Enteroviruses - revisited

[Jesse2233]

The other antidepressant discussed earlier, pirlindole, also targets 2C. I am guessing this will have some effect against non-cytolytic enteroviruses.

Do we know of anyone who has tried pirlindole at the right dosage?

And forgive me, but what is 2C?

 

[JollyRoger]

A propos .. what is a
non-cytolytic form???
Can they be harmful?
When I take the drug over a long time (many with depression take it for years) and suppress the active form of the virus I should be symptome free.
Is oxymatrine effective for the non cytolyic form?

Im a ME newbie (8 month).... not so long as the case of the immunsupressed boy.
Does this mean that changes are high for me to get a remission??

 

[Hip]

Do we know of anyone who has tried pirlindole at the right dosage?

I don't know anyone, but I would not have thought pirlindole is going to be much better than fluoxetine, and we know that fluoxetine is not really the answer for ME/CFS, although it may possibly help a bit, as so could form part of an antiviral cocktail.

And forgive me, but what is 2C?

It is a viral non-structural protein; these are proteins encoded by viral genes and synthesized by the virus, and are critical for the viral life cycle. So if a drug inhibits such viral proteins, then it inhibits the virus. Enterovirus has a number of non-structural protein, including: 2A (inhibited by nitric oxide / nitric oxide donors), 2C (inhibited by fluoxetine and pirlindole), 3A (inhibited by itraconazole and enviroxime), 3C (inhibited by rupintrivir and nitric oxide / nitric oxide donors).

what is a
non-cytolytic form???

It's explained in this post.

Im a ME newbie (8 month).... not so long as the case of the immunsupressed boy.
Does this mean that changes are high for me to get a remission??

I am not sure. I think this question has been asked before on the forum, but I can't remember the answer.

 

[JollyRoger]

The boy in this case had the virus for 1.5 years so I think he had certainly both types of the virus.
At that time, he was no longer tracking or making eye contact and started to develop difficulty with swallowing.
Even immunoglobuline didn't work.
Than he took fluoxetine and recovered slowly to a level where he could attend the school albeit he had some problems with motor skills.
If a immunsupressed child after 1.5 years of encephalititis who additionally got immunosuppressive therapy with steroids and rituximab can have a recovery why should this drug ineffective?
If it doesn't work it can't be the enterovirus

 

[JES]

@JollyRoger Yeah, one would think Fluoxetine would work for enterovirus caused CFS/ME since it worked for the kid. The dosage is the big question. As you say, brain concentrations are much higher than blood concentrations. I also read some paper where it said brain antidepressant concentrations from deceased pilots were on average a factor of 10 higher than blood concentrations. So in theory a standard starting dosage of 20 mg could give some effects. Dr. Chia has apparently used Prozac in combination with interferon according to this blog post, but it was a couple of years ago.

Anyway, the question remains why I didn't notice much positive impact from 20 mg. It's possible that I don't have an active enterovirus infection, though I have many reasons that support the premise that I have it. Or the infection is still maintained in some other parts like stomach tissues, which 20 mg might not be enough to reach. Who knows. It would be nice to have someone else trialing Fluoxetine, as my cognition is so negatively affected by going much higher than 20 mg. I couldn't imagine taking the equivalent dosage of the kid for more than a short duration, the side effects would be that massive.

@Hip Thanks for the links, I wasn't aware of mospharma.com, that certainly makes ordering within EU a lot more convenient.

 

[JollyRoger]

I think because it's a vicious cycle.
Entero in brain -> autonomic dysfunction -> weak immune system + oxidative stress + mitochondrial dysfuntion.
Cleaning up the cause is not the only think.
I think that's the reason why the virus reappears after interferon.
Maybe you try in combination with oxymatrine.
I think I will give it a try because it also has anti neuroinflammation effects and one study says that it can help to rebuild brain mass.... so its a win-win situation.

 

[Hip]

If a immunsupressed child after 1.5 years of encephalititis who additionally got immunosuppressive therapy with steroids and rituximab can have a recovery why should this drug ineffective?
If it doesn't work it can't be the enterovirus

I mentioned above, it may not be a brain infection that is the primary cause of ME/CFS. It could be an enterovirus infection of another organ that causes ME/CFS, such as a vagus nerve infection (see Michael VanElzakker's vagus nerve infection hypothesis of ME/CFS).

Or ME/CFS might only occur when the enterovirus triggers autoimmunity. Lots of people have enterovirus infections, but do not have ME/CFS. So enterovirus alone is not a sufficient cause of ME/CFS.

