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

[cporro]

@Learner1
i had a doctor at one point (dealt with vets and combats sports) that was convinced injuring to the brain was causing inflamation and then downstream hormone disruption. So his thing was the best done hormone replacement. that is, with least side effects, lowest dosages, etc. For guys the most common was testosterone.

i was shocked to find my testosterone was low. has been for 10 years. And i did try replacement. more boners for sure. but depression, lack of focus, energy did not change. this was a 6 week trial. I feel like once you get on that bus it's hard to get back off. the erections were nice....but not at the cost of being on T for the rest of my life some what may in terms of side effects. I did realize one thing: my hormones (T, cortisol, maybe thyroid) are not where they should be.

there is also an anti inflammatory theory on how many antidepressant drugs work. and in fact many do take 1-3 months to kick in. that was the case with me and wellbutrin. i know this theory has been attacked but I have found good evidence that at least wellbutrin dramatically reduced some inflammation markers. however i suspect "inflamation" is about as general a terms as depression of CFS. And even if it does this there is no proof that it's the mechanism. the official theory is also far from solid imo. re-uptake.

my personal experience has told me i should not get over invested in any theory or treatment no matter how much sense it makes on paper. i spent 2 years devoted to chelation. that should have been 6 months. i basically ask my doctors these days how long it will take for thier suggestions to bare results. no results and i'm done. most doctors have a blind spot when it comes to admitting their approach isn't working.

i am dabbling with herbs at the moment. Tulsi, bacopa, artemisia. The tulsi showed a lot of promise after maybe 3 week on and now has waned to the point i'm unsure. In my mind the anti inflamatory window of response is 3 months. no effect in that time and i move on.

 

[frozenborderline]

Isn't it odd your inflammation is still high after so many successful interventions for infections and toxins?[/QUO

Appreciate the revival of this thread @pattismith, some of it chimes with me.

Particularly the stuff about IL-6 and TNF-alpha - I've recently discovered cumin has significant effects on my fatigue and the active ingredient cuminaldehyde suppresses these...

Has anybody on PR been known to have tried Suramin?

Or has anybody tried anything based off this thread?

Rupatadine suppresses tnf alpha , as well as histamine and stabilizing mast cells

 

[Learner1]

@cporro

My doctor, a ME/CFS specialist, told me the reason I'm on naltrexone is to reduce brain inflammation.

Normalizing hormone levels can be extremely helpful. Many have low thyroid or cortisol levels which can dramatically affect metabolism or energy production.

I've found two concepts are worthwhile:

1) interventions work as part of complex biochemical systems. Adding a single intervention while neglecting other necessary substrates may create a situation that makes the intervention less than successful.

2) improving multiple processes over time takes a great deal of patients. It's not as simple as getting fixed by finding the right pill - we may have had one or more initiating triggers, but a cascade of other issues has happened since, so it's not easy to put the genie back into the bottle. A systematic approach is better.

 

[Ema]

I have some dipyridamole here, which I have not tried, but will do soon. Increasing extracellular adenosine with dipyridamole has some benefits in schizophrenia — see here.
.

Hi there, @Hip, so glad to see that you are, as always, a few steps ahead of me! Hope you are as well as possible these days.

Did you ever try dipyridamole? Do you remember what dose you considered? It's next on my list.

I found this article that got me curious, but I can't remember your formula for converting test tube doses at all.

Importantly, DIP concentrations used in the present study were close to the range of the plasma concentration attained after oral administration in humans (Grem and Fischer, 1989). Remarkably, overdose case reports showed that higher DIP doses might be tolerated in humans, suggesting that even higher dosing could be used in new clinical settings (Lagas et al., 2011).

Any thoughts?

 

[Hip]

Hi there, @Hip, so glad to see that you are, as always, a few steps ahead of me! Hope you are as well as possible these days.

Did you ever try dipyridamole? Do you remember what dose you considered? It's next on my list.

Hi @Ema, nice to see you. Hope your ME/CFS still remains improved.

I found this article that got me curious, but I can't remember your formula for converting test tube doses at all.

I don't think you are going to have much luck in trying to get the same dipyridamole concentrations in vivo as they used in vitro. Looks like the anti-EBV effect of dipyridamole was obtained at a concentration of 10 μM and higher.

