Effect of Ivermectin on COVID-19 Infection and Mortality

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His latest mid week Ivermectin update shows how Mexico has crushed Covid-19 due to widepsread Ivermectin use as has Panama. Meanwhile, regions of India that use Ivermectin such as Uttar Pradesh (population 210 million) has much lower rate of infection/mortality than regions such as Marashtra which don't use it.

 
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nerd

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Ivermectin, can make novel drug research redundant because of its high efficacy, low cost, generic availability, in any phase of the disease. It would not require experimental approval such as vaccines still do. This makes it a threat for big pharmaceutical companies and their investments into novel drugs and even vaccines.

It is possible via study design modifications to create manufactured outcomes. We've seen this with the JAMA study. We've seen this with studies on vitamins. We've seen this with many psychiatric studies in the CFS/ME field. I estimate that some of the big new RCTs that are scheduled to evaluate Ivermectin, including the one by the Gates Foundation who has taken a huge interest and investment into other research, will create faulty results and these studies will be held up like it's the only thing that counts. Just like with the Oxford study on dexamethasone that used too low doses that underachieved in its potential efficacy. Their dosage ultimately ended up in the guidelines. An underachieving dosage. When you use insufficient Ivermectin, too late, in geographically confounded areas, and select only the single endpoint that doesn't show statistical significance after all this, which will most likely be measured in days because days are an imprecise measure on its own, then I guarantee that this study will have the same conclusion, namely that Ivermectin can not be recommended. And everyone will reference this study, not because it was well designed, but because it was large. The JAMA study is just the blueprint.

This will ultimately endanger the approval process of Ivermectin globally. Every media outlet will report this study when they ignored all the smaller and well-designed studies favoring Ivermectin's use. Most medical doctors will follow the public opinion. It will be just another Hydroxychloroquine case to them. However, I think that the mass of other RCTs and epidemiological data can not be ignored endlessly. And there are many RCTs to come. It will be a race between Ivermectin and these new drugs that are in the pipelines for overlapping purposes. Once these novel drugs are approved, Ivermectin won't receive sufficient attention among them to be such a great financial threat.
 
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The UK antiviral taskforce needs to authorize emergency use for Ivermectin for prophylactic purposes.
The FLCCC have just had another paper published in the American Journal of Theraputics that was peer reviewed by senior scientists from NIH:

Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19
doi: 10.1097/MJT.0000000000001377

Don't get me started on monoclonal antibody drugs which are very expensive and have low efficacy.
 
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Hip

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The general public on social media do not use language in such a precise way, but scientists are very careful and disciplined about their statements, and will not state something is true unless there is sufficient evidence.

Coronavirus vaccine researchers for example were very careful with their language, not overstating what the vaccines might achieve. These researchers for example did not claim in advance that the vaccines would reduce coronavirus spread, because they had no evidence for this (even though it was very likely to be the case). Now that we have evidence that vaccines do reduce coronavirus transmission by about 50%, researchers can now go ahead and make this statement.


It's fine to have enthusiasm about ivermectin, and it is possible it may turn out to have some benefit for coronavirus. I've spend many hours looking at ivermectin and its mechanisms of action.

But in the disciplined use of language that scientists employ, statements of fact must always be backed up by solid evidence. Small scale trials are not solid evidence.


There are thousands of experimental COVID treatments that might potentially work; obviously we cannot give COVID patients thousands of pills just on the off-chance some might work. That is why medical authorities tend to reject speculation and hearsay about the efficacy of a treatment until evidence is provided.



It is possible via study design modifications to create manufactured outcomes.
But it is universities or hospitals which carry out most studies, not pharmaceutical companies.
 
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There are now several meta analysis of Ivermectin proving its efficacy.
Apex medical bodies, primarily in rich developed countries, routinely dismiss the science around Ivermectin from mainly low-middle income countries which borders on hubris.
Besides, the 52 medical trials involving 17,557 patients, of which 27 are RCT's show how Ivermectin crushed infections/mortality rates.
Dr. Pierre Kory's latest webinar presents compelling epidemiological evidence from Mexico, Panama and regions of India that prove the efficacy of Ivermectin.
 
