Combo Metformin And Syrosingopine!!!! Looks Awesome!  

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John Pizzuto
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28/11/2019 10:23 am  

Thank you for this paper. 

"Because there is no pharmacologic inhibitor for MCT4, we designed genetic experiments to knockout..."

"The most remarkable finding is that ablation of lactic acid export induced only cytostasis with minimal loss of cell viability (data not shown). The bioenergetic plasticity reported above is certainly the basis of this acquired tumor cell viability under MCT blockade."

There is no mention of inhibition of NAD+ and NADH recycling, as done in the syro/metformin patent.  Apparently that is the bullet in the syro patent.  Cytostasis (?) as the lactate increases, then apoptosis by blocking NAD+ recycling.

What is the kill mode used in this paper?  Phenformin + MC1/MCT4 inhibitors?  Further reading required, I had to come up for air...


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John Pizzuto
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28/11/2019 10:34 am  

"As mentioned above, phenformin treatment abolishes OXPHOS (Supplementary Fig. S5B). This resulted in decreased mitochondrial ATP and led to a compensatory increase in glycolysis with increased lactate production and extracellular acidification (Supplementary Fig. S5A)."

From the text in figure 4:  "BSG/MCTs disruption combined with phenformin induces a major drop in cellular ATP, leading to rapid cell death."

 


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John Pizzuto
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28/11/2019 10:48 am  

"After tumor appearance (>30 mm3), mice received 200 mg/kg/d phenformin in the drinking water, and/or, when specified, 100 mg/kg MCT1 inhibitor AZD3965 twice daily by oral gavage for 10 days. Interestingly, even if no relevant differences were seen in vitro, knockout of either MCT4, BSG, or both induced in untreated mice a modest (20%–25%) decrease in tumor growth (Fig. 5A–D)."

"...reduced further lactate export, leading to substantial intracellular accumulation of lactate, pyruvate, and H+. This drastic metabolic and acidic stress inhibited further the glycolytic rate thereby mirroring a sharp increase in oxygen consumption. This metabolic plasticity, observed within minutes of addition of MCT1i, explains the cell survival by rapid maintenance of ATP levels."

"...the novel specific MCT4 inhibitor in current development by AstraZeneca (46)."  Reference says AZD3965, which was also used in the syro/metformin research.

 

So, keep doing what we are doing:  syro/metformin + cimetidine + loratadine, and look into adding phenformin and AZD3965?


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Matsim
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28/11/2019 12:51 pm  

Hi all,

You are making amazing discussion here. Everything that were discussed here opening many reasonable questions, especially about need for additional MCT1 depletion.

But I'm thinking, is it possible just Syrosingopine and Metformin to achieve enough synthetic lethality in cancers cells, as is described in Dr.Benjamin paper? Yes, Syrosingopine is 60 times or so more potent in MCT4, but still have potency on MCT1. So, it block it in some level. As Daniel pointed, MCT1 is used mainly for lactate import, and only in some cases is used for export with low efficiency. Is it possible to figure out that from existing studies?

 

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johan
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28/11/2019 3:17 pm  
Posted by: @gge
Posted by: @johan

Hi G,

though there's good research on widely available probiotics that show anticancer effects.

Please, post some links. It would be a good thing to know them.

The ones I have found seem to be contradicted by other studies. At times the same bacteria have good effects in one type of cancer and bad ones in another. It is an area of flux that is being researched.

I hope they make available soon probiotics containing those microbes that have proven strong anti-cancer effects beyond a doubt, and tests for us to find out who can benefit from them.

 

here's one: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336716/


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GgE
 GgE
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29/11/2019 1:51 am  
Posted by: @jcancom

It's important that we talk through the use of metformin concentration, as otherwise it is simply attributed to a somewhat mystical,unknowable process.

