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

frozenborderline

frozenborderline

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BACKGROUND: Lidocaine has been widely used to relieve acute pain and chronic refractory pain effectively by both systemic and local administration. Numerous studies reported that lidocaine affects several pain signaling pathways as well as voltage-gated sodium channels, suggesting the existence of multiple mechanisms underlying pain relief by lidocaine. Some extracellular adenosine triphosphate (ATP) receptor subunits are thought to play a role in chronic pain mechanisms, but there have been few studies on the effects of lidocaine on ATP receptors. We studied the effects of lidocaine on purinergic P2X3, P2X4, and P2X7 receptors to explore the mechanisms underlying pain-relieving effects of lidocaine.
METHODS: We investigated the effects of lidocaine on ATP-induced currents in ATP receptor subunits, P2X3, P2X4, and P2X7 expressed in Xenopus oocytes, by using whole-cell, two-electrode, voltage-clamp techniques.
RESULTS: Lidocaine inhibited ATP-induced currents in P2X7, but not in P2X3 or P2X4 subunits, in a concentration-dependent manner. The half maximal inhibitory concentration for lidocaine inhibition was 282 ± 45 μmol/L. By contrast, mepivacaine, ropivacaine, and bupivacaine exerted only limited effects on the P2X7 receptor. Lidocaine inhibited the ATP concentration-response curve for the P2X7 receptor via noncompetitive inhibition. Intracellular and extracellular N-(2,6-dimethylphenylcarbamoylmethyl) triethylammonium bromide (QX-314) and benzocaine suppressed ATP-induced currents in the P2X7 receptor in a concentration-dependent manner. In addition, repetitive ATP treatments at 5-minute intervals in the continuous presence of lidocaine revealed that lidocaine inhibition was use-dependent. Finally, the selective P2X7 receptor antagonists Brilliant Blue G and AZ11645373 did not affect the inhibitory actions of lidocaine on the P2X7 receptor.
CONCLUSIONS: Lidocaine selectively inhibited the function of the P2X7 receptor expressed in Xenopus oocytes. This effect may be caused by acting on sites in the ion channel pore both extracellularly and intracellularly. These results help to understand the mechanisms underlying the analgesic effects of lidocaine when it is administered locally at least.
 
roller

roller

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necessary8 said:
But since this directly contradicts what Naviaux has said in his presentation, I think it's time we ask him directly about it, so I've sent an email to him. I'll let you know once he responds.
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would you kindly telling us too, what naviaux replied ?
 
frozenborderline

frozenborderline

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From Goldstein around 1990: “For the second year in a row, Yamazaki and colleagues (2000) have correlated central TGF-beta elevations with fatigue after exercise. I emphasized that elevated TGF-beta (Goldstein JA, 1990) was re- lated to stress and possibly involved in CFS pathophysiology. TGF-beta has poorly characterized effects in the adult CNS but is a powerful immunosuppressant. It inhibits TNF-alpha, a cytokine elevated in inflammation and by antidepressants. TGF-beta is inhibited by suramin, an ATP blocker and reverse transcriptase inhibitor that is too toxic for clinical use. Perhaps TGF-beta affects Trk, as many other growth factors do, and could be inhibited by genistein. Among the many properties of TGF-beta that I listed in 1990, two stand out today: TGF-beta (1) regulates the gene and promotes the transcription of plasminogen activator and (2) is dramatically in- creased by phorbol esters.” Interesting, TGF-beta is talked about as a marker for CIRS/mold illness by Shoemaker, and is also one of the cytokines that was elevated in Montoya’s cytokine study. I’m also surprised that Goldstein knew something about the role of purinergic receptors ans suramin In 1990. He also achieved dramatic results often with adenosine. @Hip you May have already seen this connection but it’s interesting
 
Learner1

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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.
 
shannah

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Learner1 said:
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.
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@Learner1

Thanks for relaying your conversation with Dr. Naviaux.

This has brought up some questions that don't seem to have clear cut answers. I'll just throw them out here for possible discussion.

So if we still need to treat pathogens first, given the theory that autism harbours underlying pathogens, what would be the explanation I wonder for the autism kids in the initial study having such a dramatic response to suramin?

Many of us have been treating underlying pathogens for years with no success. What hope is there for us?