Now I have a note on my computer saying that the peak blood level of dipyridamole attained after a typical 200 mg oral dose is around 4 μM. So to begin with, that looks good.

But unfortunately dipyridamole has very high plasma protein binding of 99%. That means you lose 99% of the dipyridamole in your blood when it binds to proteins.

So the effective free dipyridamole concentration in the blood will be 100 times less, at 0.04 μM. That would be far too low to have an antiviral effect against EBV, assuming my calculation here is right.

Most of the time in these in vitro studies they use concentrations which are far too high to be achieved in vivo. So you get lots of studies showing antiviral effects in vitro, but they don't pan out in vivo.



I did try dipyridamole myself for a short period, but for a different reasons (I hoped it might help certain mental health symptoms). I used 200 mg daily. I found it made me a tired, but when I switched to taking it before bed, this worked to advantage, as dipyridamole then promoted a nice deep long sleep.



A couple of new EBV treatments you might like to look into are: spironolactone and ritonavir (one ritonavir recovery story here).



I have currently just started Dr Markov's autovaccine treatment for ME/CFS, which he claims has permanently cures 93% of all ME/CFS patients. He has a unique theory on what causes ME/CFS, and a unique cure. Unfortunately the cure requires 2 to 3 years of treatment.

 

[serg1942]

No, but I'll take some of that ATP disodium salt, please!

Seriously, I had a long conversation with Dr. Naviaux about the CDR and discussed with him the kinds of metabolomic manipulation I have been doing with my naturopathic doctor as well as attacking my infections. He was very supportive of this approach abdcsaid th st suramin (ow whatever alternative you find) woukd be useful only AFTER moving each of the biichemical processes from winter metabolism to sumner metabolism in the diagram in his paper.

That is, you kill off ant infections and fix all of the biochemistry And see if the body kicjs into gear and starts behaving normally. If it does, you dont need suramin.only Only if it doesn't, do you use it.

So, the work at hand is to ferret out any infections and treat them (dealing with any immune issues on rhe way), identify any deranged biochemistry, like amino acids, B vitamins, mineral imbalances, oxidative and nitrisative stress, Krebs cycle alterations, sphingolipids, etc. and fix those first.

And, only then try suramin or something on that research lab supplier's list.

Hi @Learner1

I guess you meant to say that we need to move the biochemistry from the summer to winter, right? :

https://www.google.com/search?q=Nav...biw=412&bih=831&dpr=2.63#imgrc=UBjJPhqp3dxfUM


I'm very interested in this point because I have changed my diet to a high ketogenic one and I'm still wondering if Dr Naviaux would think that ketosis is a wise movement towards getting out of the CDR state or not.

On the one hand, it makes sense to be in an anti-inflammatory state which favors mitochondrial fusion and biogenesis. However, the ketogenic state inhibits mTOR, similar to fasting, and fasting leads the Dauer worm to get into the CDR state...

May I ask what's your take on this?

Thank you!!

Sergio

 

[Learner1]

I guess you meant to say that we need to move the biochemistry from the summer to winter, right?

I did! Good point!

I'm very interested in this point because I have changed my diet to a high ketogenic one and I'm still wondering if Dr Naviaux would think that ketosis is a wise movement towards getting out of the CDR state or not.

On the one hand, it makes sense to be in an anti-inflammatory state which favors mitochondrial fusion and biogenesis. However, the ketogenic state inhibits mTOR, similar to fasting, and fasting leads the Dauer worm to get into the CDR state...

May I ask what's your take on this?

My take on it is that a lower carbohydrate diet is beneficial for many reasons, but a keto diet or fasting may be too extreme for several reasons:

1. Many ME/CFS patients need more amino acids than healthy people. We use them up too fast, and aminos are important for healing, for mitochondrial function and Krebs cycle function, making catecholamines, etc. It is not possible to get enough aminos on keto I found I needed around 1.6-1 8g/kg body weight at my sickest, and 1.2-1.4g/kg now.​

​

2 Ketosis over a lengthy period of time is stressful and can burn out adrenal function. Fasting is also stressful.​

​

3. Though keto diets can be nutrient dense, they are restrictive and it is likely one might miss out on several nutrients and either become deficient, or more deficient than at the outset. Fasting definitely promotes nutrient deficiency.​

​

These are my opinions after researching the subject extensively and experimenting with it and discussing it with others. I will say that if one is fighting cancer, a keto diet should definitely be considered and discussed with one's oncologist. Likewise, it has been proven effective for certain seizure patients.

