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Thursday, 19 March 2020

The CDC Suggests People with Severe Autism are at Elevated Risk from Covid-19 – Time to ACE it?




Elvin Jail in Iran, a hotbed for Covid-19 transmission. Iran has released 70,000 prisoners on furlough, including some foreign political prisoners


I was a little surprised to hear that people with neurodevelopmental disabilities are on the US Center for Disease Control (CDC) list of those at risk from the current Corona virus (Covid-19).  I can see no biological reason for this, but I can see the elevated risks for anyone living in an institution rather than at home, rather like cruise ships and prisons not being safe places to be living right now.

I did check that the CDC have such a list and indeed they do:



Appendix A: Underlying medical conditions that may increase the risk of serious COVID-19 for individuals of any age.

• Blood disorders (e.g., sickle cell disease or on blood thinners)
• Chronic kidney disease as defined by your doctor. Patient has been told to avoid or reduce the dose of medications because kidney disease, or is under treatment for kidney disease, including receiving dialysis
• Chronic liver disease as defined by your doctor. (e.g., cirrhosis, chronic hepatitis) Patient has been told to avoid or reduce the dose of medications because liver disease or is under treatment for liver disease.
• Compromised immune system (immunosuppression) (e.g., seeing a doctor for cancer and treatment such as chemotherapy or radiation, received an organ or bone marrow transplant, taking high doses of corticosteroids or other immunosuppressant medications, HIV or AIDS)
• Current or recent pregnancy in the last two weeks
• Endocrine disorders (e.g., diabetes mellitus)
• Metabolic disorders (such as inherited metabolic disorders and mitochondrial disorders)
• Heart disease (such as congenital heart disease, congestive heart failure and coronary artery disease)
• Lung disease including asthma or chronic obstructive pulmonary disease (chronic bronchitis or emphysema) or other chronic conditions associated with impaired lung function or that require home oxygen
• Neurological and neurologic and neurodevelopment conditions [including disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy (seizure disorders), stroke, intellectual disability, moderate to severe developmental delay, muscular dystrophy, or spinal cord injury].


Treating Covid-19

There are well established strategies in place to treat flu pandemics, but Corona virus is different, although there are similarities.

There is already a great deal of research published, thanks to very fast working Chinese researchers.

In simple terms there are two strategies:-
1.     Inhibit the spread of the virus
2.     Halt the cytokine storm that triggers pneumonia and respiratory failure, should the disease progresses that far

If you fail in these two steps you are left with the same situation as occurred in the Spanish flu epidemic, where you treating what has become a bacterial infection in your lungs and hoping for the best. Nowadays we have antibiotics and a small number of ventilators.

Fortunately, initial studies have already been completed and show positive results in both (1) and (2) above.

Some of the drugs used to inhibit the spread of the virus are cheap generics, while one is a Japanese drug originally developed to treat the flu.

The last time the world was worried about a pandemic people stocked up with an antiviral drug called Tamiflu.  Tamiflu does not work for Coronavirus.

What does work are some old drugs originally used to treat malaria that include:-

1.     Hydroxychloroquine (HCQ), sold under the brand name Plaquenil
2.     Chloroquine, a 70 year-old drug sold under names including Resochin

In France Sanofi is offering to donate millions of doses of Plaquenil to the Government and in the US Bayer has offered to donate Resochin. 

It appears that Plaquenil works better and has less side effects.

In Japan they have a drug developed to treat flu called Favipiravir (also known as Avigan).  In trials it has the same effect as the old malaria drugs, it shortens the duration of the disease by about half and so reduces severity.

In all cases the drugs that target the replication of the virus need to be taken early on in the disease progression, to give any benefit.  This makes perfect sense.

What kills people in Covid-19 is the same thing as in the Spanish flu of 1918, it is a cytokine storm when the body’s immune system over-reacts and attacks your lungs.
If the disease progresses to this point you have to look at therapies to treat cytokine storms associated with severe influenza.

Here we have at least two interesting approaches:

1.     IL-6R antibodies (Roche’s Actemra)   
2.     S1P1 receptor agonist like Fingolimod (Gilenya)

Actemra is already in trials to treat Covid-19, but is injected.

