Combo Metformin And Syrosingopine!!!! Looks Awesome!  

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John Pizzuto
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05/11/2019 7:22 am  

@gge

Where would you like me to send the files?

The google translator produced English, but it's not very usable. 

I have a friend who is trying to get a better translation from someone that reads Chinese.


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John Pizzuto
(@jpizzuto)
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05/11/2019 8:17 am  

Zip file ok or do I have to load individual files?


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John Pizzuto
(@jpizzuto)
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05/11/2019 8:18 am  

Zip file ok or do I have to load individual files?


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John Pizzuto
(@jpizzuto)
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05/11/2019 8:19 am  

I tried to upload a zip file but it didn't work.  Oh well, send me your email address.


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John Pizzuto
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05/11/2019 5:56 pm  

MY friend had the manual translated for us.  Text only, in Word.


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GgE
 GgE
(@gge)
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05/11/2019 10:44 pm  

@jpizzuto

Thanks to you and your friend! Good job!


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GgE
 GgE
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06/11/2019 6:50 am  

@jpizzuto

One more note of caution. The syrosingopine/metformin combo worked preclinically in several subtypes of breast cancer. Hopefully it will work in her subtype. If so, it will kill off the cancer cells gradually. This will give her body time to remove the dead cells and grow normal cells in their place (bone cells and soft tissues) to repair the damage.

However, it is possible to overshoot it with the treatment agents and bring in excessive killing power. If this happens, then you might kill all the tumors in her body at once within a short time. If she has a high cancer burden, this might cause her a Tumor Lysis Syndrome (TLS) which could kill her faster than her tumors…It is necessary to find a fine balance.


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John Pizzuto
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06/11/2019 12:20 pm  

Approach death, but do not touch it.  Got it.  🙂

Not satisfied with the translation of the manual, I emailed the seller and asked if he could supply one.  Voila.  🙂


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GgE
 GgE
(@gge)
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06/11/2019 5:29 pm  

@jpizzuto

Great! I thought they did not have. I wonder why wouldn't they send it in the first place...


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GgE
 GgE
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07/11/2019 7:58 am  

There is a possibility that cancer cells may survive the combined assault of syrosingopine and metformin by exporting protons (by their proton pumps such as CAIX and many other enzymes) even if syro blocks their MCTs and they can’t export lactate. This way they could maintain a higher, livable pH than otherwise.

I guess this is why Daniel wrote in his “A List of Mitochondria Inhibitors, Disrupting Cancer Cell Function” file that “combining mito inhibitors with glycolisis inhibitors makes sense... using only mito inhibitors is expected to lead to an increase of the glycolisis and systemic acidity. Therefore, if mito inhibitors are used for longer time, it may be not only good but desirable to combine them with glycolisis inhibitors (such as 2DG, high dose Vitamin C, etc.) and proton pump inhibitors (such as discussed here.)” The latter reference is to his file “pH in Cancer & Tumor Acidification: A Top Treatment Strategy.” This paper mentions several PPIs and mentions some of their pros and cons. I wonder if anyone knows of a complete, systematic review of the PPIs used in cancer studies stating their dosage, effects and side effects.

There is this list of PPIs at https://www.drugs.com/drug-class/proton-pump-inhibitors.html but they are only rated as anti-acids.


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Daniel
(@daniel)
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07/11/2019 11:47 am  

@gge

Hi, indeed this is why I reply to John with this https://www.cancertreatmentsresearch.com/community/metabolic-inhibitors/combo-metformin-and-syrosingopine-looks-awesome/paged/3/#post-1368

Some of the best known PPIs I already mentioned in here https://www.cancertreatmentsresearch.com/ph-cancer-a-top-treatment-strategy/

But if you like to search the literature you can use PubMed and search for the author Salvador Harguindey. He wrote many reviews on PPIs including dose and maybe possible side effects.

Kind regards,
Daniel


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Jcancom
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08/11/2019 4:48 am  

JohnnyP,  yes, scary was the word that I had in mind as well. The posters on this forum exhibit a great deal of initiative in their treatment efforts. It is a personal decision, though it needs to be remembered that metastatic cancer is even more scary.