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nerd

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Small scale trials are not solid evidence.
Individually, they are not. Once pooled into a meta-review, these single small to mid-sized studies are stronger evidence than a large multi-center RCT. This is just statistics and the spread of RCTs onto multiple sources, authors, and clinics, in fact, make design flaws, conflicts of interests, and bias even less likely than you can expect from a large RCT. These flaws don't have to be intentional, but there are always confounders that might not be considered. And a large multi-center trial usually is very homogeneous in its setup and design. To have multiple smaller RCTs, composed into a meta-review, gives much more insight into what potential confounders can be. When you have heterogeneously designed studies but with homogeneous and consistent results, this is of greater significance than any large-scale multi-center RCT. Meta reviews are the highest degree of evidence you can get in science. And when meta-reviews show statistical significance, this is considered evidence because it proves what I just described.

Ivermectin got its antiparasitic approval based on far less evidence than we have right now for COVID-19. Remdesivir got its approval based on less evidence.

There are thousands of experimental COVID treatments that might potentially work; obviously we cannot give COVID patients thousands of pills just on the off-chance some might work. That is why medical authorities tend to reject speculation and hearsay about the efficacy of a treatment until evidence is provided.
This isn't the same. All these drugs are experimental because their safety isn't shown yet. Safety evaluation makes the approval process more demanding and complicated. You see this with the new experimental vaccines and how some of them are already restricted due to unexpected complications. With an already approved drug with a long safety history, this is no challenge anymore. You only have to show the efficacy. I encourage you to watch the conference.

Moreover, all these new drugs have basically the problem that they focus on one mechanism of action against a virus that has many pathological mechanisms. Ivermectin, on the other end, covers multiple mechanisms of action. This is another reason why it can not be simply compared with most of the novel COVID-19 drugs. They will ultimately only work during one phase of the disease, but not all unless multiple mechanisms can be identified.
 

Hip

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Individually, they are not. Once pooled into a meta-review, these single small to mid-sized studies are stronger evidence than a large multi-center RCT.
Maybe. But the issue with ivermectin is that there is no known mechanism by which it could benefit COVID or fight coronavirus.

I believe ivermectin came to attention after an in vitro study showed it had potent antiviral effects against coronavirus. However, the authors of this study did not explain that the concentrations of ivermectin they used in vitro were far too high to ever be attained in vivo. The actual concentrations which can be safety achieved in vivo are much lower. So this means ivermectin has pretty much zero antiviral effect in the body, when taken at the normal doses known to be safe.

I was able to calculate the pharmacokinetics of ivermectin, and show that it will have no antiviral effect in the body. Later a published study also confirmed that ivermectin will have no antiviral effect in vivo.

Once you are in a situation where there is no theoretical explanation of the claimed anti-coronavirus effects of a drug, then people are naturally going to be more skeptical.



By the way, @nerd, could you please break up your posts in to paragraphs of around 3 or 4 lines, as many ME/CFS patients have difficulties in reading large blocks of text.
 

nerd

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But the issue with ivermectin is that there is no known mechanism by which it could benefit COVID or fight coronavirus.
That's what you're made to believe when you read what some media wrote about it. But it's not correct. There are dozens of interactions between Ivermectin and SARS-CoV-2. Dr. Been mentions just a few of the most relevant ones for antiviral efficacy in his conference talk. But there are even more immune-modulatory and anti-inflammatory mechanisms that he doesn't cover. My favorite study is the one on protein-protein interactions showing broad anti-viral potential by a huge range of interactions (10.1002/jcp.30055).

For SARS-CoV-2, the most important ones have been confirmed by other in vitro methods from other authors as well (10.1080/07391102.2020.1841028; 10.3389/fmicb.2020.592908; 10.21873/invivo.12134; 10.2217/fvl-2020-0342). All of these mechanisms have to contribute to the efficacy of Ivermectin. It's naive to believe that this virus, which has multiple proliferation mechanisms, can be fought just by focusing on a single interaction.

