Arbidol; a novel Antiviral and Immunomodulator

[Jesse2233]

The Rupintrivir was used as a control since it doesn't inhinbit IL-10, that is the essence of our problem. Just because it shows anti viral properties to CVB4 does not mean that a compound will be effective against the "persistent" intra- cellular infection we're dealing with.

Understood, I wonder if a combo of an IL-10 inhibitor and a CBV4 antiviral would work. I'm seeing Dr Chia on Monday, so I'll ask him then

 

[Steve4Andrea]

Just an update, last week we increased the dosage of Arbidol to 200mg. per day with an occasional day off to recover from the reaction (about 1 every 3-4 days). No significant changes to her symptoms yet. We have just started to include 1mg. of Rapamune every other day to the protocol, I'll update the progress on that in a couple of weeks.

I have also just found, while cleaning out our freezer, 2 syringes containing .10 ml. each of injectable GCMAF, this is enough for 6 injections of a dosage that we have used before. At some time I'll incorporate this into our protocol

@Jesse2233 The Rapamune should function as an IL-10 inhibitor as well as modulating other cytokines, I'm hoping that it works with the Arbidol to increase overall effectiveness. Here is some research I found regarding chronic or persistent CVB4 infection in a Pancreas model, one area of their focus was the IL-10 pathway also-

http://www.sciencedirect.com/science/article/pii/S0042682212001043

 

[ErdemX]

@Steve4Andrea Any updates about using Arbidol?

I hope your wife had some improvement after those worsenings..

 

[Hip]

Here are some calculated human doses for Arbidol:

Arbidol CVB4 study: Mice in vivo: 100, 200, and 300 mg/kg of Arbidol (umifenovir) dose-dependently inhibited the viral load in myocardial tissues in mice, and also reduced CVB4-induced IL-10 increase.

100 mg/kg in mice corresponds to a human dose of 100 / 12.3 = 8.1 mg/kg (since 12.3 is the mouse-to-human conversion factor). Thus for an 80 kg human, this is an oral dose of 648 mg of Arbidol.



Arbidol CVB5 study: Mice in vivo: 25 and 50 mg/kg of Arbidol (umifenovir) were given to groups of mice infected with CVB5:

Untreated control group of mice: by day 18 of infection, all had died.
25 mg/kg of Arbidol group of mice: by day 30, half of them had survived.
50 mg/kg of Arbidol group of mice: all survived.

So it looks from this that the best antiviral effect was obtained at 50 mg/kg.

50 mg/kg in mice corresponds to a human dose of 50 / 12.3 = 4.1 mg/kg, which for an 80 kg human is a dose of 328 mg of Arbidol.



In this article, it says you can use a dose of 4 x 200 mg of Arbidol daily. However, such a dose would cost around $10 per day.

 

[Steve4Andrea]

Here is an update on our Arbidol usage.

We are now up to 400 mg. per day (200mg. morning and night), it has been a start and stop progression to get to the 400mg. with several periods of stopping for a few days before continuing.

Andrea is still experiencing an increase in general “inflammation” symptoms such as body aches, headaches, transient “fevers”, brain fog and her ever present nausea. Her symptom of abdominal swelling has gone from “most of the day” to “daily but not all day” so we have seen some improvement as well as she is now eating a more varied diet.

During one of the breaks from Arbidol she rebounded to the point that we took a short walk down the street, this is significant because it was the first time she had left the house for a non-medical reason since January. In general we are hopeful about the Arbidol but it is a frustratingly slow process and tough for her to endure.

I had originally planned on a maximum dosage of 600mg. day but as I have continued to investigate I'm beginning to think that may not be enough. @Hip as you point out the 600mg. matches the 100mg/kg/d dose of the CVB4 study but my concern is that the MIC50 level seems to be 300mg/kg/d and from Lerner the best results occur with the MIC50 level for 85% of the day. I have found studies to indicate that a 200mg. dose generates a concentration of 1.23 ug/ml, again leading to a need for a higher dose (I also found reference that a single 800mg. dose generates 2.16ug/ml so I'm not certain about bio availability). Right now I'm leaning toward two 300mg. doses per day with a possibility of going to 3 per day.

As an aside- Arbidol does not play well with grapefruit, it changes the metabolites produced.

 

[Jesse2233]

@Steve4Andrea thanks for true update, I feel for your poor wife

Have you tried ARVs such as tenofovir? Dr Chia has reported that it has some effectiveness in certain CVB4 cases

Perhaps hyperbaric oxygen could better diffuse the Arbidol into muscle tissue to fight the virus

Forgive me if these options are impractical or have been tried, just thinking off the cuff here

 

[ErdemX]

@Steve4Andrea Thank you for the detailed update.

