Combo Metformin And Syrosingopine!!!! Looks Awesome!  

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Ray Donnelly
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01/12/2019 10:06 am  

For me, I don't know where I could get daily labs done. I could take my blood pressure but I guess that's far from enough.

I will have a blood test on Tuesday. The national health oncologists will give me a new CEA reading. For me, with relatively small rumors that aren't holding me together and given that I'm tolerating it well so far and that Steven is doing well, I don't feel caution is a luxury I can afford. I believe anyone in my situation would feel similarly.

Suggestions welcome for where I can get daily labs done without breaking the bank.

@jpizzuto, switching back to only syro and met sounds sensible to me. Is your wife on a ketogenic diet? I *think* that helps me massively.


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John Pizzuto
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01/12/2019 11:36 am  

@ray-donnelly

Shirley is not very good at keto, though she is aware of the dangers of carbs.  At first, I was very strict with her, and her second scan showed a surprising drop in activity.  Her appetite wasn't good, so a lot of it was due to unintentional caloric restriction.  Her ketones were always over 2.0, glucose in the 80's-90's.

She needs protein, but it doesn't taste good to her now.  So, I give in to her and allow a piece of toast or half a small potato, etc.  Fatty rib eyes are a turnoff.  She dissects them.  Eggs are iffy.  She does like my tuna salad, though.

Her third and fourth scans have been progressively worse.  Now there is pain in her left shoulder blade, and a broken bone, confirmed by the latest scan.  We will be asking for radiation this week.

I need to know the minimum dose of metformin.  If she can't tolerate that, is there an injectable version?  I read that some research is done with a liquid solution of metformin.  That would keep it out of the gut, so it should be better tolerated and of higher bio availability.

I wouldn't know how to do it, but how about an injectable or IV syro/met combo?  I believe this is called metronomic dosing?  I understand the medication amounts would be a lot lower, though I am not qualified to do any of the calculations to achieve the correct (or ballpark) serum concentrations.


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Jcancom
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01/12/2019 6:50 pm  

JohnnyP,

https://www.ncbi.nlm.nih.gov/pubmed/1551312

Intravenous metformin could make a great deal of sense considering the problems with gastrointestinal upset. the above article notes that this has been applied clinically.

Be careful with radiation and syromet. The dosing of syromet is on or near a binding response, implying that cotreatments (such as radiation) might greatly potentiate the effects of the combination.


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Jcancom
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01/12/2019 7:52 pm  

Ray, here's that dosing figure again (top left). Notice that around 2 mM Metformin, the cancer cells have been reduced by about a half from the zero dose. Also, notice that the slope of the line that relates response to dose is quite step around 2 mM. As a rough guess I think that this is approximately where you are on the response curve. With poster from the other thread, who was on a half strength dose of metformin, the position might have been closer to the dot one to the left of the 2 mM dose dot. 

What should also be recognized is that adding in a range of other metabolic stressors such as HBOT, hyperthermia, fasting etc. would probably have discernible treatment effects at the 2 mM dose because at this dose there is a binding effect. At a dose between 0 and 0.5 mM Metformin, there does not appear to be a binding effect. At some of these lower doses, Metformin tends to increase tumor activity. 

 

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What this means is that there is still a fair amount of therapeutic power that you have yet to tap. With careful monitoring of the labs, you would then be a position to safely continue to reduce your tumor burden. One strategy to consider is to continue with your current treatment, wait for your labs on Tuesday and then have another set of labs the following week. If you need more treatment response then it is there waiting for you. We will need to re-calibrate how often labs should be done once we see your next results (perhaps daily labs would now be superfluous). 

Typically with the research stage, very cautious exploration of dose ranges are done. With a published report from the 3-BP research, they spent about a month with low doses of 3-BP that knocked down the markers by about 50% each treatment (though then rebounded). When they got serious after about 3 months, they gave a dose of combination 3-BP and paracetamol and the LDH marker went to 0.

Ray, I totally understand that caution might be seen as a luxury. However, we must realize that even very recently on thread we were talking about perhaps having to wait 2 months to see a response. You have now reported that after a week of treatment that you saw a ~50-70% decline in your marker. We can not be sure, though a response might have even happened starting on the first day. In the future, those who  choose to treat with syromet could carefully monitor this early response with their labs and inform the thread of when such responses are detected by labs. There would clearly be a substantial difference between having to wait 2 months and having to wait one day.

