though fatality rate among women is about twice less than that of men.
btw, median age is 47.3 (Italy) vs 41.8 (South Korea). Not much diff between these 2 countries. Average age in Lombardia is 44.7 years.
Article in Daily Mail about small town in Italy claims disease progress was cut to zero after thorough testing:
https://www.dailymail.co.uk/health/article-8126899/Small-Italian-town-cuts-coronavirus-cases-zero-population-tested.html
it is difficult to do that on country scale because of shortage on test kits supply, but at least countries could decrease death rate drastically without disrupting normal life/economics by asking/forcing elders and others in risk groups to stay at home and establishing food and other supportive aid supply to them through either government, army, and/or volunteers network.
iirc, China did similar for entire population in affected province, but that is quite costly, so isolating elders from risk is at least affordable approach.
Now the genie is out of the bottle.
Kind Regards
This can be to do with the timing to start a treatment with antivirals. If started from the very beginning of the infection, then it can help, if in a full bloom of it – it does not
For example:
Data suggests that timing of antiviral initiation may be important, as administration of remdesivir with high viral loads seen after peak viral titer failed to reduce lung damage despite reducing viral loads. https://sph.nus.edu.sg/wp-content/uploads/2020/03/COVID-19-Science-Report-Therapeutics-13-Mar.pdf
HI Maxim,
What do you think about Arbidol? It looks relevant to me. You may have a better view on this as it is a Russia product that seems to be on the top list of potential (at least for some) solution against Corona. Is this easy available in Russia? Thank you.
Note: I added in the main post some information on Arbidol.
Kind regards,
Daniel
Hi Daniel
China tested it, but it works only to diminish chances to catch Corona, and a treatment of the disease did not do any good at all
French doctors published success result of hcl/azi combination few days ago:
https://www.mediterranee-infection.com/wp-content/uploads/2020/03/Hydroxychloroquine_final_DOI_IJAA.pdf
at this point one should ask whether the real problem is lack of proper treatments or inability of the established medical system to adapt to critical situations that require a fast response? just like cancer treatments, it seems to me that it’s mostly the latter.
there seems to be enough relevant potent treatments to control the rising death rates. problem lies somewhere else that also needs to be addressed.
yep, some vital trials are planning to complete in the end of june. Up to that time everybody must rely on the established treatment with the known lack effectiveness.
thing is, patients should have the right to be treated by “experimental” treatments at their OWN risk. meanwhile proper trials could be conducted with their required course.
Maxim, my 28-year-old daughter just finished nine months of chemotherapy and radiation a week ago and we are trying to keep her safe. I’ve been reading all of these posts but what would you suggest we give her? She is already taking the COC drugs minus the statins. As well as LDN As well as several vitamins and mushroom extracts and such.
Keep in isolation is the best. But if the worse comes to the worse, i would not rely on antivirus drugs. At least what you can buy wont work. The best approach is if she gets ill and the coughing appear then do as Mosato Hada wrote (thalidomide + celecoxib). Celecoxib can be taken alone at first (it’s harmless). At least i more believe in this approach, and i did not find any antivirals that could help in progressed cases.
They (antivirals) work the best when started very early. Then their effectiveness diminishes to almost zero.
Hi Daniel,
I’m in Aust & finding it difficult to access hydroxychloroquine, I wonder if you or anyone else on the site know of an online source, preferably Asia, Thailand doesn’t seem to have any on offer that I can find, would be much appreciated, am in the vulnerable class of people & using your cool post to build myself some protection from what seems the inevitable eventual infection.
This site blows me away!
G
if you want to buy it abroad, i suggest you can buy Avigan ( https://en.wikipedia.org/wiki/Favipiravir ). If taken early it has much better effectiveness than hydroxychloroquine.
You can buy it in powder form (Favipiravir) on alibaba.com, but it’s expensive (100$ per gram)
Dear G,
Fortunately, many of the anti cancer supplements and re-purposed drugs (including Metformin, Atorvastatin, Celecoxib, etc.) also have relevant potential (based on scientific literature) to work against viruses including Corona. I will send on your e-mail the link to one online pharmacy where I buy my drugs.
Kind regards,
Daniel
Hi Daniel, could I please share the online pharmacy with me as well? I’ve been looking for one, but cannot confidently validate.
In line with Masato Hada regimen Ref.
I have found info on celecoxib (how it can be helpful in treating COVID 19 pneumonia)
Avian Influenza A H7N9 Virus Induces Severe Pneumonia in Mice without Prior Adaptation and Responds to a Combination of Zanamivir and COX-2 Inhibitor ( https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0107966 )
The article shows that celecoxib alone greatly reduces lungs damage ( https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0107966 )
Also, you need to look at Anti-inflammatory effects of celecoxib in rat lungs with smoke-induced emphysema. ( https://journals.physiology.org/doi/full/10.1152/ajplung.00303.2009 )
and Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling ( https://www.nature.com/articles/s41598-018-24548-z )
Thalidomide + celecoxib is another approach to treat COVID 19 pneumonia. Instead of using antivirals, which could be helpful if the treatment is started very early, this approach relies on protection of lungs from the damage. The body clears pathogens by itself.
Viruses can be very potent inducers of inflammation, which is a primary cause of the death. Excessive inflammation can cause septic shock which causes high mortality. Leucocytes counts drop to very low marks, and the body can not cope with the infection.
At present, only tocilizumab is approved to treat septic shock. But it only reduces IL-6 levels.
Thalidomide has more complex action – immunostumulation plus antinflammation and had shown great efficacy for treatment of the hyperinflammations with fast improvements .
https://www.minervamedica.it/en/journals/gazzetta-medica-italiana/article.php?cod=R22Y2000N02A0065
https://www.minervamedica.it/en/journals/gazzetta-medica-italiana/article.php?cod=R22Y2001N02A0071
https://www.minervamedica.it/en/journals/gazzetta-medica-italiana/article.php?cod=R22Y1999N04A0121
P.S. in the abstacts there’are mistypes for thalidomide dosage: should be mg/kg/day
And you should notice that any infection (including) viruses causes an energy wasting – t.e. after a some period of the infection, the body has lower resources to fight the disease.
Pharmacologic inhibition of COX-1 and COX-2 in influenza A viral infection in mice ( https://www.ncbi.nlm.nih.gov/pubmed/20657653 )
CONCLUSIONS/SIGNIFICANCE:
Treatment with a COX-1 inhibitor during influenza A viral infection is detrimental to the host whereas inhibition of COX-2 does not significantly modulate disease severity. COX-1 plays a critical role in controlling the thermoregulatory response to influenza A viral infection in mice.
Paracetamol reduces influenza-induced immunopathology in a mouse model of infection without compromising virus clearance or the generation of protective immunity ( Reference )
CONCLUSION:
These findings indicate that administration of paracetamol or celecoxib does not compromise the development of protective
T cell-mediated immunity.
Compared with seasonal H1N1 influenza A virus, avian H5N1 differentially upregulates COX-2 in primary
human macrophages in vitro and epithelial cells in vivo, the increased expression resulting from autocrine or paracrine
mediators rather than direct effects of the virus. Expression of inflammatory cytokines is driven by COX-2 upregulation and
can be effectively inhibited with selective COX-2 inhibitors. In another murine model of avian H5N1 infection, addition of the
selective COX-2 inhibitor celecoxib to the neuraminidase inhibitor zanamivir reduced lung inflammation and virus titres
and increased survival from 13.3% to 53.3% and mean survival time from 8.4 to 13.3 days compared with zanamivir alone. It
is clear from this study and our own that attenuating the inflammatory response to influenza does not compromise virus
clearance. Indeed, overall we observed a trend for better virus control in the treated animals
Combination therapy boosts antiviral response to chronic infection ( https://news.yale.edu/2015/03/23/combination-therapy-boosts-antiviral-response-chronic-infection )
To explore the relationship between PGE2 and T cells, the research team studied mice with viral infections and observed that PGE2 levels increased, particularly during chronic infection. The enhanced PGE2 reduced both the number of T cells that attack the infected cells and their anti-viral functions.
In a final step, the researchers found they could achieve the same boost to T cells by administering celecoxib (Celebrex), a non-steroidal anti-inflammatory drug (NSAID) commonly used to manage pain. “Since these inhibitors are already in common use, we wondered if using them to decrease PGE2 signaling would also improve T-cell responses,” said Jonathan Chen, first author on the study and a resident in pathology at Massachusetts General Hospital.
Efficacy of FDA-Approved Anti-Inflammatory Drugs Against Venezuelan Equine Encephalitis Virus Infection ( https://www.mdpi.com/1999-4915/11/12/1151/htm )
VEEV infection results in the upregulation of many pro-inflammatory cytokines that can damage the blood-brain barrier which can lead to permanent damage to the central nervous system [9,10]. Elevated cytokine levels can result from microglia activation in response to a viral infection [25]. Cytokine levels from infected, inhibitor-treated and mock infected HMC3 samples were measured at 12 hpi. Cells were pre-treated for 2 h with 50 µM of Celecoxib, and subsequently infected with VEEV TC-83 (MOI = 0.1). The results demonstrate the upregulation of several cytokines following VEEV infection, which was reduced following treatment of infected cells with Celecoxib
Overall, our data demonstrates that Celecoxib, an FDA-approved COX-2 inhibitor, is capable of slowing the replication of both TC-83 and a wild-type strain of VEEV in an in vitro model of infection. Furthermore, Celecoxib treatment reduces the upregulation of pro-inflammatory cytokines that can contribute to VEEV-mediated neurological damage following infection.
Is this prescription only?
I don’t know. We (in Russia) can buy it in any Pharmacy – Celebrex around 18$ for 30 capsules.
Thalidomide is a bigger problem to buy.
so could Hanokiol be relevant too?
https://www.ncbi.nlm.nih.gov/pubmed/32032644
Hi Pouya. Indeed, this is a good paper indicating the relevance, next to the fact that we know Honokiol has anti-viral properties.
Hi!
There are many indications about Celebrex, but what about DICLOFENAC?
Very good point! Diclofenac is a fermentation inhibitor and thus has effectiveness towards inhibiting pro-inflammatory reactions as well as viral replication. Refernces:
– Targeting immunometabolism as an anti-inflammatory strategy https://www.nature.com/articles/s41422-020-0291-z
– Hijacking the Supplies: Metabolism as a Novel Facet of Virus-Host Interaction https://www.frontiersin.org/articles/10.3389/fimmu.2019.01533/full
Actually, many of the fermentation-, mitochondria- inhibitors and melavonate pathway inhibitors we often discussed are very relevant and can help fight COVID as well as the pro-inflammatory reaction triggered as a result of this infection.
Kind regards,
Daniel
It is unselective COX1 and COX2 inhibitor. Celebrex is selective COX2 inhibitor, so does not cause viruses to replicate faster.
It is better to find any research that it does not cause a harmful immunosupression.
Although one aricle states that it’s COX 2 selective
https://www.ncbi.nlm.nih.gov/pubmed/9626023
Inhibitory potency and selectivity of NSAIDs for COX-1 and COX-2 activity in blood varied greatly. Some NSAIDs (eg, flurbiprofen, ketoprofen) were COX-1 selective, some (eg, ibuprofen, naproxen) were essentially nonselective, while others (eg, diclofenac, mefenamic acid) were COX-2 selective. Inhibitory effects of NSAIDs on gastric prostaglandin E2 synthesis correlated with COX-1 inhibitory potency in blood (P < 0.001) and with COX-1 selectivity (P < 0.01), but not with COX-2 inhibitory potency. Even COX-2 "selective" NSAIDs still had sufficient COX-1 activity to cause potent inhibitory effects on gastric prostaglandin E2 synthesis at concentrations achieved in vivo. But celecoxib has its own COX independent action too
Celecoxib has 11 hours half life,
Diclofenac has 1.2–2 hours half life
https://www.clinicalcorrelations.org/2018/02/01/nsaids-are-they-all-the-same/
Thank You for this information !
Diclofenac is also available as time-release tablets/capsules.
kindly,
ieva
Maxim, re You from Russia?
So, what do You think about Grippferon reagarding to Coivid19?
https://www.rlsnet.ru/tn_index_id_14719.htm
it is Human interferon alpha (hIFN)
https://www.ncbi.nlm.nih.gov/pubmed/25757280
I’ve read reviews of those with respiratory infections.
Many say, there was no improvement (the same result – with it or without)
in serious cases hIFN is used in much larger doses, and intravenously
https://www.hindawi.com/journals/scientifica/2014/970315/
With COVID 19, it will be useless
Just to show how potent anti infalammatory properties have Thalidomide analogs (primarily Lenalidomide).
And of course, thalidomide has the same beneficial properties.
https://www.nature.com/articles/emm2016143
Inflammatory colitis was induced by intracolonic administration of TNBS and mice were treated i.p. for 3 days with lenalidomide or pomalidomide starting after TNBS instillation. TNBS-treated mice developed a severe acute illness characterized by substantial (20%) and sustained body weight loss (Figure 1a, left panel), and by bloody diarrhea, rectal prolapse and pancolitis accompanied by extensive wasting syndrome (Figure 1b), that resulted in 100% mortality within 7 days (Figure 1a, right panel). Macroscopic examination of colons revealed profound hyperemia, inflammation, necrosis and shortening (Figure 1c). Mice treated with lenalidomide were fully protected against IBD. Accordingly, lenalidomide-treated mice rapidly recovered 100% of their body weight loss within a 5-day time frame, with a significantly increased survival rate of 95% (Figure 1a).
and the same test with thalidomide https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1038/sj.bjp.0704193
impressive, thanks for sharing
By the way, Lenalidomide has more powerful protection against inflammation in rodents, probably because of a different metabolism between species. It has nonhydrolizable CH2 bond instead of CO bond (in pomalidomide and thalidomide).
And because of that, rodents dont metabolize it as quickly as pomalidomide or thalidomide (they have short half life in rodents), and perhaps the profile of metabolites is different in them.
Rodents needs very high doses of thalidomide (a 100 times higher than in man) to have an effect.
So Thalidomide has as much of protective effect in man as Lenalidomide in rodents.
SARS-CoV-2 damages lungs even before the onset of symptoms.
In these pre-symptomatic SARS CoV-2-infected lungs, Xiao and colleagues observed edema
with proteinaceous exudates. The high quality figures show patchy changes of fibrin plugs
mixed with macrophages and other inflammatory cells. In one of the two cases, abundant intraalveolar pulmonary macrophages are present. The alveolar walls or septa are expanded by proliferating fibroblasts with parallel type II pneumocyte hyperplasia. There is no significant neutrophilic exudation or infiltration, in keeping with a viral infection. There are no hyaline
membrane formations at this early stage –which were instead found at autopsy. However,
fibroblastic plugs have formed albeit focally, even in this early phase of the disease. These
findings indicate that there is progressive consolidation of the lung, which is ultimately the cause
of respiratory failure and death. Lung consolidation is not caused by the accumulation of
granulocytes and fibrin, but rather by intra-alveolar organization and fibrosis. Therefore, since
the respiratory surface of the lung is obliterated, these patients can no longer respond to
intubation and oxygen therapy: this is why they die. From this important report, we learn that
the virus can establish infection in the lungs where it produces tissue injury well before
producing symptoms, including dry cough and fever that occur later on. At this early stage, the
only clue of SARS CoV-2 infection is imaging showing ground glass opacities in the periphery
of the lung.
https://www.jto.org/article/S1556-0864(20)30190-8/pdf
Indeed, very good point! Thank you for posting.
So it’s good idea to check from time to time the oxygen level, using a (cheap and still available) finger oxygen monitor.
Kind regards,
Daniel
Certainly I am worried by COVID – 19 expansion in Madrid, this is progressing very fast , I am going to take all the necessary measures to protect myself and my family. This is a publication on cancerintegral.com (Spain) on antiviral measures. It’s very interesting
https://cancerintegral.com/19-medidas-antiviricas-tambien-antitumorales/
Kind regards
Daniel wrote:
“In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) – a publication from March 2020 indicating that Hydroxychloroquine was more potent than Chloroquine. The publication further proposes the following treatment schedule: “a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection”. Typically, the pills have 200mg. That means 2 pills 2x/day first day, followed by 2 pills/day during the coming days.”
Does anyone know what dose per kilogram was used in this study? I assume it was for a 70 kg person but I may be wrong.
Although HCQ is generally considered to be safe, it does have some activities we need to be concerned about. For example, its bactericidal activity might damage the gut biome and lessen or eliminate its control over the immune system, which could cause a cancer to grow and spread more than before. Does anyone have a study about it?
It also has serious potential side effects such as retinopathy which, although rare, can happen at doses over 600 mg a day, and it happens more often in the elderly. This study calls out for 800 mg on the first day (loading dose) which is above this “safe” dose. Luckily it is only one day. But it would be good to know the dosing per kilogram so that a small body person doesn’t get exposed to a high dose, not even on the first day.
Anyone knows for how long would following this HCQ regimen confer protection from the virus?
Please, check if HCQ is compatible with any other medications you are taking or your doctor is going to give you.
https://www.pdr.net/drug-summary/plaquenil?druglabelid=1911
The problem – it is an in vitro test. It’s very unreliable. I’ve read a lot of articles about experimental antivirals, which worked in vitro, but in vivo has little or no effect
I believe that as Daniel explains, if there are no symptoms it would be worth 200 mg since it also has a long half-life. I think a preventive cocktail could be: hydroxychloroquine 200 mg, quercetin 500 mg, magnesium 500 mg, zinc 40 mg, vitamin c 4 g, liposomes of vitamin c, artemisinin, honokiol and tetrandin
Hi Manuel,
I would use Hydroxychloroquine as preventive approach only if we are exposed constantly to areas that may be contaminated. In that case, I would indeed use 200mg/day. Due to its long half time, even using one/week would be better than nothing.
Kind regards,
Daniel
Thanks!
Very nice summary of CoV and critical care. Also discusses repurposed drugs: https://emcrit.org/ibcc/covid19/
I have some Thalidomide left from a couple of years back. it’s expired. (expiration date late 2017) kept in room temperature, in the dark. what are the risks of using it if needed?
no risk, absolutely. It’s very stable chemically. Even after 20 years it will be good.
I’ve read one person used methaqualone (left from his granddad) – 20 years (or more, old) – and it was good
thanks a lot Maxim for the valuable help. appreciated.
From my notes ( involves only substances I have an easy access to)
As prevention
Quercetin 1*500mg or Curcumin 2*320mg
Vitamin C (spread across the day) 3*1000mg
Vitamin D3 (5000IU)
Tocopherols 1*250mg
N-Acetyl Cysteine 1*600mg
Selenium 1*100mcg
Zinc 2*10mg
Cordyceps 2*500mg
Reishi 1*500mg
EGCG – 1*300mg (on empty stomach or drink 4-6 cups of green tea)
Apigenin – drink chamomile tea, eat fresh parsley
Covid-19 Protocol
Berberine: 2*500mg
(mitochondria inhibition, cholesterol inhibition, glucose regulation, relieves pulmonary inflammation and reduces necrosis, inflammatory cell infiltration, and pulmonary edema induced by viral infection, suppresses the viral infection-induced up-regulation of TLR7 signaling pathway, such as TLR7, MyD88, and NF-κB (p65), at both the mRNA and protein levels. Furthermore, berberine significantly inhibits the viral infection-induced increase in Th1/Th2 and Th17/Treg ratios as well as the production of inflammatory cytokines.)
Quercetin: 3*1000mg
Vitamin C: 6*1500mg or more
Vitamin D3: 5000IU
EGCG: 3*400mg (on empty stomach)
Apigenin – 2*50mg + eat fresh parsley and drink chamomile tea
Artemisia Annua: 3*500mg – absorption falls with exposure – discontinue after 7 days for ?7? days, then repeat???
Atorvastatin: 2*40mg
Selenium 2*100mcg
Zinc 5*10mg
Tocopherol: 1*250mg
Considerations
Panadol 500mg (if fever is over 39.5C)
Alpha Lipoic Acid 2*300-600mg
Curcumin 3*400-1000mg
Boswellia Serrata 1000 mg
Resveratrol 3*100 mg
Practise social distancing.
Wear a mask, gloves, glasses, wash your hands – your viral load will be lower even if it gets through!
If you start with a lower viral load – your body will have 2-3 days to mount the defense.
Maximum viral load is usually on day 4 and 5 after the onset of fever. Then the viral load (usually) decreases.
Covid-19 News
https://www.youtube.com/user/ChrisMartensondotcom/videos
Thank you for sharing your list Zdenek!
Kind regards,
Daniel
According to https://www.ncbi.nlm.nih.gov/pubmed/14647384/ the ACE2 was also identified for the old SARS-CoV virus.
