Volunteer opportunity: Organizing Phoenix Rising articles
This section contains all the articles that have been published by Phoenix Rising over the years. As you will see if you browse here, some of the articles are outdated--either the research has been superseded or retracted or the article features an event or campaign that is now in...
Discuss the article on the Forums.

Potential Suramin Alternatives - Sytrinol and Kudzu (Anti Purinergic Therapy)

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

  1. Rrrr

    Rrrr Senior Member

    Messages:
    1,562
    Likes:
    704
    @Jesse2233 but i think you are on the right track, as almost every medication is based on a "natural" supplement/herb. so i do wonder what the one is behind Suramin. please let me know if you try the two you mentioned at the start of this thread.
     
  2. Jesse2233

    Jesse2233 Senior Member

    Messages:
    1,930
    Likes:
    5,122
    Southern California
    Bumping this to see if anyone's benefited from high dose Kudzu
     
    pattismith likes this.
  3. pattismith

    pattismith Senior Member

    Messages:
    1,457
    Likes:
    2,183
    I take Kudzu 520 mg/day and Sytrinol 150 mg/day for four months, what do you consider a high dose of Kudzu?
     
  4. Jesse2233

    Jesse2233 Senior Member

    Messages:
    1,930
    Likes:
    5,122
    Southern California
    Good question, I don't have a good answer, though someone with more scientific knowledge than me could probably calculate it using the paper cited above

    How are you faring on those two doses?
     
  5. Jesse2233

    Jesse2233 Senior Member

    Messages:
    1,930
    Likes:
    5,122
    Southern California
    I'd be remiss if I didn't post this Kudzu precaution literature
     
    Learner1 and pibee like this.
  6. pattismith

    pattismith Senior Member

    Messages:
    1,457
    Likes:
    2,183
    interesting! I took some weight recently, and noticed signs of having more estrogens...
    I had to stop grapefruit because of it's effect on estrogen metabolism, but I knew something else was at play, so it might be Kudzu :)
    Estrogens have some neuro-protective properties, so it may have helped me a bit, but I'm not sure if I am willing to keep it on the long run, I likely will slow down on Kudzu...:thumbsup:
     
    Learner1, pibee and Jesse2233 like this.
  7. Hanna

    Hanna Senior Member

    Messages:
    715
    Likes:
    846
    Jerusalem, Israel
    Kudzu is one of the three plants that herbalist Buhner proposes for treating acute symptoms of "neuro-lyme" (and co-infections like Bartonella) - described as a sort of brain inflammation . He uses the root only.
    His average dose is 1/4 teaspoon of tincture (1:5 I presume but this need some verification) 3 times a day. I imagine that we can have a fair impression of tolerance by looking on Lyme forums and litterature.
     
    debored13, Jesse2233, helen1 and 3 others like this.
  8. Hip

    Hip Senior Member

    Messages:
    10,685
    Likes:
    17,570
    @necessary8, I have completed the pharmacokinetic calculations for some of the Panx1, P2X7 and P2Y2 inhibiting compounds listed at the bottom of this post of your ATP Signaling Theory of ME/CFS thread.

    To start with, unfortunately there is not enough data available to accurately calculate the free blood plasma concentrations that will be achieved when orally ingesting the Brilliant Blue FCF food dye.

    In order to determine free blood plasma concentrations, the most accurate results are obtained by referring to a pharmacokinetic study. Such pharmacokinetic studies will administer to humans or animals an oral dose of the compound, and then measure the concentrations of the compound achieved in the blood plasma. So you get a very accurate results, because blood levels are directly measured.

    But I could not find any pharmacokinetic studies for Brilliant Blue FCF. So the next best thing (which is not as accurate) is using the formulas I devised myself in this post. These formulas are based on the bioavailability of the compound, as well as based the compound's plasma protein binding percentage (the latter is equally important).

    Plasma protein binding is just as important as the bioavailability, because in the blood, for any compound, a certain percentage of that compound will become bound to proteins in the plasma, and when a compound is bound to such proteins, it usually has no active effect in the body. It is usually only the free, unbound percentage of the compound that has active effects in the body (this is known as the free drug hypothesis).