It would be great to know if the Basel study researchers titrated their mice plasma and tissues and if so, if they would tell us what metformin and syro levels they found. There may be some cumulative intracellular effect either from these substances by themselves or from their synergistic combination. Otherwise it is hard to understand why the combo cured 80% of the mice or why it has cured StevenK’s mesothelioma. I don’t think it is stated in their papers. Did I miss it? If it is not said Ray, could you please ask for this missing piece of info?


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GgE
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29/11/2019 2:54 am  
Posted by: @matsim

Everything that were discussed here opening many reasonable questions, especially about need for additional MCT1 depletion.

Posted by: @jpizzuto

So, keep doing what we are doing:  syro/metformin + cimetidine + loratadine, and look into adding phenformin and AZD3965?

Hi Johnny, although nobody here can tell you what you should do of course, if I were you I would hold the course and wait some time for results, unless I noticed a worsening of her condition. The syro+metformin therapy is not a silver bullet so this is an attrition war, not a speed race. As the general here you need to be patient IMO.

The chances of her having serious side effects or developing intolerance to the regimen and forcing you to stop everything for a long time probably go up exponentially with the number of drugs she receives.

Additionally, Phenformin is a tricky drug to use, with its own set of potential serious side effects (especially in a person in an altered state of nutrition) so I would hold off on it and see if the metformin is sufficient once it reaches the necessary mitochondrial concentration level.

I don’t know much anything AZD3965’s side effects. Also, I don’t know about cimetidine or loratadine yet but you seem to have done the research already.

In addition, even though I seem to want to completely block all MCT1 because of the aid it provides to cancer cells (especially in breast cancer), I would not go s far even if I could. Normal cells need some MCT1. My gut feeling is that you should not drastically alter her entire body metabolism or it might cause her serious harm.

One thing to watch out for is avoiding medications that inhibit basigin (CD147.) This link provides relevant info from page 265 to 278

https://books.google.com/books?id=2oeADwAAQBAJ&pg=RA1-PA275&lpg=RA1-PA275&dq=inhibition+of+mct4+upregulates+mct1&source=bl&ots=21aJIMrP9J&sig=ACfU3U2dLet0pT54yO5hAkhbMgsTl9Y2kw&hl=en&sa=X&ved=2ahUKEwiV1uj6rIzmAhWG4J4KHXfoBcE4KBDoATAFegQIChAB#v=onepage&q=inhibition%20of%20mct4%20upregulates%20mct1&f=true


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Jcancom
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29/11/2019 5:01 am  

JohnnyP, I am so glad that you have a team of people guiding you towards a better treatment outcome. It is too much for one person to manage for themselves. 

I agree with GgE that a wait and stay the course would be a helpful strategy. The syro met combo is one of the strongest metabolic strategies that we have encountered to date. Once a treatment response is recognized then amplifiers might be considered. One wants to give the basic treatment a fair chance by itself, as combining other treatments might abolish the gain from the published result. 

In fact, instead of throwing in the kitchen sink, creating a plan of sequential treatments has been shown to have benefit for some posters on the forum. For example, after the two rounds of syro met, perhaps metronomic 2-DG could be considered. Without combining a great number of possibly interacting treatments all at the same time, one could sequentially attempt to stress the cancer cells by depleting ATP etc..  


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Jcancom
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29/11/2019 6:30 am  

I was looking around the metabolic map wondering whether there might not be another NADH producing process somewhere and whether this might be helpful to block. critic on the compass thread was well ahead of me on this. He posted   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226516/     which appears to be yet another -formin combination metabolic stressor: here phenformin and gossypol. Shutting down OXPHOS and ALDH yielded strong synergy in a lung cancer model in mice.

 

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Ray Donnelly
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29/11/2019 3:52 pm  

Hey all,

I've been on 2x4mg of syro and 4x500mg of metformin a day as well as 3 bi-weekly chemo agents. I have some cimetidine to hand and can easily get loratadine. Should I add those to the mix or wait and see?