Gilenya is an immunomodulating drug, mostly used for treating multiple sclerosis, taken by mouth.

One feature of Covid-19 is hypokalemia.  When sick these people excrete potassium in urine and become hypokalemic, they may need 3,000mg a day of potassium supplement.  As they get better, they stop losing potassium. This all relates to the angiotensin system, disturbed by the virus.

If you take bumetanide you excrete potassium, so if you get Covid-19 you would be wise to stop bumetanide, but keep taking potassium supplements. 



ACE2 Coronavirus and Italians

The reseach has already identified how the Covid-19 virus spreads in humans.  It uses Angiotensin converting enzyme 2 (ACE2) and ACE2 receptors.

To inhibit the spread of the virus you want less ACE2.

In normal times ACE2 is a very good thing to have and it is a marker for a healthy person. In some people they have variations of the gene that produces ACE2 or its receptor.  This variation is seen in Italians and also in sportsmen - not a good time to be an Italian sportsman.

Certain drugs increase ACE2 and certain drugs you might expect to lower ACE2 appear not to.

You might think Grandma’s ACE inhibitor, she takes to lower blood pressure would inhibit ACE2, but ACE inhibitors inhibit ACE1.  It appears they increase ACE2 receptor expression and ACE2 itself.

There are two issues, the number of receptors and the amount of the enzyme, both are relevant.

Chinese research on real patients found that those taking ACE inhibitors and ARBs had elevated levels of ACE2.

Ibuprofen has been reported to increase ACE2.  In children treated in France, there condition became much worse after treatment with Ibuprofen.

Glitazone drugs, that can help treat a cytokine storm, unfortunately seem to increase ACE2.  These drugs are used to treat type 2 diabetes.

ACE inhibitors and ARBs are also useful un treating a cytokine storm, but raise ACE2 and so must be avoided.


Practical Strategies

I should start by pointing out that researchers at Imperial College in London, who have analysed the data from a town in Northern Italy where 100% of the residents were tested for Covid-19, suggest that only one in eight people with the virus actually show symptoms.

German researchers think that over the next two years 60-70% of their population will catch the virus.

It is only the at-risk groups where mortality is going to be widespread.

I started writing this post when I heard some of Donald Trump’s “experts” standing beside him talking about the virus. I was not very impressed.  Then I read a newspaper interview with an “expert” in England saying how they would treat a new patient with Covid-19.  He would use Tamiflu and later antibiotics.

Where we live, they have very few ventilators and so it really makes sense to change the course of the disease so that you will never need one.

The generic drugs to stop the virus replicating are cheap, while the modern immunomodulatory drugs to halt the cytokine storm are extremely expensive.

My choice is Hydroxychloroquine (Plaquenil).  In France the published adult dose used is 600mg for 10 days. UPDATE I would also add Azithromycin, based on the chart at the end of this post.  In a small French trial the combination is remarkable, after 5 days the virus has gone in 100% of patients. This a cheap macrolide antibiotic, with long known immunomodulatory effects. 

If you look at the half-life of this drug, it is extremely long, over one month.  If I was treating myself for Covid-19 I would start with a higher dose and then taper it.  You need the greatest effect at the start, not the end of the therapy.

I do not actually believe that a healthy boy with autism, living at home, is at elevated risk of Covid-19, but if I am wrong, I will be giving Hydroxychloroquine (Plaquenil) immediately, should Covid-19 be confirmed.

These drugs have side effects and you would not want to use them when it is just a cold or flu.

Since Ibuprofen is reported to increase ACE2, I certainly will not be using it.

Paracetamol/acetaminophen has the big problem of depleting the body’s key antioxidant GSH.

GSH itself has a benefit on inhibiting virus replication.

Since I already give a large daily dose of NAC (N-acetylcysteine) to boost GSH levels, I would use paracetamol to treat a very high temperature in Covid-19.

I think Monty’s grandparents are the ones that might need the anti-cytokine storm therapy.

People with autism often have potent immune systems.  In the Spanish flu, it was young adults with good immune health that died.  They died because they generated potent cytokine storms in their lungs, which express ACE2 receptors and then they developed bacterial pneumonia. In medical jargon they developed acute respiratory distress syndrome (ARDS) and sepsis, causing death. 

