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Archive for the ‘Roger Seheult’ Category

covid19: ivermectin, the Moderna vaccine, vitamin D

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Canto: So we were looking at the role of increased VWF and megakaryocytes in the blood, causing embolisms and clotting, and how to prevent or reduce such responses to the virus.

Jacinta: On the subject, Dr Seheult looks at a paper about the anti-malarial drug ivermectin and ‘CD147-mediated vascular occlusion’, CD147 being a protein attached to red blood cells (RBCs), which is apparently the entry pathway for malaria, and may also be a binding site for the S-protein of SARS-CoV2. However, binding to a CD147 protein on an RBC will not be a pathway for SARS-CoV2 as these blood cells don’t have nuclei, and so no mechanism for the virus to replicate. Still it’s possible, or likely, that this binding does take place, affecting the RBCs in such a way that they tend to aggregate. This is where ivermectin (IVM) comes in as a possible treatment:  

The potential for major dose-response gains is evaluated based upon studies indicating that IVM shields SARS-CoV2 spike protein and that this spike protein binds to the CD147 transmembrane receptor, as well as to ACE2. The abundant distribution of CD147 on RBCs suggests a possible ‘catch’ and ‘clump’ framework whereby virally-mediated bindings of RBCs to other RBCs, platelets, white blood cells and capillary walls impede blood flow, which in turn may underlie key morbidities of covid19. 

Now all of this is quite speculative as yet, and they quote an unpublished retrospective study with positive results from IVM treatment. Another study in Nature presents a systematic review of IVM use in covid19 and other infections – it’s apparently a medication which has ‘a good safety profile with low adverse effects when orally prescribed’. Clinical trials are necessary to appraise its use against covid19 however. 

Canto: Yes they point out that in vitro studies often involve higher dosages, and so results may not be replicable in vivo, where safety requires a lower dosage range. So now to the Moderna vaccine trials. Here’s the news from a July 14 article:

Moderna’s Covid-19 vaccine led patients to produce antibodies that can neutralize the novel coronavirus that causes the disease, though it caused minor side effects in many patients, according to the first published data from an early-stage trial of the experimental shot.

The data was published in the New England Journal of Medicine, as a preliminary report. As Seheult points out, this is a new type of vaccine, an mRNA vaccine, rather than a vaccine that introduces a protein into the body to stimulate the production of antibodies. In this vaccine the mRNA harnesses the mechanisms of the cells as the virus does, to produce the proteins that produce the immune response. Me think it mazing.   

Jacinta: Yes, this is reporting on dosage variation and response, and the data is pretty detailed, but the conclusions at this stage – and the vaccine is called the ‘mRNA-1273 vaccine’ – are that it ‘induced anti-SARS-CoV2 immune responses in all participants, and no trial-limiting safety concerns were identified’. So it’s steady as she goes at this stage. 

Canto: Quite exciting really – until someone gets really hurt. As you say, they tried different dosages, (25, 100 and 250 micrograms) and from the graphed results it seems fairly clear that they’ll go on in the next trial using the 100 microgram dose, which balances positive effects with negative effects in the most effective way, effectively. Effects seem to have been minor even in the highest dosage. 

Jacinta: And remember we’re almost two months behind the times here. Phase 3 trials were expected to begin in late July early August I think. That’s the real test, but even that won’t guarantee an entirely safe vaccine for everyone. Nothing can. 

Canto: Interesting that they required the subjects to have two injections each to get the best response. And as to side-effects, there were some severe ones at the 250μg dosage but very few at 100μg. 

Jacinta: There will inevitably be problems, I foresee that, and the anti-vaxxers will make a meal of any negative responses. In any case it’s unlikely that a virus will be available till next year. 

Canto: So now to update 97, which starts with a revisiting of vitamin D, which it seems a lot of health experts are raving about at the moment. 

