Combo Metformin and Syrosingopine!!!! Looks Awesome! (Part 3)  

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Jcancom
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01/12/2019 9:08 pm  

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The first part of the syrosingopine and metformin thread  (thread named Combo Metformin and Syrosingopine!!!! Looks Awesome!) has been a great success!!!!!

 

The original hypothesis that shutting off  NADH --> NAD+ recycling both at the OXPHOS subunit 1 with metformin and at LDH through high lactate levels enabled by syrosingopine reducing especially MCT4 [but also MCT1 and syrosingopine's effect on alpha-enolase (with non-responsiveness due to gamma-enolase)] has been tentatively established in initial anecdotal human reports. As might be expected from such a direct metabolic stressor, rapid response has been observed which should lead to caution in those contemplating this approach.

 

Rapid and very substantial tumor responses have been seen on other occasions with metabolic approaches including 3-BP and others and can be very dangerous due to tumor lysis syndrome responses etc. .  Cautious initial dosing of syrosingopine and metformin with frequent labs would be well advised when starting treatment in order to carefully monitor tumor response. Syrosingopine apparently can potentiate metformin's anti-cancer effects (as motivated by the original research investigation) and allow metformin dose manipulations to have binding effects on tumor response. Treating only with the syrosingopine and metformin combination at the start would be wise as additional treatment power might result in an unhealthy and abrupt large tumor response. It will need to be further clarified whether the syromet combination could be done without chemotherapy or should be applied more as a co-treatment with chemotherapy. 

It can be envisioned that syromet might be part of a more comprehensive anti-cancer strategy in which if necessary chemotherapy could be used as a base treatment and various metabolic treatments could be rotated through under the treatment power of chemo. Such an approach might allow for essentially a lasting response as the various treatments were able to find all paths of resistance and block them to further growth.

The syrosingopine and metformin patent noted that a lab test has been devised that could predict response given a tumor sample. Such a test could be of great value in selecting those patients who will be responders to treatment.

The side-effects that we have seen to date with syrosingopine and metformin treatment have not been pronounced. Syrosingopine is in the resperine class of drugs from the rauwolfia plant originally designed to treated hypertension. Syrosingopine was a second generation drug in the class that was able to avoid much of the psychological side effects noted with resperine as depletion of brain catecholamine is modulated. Given the significant early responses that have been reported, aggressively dosing beyond the doses reported in the literature for syrosingopine and metformin would not appear necessary as other metabolic stressors could be applied to enhance existing responses. While combination dosing of human with syrosingopine and metformin has not been reported in clinical trials, the current clinical reports for single syrosingopine and metformin have demonstrated reasonable safety as single agents.   

 

In Part three of the thread, additional exploration of the clinical application of the syrosingopine and metformin combination, along with the many similar variants, will provide further clarification of issues related to treatment, response, clinical pharmacokinetics etc. .  Clearly dual OXPHOS glycolysis is a very powerful metabolic anti-cancer strategy that should be further considered and hopefully will be of benefit.


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johan
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Jcancom
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07/12/2019 5:22 pm  

Ray, thank you for the information that a 5 on CEA can be zero. This is a very interesting and important update. As I mentioned in a previous post, given your perhaps somewhat aggressive syromet dosing, it was unclear to me why you had not reached 0; apparently you did. This helps to bring your results into stronger focus for me. Even still, it would be worthwhile if you could make any lifestyle changes that would bring down your CEA even lower, in order that an even cleaner readout of CEA could be obtained. 

After achieving this maximum benefit in a mere few weeks, it might now perhaps be a good time to start exploring some of the many other treatment options posted to this site. There are a wide range of ideas related to diet (e.g., fasting), exercise etc. that you might consider.   


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Jcancom
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07/12/2019 9:11 pm  

JohnnyP, thank you for posting the update on the Inspire thread. I was wondering when you might have your next labs. It is comforting to know that we will have a better idea of the response to treatment of your wife within about a week.

Making prospective statements about these responses can us allow to hone our understanding of syromet treatment, so I will provide my impressions now. My rough estimate is that your wife should have had at least a moderately strong response to syromet; you are using a reasonable amount as outlined in the patent. A definitive statement about such a response however cannot be assumed because there might be non-responsive due to resistance (e.g. through enolase and others).

Also, the response curves that I have already shown many times before suggest to me that the response might not be as large as that experienced by Ray. His doubling of the metformin dose (especially when in light of his likely being on the binding part of the response curve), implies to me that Ray's response might be stronger syromet. Nonetheless, this difference might not be of great relevance as the eventual response will probably wind up at the same place, though it might just take somewhat longer.

Considering that the previous labs were a few weeks ago, it is difficult to suggest a more precise prediction. Indeed, it is possible that the maximum treatment effect has already been achieved and resistant cells are growing. However, surprisingly the few syromet patients to date that we know of appear to achieve a near complete response on treatment, while it is unclear how lasting such responses might be.

We will all be anxiously waiting for these next labs and wish that they are highly favorable.