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prashant
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29/11/2019 7:39 pm  

@jpizzuto

I'm giving my mother a Withania somnifera extract to counter Estrogen.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5271386/ (Withania somnifera Root Extract Enhances Chemotherapy through ‘Priming’)

and

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675906/ (Effect of an Extract of Withania somnifera Root on Estrogen Receptor-positive Mammary Carcinomas)

I'm giving my mother (age 87, weight 50Kg) one spoon per night of this extract:
https://www.amazon.com/Patanjali-Divya-Ashwagandharista-Asawa-450/dp/B00KRK8HVC/ref=sr_1_1?crid=2C3FBW9KRRU88&keywords=ashwagandharishta&qid=1575052309&sprefix=ashwagandharis%2Caps%2C526&sr=8-1

 

Along with Metformin, Vitamin C (2g per day oral chewable), Vitamin D3 (180000 IU per month), multivitamins (including specially selenium), a mixed vegetable juice every day and breathing exercises, this has kept her cancer in check for the past 4 months - the tumor size is constant and not growing (as opposed to rapid growth at detection and before I started this treatment). Adding mebendazole to this regimen seemed to have a detrimental effect. I discovered this by accident when my supply finished and there was a pause in mebendazole. Apparently, mebendazole hinders in Vitamin C absorption.


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GgE
 GgE
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29/11/2019 7:42 pm  
Posted by: @ray-donnelly

I've been on 2x4mg of syro and 4x500mg of metformin a day as well as 3 bi-weekly chemo agents. I have some cimetidine to hand and can easily get loratadine. Should I add those to the mix or wait and see?

How long have you been on the syro + metformin? If you have not been at least 1.5 months and have not yet had a test to compare before and after and see if it is improving, I would not change anything.

You are very lucky if you are tolerating that dosage without nasty side effects. There are tons of people who would love to be in your shoes. They can’t keep that dosage because of extreme blood pressure drops, debilitating diarrhea, tremendous GI pains, depression, and other intolerable side effects. 

As Jcancom says,

Posted by: @jcancom

a wait and stay the course would be a helpful strategy. The syro met combo is one of the strongest metabolic strategies that we have encountered to date.

There will be plenty of time to add stuff if you don't improve.

But keep in mind that this is just one opinion.


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prashant
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29/11/2019 7:48 pm  
Posted by: @jpizzuto

@ray-donnelly

SteveK places it under his tongue.  Well, my scales are set up downstairs on the dining room table, my wife is upstairs in bed, so I have to carry it to her, on a small piece of tin foil I use when I measure it.  To prevent loss, I use a toothpick to surround the sample with a few drops of olive oil, then she just licks it off the square of tin foil.

I seem to remember that syrosingopine is highly water soluble, and that it's solution can last a long time in the fridge. Would it not make sense to dissolve a known weight of syro in a known volume of water, and then use a standard syringe to measure out exact quantities of your dissolved dose?

 


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Ray Donnelly
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29/11/2019 9:46 pm  
Posted by: @gge

How long have you been on the syro + metformin?

Since 13th November. I was on metformin alone (1g) for a few weeks before that.

I have had one blood test since starting the syro + met combo and my CEA dropped dramatically. That was done at the end of a 3 week chemo break for a PET scan too.


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Jcancom
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29/11/2019 11:53 pm  

Ray, this is very exciting news!

How long after starting syromet was your blood test? How long before starting it was your previous blood test? From your best estimation from any previous experiences, does your CEA levels typically stay constant after a break from chemo? Roughly how dramatic was your decline in CEA levels (percentage wise)? Did you go directly from 1 g met to 4 x 500 mg met and 2 x 4 mg syro? 

There are a great many questions to answer. My initial reaction is that amplifying this response might not be the best idea at this time. We have seen several times with metabolic therapy to date that too much response can become more of a problem than too little. The response that we have seen here should warn others how powerful syromet is and to dose cautiously. Dramatic declines in cancer viability in short periods of time is not really the objective that  should be sought after; steady and  moderate decline would be better and safer.

It might be advisable to consider having at least weekly CEA monitoring given the current response.  


