The Ivermectin discussion

AppleMuncher · 26-02-2021 1:36am

Thanks for your reply, I appreciate your interest.

Some comments:
Well, firstly the research you are referring to, as I understand it, the paper refers to in vitro research, right?
I assume you are referring to the following:

"The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro"
Link: https://doi.org/10.1016/j.antiviral.2020.104787

So Ivermectin as an anti-viral used on human cell lines placed in a test tube, a very specific scenario. And yes, you are quite correct, to see the effects described in this paper you would have to give very large doses to humans, which would be an overdose. However, humans are not simple cell lines in test tubes, i.e. human biology is enormously complex and effects and doses used in vitro cannot always be transcribed or translated to humans. Also there is no suggestion that to see any positive effect one would have to treat with such large doses. They could have used other doses and generate a dose response curve if they wished, for example, thereby showing effects at lower doses.

Also, the doses used were chosen, I assume, to give a reasonable chance of seeing a rapid effect in a laboratory environment, whereas treatment of humans may occur at much lower doses over several days, and treatment rounds (again you cannot simply equate cells in a test tube with a person battling covid-19, damage is caused not just by viral replication but also through many other well described mechanisms, cytokine storm etc.). So technically you are correct, if Ivermectin were dosed at the level used in this paper it would surely kill people.

So a more pertinent question may be: "Does Ivermectin show any benefit as a treatment for Covid-19 (the illness or pathophysiology) that occurs in humans at reasonable doses?

So one method to determine the dose need to see positive effects against a particular illness, COVID-19, for example, would be by conducting a double blind randomized placebo-controlled trial in humans (you often hear this referred to as "The Gold Standard").

For example, if you read the following paper:
"Ivermectin as a potential treatment for mild to moderate COVID-19 – A double blind randomized placebo-controlled trial"

Look at the section on dose used:

"Intervention Patients in the intervention arm were given ivermectin 12 mg on day 1 and day 2 of admission. Patients in the placebo arm were given identical looking placebo tablets."

Source: https://www.medrxiv.org/content/10.1101/2021.01.05.21249310v1

So an effect was seen at a dose not known to be toxic.

Now an obvious criticism of this particular paper is that it is on a pre-print server and has not been peer reviewed, accepted for publication etc. etc. and I accept that, however there are numerous studies, PCT trials etc in the literature.

Again the link here: https://ivmmeta.com
Collates a lot of data from the ever increasing number of trials, it is not infallible, however a meta analysis shows convincing evidence of Ivermectin's effectiveness.

Summary:
•100% of the 42 studies to date report positive effects. Random effects meta-analysis for early treatment and pooled effects shows a reduction of 83%, RR 0.17 [0.11-0.28]. Prophylactic use shows a reduction of 89%, RR 0.11 [0.05-0.23]. Mortality results show 75% lower mortality, RR 0.25 [0.14-0.44] for all treatment delays, and 86% lower, RR 0.14 [0.03-0.62] for early treatment.

•100% of the 21 Randomized Controlled Trials (RCTs) report positive effects, with an estimated reduction of 70%, RR 0.30 [0.19-0.49].

•The probability that an ineffective treatment generated results as positive as the 42 studies to date is estimated to be 1 in 4 trillion (p = 0.00000000000023).

Miike · 26-02-2021 1:54am

AppleMuncher wrote: »

Thanks for your reply, I appreciate your interest.

Some comments:
Well, firstly the research you are referring to, as I understand it, the paper refers to in vitro research, right?
I assume you are referring to the following:

"The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro"
Link: https://doi.org/10.1016/j.antiviral.2020.104787

So Ivermectin as an anti-viral used on human cell lines placed in a test tube, a very specific scenario. And yes, you are quite correct, to see the effects described in this paper you would have to give very large doses to humans, which would be an overdose. However, humans are not simple cell lines in test tubes, i.e. human biology is enormously complex and effects and doses used in vitro cannot always be transcribed or translated to humans. Also there is no suggestion that to see any positive effect one would have to treat with such large doses. They could have used other doses and generate a dose response curve if they wished, for example, thereby showing effects at lower doses.