    So for example, if 90% of your drug or compound binds to plasma proteins in the blood, only 10% of the compound is actually available for active effects in the body. So the higher the plasma protein binding of a compound, the higher the oral dose you will need to take, in order to compensate. That's why you have to factor in both bioavailability and plasma protein binding when you try to calculate the oral dose that will produce the required free plasma concentration of the compound.

    The formula I devised for calculating the oral dose necessary to achieve a free plasma concentration C of the compound is:

    Dosage in milligrams = 400 x C x W / ( B x (100 - P))

    Where:
    C = concentration of the solution in μM, used in the in vitro study
    B = percentage bioavailability
    P = percentage plasma protein binding
    W = the molecular weight of the drug or compound in grams per mole

    This is my own formula, but the rationale behind it is explained in my post. It will at least give you a ballpark figure for the oral dose.

    A pharmacokinetic study on Brilliant Blue FCF in rats provides a figure of for the percentage absorption in the gut of 5%.

    This article says that the plasma protein binding of Brilliant Blue FCF in rats is 65%.

    The Brilliant Blue FCF dosage in milligrams that achieves the Panx1 IC50 concentration of 0.27 μM in the blood plasma is:

    = 400 x C x W / ( B x (100 - P))

    = 400 x 0.27 x 792.85 / ( 5 x (100 - 65))

    = 489 mg


    Now this article says the acceptable daily intake (ADI) of Brilliant Blue FCF is 6 mg per kg of body weight per day. So for an 80 kg human, that's a daily dose of 6 x 80 = 480 mg.

    So if we use the maximum daily oral dose of 480 mg, we can achieve the IC50 concentration.



    Second method of calculating the Brilliant Blue FCF oral dose that achieves the IC50 0.27 μM concentration:

    This study provides rat pharmacokinetic data on intravenously injected Brilliant Blue G dye (a dye closely related to Brilliant Blue FCF, so we might assume the pharmacokinetics will be very similar):

    In the study, they injected rats intravenously with 10 mg/kg twice daily of Brilliant Blue G for three days in a row; this led to a Brilliant Blue G concentration of 9.94 μM in the spinal cord tissue.

    The figure of 9.94 μM is the total Brilliant Blue G in the spine tissues (including both the free and protein-bound Brilliant Blue G). If we assume that in the spinal tissues, the protein binding percentage is the same as it is in the blood, which is 65%, then the concentration of free Brilliant Blue G in the spinal tissues will be 9.94 x 35% = 3.5 μM.

    That is a concentration 13 times higher than the Brilliant Blue FCF Panx1 IC50 concentration of 0.27 μM.

    Using the rat-to-human dose conversion factor of 6.2, a rat 10 mg/kg dose corresponds to 1.6 mg/kg in humans. So for an 80 kg human, that would be an injectable dose of 128 mg of Brilliant Blue G twice daily for three days.

    But if we are just aiming to achieve the IC50 concentration of 0.27 μM in humans, then an injectable Brilliant Blue G dose of 128 / 13 = 9.8 mg twice daily is all that is required.

    So we might assume that Brilliant Blue FCF will have similar pharmacokinetics, and that an intravenous injection of Brilliant Blue FCF 9.8 mg twice daily twice daily will result in the IC50 concentration of 0.27 μM in the spinal cord tissue of humans.

    If we want to convert this to the equivalent oral dose, since orally 5% of Brilliant Blue FCF is absorbed, the corresponding oral dose would be 9.8 x 100 / 5 = 196 mg twice daily, or a total daily oral dose of 392 mg of Brilliant Blue FCF.



    So using these two different routes of pharmacokinetic calculation, we get very similar figures for the daily oral Brilliant Blue FCF dose that achieves the IC50 concentration: 489 mg from the first calculation, and 392 mg from the second calculation.
     
