Hi zdeneksipek,
It's about what we want to get from Metformin:
- if we only want it's action towards blood glucose level reduction, (such as in diabetics), I would even add an anti-oxidants to reduce the detrimental pro-oxidants (in a person without cancer we prefer not to have the additional pro-oxidants)
- if we want the glucose reduction + mithocondria inhibition/reduction we do not care that much about pro/anti oxidants
- if we want the two above but also maximise the pro-oxidant pressure on the cancer cells (which in turn can also inhibit glycolisis), we do not want to add anti-oxidants. I would take this approach for active disease (but of course it depends on the overall treatment strategy - some may want to take an anti-oxidant strategy approach). In general, for NED, I would not push on pro-oxidants.
Regarding ALA(from Metabloc)+Metformin, their main mechanism of action are opposite: one is promoting mitochondria function and the other is inhibiting. Also, one is anti-oxidant, the other is (a little) pro-oxidant ... so when Metabloc (ALA+HCA)+Meformin works, in my view it works because because two possibilities"
- Metformin reduces blood glucose, ALA redirects pyruvate to mito and HCA inhibits conversion of Citrate, leading to it's accumulation and possible glycolisiis slow-down -> anti-cancer effect
- the other option is that ALA doesen't do much but Metformin and HCA leads to a reduction in generation of Acetyl-COA and therefore lower activity of lipid synthesis with impact on various aspects essential to cancer.
I hope this answer your questions.
Kind regards,
Daniel
I've been in touch with Dr. Don Benjamin and he is aware of this thread.
I wonder if Dr. Benjamin's staff measured the blood pressure of the mice to help determine their maximum dose.
Sorry, that was a little tongue in cheek...
...Visions of mice hooked up to blood pressure machines.
JohnnyP, I wish that our comments on this forum will help you find an effective treatment for your wife.
Yud has just posted to the forum that HIF-1alpha is involved with LDHA expression. Knocking down LDHA is one of the limiting reactions with the treatment; finding other ways to reduce it should be helpful. Interestingly, I noted in an earlier post that the poster from Inspire with a response from syrosingopine and metformin included a daily aspirin. Interestingly aspirin is an OXPHOS subunit IV inhibitor(?), if so this would stop the consumption of oxygen perhaps downregulating LDHA through HIF-1a.
Most of the first glance research on oxamate seemed to suggest that it could not be effectively dosed in humans, perhaps in the combinations suggested this is not true.
The 2018 article shows how powerful adding in MCT-1 inhibitors can be with the combination. D has a list of MCT-1 inhibitors that include Phloretin and others.
D what do you think of this safety wise? Would a strong MCT-1 inhibitor be safe with the syrosingopine metformin combination? Adding in such an inhibitor could powerfully potentiate the treatment. It would seem on a purely reasonable person basis that it should be a fairly safe approach. Cancer cells have such an over active glycolysis relative to normal cells. Cutting off OXPHOS subunit 1 with metformin first would push cancer into a metabolic crisis in which they would need to become even more glycolytic. Then shutting off MCT1/4 transport would put an overwhelmingly large stress on cancer cells, while normal cells should be mostly not disturbed. By simply cautiously dosing up the MCT1 inhibitor, one could selectively hit the cancer cells well before it would be stressful to normal cells. There are some extremely potent MCT-1 inhibitors out there.
This is great that the author is aware of our thread; any suggestions from those with greater insight would be greatly appreciated. Thank you Ray for making contact. The syrosingopine metformin combination clearly has substantial anti-cancer potential, though it is not obvious how to find the correct dosing points given the data trail on line. Anyone have good pharmacokinetics of metformin? It would be very very helpful if we could have a look at the syrosingopine pharmacokinetics as D noted.
It would also be extremely interesting to see what the chemists might think up in terms of modifying syrosingopine. For example, perhaps modifying the chemical structure so that it could not transit the BBB might help reduce the side effects. Also will be very interesting to see how effective the liposomal formulation that is now available will be.