In the first stage of Covid-19 a potent immune system should be an advantage, if it identifies the virus.  In the final stage of the disease, which most people avoid, an overactive immune system might not be a good thing.

I think that Hydroxychloroquine (Plaquenil) is a good insurance policy.

If I was a US Presidential candidate, or any other rich elderly person, I would put my order in for Actemra, just in case I needed it.

Actemra (Tocilizumab) is an expensive drug to treat arthritis in adults and children.  It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many disease.  IL-6 is a key player in the cytokine storm in Covid-19.  It is taken by I/V infusion.

An advantage of the S1P1 agonists is that they are taken as tablets.


The following paper is very good and has links to the latest research papers from China, which are also very relevant:-



The most distinctive comorbidities of 32 non-survivors from a group of 52 intensive care unit patients with novel coronavirus disease 2019 (COVID-19) in the study by Xiaobo Yang and colleagues  were cerebrovascular diseases (22%) and diabetes (22%). Another study  included 1099 patients with confirmed COVID-19, of whom 173 had severe disease with comorbidities of hypertension (23·7%), diabetes mellitus (16·2%), coronary heart diseases (5·8%), and cerebrovascular disease (2·3%). In a third study, of 140 patients who were admitted to hospital with COVID-19, 30% had hypertension and 12% had diabetes. Notably, the most frequent comorbidities reported in these three studies of patients with COVID-19 are often treated with angiotensin-converting enzyme (ACE) inhibitors; however, treatment was not assessed in either study.
Human pathogenic coronaviruses (severe acute respiratory syndrome coronavirus [SARS-CoV] and SARS-CoV-2) bind to their target cells through angiotensin-converting enzyme 2 (ACE2), which is expressed by epithelial cells of the lung, intestine, kidney, and blood vessels.

The expression of ACE2 is substantially increased in patients with type 1 or type 2 diabetes, who are treated with ACE inhibitors and angiotensin II type-I receptor blockers (ARBs).

 Hypertension is also treated with ACE inhibitors and ARBs, which results in an upregulation of ACE2.

ACE2 can also be increased by thiazolidinediones and ibuprofen. These data suggest that ACE2 expression is increased in diabetes and treatment with ACE inhibitors and ARBs increases ACE2 expression. Consequently, the increased expression of ACE2 would facilitate infection with COVID-19. We therefore hypothesise that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19. 



Severe influenza remains unusual in its virulence for humans. Complications or ultimately death arising from these infections are often associated with hyperinduction of proinflammatory cytokine production, which is also known as ‘cytokine storm'. For this disease, it has been proposed that immunomodulatory therapy may improve the outcome, with or without the combination of antiviral agents. Here, we review the current literature on how various effectors of the immune system initiate the cytokine storm and exacerbate pathological damage in hosts. We also review some of the current immunomodulatory strategies for the treatment of cytokine storms in severe influenza, including corticosteroids, peroxisome proliferator-activated receptor agonists, sphingosine-1-phosphate receptor 1 agonists, cyclooxygenase-2 inhibitors, antioxidants, anti-tumour-necrosis factor therapy, intravenous immunoglobulin therapy, statins, arbidol, herbs, and other potential therapeutic strategies.
  






Cytokine storm in the lung following severe influenza infection. (1) Viruses infect lung epithelial cells and alveolar macrophages to produce progeny viruses and release cytokines/chemokines (mainly contains interferons). (2) Cytokine/chemokine-activated macrophages and virally infected dendritic cells lead to a more extensive immune response and the initiation of cytokine storm. (3) Released chemokines attract more inflammatory cells to migrate from blood vessels into the site of inflammation, and these cells release additional chemokines/cytokines to amplify cytokine storm.