For ME/CFS, a nutrient dense diet is essential, along with a thoughtful and comprehensive supplement program. Avoiding processed foods and added sugar is also wise - helps to avoid swings in blood sugar which can affect energy and functioning upright.

 

[serg1942]

I did! Good point!

My take on it is that a lower carbohydrate diet is beneficial for many reasons, but a keto diet or fasting may be too extreme for several reasons:

1. Many ME/CFS patients need more amino acids than healthy people. We use them up too fast, and aminos are important for healing, for mitochondrial function and Krebs cycle function, making catecholamines, etc. It is not possible to get enough aminos on keto I found I needed around 1.6-1 8g/kg body weight at my sickest, and 1.2-1.4g/kg now.​

​

2 Ketosis over a lengthy period of time is stressful and can burn out adrenal function. Fasting is also stressful.​

​

3. Though keto diets can be nutrient dense, they are restrictive and it is likely one might miss out on several nutrients and either become deficient, or more deficient than at the outset. Fasting definitely promotes nutrient deficiency.​

​

These are my opinions after researching the subject extensively and experimenting with it and discussing it with others. I will say that if one is fighting cancer, a keto diet should definitely be considered and discussed with one's oncologist. Likewise, it has been proven effective for certain seizure patients.

For ME/CFS, a nutrient dense diet is essential, along with a thoughtful and comprehensive supplement program. Avoiding processed foods and added sugar is also wise - helps to avoid swings in blood sugar which can affect energy and functioning upright.

Thank you for replying and for sharing your opinion on the keto diet!

So do you think Dr. Naviaux thinks that a keto diet might be beneficial to prepare the body to get out of the CDR state?

Let me tell you my experience just out of curiosity: I am having to follow a carnivore/cero carb diet out of obligation, in order to heal my very severe SIBO/IBS, and my experience so far has been positive. Not only I am healing from the terrible IBS, but my blood tests are better than ever. For example, my platelets are normal for the first time in 16 years of disease. Also, most of my blood vitamins/minerals are higher than usual , including folic acid, B12, zinc, copper or vitamin A (blood is unreliable, but I guess it is good to have levels higher) . And even my lymphocytes and total leukocytes are higher than ever, not to mention my excelent lipid profile (high HDL, low TG, low insulin...). If only I didn't suffer from severe ME/CFS I'd be happy!!

As for the adrenals, I don't think I am exhausting them, because my cyrcadian rhythm is normal for the first time in 16 years. (It used to be reversed).

Regarding aminoacids, I am not that worried, given my high protein intake plus the fact that my albumin, prealbumin and total blood protein are higher than normal, and my total IgM, IgG are also higher than usual. But it is impossible to know for sure without proper tests...

And, as for my ME/CFS, well, I feel just a bit better, with better cognitive capacity.

But I have to say that I passed a terrible month getting adjusted to ketosis, where I could barely move due to the terrible muscle weakness and heaviness. It is really hard to get used to burning fat!!

But I agree with you that it is necessary to pay attention to possible nutrients deficiency when in ketosis, such as electrolytes, B1, iodine or omegas. In this regard adding organ meats to the diet I think it is mandatory.

Thank you so much for the magnificent work you do on the forum. It's always enlightening reading your posts!

Take care!
Sergio

 

[Learner1]

So do you think Dr. Naviaux thinks that a keto diet might be beneficial to prepare the body to get out of the CDR state?

I did not discuss it with him. I don't know what he would think. You could try writing to him, although I have not found him to be terribly responsive to emails.