Also, the doses used were chosen, I assume, to give a reasonable chance of seeing a rapid effect in a laboratory environment, whereas treatment of humans may occur at much lower doses over several days, and treatment rounds (again you cannot simply equate cells in a test tube with a person battling covid-19, damage is caused not just by viral replication but also through many other well described mechanisms, cytokine storm etc.). So technically you are correct, if Ivermectin were dosed at the level used in this paper it would surely kill people.

So a more pertinent question may be: "Does Ivermectin show any benefit as a treatment for Covid-19 (the illness or pathophysiology) that occurs in humans at reasonable doses?

So one method to determine the dose need to see positive effects against a particular illness, COVID-19, for example, would be by conducting a double blind randomized placebo-controlled trial in humans (you often hear this referred to as "The Gold Standard").

For example, if you read the following paper:
"Ivermectin as a potential treatment for mild to moderate COVID-19 – A double blind randomized placebo-controlled trial"

Look at the section on dose used:

"Intervention Patients in the intervention arm were given ivermectin 12 mg on day 1 and day 2 of admission. Patients in the placebo arm were given identical looking placebo tablets."

Source: https://www.medrxiv.org/content/10.1101/2021.01.05.21249310v1

So an effect was seen at a dose not known to be toxic.

Now an obvious criticism of this particular paper is that it is on a pre-print server and has not been peer reviewed, accepted for publication etc. etc. and I accept that, however there are numerous studies, PCT trials etc in the literature.

Again the link here: https://ivmmeta.com
Collates a lot of data from the ever increasing number of trials, it is not infallible, however a meta analysis shows convincing evidence of Ivermectin's effectiveness.

Summary:
•100% of the 42 studies to date report positive effects. Random effects meta-analysis for early treatment and pooled effects shows a reduction of 83%, RR 0.17 [0.11-0.28]. Prophylactic use shows a reduction of 89%, RR 0.11 [0.05-0.23]. Mortality results show 75% lower mortality, RR 0.25 [0.14-0.44] for all treatment delays, and 86% lower, RR 0.14 [0.03-0.62] for early treatment.

•100% of the 21 Randomized Controlled Trials (RCTs) report positive effects, with an estimated reduction of 70%, RR 0.30 [0.19-0.49].

•The probability that an ineffective treatment generated results as positive as the 42 studies to date is estimated to be 1 in 4 trillion (p = 0.00000000000023).

The one study (preprint) you quoted in your long winded answer was a sample size of 112 where n=54 in the intervention arm. Are we going to ignore rigor? Imagine a world where vaccines were recommended based on a study of a total of 112 trial participants.

The curated website you keep quoting I have my doubt about. If their quoted stats are accurate why aren't they publishing a peer reviewed systematic review or meta analysis? a large number of studies they curate and publish are highly criticized for their rigor. If you're going to blindly follow an academic curation, you need to be highly critical of their methodology.

Johnboy1951 · 26-02-2021 2:22am

So the only study you quoted is one carried out in a lab and using the equivalent of a toxic dose for humans.

Are there any studies you can link to that are carried out in a manner acceptable for peer review, that have shown Ivermectin to be ineffective?

In the absence of such a study or studies, the best we have at this time is a multitude of 'not so good' studies which all appear to show efficacy.

Quite the conundrum.

AppleMuncher · 26-02-2021 2:34am

Miike wrote: »

The one study (preprint) you quoted in your long winded answer was a sample size of 112 where n=54 in the intervention arm. Are we going to ignore rigor? Imagine a world where vaccines were recommended based on a study of a total of 112 trial participants.

The curated website you keep quoting I have my doubt about. If their quoted stats are accurate why aren't they publishing a peer reviewed systematic review or meta analysis? a large number of studies they curate and publish are highly criticized for their rigor. If you're going to blindly follow an academic curation, you need to be highly critical of their methodology.

Thanks again for your comments. Great to know I’m long winded, I’m usually accused of being terse.

The one study I quoted? Did you look at the outcome of that trial, I.e decreased mortality? Do you deem it significant, important? Who decides? Me, you? Why don’t you publish a peer reviewed, systematic review? Why didn’t you refer to the papers from that site that were peer reviewed? Why don’t you learn some more about basic biology. Why is the sky blue? Who shot JFK? If we are going to have an unlimited Why? and What-if question session we will be here till doomsday. Have you read all the papers published on Ivermectin, numbers in the thousands BTW, because I certainly haven’t.