Summary of immunomodulatory therapy or strategies against severe influenza

Therapeutic agents or strategies
Summary
Corticosteroids
Alleviated the 2009 pandemic H1N1 influenza-infected patients with pneumonia.30 Ineffective as monotherapy in H5N1 influenza-infected mice.29 Increased long-term mortality in influenza-infected patients with pneumonia.27
PPARs agonists
Ciglitazone and troglitazone decreased the mortality of influenza-infected mice.34 Bezafibrate partially protected patients with influenza-associated encephalopathy.33 Gemfibrozil also decreased the production of IL-1, IL-6, and IFN-γ, but has no effects on the mortality of H5N1-infected mice when administered 48-h post-infection.31,32
S1P1 receptor 1 agonists
Reduced mortality of 2009 pandemic H1N1 influenza-infected mice over 80%, compared with 50% protection of oseltamivir.36
COX inhibitors
Ineffective as monotherapy in H5N1 influenza-infected mice, while effective when in combination with neuraminidase inhibitors.32
Antioxidants
N-acetylcysteine and glycyrrhizin inhibited H5N1 replication and pro-inflammatory gene expression in vitro39,40 but ineffective as monotherapy in vivo.45
Anti-TNF therapy
Effective in reducing the cytokine production and inflammatory cell infiltrates in influenza-infected murine lung but ineffective in improving survival of infected mice.47,48
IVIG therapy
Reduced 26% to 50% mortality of 2009 pandemic H1N1 and 1918 Spanish H1N1 influenza-infected patients.50,52
ACEIs or ARBs
Combined with caffeine or antivirals, alleviated lung injury and inhibited viral replication in H1N1, H3N2, and H5N1 influenza-infected mice.54 Ineffective in protecting 2009 pandemic H1N1-infected patients.55
CCR inhibitor
Increased survival of influenza-infected mice by 75%.58
AMPK activators
Increased survival for influenza-infected mice by 40%, while a combination with pioglitazone improved survival by 60%.59
OX40
Imparted a survival signal to the T cell via upregulating anti-apoptosis gene expression and eliminated weight loss in influenza-infected mice.60
SOCSs
Participated in a negative feedback loop in the JAK and epidermal growth factor receptor pathway to protect against severe cytokine storm during severe influenza.61
Macrolide
Decreased mortality, pro-inflammation, and inflammatory cell counts of influenza-infected mice.62
Arbidol
Reduced the mortality, lung lesion formation, and inflammation of severe influenza-infected mice.64
Herbs
Favorable in laboratorial data but limited clinical data for severe influenza.65,66,67,68,69,70,71

Polytherapy - Hydroxychloroquine plus Azithromycin (a macrolide, from the table above)

Click on figure below to enlarge it











38 comments:

  1. Where I live, apparently the state has pulled all Chloroquine from pharmacies into hospitals. To be honest, fair enough. It would be horrible if someone was panting in a hospital while I watch a movie with the medication in my closet. If someone of mine got sick, I would quite simply sit on the doctors head until they gave this person the right treatment. In microlocal news, we started 2.5mg Zoloft today, great mood lots of chatter, anxiety maybe 10 percent lower, no drunken behaviours or otherwise significant visible psych developments. Lets see what it does long term.

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    1. I suppose it depends where you live. Where I am you can only expect basic care in a hospital, if you want more you will have to organize it yourself and now is the time.

      The smart thing would be emergency production of these drugs. Countries have already blocked exports, so the world is not a fair place at the moment.

      Delete
    2. We live in the same place. I am able to pull strings so I hope it will work out fine for my family if smtg happens but I just think its fair they pulled the meds. Also, to note, pharmacy told me bumetanide has been rationed. Makes sense too, removes fluid.

      Delete
  2. Hello Peter, can Ambroxol prophylaxis be of help? Not to prevent infection but so if you get sick it doesn't escalate to the worst part. I came across these studies:
    https://www.ncbi.nlm.nih.gov/pubmed/16820995
    https://moh-it.pure.elsevier.com/en/publications/ambroxol-for-the-prevention-of-chronic-bronchitis-exacerbations-l
    https://www.researchgate.net/publication/332589578_Protective_effects_of_ambroxol_in_psoriasis_like_skin_inflammation_Exploration_of_possible_mechanisms

    Thank you!

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    1. Lisa, there are many possible therapies.