Jacinta: So it’s a lipid-soluble vitamin, which means it retains its value in cooked foods, it’s stored in the liver, and when you’re exposed to ultraviolet light, it can transform cholesterol derivatives in the body to a form of this vitamin. Really sunlight exposure seems to be the best way of improving vitamin D levels. 

Canto: So this update looks at a paper published in early July, called ‘Vitamin D status and risk of all-cause and cause-specific mortality in a large cohort: results from the UK Biobank’. The results are a bit technical, but over a nine-year period for this cohort of older subjects, ‘higher 25(OH)D [that’s the active type of the vitamin] concentrations are non-linearly associated with lower-risk of all-cause, CVD [cardiovascular disease] and cancer mortality’. They recommend a particular threshold level of the vitamin as ‘an intervention target to reduce the overall risk of premature death’. 

Jacinta: Yes it certainly was a large cohort – over 365,000 subjects in a retrospective study. And Dr Seheult highlighted a comprehensive review article, ‘The immunological effects of vitamin D on human health and disease’, which I plan to read  in full, in order to live forever, but the key element for now is the effect of vitamin D on innate immunity. It ‘exhibits direct antiviral activities against many respiratory viruses by disrupting viral envelopes and altering viability of host target cells’. Further to this it has a section on ‘endothelial fuction and vascular permeability’. It’s pretty technical but the bottom line, they reckon, is that vitamin D3 is a helluva good product, in the correct form, for stabilising the endothelium, and Dr Seheult speculates that this is why it’s associated with a lower risk of mortality in covid19. It also appears to be associated, in the 1,25(OH2)D3 form, with increased endothelial production of nitric oxide. They make these interesting concluding remarks – ‘it is evident that vitamin D and its metabolites exert pleiotropic effects on the vascular endothelium that are protective against vascular dysfunction and tissue injury as a result of local and systematic inflammation’. Pleiotropic meaning multiple effects from a single gene. Vitamin D also has an effect on adaptive immunity – the helper and memory T cells, important as we don’t know whether these will develop a memory with respect to covid19.

Canto: The question of re-infection.

Jacinta: Indeed. But the review goes on and on about the positive effects of high vitamin D levels as a risk reducing factor in a range of conditions. And it goes specifically to covid19 which is, or starts as, an acute respiratory infection. Here are some fascinating results:

A prospective cohort study in healthy adults living in New England showed a two-fold reduction in the risk of developing acute respiratory tract infection (ARI) in those with serum 25(OH)D levels of 38ng/mL (95nmol/L) or more. A case-control study in children aged less than 2 years reported that children requiring hospitalisation for ARI had significantly 1.7 times higher odds of vitamin D deficiency as compared with those with mild ARI. This indicates the protective effects of sufficient vitamin D status against respiratory viral infection. 

And they go into the reasons why vitamin D might be protective, which I won’t detail here, but on covid19, they very reasonably claim that ‘one should maintain adequate vitamin D intake to achieve the desirable serum 25(OH)D level of 40-60ng/ml in order to minimise the risk and severity of covid19 infection’.    

Canto: Yes I notice they’re generally emphasising that 40ng/ml lower limit, which so many people are below. 

Jacinta: Yes, as they say, it’s been documented that about 60% of children and adults have circulating levels of less than 30ng/ml of 25(OH)D. So they reckon it reasonable that presenting covid19 patients will have insufficient vitamin D levels and so should be given supplementation on admission to hospital. However, overdosing on vitamin D can be an issue, so be very aware of dosage levels in consultation with your physician, if you’re self-medicating. 

Canto: Which I’m not sure if you should be doing.. please take my advice…

References

Coronavirus Pandemic Update 96: RNA Vaccine; Ivermectin; von Willebrand Factor and COVID-19

Coronavirus Pandemic Update 97: Vitamin D & COVID-19 Immunity, The Endothelium, & Deficiencies

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257661/

https://www.mdpi.com/2072-6643/12/7/2097

Written by stewart henderson

September 14, 2020 at 12:21 pm

covid19: corticosteroids, male susceptibility, evaluating health, remdesivir, coagulation factors

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from The Lancet, ‘the four horsemen of a viral apocalpse’

 

Canto: So short-course use of some steroids was being advocated in the medcram update 88, though without thorough RCT evidence. 