Let me tell you my experience just out of curiosity: I am having to follow a carnivore/cero carb diet out of obligation, in order to heal my very severe SIBO/IBS, and my experience so far has been positive. Not only I am healing from the terrible IBS, but my blood tests are better than ever. For example, my platelets are normal for the first time in 16 years of disease. Also, most of my blood vitamins/minerals are higher than usual , including folic acid, B12, zinc, copper or vitamin A (blood is unreliable, but I guess it is good to have levels higher) . And even my lymphocytes and total leukocytes are higher than ever, not to mention my excelent lipid profile (high HDL, low TG, low insulin...). If only I didn't suffer from severe ME/CFS I'd be happy!!

I don't doubt that your experience has been positive given the circumstances you describe. From the information I've gathered, keto diets for a particular purpose can be greatly successful. Long term, though, the risks may outweigh the benefits. There are exceptions, as in epilepsy or cancers.

SIBO/IBS rob you of nutrients and promote food allergies, so stopping that process would definitely be beneficial.

As for the adrenals, I don't think I am exhausting them, because my cyrcadian rhythm is normal for the first time in 16 years. (It used to be reversed).

Again, I think given your circumstances, it makes sense. My question is whether long-term you wouldn't experience negative effects. You might enjoy reading through Peter Attia's Eating Academy, his experimentation with ketosis.

Regarding aminoacids, I am not that worried, given my high protein intake plus the fact that my albumin, prealbumin and total blood protein are higher than normal, and my total IgM, IgG are also higher than usual. But it is impossible to know for sure without proper tests.

I'm a little mystified by your being high protein and in ketosis. The reason I couldn't continue doing ketosis was my protein needs were too high. Keto usually means 10% of calories from protein or less. My need tends to run between 20 and 25%.

And, as for my ME/CFS, well, I feel just a bit better, with better cognitive capacity

keto diets are known to do that, and SIBO/IBS are known to produce brain fog.

I have to say that I passed a terrible month getting adjusted to ketosis, where I could barely move due to the terrible muscle weakness and heaviness. It is really hard to get used to burning fat!!

I don't doubt that. The keto flu is well known. I went keto from being low carb to start with, but cutting carbs all of a sudden would be difficult.

But I agree with you that it is necessary to pay attention to possible nutrients deficiency when in ketosis, such as electrolytes, B1, iodine or omegas. In this regard adding organ meats to the diet I think it is mandatory

those aren't the nutrients that one is lacking on a keto diet. Antioxidants, folate, and certain minerals are. Organ meats would give you vitamin C, though. There's a book called Healthiest Foods on Earth That goes through the different nutrients and shows you what the best sources of each are and some of the lists only contain plant foods.

Thank you so much for the magnificent work you do on the forum. It's always enlightening reading your posts!

You're welcome. Sounds like you're on a good track. Just ensure that you're getting enough of all of the nutrients your body needs.

 

[serg1942]

Thanks again for sharing your thoughts. I will probably write to Dr Naviaux, since this is a crucial question.

As for keto, actually for the moment, I think that that ketosis is the default metabolic state imprinted in our genes, at least for many of us, so I am not worried about long term, specially if I feel better (for example my mom is keeping a mild degree of CFS thanks to keto. Otherwise she would be severe).

(BTW, if you have literature showing otherwise please do let me know. The studies I have reviewed show that for a couple of million years we were mostly carnivores, so ketosis should have been the default state.. But I'm open to read different views on this!)

Anyway, I am not just doing keto, but carnivore, and this alone is a different world, where B9 for example is not a problem, but electrolytes, B1 and vitamin C could be.

Thanks for the recommendation. I will read Peter Attia's experience! And will also take a look at the book you recommend.

Oh! As for the protein, well, 80% of my calories come from fat and 20% from protein (a ratio of 2:1 fat to protein). I'm following this ratio because it is the one recommended by Dr. Zsofia Clemens from Paleomedicina for many autoimmune diseases. And this ratio allows me to take abut 100-120 grams of protein daily, with a high degree of ketosis.

Thanks again and take care!
Sergio

 

[hapl808]

(BTW, if you have literature showing otherwise please do let me know. The studies I have reviewed show that for a couple of million years we were mostly carnivores, so ketosis should have been the default state.. But I'm open to read different views on this!)

I think this literature is speculative, so it's very hard to 'know' with any degree of certainty. For the first couple of million years we did not have hospitals or planes, but I'm not sure they are bad for us (well, hospitals are probably bad for us).