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Ray Donnelly
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30/11/2019 1:12 am  

Would it not be dependent on where the cancer is on whether a fast decline is problematic or not? Mine is in my paraaortic lymph nodes only at present and not, for example in my bones, so AFAIK, I shouldn't have 'structural' issues requiring healthy cell re-population, or am I missing some details here?

I'll get the details for the CEA levels tomorrow, but it was well above 10 a test done about 4 weeks ago (I remembered it as 18-odd but my wife says 13) and it was below 6 last week. The variables were the cessation of chemo and the introduction of syro and metformin.

In terms of tolerating this protocol, the chemo's the only think I have serious trouble with. Apart from feeling 10% worse after each bout, it causes me to throw up some mornings and that's always a bit of a disaster metabolically and nutritionally. The metformin is probably giving me some stomach pain and I hope slow release will improve that. I think the ketogenic diet is helping me to avoid the worst effects of diarrhea (last time I was on chemo - which stopped about a year ago for my operation - I wasn't on a keto diet and I had worse problems in that regard back then).

To add some confusion, I also did a few sessions in a sauna a few chemo sessions ago, still I got the high CEA value after that so I don't think that did much.

I am looking into options for private oncology here in Spain so I can start to track things better.


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Matsim
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30/11/2019 3:25 am  

@gge, Thank you for your answer.

Do you have a real concerns whether this combination plus another MTC1 inhibitor (Claritin?) can block MCTs not only in cancer cells but in healthy cells too? BTW, I really appreciate your strong common sense and your careful approach. Please, keep doing it!

I have some concern about side effects of the combo, especially about lactic acidosis, because of high dose Metformin enhanced by Syrosingopine.

@prashant, Are you sure about solubility of Syrosingopine in water? As I know it's soluble in acetic acid, and earlier Daniel mentioned a ethanol and some other solvent too, but not water.

I will be great if Syrosingopine can be stored as liquid solution. One can prepare it for a week ahead and easily can be dosing with a dropper daily. But how we can know if it possible to store it in this way without being spoiled?


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prashant
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30/11/2019 5:27 am  
Posted by: @matsim

@prashant, Are you sure about solubility of Syrosingopine in water? As I know it's soluble in acetic acid, and earlier Daniel mentioned a ethanol and some other solvent too, but not water.

Apologies. I must have remembered wrong. I just checked. Sigma Aldrich lists it as soluble in DMSO. 10mg/mL

https://www.sigmaaldrich.com/catalog/product/sigma/sml1908


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Ray Donnelly
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30/11/2019 9:05 am  

It really isn't that big a chore to weigh it provides toy have good scales. Still good scales can be expensive so having a liquid based option could be good.


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Matsim
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30/11/2019 3:59 pm  

@ray-donnelly

, how you are storing your Sirosingopine? I've read that it should be stored in dry and cold conditions in 2-8°C range. The refrigerator meets these conditions, except that there could be not so dry in some circumstances. Maybe put it in some vacuum bag will be solution to not going wet?

About storing it as liquid. Have somebody any thoughts about dissolving 10-15mg of Syrosingopine in some 15-20ml vinegar and store it for 5 day or so? It will be safe?


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John Pizzuto
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30/11/2019 4:36 pm  

@matsim

DMSO is a solvent for Syrosingopine.  One place to order:

https://dmso.com/


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Manuone
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30/11/2019 4:54 pm  

Hi all!
I am passionate to see how the forum is growing and this discussion in particular, this is the way!
The met + syro combo seems very interesting, saving the source of supply and its quality.
It would really be very interesting to dissolve it in DMSO, very possibly it would improve its bioavailability.  I remember that a minimum amount could be taken orally from DMSO. I have used dmso iv up to 4ml without problems. Although on the other hand the most sensible thing is to take met + syro in the normal way to observe tolerance without anything that enhances it


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Daniel
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30/11/2019 6:32 pm  

@matsim

If I would want to dissolve Syro in solution and make sure that solution can be stored for long term usage, I would solve it in ethanol min 96% like this one. The solution can be stored in the freezer at -20C and could be used at any time (since ethanol will not freeze) - no waiting time required. I to not know exactly the solubility of Syro in ethanol, but I would expect at least 2mg syro/ml ethanol. DMSO is also good solution to solve Syro but not so practical for long term usage as DMSO is freezing below 18C (just below room temperature it becomes solid). 


