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Jcancom
(@jcancom)
Joined: 3 years ago
Posts: 502
04/12/2019 4:30 am  

JohnnyP, this is great that you have found a formulation of metformin that might avoid the side effects encountered to date. I am glad that you are cautious about the route of administration as syromet is a very powerful combination and must be carefully applied.

In your previous post that mentioned ketones and MCT-2, you mentioned me at the start, though this forum does not allow us to traceback which post is being referred to. Might you note which post of mine that you are referencing?

Best Wishes, J 

 


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John Pizzuto
(@jpizzuto)
Joined: 1 year ago
Posts: 200
04/12/2019 7:00 am  

@jcancom

The syro/met combo blocks MCT1 and MCT4 and NADH recycling--->cancer cell death.

Wondering how normal cells survive, without going back to read the Benjamin research paper, I went off on a tangent, thinking ketones can save normal cells.  But what transporters can use ketones?  Oh crap, the paper I linked you says MCT1 is the main ketone transporter and is upregulated in ketosis.

So, is a keto diet helping or hurting when using syro/met?

I noted that ketones can also enter via MCT2.

 


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Ray Donnelly
(@ray-donnelly)
Joined: 11 months ago
Posts: 55
04/12/2019 11:18 am  

Hey all.

 

New readings:

04/12/2019 CEA 5.4 C199 152.

Of note is that my cholesterol levels are high, 401 and 265. Any recommendations for that?


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Matsim
(@matsim)
Joined: 10 months ago
Posts: 12
04/12/2019 12:08 pm  
Posted by: @jcancom

You would then have a much better idea when syromet was losing effectiveness far in advance of when your CEA readings finally called the turn.

Which way you considering for cancer cells to escape from this combination? And can we block it in some way?

Thank you personally for your very exhaustive information, you provide us every time.

Regarding the lactate monitoring. What information would it give us after we try to keep the lactate inside the cancer cells? Or we expecting when cancer cells dying to release the lactate in the blood? I can't find lactate examination in the sites of the labs in my city. Will Lactate dehydrogenase(LDH) will give some appropriate information instead?

 


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Matsim
(@matsim)
Joined: 10 months ago
Posts: 12
04/12/2019 12:57 pm  

To all,

According the information Ray Donnelly gave us about his labs data (Thank you, @ray-donnelly very much for sharing it), which is the best approach to start this combination? How you are considering approach with escalating doses? I mean to start for example with 1 mg Syrosingopine and add 1mg for every next 3 days, when the dose reach 4mg per day to wait 2 weeks and then check the tumor marker for response, and then to considering for adding more.

Is this approach too risky regarding possibility for give a chance to cancer cells to find a route for escaping? Or it's better from lactic acidosys and/or TLS prevention point of view?

I'm stick to the that passage from the pattent page of the combo. From there, it's supposed to not using too high dosage:

... 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. ...


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John Pizzuto
(@jpizzuto)
Joined: 1 year ago
Posts: 200
04/12/2019 3:12 pm  

@matsim

Thank you for the patent link.  I'm embarrassed to say I have looked at it but never studied it until now.  It states the weight to weight ratio between syro and metformin should be in the range from 1/100 to 1/200, preferably 1/130.

Admin note: part of this post was deleted at the request of jpizzuto due to calculation error


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Ray Donnelly
(@ray-donnelly)
Joined: 11 months ago
Posts: 55
04/12/2019 4:17 pm  

I've done a bit more looking into my details of when I had the chemo break and started syromet.

My last chemo before the break on 20th October and I had the scan on the 5th November. Chemo resumed around 20th November.

My interpreter told my oncologist that I was on metformin (but not syro) when we tried to ask about the CEA drop. She said that chemo can have a delayed effect like that. This is news to me. AFAIK chemo has short half lives on the order of hours and is only killing cancer when it's floating around your bloodstream.

My cholesterol readings are making me consider going back to carbs and ditching keto for a while. Does this sound reasonable or should I try to reduce the fats from dairy and meat preferring avocado and olive oil?

Thanks!


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Daniel
(@daniel)
Admin
Joined: 5 years ago
Posts: 903
04/12/2019 4:21 pm  

@ray-donnelly

Ray, HCA and others discussed here may help with that https://www.cancertreatmentsresearch.com/reduce-cholesterol-in-cancer-cells-to-fight-cancer/


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Manuone
(@manuone)
Joined: 2 years ago
Posts: 124
04/12/2019 4:47 pm  

 

Hi guys!