     


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John Pizzuto
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07/12/2019 10:21 pm  

@jcancom

They started her on Faslodex about six weeks ago, shorty after her last PET scan showed progression, saying the letrozole isn't strong enough.

I just did a search on CA15-3 and faslodex and found this long term (90 months) case study showing complete response with faslodex:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919988/

I don't know what is normal, but that's very encouraging.

I don't think we will get a real picture of how the syro/met combo is doing.


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Jcancom
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07/12/2019 11:01 pm  

That is interesting the below is open access on google scholar but not on pubmed. Article notes that only 1% on 500 mg Faso had a complete response and that only 3 of 33 on this dose had a partial response within 12 weeks of starting treatment. A strong response on the next labs would likely mean that syromet was the cause.  

https://www.ncbi.nlm.nih.gov/pubmed/20855825


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Jcancom
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08/12/2019 1:03 am  

johan, thank you for the berberine citation. I was unsure about the mechanism of action of metformin in generating lactic acidosis. The article equivocates somewhat on this point, though notes that mitochondrial subunit I has been suggested to be involved. The finding that berberine might be of help with metformin associated lactic acidosis is potentially highly useful. 


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John Pizzuto
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08/12/2019 6:01 am  

@jcancom

Well, there was this in my link:

Conflict of Interest

Dr. Hawle received honoraria from AstraZeneca for the preparation of this manuscript.

 


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Manuone
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08/12/2019 4:14 pm  

@johan

Very interesting! Thanks for sharing Johan!
Berberine was always one of my favorite natural molecules but a big problem arises: Absorption.
One study and one quote about it: "Although berberine has a wide therapeutic potential, in vivo pharmacokinetic studies show that its apparent permeability coefficient (Papp) through intestinal tissue is of the order of only 10 −7 cm / s ( 19) The poor absorption characteristic is probably due to the P-gp expressed in intestinal cells and the important first-pass metabolism by CYP 450-dependent processes (20, 21). The background of the literature suggests that its metabolism in humans it is mainly based on phase I demethylation and phase II glucuronidation and / or sulfate conjugation (9, 22) Higher levels of berberine chloride in plasma are essential when the drug is intended to treat disorders systemic. "
In this study they improve oral administration:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2974104/ but it is not accessible to the commons of mortals like me 🙁
I need to carefully measure each addition to the cocktail to avoid the huge intake of pills and capsules ...
Lactic acidosis is an issue that concerns me not only for long-term metformin but also for the combination of drugs taken together that increase this risk, especially NSAIDs and acetozolamide. I am not sure if other mitochondrial inhibitors would exarcebar this risk (doxycycline, honokiol ... etc.).

I can only think of using a high dose of berberine taken on an empty stomach with "empty liposomes" that theoretically can improve bioavailability.

kind regards


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johan
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08/12/2019 4:36 pm  

Hi Manuel,

Indeed, just like curcumin, berberine's potential is limited by its poor absorption. Liposomal and nanoformulations could significantly improve therapeutic potential. Also, in combination with some other natural compounds, it could be more effective (curcumin, d-limonene, Triphala, probiotics).  The advantage also being berberine has other anti-cancer properties.

@jcancom

Hi J, I haven't had time to continue with the RSS project, it's been a tough month in Chile because of the social unrest in the country and I've needed to shift my focus 100% to my business and family.


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Jcancom
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09/12/2019 2:00 am  

johan, I wish the social unrest that you referred to can be resolved amicably and quickly. I am very awkward about such circumstances so I wanted to avoid addressing it, if at all possible, though it is good that you have brought this into the open, so at the very least we can offer you our comforting words.

We have been been making very impressive progress of late, thinking through various aspects of syrosingopine and metformin treatment, with your comments being of particular thoughtfulness and applicability. With your latest citation of berberine, we can continue to see how the list of mitochondrial inhibitors that D has created might be integrated into more comprehensive metabolic strategies. We can begin to imagine a nearly endless frontier of metabolic combinations similar to syromet. The sooner you can rejoin the conversation at full strength the sooner we can explore these possibilities further.  

Thank you for taking up my suggestion and migrating to the new thread page. I understand how the others felt about the previous page for this thread; there is a certain homeliness that develops when you are at a place in cyberspace and you just want to stay put. Fortunately, I believe that we can will be able to overcome this brewing thread revolt by rekindling the discussion here.    


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GgE
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09/12/2019 6:24 am  
Posted by: @jpizzuto

I just did a search on CA15-3 and faslodex and found this long term (90 months) case study showing complete response with faslodex:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919988/

I don't know what is normal, but that's very encouraging.

I don't think we will get a real picture of how the syro/met combo is doing.

Posted by: @jcancom

The below is open access on google scholar but not on pubmed. Article notes that only 1% on 500 mg Faso had a complete response and that only 3 of 33 on this dose had a partial response within 12 weeks of starting treatment. A strong response on the next labs would likely mean that syromet was the cause.  

https://www.ncbi.nlm.nih.gov/pubmed/20855825

I agree with Jcancom. The complete pathological response to Faslodex or any anti-hormonal therapy is extremely rare, as the study abstract itself acknowledges: "The pharmacokinetic profile provides evidence to hypothesize a unique sensitivity to fulvestrant in this patient which might explain both: toxicity and extraordinary efficacy." Most breast cancer patients have limited or no response and develop resistance to Faslodex eventually. I wish it wasn't this way. 