Jacinta: Well, data was presented from the Oxford RCT on those on oxygen or on ventilators showing a statistically significant reduction of mortality from short-course (up to 10 days) low dosage of dexamethasone, a freely-available steroid medication. The study involved some 2000 patients, but only those severely afflicted were helped by the medication. 

Canto: An interesting aside to the data is that in the study males outnumbered females by almost 2 to 1, and that accords with the overall ratio of male to female covid19 patients Dr Seheult is finding, which rather shocked me. Why would more males be coming down with the disease? Presumably that’s not the infection rate, but the rate at which they need to be hospitalised. 

Jacinta: Yes, you’re right, according to this Australian site (unfortunately undated):

Reports continue to emerge that men are significantly more vulnerable to COVID-19 than women. The commonly held perception that more men smoke and this makes them more susceptible along with other lifestyle factors does not tell the whole picture. White House COVID-19 Task Force director Dr Deborah Birx highlighted a “concerning trend” that men in all age brackets were becoming seriously ill from the virus at a higher rate than women, including younger males.

They’re suggesting more research needs to be done on this gender difference, for health issues in general. Some are claiming that estrogen makes a difference. In any case I think cardiovascular problems are more common in males – but maybe not so much in younger males. 

Canto: So update 89 is fairly short, and deals with US data about cases and deaths, most of it out of date now, and more on corticosteroids and the dangers of unsupervised use. Update 90 introduces us to a tool I’ve never heard of called ‘Discern’. Very useful for we autodidacts in helping us, for example, to enlighten our doctors as to our condition. Discern is a tool for evaluating internet health info, such as medcram’s updates on youtube, or anything else on youtube. The instrument asks you to evaluate the material according to 16 different criteria. Interestingly, this tool has been tested on covid19 material by a study out of Poland done in March. The results weren’t so good, especially for news channels. 

Jacinta: Yes, physicians’ information did best – but of course we don’t go to news channels for health information, and we’d advise against anyone else doing so. The study evaluated the Discern tool itself and found it excellent, then used the tool to evaluate health information, specifically on youtube. Of course know that there’s ‘viral misinformation’ from various news outlets that gets posted on youtube. And good to see that the medcram updates were some of the most highly rated using the Discern tool. 

Canto: So we’re now into reporting from early July with update 91. It starts by looking at a ‘covid risk calculator’ in which you can type in your age, gender, BMI, underlying conditions, waist circumference, and other data which you might need a full medical checkup to find out about (and that’s overdue for me), including, for example, %FMD, a measure I’ve never heard of, but which has to do with endothelial function. 

Jacinta: FMD stands for fibromuscular dysplasia. The Johns Hopkins medicine site describes it as a rare blood vessel disease in which the cells of some arteries become more stiff and fibrous and less flexible. This leads to weakness and damage. Not sure how it relates to covid19 but surely any pre-existing blood vessel damage is a danger for those contracting the virus. 

Canto: Right, so it’s unlikely anyone will know offhand their percentage of FMD. I don’t even know my HDL and LDL levels, never mind my HbA1c or lipids. I’d love to be able to take measures of all these myself, without visiting a doctor.

Jacinta: Typical male control freak. So all of this is to measure your risk of covid19 hospitalisation, ICU admission or mortality. Fun times. So next the update looks at Gilead, the makers of the antiviral remdesivir, who donated all their supplies of the drug to the USA in early May. But of course they kept manufacturing the drug and have to recoup the money they spent researching, developing and trialling it etc. The Wall Street Journal reports that a typical course of the drug will cost over $3000 per patient. Interestingly the Trump administration is wanting the drug to stay in the USA as much as possible, rather than be available overseas, and is spending money to that effect. 