    Last edited: Mar 29, 2018
  9. Hip

    Hip Senior Member

    Messages:
    10,685
    Likes:
    17,570
    Some of the other P2X7 and P2Y2 inhibiting compounds listed at the bottom of my post in your ATP Signaling Theory of ME/CFS thread are also orally viable:

    High dose magnesium injections (or high dose transdermal magnesium cream) may be a viable P2X7 receptor inhibitor. Magnesium injections and transdermal magnesium are a classic treatment for ameliorating ME/CFS symptoms, and perhaps high dose magnesium's effect on P2X7 explains why.

    Calcium supplementation may have some useful P2X7 receptor inhibition, but I am not sure about this.

    Emodin looks like a potent P2X7 receptor inhibitor. Emodin is found in the herb Rheum palmatum (Rheum palmatum contains 5.87 mg of emodin per gram. Ref: 1). The normal daily dose of Rheum palmatum is 3 to 30 grams. Unfortunately though, emodin and Rheum palmatum have laxative effects, and also should not be used for more than two weeks in a row, because liver or kidney toxicity can appear in some people.

    However, emodin and Rheum palmatum would be useful as a short-term test on the efficacy of P2X7 receptor inhibitors for ME/CFS.

    Kaempferol has useful P2Y2 receptor inhibition, but unfortunately is not available as a supplement. However, it is found in high concentration in canned capers, and by my calculation, eating 9 x 100 gram jars of capers would reach the IC50 concentration for P2Y2 inhibition (but that's a lot of capers!).



    I also calculated that other P2X7 and P2Y2 inhibiting compounds listed in my post like rhein (cassic acid), zinc, copper, colchicine, tangeretin, apigenin and rutin are non-viable when taken orally. This is because when taken at safe dose levels, they do not achieve anywhere near the necessary IC50 concentrations in the blood plasma.



    If you want to see the pharmacokinetic calculations I performed for the above compounds, click on the spoiler:
    Rhein (Cassic Acid) Pharmacokinetics

    Rhein molecule weight 284.22 g/mol

    Rhein plasma protein binding P = 99%. Ref: 1

    This pharmacokinetic study orally administered rhubarb extract (150 mg/kg) to dogs. The contents of the rhubarb extract included: aloe-emodin, rhein, emodin, chrysophanol and physcion at 87, 115, 231, 263 and 176 mg per gram, respectively.

    So 150 mg of rhubarb extract contains 115 x 150 / 1000 = 17.25 mg rhein.

    So dogs were administered 17.25 mg/kg of rhein.

    After oral administration of rhein to dogs, Cmax = 3.39 mg/L = 3.39 µg/ml.

    Dividing 17.25 mg/kg by the dog-to-human conversion factor of 1.8 gives a human dose of 9.58 mg/kg, which for an 80 kg human is an oral dose of 766 mg.

    So 766 mg in humans would lead to a Cmax 3.39 µg/ml (= 11.93 µM). Thus:

    R = Cmax peak blood plasma concentration (in μM) from 1 mg oral human dose = 3.12 / 100 = 0.0312

    Calculated Oral Dose (in mg) That Achieves IC50 Concentration C = 1.31μM in Bloodstream

    = (100 / (100 − P )) x C / R

    = (100 / (100 − 99 )) x 1.31 / 0.0312

    = 4,199 mg

    Now 50 mg rhein twice per day was shown to be safe, 1 so 4,199 mg is well beyond the safe dose. So rhein is not a viable P2X7 receptor inhibitor.



    Calcium Pharmacokinetics

    Plasma ionized calcium is 2.5 mmol/L = 2.5 mM = 2500 µM. Of this, 50% is ionized free calcium. Ref: 1 So ionized free calcium in plasma = 50% x 2500 = 1250 µM.

    Thus at normal physiological levels of up to 1250 µM, free calcium ions in the blood are a bit below the P2X7 receptor IC50 of 2,900 µM. Increasing calcium ion concentrations should increase P2X7 antagonism, but I am not sure if normal calcium supplementation will substantially increase free calcium ion levels in the plasma.

    So calcium may be a viable P2X7 receptor inhibitor.