      In the link below is a long list, which does include Ambroxol

      https://www.guidetopharmacology.org/coronavirus.jsp

      It all depends where you live, what drugs hospitals locally use, and whether or not you can access additional drugs yourself.

      Some of these drugs are cheap and some are very expensive. Many have already been trialed in China.

      Delete
    2. Thank you Peter for the information!

      Delete
  3. Peter--thank you for this information and thank you for all you do. Your thoughts on melatonin for the cytokine storm? I remember researchers trying to get out information about the potential effectiveness of melatonin (starting as low as 20mg) in treating Ebola. Melatonin also seems to have some protective effects for the lungs. Here are links to research including a recent article that talks about melatonin reducing IL-6 and TNF-a.
    Melatonin possesses an anti-influenza potential through its immune modulatory effect
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593141/

    Protective Effect of Melatonin Against Polymicrobial Sepsis Is Mediated by the Anti-bacterial Effect of Neutrophils

    https://www.sciencedirect.com/science/article/pii/S1756464619302452

    Melatonin buffering the immune system
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3645767/

    Melatonin as an Anti-Inflammatory Agent Modulating Inflammasome Activation
    https://www.hindawi.com/journals/ije/2017/1835195/

    Ebola virus disease: potential use of melatonin as a treatment
    https://www.ncbi.nlm.nih.gov/pubmed/25262626

    Ebola virus: melatonin as a readily available treatment option
    https://www.ncbi.nlm.nih.gov/pubmed/25611054

    There are many more!

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    1. This Chinese paper below, published 4 days ago, does support your idea. In fact melatonin affects ACE2 expression and so might well slow the virus as the paper suggests.

      20mg is very much higher than the melatonin dose for sleep.

      Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2
      https://www.nature.com/articles/s41421-020-0153-3

      Delete
    2. I think it would be a good question about the dose. There are reports on successful melatonin use in sepsis and other severe infections with cytokine storm. High doses are usually proposed.

      Delete
    3. I have used, and upheard of doses up to 100mg a day without side effects other than maybe feeling groggy. I would say it's anti-inflammatory on how it feels to me. I have been using more since covid just because I'm stressed.

      Generally, I only take one 10mg extended release with 10mg pyridoxine hydrochloride. I keep immediate release if I can't fall back asleep or have a pounding migraine.

      Delete
    4. Researchers were proposing a minimum of 20mg several times per day in the Ebola outbreak.

      "Key issues related to the use of melatonin probably include early intervention with a large dose (20 mg or more for a single dose; as there is no precedent for an effective melatonin dose, some upward adjustment of the dose may have greater efficacy); this dose should be given several times per day for a prolonged period. The treatment should be initiated as soon as possible after the infection is diagnosed; presumably it would never be too late to begin treatment (orally or i.v.). Considering the current lack of effective treatments for this devastating disease and with no vaccine available for EVD, the use of melatonin would be worth consideration."

      https://onlinelibrary.wiley.com/doi/full/10.1111/jpi.12186

      Delete
  4. From what I hear a combo of quercetin and melatonin is really effective in reducing symptoms if yiu catch the virus.

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  5. Hi Peter,

    Thanks for great summary and highlighting hypokalemia issue, clearly important for Bumetanide users.

    I mentioned ACE2 issue and ibuprofen in your blog few days ago, but today I am not that sure. French minister of health advised against ibuprofen, but also against other NSAIDs in LeMonde suggesting there were cases of young people who developed severe COVID-19 after using NSAIDs. It went viral on social media, but hospital in Toulouse mentioned as the place where it happened denied: https://www.chu-toulouse.fr/coronavirus-mise-au-point-sur-une-information.

    There were no formal studies, but I wonder if ibuprofen detrimental effect would not have been noticed in China by doctors and reported even if only anecdotally? Would you expect significant impact if there are really few severe cases in a group of ~1000 children with COVID-19 described in one of Chinese papers?

    WHO announced two days ago they were consulting doctors treating COVID-19 and none confirmed the ibuprofen issue. This was official WHO statement, well not in a renowned medical journal, but on Twitter. That's the new pandemics evidence based medicine reality.

    Anyway the conclusion for me is that one needs to be very careful about the information verification, more than usually. Which is not easy if you need answers right now.

