Which antivirals are able to cross the BBB?

Nuno

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Ok so, we know viruses can affect the CNS, that is undeniable.
Assuming a virus has crossed once a weakened Blood Brain Barrier, at some point in time, what would be possibilities for one to target it?

I have been wrapping my head around this for a while, but not much information online, only about how it happens. But what about possible treatments?

Attention, this is all in theory and I just plan on hearing some insights from other people:

1- We could temporarily breach the barrier with drugs like Amitrypiline or bee venom peptides, to deliver antiviral drugs to the brain. Would that be doable, or possibly dangerous?

2- One could use venom peptides with antiviral properties, like scorpion or snake venom, https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC5217322/ - antiviral properties of animal venom peptides

3- One could use immune modulators? Though not sure how this would benefit, for some reason the immune system is not clearing the virus in the brain already right?

4- Possible traditional medicine herbs used for encephalitis in the past could be able to cross the BBB with antiviral properties? https://www.nature.com/articles/s41598-021-96917-0

Let me hear your insight guys, as the main reason I'm writting this post is to grab more knowledge on possibilities for this!
 

nerd

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Thanks for bringing this up. I'm also looking for good antiviral candidates.

Suppressing the BBB is very risky. You'd rather infect the brain and deliver toxins into the brain than reach good efficacy of an antiviral this way.

Only few compounds with antiviral activity in vitro can reach the necessary concentration in vivo. The potential of toxins to cause toxicity has to be considered as it has to be considered for typical antivirals. The same applies for herbs.

Immune modulators can be antiviral by suppressing the viral signaling but it won't eliminate the viruses from the respective cells just like a virustatic can.

Even for compounds that show such a good interactivity as the bioflavonoids from the referenced study, a substantial amount would have to be taken. Further study is necessary to determine IC50s and biomolecular characteristics to be able to make predictions. The issue isn't necessarily the BBB per se but the insufficiency of plasma concentrations in the first place.

It's generally unfortunate that natural compounds aren't studied well. China and Japan directly fund research on it but I don't think it's common in western countries to pursue an approval of these for therapeutic use. This means that there's only very limited data on safety when taken in high doses. This also means the most data is and remains available for synthetic virustatics. The most interesting ones, unfortunately, are still patented or in pipelines.

Apart from the BBB issue which can involve neurotoxicity, nephrotoxicity and mutagenicity remain important topics in antiviral research. Nephrotoxicity is actually the most important one since it's so prevalent at the moment.
 

nerd

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I did a quick check for supplements to support glial cells (the brain's immune cells), but didn't find anything.
But they might already be hyperactivated. If they are infected with a herpes virus targeting infected cells, the therapy has to target the signaling that mediates the immune evasion.

I think the theory of a hyperstimulated vagus nerve by microglia is applicable. It explains a lot of otherwise unexplainable symptoms. I also think the theory of HSV dual infection with other herpes viruses makes a lot of sense and that this might be the reason for the glial hyperactivity.

Which ones do you consider interesting if you dont mind me asking?
I'll come back to this once I have the strength to work at my computer. At the moment, I'm just writing with my smartphone.
 

sometexan84

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Unfortunately, I have VERY little knowledge on this. As one who believes viral infection of the brain is rare, I've never looked into antivirals like this.

If you look at COVID, while there's strong evidence of neural disruption, it's not often they actually find SARS-CoV-2 in the brain.

https://www.nature.com/articles/d41586-021-01693-6
A study published on 21 June compared the brains of 8 deceased people who had COVID-19 with the brains of 14 controls. The researchers found no trace of SARS-CoV-2 in the brains of the infected people, but they did find that gene expression had been affected in some astrocytes, which were not working properly
And remember, in the autopsies they do, these are people that had such severe COVID, they died from it. So you might expect to find more in the brain.

Same w/ the Enterovirus in ME/CFS, the autopsies done were insanely severe ME/CFS patients. And I believe Dr. Chia said it was found in one-third (in his latest presentation). Again, very severe patients. All his studies use only the most severe patients.

But I will keep an eye out for this type of antiviral.
 

Hip

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Which viruses are you planning to target? Antiviral drugs are target specific, so it needs viral testing to see which viruses are associated with your ME/CFS.

You can look up on Google whether a drug crosses the blood-brain barrier. Many drugs cross the BBB easily, others cross it to a degree, and others cannot cross at all, and so do not really enter the brain.

The antivirals which are usually used to target herpesviruses in ME/CFS, Valtrex, Famvir and Valcyte all cross the BBB reasonably easily. Cidofovir crosses it to a degree.