Reviewing the publication on Daniel's "a list of mitochondrial inhibitors" I saw an update of the month of July with the following article in Nature: https://www.nature.com/articles/s41586-019-1005-x
The Panhematin drug seems to make mitochondrial respiration more dependent on cancer cells and possibly more sensitive to mitochondrial inhibition by drugs such as metformin.
This was a great update from Daniel that we may not have contemplated sufficiently .....


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John Pizzuto
(@jpizzuto)
Joined: 1 year ago
Posts: 200
04/12/2019 7:23 pm  

Looking for a way to administer metformin, studying this paper about rectal suppositories:

https://www.frontiersin.org/articles/10.3389/fphar.2019.01196/full


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finnan
(@finnan)
Joined: 2 years ago
Posts: 10
04/12/2019 8:33 pm  

@ray-donnelly

Have you considered going in a vegan keto direction to lower your cholesterol: https://www.facebook.com/groups/320351758396552/


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Matsim
(@matsim)
Joined: 10 months ago
Posts: 12
05/12/2019 2:18 am  

@jpizzuto

,
I'm not sure how you achieve your calculations, and 2.55g max Metformin dosage. The result showing 19.6mg Syrosingopine for a 70 kg person really bothers me. Please, let me share my calculations and thoughts.

We have couple examples about Syrosingopine Metformin ratio, but for the blood concentration only, and they vary vastly:

https://patents.google.com/patent/GB2487351A/en

... Fig 1A 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 μΜ syrosingopine. ...

So, we have:
syrosingopine (2.5 μM), metformin (5000 μM)
Syrosingopine/Metformin ratio = 1/2000

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5182053/
syrosingopine (5 μM), metformin (5000 μM)
Syrosingopine/Metformin ratio = 1/1000

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302548/
metformin (4000 μM) or syrosingopine (0.5 μM)
Syrosingopine/Metformin ratio = 1/8000

 

But we still don't have the clue about how these concentrations was achieved.

Only from one of the studies we have information about exact quantities they really used:

... Mice were injected intra-peritoneally daily with metformin (250 mg/kg body weight), syrosingopine (2 mg/kg body weight) ...

This points us to (weight to weight?) Syrosingopine/Metformin ratio = 1/125

But that don't give us information about which exact blood concentration they achieved with this dosage.

Then we have that statement, which even more confused me:

6. The pharmaceutical composition of any one of claims 1 to 5 wherein the relative amount (weight per weight) of syrosingopine and the mitochondrial inhibitor is between 1 to 10 and 1 to 1Ό00.

7. The pharmaceutical composition of claim 3 wherein the relative amount (weight per weight) of syrosingopine and metformin is between 1 to 10 and 1 to 200.

I think mostly about these statements :

... 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. ...

... Syrosingopine sensitized cancer cells to metformin and its more potent derivative phenformin far below the individual toxic threshold of each compound. ...

Here are pictures of original Singoserp(Syrosingopine) bottle, where we can see it's regular dosage. It's in 0.5 - 3 mg range. I suggest that these dosages were approwed for use due to being "far below the individual toxic threshold".

Then we have something a little bit specific from the authors:

... 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. ...

They describe their preferable dosage as 0.25 - 1.5 g. That mean 250 mg - 1500 mg Metformin, which is pretty normal dose. From here we again can't understand about how much Syrosingopine we should put with that quantity of Metformin, but considering a lower threshold(0.25mg), not so much.

Something for considering abut Metformin concentrations:
https://www.ncbi.nlm.nih.gov/pubmed/29574345

... On average, metformin concentrations were 1846ng/mL (<LoQ-5560ng/mL) and independent of the prescribed daily dose. ...

It makes sense for me to use close to the normal for the original purpose dosage for every drug. But here comes the fear of being too little and risk for resistance. Please, share any thought you have.

I also need opinion about combining Fenbendazole(222mg Joe Tippens protocol) and the combo Metformin and Syrosingopine. It is make any sense? It will be safe?