    The study on losartan for COVID-19 has been registered in the US and there was a study announced on soluble ACE2 as treatment in China, but it seems like it's withdrawn (no more COVID-19 cases there?).

    Here is one of these papers that highlight beneficial effect on ACE2 in acute lung injury - but not due to coronavirus. DMF is mentioned as well:
    https://www.ncbi.nlm.nih.gov/pubmed/31805278

    "After injection of ACE2, lung function and lung pathological injury were
    significantly improved, and that effect was accompanied by attenuated inflammation, and inactivation of the LPS-TLR4 pathway. Cell studies showed similar results. The above observations were further enhanced when there was a combined treatment with DMF and pm-ACE2."

    I wonder what's your opinion on this?

    Having said so much about being cautious with regard to unpublished data, here is small study in press on hydroxychloroquine and azithromycin in COVID-19:
    https://www.mediterranee-infection.com/hydroxychloroquine-and-azithromycin-as-a-treatment-of-covid-19/

    ReplyDelete
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    1. Agnieszka, I did look up Covid-19 and DMF, and all you find is advice to people with MS that their immunomodulatory therapy may be a risk factor. If you read about cytokine storms, immunomodulatory therapy is exactly what you need.

      Many of the suggested therapies are re-purposed from arthritis and some from MS.

      DMF may well be therapeutic, I expect someone will get round to testing it.

      I think taking MS levels DMF before exposure to the virus is not the same thing as taking DMF as a therapy for a cytokine storm. I do not think tiny doses of DMF will make you vulnerable to the virus, but it is easy to take a break for a few months till the virus has hopefully faded away.

      Antibiotics as an immuno-modulator is interesting. Macrolide antibiotics are listed in the table in the above post.

      When the virus impacts Africa they will need affordable drugs and hydroxychloroquine with azithromycin would not be pricey.

      Delete
    2. Agniezka- Could the Ibuprofen issue been an individual response? A metabolic inflammatory type of response that aggravated those with current COVID? I just found out that my son has issues with Salicylates and this is very complex in of itself? I was noticing various sensitivities and taking notes of the chemical properties of the most serious offenders. One of my relatives went undiagnosed while going through it. Because her test was misplaced she was treated with Nebulizer steroids, azithromycin, and low dose Klonopin. She survived. The Melatonin research sounds very promision.

      Delete
  6. Peter, do you have any thoughts or wishes about migrating the blog from blogspot to some other platform? Requirements?
    I can't promise anything yet, but I want to know if it's worth the effort to look into it.

    /Ling

    ReplyDelete
    Replies
    1. Ling, unless Google shut down the platform, it is best to leave the blog where it is. It works, it is free and has no advertising.

      It is not a commercial operation trying to sell things, so it does not need to be super slick.

      Delete
    2. Okido. I remember the topic was up a while ago and I thought you maybe even asked for technical help at some point(?) I happened to have someone close who'd be able to work on it now, pro bono, which is why I'm asking.

      ANyway, just don't underestimate how valuable this blog is. While it doesn't sell stuff, it saves families. That has to count as something.

      /Ling

      Delete
  7. 3 days in I am overwhelmed by the amazing things 2.5mg of Zoloft has brought us. Great mood, spontaneous shows of knowledge (at dinner time we do some typing on the Ipad, more as a typing exercise and general letter skills than real writing - she sent me for a glass of water and typed the whole alphabet in the meantime, which she has only seen in an app not even designet to teach you the alphabet), more direct communication. Love it!!!

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    1. tpes, that is great.

      The idea of 1/10 dose SSRIs was covered here:-

      When is an SSRI not an SSRI? Low dose SSRIs as Selective Brain Steroidogenic Stimulants (SBSSs) via Allopregnanolone modifying GABAa receptors and neonatal KCC2 expression

      https://epiphanyasd.blogspot.com/2018/11/when-is-ssri-not-ssri-low-dose-ssris-as.html

      It only seems to work in some people. Some Aspies have tried it and complain it has no effect.