Very interesting chemistry behind syrosingopine. Syrosinopine irreversibly blocks VMAT-2. VMAT-2 is a transporter for catecholamines; it is involved in drug induced Parkinson's. There is also mention of it in terms of schizophrenia etc. Perhaps the Inspire poster might disclose any interesting features of his VMAT-2 exome or related genetics. The idea is that in the 1950s and probably until fairly recently, drugs had to be approved on the basis of average responses in the community. So when they say this drug is safe at 1 mg per day what they probably mean is that close to 100% of people tolerate the drug at 1 mg, though likely 95% of people would also tolerate the drug at 10 mg per day; in the past it was never obvious how to identify those 95%, so they basically had to go with a dose of 1 mg per day (even when the 95% would have significantly benefited from the higher dose).
We have the technology now to start looking into the box and understanding who will and who will not respond and why according to their genetics. This clearly will be very very powerful medical information. We saw with 3-Bromopyruvate that the 2 published patients had a truly overwhelmingly extreme response to treatment; determining their genotypes could help lead us to other caner patients would have similar responses. Pursuing such a strategy might also be of similar benefit with the syrosingopine metformin combination. Exome scans only cost about $200 now even full genome is only about $600; seems well worth.
Figure from 2018 article: shutting off cancer cell OXPHOS results in a loss of 36 ATP!! (Is this selective to cancer cells?)
I raised the syro to 3mg 2x/day with no ill effects. Still only 250mg metformin 2x/day until we get slow release. Also a baby aspirin 2x/day.
How does the article about antibiotics and the gut microbiome promoting cancer, posted by Gge on page 5, affect the thinking about doxycycline?
How does the article about antibiotics and the gut microbiome promoting cancer, posted by Gge on page 5, affect the thinking about doxycycline?
Hi John, here's what Daniel wrote about the use of antibiotics recently:
https://www.cancertreatmentsresearch.com/community/others/is-cancer-an-infectious-disease/#post-1342
@johan
Thank you Johan for posting the reference!
As we once discussed, I have mixed feelings about antibiotics. We don't like the impact on the immune system, but when that doesn't do it's job, the direct anti cancer effects of antibiotics may be more valuable. In the end it's again about the anticancer strategy we use.
I would not touch antibiotics when going for immuno therapy. But there are situations when it makes sense to use them. I still want to write/finish that post on antibiotics ... but so much to do. However, Salinomycin is one of the antibiotics I like a lot.
{]
I think I have it!
Yud's post on the Technical Issues thread and Johan's reply got me thinking about my idea of adding searchability into posts by embedding search keys. My idea has now been expanded to include a programmatic interface with web browsers.
What would happen is that a symbol could be placed (preferably at the start of a post to indicate that the browser should expect programming instructions within the post (For example, " {]" ). In this activated mode various programming instructions could be given to the browser. For example, my previous idea of including treatment assessments using [[[ ]]] notation, or perhaps {{{ }}} summary statements etc.
Another idea would be to allow remixing of thread content. This thread is now long and there are numerous off-topic posts (many of them are mine). What could happen is a post by any user could instruct the browser how to programmatically arrange posts into a hierarchical tree. The thread could then be reorganized for all other users to enjoy even if the raw unprogrammed thread state remained highly disorganized. This remix post might be permanently maintained at the end of the thread, so that those who wanted a cleaned up version of the thread could click onto the remix post and be shown a version that organized the information effectively and efficiently. All of this could be done in such a way that those who were not interested in participating would not have to. It could be done passively in the background. One could imagine layers and layers of programmed organization that could work in the background. One could also imagine that a remixed version might even be felt to be clearly superior to the original and would be the default when surfing to a forum.
There are so so many programming features that could be simply embedded into a thread post which would greatly enhance the information flow from our forum, yet it could all begin very simply and co-evolve with user input. Various implementations might be attempted including a GUI when landing on the website to control the information reformatting at a more granular level or adding in global features to a url. The content from our forum could be remixed by various features of the posters (such as by the number of posts, etc.), into treatment assessments, summary statements, by self-reported index values (e.g. to indicate excitement levels at different time points etc.). It really would be: What do you want to do with this technology? Clearly there would be a range of applications that would be entirely unanticipated.