There is 2011 dated paper including mice tests on Urtica Dioica on old sars-cov virus:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085190/
Could we use stinging nettle as possible prevention medicine for the newest coronavirus version?
What a interesting thread
“The mean viral load of severe cases was around 60 times higher than that of mild cases, suggesting that higher viral loads might be associated with severe clinical outcomes.”
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30232-2/fulltext
Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods
https://www.sciencedirect.com/science/article/pii/S2211383520302999
Thanks a lot Johan. This is very helpful. I will include this in the post above.
Kind regards,
Daniel
Great D, thank you!
OLEANOLIC ACID: Apples,pomegranate,lemon,mandarin,billberries,pears,grapes,jujube,olives,raisins,cranberries. Note that cranberries are also rich in quercetin.
ROSMARINIC ACID: Rosemary (romero in spanish), salvia offcinales,thymus vulgaris, melissa officinales, ocimum basilicum
SILYBIN: Milk thistle
HESPERIDIN: dried peppermint, citrus (peels)
Curious as to how sulforaphane may play a role with the proliferation of bacteria — more specifically, how isothiocyanates may help combat communication among bacterial pathogens.
https://data.epo.org/gpi/EP3246024A1-USE-OF-TAURINE-IN-PREVENTION-AND-OR-TREATMENT-OF-DISEASES-INDUCED-BY-VIRUSES-OF-GENUS-CORONAVIRUS-AND-OR-GENUS-ROTAVIRUS
I think taurolidine can have an important antiviral effect by preventing the adherence of microorganisms to biological surfaces such as epithelial cells. https://sfamjournals.onlinelibrary.wiley.com/doi/abs/10.1111/j.1472-765X.1987.tb01593.x
thanks, Manuel. fuerza amigo!
In one of the previous comments, I saw that user Carl says NAC should be avoided if cancer is present. Can anyone elaborate?
HI Madleo,
It was probably meant as a warning for those on chemo-, radio- therapy as NAC is a strong-anti oxidant and the conventional cancer treatments most of the type rely on a pro-oxidant action. It is indeed important not to use NAC in that case.
Kind regards,
Daniel
Thanks Daniel!
Are there stats on large sample for smoking and associated covid-19 risks?
From what i had seen small scale based findings contradict official (who and others) opinion on increased risk of disease for smokers group.
http://www.tobaccoinduceddiseases.org/COVID-19-and-smoking-A-systematic-review-of-the-evidence,119324,0,2.html
Thanks Manuone
Should i interpret figures in above article as – smokers were more severe affected by disease, but overall number of smoking patients were less than smokers distribution among population?
A few weeks ago I read some information coming from China about high risk groups and it said smokers have x2 risk of suffering from severe complications. I can’t find the article now though.
Maybe you can find something here. Anyway nice overview https://www.covidgraph.com/p/coronavirus.html
Kind regards,
Daniel
Randomized Controlled Trial of Losartan for Patients With COVID-19 Requiring Hospitalization
https://clinicaltrials.gov/ct2/show/NCT04312009
@johan: if they are not getting any anti-viral treatment, the enrolled patients are going to be human guinea-pigs (only people with Acute Respiratory Distress Syndrome included). They exclude patients taking an ACE inhibitor, or an ARB.
Losartan is a selective, competitive angiotensin II receptor type 1 (AT1) antagonist, reducing the end organ responses to angiotensin II.
It blocks the receptor, the virus can not bind to it too, if it’s blocked.
P.S.
You confuse it with angiotensin-converting enzyme (ACE) inhibitor (such as Lisinopril), which prevents angiotensin synthesis. In this case it does not block the receptor, and any ACE ligand (in this case the virus) can freely bind to it
I read that Lauric acid or Virgin Coconut oil, in addition to zinc + chloroquine/ is recommended by the scientific community in the Philippines.
Thank you maldeo! Very interesting. Here is the origin of the Lauric acid with Coconut proposal, and I do believe in this option https://www.icp.org.ph/2020/01/the-potential-of-coconut-oil-and-its-derivatives-as-effective-and-safe-antiviral-agents-against-the-novel-coronavirus-ncov-2019/
Kind regards,
Daniel
Resveratrol is another substance with a solid antiviral/anticorona potential.
https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-017-2253-8
Lactobacillus Gasseri:
“Professor Jeong Goo-bo of Gachon University Lee Gil Ya Cancer and Diabetes Institute, also said, “I believe L. gasseri, derived from plants, can be effective in preventing COVID-19 spread because it affects the activation of purine enzyme, the energy source for AIDS, hepatitis, Ebola, and COVID-19 virus.”
http://www.koreabiomed.com/news/articleView.html?idxno=7744
Preventing a covid-19 pandemic – Is there a magic bullet to save COVID-19 patients?
https://www.bmj.com/content/368/bmj.m810/rr-24
https://vitamindwiki.com/Coronaviruses+attach+to+cells+via+ACE2%2C+may+be+reduced+by+Vitamin+D
@Daniel: recent research shows that people with low lymphocytes (and high neutrophils) are at risk from Covid-19, and this imbalance seems to apply to elderly.
There must be some info on the site about boosting lymphocytes, maybe you could find it and repost it here.
Hi Ovidiu,
Yes you are right, we should have this info in the website. Mushrooms should help on this line.
Kind regards,
Daniel
A potential way to reduce inflammation in the lungs, is to use Low-Level Laser Therapy.
I couldn’t find any related articles specifically pertaining to Covid-19, but I assume there may be an application here from early to ongoing spread.
This ‘red light’ is credited to be safe and is used in a number of consumer applications — hair growth for one.
Found a study done on COPD patients using LLLT.
Below is a link along with an excerpt:
“Our results showed that LLLT significantly reduced the number of inflammatory cells and the proinflammatory cytokine secretion such as IL-1β, IL-6, and TNF-α in bronchoalveolar lavage fluid (BALF). We also observed that LLLT decreased collagen deposition as well as the expression of purinergic P2X7 receptor. On the other hand, LLLT increased the IL-10 release. Thus, LLLT can be pointed as a promising therapeutic approach for lung inflammatory diseases as COPD.”
https://www.hindawi.com/journals/omcl/2018/6798238/
Tested on mice only. They have tiny lungs in comparison to human lungs
By the way, in 2015 the EcoHealth Alliance sponsor the research to create an artificial virus: https://www.nature.com/articles/nm.3985
A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence
Here we examine the disease potential of a SARS-like virus, SHC014-CoV, which is currently circulating in Chinese horseshoe bat populations. Using the SARS-CoV reverse genetics system, we generated and characterized a chimeric virus expressing the spike of bat coronavirus SHC014 in a mouse-adapted SARS-CoV backbone.
The results indicate that group 2b viruses encoding the SHC014 spike in a wild-type backbone can efficiently use multiple orthologs of the SARS receptor human angiotensin converting enzyme II (ACE2), replicate efficiently in primary human airway cells and achieve in vitro titers equivalent to epidemic strains of SARS-CoV. Additionally, in vivo experiments demonstrate replication of the chimeric virus in mouse lung with notable pathogenesis.
But what is interesting and useful to understand that at equal viral loads different strains have different lethality
Animals infected with SARS-MA15 experienced rapid weight loss and lethality by 4 d post infection (d.p.i.); in contrast, SHC014-MA15 infection produced substantial weight loss (10%) but no lethality in mice (Fig. 1e). Examination of viral replication revealed nearly equivalent viral titers from the lungs of mice infected with SARS-MA15 or SHC014-MA15 (Fig. 1f).
Reported studies were initiated after the University of North Carolina Institutional Biosafety Committee approved the experimental protocol (Project Title: Generating infectious clones of bat SARS-like CoVs; Lab Safety Plan ID: 20145741; Schedule G ID: 12279). These studies were initiated before the US Government Deliberative Process Research Funding Pause on Selected Gain-of-Function Research Involving Influenza, MERS and SARS Viruses (http://www.phe.gov/s3/dualuse/Documents/gain-of-function.pdf). This paper has been reviewed by the funding agency, the NIH. Continuation of these studies was requested, and this has been approved by the NIH.
Quite realistic prediction of covid-19 pandemic in Robert Koch report to Bundestag dated 10.12.2012 number: 17/12051 (starts from page 55):
https://www.docdroid.net/zYVIAnL/bt-bericht-schmelzhochwasser-en-converted.pdf
“The hypothetical mode SARS virusis identical to the natural SARS-CoV in almost all characteristics. The incubation period, i.e. the time from the transmission of the virus to a human being until the first symptoms of the disease appear, is usually three to five days, but can range from two to 14 days. Almost all infected people also fall ill. The symptoms are fever and dry cough, the majority of patients have difficulty breathing, changes in the lungs visible in X-rays, chills, nausea and muscle pain. Diarrhoea, headaches, exanthema (rash), dizziness, cramps and loss of appetite may also occur. The lethality rate 1 is high at 10% of the patients, but varies in different age groups. children and young people generally have milder courses of disease with a lethality rate of around 1%, while the lethality rate for people over 65 years of age is 50%. The duration of the disease also differs depending on the age of the patients; younger patients often get over the infection after only one week, while more seriously ill, older patients have to be hospitalized for about three weeks, and treatment needs of up to 60 days have also been described for SARS-CoV. This age-related course of SARS-CoV infection was not assumed for mode SARS. For modelling the numbers of patients and affected persons in the scenario, we assume that all age groups are equally affected.”
and so on…
May be they modeled that from previous outbreak of sars-covid case.
Looks like Germany took necessary precautions after that report and stats quite good compared to other countries .
Today Iceland’s newspaper reported a patient case of double covid-19 infection with 2 different covid-19 strains at same time.
covid-19 lung invasion video was posted on telegram channel:
https://t.me/bazabazon/3238
Reddit hosts a topic/discussion on wearing mask reuse that could be interesting amid mask supply shortage.
Btw, from Chinese doctors photos it could be seen that double sided tape bands (put between face skin and mask) are used to avoid air leakage and possible infection.
@Daniel: There are actually some doctors and researchers that believe that the
expression of ACE2 should be increased to protect the sites from being used by
the Covid virus.
https://www.youtube.com/watch?v=oedBWm7Ins8&feature=emb_logo
https://www.youtube.com/watch?v=1vZDVbqRhyM
What is your take on this?
Dear ponson01,
It is clear that there is a debate on this in the scientific community and here is a recent article addressing that https://jamanetwork.com/journals/jama/fullarticle/2763803
I need to find the time to look deeper into the debate – they videos you mentioned have not enough scientific fundamental to conclude. They essentially represent opinions.
Until more clarity, if possible, I would avoid adding medication such as Ibuprofen known to increase ACE2 expression. For those already on medication increasing ACE2, I have no hard conclusion.
Btw, one of the mechanisms possibly related to chloroquine effectiveness against COVID is interference with ACE2 https://virologyj.biomedcentral.com/articles/10.1186/1743-422X-2-69
Kind regards,
Daniel
Governments appear to have restricted the sale of chloroquine and hydroxychloroquine, needing a special prescription with inspection for already approved chronic treatments for arthritis and other ailments such as lupus.
There has been a compulsive purchase of both drugs and governments have taken action on the matter by securing the stock for hospitals. It is something that I understand but it will harm many of us who use it in our cocktails against cancer.
http://news.mit.edu/2020/covid-19-treat-respiratory-patients-plasminogen-0324
A stopgap measure to treat respiratory distress
Repurposing a drug used for blood clots may help Covid-19 patients in danger of respiratory failure, researchers suggest.
“Researchers at MIT and the University of Colorado at Denver have proposed a stopgap measure that they believe could help Covid-19 patients who are in acute respiratory distress. By repurposing a drug that is now used to treat blood clots, they believe they could help people in cases where a ventilator is not helping, or if a ventilator is not available.
Three hospitals in Massachusetts and Colorado are developing plans to test this approach in severely ill Covid-19 patients. The drug, a protein called tissue plasminogen activator (tPA), is commonly given to heart attack and stroke victims. The approach is based on emerging data from China and Italy that Covid-19 patients have a profound disorder of blood clotting that is contributing to their respiratory failure.”
p.s. and what is about garlic repurposing as old known blood thinner?
The most important part in this article:
The idea to try this treatment in Covid-19 patients arose, in part, because the Colorado and MIT research team has spent the last several years studying the inflammation and abnormal bleeding that can occur in the lungs following traumatic injuries. It turns out that Covid-19 patients also suffer from inflammation-linked tissue damage, which has been seen in autopsy results from those patients and may contribute to clot formation.
That is inflammation causes this. Then, treat inflammation first and there won’t be blood clots. Simple.
Blood clots are only a consequence of inflammation.
https://www.dailymail.co.uk/news/article-8150589/Chinese-state-media-suggests-coronavirus-pandemic-originated-Italy.html
“Professor Remuzzi, Director of the Mario Negri Institute for Pharmacological Research in Milan, said in an interview last week that local doctors ‘remember having seen very strange pneumonias [sic], very severe, particularly in old people, in December and even in November.’
He told American news organisation NPR: ‘It means that the virus was circulating at least in Lombardy before we were aware of this outbreak occurring in China.’
While state broadcaster CCTV cited another interview of professor Remuzzi to stressed that ‘unknown pneumonia appeared in Italy as early as October last year’.
…
In another interview with independent Chinese outlet DeepTech, the professor said the key point of his comments was how far the virus had spread before it was discovered, not where it came from. “
@asafsh: It’s a tactic of blame shifting. If Covid-19 would have been present in Italy in November, what we are seeing now in Italy would have happened two months ago.
@ovidiu
May be you are correct. cui bono, cui prodest …
Just one question i am not capable to answer – significance of seasonal changes in immune system.
We get stronger during summer. Winter requires more energy to sustain, and results in immune deficiency.
Winter/spring transition is our weakest time. Could this factor influence covid spreading speed?
Chinese guideline for covid-19 treatment (Russian language):
https://ria.ru/ips/op/COVID_19_Book.pdf
Contrasting Effects of Cyclooxygenase-1 (COX-1) and COX-2 Deficiency on the Host Response to Influenza A Viral Infection
https://www.jimmunol.org/content/jimmunol/175/10/6878.full.pdf
NSAIDs are used clinically for fever control and alleviation of symptoms during influenza viral infection. If we extrapolate our results to a clinical setting, treatment with NSAIDs such as ibuprofen or aspirin, which have predominantly COX-1 inhibiting activity , may produce more severe inflammation whereas the use of COX-2 inhibitors such as celecoxib or rofecoxib during influenza infection may improve the clinical course.
In summary,our findings suggest that COX-1 and COX-2 have critical but contrasting effects on the host immune response to influenza viral infection, possibly mediated via altered production of PGs and LTs following infection. Deficiency of COX-1 results in an enhanced inflammatory response and earlier release of proinflammatory cytokines. In contrast, deficiency of COX-2 results in reduced inflammation and proinflammatory cytokine release, reduced morbidity, and, despite higher viral titers, enhanced survival.
what’s up with Italy’s death rate? 969 in the past 24 hrs I THINK. does having an older population justify this number? what’s their treatment strategy? anyone care to shed some light on this?
I’ve seen an opinion on extensive antibiotics usage in Italy possibly resulted in weakened immune system in population.
there is an article about antibiotic practice in Italy:
https://www.thelocal.it/20191108/italian-dcotors-warned-to-stop-overprescribing-antibiotics
Coronaviruses attach to cells via ACE2, Vitamin D might reduce ACE2
https://vitamindwiki.com/tiki-index.php?page=Coronaviruses%20attach%20to%20cells%20via%20ACE2%2C%20Vitamin%20D%20might%20reduce%20ACE2
Not via ACE2, but by via ACE2 receptors – which are different things.
So, if vitamin D reduces ACE2, then it upregulates the ACE2 receptors doing the opposite effect (because with a lower ACE2 the receptors becomes more expressed).
I think an ACE2 receptor is ACE2, just membrane bound. In fact, the ACE2 found in plasma is shed from the cell membrane. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327712/
Yes, you right. It is a protein bound to the cell membranes. The more a cell surface has of it the more it is expressed in it.
The highest expression of ACE2 is observed in the kidney, the endothelium, the lungs, and in the heart. The extracellular domain of ACE2 enzyme contains a single catalytic metallopeptidase unit that shares 42% sequence identity and 61% sequence similarity with the catalytic domain of ACE.
Anyway it is unclear, how vitamin D would affect its expression in the cells membranes vs extracellular.
Looks like pneumonia is not the only problem, hypokalemia has also severe implications to the heart function.
Hypokalemia and Clinical Implications in Patients with Coronavirus Disease 2019 (COVID-19)
https://www.medrxiv.org/content/10.1101/2020.02.27.20028530v1
93% of severe and critically ill patients had hypokalemia which was most common among elevated CK, CK-MB, LDH, and CRP. Urine K+ loss was the primary cause of hypokalemia. severe hypokalemia patients was given 3 g/day, adding up to an average of 34 (SD=4) g potassium during hospital stay. The exciting finding was that patients responded well to K+ supplements when they were inclined to recovery.
CONCLUSIONS: Hypokalemia is prevailing in patients with COVID-19. The correction of hypokalemia is challenging because of continuous renal K+ loss resulting from the degradation of ACE2. The end of urine K+ loss indicates a good prognosis and may be a reliable, in-time, and sensitive biomarker directly reflecting the end of adverse effect on RAS system.
Irbesartan may be useful against Covid-19. I bought some today, it’s cheap.
Anti-hypertensive Angiotensin II receptor blockers associated to mitigation of disease severity in elderly COVID-19 patients.
https://www.medrxiv.org/content/10.1101/2020.03.20.20039586v1
Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. PMID: 32194980
Thank you Ovidiu!
Thanks for the link. It does not protect fully – according to that link 3 out of 10 patients who took ARBs still had severe cases.
And they were taking it as antihypertensive treatment – that is starting before they catched the COVID 19.
So, it is better to start taking them before anyone catches the disease.
The French minister who cautioned against the use of ibuprofen in COVID 19 had no sound basis for doing so and was severely criticized by better informed scientists. Ibuprofen was, in fact, used very successfully with another lipid enveloped virus, Ebola. Naproxen seems to be the NSAID of choice for COVID in combination with hydroxychloroquine and azithromycin. There is evidence, however, that doxycycline would be a better choice than azithro, owing to the fact that doxy encounters less resistance and has a broader spectrum against coronavirus associated pneumonias. It also has significantly fewer serious side effects. NSAIDS are, in general, protective against cytokine storm, not contributive. Neem therapeutically docks with coronaviral nucleoprotein in the same way that Naproxen does. Good luck, meanwhile, finding any hydroxychloroquine. But, good news: quercetin has similar ACE 2 activity. Enzymatically modified isoquercetin will take you a lot further than standard quercetin. And astragaloside iv, mung bean and EGCg are good umbrellas to have if you are anticipating a cytokine downpour.
Any links to the articles supporting this info would be appreciated
I have found only in vitro evaluation of ibuprofen against Ebola virus and it’s not related to its COX inhibitory activity
https://f1000research.com/articles/4-104
but the WHO warns about ibuprofen and aspirin causing more severe bleeding in vivo
https://www.who.int/csr/disease/ebola/photos/ebolablock-poster15.jpg?ua=1
Inhibition of SARS-CoV 3C-like Protease Activity by Theaflavin-3,3′-digallate (TF3)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142193/#__ffn_sectitle
“We found that caffeine, (—)-epigallocatechin gallte (EGCg), epicatechin (EC), theophylline (TP), catechin (C), epicatechin gallate (ECg) and epigallocatechin (EGC) did not inhibit 3CLPro activity. Only theaflavin-3,3′-digallate (TF3) was found to be a 3CLPro inhibitor. “
https://www.u-tokyo.ac.jp/focus/en/articles/z0508_00083.html
According to the new research, Nafamostat can prevent the fusion of the envelope of the virus with host cell surface membranes, the first step in infection with the causative virus SARS-CoV-2. Nafamostat can inhibit the membrane fusion at a concentration less than one-tenth that of Camostat mesylate (brand name: Foypan), which was recently identified by a German group as an inhibitor of SARS-CoV-2 infection (Reference 1).
Nafamostat is administered clinically by intravenous infusion. The research group speculated that the blood concentration of Nafamostat after administration would exceed the concentration needed experimentally to inhibit membrane fusion via the SARS-CoV-2 S protein. Therefore, it is expected that Nafamostat will prevent SARS-CoV-2 from entering human cells. Camostat is an oral drug. Blood levels after oral administration may be inferior to Nafamostat.
Thanks a lot Asaf! Great finding! I created a new section in the post above to address this one.
