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Does the anti-parasitic Ivermectin work in actual human studies versus the Petri dish in vitro studies, when treating coronavirus COVID-19 infection? And if so, is it safe in humans?

An in vitro study was done.

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There is a paper which suggest that ivermectin is unlikely to be an effective antiviral vs. SARS-CoV-2 at recommended dosing.

Please find this preprint or this paper.

This paper has the following description.

Recently, an article by Caly et al. reported that ivermectin inhibited severe acute respiratory syndrome‐coronavirus (SARS‐CoV‐2) in vitro causing an ~ 5,000‐fold reduction in viral RNA at 48 hours with ivermectin at 5 μM. The concentration resulting in 50% inhibition (IC50) of 2 μM (1,750 ng/mL) is > 35× higher than the maximum plasma concentration (Cmax) of 0.05 µM (46.6 ng/mL)2 after oral administration of the approved dose (~ 200 μg/kg) and ivermectin showed little to no activity 1 μM in vitro. Because ivermectin is highly bound to serum albumin (93%), the IC50 is orders of magnitude higher than the unbound plasma Cmax after approved doses of ivermectin (0.0035 µM; 3.26 ng/mL).

Therefore, a large estimate is that the plasma concentration is 2 μM /0.0035 µM =571 times insufficient.

I think the key points of above paper are as follows;

  • The development of methods to realize enough concentrations of ivermectin in the lungs/plasma.
  • Is ivermectin still safe when the enough concentration is achieved in the lungs/plasma?

These questions follow naturally from the preprint/paper above.

However, as described in the @Matthew Elvey 's answer, as of December 5, 2020, there are many clinical results which suggest that we can get enough efficiency with far less dosage than would be assumed from pharmacokinetic considerations; formulas that combine several things such as zinc and vitamins seem to be more desirable.(Added on December 5, 2020)

The gap between inadequate blood levels and a strong clinical effect is one puzzle. It is an exciting scientific topic. This gap will be bridged as the mechanism of action of ivermectin is elucidated.

So far, various mechanisms have been proposed, but it has not been decided which one is the mainstay. That's what Satoshi Omura said in his open youtube lecture (In Japanese, the relevant part has been headed out.) at Showa Pharmaceutical University at the end of October, 2020.

The following is a summary of the youtube lecture by Satoshi Omura.

  • There are various proposed mechanisms of action by which ivermectin inhibits coronaviruses, and it is not clear which theory is definitively correct. He introduced the following two mechanisms as examples.
  • One is that ivermectin inhibits the process by which the viral spike joins ACE2 and enters the cell. This is an example of the idea of inhibiting viral entry. (Figure 1, left)
  • Dr. Maruta and colleagues in Australia have proposed a different mechanism. In that theory ivermectin acts on the human body. Briefly, when the virus binds to receptors such as ACE2, a kinase called PAK1 is induced. This is a release kinase, which appears to be released when infection occurs and suppresses the immune system. Their idea seems to be that ivermectin also protects the immune system by inhibiting PAK1. (Figure 1, right)

enter image description here
Fig.1 Examples of proposed mechanisms of action. Adapted from a lecture given by Satoshi Omura at the end of October 2020, partially written in Japanese.


In September 2020, Japan's Kitasato University appears to have begun a physician-led clinical trial for COVID-19. Kitasato University is where Satoshi Omura, one of the discoverers of ivermectin, is affiliated.

  • jRCT2031200120:A placebo-controlled, randomized, double-blind study in Covid-19 patients with ivermectin; An investigator initiated trial

They will administer the Ivermectin Tablets, sold under the brand name STROMECTOL, orally. According to a Japanese newspaper article (written in Japanese), the trial is expected to be completed in March 2021. (Completion = LPI?)

On the other hand, scandalous clinical data also exists. It seems that one data analysis company, Surgisphere published a preprint saying that ivermectin was beneficial based on analysis of real world data, but it was later retracted. According to this article, it seems to have pointed out many unnatural aspects of the data.


