SARS-CoV-2 spike protein induces the clumping of red blood cells, a phenomenon known as hemagglutination that can cause blood clots.
It is well known that covid-19 increases the risk of serious blood clots (known as venous thromboembolism or VTE).
Therefore, a drug that could inhibit hemagglutination would most likely be of high value for Covid patients.
It happens that a team of French researchers has recently published a study showing that Ivermectin precisely do that, ie inhibits hemagglutination.
At physiological concentrations?
It is well known that severe COVID-19 causes an inflammatory cascade, part of which causes VTE.
Hemagglutination isn’t the same phenomenon as clotting, and only if it works at physiological concentrations.
It included an American.
But does it do so at physiological concentrations? This question applies to both the spike protein and ivermectin. It’s not addressed in the paper, but if you want to be critical, you can figure it out.
That this was published in an MDPI journal is not a good marker for its quality, Gil. Nor are sentences that start with massive redundancies like, “The results for quantification analysis by Western blot…”
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This is a pretty important caveat:
Finally, HA could be tested as in this experiment but using RBCs supplemented with human serum albumin (HSA) at a physiological concentration. If IVM were to bind to spike protein glycans at the same molecular region as that which binds to HSA, that could significantly limit its HA-inhibitory effect, since 93% of IVM binds to serum proteins, mainly HSA, in blood [82], and 93% of IVM would then be rendered inactive for this effect.
Looking at the predicted binding sites of ivermectin with the spike protein, I have a hard time imagining it being able to simultaneously bind with HSA, meaning there would be competition and suddenly the required ivermectin dose has to increase by 20+ times beyond what is physiologically feasible.
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MDPI living down to my expectations of them, I see…
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You may be right, or wrong, and we will have to wait, probably not for too long, before getting the final answer. Meanwhile, the data presented in fig 6 as well as the observations on zebrafish embryos are consistent with the authors hypothesis regarding the MoA of IVM.
You’re wrong, the authors have a whole paragraph in the discussion section that precisely addresses this issue. Here it is:
The inhibition of HA by IVM as reported here parallels the prevention of RBC clumping in zebrafish embryos by heparan sulfate, a glycosaminoglycan likewise indicated to strongly bind to SARS-CoV-2 spike protein [49,72], when co-injected with spike protein [49]. It is noteworthy that the scattered RBC clumps observed in this zebrafish embryo study, as with those observed in the blood of COVID-19 patients [26,27,28], are much smaller than the macroscopic-scale HA—clusters of extensively interlaced RBCs—observed in this study. It is therefore likely that smaller concentrations of spike protein and IVM would be required to, respectively, induce and reverse RBC clumps of clinical relevance. Thus, the peak plasma level of IVM of approximately 412 nM, as attained about four hours after a standard oral dose of 200–350 µg/kg [1], appears to be in a range that could achieve clinical effects analogous to HA reversal observed in this study at IVM concentrations of 1–2 µM.
That’s really rude, Gil, especially since I’m not wrong.
No, it dances around it. I read it before posting.
Note that I wrote, and you ignored,
If it “precisely addressed” it, it would have addressed the precise concentration of spike protein. It doesn’t, so no, I’m not wrong.
I don’t see why it would be likely. What’s silly about this dancing is that a good journal would have rejected (probably several already have done so) because those “smaller concentrations” should have been tested. Or, more likely, they were tested, didn’t do anything, and aren’t mentioned.
That’s my whole point!
What does “peak” mean here, Gil? Did you bother to read reference #1? It’s a ridculous exercise in tapdancing and handwaving:
To obtain a 1000-to-1 ratio of trimeric spike protein molecules per RBC using a 10% solution of human RBCs in a microwell filled to 0.2 mL would require 68 ng of spike protein per microwell (see Appendix A.2 above). Although under clinical conditions, the ratio of spike protein molecules to RBCs would likely be less, characteristics of the in vitro environment might require a higher ratio of spikes to RBCs for hemagglutination to be readily detectable.
No, it doesn’t appear that way. The peak is literally fourfold less than what was clearly required for anything to happen.
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You could be a little nicer about that, maybe giving that paragraph a careful re-read and try to think about it as a biochemist would, and asking WHY there is disagreement.
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Colour me unimpressed by figure 6. Tiny sample sizes and a lack of proper standardisation or controls make it pretty meaningless. There are also many ways to increase SPO2 that are completely unrelated to hemagglutination.