Similar to type 1 diabetes: there is evidence that type 1 diabetes may be due to coxsackievirus B4 causing autoimmune attack on the insulin producing cells of the pancreas. But lots of people (like me) have coxsackievirus B4, but do not have diabetes. So the theory is that you get diabetes not directly from CVB4, but when CVB4 triggers autoimmunity to insulin cells.

 

[Hip]

@JollyRoger, I think I have noticed a problem with fluoxetine:

As you found out, fluoxetine concentrates into the brain and central nervous system at levels 20 times higher than in the blood. And so low oral doses of 20 to 40 mg of fluoxetine have been shown to produce high concentrations of 14 μM in the brain (much higher than its EC50 concentration of 2.3 μM). Ref: 1

However, it seems the antiviral effects of fluoxetine are not linearly dose dependent (see Fig 1B of this study, and Fig 2C of this study). So although you get a 50% reduction in viral replication at the EC50 concentration of 2.3 μM, as you further increase the fluoxetine concentration, you don't get much further increase in antiviral efficacy. In fact the second study says:

Peak antiviral activity of both compounds was achieved at a concentration of 6.25 μM.

So it seems that going higher than a concentration of 6.25 μM will not give you any increased antiviral effect. By my calculation, 6.25 μM corresponds to an oral dose of around 110 mg.

So the really high 14 μM concentrations that your study reported in the brain are not going to have as much antiviral effect as one would think.



You get a similar thing with pirlindole: after a 1.5 μM tissue concentration of the drug is reached, you get no further increases in antiviral efficacy as you raise the concentration eve further (see Fig 4B).

 

[JollyRoger]

But it was sufficient to heal him.
Im not interested in the concentration but In the effect.

Another example;

Group B Coxsackieviruses (CVB) are involved in various acute clinical features and they can play a role in the development of chronic diseases like type 1 diabetes. The persistence of CVB has been described in vitro and in vivo in various models. Fluoxetine was reported to inhibit the replication of CVB1-3, which prompted us to study the in vitro antiviral activity of fluoxetine against CVB4 in models of acute infection. In addition we took advantage of a chronically CVB4-infected Panc-1 cell line to evaluate the antiviral effect of fluoxetine in a model of persistent CVB4 infection. An inhibition of the CVB4 replication was obtained when fluoxetine was added at 5.48 μM to Hep-2 cell cultures. No inhibitory effect was observed when CVB4 was mixed with fluoxetine for 2h and filtered to eliminate fluoxetine before inoculation to cells, or when cells were treated up to 96h and washed before viral inoculation. Fluoxetine (5.48 μM) reduced viral replication by more than 50% in acutely infected Panc-1 cell cultures. A dramatic decrease of infectious particles levels in supernatants of Panc-1 cells chronically infected with CVB4 was obtained a few days after treatment with fluoxetine and no infectious viral particle was found as soon as day 21 of treatment, and intracellular enteroviral RNA was undetectable by RT-PCR after three weeks of treatment. These data display that fluoxetine can inhibit the replication of CVB4 and can cure Panc-1 cells chronically infected with CVB4

A chronic infection healed....
I think eradicating the infection is one think... cleaning up the mess like autoimmunity or mitochondrial dysfunction another.

 

[Hip]

Im not interested in the concentration but In the effect.

This finding of 6.25 μM representing the concentration of maximum antiviral effect implies that after you reach certain dose level of fluoxetine, increasing the dosage higher still produces no further benefits (at least in the particular cell line tested). By my calculation, 6.25 μM corresponds to an oral dose of around 110 mg.

 

[JollyRoger]

110mg for how much weight?
In the chronic pancreatitis example a dose of
5.48 was enough to eradicate the virus in 21 days.

In combination with Ldn and oxymatrine the ideal entero bomb

 

[Hip]

110mg for how much weight?

I based it on an 85 kg person, a fluoxetine concentration C = 6.25 μM, a fluoxetine molecular mass M = 309.33 grams per mole, and a fluoxetine oral bioavailability B = 70%. The basic equation I devised is:

Oral human dosage in grams = C x M / (B x 250).

The rationale for this equation is given here.

Note that this is a rough calculation, because there is no reliable way to accurately convert micromolar (μM) concentrations used in cell line studies in vitro, into oral doses for humans, due to multiple factors affecting the result.

In the chronic pancreatitis example a dose of
5.48 was enough to eradicate the virus in 21 days.

It was not actually pancreatitis in a human, but an in vitro study, using pancreatic cells in a dish. Nevertheless, it is an interesting finding.

I just found this paper: Hypoglycemia associated with fluoxetine treatment in a patient with type 1 diabetes

This paper found that after taking fluoxetine 20 mg daily for depression, this type 1 diabetes patient found she needed less insulin to treat her diabetes. Since we know type 1 diabetes is linked to CVB4 infection of the pancreas, this perhaps suggests that fluoxetine reduced the viral infection in the pancreatic beta cells which make insulin, so that these infected beta cells could recover to a degree, and recommence their natural production of insulin.