Incidentally, I have no regard for that website, either positive or negative. I’m merely highlighting it if you are interested in the studies. So I don’t rate it, depend on it, endorse it. Use it, ignore it I don’t care. It conveniently contains links to papers, that’s all.

I’m not endorsing that particular study, in fact I highlighted the fact that it has not been peer reviewed etc. I was using it as a counterpoint to your claim that Ivermectin is only effective at overdoses, so I don’t know what the **** your talking about.

Deeper Blue · 26-02-2021 3:30am

Surely if Ivermectin was any good we'd have gotten data to confirm that by now? It was first mooted as a potential treatment at least 9 months ago at this stage.

Miike · 26-02-2021 10:20am

Deeper Blue wrote: »

Surely if Ivermectin was any good we'd have gotten data to confirm that by now? It was first mooted as a potential treatment at least 9 months ago at this stage.

A certain cohort firmly believe this is some kind of "cover up by big pharma". When you engage in a civil discussion with those people, they throw the baby out with the water.

Johnboy1951 · 26-02-2021 11:06am

Deeper Blue wrote: »

Surely if Ivermectin was any good we'd have gotten data to confirm that by now? It was first mooted as a potential treatment at least 9 months ago at this stage.

There were no trials carried out as funding was not available, I believe.
I understand a properly funded trial is being (to be) carried out in the UK this year.
If this happens it wll be the first properly funded, double blind, randomised etc etc

Mike wrote:

A certain cohort firmly believe this is some kind of "cover up by big pharma".

I am not so sure about that cohort, but certainly there are those who will question the results of any trial funded by 'big pharma'.
That is hardly a surprising attitude for anyone to take.

The Continental Op · 26-02-2021 11:13am

Why carry out a trail in the UK where there is no clearance for using Ivermectin when a trail could be carried out in Africa where Ivermectin has been prescribed for years?

Piollaire · 26-02-2021 12:15pm

Deeper Blue wrote: »

Surely if Ivermectin was any good we'd have gotten data to confirm that by now? It was first mooted as a potential treatment at least 9 months ago at this stage.

In an ideal world that would be true but you need to unplug yourself from the matrix where you think everyone is operating for the common good. Merck/MSD will eventually be outed for their sharp business practice.

speckle · 26-02-2021 6:33pm

Glad to see this thread still going...what some people forget is that at the top end vaccines are maybe 90/95 %ish potentialy effective but that still leaves 5%. of people they do not seem to work for..on top of the small cohort that cannot take one.. due to pregnancy/previous reaction/medicine protocols/age/or developing nations etc etc..should these people be forgotten about?
We still need to be looking at treatments and ivermectin may be one.

Miike · 26-02-2021 9:39pm

Johnboy1951 wrote: »

So the only study you quoted is one carried out in a lab and using the equivalent of a toxic dose for humans.

Are there any studies you can link to that are carried out in a manner acceptable for peer review, that have shown Ivermectin to be ineffective?

In the absence of such a study or studies, the best we have at this time is a multitude of 'not so good' studies which all appear to show efficacy.

Quite the conundrum.

The point I'm trying to highlight there Johnny, is that in terms of feasibility (which is typically decided in lab tests) the lab tests conducted show the antiviral activity is at very high, unsafe doses. There is quoted posological and pharmacodynamic data on Ivermectin within those studies and to go back to an earlier comment I made on this thread - I recommend listening to the podcast "This Week in Virology" episodes I listed, it's hosted by Vincent Racaniello who is a renowned expert in this field and his guests for this topic are highly esteemed.

I certainly hope a high quality RCT shows Ivermectin is an effective treatment, it would be great. Doesn't necessarily mean I think it's a realistic expectation from the research that's been conducted to date. Look at how this bangwagonism worked out for hydroxychloroquin, azithromycin, chorloquin etc. I'm not saying we stop looking, I'm saying these need to be based on rigor.

Johnboy1951 · 26-02-2021 10:34pm

Miike wrote: »

The point I'm trying to highlight there Johnny, is that in terms of feasibility (which is typically decided in lab tests) the lab tests conducted show the antiviral activity is at very high, unsafe doses. There is quoted posological and pharmacodynamic data on Ivermectin within those studies and to go back to an earlier comment I made on this thread - I recommend listening to the podcast "This Week in Virology" episodes I listed, it's hosted by Vincent Racaniello who is a renowned expert in this field and his guests for this topic are highly esteemed.