I believe ivermectin came to attention after an in vitro study showed it had potent antiviral effects against coronavirus. However, the authors of this study did not explain that the concentrations of ivermectin they used in vitro were far too high to ever be attained in vivo. The actual concentrations which can be safety achieved in vivo are much lower.
Their calculation was a preemptive approach considering data available at the time. But they had to compare the in vitro antiviral efficacy with attained concentrations in rat or mouse kidney tissue. SARS-CoV-2 main pathology doesn't happen in kidney tissue but in lung tissue. Ivermectin attains much higher concentrations in lung tissue. Dr. Paul Marik already debunked this theory months ago and recalculated, based on attainable concentrations in lung tissue, that antiviral efficacy can be achieved by the already-approved dosage of 200mcg/kg.

So this means ivermectin has pretty much zero antiviral effect in the body, when taken at the normal doses known to be safe.
Even if you'd don't achieve an IC50, which is the case in kidney tissue, this doesn't mean you don't achieve an EC50. Ivermectin is also host-directed, after all, and this isn't reflected in virus inhibitory concentrations. Nevertheless, even if you don't achieve an EC50, "pretty much zero effect" is a completely inconsistent interpretation. The body responds to SARS-CoV-2 with or without Ivermectin, hence a lower efficacy than EC50 is still beneficial.

Later a published study also confirmed that ivermectin will have no antiviral effect in vivo.
In the conference, the Israelian team of Prof. Schwartz showed their preliminary results of ex vivo cell viability. Ivermectin's viral inhibition is not only clear in PCRs, it's even clearer in their cell viability model. PCRs don't show active virus replication, after all, but also dead viral residue. Cell viability research isn't confounded this way.

By the way, @nerd, could you please break up your posts in to paragraphs of around 3 or 4 lines, as many ME/CFS patients have difficulties in reading large blocks of text.
I try whenever I can. On my end, the latest comment had a paragraph of 5 lines. Is it different in your browser?
 
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Hip

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My favorite study is the one on protein-protein interactions showing broad anti-viral potential by a huge range of interactions (10.1002/jcp.30055).
Let's go through the pharmacokinetics for this coronavirus antiviral study you linked to:

This study added ivermectin at a concentration of 20 μmol/L (20 μM) to a cell line in vitro.

But what kind of concentrations of ivermectin can realistically be achieved in vivo, in the body fluids and tissues, when ivermectin is given to a patient? Typically a 12 mg to 18 mg daily ivermectin dose is given to COVID patients in studies.

Well, we can look at pharmacokinetic studies to get an answer to this question: this pharmacokinetic study found that a 36 mg oral dose of ivermectin led to peak blood level (Cmax) of 78 ng/ml (= 0.09 μM) in humans.

So already we see that the 0.09 μM blood concentration of ivermectin is over two orders of magnitude smaller than the concentration used in the study you linked to.

But it gets worse: the plasma protein binding of ivermectin is quite high, at 93%, and given that usually the protein-bound portion of a drug or supplement becomes inactive, and only the free portion of the drug is active (this is known as the free drug principle or free drug hypothesis), the actual blood concentration of the free ivermectin is even lower.

The free concentration of ivermectin in the blood we can calculate as: 0.09 x 7% = 0.006 μM.

So now we see that the blood concentration of free ivermectin is over 3000 times smaller than the concentration used in the cell line in the study that you linked to.


So while ivermectin may have antiviral effects at the very high concentrations used in cell lines in vitro, in the body the concentrations of free ivermectin are over 3000 times smaller, so those antiviral effects will all but vanish, unfortunately.



It's naive to believe that this virus, which has multiple cell invasion mechanisms, can be fought just by focusing on a single interaction.
Antiviral drugs have a variety of mechanisms of action. Some antivirals are entry inhibitors, which prevent the virus entering the cell in the first place. But I believe the majority of antiviral drugs are replication inhibitors, which block the virus from replicating once the virus has entered the cell.

The antivirals sometimes used to treat ME/CFS (Valtrex, Valcyte, Famvir, cidofovir, Epivir) are all replication inhibitors. The antiretroviral drugs used to treat HIV are replication inhibitors.

With replication inhibitor antivirals, it does not matter how the virus enters the cell, because you are not blocking viral entry, but inhibiting viral replication.



Ivermectin attains much higher concentrations in lung tissue.
In the all-important lung tissue, ivermectin appears to attain concentrations around 3 times higher than its concentrations in the blood (at least in a goat study).