Perhaps fluoxetine + dihydroquercetin + Tamiflu + Arbidol, which all target CVB4, could be a good treatment to reduce the severity of type 1 diabetes.

 

[Jesse2233]

@JollyRoger

Here's a story about a woman who fully recovered from ME/CFS using Prozac. Her doctor had his own theory, but recovery may have been from an enterovirus being cleared from her brain

Heather and Dr David Smith's Protocol

Source: http://www.angelfire.com/stars/cfsrecovery/conventional.html

I first felt ill about 300 metres from where I am writing this now, but I have been around the houses quite a bit since. I was in my first year of university in Nottingham, UK in 1993, aged 18, and studying physics of all things. When I came back from the Easter break it all went a bit pear shaped.

Over the Easter holidays I had not felt quite right. To use a quote from 'Withnail and I', I felt 'unusual'!! I was needing more and more sleep, my appetite decreased and my get up and go had got up and went. I went to stay with a friend over the holidays and where before I had always been dying to go out and party I just wanted to lie down in front of the TV. All this, however, only became clear in hindsight at the time I didn't really notice anything as it was all so subtle and gradual and at no time did I actually feel 'ill'.

When I returned to University and had lot to do and a few late nights catching up with friends but I got to the stage when I found it almost impossible to get out of bed. It wasn't a physical impossibility, my legs still worked but it was sort of like having a hangover and flu at once, 'just 5 more minutes' repeated over the whole day. This was the time when I lay in bed for 23 hours and didn't move a muscle!!

My friends got worried and took me to the doctor who couldn't really do much as it could have all manner of viruses/bugs that go round halls of residence. There the fun began

Lots of useless, sometimes even spiteful, doctors saw me and diagnosed pregnancy (no chance!), drug abuse (I offered blood to disprove this but they seemed to prefer to accuse me!), exam phobia etc etc.

The fourth GP I saw was excellent and guessed at ME/CFS and sent me to a pathologist to rule out everything else. At last a diagnosis - one that we had already guessed at but I was told to 'come back if I had any problems' - not very helpful as I thought that that was the whole reason I was there, how naive of me!

Anyway I did gradually improve over the next couple of years by learning to deal with it, getting lots of sleep, pacing myself etc. and felt ready to return to university in 1995, this time to study psychology. In a way this was the most frustrating part of my illness. I was sodetermined to do and beat the illness through willpower alone yet even that was not enough. I lasted a term and by the end (10 weeks) I had lost 2 stone (28 pounds for those in the US!) through feeling continuously nauseous, always a problem symptom for me, my grades had dropped to borderline fails when I was used to As, and I never got to see the handful of friends I had made because all my spare time was spent sleeping.

In my own stupid way, however, I hid all this at Christmas as everyone, including myself, was so proud that I had beaten my illness to some degree. Nonetheless it all came out when my parents wanted to watch the home video my flatmates and I had made during our last week. I freaked. I could see how ill I looked, and knew what was going through my mind. A near panic attack ensued and everything came out but I felt huge relief to admit that I wasn't coping.

This was the turning point. I did not return to college and finally decided to go and see a doctor that had got a friend of mine better. Somehow I did not consider that I was a serious enough case to 'waste' his time before, despite the fact I had no life!!

I had to wait quite a while for the first appointment but when it came I had 2 hours to give the whole gory story and he told me he would get me better.

There started 3 years of steady improvement and the near 2 years of full health I have enjoyed since.

The treatment involved very carefully controlling what I did each day, starting from a ridiculously low level and therefore allowing myself to get better while starting on a regime of two drugs. He used tripmipramine to help me sleep and therefore feel rested and prozac as stimulant and to help my brain recover. There are more details of the treatment at Dr. David Smith's website but here is an overview...

The brain has a membrane that protect it from various things that you find in the rest of your body because it needs an 'unpoluted' environment. If you are under pressure this can become leaky and it will also be affected if you are ill (colds, flu etc.) In CFS the sufferer may be burning the candle at both ends, stressing about stuff (for me I wasn't happy with my course but wasn't brave enough to change it, there was all kinds of personal stuff too) then on top gets an illness.

If the barrier gets leaky the brain is affected but it is up to the brain to repair it. Thus if the brain is too severely affected it is not able to repair itself and you get stuck, hence CFS. (We all know that fuzzy head during a cold feeling or during stressfull times but it usually goes.) This means the whole brain is affected and explains the huge range of symptoms.