By the way, Ivermectin's 'birthplace' features hot news about Ivermectin. Note that a bit slow in terms of information; as of 5 December 2020, the introduction of the paper published on 10 November is the most recent. Even more unfortunate is that the information is in Japanese. However, it will be helpful to see the trends. For many people, though, they may need the help of machine translation.
https://kitasato-infection-control.info/ (Written in Japanese)

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  • @ Matthew Elvey  The evidence you have shown me certainly looks promising. An oversight on my part. I'll correct my answer. Satoshi Omura is my senior at Tokyo University of Science; he is much older than me, though. In that sense, I am delighted with the paper you introduced to me. Dec 4 '20 at 15:12
  • Cool. So nice to see the warm reception here on SE to this info. (Seeing my answer has taken first place in < 24 hrs. First time I've seen anything like that even when my answer was irrefutable.) Dec 4 '20 at 19:09
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    Do you still "think that the ivermectin is unlikely to be an effective antiviral vs. SARS-CoV-2 at recommended dosing?" It kind of depends on what dosing is recommended too. In the Covid trials so far, the dosing has been low, and effective. But in safety studies, 10x higher doses were found to be safe in humans, or at least to have minimal side effects - small n so hard to say. But with (correction: >3) billion standard doses, the adverse reports indicates is about as safe as medicine gets. Dec 4 '20 at 19:16
  • I've further revised my answer. I think it's a mystery of sorts that the dose should be much less than 5000 times less. But this drug probably inhibits the impotin, not directly 'killing' the virus. So maybe the idea of DI itself doesn't fit. Dec 5 '20 at 2:55
  • I looked at the original paper and the dosing concentration, as I recall, wasn't anything like 5000x less. I should double check. Also, I recall reading that ivermectin concentrates in lung tissue and stays there for weeks. Impotin? You mean reproduction? Dec 10 '20 at 23:08
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Yes. Prevents it too. 100% in some studies, but not others, but then, the vaccines aren't proven stop it 100%, and ivermectin's safety profile is far superior.

What's established/true has changed a lot since this question was asked and initially answered.

CHEST

Does CHEST only publish results of INvalid clinical evidence? No. It's v. reputable. Yes, this retrospective study shows it works, and likely works much better than the other treatments already in use.

Chest Article : Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019 (Title, Link)


FLCCC review

And in addition to reliable clinical evidence (which Cochrane says evidence shows is as reliable as RCT evidence) there are a great many preprint results from RCT and published results from RCT. Rather than put up a static, soon to be wrong summary, I point to this:

The FLCCC's comprehensive review of the emerging evidence for Ivermectin use in our I-MASK+ protocol (PDF, continuously updated) (It recently had 87 citations and resolves to this URL but that has changed or is sure to change.)

Also, it is more than an incredibly popular preprint that has surely saved tens of thousands of lives; it has now passed peer review for publication in Frontiers in Pharmacology. doi: 10.3389/fphar.2021.643369.

They put it thus in their review:

To our knowledge, the current review is the earliest to compile sufficient clinical data to demonstrate a strong signal of therapeutic efficacy based on numerous clinical trials in multiple disease phases, however it is limited by the fact that only a minority of studies have been published in peer-reviewed publications, with the majority of results compiled from manuscripts uploaded to medicine pre-print servers or from registered trials that have posted preliminary results on clinicaltrials.gov.

] But "minority" != 0. Overall, the results are largely highly significant. Results from 16 clinical trials and 3 large case series are reviewed.

They even mention:

Two manuscripts reviewing the scientific rationale and evolving published clinical evidence base in support of the MATH+ protocol passed peer review and have been accepted for publication in major medical journals at two different time points in the pandemic (2, 3).

E-BMC for Cochrane's Tess Lawrie

e-bmc.co.uk : This organization has published a meta-analysis to the rigorous standards of the WHO by these extremely experienced and prolific Cochrane authors.

Their Tess Lawrie discusses it here. ESSENTIAL.

Ivermectin has helped Billions of patients, is helping Millions fight the pandemic.

People have already received far over three billion < sic > doses, and the record of significant adverse reports indicates is about as safe as medicine gets.

Another retrospective study is based on over 1 million doses distributed in one of each of several paired Brazilian cities. Another compares regions in Paraguay that did and didn't receive ivermectin. Another compares African states where ivermectin is and isn't distributed nationwide. In each study, cases and deaths, tracked over time, diverge, strongly according to ivermectin distribution.