I certainly hope a high quality RCT shows Ivermectin is an effective treatment, it would be great. Doesn't necessarily mean I think it's a realistic expectation from the research that's been conducted to date. Look at how this bangwagonism worked out for hydroxychloroquin, azithromycin, chorloquin etc. I'm not saying we stop looking, I'm saying these need to be based on rigor.

I too hope for a treatment, rather than a manipulation by mRNA as I fear that might have unwelcome consequences in the long term.

On the matter of chorloquin/hydroxychloroquin I don't believe the final definitive result is yet in, particularly in combination with other substances.
Whether the will is there to investigate more fully or not is the real question.
Unless that will is there we could be in for a very long division of opinions on the efficacy of such substances.

Miike · 26-02-2021 10:59pm

Johnboy1951 wrote: »

I too hope for a treatment, rather than a manipulation by mRNA as I fear that might have unwelcome consequences in the long term.

On the matter of chorloquin/hydroxychloroquin I don't believe the final definitive result is yet in, particularly in combination with other substances.
Whether the will is there to investigate more fully or not is the real question.
Unless that will is there we could be in for a very long division of opinions on the efficacy of such substances.

Hydroxychorloquin was proven to be ineffective by both the Solidarity and RECOVERY trials. FDA and NIH TxG have both explicitly stated there is no treatment benefit and revoked the authorization.

Johnboy1951 · 26-02-2021 11:04pm

Miike wrote: »

Hydroxychorloquin was proven to be ineffective by both the Solidarity and RECOVERY trials. FDA and NIH TxG have both explicitly stated there is no treatment benefit and revoked the authorization.

Going on failing memory ....... but as I recall there are a lot of questions around the dosages which were nowhere close to what those who claim to have positive results used, both in timing and amounts.

Miike · 26-02-2021 11:16pm

Johnboy1951 wrote: »

Going on failing memory ....... but as I recall there are a lot of questions around the dosages which were nowhere close to what those who claim to have positive results used, both in timing and amounts.

I don't remember off the top of my head regarding Solidarity but the RECOVERY Trial in protocol 6 tested recommended, below threshold and above threshold for hydroxychloroquin. Zero benefit but excess cardiac events detected in the treatment arm.

Timistry · 27-02-2021 11:57pm

Defies logic that a Pharma company would not pursue an API it produces if it was aware it had an efficiency against COVID19 or has the potential to have

speckle · 28-02-2021 5:15am

Eagle eye who brought Ivermectin onto our radsr originally has just posted this on the main thread.. tropical drug to be tested on critcal ill patients in Ireland as part of an international clinical trial..

https://m.independent.ie/irish-news/tropical-drug-to-be-tested-on-critically-ill-patients-here-40140143.html

Johnboy1951 · 28-02-2021 10:31am

speckle wrote: »

Eagle eye who brought Ivermectin onto our radsr originally has just posted this on the main thread.. tropical drug to be tested on critcal ill patients in Ireland as part of an international clinical trial..

https://m.independent.ie/irish-news/tropical-drug-to-be-tested-on-critically-ill-patients-here-40140143.html

It was my understanding that Ivermectin was most effective as a prophylaxis and an early treatment, for Covid 19.

Is this trial designed to measure that effect?
Apparently not as it is being administered to critically ill patients, according to the linked page.

Seems rather late in the disease progress to be administering Ivermectin.

....... maybe I misunderstood where it is most effective ....

Piollaire · 28-02-2021 3:59pm

Timistry wrote: »

Defies logic that a Pharma company would not pursue an API it produces if it was aware it had an efficiency against COVID19 or has the potential to have

The main focus of a pharma company is to maximise shareholder value. It is quite logical for Merck/MSD to pursue therapeutics that are much more profitable than Ivermectin.

Piollaire · 28-02-2021 4:13pm

Johnboy1951 wrote: »

It was my understanding that Ivermectin was most effective as a prophylaxis and an early treatment, for Covid 19.

Is this trial designed to measure that effect?
Apparently not as it is being administered to critically ill patients, according to the linked page.