I am glad that TLS was noted by GgE. Some of these metabolic approaches do open up that potential ( I would still love to see a continuous monitor that could keep an idea on biomarkers for TLS; it remains unclear to me why this does not appear to be part of the tool kit of clinics). 

J


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John Pizzuto
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12/11/2019 12:17 am  

@jcancom

J:

Our oncologist has been providing a low dose of metformin for a few months, 250mg (1/2 a pill) twice a day.

I started Shirley on the syro/met combo Friday.  I doubled the dose of metformin to 500mg,  and added 3mg syro, twice a day.  But, that gave her diarrhea.  Don't know yet if it was the higher dose of metformin, the syro, or the combo, so, we are back to the low dose metformin for a while.  She took half a pill this morning with a little food, then 2mg syro, and all is well.  I will gradually raise the syro dose to see if diarrhea returns.

The scales I bought work really well, but you can get by without them.  I also ordered a set of mg spoons from amazon.  I found that a level scoop in the smallest spoon (the blue one) measured 2.9mg.  To measure, I place a 1" square of aluminum foil on the measuring tray, zero the scale, then dump the scoop of syro onto the foil.  If I am satisfied with the quantity, I carefully retrieve the foil, then surround the syro with a couple drops of olive oil to stabilize it for transport.

As far as I can tell, the pills we have are quick release, which give a higher serum concentration, so I think we should stick with those if we can.

I've been studying the research paper, trying to determine the minimum dose of metformin required to achieve "x" umol/L concentration in the blood.  Also would like to know the minimum syro dose.

The research paper also talks about adding the MCT1 inhibitor ARC155858.  Refer to figure 5 here:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302548/#mmc1

The graphs show a dramatic reduction in the required quantities of syro and metformin to work.


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Yudaitheska
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12/11/2019 2:52 am  

@jpizzuto

Hello Jhon! I believe the diarrhea was caused by metformin. It is a common side effect, many patients complain of that, lowering the dose was the right choice if you decide to give a higher dose try little by little to check her tolerance. Saludos! 


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Jcancom
(@jcancom)
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12/11/2019 3:44 am  

JohnnyP, D suggested a starting dose of syro of 1 mg/day. Did I read your post correctly? You started on 3 mg twice daily? Titrating up would always seem the best approach.

 

I was reviewing the patent and literature on Met/Syro. The patent described an in vitro method that could be used to determine efficacy pretreatment.

When I reread the 2016 article on Met/Syro, my attention was drawn to the description of the combo as a glyco/OXPHOs inhibition strategy. This is THE goto strategy of the forum. Simultaneously shutting down  glycolysis and OXPHOS (selectively) is an extremely powerful anti-cancer approach.{In my original post I focused in on the idea that the combo shut down NAD recycling.} Starting off cautiously would be especially in order for such a strong combo.

The article goes on to note that almost all the OXPHOS inhibitors aside from metformin were also effective. The one notable inhibitor not mentioned was methyglyoxal. MG is an OXPHOS subunit 1 inhibitor, as is metformin, that D has written about elsewhere. Of particular interest is that MG selectively inhibits OXPHOS I in cancer cells. Having NanoMG might be a very powerful way to amplify syrosingopine.  

Thank you for your citation of the recent MCT syrosingopine article. The escape routes for cancer cells are being identified and closed off.

Yes, I believe I recall also going through the metformin calculations.The patent does not seem overly helpful in this regard as it gave an order of magnitude range to choose from. It is so often frustrating that there are effective anti-cancer drugs such as metformin though they can be dose limited. This dose limitation problem is what inspired the search for a synergistic combo and syro was found.

 

The mito-Met research is startling!

Recent article:

https://www.ncbi.nlm.nih.gov/pubmed/31191823

Earlier research:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930686/

"In particular, the analogue Mito-Met10, synthesized by attaching TPP(+) to Met via a 10-carbon aliphatic side chain, was nearly 1,000 times more efficacious than Met at inhibiting cell proliferation in pancreatic ductal adenocarcinoma (PDAC). Notably, in PDAC cells, Mito-Met10 potently inhibited mitochondrial complex I, stimulating superoxide and AMPK activation, but had no effect in nontransformed control cells."

These mitocans are extremely powerful anti-cancer drugs. Synthesizing them might be of great help. 

 


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