So, if her tumor starts shrinking, it might be caused in part by Faslodex but if it shrinks relatively fast and continues shrinking beyond a partial response, then I would think it most likely will be due to the syromet (I like this name, J; you should copyright it!)


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GgE
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09/12/2019 7:06 am  

Lactic acidosis seems to be one of the biggest fears among this site's syromet users even though "The postmarketing Metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment." From the Metformin insert: at https://www.drugs.com/pro/metformin.html

Maybe we can share here the risk factors we know of that affect it so that we all can try to reduce exposure.

Also from the Metformin insert:
"Risk factors for Metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater*, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment."

And "Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. Metformin hydrochloride tablets should be temporarily discontinued while patients have restricted food and fluid intake."

"Lactic acidosis can accompany dehydration" from https://www.labcorp.com/test-menu/30171/lactic-acid-plasma

Another risk factor may arise from getting CT scan imaging with iodine contrast done while on this regimen. The reason being that both the iodine agent and metformin are eliminated mostly through the kidneys and the two drugs together can overwhelm and damage the kidneys. Then metformin does not get eliminated fast enough and lactic acidosis can occur.

It would seem wise to me to stop taking metformin a few days before any CT scans with iodine and resume taking it a few days later. I don't know of any similar problem with the syro. If there are none, I would continue taking the syro during those days not to give the cancer a break. Since metformin accumulates in large quantity inside the cells, the cancer cells will continue to have lots of metformin during those days and the syro should continue to have anti-cancer action. 

From the Metformin insert: "Discontinue Metformin hydrochloride tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart Metformin hydrochloride tablets if renal function is stable."

I have read this in a paper regarding phenformin:

Risk factors for the development of lactic acidosis include renal deficiency, hepatic disease, cardiac disease, and drug interaction such as cimetidine.” From   https://www.ncbi.nlm.nih.gov/pubmed/9848705

I may be wrong, so please let me know your thoughts on this issue.


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johan
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09/12/2019 11:18 pm  
Posted by: @jcancom

johan, I wish the social unrest that you referred to can be resolved amicably and quickly. I am very awkward about such circumstances so I wanted to avoid addressing it, if at all possible, though it is good that you have brought this into the open, so at the very least we can offer you our comforting words.

We have been been making very impressive progress of late, thinking through various aspects of syrosingopine and metformin treatment, with your comments being of particular thoughtfulness and applicability. With your latest citation of berberine, we can continue to see how the list of mitochondrial inhibitors that D has created might be integrated into more comprehensive metabolic strategies. We can begin to imagine a nearly endless frontier of metabolic combinations similar to syromet. The sooner you can rejoin the conversation at full strength the sooner we can explore these possibilities further.  

Thank you for taking up my suggestion and migrating to the new thread page. I understand how the others felt about the previous page for this thread; there is a certain homeliness that develops when you are at a place in cyberspace and you just want to stay put. Fortunately, I believe that we can will be able to overcome this brewing thread revolt by rekindling the discussion here.    

Thank you, J.

Here are more natural compounds capable of lowering lactate dehydrogenase:


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Jcancom
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10/12/2019 3:15 am  

From syromet, we could pivot to a range of other nearby combination treatments. Perhaps one could treat in the morning with metformin and DCA etc., and then syromet in the afternoon. Such treatments could expose lurking vulnerabilities of cancer cells treated with monotherapy.    

metformin and DCA

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184194/

DCA and 2-DG

https://www.ncbi.nlm.nih.gov/pubmed/27685525


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Jcancom
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11/12/2019 4:17 am  

D, I notice that you have also mentioned potential combinations using metformin and/or 2-DG and/or  DCA. Could you provide any impressions that you have given your awareness of anecdotal patient reports using such combinations?

https://www.cancertreatmentsresearch.com/a-new-approach-to-improve-effectiveness-of-cancer-therapies-is-getting-ready-to-begin-human-trials/


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Jcancom
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11/12/2019 4:22 am  

Now this is something that perhaps should be investigated more fully. No ATP from glycolysis of galactose? I suspect cancer cells would be especially unhappy to receive no energy payment for processing it.

"Oxidation of galactose to pyruvate through glycolysis yields no net ATP 31"

https://www.nature.com/articles/s41598-019-55296-3


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Manuone
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12/12/2019 6:32 pm  

@jcancom

Dear J,
I have used and I am using those combinations:
2- DG + metformin + DCA + fenbendazole + sodium phenylbutyrate + tamoxifen + canagliflozin (far from 2-DG) + doxycycline + simvastatin + vitamin c iv + salinomycin iv ......
Recently "high dose honokiol" combined with everything else. I think I have managed to stop the disease for a long time but unfortunately gbm is still there taking over my mother slowly.
I have not given up, nor will I give up as you well know 🙂


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