Kind regards,
Daniel
https://docs.google.com/document/d/1SesxgaPnpT6OfCYuaFSwXzDK4cDKMbivoALprcVFj48/mobilebasic
https://mobile.twitter.com/michaelcoudrey/status/1242567020673003520
“Here is an open letter by Dr. Vladimir Zelenko from NY containing a COVID-19 treatment plan.
Dr. Zelenko successfully treated 350 patients with Coronavirus infection using a cocktail of hydroxychloroquine, azithromycin, and zinc sulfate.”
1. Hydroxychloroquine 200mg twice a day for 5 days
2. Azithromycin 500mg once a day for 5 days
3. Zinc sulfate 220mg once a day for 5 days
Thanks a lot Carl! I included this combo in the post above with the reference you provided, as I think the combo makes sense.
Kind regards,
Daniel
Just keep in mind that 500 mg daily Azithromycin may result in vomiting (irritation of the stomach). Too bad the extended release is not on the market anymore, it distributed the irritation (from 2 grams) in the intestines and was tolerable.
Thanks Ovidiu. It’s true antibiotics come with side effects. But I think it’s a good idea to have this one at home and use it in case of emergency, if no medical support is available – which could be often the case with the overloaded hospitals.
by the way, russian ministry of health said that mefloquine https://en.wikipedia.org/wiki/Mefloquine
will be used instead of hydroxychloroquine.
I has better safety profile and a longer half life.
using 1,5 – 2,0 grams at once
https://www.plenglish.com/index.php?o=rn&id=53950&SEO=russia-presents-trial-to-fight-against-covid-19
It has anti inflammatory activity
The treatment of inflammatory disorders https://patents.google.com/patent/WO2002019994A2/en
Abstract
A method of treating an inflammatory disease or an autoimmune disease in a subject, comprises the administration of mefloquine. The inflammatory disease is rheumatoid athritis, osteoarthritis, psoriatic arthritis, psoriasis, Crohn’s disease, systemic lupus erythematosus, ulcerative colitis, COPD or asthma.
Thanks Maxim. I like Mefloquine as a repurposed drug against cancer. It’s good to know that is now part of the anti Corona arsenal.
I included this and the reference in the summary post above.
Kind regards,
Daniel
Daniel, you also need to take heed at the article Evaluation of Immunomodulators, Interferons and Known in Vitro SARS-CoV Inhibitors for Inhibition of SARS-Cov Replication in BALB/c Mice
https://journals.sagepub.com/doi/10.1177/095632020601700505
Anti-inflammatory agents, chloroquine, amodiaquin and pentoxifylline, were also inactive in vivo, suggesting that although they may be useful in ameliorating the hyperinflammatory response induced by the virus infection, they will not significantly reduce the replication of the virus, the inducer of inflammatory response
Although chloroquine when tested in vitro was active against SARS-CoV, but in vivo it did not reduce the viral load. So, maybe the only positive effect it does now, treating SARS-CoV2, is immunomodulation and anti-inflammatory (no anti-viral effect).
Mefloquine is probably in line with chloroquine, only has a better safety profile.
For the large scale usage of HCQ, this might be useful:
High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine. PMID: 29623120
https://jamanetwork.com/journals/jama/fullarticle/2763983
Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma
Thanks, very interesting article.
Especially the part on the treatment with antivirals. The patients were treated at least 10 days with different antivirals (Darunavir , Favipiravir, Lopinavir/Ritonavir). They were probably started late in the disease, so did not help in these cases.
I’ve read an article that antivirals (oseltamivir, zanamivir) when treated influenza were effective when started early (max 24 hours since the infection).
Looks like if started early, they lower the initial viral load and give the body a chance to produce antibodies. Then the body can cope with the infection by itself. The longer the disease, the less chances the body could produce antiviral antibodies itself or without a help (reducing cytokines, immunomodulation).
https://www.medrxiv.org/content/10.1101/2020.03.24.20042937v1
Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study
A very nice overview about coronaviruses and their mechanisms:
Coronaviruses — drug discovery and therapeutic options
https://www.nature.com/articles/nrd.2015.37/figures/2
https://www.nature.com/articles/nrd.2015.37#Sec5
Possible reasons for baicalin and glycyrrhizin working against coronaviruses.
Potential Natural Compounds for Preventing SARS-CoV-2 (2019-nCoV) Infection
SARS-CoV-2 (2019-nCoV), a novel coronavirus, caused the pneumonia outbreak in China and continue to expand. The host receptor for 2019-nCoV Angiotensin-converting enzyme 2 (ACE2), is the same as the host receptor for SARS-CoV. Targeting ACE2 holds the promise for preventing and inhibiting 2019-nCoV infection. Chinese Medicine herbs could be a valuable pool for identifying active compounds for treating infection of 2019-nCoV. In this study, we summarize several active compounds, including baicalin, Scutellarin, Hesperetin, Nicotianamine and glycyrrhizin that could have potential anti-2019-nCoV effects. We conduct molecular docking to predict their capacity for binding ACE2, which may prevent the 2019-nCoV infection. We propose that these selected compounds worth further investigation for preventing 2019-nCoV.
https://www.preprints.org/manuscript/202001.0358/v3
By the way, chloroquine could be a hoax (possibly unintentional but a hoax)
https://www.france24.com/en/20200329-french-expert-says-second-study-shows-malaria-drug-helps-fight-coronavirus
“This is an observational study (i.e. not controlled) following 80 patients with fairly mild symptoms. The majority of patients recover form #COVID19 infection, with or without #Hchloroquine and #Azithromycin treatment.”
According to his latest study, 65 of the 80 patients treated improved and were discharged from hospital in an average of less than five days. One patient aged 74 was still in intensive care and another aged 86 died.
But his critics say such results were fairly typical of the virus.
Two Chinese studies have shown that “10 days after the start of symptoms, 90 percent of people who have a moderate form (of the disease) have a controlled viral load,” epidemiologist Dominique Costagliola, of the French health research institute Inserm, told AFP.
The fact that they got these results using hydroxychloroquine “does not make the case for its effect,” she said.
Another useful study shows as it is active in vitro, it is not active in vivo
https://journals.sagepub.com/doi/10.1177/095632020601700505
Literature Review on HCQ: https://www.medrxiv.org/content/10.1101/2020.03.24.20042366v1
Excerpts:
– CQ has been found to cause inhibition of the replication of SARS-CoV in Vero E6 cells
– CQ has been found to be effective in inhibiting the infection and spread of SARS CoV in cell culture
– CQ has been found to function at both entry as well as post-entry stages of the COVID-19 infection in Vero E6 cells. The immune-modulating activity of CQ may also synergistically enhance its antiviral effect in vivo.
– So far, results of more than 100 patients treated with CQ has shown that chloroquine phosphate is superior to the control treatment as it inhibits the worsening of pneumonia, improves the lung imaging findings, promotes a virus-negative conversion, and shortens the course of the disease
– HCQ has been found to be more potent than CQ at inhibiting SARS-CoV-2 in vitro
– In a recent trial using HCQ as a single drug and HCQ in combination with azithromycin, the proportion of patients with negative PCR results in nasopharyngeal samples had a significant difference between the two groups. At day six post-treatment, 100% of patients treated with HCQ and azithromycin combination had been virologically cured compared to 57.1% in patients treated with only HCQ and 12.5% in control group.
– Contraindications and relative contraindications include NOT to use CQ in people below 18 years and above 65 years, pregnant women, persons allergic to 4-aminoquinoline, patients with hematological disorders or G6PD deficiency, patients with chronic liver or kidney disease, patients with arrhythmia and chronic heart disease, patients with a history of retinal disease or hearing loss, patients known to have a mental illness, Skin diseases like a rash, dermatitis, psoriasis
– CQ is known to have drug interactions with various drugs, and expert medical opinion, regarding its interaction with the medicines already taken by patients, is a MUST
– CQ, and its derivatives have shown early promise to treat COVID-19 infection and should be explored as a potential drug in the preventive and therapeutic role to turn the tide in this rapidly evolving pandemic
Thank you Carl! Totally agree. We need to look at the clouds of evidence. Otherwise there will always be some stating the opposite.
Kind regards,
Daniel
Hi Daniel
Maxim actually rephrases those practical findings from Chinese dr’s about hydroxychloroquine and chloroquine phospate.
Those are listed in the document link i posted before (in Russian translated from Chinese).
I’m not a doctor to claim that but I suppose there could be ethnicity and population wide differences.
Let say according to the article previously posted here – ACE2 is most expressed in Asian males. But we see that Caucasian origin is affected at least as much as Asian males.
Also, let say there are differences in vaccination among different countries and the document “Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study” shows some evidence about its importance (even if actual vaccine is unrelated to covid-19).
So may be the truth is somewhere between, and each country must use what works best for them.
Sure i understand that drug business became even more political subject than economical nowadays. We live in crazy world, unfortunately.
Best Regards
p.s. There is a new document circulating in Russian internet claiming prepared by Russian’s Ministry of Defense concerned covid-19 treatment protocol. I can’t verify its origin, indeed.
According to that document – HCL is in the trial area and actual treatment is based on other drugs.
I may try to translate it but it might take time.
for those who are interested in this document and know Russian language – https://t.me/mig41/4913
screenshots – https://colonelcassad.livejournal.com/5754473.html
For that article in russian, in short it says that for most people the virus affects only upper respiratory tract or bowels and can pass with minimal symptoms, but for some people with weak immune system it passes through blood in all parts of body (viremia).
Those who recovered from it becomes immune to it, but those with weak immune system or who had minimal symptoms can catch it again (because the immunity to it is not stable for them).
The blood plasma of recovered patients can be used to treat new patients.
Latent period is from 2 to 14 days (on average 5 days).
Drugs to treat it – very long list, and mostly everything already known (interferon, vitamin C, vitamin P, ibuprofen, paracetamol, acetylcystein, ribavirine, lung ventilation …). Antimalarian drugs in experimental phase.
Antibiotics as complementary to treat bacterial infections.
This is probably a bit outdated.
Hi Asaf,
I thought this is the official document https://static-3.rosminzdrav.ru/system/attachments/attaches/000/049/877/original/COVID19_recomend_v4.pdf
which seems not different than the one I saw from many countries, in terms of treatment approach.
Kind regards,
Daniel
Hi Daniel
Your document is from Ministry of Health, mine claimed to be from Ministry of Defense (MD has a specific knowledge related from WMD perspective). Probably they are cooperating also.
There are few diffs – Arbidol, ribavirin are not listed in your document.
And your document lists CL and HCL.
So may be as Maxim noted mine is a bit outdated.
Best Regards
Asaf
Yes, your document is official for civilian health service, the one i reviewed is the same from ministry of defense.
It is shorter (they don’t give doses in it, only general methods and drugs) and a bit old now.
They suggested to use ibuprofen in it, but the ministry of health recommends only paracetamol.
Otherwise the list of drugs is the same.
CL and HCL + Azitromizin is recommended based on the limited studies in France and generally based on international recommendations.
Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial: https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v1
Abstract
Aims: Studies have indicated that chloroquine (CQ) shows antagonism against COVID-19 in vitro. However, evidence regarding its effects in patients is limited. This study aims to evaluate the efficacy of hydroxychloroquine (HCQ) in the treatment of patients with COVID-19.
Main methods: From February 4 to February 28, 2020, 62 patients suffering from COVID-19 were diagnosed and admitted to Renmin Hospital of Wuhan University. All participants were randomized in a parallel-group trial, 31 patients were assigned to receive an additional 5-day HCQ (400 mg/d) treatment, Time to clinical recovery (TTCR), clinical characteristics, and radiological results were assessed at baseline and 5 days after treatment to evaluate the effect of HCQ.
Key findings: For the 62 COVID-19 patients, 46.8% (29 of 62) were male and 53.2% (33 of 62) were female, the mean age was 44.7 (15.3) years. No difference in the age and sex distribution between the control group and the HCQ group. But for TTCR, the body temperature recovery time and the cough remission time were significantly shortened in the HCQ treatment group. Besides, a larger proportion of patients with improved pneumonia in the HCQ treatment group (80.6%, 25 of 32) compared with the control group (54.8%, 17 of 32). Notably, all 4 patients progressed to severe illness that occurred in the control group. However, there were 2 patients with mild adverse reactions in the HCQ treatment group.
Significance: Among patients with COVID-19, the use of HCQ could significantly shorten TTCR and promote the absorption of pneumonia.
From the same source (below the article)
Findings
There were 2 patients showing mild secondary effects of HCQ treatment. More importantly, while 4 patients in the control group progressed to severe disease, none progressed in the treatment group.
TTCR was significantly decreased in the HCQ treatment arm; recovery from fever was shortened by one day (3.2 days control vs. 2.2 days HCQ, p = 0.0008); time to cessation of cough was similarly reduced (3.1 days control vs. 2.0 days HCQ, p = 0.0016).
Overall, it appears that HCQ treatment of patients with mild COVID-19 has a modest effect on clinical recovery (symptom relief on average 1 day earlier) but may be more potent in reducing the progression from mild to severe disease.
Study Limitations
This study is limited in its inclusion of only patients with mild disease, and exclusion of those on any treatment other than the standard of care. It would also have been important to include the laboratory values of positive RT-PCR detection of SARS-CoV-2 to compare the baseline and evolution of the patients’ viral load.
Significance
Despite its limitations, the study design has good rigor as a double blind RCT and consistent symptom checks on each day of the trail. Now that the FDA has approved HCQ for treatment of COVID-19 in the USA, this study supports the efficacy of HCQ use early in treatment of patients showing mild symptoms, to improve time to clinical recovery, and possibly reduce disease progression. However, most of the current applications of HCQ have been in patients with severe disease and for compassionate use, which are out of the scope of the findings presented in this trial. Several additional clinical trials to examine hydroxychloroquine are now undergoing; their results will be critical to further validate these findings.
your opinions on Israel covid-19 stats are kindly asked:
Total cases 5,358
Active 5,114
Recovered 224
Fatal 20
Note that garlic consumption there is part of a culture (iirc, originates from religious roots) and widespread.
So, taking into account that garlic reduces tension (previous research highlighted – patients with hypertension are at most risks), has antiviral properties, regulates ACE (couldn’t find specific research on garlic against ACE2), listed (only allicin, thanks to reductionism) in the document posted by Johan, there is a high chance that it can reduce probability of infection if administered by slow chewing on regular basis throughout a day (in absence of contraindication).
Social distancing and mask may reduce effect of smell :-\
Temperature in Israel is going slowly up but still weather is ok for covid pandemic.
It’s very encouraging to see these stats, especially since Israel is in the northern hemisphere. Let’s hope this trend continues.
We see differences among countries and it’s important to look for reasons that might explain these. It wouldn’t suprise me if high garlic consumption in a population would help explain some of the difference.
https://pubs.acs.org/doi/pdf/10.1021/acsomega.0c00772
Investigation into SARS-CoV‑2 Resistance of Compounds in Garlic Essential Oil
“The results show that the 17 organosulfur compounds, accounting for 99.4% contents of the garlic essential oil, have strong interactions with the amino acids of the ACE2 protein and the main protease PDB6LU7 of SARS-CoV2. The strongest anticoronavirus activity is expressed in allyl disulfide and allyl trisulfide, which account for the highest content in the garlic essential oil (51.3%). Interestingly, docking results indicate the synergistic interactions of the 17 substances, which exhibit good inhibition of the ACE2 and PDB6LU7 proteins. ”
if that article is true, then wrapping that smelly glove into the small amount of bread to prevent pain, and chewing slowly may help a lot by fighting disease in the first place at entrance.
New cases started grow since march 23
https://www.worldometers.info/coronavirus/country/israel/
And it goes in the same trajectory.
Not many recovered, so not many deaths (they should be counted based on completed cases)
https://www.ijbs.com/v16p1724.htm
This is an interesting article about the use of chloroquine and chlorpromazine to target the endocytic pathway and autophagy in COVID 19. And following this line of thinking I found this article ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455256/) talking about the antiviral effects of Itraconazol on Influenza A Virus where it works by priming the interferon response and negatively affecting the propagation of the virus within the first replication cycle. Perhaps Itraconazol could be used as a preventive measure in those highly exposed to the COVID19
The American Association of Naturopathic Physicians Urges Physicians and Hospitals to Utilize IV Vitamin C to Combat the COVID-19 Pandemic
https://www.benzinga.com/pressreleases/20/04/p15713936/the-american-association-of-naturopathic-physicians-urges-physicians-and-hospitals-to-utilize-iv-v
Interesting to read article https://www.medrxiv.org/content/10.1101/2020.03.24.20042655v1.full.pdf
COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome
Patients with COVID-19 have larger than normal monocytes, easily identified on forward scatter, side scatter analysis by routine flow cytometry,with the presence of a distinct population of monocytes with high forward scatter (FSC-high). On more detailed analysis, these FSC-high monocytes are CD11b+, CD14+, CD16+, CD68+, CD80+,CD163+, CD206+ and secrete IL-6, IL-10 and TNF-alpha, consistent with an inflammatory phenotype.
The article Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19 https://www.nature.com/articles/s41591-020-0819-2?fbclid=IwAR10HbvvkbGjlaLyDE0PXbkOZhZ_YqzsjO50fQxogFhbpnOjTPCixq6LstI
reviewed a case of a patient recovery and what immune response is needed for recovery
As ASCs ( antibody-secreting cells) are key for the rapid production of antibodies following infection with Ebola virus and infection with and vaccination against influenza virus, and activated circulating TFH cells (cTFH cells) are concomitantly induced following vaccination against influenza virus, we defined the frequency of CD3–CD19+CD27hiCD38hi ASC and CD4+CXCR5+ICOS+PD-1+ cTFH cell responses before symptomatic recovery.
ASCs appeared in the blood at the time of viral clearance (day 7; 1.48%) and peaked on day 8 (6.91%). The emergence of cTFH cells occurred concurrently in blood at day 7 (1.98%), increasing on day 8 (3.25%) and day 9 (4.46%) (Fig. 1d). The peak of both ASCs and cTFH cells was markedly higher in the patient with COVID-19 than in healthy control participants (0.61% ± 0.40% and 1.83% ± 0.77%, respectively (average ± s.d.); n = 5). Both ASCs and cTFH cells were prominently present during convalescence (day 20) (4.54% and 7.14%, respectively; Fig. 1d).
Thus, our study provides evidence on the recruitment of both ASCs and cTFH cells in this patient’s blood while she was still unwell and 3 d before the resolution of symptoms.
As pro-inflammatory cytokines and chemokines are predictive of severe clinical outcomes for influenza, we quantified 17 pro-inflammatory cytokines and chemokines in plasma. We found low levels of the chemokine MCP-1 (CCL2) in the patient’s plasma (Extended Data Fig. 2a), although this was comparable to results obtained for healthy donors (22.15 ± 13.81; n = 5), patients infected with influenza A virus or influenza B, assessed at days 7–9 (33.85 ± 30.12; n = 5), and a patient infected with the human coronavirus HCoV-229e (40.56).
Thus, in contrast to severe avian H7N9 disease, which had elevated cytokines IL-6, IL-8, IL-10, MIP-1β and IFN-γ6, minimal pro-inflammatory cytokines and chemokines were found in this patient with COVID-19, even while she was symptomatic at days 7–9.
http://apjai-journal.org/wp-content/uploads/2020/03/1.pdf
Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic
Increased neutrophils and decreased lymphocytes also correlate with disease severity and death.1 Furthermore, patients needing ICU care had higher plasma levels of many innate cytokines, IP-10, MCP-1, MIP-1A, and TNFα.2 These clinical features suggested the like-lihood of involvement of highly pro-inflammatory condition in the disease progression and severity. This early high rise in the serum levels of pro-inflammatory cytokines were also ob-served in SARS-CoV and MERS-CoV infection, suggesting a potential similar cytokine storm-mediated disease severity.
IMHO: that’s probably why azithromycin + chloroquine reduce the chances for the disease to progress to severe form. They have both proved anti-inflammatory activity.
Based on the accumulated data for previous coronavirus infection, innate immune response plays crucial role in protective or destructive responses and may open a window for immune intervention. Active viral replication later results in hyperproduction type I IFN and influx of neutrophils and macrophages which are the major sources of pro-inflammatory
cytokines. With similar changes in total neutrophils and lymphocytes during COVID19, SARS-CoV-2 probably induces delayed type I IFN and loss of viral control in an early phase of infection.
Individuals susceptible to CoVID19 are those with underlying diseases, including diabetes, hypertension, and cardiovascular disease. In addition, no severe cases were reported in young children, when innate immune response is highly effective. These facts strongly indicate that innate immune response is a critical factor for disease outcome.
My 28 year old daughter finished 8 months of chemo a month ago. Her immune system is flat…what would you think is best defense in this state other than complete isolation?