Seems rather late in the progress to be administering Ivermectin.

....... maybe I misunderstood where it is most effective ....

Using Ivermectin as a hail mary treatment for those already on death's door is going to do the case for Ivermectin more harm than good.

Miike · 28-02-2021 4:34pm

speckle wrote: »

Eagle eye who brought Ivermectin onto our radsr originally has just posted this on the main thread.. tropical drug to be tested on critcal ill patients in Ireland as part of an international clinical trial..

https://m.independent.ie/irish-news/tropical-drug-to-be-tested-on-critically-ill-patients-here-40140143.html

I'm not being funny but is there more to that article behind the premium wall or is it just 60 words? I'd love to know more about this test

Got it. Part of what seems to be a large multi-center trial. Heres hoping!

is_that_so · 28-02-2021 5:06pm

Piollaire wrote: »

Using Ivermectin as a hail mary treatment for those already on death's door is going to do the case for Ivermectin more harm than good.

From the Independent article it seems the trial's aim is to provide a definitive answer to clinicians.

speckle · 28-02-2021 5:17pm

Miike wrote: »

I'm not being funny but is there more to that article behind the premium wall or is it just 60 words? I'd love to know more about this test

Got it. Part of what seems to be a large multi-center trial. Heres hoping!

apologies miike... if I had realised it was behind a paywall.I would have added another link but last night when it first came out it wasnt paywalled.

Miike · 28-02-2021 7:49pm

speckle wrote: »

apologies miike... if I had realised it was behind a paywall.I would have added another link but last night when it first came out it wasnt paywalled.

Not your fault at all!

Thanks for getting back to me

Piollaire · 01-03-2021 11:20am

Found the article up on twitter:

https://twitter.com/Covid19Crusher/status/1366060019620454401/photo/1

Disappointing that the study is only focussing on critically ill patients. The real beauty of Ivermectin is its anti-viral ability which stops you from getting critically ill in the first place.

Johnboy1951 · 01-03-2021 2:52pm

I have just watched a presentation by Dr. Paul Marik and found it well worth the time spent

https://www.youtube.com/watch?v=OY8QV7lnFFo

If I could get hold of Ivermectin I would be taking it now as a preventative.
Even if it does not help a great deal, it is highly unlikely to cause any harm, and is cheaper than chips.
A no brainer it seems.

Piollaire · 01-03-2021 4:44pm

Johnboy1951 wrote: »

If I could get hold of Ivermectin I would be taking it now as a preventative.

I agree.

Our only hope is that a large scale study will prove its efficacy. Merck/MSD have let us down badly and the European and national medicine agencies have failed us too.

Johnboy1951 · 01-03-2021 5:57pm

Piollaire wrote: »

Found the article up on twitter:

https://twitter.com/Covid19Crusher/status/1366060019620454401/photo/1

Disappointing that the study is only focussing on critically ill patients. The real beauty of Ivermectin is its anti-viral ability which stops you from getting critically ill in the first place.

A trial set up to give results showing how ineffective the treatment is?

Sure seems like it .....

See19 · 14-03-2021 10:35pm

The evidence for using Ivermectin is being overlooked below, India has the largest Ivermectin usage in the world with the lowest Covid death rate. In early 2019 India was forecast to have the highest Covid deaths but due to Ivermectin has the lowest and no one has any other evidence to explain this.

Covid Deaths for 1M Pop (Worldometer 14th Feb 2021)
1. UK = 1842
2. USA = 1,646
3. India = 114

Miike · 14-03-2021 10:37pm

See19 wrote: »

The evidence for using Ivermectin is being overlooked below, India has the largest Ivermectin usage in the world with the lowest Covid death rate. In early 2019 India was forecast to have the highest Covid deaths but due to Ivermectin has the lowest and no one has any other evidence to explain this.

Covid Deaths for 1M Pop (Worldometer 14th Feb 2021)
1. UK = 1842
2. USA = 1,646
3. India = 114

Insightful first post.

Have a look at Indias median age versus your quoted comparisons and how COVID deaths are being recorded (read as: they aren't). Also Ivermectin isn't in widespread use in India - Unless you've access to data the proves otherwise? I would love to see it

The Ivermectin discussion

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