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Jcancom
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30/11/2019 6:33 pm  

Ray, as far as I know the anti-cancer response you have had with syromet is the largest that has ever occurred on this blog (anyone is free to correct me if this is inaccurate).

 

( Johan mentioned that we can include keywords in our posts such as "off-topic" that can be picked up automatically by the RSS software and sorted. I suggest that the term All Time New High for The Thread (ATNHTT)  be applied to the current and future occurrences of note for the forum/blog.) 

 

A  ~70 % (?) decline in tumor markers in one week of treatment is substantial. This is exactly the concern that I have with metabolic treatment: it can be so powerful that one almost has too much treatment power.  syromet introduces the dangers of TLS, lactic acidosis and perhaps others. You need to have regular labs to make sure that your treatment is safe. When was the time that you had a lab that checked for these concerns?

I am sure that everyone on forum is happy that I do not intend to post the response curve from the article a third time, though as we all can remember when the syromet treatment is "binding" one is on a near vertical portion of the curve. You must be somewhere on this region now. This suggests to me that amplification should indeed be possible, while at this time I would clearly recommend that this not be attempted. Roughly, when you reel in, there is going to be pull. Funnily enough, if you have had a lab in the last day or so and you had another large decline in your tumor marker, then you would be considered to be in the normal range for CEA.  

I am very interested in seeing a more complete record of your CEA reports. What was your highest CEA that has been recorded to date? When you were on chemo alone what response did your CEA show?

D, I think a Visitor page for Ray would be beneficial, in order that we can have a more complete description of  his tumor burden, treatments, etc.

Any posters who might have ideas for what the next sequential treatment for Ray might be that would logically complement syromet please post to this thread for our consideration.


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Daniel
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30/11/2019 7:09 pm  

@jcancom

J, anyone who likes to have their story shared in a main post they are welcome to send me the details on the following:

- diagnostic and time of that, and age,
- stage and tumor location at the time of diagnostic, 
- past: conventional and alternative treatments taken so far (oral and intravenous, drugs and supplements) and what was the tumor/marker evolution during this time
- present: conventional and alternative treatments taken (oral and intravenous, drugs and supplements) at this moment, tumor status at this moment, patient condition
- next steps (if any) that are proposed by the oncologist and/or considered by the patient
- any other relevant information 
- major questions that the patient or caregiver would like us to help with

In addition, the patient/caregiver has to agree that once I publish the post I will never delete it (it happened before with Ergin that he asked me to delete his post - I accepted and with that, a lot of information from our discussions and ideas shared with him were gone).

The advantage of such post it's that it gets much more attention since it will be published as any of my articles so it will be visible on the main page.

Kind regards,
Daniel

This post was modified 2 weeks ago 2 times by Daniel

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Jcancom
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30/11/2019 7:21 pm  

JohnnyP, might you have an interest in discussing topics off thread? Further, might you agree to D sending me your email for this purpose? D requires such explicit confirmation to protect the privacy of those on forum.


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John Pizzuto
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30/11/2019 9:12 pm  

Look up J&S SafeGuard, then click on the contact page.


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John Pizzuto
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01/12/2019 1:27 am  

More diarrhea today, about two hours after taking the medication:

3.0mg syro

500mg slow release metformin

200mg cimetadine

10mg loratadine

All but syro list diarrhea as a side effect.  I will omit the last two for a while, as the metformin is required.


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Matsim
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01/12/2019 3:57 am  

@jpizzuto
,
Thank you for the link, you've provided me.

@daniel
,
Thank you for the answer, and thank you very much for the advise about the alcohol solution.