Tenofovir does not cross the BBB.

For enteroviruses, Epivir crosses the BBB.

Prozac (fluoxetine) has anti-coxsackievirus B effects in vitro and in vivo, and this drug not only crosses the BBB, but is known to accumulate in the brain tissues, and in fact free fluoxetine concentrations in the brain are over 500 times higher than the free fluoxetine levels in the blood plasma, which is remarkable. Thus fluoxetine antiviral effects are much stronger in the brain compared to the rest of the body.

However, the antiviral effects in the rest of the body are pretty weak, almost non-existent, so even at 500 times the level, the antiviral effects in the brain are only moderate. Dr Chia tried Prozac for his CVB ME/CFS patients around 5 or 6 years ago, but I heard no reports of success. People on this forum who tried Prozac also reported no success.

Interferon possibly crosses the BBB to a degree, but I don't think there is any solid data on this.



As @sometexan84 says, it depends whether we think a viral brain infection is playing a major role in ME/CFS.

Dr Dan Peterson has shown herpesviruses in the cerebrospinal fluid of some ME/CFS patients (he found 15% of ME/CFS patients have HHV-6 variant A in their CSF), suggesting that a low-level brain or spinal infection might be involved in ME/CFS pathophysiology at least in some patients.

With enterovirus it is more difficult to determine possible brain infection involvement, because as Dr Chia has pointed out in one of his presentations (see timecode 9:33), even in severe acute enterovirus infection of the brain (enterovirus encephalitis), you usually do not see any enterovirus at all in the cerebrospinal fluid. I've no idea why. But if you do not get enterovirus in the CSF in acute infections, you will certainly not see enterovirus in the CSF in the low-level chronic infections that may exist in the brain in ME/CFS.

That means we have no easy way of detecting possible enterovirus brain infection in ME/CFS, except for post-mortem examinations. And over the whole history of ME/CFS research, we have only had 3 such post-mortems, all were positive for enterovirus, but nevertheless we would need to test a lot more brains to see if there is a trend.
 
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Hip

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It's generally unfortunate that natural compounds aren't studied well.
Natural compounds are often studied for the purpose of creating lead molecules for the development of new antiviral drugs. But unfortunately, as I found out for myself, usually these natural compounds have insufficient antiviral effects to be useful on their own. It requires tweaking of their molecular formula to try to make them more potent.

When I first developed ME/CFS from a coxsackievirus B4 infection, I searched high and low for any compounds which were shown in studies to have antiviral effects against coxsackievirus B and other enteroviruses, either in vitro or in vivo. I compiled a long list of these compounds in this post.

Most of the studies in that post were in vitro, and at that time, I had insufficient knowledge of pharmacokinetics, which is necessary if you want to calculate whether the antiviral effects observed in vitro will also manifest in vivo, when a patient takes the compound. I was also too brain fogged at that time to even try to learn some pharmacokinetics.

Later when my ME/CFS improved, I was able to delve into pharmacokinetics, and I then was able to calculate whether those antiviral compounds would work in vivo. Sadly, even single damn one of them turned out to be ineffective in vivo! Or only had mild antiviral effects in vivo at best.

So that search for a natural antiviral (or off-label drug antiviral) was a wild goose chase.

As I mentioned, these studies on the antiviral effects of natural compounds are not usually performed because the researchers think they will find a natural antiviral with good clinical effects, but rather they are looking for natural lead molecules from which they can develop a new antiviral drug. About one quarter of all pharmaceutical drugs are derived from natural molecules which have been tweaked and modified to create a more potent effect.
 
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Nuno

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Which viruses are you planning to target? Antiviral drugs are target specific, so it needs viral testing to see which viruses are associated with your ME/CFS.

You can look up on Google whether a drug crosses the blood-brain barrier. Many drugs cross the BBB easily, others cross it to a degree, and others cannot cross at all, and so do not really enter the brain.

The antivirals which are usually used to target herpesviruses in ME/CFS, Valtrex, Famvir and Valcyte all cross the BBB reasonably easily. Cidofovir crosses it to a degree.

Tenofovir does not cross the BBB.

For enteroviruses, Epivir crosses the BBB.

Prozac (fluoxetine) has anti-coxsackievirus B effects in vitro and in vivo, and this drug not only crosses the BBB, but is known to accumulate in the brain tissues, and in fact free fluoxetine concentrations in the brain are over 500 times higher than the free fluoxetine levels in the blood plasma, which is remarkable. Thus fluoxetine antiviral effects are much stronger in the brain compared to the rest of the body.