How many additional lines of chemotherapy are available to you? What chemo are you on now and for how long? We have seen with others posters that metabolically turbocharged chemotherapy can have very large treatment effects, though when the chemotherapy is no longer effective, the metabolic approach no longer has the same benefit. So, you are quite correct that the clock is ticking and you want to push different versions of metabolics while you can. This is a new concept: rotating metabolics. You have started out with syromet. Once the full benefit has been felt to have been achieved (assuming that the benefit will lessen through time), then you could rotate to another metabolic approach orthogonal to it (perhaps an anti-glycolytic such as in the metronomic 2-DG class); and then perhaps rotate again and again. As long as you have effective chemo, metabolics can greatly amplify the treatment effects.  

Another suggestion is that you consider trying metronomic chemotherpay. This was also tried by a poster on forum. The idea here is that taking a 3 week chemotherapy break to recover etc. gives cancer an enormous advantage. A poster on forum showed a graph of their treatment response and during the 1 month that chemo had been stopped, tumor markers increased exponentially. This seeding of large amounts of cancer  throughout the body greatly increases the difficulty of treatment even beyond looking at raw marker numbers alone, as you now have potential cancer colonies everywhere. Maintaining constant metronomic therapy makes a tremendous amount of sense.    

When you had the response to syromet after a week of dosing, when was the last time you had received chemo? I am wondering whether your response was single agent syromet or more likely a combination of chemotherapy and syromet.

Ray, the response that you have had is quite extraordinary. Those in the future can learn from your experience and be more cautious. It will be all the more easy to be cautious now that is understood that responses can occur so rapidly. Frequent (probably daily) labs for those starting out on treatment until they developed a sense of their response pattern would be very sensible. Also probably more cautious initial dosing would also be advisable, (e.g. dosing up from 1 x 1 mg syrosingopine and 1 x 500 mg daily). With frequent labs and dosing up, one could both be aggressive and safe. Perhaps also using the lab test noted in the syromet patent that talked of being able to take a tumor sample and determining whether it would respond to treatment. One could then know effectiveness even before dosing! (However, I would feel more comfortable if this could be done with a liquid biopsy. Disturbing a tumor in order to obtain a sample creates the potential danger of metastasizing the cancer.)     


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John Pizzuto
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01/12/2019 8:58 pm  

@jcancom

I just looked up all the drugs shown as an alternative to metformin.  Not encouraging.  But even water can be toxic.


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Jcancom
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01/12/2019 9:20 pm  

Everyone, the thread "Combo Metformin And Syrosingopine!!!! Looks Awesome! (Part 3)" has now launched!

The first part of the thread is already becoming somewhat unwieldy, so I thought that we should move the discussion to a new thread. We can now create end of summaries and remixes for part 1. By organizing threads in this way it might help others to find the information that they need.

Before anyone asks, Where is Part 2 of the thread?, I will say that given the notable success of part 1 of the thread i thought that we could go directly to part 3. We could typically reserve part 1s to talking about the basic preclinical aspects of treatments, part 2s could discuss possible human dosing, and part 3s to actual human dosing. We have already reached the part 3 conditions, so part 3 it is (as long as others are in agreement).

JohnnyP, yes I agree. I am not sure whether they were really serious about suggesting low dose rotenone, oligomycin, antimycin A, Na azide etc. . I am very unclear whether these would truly be clinically appliable. I am not even sure if proper formulations would be worth considering. However, one could imagine that  mito-met, mito-phen, chitosan met/phen, etc. could be highly potent OXPHOS inhibitors that could be designed to be extraordinarily cancer specific and thus safe.  Having a similarly cancer specific syrosingopine formulation would then further amplify the response and increase safety.  

     


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Jcancom
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GgE
 GgE
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01/12/2019 9:38 pm  
Posted by: @jcancom

Carefully monitoring response with daily labs.

I think that the labs you mean are standard blood tests for lactate or lactic acid, am I correct? SO that people know.


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GgE
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01/12/2019 9:48 pm  
I posted these questions some time ago but they haven’t been answered. This is no surprise since there are no Syrosingopine + metformin experts posting in these pages (yet). But those following or who plan to follow this treatment would benefit from gaining insight into this matter to decide whether or not to take supplements that contain these vitamins.
...........................
I have these practical questions that may come up during the use of syro+metformin.