I am very flexible metabolically and have experimented with keto off and on for years, and carnivore a couple times as well. I think keto is quite interesting as I find very little issue 'switching over', maybe just a few days of adaptation. But while it seems to help my SIBO a bit on its own, I've found a more varied diet with higher supplementation more effective for both my SIBO and ME/CFS. I found keto and even more so carnivore limited my tolerance to any supplements.

But of course the challenge is we're all different, so do whatever works best for you. This is where doctors can be useless, because most prescribe a one-size-fits-all regimen.

 

[bob800]

Hi @Ema,
I did try dipyridamole myself for a short period, but for a different reasons (I hoped it might help certain mental health symptoms). I used 200 mg daily. I found it made me a tired, but when I switched to taking it before bed, this worked to advantage, as dipyridamole then promoted a nice deep long sleep.

Hi @Hip , did you find that dipyridamole made your sleep more refreshing? (e.g. did you have more clarity or energy the next day?) Any side effects other than the tiredness at night when you took it?

 

[Hip]

Hi @Hip , did you find that dipyridamole made your sleep more refreshing? (e.g. did you have more clarity or energy the next day?) Any side effects other than the tiredness at night when you took it?

I only took this drug a few times, not long enough to start noticing its effects. On one occasion taking it before bed, I wrote in my notes: "woke up feeling in a reasonably good mood with better energy."

 

[serg1942]

@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.

Hi @Hip

I will be adding Brilliant blue FCF to my anti-purinergic combo next week, and I'm deciding how much will I take.

I want to congratulate you for developing the formula. I have sometimes calculated the amount of a compound to take from the bioavailability and the free fraction, but never thought to came up with the actual formula!

However I must have my calculations wrong, as the final formula I am getting is 10 times less amount than yours:

40 * W * C
---------------------- mg
%B * (100-%P)

I'm writing below my calculations, in case you have the energy to review it.

It is important to me to have this right, as I am measuring my LPS/ATP stimulated IL1-beta, and I wouldn't want to take too little or too much as this would imply to lose resources and time.

Ah! Also, why are you using 4 L of blood instead of 4.5L?

Thank you in advance!!
Sergio



So, on the bases of:

W(g/mol)* C(mcrM)* 4 L
--------------------------------------
(%B/100) *((100-P%)/100)


Given that M=mol/L, and therefore mcrM=mcrmol/L:

W(g/mol)* C(mcrmol/L)* 4 L
--------------------------------------
(%B/100) *((100-P%)/100)


For the formula to work we need to work with the same units:

mcrmol/L =1/10^-6 mol/L


W(g/mol)*10^-6*C(mol/L)* 4 L
---------------------------------------------
(%B/100) *((100-P%)/100)

We want the result in mg, so given that 1 gr = 1000 mg:

W(10^3*mg/mol)*10^-6*C(mol/L)* 4L
---------------------------------------------
(%B/100) *((100-P%)/100)


We reorganize the formula:

W(10^3*mg/mol)*10^-6*C(mol/L)* 4L * 100 * 100
---------------------------------------------
(%B) *(100-P%)

= 40 * W * C
---------------------- mg
%B * (100-%P)



Thank you!

 

[serg1942]

Hey again @Hip ,

Ok, I just re-read your post and saw that you had broken down your calculations in a previous post where you explain that you actually use 40 L of water as the total distribution volume. Hence my 10-fold discrepancy!!

Could you please give me something to read about this concept?

This makes sense for some drugs that show a volume of distribution high, but perhaps not all of them?
What do you think about including the volume of distribution in the equation? Problem is that this is a theoretical concept and sometime it is like 100 L, what would make no sense.

Thank you!