Hi Robinrae,
To try increase the defence, I would focus on food supplements such as Vitamin C, Zinc, Selenium, Vitamin D3, Mushrooms (e.g. Coriolus, Reishi), Curcumi, EGCG, Melatonin. Just in case a more intensive approach is required, I would also make sure I have in home drugs known to help against COVID19, such as Ivermectin, Hydroxychloroquine, Niclosamide as well as Colloidal Sliver.
Kind regards,
Daniel
@Daniel: please don’t follow the Ivermectin hype, the dosage would be quite toxic to humans. It’s about 10x the maximum dose given to dogs. And I know that a large dose (still much lower than that) can lead to serious problems, like an allergy or asthma attack, which for people already in ARDS would be fatal.
On the other hand, Selamectin can be given at a 10x – 15x higher dose than Ivermectin, and might be useful against Sars-Cov-2, although it was only proven against a pangolin coronavirus for now.
Thank you for sharing your view on Ivermectin, Ovidiu.
Regarding Ivermectin I have a different view: Ivermectin is one that I follow for long time as it is very relevant in the fight against cancer. We did used Ivermectin in higher doses without any side effects.
Here is a very recent study indicating that in high doses (0.8mg/kg) Ivermectin seems to have similar side effects as in low dose range https://academic.oup.com/jac/article-abstract/75/4/827/5710696?redirectedFrom=fulltext which would indicate that about 50mg/day (which is a high dose), could be safe. Of course as with any drug I would be very careful since anyone can react in a different way. Nevertheless, Ivermectin 12mg 3-4 x/day for 10 days has been used for long time by Simon Yu, MD Internal Medicine, to address various health challenges.
Thank you for mentioning Selamectin. I did not know this one and I will look into it.
Kind regards,
Daniel
@Daniel: the Ivermectin effective dosage against Covid-19 is about 260 mg initial bolus, probably followed by lower doses, for a 60 kg adult.
C-reactive protein and Interleukin-6 are indicators of progression to severe disease in Covid-19. What does Ivermectin do to them, even at low dose?
C-reactive protein and interleukin-6 are elevated in onchocerciasis patients after ivermectin treatment. PMID: 8077726
I already mentioned Selamectin as a possible treatment against TNBC, a couple of years ago.
Ovidiu, what is the origin of your statement?
“the Ivermectin effective dosage against Covid-19 is about 260 mg initial bolus, probably followed by lower doses, for a 60 kg adult.”
Reference?
@Daniel: no reference, no one yet killed a Covid-19 patient this way…
I just computed the dose from the 5 micromoles per liter, effective in vitro.
Ah, OK. Thanks. But I think we had this discussion before (about blood levels, drug accumulation, etc.). We know that in so many cases repurposed drugs add benefits even when the difference between lab tests and reachable level in humans is 100x or more. Having here only a 5x difference (280mg you calculated and 50mg found as safe) is great and the chance of effectiveness is therefore good.
Hi Robinrae, some supplements may be beneficial such as Vitamins C and D, Modified citrus pectin, melatonin, mistletoe.
Is Covid 19 actually just an existing exosome found in all of us under toxicity, stress, etc.?
Here is a totally different perspective on COVID19, by Dr. Andrew Kaufman https://www.youtube.com/watch?v=4sHqJaSZvHs&feature=youtu.be
He argues that exosomes and covid 19 are one and the same thing, i.e. exosomes, generated by our body in response to stress (induced by e.g. toxins, electromagnetic waves, etc.).
I like out of the box perspectives as these are those that help the world evolve, and this coming from a true professional Dr. Andrew Kaufman with good arguments and references in the scientific literature is very valuable.
Hi, Daniel.
Professor made a good point – the inflammation caused by viruses, bacteria, chemical agent have the same nature.
In fact it was shown that genetically modified virus became nonlethal after modifying its shell, although the lethal and nonlethal types had equal viral loads in mice.
The same was show with pneumonia inducer Streptococus strains – one caused pneumonia and another colonized lungs but did not caused pneumonia. The difference was in bacteria capsule type.
And the same was shown with Micobacteria strains – they have equal cell loads but had different disease severity (from severe to mild).
P.S. i can give references if needed
Hi Maxim,
Thank you for reacting on this. The implications of the perspective of dr. Kaufman is that there is no COVID19. There are just exosomes released by the body in response to stress such as those you mentioned. On that line, he argues that as we test more people we will find them in most of the people, and it is not COVID, and it could be something else that triggers the exosomes release. In any case, it’s an interesting perspective, and it remains to be seen if it is also true.
Kind regards,
Daniel
I enjoyed the video, so interesting. Thank you Daniel
Hi Daniel –
I watched Dr Kaufman’s March 31 2020 COVID-19 video. It raised two major red flags:
Red Flag One. Dr Kaufman appears to imply that there is not an exponential death process driven by close physical contact. For context, here is a link to a graph: https://tinyurl.com/us-vs-skorea-covid to stare at the evident exponential nature of the death in the US prior to non-pharmaceutical interventions (contact tracing, social distancing). Dr Kaufman’s has a list of factors that induce exosomes – toxic substances, stress (fear), cancer, ionizing radiation, infection, injury, immune response, asthma, diseases (unspecified in literature, many), electromagnetic radiation (5G, no research). As far as I can tell, only two of these have the potential to induce exponential growth on the time scales we are seeing: stress (fear) and disease (in the form of an infectious disease). It is not likely that the causative difference between US and South Korea is that fear was more contagious in the US. It is also possible to look at the inflection point of deaths per day (log scale) in response to state changes in social interaction. We are witnessing changes in log death rate repeatedly occurring 10-15 days after the imposition of regional social distancing efforts – in Hubei, in China as a whole, in Italy, in NYC. My brother has some excellent graphs of this that I’ll add to this comment when I find them. This repeated pattern implicates an infectious disease that requires close physical contact and transmission of some sort of material form such as a virus.
Red Flag Two. Dr Kaufman provides a misleading quote from James Hildreth (M.D., president & CEO of Meharry Medical College). Transcription of Dr Kaufman “So, I happened to be looking in the virology literature and actually they also think that exosomes and viruses are possibly the same thing. So this is Dr James Hildreth, a very prominent researcher and academic physician in the field of virology and HIV research. He is currently the president and CEO of Meharry Medical college but he was a full professor at Johns Hopkins and he wrote this paper with two of his colleagues there and what he said, and I quote, “… the virus is fully an exosome in every sense of the word.” Now this was just a great confirmation for what I was already thinking and I was kind of blown away when I read this in the paper because this was one of the last papers I looked at, to find this, after I’d already come to the same conclusion it really helped validate my opinion.
– While Dr Kaufman says “this paper” he does not include a reference. The best match is the paper `When is a virus an exosome?` in J Cell Biology by William Wells. First two sentences: “A bold new theory suggests that retroviruses have hijacked an intercellular communication system for both their biogenesis and spread. This concept, outlined by Stephen Gould, Amy Booth, and James Hildreth (Johns Hopkins University, Baltimore, MD) has implications for HIV treatment and communication strategies, and may explain why tissue rejection occurs in humans.”
– Dr Kaufman implies that Dr Hildreth was describing the coronavirus in the quote. Dr Hildreth was describing HIV.
– Very clearly, Dr Hildreth et al are not implying that HIV is not transmissible. Their theory is that HIV can hijack exosomes.
– Search for Dr Hildreth and coronavirus. He is in alignment with COVID-19 as an infectious disease (e.g. “don’t be a vector” https://uncf.org/the-latest/meharry-medical-college-president-on-covid-19-dont-be-a-vector April 6 2020).
I also like out of the box perspectives and in fact consider them necessary to help us evolve as a planet. However Dr Kaufman’s arguments are flawed and in my opinion it is not worth aligning to the possibility that there is no physical contagion occurring.
I am also cautious about anything else that he said, having thought clearly about the above two points and found his arguments misleading. However the potential for noise and high rates of false positives (80%?) in RT-PCR testing does highlight the necessity for being clear and accurate about what testing actually does, differentiating between different types of tests, and evaluating the meaning and the inferences in this light.
Also the potential hi-jacking of exosomes as part of the disease process seems to be worth exploring.
Finally, in the spirit of thinking outside the box, here is a question: is it possible for a person to manifest the disease in certain circumstances without infectious exposure? My brother was describing to me what was happening in Wuhan as soon as there was information about it in late December. I was overcome by evocations of empathy all those struggling with the worst of this – struggling to breathe, being alone, being extremely tired, lungs not functioning well. I became sick, for several weeks, with some very strong hallucinations explicitly about the virus (along with fever and bad lungs). This happened from about Dec 29 through Jan 10, with Jan 1 as the worst day.
HI Jess,
Thank you so much for your careful and balanced analysis! It’s very much appreciated!
I really enjoyed the talk because of the outside of the box thinking. But I do remember I felt the need to address many questions, after watching this. In this case I watched, I thought “interesting perspective” and I moved on. It was a short talk so it’s difficult to take this to a next level without enough background and experience and without the ability to ask question to the speaker. While I very much like new ideas (as you also like) I totally agree that before accepting something like this we need to carefully consider it and see if it can be indeed connected with the scientific knowledge. Doing this implies hard work, and it’s nice to see that you were triggered by this talk and dived deeper into the subject.
For me, exosomes subject goes on the list of the subjects I will address more carefully in the context of cancer and metastasis. It’s a large field of knowledge.
The experience of your brother and the related question (is it possible for a person to manifest the disease in certain circumstances without infectious exposure?) is very interesting. We know so little about how our body works and so little about what is outside of our body. Your question reminds me of a concept promoted in what is known as “New Germanic Medicine” (I was looking at this >5 years ago) where it is suggested that depending on the type of emotional conflict we may develop illnesses at the related organs. In that context, e.g. fear of death was suggested to initiate lung illness. I am not sure if this really works, but I am sure that strong emotion has strong impact on our body. Yet, being able to control that is challenging for most of us.
Kind regards,
Daniel
Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients
https://academic.oup.com/nsr/advance-article/doi/10.1093/nsr/nwaa041/5804736
Importantly, aberrant pathogenic Th1 cells with co-expressing IFN-y and GM-CSF exist only in ICU patients infected SARS-CoV-2, whereas little was found in non-ICU patients and healthy controls, indicating this pathogenic Th1 cells
which have correlative evidence from patients with severe disease, play a critical role for hyper-inflammatory responses in SARS-CoV-2 pathogenesis (Fig. 1B, D).
P.S.-
CD4+ helper T-cells can be divided into Thl, Th2 or ThO cells according to their cytokine-secreting profiles following activation, with ThI cells producing predominantly interferon-gamma(IFN–y), IL-12 and IL-2 , and Th2 cells producing IL-4, IL-5, IL-6 and IL-10, with ThO cells producing a combination of Thl and Th2 cytokines.
The interleukin 4 (IL4, IL-4) is a cytokine that induces differentiation of naive helper T cells (Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop.
The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Th1 cytokine production in mitogen- and antigen-stimulated human peripheral blood mononuclear cell cultures.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1534314/
Thalidomide in the Treatment of Sweet’s Syndrome and Eosinophilic Folliculitis Associated With Immune Reconstitution Inflammatory Syndrome
https://www.frontiersin.org/articles/10.3389/fmed.2019.00343/full
ON THESE ARTICLES CAN BE DRAWN A CONCLUSION:
Severe cases of COVID-19 infection can be successfully treated with thalidomide, which repares the Th1/Th2 imbalance.
That is indeed my expectation too. Thank you for the references!
HI Maxim, I just saw you tried to post this as a longer post a few times but it did not went through – sometimes WordPress is filtering the posts and those are waiting for my permission – so when that happens again just send me an e-mail or a msg and I will check and approve it.
Hi Maxim and all,
A couple of papers you posted have somewhat opposing views on the immunopathology of COVID-19 and I am curious to know which one you think is closer to the truth.
https://academic.oup.com/nsr/advance-article/doi/10.1093/nsr/nwaa041/5804736 – this paper details the evolution to cytokine storm and supposes that it is activated Th1 cells inappropriately producing cytokines, excessive immune cell infiltration, and eventual cytokine storm that causes the severity of symptoms and death in COVID-19. In other words it is the immune system’s reaction to the virus the causes the damage.
https://www.medrxiv.org/content/10.1101/2020.02.19.20024885v1.full.pdf – this study proposes that the virus is highly immuno-suppressive and that it is the virus itself that primarily causes the damage. In fact, the authors propose GM-CSF and other immuno-stimulatory therapies as potential treatment.
The treatment implications of both papers are very different, so I was wondering about your perspective. Of course, anyone who has thoughts on this, please feel free to respond.
Thank you
Hi, Shanti
Of course viruses damage tissues, they replicate inside the cells, so it kills the cells. As more virus replications, the more the damage.
But the second article stresses that – “These features suggest that the consequences in the COVID-19 patients might not be mainly due to the inflammatory reaction, especially in the non-severe cases”.
The key is here that in non severe cases – it is not the main cause , and for severe cases it could be the cause (they did not say that it is not the cause ).
The low count of lymphocytes, can be ascribed to predominantly Th1 response in severe cases.
This article: Role of innate lymphocytes in infection and inflammation https://www.ncbi.nlm.nih.gov/pubmed/22783250 shows that Th2 activity is important to fight the disease, because Th2 Cytokine-PRODUCING INNATE Lymphocytes (that is exactly Lymphocytes count what the second article shows lacks with severe cases).
So, in conclusion, if both responses Th1 and Th2 were suppressed (glucocorticoids, cyclosporine) then the body could not fight the infection. If predominantly there were only Th1 response (INF-gamma) then again then the body could not fight the infection (it is not productive response).
With Th2 response the body could produce Lymphocytes to fight the infection, and it needs Th1 response too.
The body needs to repair the imbalance to successfully start to clear the infection.
If you look at this article: Thalidomide Combined with Low-dose Glucocorticoid in the Treatment of COVID-19 Pneumonia
https://www.preprints.org/manuscript/202002.0395/v1
Then this treatment would kill that woman if the only cause of the problem were the virus cell damage.
In short, naïve CD4+ T cells can differentiate into Th1 and Th2 cells. There can be an imbalance to what type it is differentiating. Th2 cells are needed so CD4+ T cells could be produced (a feedback loop), without it there would be low count of CD4+ cells. With low count of CD4+ T cells the body can not fight the infection.
Paradoxycally, systemic inflammation causes Lymphocytopenia , or may be its a reverse process or both.
Probably strong inflammation reduces the body ability to produce new lymphocytes.
Because when the inflammation is reduced, there’s usually a lymphocyte count growth.
By the way, a stress (even a surgery) can reduce lymphocyte count.
Ratio of neutrophil to lymphocyte counts–rapid and simple parameter of systemic inflammation and stress in critically ill.
https://www.ncbi.nlm.nih.gov/pubmed/11723675
The physiologic response of circulating leukocytes to surgical stress in group A is characterized by the onset of marked neutrophilia (62.5% before surgery up to 84.4% after surgery) and significant lymphocytopenia (28.1% before surgery to 10.3% following surgery). We observed a slow decline in neutrophil counts and an increase in lymphocyte counts since the 1st postoperative day. The patients with abdominal infection (group B) had elevated counts of neutrophils already before surgery (83.2%) and low values of lymphocyte counts (9.5%). A further increase in neutrophil counts (89.9%) and marked lymphopenia (7%) were recorded during the post-surgical period in group B. Critically ill patients with severe sepsis or septic shock (group C) had significantly highest values of neutrophil relative counts (94%-93.1%-92.5%, p < 0.05 against group A) and marked lowest values of lymphocyte counts (3.8%-4%-3.7%, p < 0.05 against group A). The severity of clinical course (according SOFA and APACHE II score) correlated with the divergence of neutrophil and lymphocyte counts in the white blood picture (marked neutrophilia and lymphocytopenia).
So, the second article which observed low lymphocytes, does not contradicts with the inflammation theory, because what they observed in reality are the consequences of inflammation.
And the article: Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19 https://www.medrxiv.org/content/10.1101/2020.03.12.20035048v1
also supports severe inflammation theory. The severity of inflammation is based on phenotype.
and if you look at most COVID-19 cases the fever is typically accompanies severe infections.
To support this look at: Severe COVID-19 cases to be offered new clinical trial programme
https://www.euractiv.com/section/coronavirus/news/severe-covid-19-cases-to-be-offered-new-clinical-trial-programme/
In a 21-patient cohort infected with COVID-19, patients were found to have experienced rapidly reduced fevers and 75% of them reduced their need for supplemental oxygen within days of receiving a similar medication.
P.S. Sarilumab (trade name Kevzara) is a human monoclonal antibody against the interleukin-6 receptor. https://en.wikipedia.org/wiki/Sarilumab
So the cell damage is not the main cause.
P.S. although Kevzara can help, but it is only intravenous treatment. So, hospitalization is needed.
Thalidomide can be given peroraly with no less effectiveness. And Kevazara treats the imbalance of only one interleukin (IL-6), thalidomide can affect a broader spectrum, so it can better fit for the treatment.
Hi Maxim,
Wow, what an amazing summary! I am truly appreciative of the time you put into this and how comprehensive it was, it definitely helped me to reconcile the two studies and understand the pathology. It makes me wonder if some of the conclusions from the second study (https://www.medrxiv.org/content/10.1101/2020.02.19.20024885v1.full.pdf) are inappropriate unless early in the pathology of COVID. For example the suggestion to use GM-CSF seems like it could exacerbate a Th1 situation since macrophages are stimulated by Th1 cytokines: “Current treatments do not suggest using specific drugs to improve the activity of immune systems, such as the GM-CSF or other immune stimuli, in fearing of the exaggeration of inflammatory reactions and cytokine storm[18]. However, based on our clinical findings, we should seriously consider using immune-activating treatments for COVID-19 patients, which will be helpful to compensate the dysfunctions in the adaptive immune system and accelerate virus clearance process in vivo.”
The use of Thalidomide with low-dose glucocorticoids really makes so much sense in the context of dysfunctional Th1 dominance. Since the virus seems to create this dysfunctional Th1 dominance, I wonder if people who tended toward Th2 immune reactions (with the exception of asthma) or who have parasitic infections causing Th2 reactions, would do any better against the virus? Or if whatever Th1/Th2 predispositions we have would only be like a feather fighting against a bulldozer.
If I understand, the lymphocytopenia is cytokine controlled and caused by the following:
• Inflammation- suppresses lymphocyte propagation
• Decrease in B- lymphocytes caused by Th1 dominance (also, the second study postulated that the virus could infect ACE2 expressing myeloid cells in the bone marrow, further decreasing B cells)
• Decrease in CD4+ count as part of the disfunction of Th1 dominance and possibly innate lymphocyte dysfunction.
Could a drop also be caused by Th1 cells migrating out of circulation and to the site of injury, similar to how we can see a neutrophil drop in early bacterial infection?
I also wonder why the second study noted high levels of IL-4 and IL-10, which seem to be more related to Th2: “However, the early report about COVID-19 cases found that the profile of cytokine in the blood of patients was different from that from SARS-Cov cases: not only pro-inflammatory cytokines but also anti-inflammatory cytokines (IL-4, IL-10, etc.) increased in the COVID-19 cases[4].” Maybe the body trying to calm things down? Well, as they say, “the proof is in the pudding”, and the study you referenced with Kevzara (https://www.euractiv.com/section/coronavirus/news/severe-covid-19-cases-to-be-offered-new-clinical-trial-programme/) is one of a number of proofs that blocking, not stimulating immune function is most appropriate in severe COVID.
I know some of my follow-up questions may be unanswerable, you have already helped me very much, please don’t feel you need to address them all.
With Gratitude,
Shanti
Yesterday, I have found this article “COVID-19 infection: the perspectives on immune responses” https://www.nature.com/articles/s41418-020-0530-3
They split this disease in stages and propose to treat it in each stage accordingly:
We believe that the two-phase division is very important: the first immune defense-based protective phase and the second inflammation-driven damaging phase. Doctors should try to boost immune responses during the first, while suppressing it in the second phase.
As to CD4 decrease i think it is temporal and not associated with lymphocytes destruction. “Type I interferons directly regulate lymphocyte recirculation and cause transient blood lymphopenia” https://ashpublications.org/blood/article/108/10/3253/22794/Type-I-interferons-directly-regulate-lymphocyte
When cytokines go away, then lymphocyte count rapidly restores. (Although they tested Interferon alfa and beta, but i think it can be generalized )
One day after the induction of lymphopenia, adoptively transferred lymphocytes reappeared in blood and eventually reached numbers similar to those of PBS-treated controls. Thus, lymphocytes were sequestered from blood and at later time points reappeared, demonstrating that poly(I:C)–induced lymphopenia was completely reversible and did not involve apoptosis.