Are vitamins B3 and the Ks to be avoided?

The Basel study found that

“High NMN and NAD+ concentrations were needed to counter the effect of syrosingopine-metformin treatment but nevertheless, both NMN and NAD+ were able to restore ATP levels after syrosingopine-metformin treatment.”

“ATP levels can be partly restored by exogenous NAD+ or the NAD precursor NMN”

“NAD+ levels can be artificially increased by supplementation with quinones, such as vitamin K2 (menaquinone).”

“ATP levels are partially restored in a dose-dependent fashion by exogenous vitamin K2”

“Vitamin K2 partially rescues ATP production in syrosingopine-metformin-treated cells.”

“NAD+ and NMN are unable to prevent cell death after 48 hr of syrosingopine-metformin treatment”

“Exogenous vitamin K2 gives a temporary boost in NAD+ levels that transiently supports glycolysis despite syrosingopine-metformin treatment. The rescue is short-lived due to the depletion of exogenous vitamin K2 and the absence of NAD+/NADH-regenerating mechanisms”

1- What do you people think regarding supplements that contain vitamin K of any kind, vitamin B3, niacin, nicotinic acid, nicotinamide, or their derivatives by any names (NAM, NMN, NAD, NAD+ or vitamin V) while taking syro and metformin? Should there be a concern that they might reverse or reduce these drugs anti-cancer effects?

I imagine that high dose supplements should be avoided. But how about multivitamin pills and foods with high contents in any of them such as natto? Are they also risky or are the amounts they contain so small that they should not matter? Should they not be taken daily so as to avoid cumulative risks?

........................

I want to propose a theory and would appreciate everyone’s input.
My guess is that the increasing acidity and lactate concentration inside the cancer cells that a CONTINUOUS Syro and Metf administration induce are so stressful on these cells that eventually not even ATP, NMN, NAD+ and NADH- can save most of them, even though they might get short, temporary reliefs. Therefore, maintenance (not therapeutic or high) doses of supplements with these vitamins should not significantly delay or reduce the effects from this therapy. 
This might explain the study findings that:
“NAD+ and NMN are unable to prevent cell death after 48 hr of syrosingopine-metformin treatment” and "The rescue is short-lived due to the depletion of exogenous vitamin K2 and the absence of NAD+/NADH-regenerating mechanisms”
But I have no evidence that this is true.
Please, post here your thoughts whether or not you disagree with this theory. Especially post them if you disagree.

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Jcancom
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01/12/2019 9:54 pm  

GgE, yes I was thinking about lactate in daily labs, though perhaps other posters might suggest other alternatives.

Having a portable lactate unit might be of use:

http://www.lactate.com/index_test.htm

I believe that there have even been non-invasive models of lactate monitors which could offer real-time results! (These were used in the high performance athletic community.) This could be extraordinary. With metabolic treatments such devices might show you that a treatment such as the syrosingopine metformin combination had measurable effects within minutes! That would be very impressive!


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GgE
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01/12/2019 10:10 pm  
Posted by: @ray-donnelly

Suggestions welcome for where I can get daily labs done without breaking the bank.

If you need lactic acid or other routine blood or urine testing they can be obtained from several online companies. Some will draw your blood and test it without you having to get a doctor's order, depending on where you live. They will get a doctor to prescribe any test you want from their menu and licensed personnel will do the tests.

Companies that come to mind are: Walkinlab.com, Healthlabs.com, MyMedLab.com and others. They often give special discounts to new and repeat clients and can match other labs rates.

These other companies are the ones that actually do the test but they sometimes have to wait many days before releasing the test results to the patient. They do tests for hospitals and doctors also.

questdiagnostics.com, labcorp.com. 


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Jcancom
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01/12/2019 10:17 pm  

GgE, I am sorry but I have to tend to agree with your line of thinking (you wanted to hear more from disagreers.).  Nonetheless, what I think should be the focus is that syromet shuts down the entire            NADH --> NAD+ assembly line. Giving NAD precursors probably would not make a great deal of difference. With the assembly line off line, any supplemental boost to NAD+ might even make things worse as on the next turn you would then even have more NADH that was stranded creating an even larger NADH/NAD+ ratio which has important control functions in the cell. If I recall correctly, the body consumes truly massive quantities of NADH every day (~50 KG), so the small amount from supplemental sources that would arrive at the cancer cell might not be overly helpful, though as you noted the cell culture results from the research did find some benefit.  