    Magnesium Pharmacokinetics

    Plasma Mg2+ levels 0.845 mmol/L = 0.845 mM = 845 µM. Ref: 1

    Serum Mg concetrations in healthy subjects 0.89 mmol/L = 890 µM. Of this, 55% is ionized free magnesium. Ref: 1 So ionized free magnesium in plasma = 55% x 890 = 490 µM.

    Thus even at normal physiological levels of 490 µM, magnesium ions in the blood plasma are achieving similar concentrations to the P2X7 receptor IC50 of 500 µM. This means that any further increases in plasma magnesium ion levels through magnesium injections or high dose transdermal magnesium are likely to significantly increase P2X7 antagonism.

    So magnesium looks like a viable P2X7 receptor inhibitor.



    Zinc Pharmacokinetics

    There is not much data on human plasma free zinc ion levels, but this book says horse free zinc ion levels are about 200 pM = 0.0002 µM. This value is far below the P2X7 receptor IC50 of 11 µM, so supplementing with zinc will likely have no effect on P2X7. So zinc is not a viable P2X7 receptor inhibitor.



    Copper Pharmacokinetics

    Normal blood plasma levels of copper ions are in the range 11 to 24 µM, but I cannot find any data on free copper ions. Ref: 1



    Emodin Pharmacokinetics

    Emodin molecular weight = 270.24 g/mol

    Emodin plasma protein binding P = 90% (I could not find a plasma protein binding for emodin, so I am using the aloe-emodin figure of around 90%. Ref: 1

    In a rat pharmacokinetic study, 2.85 x 5 = 14.25 mg/kg of oral emodin led to a Cmax of 11.9 µM (see tables 2 and 5). Dividing by the rat-to-human conversion factor of 6.2, a rat 14.25 mg/kg dose converts to a 2.3 mg/kg human dose, which for an 80 kg human = 184 mg. So for a human, 184 mg of emodin would result in a Cmax of 11.9 µM. Therefore:

    R = Cmax peak blood plasma concentration (in μM) from 1 mg oral human dose = 11.9 / 184 = 0.06

    Calculated Oral Dose (in mg) That Achieves IC50 Concentration C = 0.5 μM in Bloodstream

    = (100 / (100 − P )) x C / R

    = (100 / (100 − 90 )) x 0.5 / 0.06

    = 83 mg

    This value is below some of the higher emodin doses used, which are 200 mg daily. So emodin looks like a viable P2X7 receptor inhibitor. However, note that emodin is not recommend for long term use (ie, not more than two weeks), as liver or kidney toxicity can appear in some people.

    Rheum palmatum (Chinese rhubarb, Da Huang) contains 5.87 mg of emodin per gram. Ref: 1 The normal dose of this herb is 3 to 30 grams. Ref: 1 This corresponds to doses of 17.6 to 176 mg of emodin. But Rheum palmatum is also not recommended for long term use, because of the potential for liver and kidney toxicity.



    Colchicine Pharmacokinetics

    Colchicine molecular weight = 399.44 g/mol

    Colchicine plasma protein binding P = 50%

    This pharmacokinetic study orally administered 1 mg colchicine daily to humans, and after 14 days the Cmax = 6.5 ng/ml (= 0.016 µM).

    R = Cmax peak blood plasma concentration (in μM) from 1 mg oral human dose = 0.016 / 1 = 0.016

    Calculated Oral Dose (in mg) That Achieves IC50 Concentration C = 540 µM in Bloodstream

    = (100 / (100 − P )) x C / R

    = (100 / (100 − 50 )) x 540 / 0.016

    = 67,500 mg

    This is far beyond normal doses of colchicine, which are 1 to 2 mg daily. So colchicine is not a viable P2X7 receptor inhibitor.