The prozac helps the brain to work again by replacing the chemicals it is lacking and this along with controlling activity means you get out of the viscious cycle.

The drugs are started at very low levels as CFS patients are very sensitive to all drug treatment and I was left in total control of how much I took (as much as possible with no adverse effects.) As soon as the drugs increased to a reasonable level I felt my brain was awakening once more. One of the more bizarre effects was that my eyesight improved (I didn't my glasses anymore!) because my eye muscles were controlled more!

It was hard work sticking to the whole regime, I wasn't allowed to do any activity for more than 10 minutes at a time so I didn't tire myself out but I soon got used to this as rather than try to watch a film all in one go and lose the plot totally through lack of concentration half and hour in I could enjoy the whole thing in small chunks over 2 days.

After a year or so I took up a couple of hours work a week in a charity shop, then moved on the voluntary work in a drug centre (completely by chance but something I loved and would like to do for a living) and in the Autumn of 1998 I returned to Nottingham University as a fresher for the third time. I have hardly had the time to look back since.

My full recovery linked with the knowledge that I missed out on a lot of stuff has meant that I never stop. I can study this time and even enjoy the subject, my grades have improved to As once more. I have time to play in a band and dedicate to two 4 hour practice sessions a week in the evenings. I have a full social life and can even pull the odd 'all-nighter' (going to morning lectures after no sleep) with no real adverse effects.

It is wonderful.

 

[mrmichaelfreedmen]

Here's my question, these treatments showed effectiveness for live active virema, but what about non-cytolytic intracellular EVs? Will any of these drugs be effective against stealth viruses in tissue?

Very good question...

 

[JollyRoger]

....and no infectious viral particle was found as soon as day 21 of treatment, and intracellular enteroviral RNA was undetectable by RT-PCR after three weeks of treatment. These data display that fluoxetine can inhibit the replication of CVB4 and can cure Panc-1 cells chronically infected with CVB4.

But, as hip mentioned, it's a high dose unless you have the weight of a child.
It could be effective in
combination with other drugs like oxymatrine.

If it's the cause..........

 

[Hip]

I just added a new potent coxsackievirus B and echovirus antiviral named dipyridamole to the antiviral list at the beginning of this thread.

Dipyridamole (a vasodilator) is described in this paper as a potent inhibitor of CVB3, and this paper says dipyridamole inhibits a wide range of viruses.

This patent states that:

dipyridamole itself, while having in fact no or negligible antiviral activity, is capable of remarkably enhancing the antiviral activity of IFN-α, especially HuIFN-α [human interferon alpha]

So it fights viruses by boosting the effects of interferon alpha.

This enhancement on interferon alpha might make dipyridamole useful in fighting non-cytolytic enterovirus infections in ME/CFS, since interferon alpha switches on the intracellular immune response that fights non-cytolytic infections.

The patent suggests using dipyridamole at a concentration of 1 μM. The patent indicates that dipyridamole and interferon are to be taken together, so that the former boosts the antiviral effects of the latter.

But I wonder if dipyridamole might also be of benefit in ME/CFS just on its own. Dipyridamole is quite cheap, with 100 x 25 mg tablets costing around $8.

 

[Jesse2233]

Dipyridamole (a vasodilator) is described in this paper as a potent inhibitor of CVB3, and this paper says dipyridamole inhibits a wide range of viruses.

Nice find Hip, might this also improve blood flow to the brain given it's a vasodilator?

 

[Hip]

might this also improve blood flow to the brain given it's a vasodilator?

That's a good thought. Unfortunately though, I found this study which indicates that dipyridamole does not increase cerebral blood flow and vasodilation, even though it does increase vasodilation in the coronary arteries.

Dipyridamole increases coronary vasodilation by raising blood levels of adenosine, a coronary artery vasodilator. However, the study says that adenosine in the blood does not enter the brain, as it is blocked by the blood-brain barrier.

An ME/CFS patient here claims that adenosine is "one of the best kept secrets for energy" and is prescribed by some ME/CFS doctors. So the raised blood adenosine produced by dipyridamole might be useful for boosting energy levels.

Although this study found that blood adenosine is often raised in ME/CFS anyway (but the paper suggests this may be the result of an abnormal ATP energy metabolism, among other possibilities).

 

[Jesse2233]

An ME/CFS patient here claims that adenosine is "one of the best kept secrets for energy" and is prescribed by some ME/CFS doctors. So the raised blood adenosine produced by dipyridamole might be useful for boosting energy levels.

Interesting, could the adenosine be contributing a cofactor to ATP production?

 

[Hip]

Interesting, could the adenosine be contributing a cofactor to ATP production?

Not sure.