This helps, but still the concentrations in lung will be a 1000 times smaller than the 20 μM concentrations used in the study you linked to.



In summary: from what we know, ivermectin does not appear to have any substantial antiviral effect in vivo.

I do suspect ivermectin will be proven to be effective in reducing the death rate in COVID patients once we get a large-scale study done. This paper says that mortality was lower in patients given around 15 mg ivermectin compared to the controls (13% vs 25%).

However, the mechanism by which ivermectin helps COVID remains to be elucidated. You can see from the above pharmacokinetic data that it does not appear to be an antiviral mechanism; but it could be an immunomodulatory mechanism, whereby ivermectin modulates immune function in way that helps the body better clear the virus.
 
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nerd

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But it gets worse: the plasma protein binding of ivermectin is quite high, at 93%, and given that usually the protein-bound portion of a drug or supplement becomes inactive, and only the free portion of the drug is active (this is known as the free drug principle or free drug hypothesis), the actual blood concentration of the free ivermectin is even lower.
The 93% have been calculated in a 1990 study with 5 participants. However, considering how susceptible plasma protein binding is to various factors (e.g. an infection) (10.1128/AAC.01433-10), 5 participants might not be the best representation for the use case.

Still, when Ivermectin binds to a protein that participates in SARS-CoV-2 pathologies such as cell fusion (e.g. proteins of the Angiotensin system), it can contribute to Ivermectin's antiviral efficacy. The high binding rate only suggests a high activity of Ivermectin. Moreover, cells can also provide a drug delivery vessel. Together, this relativizes the significance of this high binding rate.

Regardless, you can still try to model how much unbound Ivermectin gets into the desired tissue. I can follow this practice.

So now we see that the blood concentration of free ivermectin is over 3000 times smaller than the concentration used in the cell line in the study that you linked to.
If you mean the study that evaluated the IC50 in Vero cells, this is not the best-suited cell line for the use case. Please check this study on why a Vero cell line isn't useful for the evaluation of antiviral efficacy and why the author's new human lung-derived cell line (i.e. MRC5) provides the better medium (10.1038/s41598-021-84882-7).

So while ivermectin may have antiviral effects at the very high concentrations used in cell lines in vitro, in the body the concentrations of free ivermectin are over 3000 times smaller, so those antiviral effects will all but vanish, unfortunately.
Fortunately, it's not that simple. Your calculation is based on a very simplified idea of drug delivery. Arshad et al. used a Rodgers and Rowland model and determined that, in lung tissue, Ivermectin's recommended oral dose attains over an order of magnitude greater concentration than the reported IC50 (10.1002/cpt.1909).

Lastly, what's often overlooked, repeated doses of Ivermectin accumulate due to the long half time of Ivermectin in tissue. For the treatment of COVID-19, the FLCCC currently recommends 400 to 600 mcg/kg for 5 days in their newest version of their protocol. This could be compared to a single dose of 2mg/kg. Even this more conservative study that used a minimal PBPK model found the attainable concentration in lung tissue to be fairly close to the IC50 in the Vero cells (10.1016/j.xphs.2020.08.024).

Here is a comment of Prof. Paul Marik in response to the NIH guidelines that also reflected the same oversimplified calculation by comparison to the Vero cell findings.


Antiviral drugs have a variety of mechanisms of action. Some antivirals are entry inhibitors, which prevent the virus entering the cell in the first place. But I believe the majority of antiviral drugs are replication inhibitors, which block the virus from replicating once the virus has entered the cell.
My bad. What I really meant to describe is the proliferation of the virus itself and all the mechanisms that enable the proliferation, cell fusion and the replication of viral proteins included. You are correct that many drugs focus on replication, Remdesivir and Ivermectin included, and yet, by focusing on replication only, many drugs have to interact with physiological signaling. This can cause severe adverse effects as known from Remdesivir. If you interact with multiple mechanisms, you need lower concentrations and this also reduces the likelihood of adverse effects.

With replication inhibitor antivirals, it does not matter how the virus enters the cell, because you are not blocking viral entry, but inhibiting viral replication.
Even if you inhibit viral replication, you still need a response from the host. SARS-CoV-2 has many subpathologies, including immune suppression, which, unless tackled, relativize the IC50.