    Kaempferol Pharmacokinetics

    Kaempferol molecular weight = 286.23 g/mol

    Kaempferol oral bioavailability about 2%. Ref: 1

    Kaempferol plasma protein binding P not known, so guess to be 50%

    This pharmacokinetic study gave humans 9 mg of kaempferol, which produced a Cmax = 0.1 µM. Thus:

    R = Cmax peak blood plasma concentration (in μM) from 1 mg oral human dose = 0.1 / 9 = 0.011

    Calculated Oral Dose (in mg) That Achieves IC50 Concentration C = 6.6 μM in Bloodstream

    = (100 / (100 − P )) x C / R

    = (100 / (100 − 50 )) x 6.6 / 0.011

    = 1,200 mg

    Kaempferol is not available as a supplement, but canned capers are the food which has the highest level of kaempferol, at 135.56 mg per 100 grams. Ref: 1 So you would have to eat around 9 x 100 mg jars of capers daily to reach the IC50 concentration

    So if you like eating lots of capers, the kaempferol they contain will be a viable P2Y2 receptor inhibitor.



    Tangeretin Pharmacokinetics

    Tangeretin molecular weight = 372.37 g/mol

    Tangeretin plasma protein binding P not known, so guess to be 50%

    This pharmacokinetic study found that after oral administration of 50 mg/kg tangeretin to rats, the Cmax = 0.87 μg/ml, and T1/2 half-life = 342 mins.

    Dividing 50 mg/kg by the rat-to-human conversion factor of 6.2 gives a human dose of 8.06 mg/kg, which for an 80 kg human is an oral dose of 645 mg.

    So 645 mg in humans would lead to a Cmax 0.87 µg/ml (= 2.34 µM). Thus:

    R = Cmax peak blood plasma concentration (in μM) from 1 mg oral human dose = 2.34 / 645 = 0.0036

    Calculated Oral Dose (in mg) That Achieves IC50 Concentration C = 12 μM in Bloodstream

    = (100 / (100 − P )) x C / R

    = (100 / (100 − 50 )) x 12 / 0.0036

    = 6,667 mg

    This looks like a very high dose of tangeretin (which is not actually available as a supplement). So tangeretin is probably not a viable P2Y2 receptor inhibitor.



    Apigenin Pharmacokinetics

    Apigenin molecular weight = 270.24 g/mol

    "Apigenin has low binding affinity with plasma proteins". Ref: 1 So let's estimate its protein binding P = 20%.

    In a human study eating a source apigenin in the form of parsley, an apigenin dose of 65.8 µmol per kg (= 17.7 mg per kg) led to a mean Cmax = 127 ng/ml (0.47 µM). Ref: 1 For an 80 kg human, that is a oral dose of 80 x 17.7 = 1416 mg. Therefore:

    R = Cmax peak blood plasma concentration (in μM) from 1 mg oral human dose = 0.47 / 1416 = 0.00033

    Calculated Oral Dose (in mg) That Achieves IC50 Concentration of C = 25 μM in Bloodstream

    = (100 / (100 − P )) x C / R

    = (100 / (100 − 20 )) x 25 / 0.00033

    = 94,697 mg

    This is far beyond normal doses of apigenin, which are around 100 mg. So apigenin is not a viable P2Y2 receptor inhibitor.



    Rutin Pharmacokinetics

    Rutin molecular weight 610.52 g/mol

    Rutin plasma protein binding P = 80% to 90%. Ref: 1

    This pharmacokinetic study gave humans 662 μMol rutin orally = 404 mg rutin, and this led to a Cmax = 0.32 µg/ml (= 0.52 µM).

    R = Cmax peak blood plasma concentration (in μM) from 1 mg oral human dose = 0.52 / 404 = 0.0013

    Calculated Oral Dose (in mg) That Achieves IC50 Concentration C = 25 μM in Bloodstream

    = (100 / (100 − P )) x C / R

    = (100 / (100 − 90 )) x 25 / 0.0013

    = 192,307 mg

    This is far beyond normal doses of rutin, which are around 500 mg. So rutin is not a viable P2Y2 receptor inhibitor.



    Pyridoxal-5'-phosphate Pharmacokinetics

    Pyridoxal-5'-phosphate (P5P) molecular weight 247.14 g/mol

    P5P elimination half-life = 8 hours. 1

    Plasma protein binding is high: "Most of the pyridoxal 5'-phosphate in plasma is bound to protein". 1 So assume say 90% plasma protein binding.

    P5P, the active form of vitamin B6, inhibits expressed P2X receptors. P5P blocked two P2X receptors (namely P2X2 and P2X2/3), with an IC50 of 7 and 13 μM, respectively. 1 So assume a target plasma concentration of around 10 μM.