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John Pizzuto
(@jpizzuto)
Joined: 1 year ago
Posts: 200
05/12/2019 3:16 am  

@matsim

You are correct, I assumed 2.55g metformin for a 70kg person, which is too much.

When you open the patent, you will see there are some spelling and punctuation errors, so click the button that says download the pdf. for a better presentation.  It includes page and line numbers for easier reference.

Scroll to page 11, line 17 and it says the ideal weight to weight ratio is 1/130.  Line 18 says the max dose of metformin is 2.550g, but no body weight is specified.

Scroll to page 12, line 22, it says for a body weight of 70kg, the combination could range from 0.25g to 1.5g.  If we choose the preferred max dose of 1.5g metformin, then the ideal (daily) max amount of syro would be 11.5mg.

If you choose the minimum dose of 250mg metformin, then the proportionate ideal amount of syro is 1.9mg.

My wife is 56kg, so a proportionate max dose would be (56/70)1.5=1.2g metformin and 9.2mg syro.  Choose 1g metformin, then the ideal amount of syro is 7.7mg.

Daily regimen would be 500mg metformin plus 3.8mg syro, 2x/day.

I've been giving her from 3.0mg to 3.4mg syro 2x/day, so I need to raise the syro a bit to get the ideal ratio.


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Matsim
(@matsim)
Joined: 10 months ago
Posts: 12
05/12/2019 3:28 am  

@jpizzuto,

I didn't think there was a difference between the site and the document. Thank you for explaining it to me in detail.

Wish you to find the best ratio of both medicines and your wife to find fast improving of her condition.


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Jcancom
(@jcancom)
Joined: 3 years ago
Posts: 502
05/12/2019 5:46 am  

Ray, I am glad that you are interested in the lactate monitor and I agree that the K'Watch is unfortunately still somewhat on the horizon. It is still uncertain to me why lactate is not more of a standard measure in cancer; while it is non-specific, one would still think that the ability to measure it in real time with a simple and not overly expensive hand held monitor would be worthwhile. I am glad that there is a dialogue that has emerged on this question on thread, so that we can have a chance to thrash it out.

I am also glad that I was able to post my prediction about your lab before you posted it. It can be good to state one's understanding of a situation in order that that it can be later scrutinized as more information becomes known. Here is my revised understanding of the labs. Notwithstanding the recent thread comments about syro dosing of perhaps >10 mg per day, earlier in the thread syrosingopine dosing of 1 mg had been suggested by the source as sufficient.

If this is indeed true (dosing remains somewhat of an open question), then the dose that you are using (2 x 4mg per day) is quite a bit beyond that which is recommended and likely very very powerful. Given the putative power of the syromet combination, it perhaps should have surprised us that the treatment did not reach closer to 0 on the first lab after starting syromet.

Possibly 1-2 units of the latest CEA reading relates to cancer cells susceptible to syromet and 3-4 CEA units that are not susceptible. With this interpretation, further gains from syromet might be limited, while the non-susceptible cells might enter into an exponential growth pattern. Using the higher doses of syromet, possibly has allowed us to reach the approaching endpoint of syromet effectiveness sooner, and thus enabling us to rotate to a new strategy. 

The problem is that syromet really is one of the best treatments that I have seen to date and it might not be easy for us to replace it with something as effective. Many of our other approaches have involved prolonged metronomic dosing and even they have not always been especially effective. One of the best result we have seen is with Jess using 2-dg, hyperthermia etc, with active chemo (possibly DCA, Panhematin as suggested by Mauone, etc).  Depending upon your next lab results perhaps you should consider making such a rotation in strategy. Fortunately, there are a range of metabolic strategies that could be tried and they are centered on the same broad targets of OXHPOS and glycolysis as was so helpful with syromet. The next stress though might need to be more glycolytic as syrosingopine resistance could be related to enolase mutation, implying that an anti-glycolytic might be helpful next.  

Could you describe the findings form your last PET CT? Perhaps different metabolic approaches could be targeted more directly to the regions of interest using innovative routes of administration.  

It is quite strange that they would immediately think it was the chemo that helped, even though as you noted the chemo had been out of your system for weeks before the syromet. I find the idea that just out of the blue weeks later that chemo would be effective as highly implausible. The CEA was already on a 1 and 1/2 month doubling time; that is why they have added in another line!   