In the all-important lung tissue, ivermectin appears to attain concentrations around 3 times higher than its concentrations in the blood (at least in a goat study).
This still doesn't correct the bias from the Vero IC50 model. It's simply not translateable, even if you assume that goats and monkeys are translateable to humans - kidney and lung tissues have different IC50s, not just drug attainable concentration.

However, the mechanism by which ivermectin helps COVID remains to be elucidated.
You don't need to know which of the many mechanisms of action contribute to which degree in Ivermectin's efficacy when all the studies clearly show that Ivermectin works in the prophylaxis and treatment of COVID-19.

You wouldn't need it for CFS/ME either. The reason why pathology is so important in CFS/ME is that we don't know the disease well enough and this makes it a lottery game to find the right treatment and what to put in a trial.
 
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Hip

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The high binding rate only suggests a high activity of Ivermectin.
I don't believe that is the case. Most drugs and supplements, as well as endogenous substances, bind to proteins in the blood plasma to some degree. My understanding is that protein binding is a means of transport for some substances, especially if they have low solubility in the blood plasma.

The degree of plasma protein binding can be as low as 0%, or as high as 99% or more, depending on the drug or supplement. Most acidic drugs binds to the albumin protein in the blood; whereas basic drugs bind to alpha1-acid glycoprotein. Ref: here.

Drugs and supplements can also bind to proteins in the tissues, I understand, but I am not clear on which proteins they bind to.

It can be very annoying for drug developers when substances have high plasma protein binding, as if a substance has say 99% binding, it means its effective free concentration in the blood is 100 times lower. So in these cases, the in vitro benefits of a substance may be lost in the body due to high protein binding, and the 100-fold reduction in effective concentration.

One antifungal drug called itraconazole is a potent antiviral for enterovirus in vitro (I have enterovirus-associated ME/CFS), and I was hoping to use it; but it turns out that itraconazole has 98.2% plasma protein binding, so its antiviral effects in vivo are greatly reduced.



Your calculation is based on a very simplified idea of drug delivery. Arshad et al. used a Rodgers and Rowland model and determined that, in lung tissue, Ivermectin's recommended oral dose attains over an order of magnitude greater concentration than the reported IC50 (10.1002/cpt.1909).
It is certainly true that some drugs can have unusual tissue-accumulation effects which make simplified calculations invalid. I was looking at fluoxetine pharmacokinetics a few years while ago (it is antiviral for coxsackievirus B in vitro), and from what I could work out, the free levels of fluoxetine in the brain are about 400 times higher than free levels in the blood.

This means that fluoxetine may have useful antiviral effects in the brain, even though its antiviral effects in the blood and interstitial fluids are negligible. There are some case studies where fluoxetine has helped with coxsackievirus B encephalitis.

Unfortunately fluoxetine does not seem to help ME/CFS, even though there is evidence of enterovirus infection in ME/CFS brain autopsies. Though the chronic non-cytolytic coxsackievirus B infections found in ME/CFS are not the same as acute lytic coxsackievirus B infections, so maybe this explains the failure. Dr John Chia experimented with fluoxetine for enterovirus-associated ME/CFS some years ago, but I did not hear of any positive results.

I had to learn a little bit about pharmacokinetics, as I spent many months looking at the pharmacokinetics of off-label drugs and supplements which were shown in vitro to be antiviral for the herpesviruses and enteroviruses found in ME/CFS (here is my list of enterovirus antiviral compounds), in the hope of finding some compounds which might be useful as an antiviral treatment in ME/CFS.

Unfortunately I did not find many useful compounds, with the possible exception of very high dose genistein being effective for cytomegalovirus. Though I was only able to use simple pharmacokinetic models, like the one I outlined above for ivermectin.


I like the paper you linked to; it explains the problem with all these in vitro coronavirus studies — that not enough effort has been made to examine the pharmacokinetics, to see if these antivirals might stand a chance of working in vivo against coronavirus:
There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans.
Of the identified molecules with reported anti‐SARS‐CoV‐2 activity, the overwhelming majority are not expected to reach active concentrations within the key target compartments. However, a number of candidates were identified that are expected to exceed the concentrations necessary to provide viral suppression at doses approved for use in humans.