    P5P concentration in the blood normally 5 to 50 μg/L = 5 to 50 ng/ml = 0.02 to 0.2 μM 1

    Pharmacokinetics for regular vitamin B6: 600 mg of oral pyridoxine hydrochloride in humans led to: 1

    P5P Cmax = 945.3 nM = 0.945 μM. Thus:

    R = Cmax peak blood plasma concentration (in μM) from 1 mg oral human dose = 0.945 / 600 = 0.0016

    Calculated Oral Dose (in mg) That Achieves IC50 Concentration C = 10 μM in Bloodstream

    = (100 / (100 − P )) x C / R

    = (100 / (100 − 90 )) x 10 / 0.0016

    = 62,500 mg

    This is far beyond normal doses of vitamin B6. So vitamin B6 is not a viable P2X receptor inhibitor.

    Pharmacokinetics for P5P supplement: this patent says oral 15 mg/kg of a P5P (an oral dose of around 1,200 mg) produces a Cmax = 1 mg/L = 1 μg/ml = 4.05 µM.

    R = Cmax peak blood plasma concentration (in μM) from 1 mg oral human dose = 4.05 / 1200 = 0.0034

    Calculated Oral Dose (in mg) That Achieves IC50 Concentration C = 10 μM in Bloodstream

    = (100 / (100 − P )) x C / R

    = (100 / (100 − 90 )) x 10 / 0.0034

    = 29,411 mg

    This is far beyond normal doses of P5P. So P5P is not a viable P2X receptor inhibitor.



    Prochlorperazine Pharmacokinetics

    Prochlorperazine (at 10 μM) and trifluoperazine (antipsychotic drugs) are potent negative allosteric modulators of the human P2X7 receptor. 1 (see also table 2 of this paper)

    Prochlorperazine at an oral dose of 25 mg twice daily gives Cmax = 3.9 ng/ml = 0.01 μM. 1 Prochlorperazine plasma protein binding = 95%. So free plasma prochlorperazine Cmax = 0.0005 μM.

    So blood levels are far too low to affect P2X7 receptors.



    Duloxetine Pharmacokinetics

    Duloxetine inhibits microglial P2X4 receptor, with an IC50 value of 1.59 μM. 1

    Duloxetine at an oral dose of 40 mg twice daily gives plasma Cmax = 47ng/ml = 0.158 μM. 1 Duloxetine plasma protein binding = 90%, so free plasma duloxetine Cmax = 0.0158 μM.

    This is far too low to affect P2X4 receptors.



    Probenecid Pharmacokinetics

    Probenecid inhibits Panx1 with an IC50 of 150 μM. 1

    Probenecid molecular weight 285.36 g/mol

    Probenecid oral bioavailability = 90% 1

    Probenecid plasma protein binding = about 95% (at concentrations of 150 μM = 43 μg/ml ) 1 (see Fig 1)

    Dosage in milligrams that achieves IC50 concentration C = 150 μM in bloodstream is given by the following equation (detailed here):

    = 400 x C x W / ( B x (100 - P))

    = 400 x 150 x 285.36 / ( 90 x (100 - 95))

    = 38,048 mg

    The probenecid dose for gout is 500 daily, so this is quite a bit below our 38,048 mg figure, indicating that probenecid at normal doses will not have much affect on Panx1.



    Mefloquine Pharmacokinetics

    Mefloquine inhibits Panx1 with an IC50 = 50 nM = 0.05 μM. 1

    Mefloquine molecular weight 378.31 g/mol

    Mefloquine plasma protein binding = 98% 1

    Mefloquine half-life 3 is weeks.

    Mefloquine 1250 mg dose in humans led to Cmax = 2411 ng/ml = 6.37 μM. 1

    R = Cmax peak blood plasma concentration (in μM) from 1 mg oral human dose = 6.37 / 1250 = 0.0051

    Calculated Oral Dose (in mg) That Achieves IC50 Concentration C = 0.05 μM in Bloodstream

    = (100 / (100 − P )) x C / R

    = (100 / (100 − 98 )) x 0.05 / 0.0051

    = 490 mg

    The mefloquine dose for prevention of malaria is 250 mg taken once weekly (mefloquine has a long half life, so is only taken once a week). Thus at normal doses, mefloquine will be an effective Panx1 inhibitor.
     