There's also the point that we could very well be harbouring a pathogen for which there's no effective treatment yet. Where does it leave these people I wonder?
 
pattismith

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debored13 said:
https://www.ncbi.nlm.nih.gov/pubmed/25695577/

Lidocaine is a p2x7 antagonist, which is very interesting. The controversial cfs doc jay Goldstein used intravenous lidocaine in ME/CFS patients as one of his most used treatments. I would think lidocaine May be better tolerated than suramin.
@Iritu1021 a connection between Goldstein and naviauxs work
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lidocaine is a sodium voltage gated channel blocker. (mediating its analgesic action). I can't find any other study about a lidocaine P2XR activity, so i don't know what to think about this one you quoted...
 
frozenborderline

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pattismith said:
lidocaine is a sodium voltage gated channel blocker. (mediating its analgesic action). I can't find any other study about a lidocaine P2XR activity, so i don't know what to think about this one you quoted
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well in tuning the brain, Goldstein mentioned that sodium channel blockers could have anti purinergic activity too and that substance p is involved in purinergic signaling and that purinergic signaling has a lot to do with pain. He doesn’t provide any sources but also the fact that he mentions it and that I’m able to find a study measuring that, not done by him, lends some credence to this idea imo. It seems like purinergic signaling is relatively new stuff and may not have been mapped out fully. I don’t find it hard to believe that only one study has shown this in that context.
 
pattismith

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debored13 said:
well in tuning the brain, Goldstein mentioned that sodium channel blockers could have anti purinergic activity too and that substance p is involved in purinergic signaling and that purinergic signaling has a lot to do with pain. He doesn’t provide any sources but also the fact that he mentions it and that I’m able to find a study measuring that, not done by him, lends some credence to this idea imo. It seems like purinergic signaling is relatively new stuff and may not have been mapped out fully. I don’t find it hard to believe that only one study has shown this in that context.
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Yes, there is some studies about the P2X activity of some sodium channel blockers, but I guess we need more evidences.
Here I found a study about Lithium as a P2X7 antagonist

https://forums.phoenixrising.me/threads/pain-gone-with-ambroxol.62011/#post-1009522

;;;
 
nandixon

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debored13 said:
From Goldstein around 1990: “For the second year in a row, Yamazaki and colleagues (2000) have correlated central TGF-beta elevations with fatigue after exercise. I emphasized that elevated TGF-beta (Goldstein JA, 1990) was related to stress and possibly involved in CFS pathophysiology.
Click to expand...

It's never been clear whether the elevated TGF-beta commonly seen (and statistically shown by meta-analysis) in ME/CFS was a good actor helping to offset an inflammatory process, or if it was in fact causing more harm than good.

But in the fulltext* of the recent Klimas & company publication of this thread:

https://forums.phoenixrising.me/threads/klimas-nova-gene-expression-treatment-avenues.75491/

Klimas is now considering the possibility that it may need to be addressed and states:

While TGF-b was associated with protein kinase inhibitors, selective immunosuppressants, pyrimidine analogues, platinum compounds, anthracyclines, and antineoplastic agents, no specific FDA-approved drugs are known to target TGF-b, although this is an active area of development.66,67 As such, the TGF-b pathway was highlighted in both the male and female cohorts, was shown to be associated with several fatigue measures in the female cohort, and has been shown to be consistently elevated in ME/CFS.7 Thus, TGF-b inhibitors may prove to be a viable treatment avenue for this illness.
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(My bolding)

*The fulltext is available here as a PDF download.
 
pattismith

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oct 2019
Repurposing drugs targeting the P2X7 receptor to limit hyperinflammation and disease during influenza virus infection (nih.gov)
Our study demonstrates that the anti‐inflammatory drugs probenecid and AZ11645373, which have documented pharmacokinetics and safety profiles in humans, are effective at dampening hyperinflammation and severe influenza disease providing potentially new therapeutic strategies for treating severe or pathogenic IAV infections.
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2021
New Inhibitory Effects of Cilnidipine on Microglial P2X7 Receptors and IL-1β Release: An Involvement in its Alleviating Effect on Neuropathic Pain (nih.gov)
 
S

seamyb

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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?
 
C

cporro

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seamyb said:
Or has anybody tried anything based off this thread?
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exactly

these days i spend less and less time reading about mechanisms and more time just trying things. that's the only way to know if it works for you. i narrow things down to what look like good candidates with research. then i try them if possible. i have a big list of stuff that i now know does not work for me. check that off the list.

gone are the days of spending weeks reading studies, opinions, and forums. reading about why something works. i really don't care. plenty of drugs being used that we don't understand well. SSRIs for example.
 
Learner1

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nandixon said:
It's never been clear whether the elevated TGF-beta commonly seen (and statistically shown by meta-analysis) in ME/CFS was a good actor helping to offset an inflammatory process, or if it was in fact causing more harm than good.

But in the fulltext* of the recent Klimas & company publication of this thread:

https://forums.phoenixrising.me/threads/klimas-nova-gene-expression-treatment-avenues.75491/

Klimas is now considering the possibility that it may need to be addressed and states:



(My bolding)

*The fulltext is available here as a PDF download.
Click to expand...
Interesting. My doctor has me on Chinese herbs known to reduce. TGF-B. (Sorry for the bad image, phone is not cooperating...(
Screenshot_20211020-092629.png
 
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