This paper says that using a model developed by Rodgers and Rowland, it predicts that ivermectin will reach concentrations in the lungs which are over 10-fold higher than its EC50. At this level, ivermectin may provide some modest antiviral effects (to get strong antiviral effects, you usually need to exceed the EC50 by about 50-fold, as most commercial antivirals drugs do).

However, I would like to know more about the Rodgers and Rowland model.

The ivermectin IC50 in this study is 2 μM. Given that the blood concentration of free ivermectin are over 30000 times lower than this IC50, it is quite extraordinary that the Rodgers and Rowland model claims ivermectin can concentrate in the lungs to a level of over 10 times higher than the EC50 (see figure 4 of your paper). That is a difference of nearly 6 orders of magnitude.

I'd like to understand how the lungs are able to concentrate free ivermectin at levels which are one million times higher than you find in the blood. Would you have any insight into this?


By the way, I am not clear on the difference between EC50 and IC50 in the context of in vitro viral testing. Do you know why some in vitro antiviral studies quote EC50 and others quote IC50 figures?

I understand what the EC50 is: the concentration which reduces viral replications by 50% in a cell line. Or sometimes it means the concentration which reduces cytopathic effects in the cell line by 50%.



Even if you inhibit viral replication, you still need a response from the host. SARS-CoV-2 has many subpathologies, including immune suppression, which, unless tackled, relativize the IC50.
Indeed. One theory I have for why ivermectin may be effective for COVID is because thus drug stimulates the production of antibodies (in mice), via a mechanism involving T-cells. Ref: here.

Now one provisional study suggests coronavirus may induce autoantibodies which actually attack the B-cells and T-cells of the immune system (B-cells are responsible for creating antibodies), and some speculate this attack could explain why the immune system struggles to control coronavirus.

So maybe ivermectin's stimulation of antibody production is helpful in COVID to overcome this autoimmune attack on the immune system.



You don't need to know which of the many mechanisms of action contribute to which degree in Ivermectin's efficacy when all the studies clearly show that Ivermectin works in the prophylaxis and treatment of COVID-19.
If there is good empirical evidence for efficacy, you should not need to understand the mechanisms in order to employ the treatment. But I think scientists are usually more convinced if they know how a drug is working.
 
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Hip

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Looking more closely at the pharmacokinetic paper you linked to and the Rodgers and Rowland model for predicting lung concentrations of drugs:

If you look at figure 4 of the paper, which shows whether or not drugs achieve the EC50 concentration in the lungs, ivermectin is one of the drugs that does quite well, achieving a Cmax/ EC50 ratio of over 10.

But if you look at figure 2 of the paper, which shows whether or not drugs achieve the EC90 concentration in the lungs, ivermectin does poorly, with the Cmax/ EC90 ratio of 0.01.

I don't know why ivermectin does poorly on the EC90. But if we take the EC90 result as the correct one, then ivermectin will have only minimal antiviral effects in the lungs.



The EC50 is the antiviral concentration which reduces viral replication by a factor of 2, and the EC90 concentration which reduces viral replication by a factor of 10. The EC90 is more representative of the sort of concentrations you need to achieve to have a clinically useful effect.

So if in the lungs ivermectin only reaches concentrations which are 0.01 of the EC90, it will not have much antiviral effect.
 

nerd

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This paper says that using a model developed by Rodgers and Rowland, it predicts that ivermectin will reach concentrations in the lungs which are over 10-fold higher than its EC50. At this level, ivermectin may provide some modest antiviral effects (to get strong antiviral effects, you usually need to exceed the EC50 by about 50-fold, as most commercial antivirals drugs do).
More accurately, it's in the 25x to 30x range. So if you take the 0.4 mcg/kg single dose or 0.2 mcg/kg two day dose into consideration, it's in the 50x range.

The ivermectin IC50 in this study is 2 μM.
This is IC50 is only valid in Vero kidney tissue, to be clear. The above-mentioned MRC5 study found four orders of magnitudes of difference in antiviral activity using Remdesivir compared to Vero cells (s41598-021-84882-7). Ivermectin includes the same mechanism of action that Remdesivir primarily exhibits.