    Last edited: Nov 25, 2017
    Learner1, pibee, MastBCrazy and 2 others like this.
  10. pattismith

    pattismith Senior Member

    Messages:
    1,457
    Likes:
    2,183
    really impressive work, thank you Hip!

    I'd like to try Emodin, because it has also anti-viral properties and neuroprotection properties against glutamate.

    You quoted Rheum Palmatum, but many other plants contain Emodin. Do you think that Rheum Palmatum is the richest plant?
     
    debored13 likes this.
  11. Hip

    Hip Senior Member

    Messages:
    10,685
    Likes:
    17,570
    A while ago, I noticed that pure emodin powder was being sold cheaply on AliExpress.com. AliExpress.com were an excellent source for all sorts of bulk powder supplements, bulk herbs and pure compounds at very good prices. I've bought quite a few hard-to-obtain herbs and pure compounds from them in the past. They were a great source for this sort of thing.

    But in the last few months AliExpress seem to have dropped most of these sort of products. I am not sure why.

    You will find emodin in other plants, but Rheum Palmatum is a good source.

    Emodin is not to be confused with aloe-emodin, although these are both similar compounds.
     
    pattismith and MastBCrazy like this.
  12. dreampop

    dreampop Senior Member

    Messages:
    253
    Likes:
    595
    @Hip Did you you notice that the P2X receptors (except p2x2) are very sensitivities to changes in extracellular pH? The ATP sensitivity of P2X1, P2X3 and P2X4 receptors is attenuated when the extracellular pH<7, whereas the ATP sensitivity of P2X2 is significantly increased.

    Would another option, in addition to purinergic antagonists, be increasing extracellular pH beyond 7, if that's even possible?
     
  13. dreampop

    dreampop Senior Member

    Messages:
    253
    Likes:
    595
    I also didn't want to block up @necessary8 thread with no theory based stuff. But I was reading those stories about Spleight saying his patients got more "tired" and "sleepy" as the slowly got better. I know that feeling very well, because Dipyridamole was one of Goldstein's top 25, and it prevents cellular uptake of Adenosine, meaning more extracellular Adenosine.

    I spent a half hour looking to see if raising eAdenosine, would some how have a complementary effect or feedback mechanism that lowers eATP, but I couldn't find anything. It would obviously not work like eATP creates Adenosine, but I thought it might be an interesting back door.
     
    junkcrap50 and Jesse2233 like this.
  14. Hip

    Hip Senior Member

    Messages:
    10,685
    Likes:
    17,570
    I do remember reading that, but cannot remember which study it was in. Would you have a link?



    I would not have thought that you will be able to change tissue pH very much through things like diet, because pH is tightly controlled in the body.

    I am just thinking, though, that if increased acidity desensitizes the P2X receptors to ATP, then you might expect that physical exercise, and the lactic acid it produces, would improve ME/CFS symptoms (which we know is not the case, as ME/CFS symptoms are worsened after exercise — the phenomenon of PEM). Perhaps @necessary8 might like to comment.
     
    pattismith likes this.
  15. dreampop

    dreampop Senior Member

    Messages:
    253
    Likes:
    595
    My high quality source was, of course, wikipedia, but here are some better ones.

    p2x2
    • In summary, a lowered pHe enhanced the activity of all agonists at P2X2 receptors but, with the exception of suramin, not antagonists. Since a lowered pHe is also known to enhance agonist activity at P2X receptors on sensory neurones containing P2X2 transcripts, the sensitization by metabolic acidosis of native P2X receptors containing P2X2 subunits may have a significant effect on purinergic cell-to-cell signalling. (1)
    others
    • . P2X receptors are sensitized by extracellular pH, the most extreme example being the P2X2 subtype where responses to ATP are potentiated under acidic conditions and inhibited under alkaline conditions; pH changes as small as 0.03 units affect the size of the responses (153). Other P2X receptors are inhibited by H+ ions, so that acidic conditions greatly reduce the potency of extracellular ATP. The precise molecular basis of this inhibitory effect is still unknown. (2).
    p2x4