I want to apologise for advance for the very long post, and again for my bad English. I know for sure, it's hard to read something gramatically and linguistically not correct.

Generally, I know nothing about DMSO and because of that I'm little afraid from it for oral use. And it'seems that with DMSO one should be more precise when mixing. While the options with ethanol or (if it's a option at all) acetic acid seems more harmless by itselfs, and allows less accurate dosing, considering saturation of the solution. But for sure I can be wrong.

My information about solubility of Syrosingopine in acetic acid comes from here.

Here acetic acid is missing as solvent, but we can see some instructions about solubility. They mention solution should be stored at -20°C upto 2 weeks, with 1 hour equilibration period.

Now I see that Dr.Benjamin's team prepared their solution as 5 mM stocks in DMSO and stored at -20°C. But I'm not sure whether the fridge in the kitchen can reach -20°C. I've put a thermometer inside it to check.

Here I've found something interesting, but due to a lack of good English, I can't figure out if we can achieve salt forming between Syrosingopine or/and Metformin with some acid. My thoughts are when Syrosingopine is Alkaloid we can consider that it will form relatively stable (but soluble in water) salt with acids.

... In view of the close relationship between basic compounds and their acid addition salts, metformin or phenformin means the free base or any acid addition salt thereof, and syrosingopine means the free base or any acid addition salt thereof. Salts are especially the pharmaceutically acceptable salts of syrosingopine. ...

...Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids. ... Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid ...

A little offtopic from Syrosingopine, but strongly ontopic as general with the whole thread is this patent document. It's seems that (some particular?) Metformin salt is able to be more potent than Metformin itself due to improvement of it's bioavailability. Moreover, it can reduce the side effects.

... The metformin acidic double salt has the characteristics of good stability and improvement on bioavailability, and is converted into metformin in vivo so as to achieve the aim of killing cancer stem cells. ...

... The object of the present invention to provide - Salt, having the following structural formula just - kind of high quality, good stability, less adverse reactions metformin acid complex ...

Meanwhile I've found a some information of liquid solutions not for Syrosingopine but for Reserpine (same group Indole Alcaloids). It forms a precipitate when dissolving in 8% DMSO, but solution is achieved with acetic acid.

... I've tried to use 8% DMSO as the solvent (which will give me final conc. of 2% DMSO during the assay) but Reserpine precipitates.

I was able to obtain a solution when using 0.5% v/v acetic acid as the solvent (this gives me 0.125% acetic acid during assay). Some of the bacterial samples are showing growth retardation at this conc. of acetic acid. ...

Here it's seems that Reserpine at least keep it's anti hypertensive properties when is dissolved in acetic acid

... I was using reserpine 5 mg diluted in 10 % acetic acid to induce lactation. The animals become too drowsy and heart rate will be decreased. There was increase in respiration and shallow. ...

Another page with more detailed info about mixing

... It is freely soluble in chloroform (approx. 1 g in 6 mL), methylene chloride, glacial acetic acid, benzene, ethyl acetate. It is slightly soluble in acetone, methanol, alcohol (1 g/1800 mL), ether, and in aqueous solutions of acetic and citric acids. It is very sparingly soluble in water. ...

https://www.tjpr.org/vol6_no2/623Idowu.pdf

... Reserpine stock solution was made by dissolving 6mg in 10ml of glacial acetic acid. This gave 0.6mg/mL solution. ...

 

I've dig a little bit more in the patent page for Syrosingopine Metformin combination and found some points that seems to give us a little bit more material for thinking. I'm apologise to those that are too familiar with this document, for showing it to them again.

About solutions, suspensions, fillers and mixing. Here mannitol appears:

... Preference is given to the use of solutions of the combination of syrosingopine and metformin or other biguanides, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example in the case of lyophilized compositions comprising the combination of syrosingopine and metformin or other biguanides alone or together with a carrier, for example mannitol, can be made up before use. ...

... Suspensions in oil comprise as the oil component the vegetable, synthetic, or semi-synthetic oils customary for injection purposes. ...
... As mixtures of fatty acid esters, vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and groundnut oil are especially useful. ...