There are now several literature reviews and meta-analyses by several groups of doctors including the from FLCCC - who are some of the most experienced in emergency medicine. These are confirmed by their clinical experience as well as large population studies and medical groups in several countries on the latest research.

100% prevention???

Yup. The 100% figure comes from Carvallo. It reports:

The overall infection rate in health care workers recruited for this study was 20% with 237 testing positive for CoViD 19 during the 3 month study recruitment. Of those infected, all patients were from the comparator group of using PPE alone. This represented an overall infection rate of 58.2% ( 237 of 407) in the PPE group. No patients of the 788 treated with [IVERMECTIN] tested positive for CoViD 19 during the study.

I.e. 100% did not. And this was a multi-center study in 4 major hospitals, including the pilot, with 1,424 health care workers. Of the 919 who got ivermectin, 100% remained CoViD-19-free.

WHO endorsements

There are two recent WHO-originated and funded endorsements of ivermectin. First, on the WHO website, ivermectin is recommended for treatment of Covid-19 patients when they are being treated with immunosuppressants.

Secondly the WHO funded an evaluation of the evidence to date and Dr Hill, the expert consultant the WHO relies on for such evaluations of evidence to be used as the basis for official WHO recommendations has spoken very encouragingly regarding the evidence from randomized controlled trials demonstrating the utility of Ivermectin in treating Covid-19 that his work so far has uncovered:

Andrew Hill for WHO: https://m.youtube.com/watch?v=yOAh7GtvcOs (censored) Original is at https://medincell.com/IvermectinWorkshop/AndrewHill.mp4, (works) and I have a copy as well. https://www.dropbox.com/s/li4i3pyl52t88dy/AndrewHill%20WebOpt%2Ch265%2C0%2C-fps%2CRF31%2C%20placebo%2C%20to1920x1k%20-36%2C106%2C-94%2C-4%2CnoALL%2CHE-AAC40kbps.m4v?dl=0 (works; sign-up/login NOT needed)

https://www.who.int/news/item/17-12-2020-a-parasitic-infection-that-can-turn-fatal-with-administration-of-corticosteroids

-- (The ~Sphere data-derived paper is obviously garbage and merits scant not attention outside the tabloids.)

From Hill's presentation: Sources

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    @ Matthew Elvey I am ashamed to have given the wrong answer. The fatal part has been removed by a correction line. Let me make an excuse. It is not that I was without evidence; at the time, news of ivermectin's efficacy had not been introduced in ivermectin's "Birthplace";this site always introduced important news about ivermectin, but written in Japanese) I look now and see that the review you referred me to has been translated and presented in Japanese. Dec 4 '20 at 16:17
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    In the second report you presented, the data from Peruvian states and Alto Parana are very impressive. The improvement in prognosis of death and the timing of ivermectin administration are perfectly aligned. And without ivermectin, it wouldn't have happened. This is what clinical research should be about. On the other hand, the Utah paper, if it were real data, would have been a groundbreaking use of real-world data. Dec 4 '20 at 18:09
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    Agree! - "The improvement in prognosis of death and the timing of ivermectin administration are perfectly aligned." It's uncanny. Don't be ashamed! You're helping now! Dec 4 '20 at 21:34
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    My home country, Japan, is staggeringly conservative in clinical study, but Merck is just as conservative. Feb 19 at 14:31
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    Support for the use of ivermectin has also come from other prominent experts in Japan. Unfortunately, this one is written in Japanese... It seems to be generally agree with you. The author of this article is a top expert in health policy and is also a medical doctor. His job was as a professor at a graduate school for training Japan's senior civil servants. But Japan is so conservative in its final judgement that it will never be approved unless it is approved by a major US or European country. news.livedoor.com/article/detail/19697795 Feb 19 at 15:49
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We do not know. Until there is a phase 3 clinical trial and ivermectin gets FDA approval, it is too early to draw definite conclusions.

[The NIH has selected some of the studies performed and combined them into a table][1]. At the time, all of them had one or more methodical disadvantage or limitation such as no peer review, no randomisation or a small sample size (20 patients in each arm) and were deemed insufficient to draw a conclusion.