I second Matsim's praise of your careful and thoughtful posting. Great job!


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Ray Donnelly
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01/12/2019 10:39 pm  

Thanks for the thoughtful comments everyone. Some metformin info: https://www.foundmyfitness.com/topics/metformin .. read along with me!


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Jcancom
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01/12/2019 10:49 pm  

GgE, using NAM etc. might be a great way to reverse syromet treatment. We have seen with 3-BP that overdosing a powerful metabolic treatment can be extremely dangerous. However, most other cancer treatments do not have an obvious antitode. If too much chemotherapy were to be given, I am not entirely sure what one might do to override such an overdose. In this way, chemotherapy can be seen to be more dangerous than metabolic approaches because there is no treatment for overdose, even when chemotherapy can often be treated right up to the line where serious side effects might occur. With 3-BP, safety is enhanced as one has the option of treating an overdose with NAC or GSH.

The same might be true with syromet. Perhaps treating with NAM etc. could reduce an acute overdose. This might be explored in additional research. Metformin while blocking OXPHOS subunt 1 would be causing ROS production, perhaps antioxidants such as GSH, NAC, possibly Mito-Q would also be of help.  Having such safety measures on hand (if thought by the thread to be of value) would enhance the safety of treatment.

Ray, I anxious to know: what was your last lab number? Could you give us some more information about your illness?

Best Wishes, J

 

 


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Jcancom
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02/12/2019 1:03 am  

K'Watch! Very exciting technology preparing to launch. Continuous non-invasive glucose and lactate monitoring at a reasonable price? Sounds great!

https://www.pkvitality.com/faq/#


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John Pizzuto
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02/12/2019 11:51 am  

@ray-donnelly

Development of injectable metformin for cancer:

https://www.nature.com/articles/s41598-018-22054-w


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Ray Donnelly
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02/12/2019 1:58 pm  

@jcancom,

Here are my CEA/CA199 levels and some rough chronologies. The chemo was mostly bi-weekly, but just before the 3 week suspension, it moved to weekly for 2 sessions (dropping 5fu), I couldn't handle that too well so I'm now back to bi-weekly again but with 3 agents (5fu, irinotecan and cetuximaub) instead of two (previously 5fu and irinotecan for about 8 bi-weekly sessions).

05/07/2019 CEA=9.1 CA199=116

27/08/2019 CEA=8 CA199=?

01/10/2019 CEA=14.5 CA199=?

15/10/2019 CEA=18 CA199=188

01/11/2019 Started 1g met

chemo suspended for 3 weeks for PET CT scan.

13/11/2019 Started 8mg syro + 2g met

19/11/2019 CEA=5.9(18) CA199=144

Chemo resumed

I assume the (18) in the most recent reading is indicating the previous reading, and the real value is 5.9. So the drop does appear dramatic! I hope my next reading is good (though you've got me a bit worried about lactate acidosis!)

 


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Daniel
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02/12/2019 3:49 pm  

@ray-donnelly

Hi Ray,

Looks great! On 15/10 and 19/11 have you also performed other blood tests, such as LDH, Iron, Potassium, Liver enzymes? And if yes, can you also share that? Regardless, these are very nice results!

As long as there are no major side effects, I would continue the current treatment and not add or remove anything.

Kind regards,
Daniel


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Ray Donnelly
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02/12/2019 7:19 pm  
Posted by: @jcancom

Ray, might your source be able to provide insight into the question regarding canagliflozin?

Yes, my source was helpful and I can share:

> Canaglifozin is not an inhibitor of the mitochondrial electron transport chain. It inhibits glucose uptake by the SGLT2 transporter, reduced glucose levels often cause cells to switch to a low energy mode via AMPK signalling. This gives the appearance that mitochondrial activity is inhibited when measuring the usual parameters (oxygen consumption, mitochondrial membrane polarisation etc). However this is indirect and not due to any direct effect of canaglifozin on the mitochondria.

> Most glucose is taken up by cells via the Glut1-4 transporters. These are expressed in all tissue types. Glut4 is of particular interest in cancer. Activation of PI3k-mTOR-Akt signalling (which is a common event in cancer) causes relocation of Glut4 to the cell surface which enables chance cells to import enough glucose to support high proliferation.