However, the antiviral effects in the rest of the body are pretty weak, almost non-existent, so even at 500 times the level, the antiviral effects in the brain are only moderate. Dr Chia tried Prozac for his CVB ME/CFS patients around 5 or 6 years ago, but I heard no reports of success. People on this forum who tried Prozac also reported no success.

Interferon possibly crosses the BBB to a degree, but I don't think there is any solid data on this.



As @sometexan84 says, it depends whether we think a viral brain infection is playing a major role in ME/CFS.

Dr Dan Peterson has shown herpesviruses in the cerebrospinal fluid of some ME/CFS patients (he found 15% of ME/CFS patients have HHV-6 variant A in their CSF), suggesting that a low-level brain or spinal infection might be involved in ME/CFS pathophysiology at least in some patients.

With enterovirus it is more difficult to determine possible brain infection involvement, because as Dr Chia has pointed out in one of his presentations (see timecode 9:33), even in severe acute enterovirus infection of the brain (enterovirus encephalitis), you usually do not see any enterovirus at all in the cerebrospinal fluid. I've no idea why. But if you do not get enterovirus in the CSF in acute infections, you will certainly not see enterovirus in the CSF in the low-level chronic infections that may exist in the brain in ME/CFS.

That means we have no easy way of detecting possible enterovirus brain infection in ME/CFS, except for post-mortem examinations. And over the whole history of ME/CFS research, we have only had 3 such post-mortems, all were positive for enterovirus, but nevertheless we would need to test a lot more brains to see if there is a trend.
Hip, incredible write up as usual. Appreciate a lot your insight, where would we be without you?

I didn't know Prozac had a cumulative antiviral effect on the brain, that's interesting! It's weird people don't feel any improvement on it at all. If there is no low level viral persistence in the brain, then what could possibly be causing the neuroinflammation that has been shown in some spect scans?

Either ways, I have one more question if you don't mind.

Assuming one does have an infection in the brain, they currently use IV antivirals to treat encephalitis and meningitis right? Then does IV have any advantage on crossing the BBB or reaching the CNS over oral drugs? (While I'm saying IV, one could also say IM or Underskin, for peptides for example.)

Let's take Garlic for example, it's known to have antiviral properties against certain types. But what would be the potential of its properties to even help Brain Infections?
 

Hip

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does IV have any advantage on crossing the BBB or reaching the CNS over oral drugs?
Not that I know of.

It could be that IV is used because it gets into the bloodstream instantly, rather than waiting several hours for an oral drug to be absorbed from the stomach and reach its peak plasma levels. Especially with bacterial meningitis, which is very dangerous, you want to act quickly. And some drugs can only be given IV, as they are not orally bioavailable.
 

Shanti1

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Then does IV have any advantage on crossing the BBB or reaching the CNS over oral drugs?
Mannitol administered intraarterial has been shown to temporarily and reversibly disrupt the BBB. I have seen functional medicine doctors present this for the delivery of compounds to the brain, although I can't remember which at the moment.
 

Irat

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Hi
Not that I know of.

It could be that IV is used because it gets into the bloodstream instantly, rather than waiting several hours for an oral drug to be absorbed from the stomach and reach its peak plasma levels. Especially with bacterial meningitis, which is very dangerous, you want to act quickly. And some drugs can only be given IV, as they are not orally bioavailable.
Hi Hip,I have a question .first I have no idea what in vivo or in vitro means ,but I would like to know why you think that a bunch of natural treatments would not work.,? And why It would have been mega high doses? who does say that ?let's take a simple example of honey,it is even FDA approved for wound healing as the most potent antimicrobial agent ,and now a study for covid .and for herpes virus too
https://clinicaltrials.gov/ct2/show/NCT04323345

So why not taking things like cats claw,lysine,Zink,honey ,antiviral vegetables, wild plants ,coconut oil,Chinese herbs ,lemon balm ,algae etc etc ! .

Could you explain why this won't work ,because obviously it does for others and did for me, and has been used for thousands of years.but of course herbs don t bring money to big pharma

Or another example,urinary track infections often show better results in treating it with D mannose (a birch sugar) than with an Antibiotic.

Or i had a huge strepptococi abszess once,and the Doc said I need an Antibiotic and surgery on it.....well I got rid of it with kale pads
 
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hapl808

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I think there's also a huge difference between infections or immune system issues that affect the brain, as opposed to viral or bacterial matter breaching the BBB. As I've logged my symptoms more carefully, it's remarkable how much my gut and brain seem connected - in both directions. Too much mental concentration will trigger bad acid reflux the following day. Food that doesn't agree with me can trigger headaches. Antibiotics or anti-pathogen herbs usually trigger headaches followed by improvement. The whole category of herx and sufficient levels of drugs seems very complex and unsettled science. Things like skullcap or biofilm busting enzymes seem to complicate the picture even further.