 

[datadragon]

P2X7 receptor (P2X7R) is required for secretion of IL-1, and can be blocked by divalent cations such as magnesium (Mg). We demonstrated that Magnesium sulfate is efficacious in blocking IL-1-mediated-inflammation in HUVECs via downregulation of P2X7Rs on HUVECs https://pubmed.ncbi.nlm.nih.gov/31493768/ P2X7R is involved in the progression of atherosclerosis by promoting NLRP3 inflammasome activation. Stimulation with oxidized low-density lipoprotein (oxLDL) upregulated P2X7R, NLRP3 and interleukin (IL)-1 expression. Oxidized low-density lipoprotein (oxLDL) promotes THP-1 macrophage production and the release of interleukin-1 (IL-1) by activating the purinergic 2X7 receptor (P2X7R)/nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) pathway. P2X7R knockdown by siRNA suppressed NLRP3 inflammasome activation by inhibiting the PKR phosphorylation mediated by oxLDL. P2X7R plays a significant role in the development of atherosclerosis and regulates NLRP3 inflammasome activation by promoting PKR phosphorylation.
https://pubmed.ncbi.nlm.nih.gov/25761252/

The marginal vitamin B6 deficiency appears to relate to an increased risk of inflammation-related diseases, Recent studies have revealed that vitamin B6 treatment increases cardiac levels of imidazole dipeptides (eg, carnosine, anserine, and homocarnosine), histamine, and -aminobutyric acid (GABA) and suppresses P2X7 receptor-mediated NLRP3 inflammasome. These modulations may implicate possible cardioprotective mechanisms of vitamin B6. These modulations may also be involved in the underlying mechanisms through which vitamin B6 suppresses oxidative stress and inflammation. (the active pyridoxal 5 phosphate (P5P) NOT pyridoxine which lowers active b6) https://link.springer.com/article/10.1007/s00394-021-02665-2
Supplementation with high concentrations of the pyridoxine form of Vitamin B6 competitively inhibits the active Pyridoxal 5' phosphate (P5P) form which actually leads to decreased vitamin B6 function rather than enhancing it https://www.sciencedirect.com/science/article/abs/pii/S0887233317301959?via=ihub
Vitamin B6 normally needs Zinc, Magnesium, and Vitamin B2 (flavin mononucleotide (FMN); also known as riboflavin-5’-phosphate) in the conversion to active B6 (P5P).

The active form of Vitamin B6 (P5p) prevents IL-1β production by inhibiting NLRP3 inflammasome activation and suggest its potential for preventing inflammatory diseases driven by the NLRP3 inflammasome but not the pyridoxine form. https://pubmed.ncbi.nlm.nih.gov/27733681/

The P2X7 receptor is a cation channel activated by high concentrations of adenosine triphosphate (ATP). Upon long-term activation, it complexes with membrane proteins forming a wide pore that leads to cell death and increased release of ATP into the extracellular milieu. https://www.frontiersin.org/articles/10.3389/fnmol.2020.00124/full

Damage associated molecular patterns (DAMPs) are intracellular molecules released from infected or injured cells to activate inflammatory and reparatory responses. One of the most ancient and conserved DAMPs is extracellular ATP that exerts its phlogistic activity mainly through activation of the P2X7 receptor (P2X7R). Covers P2X7 receptor as a main player in inflammation https://pubmed.ncbi.nlm.nih.gov/29288626/

This study was also interesting showing that glucose stimulates fast ATP release that depends on the P2X7 receptor and pannexin-1 and the P2X7 receptor regulates B-cell proliferation at different glucose concentrations which means P2X7 has a bi-phasic effect on proliferation of B-Cells.

Glucose stimulates fast ATP release that depends on the P2X7 receptor and pannexin-1. The P2X7 receptor also regulates β-cell proliferation/survival. Stimulating the cells with increasing glucose concentrations ranging from 2.8 mM glucose to 25 mM showed a dose-dependent increase in the ATP release. inhibition of Panx1 and P2X7R significantly inhibited the high glucose-induced increase in intracellular ATP level, indicating that purinergic signaling was important in maintaining intracellular ATP as well as ATP release. P2X7R knockout mice had lower β-cell mass, impaired glucose tolerance and defective insulin and IL-1β and IL-1Ra secretion. glucose stimulated ATP release, which is sensitive to P2X7R and Panx1 inhibition, and further autocrine signaling via the P2X7R affects calcium signaling, insulin secretion and β-cell proliferation