Things went so amazingly great for about a week with syromet, though it is probably best that we end the celebration and be prepared for a more difficult and less certain road ahead. It was overly optimistic that cancer could be defeated by such a simple treatment; we will need to find a more complex one.

The lactate monitor might be especially helpful in this new environment in devising such a complex approach as the ability to measure lactate would give us penetrating insight into the effectiveness of anti-glycolytics.

Best Wishes, J 


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Jcancom
(@jcancom)
Joined: 3 years ago
Posts: 502
05/12/2019 6:21 am  

Matsim, thank you for your comment about the lactate monitor.

The articles on syromet, noted that there is a path through gamma-enolase for resistance. However, one might also imagine other potential routes speculatively one might wonder about MCT transporters and others. Yet, I do find it comforting that with metabolics there is a highly limited number of pathways involved. syromet has highlighted to us once again that OXPHOS - glycolysis - MCTs are right in the pocket of a very effective anti-cancer approach. If we could rotate to another strategy within this pocket if resistence emerges than we might be able to maintain ongoing tumor growth control.

Consider instead what happens when most other cancer drugs lose control. It is  amazing how unclear the next step is; there is usually no integrated strategy to work with. A very effective anti-cancer drug might experience resistance and then it often seems that it is necessary to pursue an entirely new strategy; with metabolics it seems plausible that expert treatment would permit for ongoing metabolic treatment (with rotations).

With the lactate monitoring idea, it is somewhat unclear to me how lactate levels would change after syromet treatment. Locking in the lactate by blocking MCTs, clearly should reduce plasma lactate, though I think it was also mentioned that metformin reduces liver processing that leads to increased lactate levels ( I had posted earlier that I thought OXPHOS subunit 1 inhibition might increase lactate production in normal cells though I am not clear whether this is correct now).

I realize that LDH is the typical measure of lactate though this is the enzyme level in the blood. I do not understand why lactate itself is not more of a marker of interest. Lactate is so centrally related to cancer that  it would seem to me to be an ideal marker to directly measure. With metabolics, it is possible to rapidly shut down tumor metabolism, would LDH respond immediately to such a shut down? How could it? Lactate itself might show an immediate response to such a shutdown. Such monitoring would seem to me to be invaluable. However, it is entirely possible that I am wrong about this; the smart money would probably take this side as it does not seem reasonable that lactate is not currently a larger focus of labs. I am motivated to submit these posts, in order that others on thread can consider them and find rebuttals if they exist. As of yet, I am unable to find a strong rebuttal for the lactate monitor idea. Having a lactate monitor that could rapidly identify an effective anti-glycolytic treatment could be extremely useful.  

Thank you Matsim and the entire thread for moving the whole conversation up a notch! This syromet topic is really humming. There are a great deal of questions that we are exploring as we continue to examine the related documentation more and more carefully. It takes all of us contributing to think through the many issues involved.

 

This thread feels comfortable and homey, though part 3 of the thread is now ready for your comments. Let's try and migrate to the new thread, as this thread is starting to become quite long.

See you on the part 3 thread!

https://www.cancertreatmentsresearch.com/community/metabolic-inhibitors/combo-metformin-and-syrosingopine-looks-awesome-part-3/

 


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John Pizzuto
(@jpizzuto)
Joined: 1 year ago
Posts: 200
05/12/2019 11:04 am  

@matsim

I have asked Daniel to remove the inaccurate portion of my post upthread, advocating a large dose of metformin.

For my wife, it looks like 1000mg is plenty, so I don't see a need to explore injection or suppository delivery methods.  🙂


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Ray Donnelly
(@ray-donnelly)
Joined: 11 months ago
Posts: 55
05/12/2019 6:52 pm  

@jpizzuto

Good news! Do you think I should reduce my dose too? I'm about 62kg.


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John Pizzuto
(@jpizzuto)
Joined: 1 year ago
Posts: 200
05/12/2019 7:30 pm  

@ray-donnelly

From the patent, calculating the max recommended daily amount for your weight:

62/70 x 1.5 ---> 1330mg metformin.  You could round it down to  1250mg or 1000mg.

If you choose 1250mg, then the ideal amount of syro would be 9.4mg daily.  If 1000mg, then it would be 7.7mg daily.

This assumes you are shooting for the ideal ratio of 1/130, but the patent states you could go as low as 1/200.