I wish I knew more as many things will give me a 5%-10% improvement, but then stop working (as others have experienced). My first course of Zithro ten years after CFS started made me go from mild-moderate to almost completely healed in 3 days, and then promptly started to backslide. Not sure what mechanisms are at play.
 

Irat

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I think there's also a huge difference between infections or immune system issues that affect the brain, as opposed to viral or bacterial matter breaching the BBB. As I've logged my symptoms more carefully, it's remarkable how much my gut and brain seem connected - in both directions. Too much mental concentration will trigger bad acid reflux the following day. Food that doesn't agree with me can trigger headaches. Antibiotics or anti-pathogen herbs usually trigger headaches followed by improvement. The whole category of herx and sufficient levels of drugs seems very complex and unsettled science. Things like skullcap or biofilm busting enzymes seem to complicate the picture even further.

I wish I knew more as many things will give me a 5%-10% improvement, but then stop working (as others have experienced). My first course of Zithro ten years after CFS started made me go from mild-moderate to almost completely healed in 3 days, and then promptly started to backslide. Not sure what mechanisms are at play.
As I said here already few times I can t tolerate anything anymore that causes a herx reaction and i m allergie to almost all food....but I could back than..accupuncture did support my organs and my nervous system and herbs and food and homöophatie etc helped me also to detox and restore my immunsystem and healed my gut ,it took a long time,very slowly,but it helped and i went Into remission among with other things i did. I just want to encourage people that there are more ways than just pharma drugs.....but the more compromised our detox pathways are the more difficult is any kind of treatment unfortunately
 
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Hip

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Hi Hip,I have a question .first I have no idea what in vivo or in vitro means ,but I would like to know why you think that a bunch of natural treatments would not work.,?
I am not saying supplements do not work in general. They can have benefits, and I agree that D-mannose for example can be helpful for urinary tract infections. I myself found that high-dose selenium provided the most substantial improvement to my ME/CFS that I have obtained from any treatment, whether drug or supplement.

But when I was looking for a supplement to treat the virus which triggered my ME/CFS, namely coxsackievirus B4, I found no supplements that would work, in spite of the fact that I found dozens of supplements that have been shown to have potent antiviral effects for CVB4 in vitro.

In vitro means in a test tube, whereas in vivo means in the body.

When you test an antiviral supplement or drug in vitro, it means you put a sample of live human cells into a test tube, infect those cells with a virus, and then add your antiviral substance to the test tube, and observe whether it can inhibit the viral infection in the test tube. If it stops or reduces the viral infection, then you know it has antiviral properties for that particular virus.

Many alternative health practitioners, when they say that a certain supplement is antiviral, they are often referring to in vitro tests, performed in a test tube. But this does not mean the same antiviral will have efficacy in vivo (in the body).

Usually for in vitro tests, the studies will use extremely high doses of the supplement or drug, which is why they can often get a potent antiviral effect in the test tube. But those high doses are usually not possible in vivo (in the body), because there is a safe maximum dose for any supplement or drug. So an antiviral which is potent in vitro may have very little effect in vivo.



It's a complicated subject however, because supplements and drugs can be antiviral, but they can also fight viruses by boosting the immune system, and that cannot be measured in vitro.

Dr Chia has found that the herbal extract called oxymatrine, which is an immune booster, can sometimes be pretty effective for coxsackievirus B ME/CFS. But oxymatrine has no antiviral effects in the body; it fights viruses by stimulating the immune response.

Unfortunately oxymatrine did not help me.

There are a few other supplements which boost the immune response to fight viruses, but none have proved beneficial for ME/CFS. Dr Chia finds adding astragalus herb to oxymatrine slightly improves the effects of oxymatrine, but only in a minor way.
 

Irat

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I am not saying supplements do not work in general. They can have benefits, and I agree that D-mannose for example can be helpful for urinary tract infections. I myself found that high-dose selenium provided the most substantial improvement to my ME/CFS that I have obtained from any treatment, whether drug or supplement.

But when I was looking for a supplement to treat the virus which triggered my ME/CFS, namely coxsackievirus B4, I found no supplements that would work, in spite of the fact that I found dozens of supplements that have been shown to have potent antiviral effects for CVB4 in vitro.

In vitro means in a test tube, whereas in vivo means in the body.