> SGLT2 however has very restricted expression only in certain kidney cells where its normal role is re-absorption of glucose from urine (which would otherwise be excreted and wasted). In diabetes, this function is inhibit by canaglifozin to allow diabetics to excrete a lot of glucose to help in reducing blood sugar concentrations.

> Thus the off-label use of canaglifozin as an anti-cancer agent would only make sense in tumors that have lost Glut expression and, if it is not a type of kidney cancer, have abnormally activated SGLT2 expression in a different cellular context to serve as the main glucose transporter. This would be an extremely rare occurrence and would require tumor biopsies for Glut and SGLT expression. Inhibiting SGLT2 in the presence of Glut1 or Glut4 activity would probably have no effect on total glucose uptake (rather like inhibiting MCT1 when MCT4 is present).


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John Pizzuto
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02/12/2019 8:24 pm  

@ray-donnelly

Please ask him if 500mg metformin 2x/day is adequate for 57kg body weight.  Syro dose is 3.0mg 2x/day.


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Daniel
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02/12/2019 9:11 pm  

@ray-donnelly

Thanks for sharing the view of your source Ray.

Scientific field is always in a constant debate. Scientists are looking from own perspectives and they are constantly arguing based on those perspectives. That is actually constructive since only debating we finally uncover the true. Using the recent findings of other scientists, and with all respect for your source, I would argue that:

1. Canagliflzoin is an inhibitor of mitochondria electron transport chain
The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034684/
Canagliflozin mediated dual inhibition of mitochondrial glutamate dehydrogenase and complex I: an off-target adverse effect https://www.nature.com/articles/s41419-018-0273-y

2. GLUT1 transporters are also known to be very expressed in tumours, some would argue that are more relevant compared to GLUT4. No need for references since this is a general knowledge, but here is a highly cited article discussing that https://www.ncbi.nlm.nih.gov/pubmed/23266512 In my view, most glucose transporters known to be used by tumors are relevant (including GLUTs and SGLTs) since they are used as escape routes when others are inhibited.

3. SGLT2 is actually very relevant in tumours, specifically when the glucose is very limited and so the glucose gradient is not helping absorption in tumors. Please see this post and the enclosed references https://www.cancertreatmentsresearch.com/glucose-absorption-inhibitors-to-inhibit-tumor-growth/

4. Because of the above, and because the anti cancer mechanisms behind Canagliflozin take place at clinically relevant concentrations, I find this drug as one of the very promising re-purposed drugs to be used as part of anti-cancer cocktails, specifically of those focused on ATP depletion. 

Kind regards,
Daniel

 


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Jcancom
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03/12/2019 1:44 am  

Ray, thank you for sharing the numbers. 

A 70% decline in CEA in less than a week? Not bad.

However, we need to speak explicitly about the dangers, in order to alert others. As you seem fine, the risk might have not been as severe as originally imagined. In fact one of the posters, saw CA 199 levels fall from ~115,000 to ~5,000 in a month; suggesting that the body can cope with significant tumor destruction. I think it is reasonable to be at least somewhat worried about lactic acidosis, though this likely would be of even more relevance to patients with large tumor burdens from extensive metastatic illness. Of the two, worrying about the risks and celebrating the marker decline, I would tend to lean towards celebration.

What I actually find of even greater interest regarding risk is that your numbers suggest an earlier stage of progression than I had understood. Typically pre-clinical treatments are tried by people when they have very extensive disease and they are willing to try very experimental treatments. If I had been more aware of your illness status I probably would have been even much more cautious, though given your response to date it would be difficult to now take such a stance.

This is great that you had a PET CT scan before starting up syromet. Comparing a before and after scan while using syromet will give us a very good picture of your response. I will be especially interested to see whether CEA or CA 199 correlate better with your response. CEA is down 70%, while CA199 is down 25%. I wonder which is more reflective of the actual tumor reduction.

Perhaps you should ask your medical team about the change in chemo. If you have not mentioned to them that you are taking syromet, they might be under the mistaken impression that chemo is helping. From your numbers, it does not appear that chemo has helped much at all. If they were to tell you that they are happy to see your numbers in decline and want to use more chemo to have even more benefit (thus your recent increase in dosing), you might consider telling them that you'll take a miss. 