They tried to find where they hide, but their results are inconclusive. But they state that clinically relevant immunosuppression with opportunistic infections may occur on prolonged exposure to IFN-α/β, as reported in IFN-α/β– treated patients. (and it probably can be generalized too).
As to Maybe the body trying to calm things down? there are also peace keeping macrophages along with ordinary ones – they produce calming cytokines.
Could Newly Found “Peacekeeping” Cells Be a Weapon against COVID-19? https://www.scientificamerican.com/article/could-newly-found-peacekeeping-cells-be-a-weapon-against-covid-19/
P.S. – although article states that it is good to boost the immune system in the first phase, but it is important to use anti inflammation drugs in this phase too. Because lung damage goes on in this stage as well, although it can not manifests itself with powerful systemic cytokine release.
That’s why hydroxychloroquine+azythromycin can prevent a full blown pneumonia.
For boosting immune system it is better to use mild things like vitamines, prebiotics. They don’t increase inflammation.
Interferons can increase inflammations, so it is better to avoid them
Hi Maxim, Thank you for this detailed and useful information, and the great find on the paper detailing the two stages of disease progression. I am sharing some of the papers and thoughts generated here with my colleagues in the health care profession so your insights and information are contributing to my own and others’ understanding and ability to help others. Thanks again -Shanti
IMHO: for myself i would opt (if need be) to such treatment :
in the first phase: Celecoxib – to tame down macrophages a bit (it reduces PGI2 levels), but does it mildly and a Dutch trial showed that it is beneficial for influenza treatment and it is less toxic than paracetamol in high doses.
I’m thinking about adding to it roxithromycin, which is a macrolide antibiotic but has a stronger anti inflammation activity than azythromycin.
(i’m not against hydroxychloroquin + azythromicyn, it works in the same direction, but think it’s more toxic mixture than the above and hydroxychloroquin disappeared from the pharmacies now – thanks to advertising)
I think this treatment will prevent severe pneumonia in the first place.
And if worse comes to worst (strong fever and coughing), i would opt to Celecoxib + thalidomide treatment.
Best regards!
Thank you for the valuable info, Maxim. What’s your take on curcumin as th1/th2 modulator if any?
Hi johan!
I did not research curcumin. But a quick look int wiki says:
Pharmacology
Curcumin, which shows positive results in most drug discovery assays, is regarded as a false lead that medicinal chemists include among “pan-assay interference compounds”. This attracts undue experimental attention while failing to advance as viable therapeutic or drug leads.[3][11][12]
Factors that limit the bioactivity of curcumin or its analogs include chemical instability, water insolubility, absence of potent and selective target activity, low bioavailability, limited tissue distribution, and extensive metabolism.[3] Very little curcumin escapes the GI tract and most is excreted in feces unchanged.[13] If curcumin enters plasma in reasonable amounts, there is a high risk of toxicity since it is promiscuous, and interacts with several proteins known to increase the risk of adverse effects, including hERG, cytochrome P450s, and glutathione S-transferase.[3]
As to “I wonder if people who tended toward Th2 immune reactions (with the exception of asthma) or who have parasitic infections causing Th2 reactions, would do any better against the virus?”
Probably it won’t help, because their reactions are to specific antigens (not all of them). For example, researchers when tried to create a vaccine when they used inactivated virus, it caused Th2 (allergic reactions), and when used live virus it caused Th1 reactions (fever, macrophages).
Thalidomide also helps only for Th1 reactions, mainly affecting macrophages cytokines production.
And it can activate CD8 cells (apoptosis)
“Thalidomide and a Thalidomide Analogue Drug Costimulate Virus-Specific CD8+ T Cells In Vitro”
https://academic.oup.com/jid/article/187/6/946/888583
And strange thing, it helps with Asthma
“Thalidomide inhibits alternative activation of macrophages in vivo and in vitro: a potential mechanism of anti-asthmatic effect of thalidomide.” https://www.ncbi.nlm.nih.gov/pubmed/25905462
And thalidomide helped only with lepra || reactions, but did not help with type I reactions
https://apps.who.int/medicinedocs/en/d/Jh2988e/6.html
In conclusion, there are too many ways to quantify what is caused by what.
More clinical trials are needed to find it out.
P.S. I think that government officials don’t want to use this drug (thalidomide) in an epidemic situation. Because people will want for a cure, and there will be a demand for it, so there will be a supply (including illegal, it is easy to synthesize). People will start to use it uncontrollably, and then cases of birth defects will appear.
and there are one study “Anti-inflammatory effect of thalidomide on H1N1 influenza virus-induced pulmonary injury in mice.” https://www.ncbi.nlm.nih.gov/pubmed/24912813
The results showed that Thd significantly improved the survival rate, reduced the infiltration of inflammatory cells and cytokine (e.g., IL-6, TNF-α) and chemokine (e.g., RANTES, IP-10) levels, and inhibited activated p-NFκB p65 in infected mice. These findings suggested that Thd may attenuate H1N1-induced pulmonary injury and thus may find use in the treatment of viral diseases.
Neutrophils in viral infections: Current concepts and caveats https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.4VMR1114-555R
It was demonstrated that lethal influenza infection in mice correlated better with excessive neutrophil activation than with the viral load and was linked to the presence of a proinflammatory transcriptional signature comprising TNF, IL-1, IL-6, and acute phaseresponse genes and NF-kB, JAK-STAT, and MAPK signaling cascades [21]. In addition, severe disease caused by a recombinant IAV bearing the 1918 pandemic flu HA was accompanied by production of chemoattractants such as MIP-2/CXCL2 that resulted in increased recruitment of neutrophils in the lung and augmented intra-alveolar hemorrhage [22].
Shanti, that’s an additional article showing an effect of cytokines on leukocytes count.
Acute hematologic effects of interferon alpha, interferon gamma, tumor necrosis factor alpha and Interleukin 2 https://link.springer.com/article/10.1007/BF01714980
Summary
This study was designed to investigate acute effects of various doses of the cytokines IFN-alpha, IFN-gamma Interleukin 2 and tumor necrosis factor alpha on white blood cell differential counts. Before initiation of phase II trials, a dose-determination phase was performed, where three different dose levels of each cytokine were applied as a single dose. White blood cell differential counts were assessed immediately before and 2, 12, 24, 48 and 168 h after injection. Patients enrolled suffered from metastatic cancer or chronic active hepatitis. In addition, IFN-alpha was administered to five healthy volunteers.
Results indicate that cytokines cause rapid and transient changes in the numbers of leukocyte subsets.
Hematologic changes were cell-type- and cytokine-specific:
transient lymphopenia was observed after administration of all four cytokines, reaching a nadir 12 to 24 h after subcutaneous injection.
Administration of TNF-alpha and IFN-gamma also caused transient monocytopenia.
Neutrophilia developed after administration of Interleukin 2, IFN-alpha and TNF-alpha. We conclude that cytokines play a key role in the regulation of peripheral blood cell traffic by their capacity to influence homing patterns of peripheral blood leukocytes.
Hi. I see niclosamide is mentioned as a possible antiviral, and that it is possible to get over-the-counter..
Where do you get this? Haven’t been able to find it anywhere.
Also posted on another place about TUDCA, would this also be possible to help for coronavirus considering I found some information that it has antiviral effects. Is it okay to use for cancer patients also?
Thank you and best regards,
Myra
Hi Myra,
Here is an example of Niclosamide source https://www.ebay.com/itm/Niclosamide-1000mg-Zenda-1000-for-Tapeworm-Infections-30tablets-exp-2025/133378244836?hash=item1f0df680e4:g:IfUAAOSwXqpeFrG6
TUDCA, I did not had yet the chance to look at it. As soon as I find the time to investigate it I will answer your question, in case no one else can answer.
Kind regards,
Daniel
Thank you for your reply, I was looking for a source of Niclosamide here in Europe. I am kind of scared to order from ebay.
Are there any other places where I can buy it, preferably in Europe because of shipping distances?
TUDCA, was very intrigued to read about everything it does, but I am a bit confused if this compound has any interaction with cancer cells, because found some confusing studies that I was not sure how to interpret as I am not a doctor or researcher; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888259/
It seems to have some potential great effects for the liver and eyes though. And the inhibiting of ER stress is bad or good for cancer?
This website is great.
Best regards,
Myra
VERY IMPORTANT INFORMATION: THIS IS VERY IMPORTANT BECAUSE PATIENTS DIE FROM RESPIRATORY INSUFFICIENCY CAUSED BY THE EXCESSIVE INFLAMMATORY RESPONSE OF THE IMMUNOLOGICAL SYSTEM OF THE SAME PATIENT. BICARBONATE TAKEN VIA ORAL MODULATES THE INFLAMMATORY WATERFALL
I found something very important to contain the proinflammatory cascade produced by the SARS COV 2 virus, which is the cause of the Covid 19 pathology. IT IS SODIUM BICARBONATE.
There are many anecdotal testimonials on social media of people who, upon presenting the symptom of Covid 19, used baking soda for severe sore throat and found that the symptoms disappeared or decreased.
And this has a lot of logic because of this:
Both coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS) are characterized by an over-exuberant inflammatory response, and for SARS, viral load is not correlated with worsening symptoms.
Oral NaHCO3 Activates a Splenic Anti-Inflammatory Pathway: Evidence That Cholinergic Signals Are Transmitted via Mesothelial Cells.
Abstract
We tested the hypothesis that oral NaHCO3 intake stimulates splenic anti-inflammatory pathways. Following oral NaHCO3 loading, macrophage polarization was shifted from predominantly M1 (inflammatory) to M2 (regulatory) phenotypes, and FOXP3+CD4+ T-lymphocytes increased in the spleen, blood, and kidneys of rats. Similar anti-inflammatory changes in macrophage polarization were observed in the blood of human subjects following NaHCO3 ingestion. Surprisingly, we found that gentle manipulation to visualize the spleen at midline during surgical laparotomy (sham splenectomy) was sufficient to abolish the response in rats and resulted in hypertrophy/hyperplasia of the capsular mesothelial cells. Thin collagenous connections lined by mesothelial cells were found to connect to the capsular mesothelium. Mesothelial cells in these connections stained positive for the pan-neuronal marker PGP9.5 and acetylcholine esterase and contained many ultrastructural elements, which visually resembled neuronal structures. Both disruption of the fragile mesothelial connections or transection of the vagal nerves resulted in the loss of capsular mesothelial acetylcholine esterase staining and reduced splenic mass. Our data indicate that oral NaHCO3 activates a splenic anti-inflammatory pathway and provides evidence that the signals that mediate this response are transmitted to the spleen via a novel neuronal-like function of mesothelial cells.
https://www.ncbi.nlm.nih.gov/pubmed/29661827
Oral NaHCO3 Activates a Splenic Anti-Inflammatory Pathway: Evidence That Cholinergic Signals Are Transmitted via Mesothelial Cells.
Abstract
We tested the hypothesis that oral NaHCO3 intake stimulates splenic anti-inflammatory pathways. Following oral NaHCO3 loading, macrophage polarization was shifted from predominantly M1 (inflammatory) to M2 (regulatory) phenotypes, and FOXP3+CD4+ T-lymphocytes increased in the spleen, blood, and kidneys of rats. Similar anti-inflammatory changes in macrophage polarization were observed in the blood of human subjects following NaHCO3 ingestion. Surprisingly, we found that gentle manipulation to visualize the spleen at midline during surgical laparotomy (sham splenectomy) was sufficient to abolish the response in rats and resulted in hypertrophy/hyperplasia of the capsular mesothelial cells. Thin collagenous connections lined by mesothelial cells were found to connect to the capsular mesothelium. Mesothelial cells in these connections stained positive for the pan-neuronal marker PGP9.5 and acetylcholine esterase and contained many ultrastructural elements, which visually resembled neuronal structures. Both disruption of the fragile mesothelial connections or transection of the vagal nerves resulted in the loss of capsular mesothelial acetylcholine esterase staining and reduced splenic mass. Our data indicate that oral NaHCO3 activates a splenic anti-inflammatory pathway and provides evidence that the signals that mediate this response are transmitted to the spleen via a novel neuronal-like function of mesothelial cells.
https://www.ncbi.nlm.nih.gov/pubmed/29661827
The cholinergic anti-inflammatory pathway.
Abstract
The regulation of the innate immune response is critical for controlling inflammation and for the prevention and treatment of diseases. We recently demonstrated that the efferent vagus nerve inhibits pro-inflammatory cytokine release and protects against systemic inflammation, and termed this vagal function “the cholinergic anti-inflammatory pathway.” The discovery that the innate immune response is regulated partially through this neural pathway provides a new understanding of the mechanisms that control inflammation. In this review, we outline the cholinergic anti-inflammatory pathway and summarize the current insights into the mechanisms of cholinergic modulation of inflammation. We also discuss possible clinical implications of vagus nerve stimulation and cholinergic modalities in the treatment of inflammatory diseases.
I clarify that I began to investigate the matter of sodium bicarbonate due to testimonies of people who have published, on social networks, testifying that they recovered from the symptoms of covid 19 after gargling with sodium bicarbonate.
Drinking baking soda could be an inexpensive, safe way to combat autoimmune disease
https://www.sciencedaily.com/releases/2018/04/180425093745.htm
I am thinking that if sodium bicarbonate modifies the immune response, proton pump inhibitors do the opposite effect, so it should be recommended that these inhibitors not be used in patients with covid 19
Why Mario? Can you please explain? Thank you.
Hello Daniel:
Here the summary of why
Further confirming the involvement of cholinergic signaling, methyllycaconitine (MLA), a potent and specific inhibitor of the α7 nicotinic Ach receptor, prevented anti-inflammatory macrophage polarization to oral NaHCO3 (Figure 6). Similarly, the gastric proton pump inhibitor esomeprazole, also inhibited the anti-inflammatory response to NaHCO3
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940560/
The problem here, that it is not tested in disease environment. The disease can be a much more powerful inducer than NaHCO3 and can override its action.
Maxim: Everything is feasible.
But I investigated the matter of sodium bicarbonate after listening to several cases of people (anecdotal testimonies), on social networks, who used it when they were presented with the symptoms of fever and pain in the throat, typical of covid 19, and they affirm, who had a regression of symptoms. It is little but that is what there is.
I live in Colombia, a Spanish-speaking country. In Latin America these types of home remedies are very used to flu symptoms such as: salted water, baking soda with lemon, etc.
The point here is that baking soda can be a good prophylactic measure and there is not much to lose by trying. Don’t you think?
I’ve found one interesting study which gives more clues to the disease progression.
COMPARATIVE PATHOGENESIS OF COVID-19, MERS AND SARS IN A NON-HUMAN PRIMATE MODEL
https://www.biorxiv.org/content/10.1101/2020.03.17.995639v1.full.pdf
It shows that although there were no clinical signs of the disease a damage goes on in the lungs.
And antibodies can be detected (in blood) only after a prolonged time (14 days), but the virus RNA can be detected after (only 2 days) in nasal swabs. Virus replication goes in upper respiratory tract and mainly in the lungs.
The main histological lesion in the consolidated pulmonary tissue involved the alveoli and bronchioles, and consisted of areas with acute or more advanced DAD (Fig.2B). In these areas, the lumina of alveoli and bronchioles were variably filled with protein-rich oedema fluid, fibrin, and cellular debris, a moderate number of alveolar macrophages, and fewer neutrophils and lymphocytes (Fig.2C-E). There was epithelial necrosis with extensive loss of epithelium from alveolar and bronchiolar walls. Hyaline membranes were present in a few damaged alveoli. In areas with more advanced lesions, the alveolar walls were moderately thickened and lined by cuboidal epithelial cells (type II pneumocyte hyperplasia), and the alveolar lumina were empty. Alveolar and bronchiolar walls were thickened by oedema fluid, mononuclear cells, and neutrophils. There were aggregates of lymphocytes around small pulmonary vessels. Moderate numbers of lymphocytes and macrophages were present in the lamina propria and submucosa of the bronchial walls, and a few neutrophils in the bronchial epithelium.Regeneration of epithelium was seen in some bronchioles, visible as an irregular layer of squamous to high cuboidal epithelial cells with hyperchromatic nuclei. There were occasional multinucleated giant cells (syncytia) free in the lumina of bronchioles and alveoli (Fig.2F), and, based on positive pan-keratin staining and 40negative CD68staining, originated from epithelial cells (Fig.2F, inset).
CONCLUSION:
This gives a clear picture of local inflammation in the lungs, and early treatment with anti inflammatory drugs can probably reduce the extent of the damage.
Chlorine dioxide returns to the arena. Andreas Kalcker, its promoter for more than 13 years, has stated that this substance kills bacteria, viruses and fights cancer. I just heard that you have news from Ecuador where the covid 19 is destroying the lives of hundreds of people. Its healthcare system is crowded with patients who cannot attend due to lack of healthcare capacity. He says that the people of that country, who know the use of chlorine dioxide, are reporting that in just two days it fights Sars COv 2 very effectively.
https://www.youtube.com/watch?v=RgJnoyKleRw
IT IS POSSIBLE THAT WE HAVE THE SOLUTION FOR THE “ASPIRIN” CORONAVIRUS IN OUR KIT OF DRUGS:
I am increasingly convinced that the fight against sars cov 2, the virus that supposedly produces the pathology of covid 19, should focus not on the virus but on what it produces in the patient: inflammation. The excessive response of the immune system, in the presence of the virus, is what, in the end, ends up killing the patient. The immune system becomes its main enemy, causing tissue damage to the lungs that renders it incapable of breathing, and as such generating respiratory failure so strong that it will require respiratory therapy and in more severe cases mechanical ventilation. Although the majority of patients experience only mild symptoms, a significant proportion develop a serious progression of the disease with increasing hypoxia to acute respiratory distress syndrome. The substantial number of severely ill patients has reduced intensive care capabilities to an unprecedented level.
Patients requiring mechanical ventilation did not differ in age, comorbidities, radiological findings, respiratory rate. However, elevated interleukin-6 (IL-6) was strongly associated with the need for mechanical ventilation. Furthermore, the maximum level of IL-6 for each patient during the disease predicted respiratory failure with high precision. The risk of respiratory failure for patients with IL-6 levels ≥ 80 pg / ml was 22 times higher compared to patients with lower levels of IL-6. In the current situation with overcrowded intensive care units and overcrowded emergency rooms, the correct classification of patients needing intensive care is crucial. The study shows that IL-6 is an effective marker that could predict proximal respiratory failure with great accuracy and help clinicians correctly assign patients at an early stage. Obviously ASPIRIN cancels the production of IL-6 from inflammatory cells.
I want to clarify that the use of aspirin for patients with covid 19 was only tested in a small family group where the mother (elderly) children (2, ages 45 and 55) and grandson were positive against covid 19 and all without exception with a treatment of 1,500 mg in a single dose in two consecutive days of treatment had remission of symptoms. In short, the symptoms disappeared.
Acetyl salicylic acid inhibits Th17 airway inflammation via blockade of IL-6 and IL-17 positive feedback
Abstract
T-helper (Th)17 cell responses are important for the development of neutrophilic inflammatory disease. Recently, we found that acetyl salicylic acid (ASA) inhibited Th17 airway inflammation in an asthma mouse model induced by sensitization with lipopolysaccharide (LPS)-containing allergens. To investigate the mechanism(s) of the inhibitory effect of ASA on the development of Th17 airway inflammation, a neutrophilic asthma mouse model was generated by intranasal sensitization with LPS plus ovalbumin (OVA) and then challenged with OVA alone. Immunologic parameters and airway inflammation were evaluated 6 and 48 h after the last OVA challenge. ASA inhibited the production of interleukin (IL)-17 from lung T cells as well as in vitro Th17 polarization induced by IL-6. Additionally, ASA, but not salicylic acid, suppressed Th17 airway inflammation, which was associated with decreased expression of acetyl-STAT3 (downstream signaling of IL-6) in the lung. Moreover, the production of IL-6 from inflammatory cells, induced by IL-17, was abolished by treatment with ASA, whereas that induced by LPS was not. Altogether, ASA, likely via its acetyl moiety, inhibits Th17 airway inflammation by blockade of IL-6 and IL-17 positive feedback.
Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients
Abstract
The pandemic Coronavirus-disease 19 (COVID-19) is characterized by a heterogeneous clinical course. While most patients experience only mild symptoms, a relevant proportion develop severe disease progression with increasing hypoxia up to acute respiratory distress syndrome. The substantial number of patients with severe disease have strained intensive care capacities to an unprecedented level. Owing to the highly variable course and lack of reliable predictors for deterioration, we aimed to identify variables that allow the prediction of patients with a high risk of respiratory failure and need of mechanical ventilation Patients with PCR proven symptomatic COVID-19 infection hospitalized at our institution from 29th February to 27th March 2020 (n=40) were analyzed for baseline clinical and laboratory findings. Patients requiring mechanical ventilation 13/40 (32.5%) did not differ in age, comorbidities, radiological findings, respiratory rate or qSofa score. However, elevated interleukin-6 (IL-6) was strongly associated with the need for mechanical ventilation (p=1.2.10-5). In addition, the maximal IL-6 level (cutoff 80 pg/ml) for each patient during disease predicted respiratory failure with high accuracy (p=1.7.10-8, AUC=0.98). The risk of respiratory failure for patients with IL-6 levels of ≥ 80 pg/ml was 22 times higher compared to patients with lower IL-6 levels. In the current situation with overwhelmed intensive care units and overcrowded emergency rooms, correct triage of patients in need of intensive care is crucial. Our study shows that IL-6 is an effective marker that might be able to predict upcoming respiratory failure with high accuracy and help physicians correctly allocate patients at an early stage.
https://www.medrxiv.org/content/10.1101/2020.04.01.20047381v1
Yes, it works and even used to treat lepra reactions (previously).
There’s a comparison of its effectiveness with thalidomide: WHO Co-ordinated Short-Term Double-Blind Trial with Thalidomide in the Treatment of Acute Lepra Reactions in Male Lepromatous Patients
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2427977/pdf/bullwho00199-0029.pdf
Although, Thalidomide was found to be much more effective.
What is your opinion concerning this article and proposed Covid-19 therapy?!?
Anything else could be used besides hydroxychloroquine + azithromycin + zinc combination?
http://web.archive.org/web/20200405061401/https://medium.com/@agaiziunas/covid-19-had-us-all-fooled-but-now-we-might-have-finally-found-its-secret-91182386efcb
Your red blood cells carry oxygen from your lungs to all your organs and the rest of your body. Red blood cells can do this thanks to hemoglobin, which is a protein consisting of four “hemes”. Hemes have a special kind of iron ion, which is normally quite toxic in its free form, locked away in its center with a porphyrin acting as it’s ‘container’. In this way, the iron ion can be ‘caged’ and carried around safely by the hemoglobin, but used to bind to oxygen when it gets to your lungs.
When the red blood cell gets to the alveoli, or the little sacs in your lungs where all the gas exchange happens, that special little iron ion can flip between FE2+ and FE3+ states with electron exchange and bond to some oxygen, then it goes off on its little merry way to deliver o2 elsewhere.
Here’s where COVID-19 comes in. Its glycoproteins bond to the heme, and in doing so that special and toxic oxidative iron ion is “disassociated” (released). It’s basically let out of the cage and now freely roaming around on its own. This is bad for two reasons:
1) Without the iron ion, hemoglobin can no longer bind to oxygen. Once all the hemoglobin is impaired, the red blood cell is essentially turned into a Freightliner truck cab with no trailer and no ability to store its cargo.. it is useless and just running around with COVID-19 virus attached to its porphyrin. All these useless trucks running around not delivering oxygen is what starts to lead to desaturation, or watching the patient’s spo2 levels drop. It is INCORRECT to assume traditional ARDS and in doing so, you’re treating the WRONG DISEASE. Think of it a lot like carbon monoxide poisoning, in which CO is bound to the hemoglobin, making it unable to carry oxygen. In those cases, ventilators aren’t treating the root cause; the patient’s lungs aren’t ‘tiring out’, they’re pumping just fine. The red blood cells just can’t carry o2, end of story. Only in this case, unlike CO poisoning in which eventually the CO can break off, the affected hemoglobin is permanently stripped of its ability to carry o2 because it has lost its iron ion. The body compensates for this lack of o2 carrying capacity and deliveries by having your kidneys release hormones like erythropoietin, which tell your bone marrow factories to ramp up production on new red blood cells with freshly made and fully functioning hemoglobin. This is the reason you find elevated hemoglobin and decreased blood oxygen saturation as one of the 3 primary indicators of whether the shit is about to hit the fan for a particular patient or not.
2) That little iron ion, along with millions of its friends released from other hemes, are now floating through your blood freely. As I mentioned before, this type of iron ion is highly reactive and causes oxidative damage. It turns out that this happens to a limited extent naturally in our bodies and we have cleanup & defense mechanisms to keep the balance. The lungs, in particular, have 3 primary defenses to maintain “iron homeostasis”, 2 of which are in the alveoli, those little sacs in your lungs we talked about earlier. The first of the two are little macrophages that roam around and scavenge up any free radicals like this oxidative iron. The second is a lining on the walls (called the epithelial surface) which has a thin layer of fluid packed with high levels of antioxidant molecules.. things like abscorbic acid (AKA Vitamin C) among others. Well, this is usually good enough for naturally occurring rogue iron ions but with COVID-19 running rampant your body is now basically like a progressive state letting out all the prisoners out of the prisons… it’s just too much iron and it begins to overwhelm your lungs’ countermeasures, and thus begins the process of pulmonary oxidative stress. This leads to damage and inflammation, which leads to all that nasty stuff and damage you see in CT scans of COVID-19 patient lungs. Ever noticed how it’s always bilateral? (both lungs at the same time) Pneumonia rarely ever does that, but COVID-19 does… EVERY. SINGLE. TIME.
— — — — — — — — — — — — –
Once your body is now running out of control, with all your oxygen trucks running around without any freight, and tons of this toxic form of iron floating around in your bloodstream, other defenses kick in. While your lungs are busy with all this oxidative stress they can’t handle, and your organs are being starved of o2 without their constant stream of deliveries from red blood cell’s hemoglobin, and your liver is attempting to do its best to remove the iron and store it in its ‘iron vault’. Only its getting overwhelmed too. It’s starved for oxygen and fighting a losing battle from all your hemoglobin letting its iron free, and starts crying out “help, I’m taking damage!” by releasing an enzyme called alanine aminotransferase (ALT). BOOM, there is your second of 3 primary indicators of whether the shit is about to hit the fan for a particular patient or not.
Eventually, if the patient’s immune system doesn’t fight off the virus in time before their blood oxygen saturation drops too low, ventilator or no ventilator, organs start shutting down. No fuel, no work. The only way to even try to keep them going is max oxygen, even a hyperbaric chamber if one is available on 100% oxygen at multiple atmospheres of pressure, just to give what’s left of their functioning hemoglobin a chance to carry enough o2 to the organs and keep them alive. Yeah we don’t have nearly enough of those chambers, so some fresh red blood cells with normal hemoglobin in the form of a transfusion will have to do.
The core point being, treating patients with the iron ions stripped from their hemoglobin (rendering it abnormally nonfunctional) with ventilator intubation is futile, unless you’re just hoping the patient’s immune system will work its magic in time. The root of the illness needs to be addressed.
Best case scenario? Treatment regimen early, before symptoms progress too far. Hydroxychloroquine (more on that in a minute, I promise) with Azithromycin has shown fantastic, albeit critics keep mentioning ‘anecdotal’ to describe the mountain, promise and I’ll explain why it does so well next. But forget straight-up plasma with antibodies, that might work early but if the patient is too far gone they’ll need more. They’ll need all the blood: antibodies and red blood cells. No help in sending over a detachment of ammunition to a soldier already unconscious and bleeding out on the battlefield, you need to send that ammo along with some hemoglobin-stimulant-magic so that he can wake up and fire those shots at the enemy.
Some piece of a fiction. Is it really scientific or a product of somebody’s imagination?
The iron is always bound to plasma proteins, and it is not such toxic and it can be given intravenously (Fe3+)
if you need it.
The article is unreferenced and I couldn’t find substantiation elsewhere.
Hi Shanti: It seems you are referring to this study:
https://chemrxiv.org/articles/COVID-19_Disease_ORF8_and_Surface_Glycoprotein_Inhibit_Heme_Metabolism_by_Binding_to_Porphyrin/11938173
They only researched that a virus can bind to porphyrin and enter the cell with it.
It can be toxic inside the cell. Not outside it flowing in blood.
They proposed that some drugs can inhibit that binding and prevent virus entering the cell.
Just a theory, for now.
But the damage is done by the virus itself because after it is inside the cell, that cell is doomed anyway.
it is only a matter how it manages to enter.
Hi ZdenekSipek,
if the above mentioned article has been deleted at medium.com I don’t know if it wise to reproduce it here, I believe a simple reference to archive .org suffices.
Best Regards
What is your opinion of this article and proposed mechanisms?
Any other functional combinations based on the hypothesis except for hydroxychloroquine + azithromycin + zinc?
Just using iron chelators – either synthetic or natural like quercetin, curcumin, EGCG, genistein, baicalein?
http://web.archive.org/web/20200405061401/https://medium.com/@agaiziunas/covid-19-had-us-all-fooled-but-now-we-might-have-finally-found-its-secret-91182386efcb
“The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro”
A single treatment able to effect ∼5000-fold reduction in virus at 48h in cell culture.
Thank you Asaf. We added this a few days ago in the list above.
Kind regards,
Daniel
FROM: “PARENTERAL ADMINISTRATION OF IVERMECTIN IN A PATIENT WITH DISSEMINATED STRONGYLOIDIASIS”
https://www.ncbi.nlm.nih.gov/pubmed/16282302
The dose were 15 mg for 70 kg
The pharmacokinetics of orally administered ivermectin in humans is well known. Fifty to sixty percent of ivermectin administered as a tablet or capsule is absorbed. Ivermectin is detectable in plasma within one hour and reaches peak levels ranging from 20 to 54.4 ng/mL 4–5 hours after a single dose of 200 mkg/kg
Assuming an absorption half-life in humans of approximately one day (extrapolated from animal data) and a relatively short elimination half-life of 12–56 hours, steady state should be reached within one week of multiple dosing.
5 micromol concentration = 4400 ng/ml
It is expected to take 1,5 grams to reach therapeutic dose
the problem it penetrates through blood brain barrier and causes blindness in dogs (when given in large doses)
Probably the same is in humans
Thank you Maxim for sharing very good information. Invermectin is a drug that draws my attention to treat brain tumors thanks to its ability to cross the brain blood barrier
https://www.ncbi.nlm.nih.gov/pubmed/27771251
It appears to be an angiogenesis inhibitor, modulate Akt and produce oxidative stress, something that may be relevant to complement other oxidative therapies …
Niclosamide
One study shows it’s maximum tolerated dose 500 mg –
A phase I study of niclosamide in combination with enzalutamide in men with castration-resistant prostate cancer
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198389
blood concentration is also low due to poor bioavailability
Results
20 patients screened and 5 enrolled after passing all screening procedures. 13(65%) patients had detectable CTCs, but only one was AR-V+. There were no dose-limiting toxicities (DLTs) in 3 patients on the 500mg TID cohort; however, both (N = 2) subjects on the 1000mg TID cohort experienced DLTs (prolonged grade 3 nausea, vomiting, diarrhea; and colitis). The maximum plasma concentration ranged from 35.7–82 ng/mL and was not consistently above the minimum effective concentration in preclinical studies. There were no PSA declines in any enrolled subject. Because plasma concentrations at the maximum tolerated dose (500mg TID) were not consistently above the expected therapeutic threshold, the Data Safety Monitoring Board closed the study for futility.
Hi Maxim,
t.i.d. means three times a day. According to the article you posted above, it means that some side effects can be experienced at 3000 mg/day.
I used Niclosamide at 1000 and 2000mg/day for a week with no side effects. Therefore, I would not expect serious side effects at 3000mg/day, but I would keep max 2000mg/day anyway.
It’s not well absorbed in the body and this is why it’s side effects are very limited.
Kind regards,
Daniel
Hi Daniel
Looks like side effects are mostly gastro intestinal – prolonged grade 3 nausea, vomiting, diarrhea; and colitis
Seems it’s local effects
but some people could be more susceptible.
Niclosamide, an old antihelminthic agent, demonstrates antitumor activity by blocking multiple signaling pathways of cancer stem cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777479/
This study says that its low toxicity because of low bio-availability:
Niclosamide has low toxicity in mammals (oral median lethal dose in rats >5000 mg/kg)[17], which is obviously associated with poor absorption
P.S. they prepared a phosphate of niclosamide (Synthesis of water-soluble p-niclosamide) for better bio-availability
Thanks Maxim. Btw, the nice thing about Niclosamide is that is sold as lozenge – typically medicated tablet intended to be dissolved slowly in the mouth which makes it even more suitable to address initial phase of COVID19 infection, if identified.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835698/
I think we have a new ally in many directions. Therapeutic laboratory concentrations are achievable with the stipulated doses in humans, something not achieved with other drugs such as fenbendazole, which has low bioavailability.
Totally agree. I like a lot Ivermectin and wanted to write a post on this one for long time …. but what to write on first?! so many interesting and relevant aspects … 🙂
Kind regards,
Daniel
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929173/
It does not seem to go through BBB and, if accessed, it seems to produce neurotoxicity, as Maxim previously commented
Ivermectin safety is well known. But it is indeed challenging for this specific case, when trying to get it to the brain in doses that may be relevant to brain tumors. Nevertheless, even that is a case that I would study carefully and see what is the dose that can still get to the brain without major side effects to the brain or to the whole body. There is enough literature on this to be able to get a good feeling on this.
Kind regards,
Daniel
Maybe some species are more susceptible to it
for example Lions
https://bmcvetres.biomedcentral.com/articles/10.1186/s12917-015-0603-6
or dogs
http://www.pethealthnetwork.com/dog-health/dog-diseases-conditions-a-z/ivermectin-toxicity-dogs
collies
https://www.ncbi.nlm.nih.gov/pubmed/11822811
german shepherd
https://www.ijcmas.com/6-11-2017/Sheikh%20Tajamul%20Islam2,%20et%20al.pdf
Of course Daniel! I have not ruled out this drug even though it seems very relevant to me 🙂
🙂
https://www.artsenauto.nl/msd-ivermectine-bij-covid-19-niet-geschikt/
Medicines company MSD has been producing ivermectin in Haarlem for more than thirty years, which is used for a medicine against river blindness and a medicine against, for example, scabies. In Australia, researchers using laboratory tests have found that ivermectin can kill the COVID-19 virus in two days. MSD spokesperson Jurgen Theissen tempered the expectations of the drug to fight the pandemic: “Our expert team of scientists assessing external studies of MSD drugs has calculated Australian research results and has concluded that for the same effect in humans, the dose should be at least a hundred times the dose that is currently approved and that we know is safe and well tolerated. “
Thanks Ovidiu. It’s clear the world is full of opinions at this point. We need to check the data in order to conclude.
The questions here is what are our options.
For someone dealing with COVID19 and with worsening conditions while not receiving medical attention, and receiving no other drugs, using Ivermectin at a dose that is known to be safe is a better choice in my view than doing nothing.
What would you do Ovidiu, if you would have to chose between Ivermectin or nothing?
Kind regards,
Daniel
@Daniel: why should I choose between Ivermectin and nothing, since I already bought Plaquenil, and there are other options, like Azithromycin?
There’s no point discussing Ivermectin anymore, you’d have better luck against Sars-CoV-2 with Opipramol at 200 mg (caution: 600 mg can be life threatening).
Ovidiu, as you argue against Ivermectin, there are many arguing about Plaquenil. I understand its your choice and perspective on this and I think its a good idea to stop this discussion indeed and move on.
Here’s a great talk on the subject, with a scientist who worked on ivermectin at merck:
https://www.virology.ws/2020/04/10/twiv-599-coronavirus-update-we-need-a-plan/
Thanks a lot Johan. This is very helpful one!
I like that through her statements, the MERK scientists (Dr. Doris Cully) demonstrates she is not biased while she is very balanced. Her approach and way of thinking is an example of true scientist – looking at facts in an unbiase manner and be open to new.
While the moderator seems a bit negatively biased towards Ivermectin stating that a too high dose would be required to active activity against Ivermectin in humans, the MERK scientists responds: “Well … we don’t know that”.
Important points Doris makes:
– at the current dose is very effective against the health challenges that is addressing “with little to no adverse effects seen” while it has been given in hundreds of million of doses in patients. Because of it’s effectiveness at these low doses (0.1 to 0.2mg/kg), higher doses have not been much tested. It is possible that you may get efficacy at higher dose.
– multiple days of doses were not used much in clinical trial (normally used once every year; in some cases once every two weeks) (sometimes used in the clinic once every other day in some cases). Due to its high lipid solubility, Ivermectin is widely distributed within the body and it’s going to accumulate in tissue. Multiple doses may help the accumulation to reach an effective local dose.
This is similar to the story of Metformin and so many others that have shown effectiveness not only in the lab but also in humans. However, based on the lab results and calculating the blood levels we would need to achieve, we should never use most of the (re purposed) drugs and supplements, and we should stop even speaking about them. But we do not stop because they do show effectiveness not only in the lab but also in real life.
Kind regards,
Daniel
@ovidiu
I wonder if tetracycline would be a better option (over azithromycin)? what do you think?
@johan: there’s one article about possibly using tetracyclines against Covid-19, but it’s speculation for now;
I suppose if a tetracycline would be effective, it would be part of the hits (and it’s not) in the Marseille in vitro study (which led to Dr. Raoult’s protocol)… well, assuming a tetracycline would be part of the Prestwick library that they tested against Sars-CoV-2.
Actually, I was surprised how good Azithromycin is in this case; I knew for a long time that it was useful against papilloma viruses, and more recently against the Zika virus, but it seems more effective (in vitro) than HCQ against Sars-CoV-2. I’ll put a link to the discontinued Zmax by Pfizer, maybe someone tells them to restart production:
http://labeling.pfizer.com/ShowLabeling.aspx?id=650
@ovidiu
thank you!
Here is an article about a doctor that hypothesized that Doxycycline is a better option than AZT.
“Doxycycline is an anti-inflammatory with properties similar to azithromycin but without the safety concerns and without cardiac toxicity,”
https://nypost.com/2020/04/04/long-island-doctor-tries-new-hydroxychloroquine-for-covid-19-patients/
@Johan: an article about in vitro Doxycycline against Sars-CoV-2 was published, and my take on it is that it’s promising, but they should have tested for synergy with HCQ.
https://www.mediterranee-infection.com/in-vitro-antiviral-activity-of-doxycycline-against-sars-cov-2/
Friends more information about aspirin. I assure you that this is more potent than ivermectin and hydroxychloroquine. Viral load is not the problem. The problem is the excessive immune response to the presence of the virus. You just have to fight severe inflammation and the rest is done by the patient’s body.
Antiviral activity of aspirin against RNA viruses of the respiratory tract — an in vitro study
Abstract
Aim
Aspirin (acetylsalicylic acid) has been used for more than 115 years in medicine. Research exists to show that aspirin has antiviral effects in vitro, for example, by blocking influenza virus propagation via NF ‐ κB inhibition when used at high concentrations and short ‐ term incubation steps. The aim of this study was to confirm the antiviral activity of aspirin against influenza virus and further elucidate the activity of aspirin against other respiratory viruses.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155651/
Dear Mario,
Thank you for sharing this study on Aspirin. It’s good to note that aspirin is yet another drug that is very effective against cancer. It has been used intravenously, in combo with another NSAID, at high dose, and demonstrated to be effective in inducing remissions in cancer patients. Some years ago I was in contact with a pancreatic cancer that experienced complete remission after intravenous Aspirin and Diflunisal. This subject has been discussed elsewhere on this website but it’s interesting to see how all these drugs are both antiviral and anticancer at the same time. This is something for us to keep in mind and I agree with you that there is good potential behind Aspirin.
In the paper you shared, the authors state that the anti-viral action of Aspirin is observed but it is not clear what is the mechanisms behind. I think it is possible to be related to the ER-stress. Here is a paper from an University in Brazil indicating the relation between ER-stress response and Aspirin. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569067/ And as we discussed before, interference with the ER during viral replication is one way the anti-viral drugs work https://www.cancertreatmentsresearch.com/from-cancer-to-coronavirus-therapeutic-strategy-based-on-the-similarities-between-cancer-and-virus-infected-cells/#comment-10133
Kind regards,
Daniel
Hello Daniel
I actually investigated this for aspirin due to a testimonial from one family (5 members) that all were infected with coronavirus (covid 19 confirmed by PCR examination). They took from those homemade recipes that we are used to here in Latin America: 3 aspirins mixed with lemon and honey (to make them easier to take). The experience they have is that everyone recovered without going to the hospital. The members of that family are the mother older than 75 years, the father older than 75 years, two men older than 50 years and a boy (grandson of unspecified age).
I thought it was important to share this, since there are regions that do not have access to medicines and that aspirin could help them.
Hi Mario,
Very nice to hear that. What was the dose of aspirin used/day and how many times/day, or all at once?