High concentrations of a more specific P2X7R agonist BzATP (mM) and the P2X7R inhibitors decreased BrdU uptake by either decreasing proliferation or by promoting cell death. the inhibitory effects of high concentration of,BzATP, and P2X7R inhibitors, on BrdU incorporation were most likely due to suppression of cell proliferation. There was a tendency that BzATP 10–100 μM also increased BrdU incorporation. Notably however, increasing BzATP concentration to 1000 μM markedly reduced BrdU incorporation, both in control condition and when applied together with high glucose. These concentration-dependent and seemingly opposite effects of BzATP are one of the signatures of P2X7R multifunctionality. in INS-1E cells even 1 mM BzATP does not seem to kill the cells, it just decreases their proliferation in both low and high glucose concentrations. https://www.nature.com/articles/s41598-018-27281-9

 

[Hip]

Hi Serg

The first method of calculation, using the formula: 400 x C x W / ( B x (100 - P)) I derived, is less reliable than the second method based on a pharmacokinetic study.

This is because if the volume of distribution is high, then the first calculation method may not give a reliable result. I only use the first method when no pharmacokinetic studies are available.


With the first method, I assume around 40 litres of accessible water in the body. The exact amount of accessible water will depend on whether the drug can cross cellular membranes and enter the intracellular reservoir of water. But we may not know whether it can enter into cells, so I chose 40L as an approximate figure.

Then using the blood plasma protein binding percentage P, we can work out how much free (unbound) drug there is in this 40L. It's usually only the free drug concentration which has an active biological effect.

However, there is an assumption here, which is that the blood plasma protein binding will be similar to the tissue binding. But this might not be true: the binding to tissue proteins might be higher or lower than the binding to plasma proteins.

The volume of distribution gives a better picture of the tissue binding. But volume of distribution information is often not available, so that's why I use the plasma protein binding percentage instead in my equation.



Ideally you want a pharmacokinetic study which tells you the exact concentration of the drug achieved in the blood for a given oral dose. If you have such study, then you have a much more accurate result.

With such a pharmacokinetic study, all you then need to know is the plasma protein binding, to work out the free percentage of the blood concentration found in the study.

I could not find a pharmacokinetic study for Brilliant Blue FCF which used oral dosing; the study I found used an IV injection. But I was able to use this study, since we known the oral bioavailability is 65%.



Pharmacokinetics is a complicated subject, and I only really understand the basics. You can find some tutorials on pharmacokinetic science via this Google search.

 

[Rufous McKinney]

Move to Alabama and start grazing:

the famous movie, which includes President Jimmy Carter, is about Kudzu.

 

[datadragon]

Flavones are antagonists of the purinergic P2Y2 receptor

A series of 40 flavonoids were investigated as antagonists at P2Y2 receptors expressed in NG108-15 cells (mouse neuroblastoma×rat glioma hybrid cell line) in a functional assay measuring the inhibition of UTP-stimulated intracellular calcium release. Several flavonoids were identified as potent antagonists at P2Y2 receptors with IC50 values in the low micromolar concentration range; they were similarly potent or more potent than the standard P2Y2 antagonists Reactive Blue 2 and suramin. Flavone derivatives proved to be more potent than flavanones. The flavone derivatives catechin and epicatechin were inactive. However, a bicyclic benzopyranone ring system was found to be not an absolute prerequisite for P2Y2 antagonism, since the chalcone derivative β-oxo-aurentiacin (14) was also relatively potent (IC50 19 µM). Investigated flavone glycosides were completely inactive. The most potent P2Y2 receptor antagonists of the present series were kaempferol (19), heptamethoxyflavon (29), and tangeretin (25), with IC50 values between 6–19 µM. Increased lipophilicity by introducing (additional) methyl groups did not generally increase antagonistic potency. https://www.researchgate.net/public..._the_development_of_P2Y2_receptor_antagonists

Kaempferol content: https://en.wikipedia.org/wiki/Kaempferol

Flavones are widely present in leaves, flowers and fruits as glucosides. Celery, parsley, red peppers, chamomile, mint and ginkgo biloba are among the major sources of flavones. Luteolin, apigenin and tangeritin belong to this subclass of flavonoids. The peels of citrus fruits are rich in the polymethoxylated flavones, tageretin, nobiletin and sinensetin https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465813/

@serg1942