The most recent study published in The Lancet (one of the most prestigious scientific journals) found no statistically significant difference in clinical endpoints for the usage of ivermectin, and maybe smaller viral loads but no difference in vital signs etc. This study also had a very small sample size (12 patients in each arm, all at low risk).

[1]: Table 2c. Ivermectin: Selected Clinical Data. NIH.gov Last Updated: February 11, 2021.

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This in-vitro study reveals exciting data regarding Ivermectin, which is typically used for treatment of scabies.

I was unable to find any clinical data to support use of Ivermectin for COVID-19. But this study definitely supports starting a clinical trial given the widespread availability of Ivermectin. Overall ivermectin is well-tolerated in both children and adults, with rash being one of the most common side effects. It may have fewer severe adverse effects than hydroxychloroquine, which can cause fatal arrhythmias like Torsades de Pointes(though this is more with chronic use; https://www.ncbi.nlm.nih.gov/pubmed/16615675). This supports ivermectin as a good candidate drug to study.

It is important to note, however, that many drugs that have shown to be effective in-vitro will fail to produce any clinical benefit when given to animals or humans. For instance, for ebola virus, chloroquine was effective in-vitro but not in guinea pigs (https://www.ncbi.nlm.nih.gov/pubmed/26459826). There are many factors that could contribute to these discrepancies, including issues with bioavailability, distribution to the appropriate tissues, entrance into cells, and breakdown of the drug by cellular or viral mechanisms.

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(What's true has changed even further!! A lot changed AGAIN - since this question was asked and initially answered, AND THEN since it was (last month) initially answered by me! So time for another new answer!)

YES! In addition to several literature reviews by several groups of doctors including some of the most experienced in emergency medicine, and confirmed by their clinical experience as well as large population studies and medical groups in several countries on the latest research, there are two recent WHO-originated and funded endorsements of ivermectin. First, on the WHO website, ivermectin is recommended for treatment of Covid-19 patients when they are being treated with immunosuppressants. Secondly The WHO funded an evaluation of the evidence to date and the expert consultant the WHO relies on for such evaluations of evidence to be used as the basis for official WHO recommendations has spoken very encouragingly regarding the evidence from randomized controlled trials demonstrating the utility of Ivermectin in treating Covid-19 that his work so far has uncovered.

Andrew Hill for WHO: https://m.youtube.com/watch?v=yOAh7GtvcOs (censored) Original is at https://medincell.com/IvermectinWorkshop/AndrewHill.mp4, (works) and I have a copy as well. https://www.dropbox.com/s/li4i3pyl52t88dy/AndrewHill%20WebOpt%2Ch265%2C0%2C-fps%2CRF31%2C%20placebo%2C%20to1920x1k%20-36%2C106%2C-94%2C-4%2CnoALL%2CHE-AAC40kbps.m4v?dl=0 (works; sign-up/login NOT needed)

https://www.who.int/news/item/17-12-2020-a-parasitic-infection-that-can-turn-fatal-with-administration-of-corticosteroids

Sources

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    An update: On February 4th, Merck, producer of Ivermectin, published a paper stating that they "do not believe that the data available support the safety and efficacy of ivermectin beyond the doses and populations indicated in the regulatory agency-approved prescribing information." (merck.com/news/…) Feb 8 at 6:36
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    @Matthew Elvey Long time no see. I would like to tell you about the following. The Youtube video you quoted has been removed. Also, the WHO link is about "the risks of using systemic corticosteroids and other immunosuppressive therapies in populations at high risk of thrombocilosis", which does not seem to have a clear relationship to your description. Feb 15 at 18:36
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    Added alternate links for the censored video. Not sure what you mean about who.int/news/item/…. Mentions: COVID: 8. SARS-CoV-2: 2. Ivermectin: 7. There's no such thing as "thrombocilosis". In this particular article, they're not talking about ivermectin's abilities to stop SARS-CoV-2 directly. But they are talking about using it to treat patients with Covid. We do see: ivermectin is recommended for treatment of Covid-19 patients when they are being treated with immunosuppressants. Feb 19 at 7:36
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    Yes, I think you're right - it is taken from his presentation, which is from his paper. Feb 19 at 7:39

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