I'm happy to hear about the short walking outside the house. I hope your wife can start having very noticeable improvements after she passes a certain point.

 

[perrier]

Here is an update on our Arbidol usage.

We are now up to 400 mg. per day (200mg. morning and night), it has been a start and stop progression to get to the 400mg. with several periods of stopping for a few days before continuing.

Andrea is still experiencing an increase in general “inflammation” symptoms such as body aches, headaches, transient “fevers”, brain fog and her ever present nausea. Her symptom of abdominal swelling has gone from “most of the day” to “daily but not all day” so we have seen some improvement as well as she is now eating a more varied diet.

During one of the breaks from Arbidol she rebounded to the point that we took a short walk down the street, this is significant because it was the first time she had left the house for a non-medical reason since January. In general we are hopeful about the Arbidol but it is a frustratingly slow process and tough for her to endure.

I had originally planned on a maximum dosage of 600mg. day but as I have continued to investigate I'm beginning to think that may not be enough. @Hip as you point out the 600mg. matches the 100mg/kg/d dose of the CVB4 study but my concern is that the MIC50 level seems to be 300mg/kg/d and from Lerner the best results occur with the MIC50 level for 85% of the day. I have found studies to indicate that a 200mg. dose generates a concentration of 1.23 ug/ml, again leading to a need for a higher dose (I also found reference that a single 800mg. dose generates 2.16ug/ml so I'm not certain about bio availability). Right now I'm leaning toward two 300mg. doses per day with a possibility of going to 3 per day.

As an aside- Arbidol does not play well with grapefruit, it changes the metabolites produced.

Thank you very much. Is Dr Chia overseeing this? Or are you venturing on your own?

 

[Hip]

I had originally planned on a maximum dosage of 600mg. day but as I have continued to investigate I'm beginning to think that may not be enough. @Hip as you point out the 600mg. matches the 100mg/kg/d dose of the CVB4 study but my concern is that the MIC50 level seems to be 300mg/kg/d and from Lerner the best results occur with the MIC50 level for 85% of the day.

I am not familiar with the term MIC50, but I think it may be the same as the EC50. Usually in vitro antiviral studies use the term EC50 or IC50 (which I think are both synonymous), and the EC50 is the concentration of the antiviral compound that results in 50% reduction in viral replication in the cell line (or in some studies, a 50% reduction in virus-induced cell death in the cell line).

In the Arbidol in vitro antiviral studies on CVB3, CVB4 and CVB5, the EC50 concentrations that resulted in 50% viral inhibition in the cell were in the range of 6 to 9.5 μg/ml. So if you introduce Arbidol at these concentrations to virally infected tissues, you would expect around a 50% reduction in viral replication or in virus-induced cell.

I have found studies to indicate that a 200mg. dose generates a concentration of 1.23 ug/ml

I have seen pharmacokinetic studies come up with similar figures: for example, this pharmacokinetic study found that after one week of dosing Arbidol at 200 mg three times day in a group of human subjects, the mean peak blood plasma concentration of Arbidol was 0.41 μg/ml.

However, there is a further complexity here, because when a drug enters the bloodstream, a certain percentage of that drug will bind to proteins in the blood, and the remaining percentage of the drug will dissolve in the blood plasma, and become what is known as the free drug.

Now the free drug hypothesis states that it is only the free drug dissolved in the blood (or dissolved in the interstitial fluids) that has an active pharmacological effect in the body, whereas the portion of the drug bound to proteins in the blood (or bound to tissues of the body) becomes pharmacologically inactive.

Arbidol happens to have a high plasma protein binding of 90%, which means that 90% of the Arbidol in the bloodstream becomes "wasted" and inactive as it binds to these blood proteins, and it's only the remaining 10% of the Arbidol that is free and unbound that is active in the body.

So that means although Arbidol reaches a concentration of 0.41 μg/ml in the blood, only 10% of that is actually active, so the effective concentration of Arbidol in the blood is ten times smaller, at 0.041 μg/ml.

I did not know about the free drug hypothesis or about drug plasma protein binding until recently, but learnt about it after I reading a little bit about pharmacokinetics.


However, there is a further consideration here, which suggests that in spite of the low blood concentrations of Arbidol resulting from its high plasma protein binding of 90%, Arbidol will still have a reasonable antiviral effect in the body. This is because I think Arbidol may be one of the few drugs that does not follow the free drug hypothesis (most drugs obey the free drug hypothesis rule, but there are a handful that don't, and my guess is that Arbidol may be one of the exceptions to this free drug rule).

If you are interested in more details, I have put some further info in the following spoiler:

Spoiler: Does Arbidol break the free drug hypothesis rule?

