Phoenix Rising tells QMUL: release the PACE trial data
Mark Berry, Acting CEO of Phoenix Rising, presents the Board of Directors’ open letter to Queen Mary University of London (QMUL) urging them to release the PACE trial data, and hopes that other non-UK organisations will join British charities in the same request...
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Potential Suramin Alternatives - Sytrinol and Kudzu (Anti Purinergic Therapy)

Discussion in 'General Treatment' started by Jesse2233, Jun 23, 2017.

  1. necessary8

    necessary8

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    Oh wow. I didnt notice that before. You really did. Amazing work.

    Not really. I mean, there is some evidence that such a thing can maybe happen sometimes, but right now that evidence is very limited and of poor quality. I wrote about it in Part 1 of my ponderings.
    So far we only know for sure that eATP opens Panx1, in most cases.

    I still think suramin probably directly closes Panx1, even at the dose used in the autism trial. Because that's what Naviaux said in his presentations. I'm happy to be proven wrong by @nandixon or anyone else, but I need to see their math, with sources for all the important values. So far he hasn't produced those. (And I dont blame him, I know we all have very limited energy. But when someone proposes a speculation that is pretty much the direct opposite of what one of the best researchers is saying, and what half the research points to, I think we need to at least see some sources, before we consider that notion seriously)
     
    Last edited: Nov 22, 2017
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  2. Hip

    Hip Senior Member

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    @necessary8, I found a four more compounds that are of interest: pyridoxal-5'-phosphate blocks P2X, prochlorperazine is a potent negative allosteric modulator of the human P2X7 receptor, duloxetine inhibits microglial P2X4 receptors, and spironolactone blocks Panx1. The spironolactone study is here.

    However, when I performed a pharmacokinetic calculation on the first three, I found that blood levels from normal oral doses are far too low to have any effect in the body. So the first 3 compounds are of no use. I have added these pharmacokinetic calculations to the other calculations I previously performed in this post.

    The spironolactone study does not mention the concentration level at which it works, so I cannot do any pharmacokinetic analysis on spironolactone.



    I have just bought 10 grams of Brilliant Blue FCF powder from this supplier on eBay, and I will be trying this food dye shortly, at doses within the safe 480 mg daily limit.
     
    Last edited: Nov 24, 2017
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  3. Sushi

    Sushi Senior Member Albuquerque

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    @nandixon Back to clemastine, I just discovered that it is an inhibitor of P450 CYP2D6. I have a mutation there and I wonder if this is why I can only tolerate a tiny dose? Anyone else who is trying it know whether they have a mutation in this pathway? I am also wondering how common this mutation is in ME/CFS patients.
     
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  4. Learner1

    Learner1 Professional Patient

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    What dose of P5P would be useful?
     
  5. Learner1

    Learner1 Professional Patient

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    I used to do horribly on clemastine when taking it for allergies, didn't help, and knovjef me out. I have CYP2D6.

    Then I learned it has lactose and cornstarch, which I'm allergic to, excepting the liquid form, which has alcohol. The pills have earnings about not taking them with alcohol...

    More and more, I'm finding the supposedly inert ingredients aren't, and can exacerbate symptoms.
     
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  6. Hip

    Hip Senior Member

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    To achieve the IC50 concentrations in the plasma, an oral dose of around 30 grams of P5P would be required, by my calculation. This is obviously well, well beyond the safe oral doses of P5P, so P5P is of no practical in vivo use for blocking P2X receptors.
     
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  7. dreampop

    dreampop Senior Member

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    @Hip if you get a chance, could you check probenecid. There's a ton of information on it in the first article I linked on the previous page, and the second article. Both have IC50 values for it, and all the other drugs in the article, and since it's a well studied drug, I figured it might be easier for you to find info on.
     
  8. debored13

    debored13 Senior Member

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    Vermont, school in Western MA
  9. debored13

    debored13 Senior Member

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    also isn't P5P vitamin b6? It seems to be orally active but do you mean the doses needed for it to bind to P2x receptors are higher?
     
  10. necessary8

    necessary8

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    This is interesting, and also confusing as fuck, because they say Panx1 inhibition causes vasodilation. This is directly opposite to multiple other sources, which state eATP promotes vasodilation. So inhibiting Panx1 should limit eATP release, and promote vasoconstriction instead.
     
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  11. Hip

    Hip Senior Member

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    OK, your citied paper says probenecid inhibits Panx1 with an IC50 = 150 μM, and your other cited paper says the malaria drug mefloquine inhibits Panx1 with an IC50 = 50 nM.

    By my pharmacokinetic calculations (detailed in this post), at normal doses probenecid will not have much affect on Panx1 (maybe just some very slight effects). However, at normal doses of 250 mg once weekly, I calculated that mefloquine will significantly inhibit Panx1.

    This is because my calculation showed that a mefloquine dose of 490 mg will achieve the IC50 concentration in the blood plasma. So since the normal malaria prevention dose of 250 mg is pretty close to 490 mg, this normal dose will significantly inhibit Panx1.