Kind regards,
Daniel
Daniel, they say they took three typical 500 mg pills in a single dose. Use was at a very early stage and they only used one dose in a single day. One of the cases, with more pronounced symptoms (He could not get out of bed) three hours after taking it, also felt that he got out of bed, and was the one who repeated the dose the next day. They found out it was covid 19 several days later when the test results for covid 19 arrived.
Have you not investigated the use of chlorine dioxide for cancer and for covid 19?
I leave you the website of its promoter:
https://andreaskalcker.com/coronavirus-informacion-especial-para-medicos-e-investigacion/
https://andreaskalcker.com/
Thanks a lot for the dose and the story behind! This is very helpful.
Regarding chlorine dioxide for COVID I did not had the chance to look into that yet. I am still “fighting” with the e-mails. But as soon as I have the time it will be my pleasure to read about it.
Indomethacin has a potent antiviral activity against SARS coronavirus
https://www.intmedpress.com/servefile.cfm?suid=35d8dc5e-70f4-491f-acad-e35f99be9211
Thank you Zdenek.
https://chemrxiv.org/articles/COVID-19_Disease_ORF8_and_Surface_Glycoprotein_Inhibit_Heme_Metabolism_by_Binding_to_Porphyrin/11938173
COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism
Too bad they can not support it with hemoglobin levels tests in patients who had COVID 19.
Patients, would obviously have low levels of hemoglobin in their blood.
First case of COVID-19 in a patient with multiple myeloma successfully treated with tocilizumab
https://ashpublications.org/bloodadvances/article/4/7/1307/454259/First-case-of-COVID-19-in-a-patient-with-multiple
Experimental research findings indicate that an excessive immune response and a strong cytokine storm, which may include high levels of granulocyte-macrophage colony-stimulating factor and interleukin-6 (IL-6), are activated in severe COVID-19.2 Here, we report the first case of COVID-19 in a patient with multiple myeloma (MM) successfully treated with the humanized anti–IL-6 receptor antibody tocilizumab.
P.S. Tocilizumab blocks the inflammatory protein IL-6
Why Some COVID-19 Patients Crash: The Body’s Immune System Might Be To Blame
https://www.npr.org/sections/health-shots/2020/04/07/828091467/why-some-covid-19-patients-crash-the-bodys-immune-system-might-be-to-blame
Interleukin-6 Use in COVID-19 Pneumonia Related Macrophage Activation Syndrome
https://www.researchgate.net/publication/340266188_Interleukin-6_Use_in_COVID-19_Pneumonia_Related_Macrophage_Activation_Syndrome
Is this understood as an individual response? or boosting the immune system as we are doing many can become a bad option?
That man did not have any fever at all. The temp was 36,6. He was not given any antivirals.
He was on thalidomide maintenance only, because he had multiple myeloma several years before.
Looks like even tocilizumab was redundant in this case.
And look, even poor health Harvey Weinstein recovered from it.
The worst comorbidities for COVID 19 are hypertension and diabetes.
P.S. i think that antivirals which everybody think are a cure is really of little help.
Immunomodulation can cure it better. (COX2 inhibitors, plus thalidomide)
One study proves that Thalidomide inhibits IL-6 production in vivo (humans)
https://www.ncbi.nlm.nih.gov/pubmed/17964516
and also in vitro
https://www.fertstert.org/article/S0015-0282(01)03097-7/fulltext
Maxim, I agree 100% with you, you should focus on inflammation, not antivirals.
On the other hand, niclosamide is antiviral and anti-inflammatory, the problem is its low absorption in the gastrointestinal tract. They are experiencing its use via the nose. But on the other hand there is a version of noclosamide in the form of salt: Niclosamide ethanolamine (NEN) salt that is much better absorbed than niclosamide alone.
I forgot to give the reference
Niclosamide repurposed for the treatment of inflammatory airway disease
Inflammatory airway diseases, such as asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD), are characterized by mucus hypersecretion and airway plugging. In both CF and asthma, enhanced expression of the Ca2+-activated Cl– channel TMEM16A is detected in mucus-producing club/goblet cells and airway smooth muscle. TMEM16A contributes to mucus hypersecretion and bronchoconstriction, which are both inhibited by blockers of TMEM16A, such as niflumic acid. Here we demonstrate that the FDA-approved drug niclosamide, a potent inhibitor of TMEM16A identified by high-throughput screening, is an inhibitor of both TMEM16A and TMEM16F. In asthmatic mice, niclosamide reduced mucus production and secretion, as well as bronchoconstriction, and showed additional antiinflammatory effects. Using transgenic asthmatic mice, we found evidence that TMEM16A and TMEM16F are required for normal mucus production/secretion, which may be due to their effects on intracellular Ca2+ signaling. TMEM16A and TMEM16F support exocytic release of mucus and inflammatory mediators, both of which are blocked by niclosamide. Thus, inhibition of mucus and cytokine release, bronchorelaxation, and reported antibacterial effects make niclosamide a potentially suitable drug for the treatment of inflammatory airway diseases, such as CF, asthma, and COPD.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693830/
Hi Mario. Indeed the challenge with Niclo is the absorption but the good aspect is that we find them as lozengez so they may help at least in the first phase of infection via a more direct contact with the infected areas.
Hi Mario
I did not mention Niclosamide there. I mentioned Thalidomide only, which is a quite different drug.
Another case supporting this view of Maxim and Mario that anti-inflammatory drugs alone may help overcome the COVID19 related challenges:
A Case of Coronavirus Disease 2019 Treated With Ciclesonide https://els-jbs-prod-cdn.jbs.elsevierhealth.com/pb/assets/raw/Health%20Advance/journals/jmcp/jmcp_ft95_4_7-1586530306960.pdf
and coadministration of antibiotics can prevent secondary bacterial infections.
Belgian-Dutch Study: Why in times of COVID-19 you should not walk/run/bike close behind each other.
https://cancerjourneysfoundation.org/safe-running-and-cycling-distance-in-the-age-of-covid-19/
Curious, if mild hyperthermia (<40C) done before major symptoms, but right after positive diagnosis may help for better outcomes.
This may indeed help. (I think you meant whole body hyperthermia as done in cancer clinics.)
Kind regards,
Daniel
Yep, whole body of course.
And if that helps, those who can’t rely on clinics due to overload may try to use hot water bath at home.
Best Regards
Asaf
Some people can be cured without producing antibodies to the virus. https://www.medrxiv.org/content/10.1101/2020.03.30.20047365v1
Maybe it can go latent inside the cells instead of a cure?
https://www.bloomberg.com/news/articles/2020-04-09/coronavirus-may-reactivate-in-cured-patients-korean-cdc-says
Sorry for asking… Anyone in this comment section know where you can get niclosamide? In Europe or close. It seems it could be potentially helpful, for both coronavirus and cancer.
Dear Myra,
One option is this brand at German pharmacies https://www.medizinfuchs.de/preisvergleich/yomesan-4-st-bayer-vital-gmbh-gb-pharma-pzn-1140720.html You can probably find the same brand in other countries.
However, this may be too expensive, so I bought mine from Thailand from sources such as this one http://smartproduct4u.com/?ref=285
Kind regards,
Daniel
Thank you, the German site seems to be the best place for me to buy it.
What is the exact dosage to take for cancer benefits?
Best regards,
Myra
Hi Myra,
I would need to investigate the subject closer to have a more informed response on your question. But based on the information I have at this point, I would consider the typical admin protocol that is 2000mg/day in the first day and 1000mg/day during the next 6 days. After that I would take a brake of one week and restart. I would move forward with this dose, one week ON and one week OFF. A little bit similar approach with that used for Fenbendazole but with longer ON/OFF cycles. Taking it with a bit of alcohol may increase it’s absorption.
Kind regards,
Daniel
Dear Daniel: I bought Niclasamide from a Chinese supplier. I bought it as raw material. I bought ethanolamine salt of niclosamide.
The advantage of niclosamide salt is that it is more bioavailable, absorbing up to 33% at the gastrointestinal level.
That is very nice Mario, but make sure you have exactly what you ordered. My experience with ordering from China is positive but I know others who received something else vs. what they ordered.
Kind regards,
Daniel
Hello Daniel: You have the voice of a prophet, these Chinese are definitely bandits without a mask. I paid them the product and now they tell me that that was not the price that I must pay a surplus.
Hi Daniel, how long time did it take for you to receive your order?
https://www.medrxiv.org/content/10.1101/2020.04.08.20057794v1
“Conclusions: Age and comorbidities are powerful predictors of hospitalization; however, admission oxygen impairment and markers of inflammation are most strongly associated with critical illness.”
China’s Data on Symptom-Free Cases Shows Most Never Get Sick
https://www.bloomberg.com/news/articles/2020-04-15/china-s-data-on-symptom-free-cases-reveals-most-never-get-sick
“Among 6,764 people who tested positive for infection without showing symptoms, only one fifth of them — 1,297 — have so far developed symptoms and been re-classified as confirmed cases, China’s National Health Commission spokesman Mi Feng said at a briefing in Beijing Wednesday.”
BTW, Is worldwide per country stat on seasonal flu vaccination for 2019 available online?
Maybe the virus is inside and waits for reactivation trigger.
Another interesting finding after antibody detection kits test started:
https://tass.ru/obschestvo/8272305
Looks like, here is more panic than the real problem.
Another similar article https://news.mail.ru/incident/41429081/
31 out of 155 and no sign of the real disease.
Maybe i had it too, but don’t know it.
another possibility that the antibody tests are testing for something close but not the real coronavirus.
There are multiple antibodies and some can be the same even on different viruses if they have the same type of proteins.
Pentagon tested sailors of the aircraft carrier Theodore Roosevelt.
600 was positive, but 60% of them don’t have any signs of the disease.
Looks like all the lockdowns are more a problem than the cause. And in the end
it won’t prevent spreading of the virus.
Another article https://cmr.asm.org/content/20/4/660 (albeit old and dedicated to SARS) gives the clue that the damage in the lungs is done not by viral load but by inflammation. That inflammation is specific to the lungs, because virus particle can enter pneumocyte and they can activate macrophages which produce a large amount of cytokines:
No tissue destruction or severe inflammatory process associated with viral infection was noted in other organs or tissues, but viral particles could be detected in pneumocytes and enterocytes by in situ hybridization (331). Inflammation,cellular apoptosis, or microvillus atrophy of a significant degree was not found in the intestinal mucosa to account for the watery diarrhea. Immunohistochemical staining showedthe presence of viral nucleoproteins in type II pneumocytes and occasionally pulmonary macrophages. Necrosis or atro-phy in the lymphoid tissue of lymph nodes and white pulp ofthe spleen are commonly observed extrapulmonary pathologies.
Paradoxically, little cytopathic effect or inflammation was found in intestinal biopsy specimens of SARS patients despite marked viral replication seen with electron microscopy (205).
IP10 expressed on pneumocytes is a potent chemoattractant for activated cytotoxic T lymphocytes, natural killer cells, and mono-cytes, which may therefore infiltrate the interstitium and alveoli of lungs of SARS patients.
CONCLUSION: ONLY in the lungs which have pneumocytes the damage is high. the Other organs even with high viral load are not significantly damaged.
and another related article “Influenza A Viruses Target Type II Pneumocytes in the Human Lung ”
https://academic.oup.com/jid/article/206/11/1685/895991
Background. Highly pathogenic avian H5N1 influenza viruses preferentially infect alveolar type II pneumocytes in human lung. However, it is unknown whether this cellular tropism contributes to high viral virulence because the primary target cells of other influenza viruses have not been systematically studied.
The pneumocytes seems to be involved in different lungs pathology.
“Involvement of type II pneumocytes in the pathogenesis of chronic obstructive pulmonary disease”
https://www.resmedjournal.com/article/S0954-6111(10)00297-0/fulltext
https://www.sciencedirect.com/science/article/pii/S0264410X19313647
“Influenza vaccination and respiratory virus interference among Department of Defense personnel during the 2017–2018 influenza season”
“On the other hand, recently published studies have described the phenomenon of vaccine-associated virus interference; that is, vaccinated individuals may be at increased risk for other respiratory viruses because they do not receive the non-specific immunity associated with natural infection [7], [8], [9], [10]. There has been limited evidence that the influenza vaccine may actually be associated with the virus interference process [8], [11]. Other studies have found no association between influenza vaccination and increased respiratory virus risk [10], [12].”
Conclusions
…
Vaccine derived virus interference was significantly associated with coronavirus and human metapneumovirus; however,
…
Extensive flu vaccination done in many countries might worsen the pandemic outcome?
2019/12/14 Influenza, «boom» di vaccinazioni
https://www.bresciaoggi.it/territori/città/influenza-boom-di-vaccinazioni-1.7834787
EPA fatty acid + Artemisia Annua extract in clinical trials for COVID19 https://www.nutritioninsight.com/news/fatty-acid-and-sweet-wormwood-on-road-to-clinical-trials-for-covid-19.html
Multidrug treatment with nelfinavir and cepharanthine against COVID-19
https://www.biorxiv.org/content/10.1101/2020.04.14.039925v1
Latest study by Didier Raoult’s team:
EARLY TREATMENT OF 1061 COVID-19 PATIENTS WITH HYDROXYCHLOROQUINE AND AZITHROMYCIN, MARSEILLE, FRANCE
https://www.mediterranee-infection.com/early-treatment-of-1061-covid-19-patients-with-hydroxychloroquine-and-azithromycin-marseille-france/
Thank you for the update, Ovidiu! Nice results!
A new study identifying a long list of repurposed drugs with anti-COVID19 potential:
Network Medicine Framework for Identifying Drug Repurposing Opportunities for COVID-19 https://arxiv.org/pdf/2004.07229v1.pdf
Here is the list of identified drugs:
Isoniazid, Troleandomycin, Cilostazol, Chloroquine, Rifabutin, Flutamide, Dexamethasone, Rifaximin, Azelastine, Folic Acid, Rabeprazole, Methotrexate, Digoxin, Theophylline, Fluconazole, Aminoglutethimide, Hydroxychloroquine, Methimazole, Ribavirin, Omeprazole, Bortezomib, Leflunomide, Dimethylfumarate, Colchicine, Quercetin, Mebendazole, Mesalazine, Pentamidine, Verapamil, Melatonin, Griseofulvin, Auranofin, Atovaquone, Montelukast, Romidepsin, Cobicistat, Lopinavir, Pomalidomide, Sulfinpyrazone, Levamisole, Calcitriol, Interferon-β-1a, Praziquantel, Ascorbic acid, Fluvastatin, Interferon-β-1b, Selegiline,, Deferoxamine, Ivermectin, Atorvastatin, Mitoxantrone, Glyburide, Thalidomide, Sulfanilamide, Hydralazine, Gemfibrozil, Ruxolitinib, Propranolol, Carbamazepine, Doxorubicin, Levothyroxine, Dactinomycin, Tenofivir, Tadalafil, Doxazosin, Rosiglitazone, Aminolevulinic acid, Nitroglycerin, Metformin, Nintedanib, Allopurinol, Ponatinib, Sildenafil, Dapagliflozin, Nitroprusside, Cinacalcet, Mexiletine, Sitagliptin, Carfilzomib, Azithromycin
Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19
https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v1.full.pdf
CONCLUSIONS: In this study, we found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone. These findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs.
Maybe the HQ treatment was based on the severity, but anyway it does not help if you have a serious disease.
If Covid-19 progresses to the severe form, it may trigger hypokalemia, and this is a risk factor for QT prolongation from HCQ. Anyway, we already knew that HCQ and AZM should be given early, to prevent progression to the severe phase.
I know that I wrote that’s no point to discuss Ivermectin anymore, but some new info emerged. The official FDA position on the matter, and an article which tries to discuss the possible use.
https://www.fda.gov/animal-veterinary/product-safety-information/faq-covid-19-and-ivermectin-intended-animals
Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view
https://www.medrxiv.org/content/10.1101/2020.04.11.20061804v1.full.pdf
However, Ivermectin might be useful at the normal dose, in managing the symptoms of the severe phase of Covid-19. There was a preprint, which was withdrawn in the mean time, and a report of a doctor using it (dosage not mentioned) in combination with HCQ and AZM.
https://www.nbcmiami.com/news/local/local-doctor-tries-new-coronavirus-drug-treatment/2219465/
Hi Ovidiu,
Thanks for the update and for balancing your post, addressing both challenges and potential.
Kind regards,
Daniel
The paper re-appeared, here is the link, they used a rather low dose (I took Ivermectin at double that dose some 11 years ago).
https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3580524
Gilead antiviral drug remdesivir flops in first trial
Exclusive: Disappointing results revealed in draft documents published accidentally by WHO
https://www.ft.com/content/0a4872d1-4cac-4040-846f-ce32daa09d99
The Chinese trial showed remdesivir — developed by California-based Gilead Sciences — did not improve patients’ condition or reduce the pathogen’s presence in the bloodstream. Researchers studied 237 patients, giving the drug to 158 and comparing their progress with the remaining 79. The drug also showed significant side effects in some, which meant 18 patients were taken off it.
https://www.cell.com/pb-assets/products/coronavirus/CELL_CELL-D-20-00767.pdf
SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues
Several studies show that NETs (Neutrophil extracellular traps) are the source of problems in COVID 19 infections.
Neutrophil extracellular traps in COVID-19 (https://insight.jci.org/articles/view/138999)
Targeting potential drivers of COVID-19: Neutrophil extracellular traps (https://rupress.org/jem/article/217/6/e20200652/151683/Targeting-potential-drivers-of-COVID-19-Neutrophil)
They are causing thrombosis – Propagation of thrombosis by neutrophils and extracellular nucleosome networks (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5286929/)
NETosis can also be detected in viral infections and various viruses (such as influenza and human immunodeficiency virus-1) are able to induce the formation of NET, which may bind and thereby neutralize viruses.
Also NETs involved in Leprosy 2 reactions and can be effectively inhibited by thalidomide
Neutrophil extracellular traps contribute to the pathogenesis of leprosy type 2 reactions (https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0007368)
The apparently in vivo inhibitory effect of thalidomide on NETs production in T2R patients observed both at the lesion site (Fig 1B) and in peripheral neutrophils (Fig 3) raised the hypothesis that the drug might be acting directly in this process.
P.S.
Interestingly, a study by Lapponi et al. (2013) observed no inhibitory effect of dexamethasone on NET formation, both in vitro in isolated human neutrophils, as well as in vivo using a mouse model of peritonitis [29].
Also goo to read: Novel cell death program leads to neutrophil extracellular traps (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063942/)
Anoner good to read: Neutrophil extracellular traps drive inflammatory pathogenesis in malaria (https://immunology.sciencemag.org/content/4/40/eaaw0336)
This is a full text article of the above: https://edoc.hu-berlin.de/bitstream/handle/18452/20563/dissertation_knackstedt_sebastian_lorenz.pdf
Once neutrophils reach their destination they activate various components of their arsenal to combat the infectious agent. Neutrophils produce proinflammatory cytokines to recruit additional immune cells and contribute to microbial clearance through degranulation, production of reactive oxygen species (ROS) and formation of neutrophil extracellular traps (NETs) (Fig.4). These mighty antimicrobials are however indiscriminate in their destructive potential, destroying microbes and host tissue alike (Amulic, Cazalet et al. 2012).
….
Unfortunately, excessive or systemic NET formation and impaired degradation of NETs are associated with exacerbated immune responses and can lead to tissue injury (Liu, Su et al. 2016) and unwanted coagulation and thrombus formation (Kaplan and Radic 2012). Interestingly,this effect has been described both in non-infectious autoimmune as well as in infectious settings, some of which are described below.
Another one: The double-edged role of neutrophil extracellular traps in inflammation. (https://www.ncbi.nlm.nih.gov/pubmed/31754705)
“In sickness and in health” – how neutrophil extracellular trap (NET) works in infections, selected diseases and pregnancy https://journal-inflammation.biomedcentral.com/articles/10.1186/s12950-019-0222-2
Influenza type A virus is another virus that can induce NETosis.
The virus is associated with ARDS (acute respiratory distress syndrome) which causes NET formation following activation of epithelial cells of the lungs [47]. Other inducers of NETosis include oxidoreductases active in infection, super-oxidized ions and H2O2, from epithelial cells [43]. Hantaan virus also generates NET release and the cytotoxic properties of the network may exacerbate pathological changes of the organism induced by the virus infection [48]. NET histones generated in Hantaan virus infection facilitate thrombin generation and intravascular coagulation. They increase the permeability of vascular endothelial cells and induce production of antibodies thus exacerbating the pathological condition caused by the virus [48]. NS1 (non-structural protein 1) is the key protein that activates NETosis in Dengue virus infection [49]. The protein activates cells that have not been infected, including endothelial cells, via TLR4. As a result, endothelial cells stimulate neutrophils to form NETs. IL-8 produced by activated endothelial cells facilitates NET.