I will be interested to see how chemo and syromet might synergize. It is especially impressive to me that syromet apparently can have powerful anti-cancer effects as a combination without chemo support. This is a large step forward for our forum as until now we have relied on chemo as the lead treatment to be supplemented by metabolic approaches. syromet offers the potential to be used if chemo has failed. Apparently, chemo can condition cancer cells to become susceptible to metabolic approaches.

  https://immunomet.com/im156-cancer-metabolism-and-drug-resistance/  

  https://immunomet.com/im188-immunometabolism-and-immunotherapy/

 

Ray, honestly, I have been pushing the idea that lactate monitors should be used in cancer for years on this forum and on the compass. Your mentioning of lactic acidosis has reminded me how good an idea this would be. It was startling to me when I realized that metformin/phenformin induces this lactic acidosis response because it shuts down OXPHOS subunit 1 in healthy cells of diabetics and then normal cells start creating lactate. Syro can then lock in this lactate in the cells. Thus, it is not even so much lactic acidosis that is the only danger, but that healthy cells as well as cancer cells could become pickled. My working guess is that you really do not want a lactic acidosis response to happen with syromet.

There must be extensive research in diabetics that consider this question at different dose levels of metformin. The FDA has a black box warning for acidosis in diabetics for metformin; given what I perceive as an even more dangerous type of acidosis ( D's banana in the tailpipe) that could lock in the acid into normal cells, perhaps they could add another black box warning that describes this additional risk to cancer patients.     

I would like to ask the thread's opinion on the question of lactate monitoring for Ray. The online lactate monitors cost about $300 and ~$2 a test strip. Given the dangers involved with metformin dosing especially in cancer, this would seem to be a wise investment. Ray could then monitor lactate frequently (though the needle pricks would be a drawback). Without knowing lactate levels, syromet dosing presents risk. If there were to be a large tumor response, then one could have a large acidosis spike and it would not be obvious, though it could pose significant risk. However, it is true that this risk is now diminishing as there does not appear to be a great deal of tumor remaining. One problem is that given that cancer produces lactate, it would not be clear how much lactate normal cells were producing after a dose of metformin (This would be the lactate that would become locked into normal cells posing risk to cell viability). 

Another benefit would be rapid recognition of responses. Shutting down NAD+ recycling should reasonably have large and rapid effects on lactate production. A lactate monitor probably could report such changes. This would give you an idea of how much of the tumor mass might be susceptible to syromet. For example, in the instance of the 3-BP melanoma patient, LDH levels gyrated to a large extent with an initial large decrease and then spiking up almost back to the starting level. Knowing how much of the tumor showed signs of such vulnerability would indicate how much more tumor destruction was possible. Finally, Ray could try and fork his lactate levels. When you can measure and possibly manipulate a marker as important as lactate, it would seem too good an opportunity to forego. If you could learn what to do to lower lactate levels this could be of great benefit in cancer management. Lactate is bad in so many ways related to cancer progression.   

In short, I think it would make a great deal of sense for Ray to buy a lactate monitor. Comments please!

 

Where are the metformin formulations? It is surprising that such a popular and widely used drug does not have formulations available. Systematic dosing of raw drug to treat cancer seems extremely primitive. pubmed notes chitosan metformin formulations for cancer that look quite exciting. Being able to deliver metformin directly to cancer cells would move syromet light years forwards. I would like to have a better idea of where else in the body acidic conditions typically exist and to what extent, though the research to date suggests that chitosan metformin truly can selectively deliver metformin to cancer cells. Very imprssive! This would avoid the problem of exposing the risk of pickling normal cells when OXPHOS subunit I is shut down by metformin.

 

D, I remembered that article too that describes the OXPHOS subunit I inhibition by canagliflozin and was unsure about the source's rebuttal. Here instead of an endless debate, one might simply run cana with syro and observe what happens. This would be a useful experiment because cana appeared to be binding even without co-treatments; adding syro (if cana is an OXPHOs inhibitor) would be expected to have very large anti-cancer effects.    

 

Thank you again Ray. Sharing your treatment results is helping us all grow our understanding of cancer and hopefully this will help you have a better treatment outcome.


