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Enteroviruses - revisted

Discussion in 'Antivirals, Antibiotics and Immune Modulators' started by globalpilot, Feb 3, 2012.

  1. Jesse2233

    Jesse2233 Senior Member

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

    And forgive me, but what is 2C?
     
  2. JollyRoger

    JollyRoger Senior Member

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    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??
     
    Last edited: Jun 15, 2017
  3. Hip

    Hip Senior Member

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    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.


    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).


    It's explained in this post.


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

    JollyRoger Senior Member

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    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
     
    Last edited: Jun 15, 2017
  5. JES

    JES Senior Member

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    @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.
     
  6. JollyRoger

    JollyRoger Senior Member

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    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.
     
    Last edited: Jun 15, 2017
  7. Hip

    Hip Senior Member

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    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.
     
    Last edited: Jun 15, 2017
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  8. Hip

    Hip Senior Member

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    @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:
    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).
     
    Last edited: Jul 16, 2017
  9. JollyRoger

    JollyRoger Senior Member

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    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.
     
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  10. Hip

    Hip Senior Member

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    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.
     
  11. JollyRoger

    JollyRoger Senior Member

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    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 :)
     
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  12. Hip

    Hip Senior Member

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    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.



    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.
     
    Last edited: Jun 16, 2017
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  13. Jesse2233

    Jesse2233 Senior Member

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    @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

     
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  14. mrmichaelfreedmen

    mrmichaelfreedmen

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    Very good question...
     
  15. JollyRoger

    JollyRoger Senior Member

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    ....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..........
     
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  16. Hip

    Hip Senior Member

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    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:
    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, which by my calculation works out to an oral dose of around 30 mg. 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.
     
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  17. Jesse2233

    Jesse2233 Senior Member

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

    Hip Senior Member

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    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).
     
  19. Jesse2233

    Jesse2233 Senior Member

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

    Hip Senior Member

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    Not sure.
     

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