By the way, chloroquine reduces Neutrophil Extracellular Trap Formation too –
Enhanced Neutrophil Extracellular Trap Formation in Acute Pancreatitis Contributes to Disease Severity and Is Reduced by Chloroquine
https://www.frontiersin.org/articles/10.3389/fimmu.2019.00028/full
This action probably reduces chances of the disease (COVID 19) to grow into severe form
Chlorine dioxide is working very well to fight the coronavirus, its promoter Andreas Kalcker and doctors in Spain, Colombia and Ecuador have already tested it with an effectiveness of 97% in patients up to 40% oxygen saturation. Here is a video where he explains why it works:
https://lbry.tv/@AndreasKalcker:f/ClO2—Simple-and-effecitive-coronavirus-treatment:0
Hi!
About trombosis and my case:
I am not sure, what I had last month, as I am battling with stage 4 BC. But usually my d-dimer was within norms. My d-dimer suddenly jumped to 30mg/L (~30 000 microg/L). I started enoxaparinum injections. D-dimer dropped to 5 mg/L now. Last month I felt good, just some fever outbreaks every 5-10 days. But no more fever last 1,5 weeks. So I think maybe it was corona. Alsomy daughter had one night very high fever and chest pain, even could not swallow water. But just for 1 day. I also had chest angio ct and liver MRT, so every thing within norms. Massive multiple liver mets were srinking (I am on off label + Avastin+ Xeloda).
I also took zinc every day and Hydroxychloroquine 1 week every day, then 1 tablet per week.
I can say that this was very strange medical situation.
In the end of march I get sick with fever and high temp, cough and also loss of smell, but not taste. My covid19 test result was negative. So I thought I was battling with some other virus.
Hi Ieva,
I am glad to hear the liver mets were shrinking!
Do you feel the shrinkage of the mets happened due to Avastin+Xeloda alone or something else either related to Zinc+HCQ pr some infection you encountered?
Kind regards,
Daniel
Kind regards,
Daniel
Daniel,
The full story of my liver mets: discovered in 2017 sep, then carbo+docetaxel, then shrinkage, but still there. Then 2018 august/sept liver sirtex for both globes for multiple mets. Pet/ct in 2019 jan was clear. June 2019 few new liver mets – went on laser thermal ablation for 3 mets. This resulted in pneumotorax and also promoted massive new multiple mets in liver in MRI august 2019. Xeloda+Avastin started in sep 2019 – drop in markers and shrinkage of liver mets. But bones continue to full fill with mets. There is something new in medial lymph nodes. And markers are not constant, they go up and down. Ca153 is around 300IU/mL, but CEA around 200IU/mL.
From off label I take metformin, simvastatin, dipyridamole, Loratadin, Mebendazole, broccoli seeds extract (sulforaphane), resveratrol, vit D, mk7, so I am not on something special. And now also Zinc and Hydroxychloroquine (last two from end of march).
As my liver MRT showed shrinkage before Zinc and Hydroxychloroquine, I suppose that big guns are Avastin+Xeloda and plus off label. I am not sure about metformin with Xeloda – I must take Xeloda 2 weeks on 1 week off.
But what about Metformin – it puts cancer cells to sleep. So maybe I must go off metformin in these two weeks while on Xeloda?
kindly,
i.
I forgot Melatonin 40mg every night
Hi Ieva,
Thank you for the response.
I never like the thermal ablation due to the risks related to mets. Or at lease it needs to be strongly supported by anti-metastasis drugs and supplements.
It’s a little challenging to create a dynamic strategy when the chemo is oral and taken each day. In this case, if I would want to try and maximise the effectiveness, an idea could be to stop Metformin a few days prior to Day1 of Xeloda, and start again with Day1 of Xeloda. Btw, have you considered to pulse some of the repurposed drugs and supplements mentioned in the last post (on Pro-oxidant strategy)?
Kind ergards,
Daniel
Apologies for the delayed response. Wouldn’t a course of Doxycycline + Azythromycin stop/reduce incidences of new metastasis?
Hi!
In Russia doctors don’t believe the COVID 19 tests, they fail so often that they rely mostly on CT imaging results (a doctor in the hospital said it – my uncle in there with pneumonia).
I think that the virus is the same only the test is unreliable.
2 More Studies Throw Cold Water on Hydroxychloroquine as COVID-19 Treatment
https://www.usnews.com/news/health-news/articles/2020-05-15/2-more-studies-throw-cold-water-on-hydroxychloroquine-as-covid-19-treatment
The issue of HCQ has been politicized, because Trump endorsed it. I would take any mainstream media news on the matter with a spoon of salt… However:
Treatment Response to Hydroxychloroquine, Lopinavir–Ritonavir, and Antibiotics for Moderate COVID-19: A First Report on the
Pharmacological Outcomes from South Korea
https://www.medrxiv.org/content/10.1101/2020.05.13.20094193v1.full.pdf
https://www.scmp.com/news/hong-kong/health-environment/article/3084779/coronavirus-hamster-research-proof-effectiveness
Coronavirus: hamster research shows effectiveness of masks ‘huge’ in Covid-19 battle, Hong Kong scientists say
“After seven days, 10 out of 15 healthy hamsters, or 66.7 per cent, placed in cages with no partition had become infected. But when surgical mask barriers were placed on the infected hamsters’ side, only two of 12 subjects in the adjoining cage, or 16.7 per cent, tested positive for the coronavirus.
The study also found that hamsters infected with Covid-19 via direct injection had more severe symptoms than those that contracted it through the mask partitions. The latter group experienced lower clinical scores, milder histopathological changes, and lower viral loads in respiratory tract tissues.”
Thanks for posting this Johan! Mask use in the US is often debated, even though the CDC has suggested all persons use one while in public areas.
I don’t go outside without my N95! It’s a nasty virus, my neibourgh, an MD, 44, has been hospitalized for almost week now. Take care!
Doxycycline And Ivermectin Combo:
https://medicaldialogues.in/medicine/news/doxycycline-and-ivermectin-combo-may-be-new-effective-covid-19-treatment-65868
https://www.theguardian.com/world/2020/jun/03/covid-19-surgisphere-who-world-health-organization-hydroxychloroquine
Surgisphere: governments and WHO changed Covid-19 policy based on suspect data from tiny US company
Thanks asafsh. I saw this one too … amazing what politics can do out of science, no? Representative of the world we live in.
Kind regards,
Daniel
Dear Daniel, unfortunately.
More data in favor or Ivermectin: https://www.medrxiv.org/content/10.1101/2020.06.06.20124461v2
ICON (Ivermectin in COvid Nineteen) study: Use of Ivermectin is Associated with Lower Mortality in Hospitalized Patients with COVID19
Patients in the Ivermectin group received at least one oral dose of ivermectin at 200 micrograms/kilogram in addition to usual clinical care.
Abstract
Abstract Importance: No therapy to date has been shown to improve survival for patients infected with SARS-CoV-2. Ivermectin has been shown to inhibit the replication of SARS-CoV-2 in vitro but clinical response has not been previously evaluated. Objective: To determine whether Ivermectin is associated with lower mortality rate in patients hospitalized with COVID-19. Design and Setting: Retrospective cohort study of consecutive patients hospitalized at four Broward Health hospitals in South Florida with confirmed SARS-CoV-2. Enrollment dates were March 15, 2020 through May 11, 2020. Follow up data for all outcomes was May 19, 2020. Participants: 280 patients with confirmed SARS-CoV-2 infection (mean age 59.6 years [standard deviation 17.9], 45.4% female), of whom 173 were treated with ivermectin and 107 were usual care were reviewed. 27 identified patients were not reviewed due to multiple admissions, lack of confirmed COVID results during hospitalization, age less than 18, pregnancy, or incarceration. Exposure: Patients were categorized into two treatment groups based on whether they received at least one dose of ivermectin at any time during the hospitalization. Treatment decisions were at the discretion of the treating physicians. Severe pulmonary involvement at study entry was characterized as need for either FiO2 ≥50%, or noninvasive or invasive mechanical ventilation. Main Outcomes and Measures: The primary outcome was all-cause in-hospital mortality. Secondary outcomes included subgroup mortality in patients with severe pulmonary involvement and extubation rates for patients requiring invasive ventilation. Results: Univariate analysis showed lower mortality in the ivermectin group (25.2% versus 15.0%, OR 0.52, 95% CI 0.29-0.96, P=.03). Mortality was also lower among 75 patients with severe pulmonary disease treated with ivermectin (38.8% vs 80.7%, OR 0.15, CI 0.05-0.47, P=.001), but there was no significant difference in successful extubation rates (36.1% vs 15.4%, OR 3.11 (0.88-11.00), p=.07). After adjustment for between-group differences and mortality risks, the mortality difference remained significant for the entire cohort (OR 0.27, CI 0.09-0.85, p=.03; HR 0.37, CI 0.19-0.71, p=.03). Conclusions and Relevance: Ivermectin was associated with lower mortality during treatment of COVID-19, especially in patients who required higher inspired oxygen or ventilatory support. These findings should be further evaluated with randomized controlled trials.
HI Shanti,
Thank you. Great to see this for two reasons:
– positive results at a normal dose (relatively low compared to what can be used and still safe)
– a more fundamental one: it shows again that just measuring the achievable blood level of a drug and comparing with the dose used in the lab to kill a virus or cancer cells is not enough to be able to anticipate effectiveness. In other words, much lower blood levels vs. lab tests can still be effective in humans (as it has been shown with so many others drugs). This is why, if a drug or supplement has potential and comes with less risks compared to the disease itself, I would try it if I don’t have a better option.
Kind regards,
Daniel
Very important observation regarding lower than “effective” dose, Daniel! Already quite a few studies are showing equal or even better results at lower doses of chemo. Add to that the benefit of lower toxicity. Same with supplements, if the “effective” dose is out of reach, look for synergies.
Yes Johan. Very good point indeed. Synergies will further help to increase effectiveness.
Kind regards,
Daniel
@Daniel: this has nothing to do with the theoretical anti-viral properties of Ivermectin. The conclusions state this:
“Ivermectin was associated with lower mortality during treatment of COVID-19, especially in patients who required higher inspired oxygen or ventilatory support”. Those patients who required high flow oxygen, or ventilator support, are always in the severe phase of the disease, when any anti-viral isn’t helping much. On the other hand, as I mentioned earlier, Ivermectin has a protective effect on the lungs (and possibly other organs too?).
Anti-inflammatory Effects of Ivermectin in Mouse Model of Allergic Asthma. PMID: 21279416
“Ivermectin at 2 mg/kg significantly diminished recruitment of immune cells, production of cytokines in the bronchoalveolar lavage fluids … Histological studies indicated that ivermectin suppressed mucus hypersecretion by goblet cells in the airway.”
@Ovidiu Thanks for adding your perspective.
PERSPECTIVEVIEWPOINT: COVID-19 Can existing live vaccines prevent COVID-19?
https://science.sciencemag.org/content/368/6496/1187
Very interesting … considering the similarities between viruses and cancer cells, vaccination with live attenuated virus vaccines may have an impact on cancer. We see new generation oncolytic viruses, applications with Zika virus, polio, measles … etc. All of them modified but … and if the old vaccines offer therapeutic impact anyway?
Pre exposure Hydroxychloroquine use is associated with reduced COVID19 risk in healthcare workers
https://www.medrxiv.org/content/10.1101/2020.06.09.20116806v1
Does not specify the dosage though, so I had to search a bit, and it seems the recommended prophylactic dosage in India is 400 mg twice daily on the first day, followed by 400 mg once weekly.
Thanks, ovidiu. A lot of good data coming out of India it seems.
“Seat Belts and Face Masks”: https://www.calculatedriskblog.com/2020/06/seat-belts-and-face-masks.html
Hi @Daniel
Do you know where can be bought ivermectin online? The Thai shop sell it but it cost 100 €,…
Thank you
Hi Inabari,
I actually order it for myself from that Thai shop and after 3 months I still did not get the package … I know its challenging with sending packages around the world but this is too much. So I would not order again from that (if we are speaking about the same). I was always happy with the buypharm and I see they have it. Here is one they have with more capsules, but there are a few more available as I’ve seen https://www.buy-pharma.md/Ivermectin-p-2729.html
If this doesn’t work please let me know and I will send you another one.
Kind regards,
Daniel
Hi Daniel,
Is this case the problem is the shipping countries are limited, and they don’t ship to Spain.
If you could share another link i´d be great.
Kind regards,
Inaki
Hi Inabari,
I do not know if they ship to Spain, but they have Ivermectin https://www.inhousepharmacy.vu/. I have used this pharmacy a few times over the years with no trouble.
Thank you Shanti! Following your comment I just added this one to the list on this website under “suppliers”.
Kind regards,
Daniel
HI Inaki,
I will send the other one to u just in case.
Kind regards,
Daniel
Does anyone know if it’s possible to buy Camostat from Japan, without a prescription? I found a site, it’s cheap, but I bet they require a prescription…
https://bio-japan.net/camostat-tablets-100mg
Hi Ovidiu, it may be a good idea to ask Dr. Hada. Kind regards, Daniel
Hello,
How can Ivermectin be more efficient, have better bioavailability ?
– With empty stomach ?
– After a meal that contains fat ? (um, statins doesn’t help his absorption in this case ?) I check his point and see that there isn’t known problem “but it doesn’t mean they don’t exist”.
https://www.drugs.com/interactions-check.php?drug_list=3167-0,1407-0
For animals and against virus, it’s OK with meals. But against cancer ? Chemo are often more efficient with empty stomach…
Good luck to everyone !
Half a year ago we were discussing Ivermectin as a potential solution to COVID.
Here is a very interesting video where Pierre Kory, M.D., Associate Professor of Medicine at St. Luke’s Aurora Medical Center, delivers passionate testimony during the Senate Homeland Security and Governmental Affairs Committee hearing on the high effectiveness of Ivermectin against COVID https://www.youtube.com/watch?v=Tq8SXOBy-4w
Again this demonstrated that the subjects addressed on this website are ahead of their time.
Here is the preprint of the article by Pierre Kory et al.: Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19 https://osf.io/wx3zn/?fbclid=IwAR3eqil6nDsaD96QRDosGgjPF9JO_fbz1BVkiL8GuiibzIfdc_LT156INYI
Exactly Daniel.
Unfortunately, the situation in the Czech Republic is bad due to many government mishaps. It´s from one partial lockdown to the next. Schools and factories being especially dangerous. The medical system is “holding” only due to staff being constantly working overtimes for months, people slowly collapsing under pressure, despite redundancies in facilities and equipment…but many doctors and nurses fell ill and a few died.
Academia is failing us and the official protocol used in hospitals is flawed. Casulties have been between 100-200/day since October (among the worst in the world).
The government is unable to even recommend D3 to people and their only goal is to keep corporate factories running.
GPs are mostly unable to recommend anything beyond paracetamol and hospital doctors mostly don´t understand the sequences of Covid-19 as described by The FLCCC Alliance (led by Marik and Kory) and still treat with almost useless remdesivir and favipiravir even when viral replication phase is over and pulmonary inflammation advancing, applying steroids too little and too late, limiting supporting care to ATBs + IVC + low dose D3 even in the best of cases.
Of course, I-MASK+ protocol (https://www.evms.edu/media/evms_public/departments/internal_medicine/EVMS_Critical_Care_COVID-19_Protocol.pdf)
is obscurity to them and their knowledge of ivermectin is close to zero…being it something to kill worms in pigs and horses.
Meanwhile, it is more and more clear to me how viral infections and cancer are in many ways similar – metabolically for sure (https://www.nature.com/articles/s42255-020-0237-2) and how inflammation is again a critical factor in prognosis.
Ivermectin is not even registered for humans in the Czech Republic (only as an anti-inflammatory cream), so I got it in drops for rodents from Hungary (using it for prophylaxis when having a risk exposure – 10mg dose).
Personally, I might have a mild case of Covid-19 in September – little fatigue, very short extreme sore throat and a long and equally extreme runny nose and cold (3 weeks) but not confirmed by test. (Took what my sistser is taking + Scutellaria 3*800mg).
Sister has it as we speak – antigen test positive on 23.12., PCR tomorrow.
Her protocol: quercetin 3*750mg + bromelain, EGCG 3*320mg, C – 6*1000mg, D3 8000IU, berberine 3*500mg, resveratrol 250mg + bioperine 10mg, NAC 2*600mg, B, zinc 75mg, selen 100ug, magnesium, Omega3 – 2000+mg, cordyceps 3*1000mg, melatonin 20mg, aspirin 100mg. Symptoms are mild – fatigue, temperature 37.5 in the afternoon, little sore throat. No ivermectin as she doesn´t have it (living 100km away).
In my opinion, there is no interest to use ivermection or I-MASK+ because of health business. Kory received nothing but lip service in the Senate and NY Times hurried to denunciate his work.
https://www.nytimes.com/2020/12/07/us/politics/ron-johnson-coronavirus.html?ref=oembed
Meanwhile, in Uttar Pradesh
https://twitter.com/drakchaurasia
Anyways,
The best of health to everybody and as happy and successful 2021 as possible!
https://www.youtube.com/watch?v=bJZcDBTEGio
https://www.youtube.com/watch?v=xy8XcBodQv0
The Possible Role of Vitamin D in Suppressing Cytokine Storm and Associated Mortality in COVID-19 Patients
https://www.medrxiv.org/content/10.1101/2020.04.08.20058578v4
“Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456194/
Vitamin D and survival in COVID-19 patients: A quasi-experimental study
https://www.sciencedirect.com/science/article/pii/S096007602030296X?via%3Dihub
Study finds over 80 percent of COVID-19 patients have vitamin D deficiency
https://www.endocrine.org/news-and-advocacy/news-room/2020/study-finds-over-80-percent-of-covid19-patients-have-vitamin-d-deficiency
Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231123/
Immunologic Effects of Vitamin D on Human Health and Disease
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400911/
Thank you Zdenek for sharing your views, the protocol and the links. Very helpful! Yes, a crazy World … we just have to keep our motivation, goals, and do the best we can to the best of our knowledge. To the protocol I would also add 6g Vitamin C/day, one gram every hour for 6 hours, at least a few days as we feel the virus is in.
Have a very Happy 2021!
Daniel
“L-Carnitine Tartrate Downregulates the ACE2 Receptor and Limits SARS-CoV-2 Infection ”
“In this study, we show that L-carnitine tartrate supplementation in humans and rodents led to significant decreases of key host dependency factors, notably angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), and Furin, which are responsible for viral attachment, viral spike S-protein cleavage, and priming for viral fusion and entry. Interestingly, pre-treatment of Calu-3, human lung epithelial cells, with L-carnitine tartrate led to a significant and dose-dependent inhibition of the infection by SARS-CoV-2. Infection inhibition coincided with a significant decrease in ACE2 mRNA expression levels. ”
https://pubmed.ncbi.nlm.nih.gov/33919991/
Thank you! Very good to know this!
Efficacy of broccoli and glucoraphanin in COVID-19: From hypothesis to proof-of-concept with three experimental clinical cases
“COVID-19 is described in a clinical case involving a patient who proposed the hypothesis that Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-interacting nutrients may help to prevent severe COVID-19 symptoms. Capsules of broccoli seeds containing glucoraphanin were being taken before the onset of SARS-CoV-2 infection and were continued daily for over a month after the first COVID-19 symptoms. They were found to reduce many of the symptoms rapidly and for a duration of 6–12 h by repeated dosing. When the patient was stable but still suffering from cough and nasal obstruction when not taking the broccoli capsules, a double-blind induced cough challenge confirmed the speed of onset of the capsules (less than 10 min). A second clinical case with lower broccoli doses carried out during the cytokine storm confirmed the clinical benefits already observed. A third clinical case showed similar effects at the onset of symptoms. In the first clinical trial, we used a dose of under 600 μmol per day of glucoraphanin. However, such a high dose may induce pharmacologic effects that require careful examination before the performance of any study. It is likely that the fast onset of action is mediated through the TRPA1 channel. These experimental clinical cases represent a proof-of-concept confirming the hypothesis that Nrf2-interacting nutrients are effective in COVID-19. However, this cannot be used in practice before the availability of further safety data, and confirmation is necessary through proper trials on efficacy and safety.”
https://www.worldallergyorganizationjournal.org/article/S1939-4551(20)30401-4/fulltext
Interesting. Multiple drugs known for their anticancer effects, now identified as effective against coronavirus:
Identification of Atovaquone, Ouabain and Mebendazole as FDA Approved Drugs Targeting SARS-CoV-2
Hi @Daniel
Is possible to find a source to get Ribavirin ?
Thank you
Hi Inabari !
https://otc-online-store.com/
Here you have a great option to buy!
Kind regards
thank you 🙂