    A concern with mefloquine (Lariam) is that mefloquine is the anti-malarial drug that is causing soldiers in the armed forces to suffer from side effect symptoms such as hallucinations, severe depression, sleep deprivation and anxiety. See: British armed forces set to ban most prescriptions of controversial anti-malarial drug Lariam
     
    Last edited: Nov 25, 2017
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  12. Hip

    Hip Senior Member

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    Yes, I calculated that to reach the target IC50 concentration in the blood that inhibits PX2, you would have to take an extremely high oral dose of the supplement P5P, which for practical purposes makes it non-viable for inhibiting PX2 in vivo.

    A lot of the time you find that drugs or compounds that have a good effect in vitro are not actually useful in vivo, because it turns out that the oral dose needed to achieve the vitro concentrations is far too high.
     
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  13. nandixon

    nandixon Senior Member

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    In your ponderings you're thinking about pannexin-1 (Panx1) in terms of its relationship with P2X7.

    But it was discovered in 2008/2009 by at least two different groups (Qiu et al and Ma et al) that Panx1 actually has its own receptor for external ATP (eATP) that operates independently of P2X7. External ATP is able to inhibit Panx1 via this receptor.

    This eATP receptor acts as negative feedback mechanism to help prevent too great an outflow of ATP from the cell due to activation of P2X7 (by eATP). As a 2013 review states:


    The binding site on Panx1 for inhibition by eATP is very similar to the one on P2X7 for activation by eATP, and most of the same ligands/drugs that bind to P2X7 also bind to Panx1. Interestingly, when such a ligand binds to Panx1 it acts as an inhibitor of Panx1 regardless of whether it is an antagonist or agonist at P2X7. Additionally, the concentration of such a ligand required to inhibit Panx1 is greater than that to inhibit P2X7. (This includes, e.g., suramin.)

    Note that Brilliant Blue FCF (BB FCF), which inhibits Panx1 but not P2X7, binds to a binding site that overlaps with the eATP binding site on Panx1 but is distinct. So BB FCF acts on Panx1 in a very similar way to eATP. (Reference)

    I gave the values/sources I'm using previously:

    Based on these numbers, one could say as a very crude estimate that suramin might be giving a 10% inhibition of P2X7 in Naviaux’ human trial, and this small amount would be offset by the increase in mRNA gene expression of P2X7 that is indicated to happen by Naviaux’ poly(IC) autism mouse model study upon treatment with suramin, where a 60% reduction in P2X7 expression was mostly normalized.

    Naviaux would say that this increase in P2X7 expression was due to a decrease in (an excess) of eATP, and that may be correct. But eATP can't be properly measured due to local concentration effects, as Naviaux points out in the mouse study, so we don't know.

    So the idea with clemastine is just to try to capture what is outwardly an apparent net effect of an up-regulation at P2X7 and see what happens.

    How a biochemical result is achieved can obviously be just as important as the result itself but note that clemastine effectively up-regulates P2X7 by making it more sensitive to eATP while apparently not affecting Panx1:

    (Clemastine is an allosteric modifier of P2X7 and doesn't actually bind to the eATP binding site which would trigger involvement of Panx1.)
     
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  14. nandixon

    nandixon Senior Member

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    Maybe as long as 2 hours.

    Me too.
     
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  15. nandixon

    nandixon Senior Member

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    Hard to say. Another possibility is that your P-glycoprotein transporter (P-gp; gene = ABCB1) isn't working well. I may have that problem as well. That transporter is responsible for helping to clear drugs and excess endogenous substances from within cells.

    Clemastine has some negative effect on P-gp. (Reference) This is a common issue with a lot of drugs though.
     
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  16. debored13

    debored13 Senior Member

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    this is incidentally what ray peat told me about progesterone. He said he's not sure that the bulk manufacturers of it test it for purity and that he wouldn't be surprised if there was trace estrogen in it. which could explain estrogenic effects
     
  17. debored13

    debored13 Senior Member

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    spironolactone is the acne drug?
     
  18. dreampop

    dreampop Senior Member

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    Thanks Hip- I went back using your formula and checked most of the interesting the drugs in the first paper, and all were way out of range. The only one I couldn't find info on was Arachidonic Acid. I did some extensive researsh on Mefloquine. I thought I was willing to try anything, but not that. Big Nope from me. Anyway, thanks for your help.
     
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  19. pattismith

    pattismith Senior Member

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    yes this drug is also used sometimes for acne. Be careful if you take it, as it also increases blood potassium level, and this should be monitored...
     
  20. debored13

    debored13 Senior Member

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    spironolactone is sometimes used for transitioning/HRT. there was a poster on the /r/cfs forum who said that HRT had cured them or caused remission. something to keep in mind. Of course its just one anecdote but not that many of the population are transitioning. maybe it would be interesting to get a poll of people here who have taken spironolactone
     
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