When you test an antiviral supplement or drug in vitro, it means you put a sample of live human cells into a test tube, infect those cells with a virus, and then add your antiviral substance to the test tube, and observe whether it can inhibit the viral infection in the test tube. If it stops or reduces the viral infection, then you know it has antiviral properties for that particular virus.

Many alternative health practitioners, when they say that a certain supplement is antiviral, they are often referring to in vitro tests, performed in a test tube. But this does not mean the same antiviral will have efficacy in vivo (in the body).

Usually for in vitro tests, the studies will use extremely high doses of the supplement or drug, which is why they can often get a potent antiviral effect in the test tube. But those high doses are usually not possible in vivo (in the body), because there is a safe maximum dose for any supplement or drug. So an antiviral which is potent in vitro may have very little effect in vivo.



It's a complicated subject however, because supplements and drugs can be antiviral, but they can also fight viruses by boosting the immune system, and that cannot be measured in vitro.

Dr Chia has found that the herbal extract called oxymatrine, which is an immune booster, can sometimes be pretty effective for coxsackievirus B ME/CFS. But oxymatrine has no antiviral effects in the body; it fights viruses by stimulating the immune response.

Unfortunately oxymatrine did not help me.

There are a few other supplements which boost the immune response to fight viruses, but none have proved beneficial for ME/CFS. Dr Chia finds adding astragalus herb to oxymatrine slightly improves the effects of oxymatrine, but only in a minor way.
Thanks for clarification.......i just don t know if this is really true.you know I have grown up with my grandparents and for a flu we were treated with fresh elderberry syrup,for a couph with hot potatoes on the breast and for ear infection with onion pads,I also treated my dog with natural things for diagnose where doctors said he will need to be on steroids for the rest on his life...,so I don t really by into this.plus every one is different and what helps for one does n t for another,no matter what a study says .for me acupuncture did help more than anything else......no matter what a study would say about it.who heals is right
 
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Hip

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I have grown up with my grandparents and for a flu we were treated with fresh elderberry syrup
Elderberry may be effective for influenzavirus infection in vivo (this small in vivo study provides some evidence of efficacy). But that does not mean elderberry will work for other species of virus, and there are many other viruses.

For a given virus or disease, there may nothing available to help, neither supplements or drugs. Sometimes you can be lucky that a treatment is available for your infection or disease, but other times you may be out of luck.

Before HIV drugs were developed, people used to die of AIDS, in spite of trying many natural supplements.

There are 17 million people with ME/CFS, but nobody has found an effective treatment that works for these 17 million, in spite of the fact that ME/CFS patients are always trying thousands of supplements and drugs.

Type 1 diabetes is linked to CVB4 infection of the pancreas, but no natural treatment or drug can eradicate the virus and cure T1D. These are the realities.

But we are taking this thread off topic.
 
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Wishful

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If there is no low level viral persistence in the brain, then what could possibly be causing the neuroinflammation that has been shown in some spect scans?
Glial cells activate in response to cytokines produced elsewhere in the body. As I understand it, many of the symptoms you get from a cold or flu are the result of t-cells releasing cytokines, which activate glial cells, which in turn affect neural function and create neurotoxins (such as quinolinic acid), which make you feel those symptoms. It seems quite reasonable to have chronic neuroinflammation despite not having an infectious agent in the brain.

There are also feedback loops involving the gut, gut microbiome, and vagal nerve. I think just yesterday I read that immune activation caused gut bacteria to change their RNA transcription rates within hours. That in turn can affect gut permeability, causing more immune activation and thus glial activation. It's all interconnected.
 

Wishful

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Elderberry may be effective for influenzavirus infection in vivo (this small in vivo study provides some evidence of efficacy). But that does not mean elderberry will work for other species of virus, and there are many other viruses.
FWIW, elderberry extract is my go-to for viral infections. It seems to provide a very strong boost for my t-cells. Even without a viral infection, it would stimulate my immune system and worsen my ME symptoms. :grumpy:
 

Nuno

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There are also feedback loops involving the gut, gut microbiome, and vagal nerve. I think just yesterday I read that immune activation caused gut bacteria to change their RNA transcription rates within hours. That in turn can affect gut permeability, causing more immune activation and thus glial activation. It's all interconnected
I also thought of that, the gut microbiome disruption and the toxins it might send signaling. But at the same time, people with really disrupted microbiomes, like in C Difficile, they dont have such neurological problems as some people with ME/CFS.

But of course, its way more complicated than it seems, as just recently we are unraveling the relation between bacteria/virome and the brain.

Btw, do you know how does one turn down the glial cells over activation?