      Delete
  8. Can anybody tell me where to buy azosemide , I can not find it
    Thank you

    ReplyDelete
  9. What are the scientific evidences for variations in the gene that produces ACE2 in italian people? ..anyway the first patient in Codogno (Lombardia) was a marathon runner...this 38 y.o. man is now recovered but his father died carla marta locked since 11 march

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  10. Peter -
    Regarding IVIG, my 19 yo son is currently getting monthly IVIG treatments...so from the above, it appears that IVIG is helpful and not contra-indicated in this Covid-19 environment. Is that your understanding, as well? Your thoughts would be appreciated!

    ReplyDelete
  11. Alinia an anti malarial has broad anti viral effects including against a number of animal and human corona viruses. Paper by Chinese researchers and table 1 summarizes: https://mmrjournal.biomedcentral.com/articles/10.1186/s40779-020-00240-0

    Other Chinese researchers published a w/holistic meta analysis outlining Cv interventions used in China. It spans vitamins, traditional Chinese medicine, to anti virals. https://onlinelibrary.wiley.com/doi/10.1002/jmv.25707

    Canadians are also trialing quercetin in China for Cv; it worked in animal trials against SARS, MERS, Zika.
    https://journal.com.ph/news/world/breaking-news-can-quercetin-help-us-avoid-threat-coronavirus-infection

    Flavonoids like quercetin also have an inhibitory effect on ACE1 which Cv evidently uses to trigger ACE2 invoking cytokine storms
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504033/

    ReplyDelete
  12. Peter,this is very interesting.There are a few things I was not aware of ,that I learned here.One of my main medical issues is a severe inflammatory neuropathy,in all four limbs.I was not aware neuroopathy was a risk factor,for increased complications of COVID-19.

    My neuropathy is autoimmune,so it might make sense,in cases like mine,but why would this be the case for neuropathies as ba whole?

    This is also the first I had read about melatonin as an anti-inflammatory agent.I wonder if it helps with more severe conditions.I had tried melatonin years ago,as a sleep aid,and it did nothing for me.I noticed no anti-inflammatory effects.Could this be either because I was not taking a high enough dose,or did not stay on it long enough?

    ReplyDelete
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    1. Roger, your neuropathy is autoimmune - have you read it is best to avoid use of melatonin if there is an autoimmune condition? I have read about a mouse study where lupus in male mice treated with melatonin worsened, but improved for the female mice
      ~Tanya

      Delete
  13. I have been pleasantly surprised to hear in my Pandas groups on FB that the british NHS has put Pandas children in the highest risk group and they all received phonecalls/sms/letters urging them to stay put for 12 weeks. Its good to know that the condition which often accompanies asd is taken seriously at least by some. I have asked the members to tell me more, if there are any interesting infos I will pass them on. Its devastating that children with asd, of whom I can bet not one has a properly functioning immune system, will not get this treatment.

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  14. question about the ssri use: the past 2 days we have seen a very visible routine. in the morning absolutely blowing us away. after bumetanide, sort of whiny, closed off, wants to do what she wants. ssri around 15h. around 18h a spirt of energy, playing, communicating. normal bedtime behaviour, maybe bit increased silliness. we worry that the noon whinging is caused by some overlap of the ssri with the bumetanide. all her other therapies are immunity related and should not be overlapping with this. any ideas?

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    1. tpes, drug interactions are common and may not relate to the therapeutic function of the drug. Your SSRI may interact with your immune therapies.

      It is best to look up all the drugs and see if they have a listed interaction with Sertraline (Zoloft).

      https://www.drugbank.ca/drugs/DB01104

      Your tiny 1/10th dose of Sertraline is likely to increase Allopregnanolone. This modifies the response from GABAa receptors and may benefit some people.

      There is no listed interaction with Bumetanide. But if someone has autism, there is an interaction, because both drugs can affect GABAa receptors. Sertraline has a long half life and the effect of bumetanide on GABA also has, in effect, a long half-life. So the timing of the low dose of Sertraline and the bumetanide dose should not really matter (in theory), but you can always vary the timing and see if it has an effect.

      The more drugs and supplements you use, the greater the chance of some kind of interaction, but that does not mean it is a harmful interaction; winging is not really harmful. The listed interactions are the potentially harmful ones.