Canto: Hmm. Is that protectionism? 

Jacinta: Yes I suppose. It’s not surprising that a country wants to look after its own first, especially via a product produced within its own borders. But I suspect this government would’t be interested in helping any other country – unless there was a quid pro quo. And there’s another antiviral, favipiravir, currently being trialled in Japan and the USA (I mean as of early July), and a vaccine, developed in China, is being used on the Chinese military in what seems a rather rushed and somewhat secretive fashion – we don’t know if they got the soldiers’ permission on this seemingly untried vaccine. At least at the phase 3 level.

Canto: Very CCP. 

Jacinta: So onto update 92, and we revisit the electron transport chain, with four successive electron transfers converting molecular oxygen into water. Problems within this chain can produce reactive oxygen species (ROS) such as superoxide, hydrogen peroxide and hydroxy radicals, which are destructive in excess. We also look, yet again, at covid19’s impact on angiotensin and particularly the production of superoxide, which in turn causes endothelial dysfunction, increased von Willebrand factor activity, which leads to thrombosis. People were presenting as ‘happy hypoxics’, looking and feeling fine but with very low oxygen levels, and autopsies revealed ‘microthrombi in the interalveolar septa’ of victims’ lungs. All this leading to a paper published in The Lancet which looked at factors in this process of coagulation and thrombosis:

We assessed markers of endothelial cell and platelet activation, including VWF antigen, soluble thrombomodulin [a marker of endothelial cell activation], soluble P-selectin [a marker of endothelial cell and platelet activation], and soluble CD40 ligand [a marker of platelet and T-cell activation], as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes.

So this was about getting to the bottom of the increased clotting. And the results were hardly surprising, but the final discussion section is worth quoting at length, as it seems to capture much that we know about covid19’s effects (at least short-term effects) at the moment: 

We therefore propose that COVID-19-associated coagulopathy is an endotheliopathy that results in augmented VWF release, platelet activation, and hypercoagulability, leading to the clinical prothrombotic manifestations of COVID-19-associated coagulopathy, which can include venous, arterial, and microvascular thrombosis. The factors responsible for this endotheliopathy and platelet activation are uncertain but could include direct viral infection of endothelial cells, collateral damage to the tissue as a result of immune infiltration and activation, complement activation, or any number of inflammatory cytokines believed to play a role in COVID-19 disease.

They suggest anti-platelet therapy and endothelial cell modification treatments as well as anticoagulation treatments, and they suggest some agents ‘which might have therapeutic potential’.

Canto: Potential? You’d think they’d be onto all this by now. 

Jacinta: Well there’s also potential for untried medications – at least untried in this context – to go terribly wrong. And it’s also likely that some hospitals are already onto using the safer forms of treatment. Dr Seheult speaks of the antioxidant N-acetylcysteine (NAC) in this context, as it has been shown to be a thrombolytic when used intravenously. There are studies pending on the effects of NAC in treating covid19 patients. 

Canto: Now, I’ve just been watching something on monoclonal antibodies as perhaps the most promising treatment yet, short of a vaccine. Can you explain….

Jacinta: Yes I’ll try, maybe next time.

References

Coronavirus Pandemic Update 88: Dexamethasone History & Mortality Benefit Data Released From UK

Coronavirus Pandemic Update 89: COVID 19 Infections Rising in Many States; Dexamethasone Cautions

Coronavirus Pandemic Update 90: Assess The Quality of COVID-19 Info With A Validated Research Tool

Coronavirus Pandemic Update 91: Remdesivir Pricing & Disparities in Drug Availability

Coronavirus Pandemic Update 92: Blood Clots & COVID-19 – New Research & Potential Role of NAC

amhf.org.au/covid_19

http://www.discern.org.uk

https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(20)30216-7/fulltext