... Suitable carriers for preferred solid oral dosage forms are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/or calcium phosphates ...

About dosage. Showing that we don't need huge dosage, a ratio Syrosingopine Metformin also :

... The compositions comprise syrosingopine and metformin or other biguanides alone or, preferably, together with a pharmaceutically acceptable carrier. The dosage of the combination of syrosingopine and metformin or other biguanides depends upon the disease to be treated and upon the species, its age, weight, and individual condition, the individual pharmacokinetic data, and the mode of administration.

... Further dosage forms are, for example, ointments, creams, pastes, foams, tinctures, drops, sprays, and dispersions. Examples are capsules containing from about 0.05 g to about 1.0 g combination of syrosingopine and metformin or other biguanides. ...

... In the case of an individual having a bodyweight of about 70 kg the daily dose administered is from approximately 0.05 g to approximately 3 g, preferably from approximately 0.25 g to approximately 1.5 g, of a combination of the present invention. ...

... The best hit identified was syrosingopine. Fig IA shows, that metformin alone at 5 mM triggers 20% inhibition of growth (left panel), while syrosingopine alone is virtually non-inhibitory (right panel, straight line). However, when increasing concentrations of syrosingopine are combined with 5 mM metformin (right panel, dashed line), a dramatic inhibition is seen with 2.5 pM syrosingopine. Similar findings were made with a series of human cancer lines ... Notably, in these cell lines the combined activity showed potent activity at a concentration range where each compound used singly had only a marginal effect. ...


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Jcancom
(@jcancom)
New Member
Joined: 3 years ago
Posts: 250
01/12/2019 6:59 am  

I think that the need for caution needs to be restated.

Reducing tumor burden by 50% or more within a week is dangerous especially if the actual tumor mass is large.  A strategy that should be carefully considered when beginning treatment with the syrosingopine metformin combination is to gradually increase the doses of syrosingopine and metformin all the while carefully monitoring response with daily labs. It is very dangerous to use maximal dosing especially when labs are not being performed regularly. It can be dangerous even to use more moderate dosing with such a powerful combination when regular monitoring is not occurring. It would also be quite dangerous to try and amplify a dose before establishing the magnitude of the response of the straight combination. It is not entirely obvious whether such combinations might be additive, synergistic or even super-synergistic. It seems likely that if syromet were ever to complete clinical trials, then the marketed treatment would only have modest effects that possibly could require months to reach a complete response.

Patients often are not overly patient when waiting for responses, however, it should be noted that responses can apparently occur rapidly with this combination. It is even possible that a lab taken on the first day of treatment before administering the first dose and a lab taken a few hours after the treatment might already show a treatment response. Such rapid changes in tumor biomarkers are a strength of metabolic therapy. If one quickly knows that treatment will be effective, then would be not as urgent to aggressively (and dangerously) push for maximal dosing. It had been speculated that it might take up to 2 months to see responses (This had seemed counter-intuitive to me as here shutting off NAD+ recycling would presumably have a more immediate effect on tumor biology.), though more rapid reductions have now been seen.

I realize that some might want to save some expense, though saving expense on lab testing is not a good strategy. By dosing up with labs ongoing, you could develop an understanding of the dose response relationship and then have a feeling for where on the response curve you might be. You would know where the dosing would start to have a binding effect on response. 

The poster on another thread who had success with the syromet combination, treated with 2 x 4 mg syrosingopine and 1 x 1000 mg slow release metformin and 2 x junior aspirin per day.  This apparently resulted in a moderate response rate over months.

We have been very fortunate that more serious side effects have not been reported. Nonetheless, we need to learn from our good fortune and be much more careful with dosing levels, avoiding co-treatments and monitoring responses frequently. The combination of syrosingopine and metformin has now been seen to be a powerful anti-cancer treatment in a very small number of patients as reported anecdotally here and elsewhere; this should be taken as a caution to treat with greater care and with less haste.   


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