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John Pizzuto
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03/12/2019 3:56 am  

@jcancom

According to this, ketones can also enter via NCT2:

https://www.cell.com/trends/endocrinology-metabolism/fulltext/S1043-2760(13)00156-2

From the link:

βOHB transport, utilization, and conservation

βOHB transport is relatively less well understood than its synthesis and utilization. A small, polar molecule, βOHB is readily soluble in water and blood.  Several monocarboxylic acid transporters, including MCT1 and MCT2, carry it across the blood–brain barrier.  Of interest, upregulation of MCT1 in particular is associated with high utilization of ketone bodies in the neonatal period and on a ketogenic diet."
 
I don't know if we want to upregulate MCT1 when we are trying to shut it down with syro/met.

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John Pizzuto
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03/12/2019 3:57 am  

Sorry, MCT2


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GgE
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03/12/2019 7:41 am  
Posted by: @jpizzuto

Development of injectable metformin for cancer:

https://www.nature.com/articles/s41598-018-22054-w

This will be great one day and will help people avoid all the GI side effects that lead many to stop this drug.


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John Pizzuto
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03/12/2019 8:25 am  

@gge

I'm trying to find an injectable metformin that's available now.  So far, I've learned the powder is soluble in water.  A solution is available by prescription, trade name is Riomet.  5cc (1 teaspoon) is equivalent to a 500mg tablet.

BUT, if it were injected, I imagine the dose would be much less to achieve the serum concentrations specified in the research paper.

Three methods of injection.  IV, SC, and IM.  Dose and delivery times would be different as well.

I'm guessing that sub cutaneous would be the safest, and give the slowest, longest lasting release.  Then the nest step would be do the same with the syro.

Both drugs can be lethal, so the calculations and preparation would be very important.  But, I think it would be a good way to provide a sustained pressure against the cancer.


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Manuone
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03/12/2019 6:16 pm  

@jcancom

The lactate meter is very interesting, I am seriously considering it. My drug cocktail increases the risk of lactic acidosis and doctors do not want to include lactate levels in control analytics.


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Jcancom
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04/12/2019 1:19 am  

Thank you, Manuone! Thank you! I have been out in the wilderness for a few years with the lactate monitor idea and no one seemed interested.

I did not like trying to shake down Ray for the 300, though it really does seem like a good idea. I had thought it would make especial sense with the syromet combination. I would love to know what would happen to lactate levels when the cancer cells are basically blocked from exporting lactate. The liver might then have a clear chance to clear the lactate from the circulation. Calculating this flow rate could give you approximations from the lactate production flow from the tumors. There might be reference standards for how much lactate the liver can process in a given time which could add even further insight into the dynamics.

Monitoring for lactic acidosis (as you noted) would also be of importance. Keeping a close watch on lactate levels (i.e., approaching real time) for either use seems valuable to me. It is very unclear to me why this is not considered a standard procedure. The K'Watch for Athletes that is approaching the market will allow for such real time monitoring of blood lactate levels. This would be ideal for cancer patients. Understanding what is happening with lactate 24/7 could yield very important clues to the biology of one's cancer.  The current lactate monitors are somewhat annoying with their needle prick technology (non-invasive technology is ion the horizon), though at the very least one could a careful eye on lactate levels more so than is typical available with labs only. It is surprising that some of the people reported in the literature that developed TLS, apparently can be in this danger state for days without anyone being aware. (This is possibly what happened with the Bracht patients). While a lactate monitor might not be ideal for monitoring TLS, it would probably reveal information regarding large scale metabolic collapse of a tumor mass (This is an important point, please post comments that address this issue.). 

 

Oftentimes I put out my ideas to the forum and they are not taken up. There are perhaps a few issues to work through with the lactate monitor, though it would seem well worth giving this a try considering the potential benefits that it would offer. Without such a monitor almost the only responsible advice that you can give to someone is to restrain trying to overtreat. Yet, with a monitor one would have a much clearer idea of where such risk boundaries might exist and, thus, one might be in the position to treat closer to such boundaries.

We have already seen quite a few times how metabolic therapies can have extreme anti-cancer effects, though this extraordinary success has been counter-intuitively counter-balanced by the problem of too much anti-cancer power. Yet at the same time the actual immediate effect of large scale responses have been almost unnoticed. Such side effect free very large responses were reported for both published patients treated with 3-BP.

Interestingly, Ray also mentioned no side-effects from a 70% reduction in CEA in less than a week, while he noted that his chemo had to be reconfigured because he found it difficult to tolerate. Of even greater interest was that even with all the toxicity of his chemo (with no toxicity with his metabolic therapy) his tumor markers doubled in the three months on chemo. It certainly could make one question what exactly the point of the chemo treatment is. Metabolically turbocharged chemo has a certain logic, though using up 3 lines of chemo without metabolic leverage is difficult to rationalize.