    • ATP (0.1–100 μM, at pH 7.5), evoked inward currents via rP2X4 receptors (EC50 value, 4.1±0.98 μM; nH, 1.2±0.1). ATP potency was reduced 2 fold, at pH 6.5, without altering maximal activity. ATP potency was reduced by a further 4 fold, at pH 5.5, and the maximal activity of ATP was also reduced. Alkaline conditions (pH 8.0) had no effect on ATP-responses. (3) This study also says suramin doesn't work well on p2x4.
    p2x7


    Anyway, you're right, it probably doesn't matter, I don't even know if the change from mild exercise would be enough to significantly lower even a specific tissue area (and wouldn't matter for p2x7).

    Though it makes intuitive sense, in healthy people, if exercise caused a CDR response, that would be a problem.
     
    Last edited: Nov 2, 2017
  16. dreampop

    dreampop Senior Member

    Messages:
    253
    Likes:
    595
    OK, last one, because I'm still trying to understand it. Alcohol, well Ethanol, is not a p2x antagonist. However,

    It makes it harder for ATP to interact with and activate p2x receptors.

    It works outside the cell, but not inside.

    The molecular volume of alcohol mattered

    From another study

    Which is also confusing given alcohol intolerance that many of us experience - although some report alcohol improves their symptoms. However, I don't know if this is meaningful in a treatment context.
     
    pattismith likes this.
  17. necessary8

    necessary8

    Messages:
    81
    Likes:
    274
    @Hip Great analysis, as expected you did it better than me, I wouldnt think about protein binding.

    So I guess in regard to Brilliant Blue FCF, we'll just have to try the maximum safe dosage and see if it makes a difference. I might do it myself, but I'm kinda worried about irritating my stomach with this, as I have pretty bad gastritis.

    @dreampop I might touch on the pH connetion in Part 2 of my ponderings. Thanks for reminding me about this.
     
    dreampop likes this.
  18. Hip

    Hip Senior Member

    Messages:
    10,685
    Likes:
    17,570
    I only recently learnt about plasma protein binding myself (I taught myself a bit about pharmacokinetics recently, in order to try to calculate in the in vivo potency of various antiviral compounds).

    I think emodin might be a more reliable option than Brilliant Blue FCF, just because my pharmacokinetic calculation for emodin is more accurate (it's based on precise pharmacokinetic data, whereas the Brilliant Blue FCF calculation is half guessing).

    My emodin pharmacokinetic calculation indicates that 83 mg of emodin orally will achieve the IC50 inhibition of the P2X7 receptor. The herb Rheum palmatum contains 5.87 mg of emodin per gram (ref: 1), so that means around 14 grams of this herb will provide 83 mg of emodin.



    By the way, enterovirus can cause gastritis, as well as being linked to ME/CFS. Have you been tested for this virus? Oxymatrine is an immunomodulator that Dr Chia uses to treat enterovirus-associated ME/CFS.
     
    dreampop likes this.
  19. Hip

    Hip Senior Member

    Messages:
    10,685
    Likes:
    17,570
    @necessary8, something else of interest: I got major improvements in my ME/CFS from my high dose selenium protocol. I am not sure why selenium helped so much, but one of the things selenium does is enhance the activity of T-regs. Ref: here. By your theory, these activated T-regs may be mopping up the extracellular ATP.
     
    Last edited: Nov 4, 2017
    dreampop likes this.
  20. necessary8

    necessary8

    Messages:
    81
    Likes:
    274
    I have no way where I live to do the advanced tests that Chia does. But I know all about his theories and gave Oxymatrine a long, proper try. Didn't do shit for me. Made it worse if anything. I'm managing now with PPIs and probiotics, but I still have to be kinda careful.
     
    dreampop and Hip like this.

See more popular forum discussions.

Share This Page