For 1000mg metformin at the 1/200 ratio, you could go as low as 5mg syro, daily.


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Ray Donnelly
(@ray-donnelly)
Joined: 11 months ago
Posts: 55
05/12/2019 7:33 pm  

@jcancom, my latest pet report is in Spanish and it's been such a whirlwind (as has life outside of cancer, but not in a bad way all the time) that I've not translated it yet. I'll do a Google translate when I stop spinning from chemo if I pluck up the courage, but I was so happy to get my CEA reduction news at the same time I kind of rested easy on hearing news of "a reduction" from the scan, and no reseeding in colon or liver, no new tumors elsewhere (we had a kidney scare a few weeks previous from a CT scan.. Those things are pointless for my situation IMHO!)

 

 


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Ray Donnelly
(@ray-donnelly)
Joined: 11 months ago
Posts: 55
05/12/2019 7:38 pm  

Thanks @jpizzuto, it's good to lay it out so clearly, I'll probably keep my dosing where it is for now. I need to sort out my cholesterol ASAP though.

 


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Jcancom
(@jcancom)
Joined: 3 years ago
Posts: 502
06/12/2019 12:57 am  

Ray, would you like to go off thread for additional discussion? D requires explicit consent to release poster's email addresses.  

 

Let's join johan's good example and migrate to the part 3 thread. I'll try and follow my own advice.

https://www.cancertreatmentsresearch.com/community/metabolic-inhibitors/combo-metformin-and-syrosingopine-looks-awesome-part-3/#post-1782


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Ray Donnelly
(@ray-donnelly)
Joined: 11 months ago
Posts: 55
06/12/2019 1:02 am  

@jcancom

Sure thing.


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Jcancom
(@jcancom)
Joined: 3 years ago
Posts: 502
06/12/2019 1:32 am  

@daniel, D might you share Ray's email with me? Best Wishes, Jcancom


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Daniel
(@daniel)
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Posts: 903
06/12/2019 1:25 pm  

@jcancom

Yes J, I will send it now. Kind regards, Daniel


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GgE
 GgE
(@gge)
Joined: 2 years ago
Posts: 225
09/12/2019 8:06 am  
Posted by: @manuone

The lactate meter is very interesting, I am seriously considering it. My drug cocktail increases the risk of lactic acidosis

Can you tell us what drugs are included in your cocktail and why they raise the acidosis risk, please? Forgive me if you already posted this info.

Thanks!


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GgE
 GgE
(@gge)
Joined: 2 years ago
Posts: 225
09/12/2019 8:16 am  
Posted by: @jpizzuto

Cimetidine raises blood pressure, which could offset the drop in blood pressure when using syrosingopine.

Johnny, can you tell me where you read the above? I can't find anything about Cimetidine raising blood pressure.

I understand that one needs to be careful with Cimetidine while on metformin because it causes metformin to stay longer in the system, thus raising its concentration level and may lead to lactic acidosis.


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John Pizzuto
(@jpizzuto)
Joined: 1 year ago
Posts: 200
09/12/2019 12:43 pm  

@gge

Nope, I can't find that reference.


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Daniel
(@daniel)
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09/12/2019 9:13 pm  
Posted by: @gge
Posted by: @manuone

The lactate meter is very interesting, I am seriously considering it. My drug cocktail increases the risk of lactic acidosis

Can you tell us what drugs are included in your cocktail and why they raise the acidosis risk, please? Forgive me if you already posted this info.

Thanks!

I think for the SyroMet combo, the risk is fairly low. Assuming Syro does the job and reduces MCT4 activity, the risk should be lower compared to the use of Metformin alone (which has a well known profile in terms of acidosis risks).

I would expect a higher risk of lactic acidosis when multiple mitochondria inhibitors are used and no effective MCT4 inhibitor. 

Kind regards,
Daniel


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Manuone
(@manuone)
Joined: 2 years ago
Posts: 124
09/12/2019 10:00 pm  

Thanks Daniel,

In my particular case the use of "reformulated honokiol", alternating NSAIDs such as celecoxib and diclofenac. On the other hand doxycycline and my mother's liver disease could increase the risk.
The lactate meter may be a good idea but even knowing an increase in lactate would not prevent me from the problem of lactic acidosis.
I think I should take risks

Kind regards


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