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Ray Donnelly
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04/12/2019 1:47 am  

I am happy to get a lactate monitor. I don't think waiting for this K'Watch one sounds wise as there's no indication of when or even if I can get one.

I'll have to be brave and draw blood for you guys (and myself of course.. I'd like to know what's going on here and keep as safe as I can).

If anyone knows any athletes with knowledge of these can you ask for recommendations? Otherwise I'll just Google it tomorrow.. meant to have chemo, not feeling up to it. Think I'll try to refuse it this time.

Thanks all.


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Jcancom
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04/12/2019 4:24 am  

Ray, this is how I understand the lab reports that you posted.

For the first 2 months, your chemo was able to slightly depress your CEA. So there was at least some chemo restraining power. This would have been a great time to have added in some metabolic support ( With the example of Jess, we saw that the first line of chemo took 4 months to reduce the     CA 19.9 number (without metabolic support). When a 2 month drug holiday was taken to recover, the CA 19.9 went nearly vertical: It increased ~25 fold in 2 months. The cancer cells had become conditioned to slow growth in the presence of  chemo; without it the marker skyrocketed.

https://www.cancertreatmentsresearch.com/case-report-stage-iv-pancreatic-cancer-good-news-from-jess/

)

After this initial success, your numbers then doubled over the next month and a half even with chemo support. What we seem to be seeing is that the chemo is no longer able to restrain growth as it had.

 

One interpretation of how the tumor responded in the time just before you started syromet is that for the first 2 weeks (after the lab before starting syromet) your CEA might have increased ~25%. Once the chemo was stopped, (not clear when this happened, will assume 01/11), the cancer could have become highly aggressive. CEA might have doubled in the 2 weeks before starting syromet (This would take it to around 50).  If this thinking were correct, then the syromet response effect is much larger than we had originally guessed. Instead of 18 -->6, it might have been ~50 --> 6. (Without the labs it is difficult to be sure.)

(The lactate monitor would be very helpful to clarify such matters as you could perhaps keep daily measures of your lactate levels. This would allow you to know where the bottom of the lactate was after a syromet treatment. 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.)

This is all somewhat imprecise as we don't have more labs or lactate readings to work with. However, this line of thinking does offer some hypotheses. For instance, I had not been clear about why they added in another line of chemotherapy. It is now clear to me that they also noticed that the CEA doubled over a month and a half and now realize that more chemotherapy will be needed to hold the line. Of course what they do not know is that you have syromet on your side. One strategy (a fairly good one) might be to take advantage of the chemo cover and co-treat with syromet. (Apparently this is what you have been doing, so we will know soon how this has fared with your most recent lab. I would have had to think carefully about whether adding in chemo on top of syromet would have been a good idea, though it seems that you have already included this combination.)  Until now syromet has had to carry the full load without the help of chemo. One certainly wonders what might happen if chemo were on side with you along with syromet. The numbers could be especially good.   

Another suggestion is that syromet might be even more powerful than we had at first expected. If syromet actually reduced CEA from ~50 to 5.9 in less than a week, then, given this, one might expect a largish percentage decline in your next labs. It is not easy to make such predictions as typically the low hanging fruit is picked first and the second round of harvesting involves the higher hanging fruit. With cancer the first mile is always the easiest, the last inch is the tough part. Nonetheless, one of the more impressive results that we have seen with metabolic treatment, for example the Inspire poster and others, is that targeting OXPHOS (and the cancer stem cells) can result in complete responses. So, it might not only be the top line lab numbers but also the actual stem cell counts (which are not reported in the labs) that is important. Fortunately, syromet appears to target the bulk of the tumor mass and the stem cells, so a good lab number can be reported at the same time that the stem cells are depleted. If the stem cells can be depleted, then the bulk of the tumor mass is highly vulnerable to further reduction (using various metabolic strategies including syromet). 

 

All of this is to say that staying with the standard of care, while we monitor the lab numbers, might be the best strategy at this time. I am not overly enthusiastic about such an approach, though it will give you an opportunity to see what metabolically supported chemotherapy might be able to achieve. We can recalibrate as we see additional lab and other results. Other posters are welcome to add comments to this topic.


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