The zebrafish embryo study has nothing to do with the proposed mechanism of ivermectin. The observation that heparin can reduce spike-protein induced hemagglutination in vivo doesn’t show that ivermectin would do the same thing, or that either are even of any clinical relevance.
There’s a lot of broad connections and conclusions being made in this paper without particularly strong support. If ivermectin had a significant beneficial effect, we should have found good evidence of it by now. You can come up with all the tiny trials and proposed interesting MoAs you like, but if it doesn’t show a clinical benefit in large controlled trials, it’s worthless.
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And it can very easily cause far more problems than it allegedly resolves.
I dispute the claim that there is no clinical evidence in favor of IVM (see below). A question: if someone you loved had a very severe form of Covid19, with no hope of recovery, wouldn’t you want him to try IVM, given it’s one of the safer drug ever prescribed?
This comes up in medical ethics, and the answer is generally “no”, because it’s unethical to offer false hope of a cure.
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Of course you would, but there’s a reason you have to resort to linking that ridiculous site rather than proper peer-reviewed meta-analyses (see below).
What I might do in an emotional state in a situation where there are literally no other alternatives is completely irrelevant to the question of whether there is evidence ivermectin is effective. The fact that you would even ask the question is baffling.
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Absolutely not.
Cherry-picking evidence, as you do here and repeatedly elsewhere, is profoundly unethical.
To be scientific, you have to address ALL of the evidence, not just the evidence that supports your position. This is why portraying science as some sort of high-school debate, or as a court case, is so wrong.
The weak effects shown in the web page you cited can easily be explained by publication bias. Apparently, even given all of the predatory journals available, it couldn’t be published. Doesn’t that tell you something?
I think that Gil asks the question because he is well aware that his position is not supported by the evidence.
No. There are a huge number of unnecessary and ineffective treatments, with no reason to choose IVM over any of the others, no reason to try any of them, and two reasons not to: a waste of their remaining time and a waste of your money.
If someone you loved had a very severe form of Covid19, with no hope of recovery, wouldn’t you want her to try homeopathic remedies, colour therapy and crystal power, given that none of them have any effect at all so are even safer than IVM?
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I would think he’d at least want sacrifices offered to Cthulhu for the loved one’s recovery. And all of the other gods whose thirst for human suffering might be slaked by a lovely gift. Sacrifice and pledge fealty to them all. If they don’t exist, no harm done. If they do, life saved.
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If this dying loved one begged me to give her one of these harmless remedies because she strongly believed in its effectiveness, had I the power to do so, I would certainly give it to her, wouldn’t you?
As for your comparison of IVM with these remedies, show me for one of them the equivalent of the data shown in fig 6 of the paper discussed in this thread.
Humor aside, there is a very serious ethical question to consider. Someone who is dying might ask for, or agree to almost anything, if they think it will help them. Family of the dying person are often in the same state of desperation. There is enormous potential to do very real harm, even with the best of intentions. Patients and families in this situation are very vulnerable, and the potential for abuse is enormous.
Some possible examples:
A harmless placebo won’t do any harm, but what if I charge $100 dollars for it? $1000? $10,000, $100,000? If you think about it, the number of zeros is irrelevant.
False hope can be harmful, even deadly, if it prevents or delays effective treatment.
@Giltil: I suggest you consider this very carefully, and maybe do a little reading on medical ethics. I think you will end up far less certain about this situation, and better off for it.
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If you look at the pros and cons of IVM vs Remdesivir for the treatment of Covid19 patients, particularly the relative costs and the adverse side effects, it is clear that IVM is a better drug than Remdesivir. Why then the FDA and EMA approved Remdesivir but not IVM? Is it ethical ?
https://www.science.org/content/article/very-very-bad-look-remdesivir-first-fda-approved-covid-19-drug
Was it ethical to lockdown whole populations for a virus, SARS2, whose IFR is about the same than the one of the flu, when we knew the appalling damage that such a decision would entail, in particular for the most economically fragile segment of these populations.
Was it ethical to close the schools when we knew that kids weren’t at risk to develop a severe form of Covid ?
Was it ethical to censor the numerous competent professionals who had another point of view regarding the management of the pandemic?
Do you find the situation depicted in the picture below ethical?