I'd like to understand how the lungs are able to concentrate free ivermectin at levels which are one million times higher than you find in the blood.
It's not one million times higher. You just have a different IC50/EC50 in lung tissue than in the blood or kidneys.

The MRC5 study gives an explanation for this:

Monkey-derived Vero cells are highly [susceptible] to infection with SARS-CoV-2, although they are not suitable for the study of antiviral effects by small molecules due to their limited capacity to metabolize drugs compared to human-derived cells.
I hope this makes things clearer. You could also have a look at the presentation of Dr. Paul Marik who did his own calculation or took it from another study.

One antifungal drug called itraconazole is a potent antiviral for enterovirus in vitro (I have enterovirus-associated ME/CFS), and I was hoping to use it; but it turns out that itraconazole has 98.2% plasma protein binding, so its antiviral effects in vivo are greatly reduced.
I wonder how liposomal delivery changes the interaction with plasma proteins. Many new studies use liposomal, or engineered nanoparticles, which are similar in nature, to improve drug delivery. I think it's not only the absorption rate that changes.

I understand what the EC50 is: the concentration which reduces viral replications by 50% in a cell line. Or sometimes it means the concentration which reduces cytopathic effects in the cell line by 50%.
EC50 leaves it up to the author to choose the desired endpoint. The Arshad et al. study wasn't picky in this aspect.

half‐maximal effective concentration (EC50) OR half‐maximal inhibitory concentration OR antiviral
So they used the IC50 as the baseline for Ivermectin.

But if you look at figure 2 of the paper, which shows whether or not drugs achieve the EC90 concentration in the lungs, ivermectin does poorly, with the Cmax/ EC90 ratio of 0.01.
This isn't lung tissue-specific but a systemic EC90, based on plasma concentrations.

KpUlung was then used along with fraction unbound in plasma (fu) and plasma Cmax values to calculate a predicted Cmax/EC50 (Figure 4) and Cmax/EC90 in the lungs (data not shown).
The lung-specific EC90 is not shown. Quite disappointing that it's not even in the supplementary. This study isn't easy to validate. I can only trust that the peer-review was thorough.
 

nerd

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Hip

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The above-mentioned MRC5 study found four orders of magnitudes of difference in antiviral activity using Remdesivir compared to Vero cells
It's certainly true that the in vitro effect of antiviral drugs on a given virus can vary substantially from one cell line to another. But to my knowledge, we have not got in vitro data for the antiviral effect of ivermectin on the relevant cells in the lungs.

So I don't know how anyone can claim that ivermectin can reach antiviral concentrations in the lungs, given only in vitro data I know of is the study in vero cells mentioned earlier.

And I am not sure how valid it is to take data from a different drug like remdesivir, and assume that ivermectin will behave in the same way.


It is also worth mentioning that in the paper you mentioned earlier, their model predicted that hydroxychloroquine would be the most potent antiviral for coronavirus, since figure 4 indicates the model predicts hydroxychloroquine reaches concentrations of 1000 times higher than the EC50. This in theory would make hydroxychloroquine an extremely potent antiviral.

But we know from the many empirical clinical trials that hydroxychloroquine's performance is rather lackluster.



I wonder how liposomal delivery changes the interaction with plasma proteins. Many new studies use liposomal, or engineered nanoparticles, which are similar in nature, to improve drug delivery. I think it's not only the absorption rate that changes.
I have looked into liposomal delivery.

But the issue with any drug or supplement is that you are limited to the established maximum safe dose, and if you go higher, you may start getting adverse effects.

Now if you use liposomal delivery, you may increase the concentration of the drug inside cells, but potentially this may also increase adverse effects, so that your maximum safe dose becomes lower, because liposomal delivery has made the drug more potent.

This may not necessarily happen, but I think it would be hard to predict.
 

Hip

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Do you know what viruses may underlie you own ME/CFS, @nerd? Have you been appropriately tested for the usual culprits (coxsackievirus B, echovirus, EBV, cytomegalovirus, HHV-6 and parvovirus B19)?