      Delete
  15. There are no listed interactions. I was thinking along the lines of Gaba. The whinging I take as a sign that something is off - maybe she needs more precursors for gaba or dopamine or serotonin if ‘spending’ is more increased now? Just trying to fine tune this, because the whinging is impeding her learning and social interactions.

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    1. Bumetanide and low dose Sertraline/Zoloft are changing the effect of GABA rather than "using it up". You could try using less Sertraline/Zoloft or giving it every second day.

      You should realize that you are, in-effect, giving your daughter Allopregnanolone

      https://en.wikipedia.org/wiki/Allopregnanolone

      Read about its effects other than on GABA and how it has a biphasic action on GABAa receptors.

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    2. Can a smaller sertraline dose be added to fluvoxamine?

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    3. It looks like the effect on neurosteroids in the brain varies between SSRIs.

      Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC23979/

      Our results indicate that the SSRIs fluoxetine, sertraline, and paroxetine decrease the Km of the conversion of 5α-dihydroprogesterone to allopregnanolone by human 3α-HSD type III 10- to 30-fold. Only sertraline inhibited the reverse oxidative reaction. SSRIs also affected conversions of androgens to 3α- and 3α, 17β-reduced or -oxidized androgens mediated by 3α-HSD type IIBrain. Another antidepressant, imipramine, was without any effect on allopregnanolone or androstanediol production

      I suppose nobody has considered combining SSRIs.

      The 1/10th dose of Sertraline is not supposed to have an effect on serotonin, but if you are already taking a regular dose of Fluvoxamine, that might not hold true.

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    4. Hi Peter,

      Does the sertraline have to microdosed to get the effect of sertraline described above?

      I have been trying 50mg sertraline with 150mg fluvoxamine without increase in side effects. Another thought I had was sertraline only in the morning and fluvoxamine only at night. Right I take them together every 12 hours

      I'm also trying to get a leucovorin prescription from my neurologist or psychiatrist.

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    5. Martin, for an adult the low dose sertraline would be about 10mg a day. You would have to experiment to see the effect.
      The effect on neurosteroids may also be present at high doses and partly cause their therapeutic effect.

      The interest in low dose Sertraline is because it would likely be free of the common SSRI side effects and be suitable for long term use. Many people find SSRIs problematic.

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    6. Peter,
      I am currently using 50mg sertraline tabs with an indented middle. I am planning on trying 25 twice a day starting tonight or tomorrow. I can try asking for 25mg tabs on my psychiatrist appointment this week. I just worry that won't even consider it. If that's the case I'm just keeping my fluvoxamine since it's harder to get. My formulary has sertraline 20mg/ml oral concentrate I just saw, but I'm not sure that's needed vs a 25mg tab since I'm an adult?

      Thanks Peter & all
      -Martin

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    7. Martin, you can subdivide pills by crushing them and then using cheap micro-scales to weigh small amounts.

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  16. Big thanks to everyone helping out to navigate autism drugs during the pandemic. I posted a question on Ibudilast which probably was lost during transmission, but I might have found the answer anyway. I wondered if it would be OK with Ibudilast for someone with corona symptoms, and while the below is part of a press release (so comparable to an advertisement), it indicates someone believes it would:

    10 March 2020
    "MediciNova today announced that it plans to initiate development of MN-166 (ibudilast) for severe pneumonia and acute respiratory distress syndrome (ARDS). (..)
    Results of this preclinical study showed that ibudilast treatment reversed histological changes observed in the ARDS mouse model including inflammation, hemor­rhage, alveolar congestion, and alveolar wall edema. (..)
    Results of this study also showed that ibudilast significantly reduced the levels of inflammatory cytokines including TNF-alpha, IL-1beta, IL-6, and MCP-1 in a dose-dependent manner, indicating that ibudilast suppressed the inflammatory response.
    (..)
    Infections are the most common risk factors for ARDS. These infections may include the flu, coronavirus or other viruses, and sepsis." https://apnews.com/Globe%20Newswire/90bc10948a0c9ce68d8417ab9b944d7a

    /Ling (sorry for the bad reliability of my source this time)

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