OK, so we have seen above how when dosing at 3 x 200 mg daily, Arbidol only reaches an effective 0.041 μg/ml concentration in the blood, which is well below the EC50 antiviral concentration of 6 to 9.5 μg/ml. So it seems at first glance that Arbidol's antiviral effects in the body would be pretty weak.

However, we know from the in vivo mice studies that Arbidol's effects in the body are in fact quite reasonable. Which contracts the calculation that Arbidol's antiviral effects in the body would be weak. So what's going on? Why the discrepancy between the in vivo results, and these pharmacokinetically calculated results?

After thinking about this issue for some time, I came to a possible explanation of this discrepancy: it turns out that Arbidol has affinity for cell lipid membranes (which may underpin its antiviral effects). Ref: 1

So if membrane-bound Arbidol takes part in its antiviral effects, it is not just the free Arbidol in the blood and tissues that has antiviral actions, but is also the Arbidol which is bound onto the cell membrane that participates in the antiviral effects.

Thus it seems to me that Arbidol might be an exception to the free drug hypothesis, based on the possibility that bound Arbidol as well as free Arbidol is active in the body.

So if the Arbidol bound to cell membranes is pharmacologically active in terms of its antiviral effects, this might explain the above discrepancy. Because above in our calculation we were assuming that only the free Arbidol has an active antiviral effect; but the tissue-bound Arbidol attached to cellular membranes may also have an antiviral action.

So that's my best explanation for the discrepancy. But really we would need an expert in pharmacokinetics to comment on this, because pharmacokinetics is complex, and I only know the basic rudiments of it.

Right now I'm leaning toward two 300mg. doses per day with a possibility of going to 3 per day.

The plasma half life of Arbidol is around 17 hours, which is a reasonably long half life, so dosing twice a day should be fine.

 

[knackers323]

@Steve4Andrea where did you get the EWF?

 

[Steve4Andrea]

@Steve4Andrea where did you get the EWF?

I bought 1 kilo. of dried flowers & leaves from a supplier on Indiamart (I can't find my records of which one but there are several listed https://dir.indiamart.com/impcat/woodfordia-fruticosa.html ), as I recall it was less than $50 US for the material & shipping.

I then ground batches of 40g. of flowers & leaves in a coffee grinder and extracted that in 375 ml. of 95% ethanol (Everclear in the US) for several days at about 150 deg. F. After extraction I filtered it and we started with 4 ml. per day and eventually increased to 15 ml. per day. If you need more info on extraction let me know. I probably have a couple of hundred grams left from the original kilo.

After reaching a dose of 12 ml./day Andrea began to feel better and made significant improvements over several months, we got lazy and didn't keep to the protocol and then she was hit with several "high stress" events in a couple of days and regressed.

After the regression we could never replicate the success, this is consistent with the reporting of Dr. Chia's use of Equilibrant, the moral of the story is- if you get better, be careful until you are good, not just better.

My use of EWF was based on these studies-

http://www.kpubs.org/article/articleDownload.kpubs?downType=pdf&articleANo=MSMSBV_2014_v42n2_207

http://onlinelibrary.wiley.com/doi/10.1111/j.1472-765X.2010.02805.x/full

I have also bought three other Chinese herbs for use against CVB4 but I have tabled them for now while we pursue the Arbidol.

 

[knackers323]

What is chias thinking behind only getting one shot at it? The vurus develops immunity?

 

[Steve4Andrea]

I've never seen a written explanation and it's never come up in conversation with him, I don't remember where I've seen it reported, maybe @Hip will know.

My guess is that the most sensitive virus population dies first and so you are left with the most resistant virus at the end of treatment, sort of a survival of the fittest situation. It could be some form of mutation to create drug resistance but it occurred over the span of 6 months in our case so I would think not.

I've not seen these reports from actual pharmaceutical products so I'm hoping for better results using Arbidol.

 

[knackers323]

@Steve4Andrea sorry if youve mentioned this already but does your wife feel better when having not eaten?

and improves more the longer (to a point where it plateaus-about 3 days for me) without food?

 

[Hip]

I've never seen a written explanation and it's never come up in conversation with him, I don't remember where I've seen it reported, maybe @Hip will know.

I don't think there is any general rule that antiviral or immunomodulatory treatment for enterovirus-associated ME/CFS only works the first time.

In the case of oxymatrine, after it worked the first time but was then discontinued, in a few cases it did not work the second time, but I believe in most cases it will work the second time too.

In the case of interferon treatment for ME/CFS, this may not work the second time after a first course, but the reason for that is likely because the body will often make antibodies to interferon after several months of interferon treatment, which then disables the interferon and stops it from working.

I suspect that the interferon suppository treatment I detailed in others post may get around this problem of antibodies developing; but in any case Dr Chia says interferon does not work for CVB4.