What is very encouraging about this is that a grassroots effort could begin without a great deal of boring and tedious bake sale etc. Threads have become a ubiquitous feature of modern existence. Yet, when you look around they all pretty much look like this one. They largely all have the same problems that we are encountering. Sometimes thousands and thousands of posts put together in a linear format without any obvious organization. Does anyone have books on their book shelf that are discursive as most threads? I don't think any book has ever been written that displays the nearly constant shifting of topics as found on most threads.
Posters could vote for this idea by simply tagging the start of their posts with the " {] " . This can start to happen immediately. The even better part of this is that it would seem that software companies that ignored it might find that someone had eaten their lunch. Basically, one could go to a url that reformatted the websites in the way that the people wanted and then I suppose they would access the revenue stream available from such web traffic. Most of my ideas never have had such a plausible consequence for non-compliance.
There is an information science aspect of cancer research. So much cancer research needs to be processed and then presented to others in a way that will benefit from. My idea above could help solve the problem that results from having linear threads. It is ridiculous that the thread software is using the same information presentation approach as the old written scrolls that required people to read everything sequentially; the software idea could avoid much of this. This might seem to be very far off topic, though it really is not. Being able to communicate important insights to others is critically central to what we are trying to accomplish.
The TLDR version of the above is that a grassroots effort to achieve better communication on threads using a user generated programming language appears plausible. Considering that thread posting is now a global way of life for at least tens of millions of people, quite a few people (incluidng all of us on this forum and blog) would live a higher quality of life if we can make this happen. To initiate the awareness of this idea and indicate the level of its support to software companies, users might choose to add "{]" to the start of forum, blog, and perhaps other user generated online content. The actual software programming needed on the browser side might not need to be overly elaborate; to start with at least it could take some time to work out all the features that might be requested by users.
For those who really are not sure what to make of all this, perhaps it would be best to wait for someone technically inclined to provide an assessment before we all jump on the thread user programming bandwagon. However, if this were to work out it would make the lives of many many people more productive.
J, I was thinking along those lines last night when it was mentioned that Dr. Benjamin is aware of the thread. I cringed a little, thinking of all the off topic posts he would have to scroll through (and may decide to click away), and wished there was a way to have a cleaned up subset of this thread.
Dr. Benjamin asked me to keep him updated with my progress and Steven's also in touch with him.
.
OK, I nominate YOU to ask him what he thinks is the minimum effective dose (in mg/kg body weight) of metformin and syrosingopine.
OK I have asked. Got any tips on measuring out small amounts and best way to get it to the right place under the tongue?
Thank you very much Ray!
Do you have 0.1mg scales? Then it's easy. I can adjust the weight by just a few tenths of a mg if I need to.
I use the Blue spoon in this kit: https://www.amazon.com/gp/product/B077VSD8H2/ref=ppx_yo_dt_b_asin_title_o01_s00?ie=UTF8&psc=1
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.
When I had to deal with such small quantities, I used to buy empty capsules and put the powder in those. It's much easy to work with. Here is an example of empty capsules available and cheap https://nl.iherb.com/pr/now-foods-healthy-foods-single-0-gelatin-caps-1000-empty-capsules/893
I bought a pack of 1000 with that in mind, but there is no way to get the complete sample off the measuring platform and into the capsule. She said it's not worth the trouble, I'll just lick it off the foil.
Thinking about it again, one way to do it would be set the capsule on the platform, zero the scale, then dump the contents of the spoon into the capsule, close the door, take the reading, adjust the sample amount if necessary.
I understand. What if you put the powder on an aluminium foil, get to the desired amount and with the help of the aluminium foil you transfer it inside the capsule.
The other way I used to work with such difficult substances (like Salinomycin that requires 0.2mg/kg) was to convert them into solution. Once we can convert such as substance into solution, it is much easier to work with it. For example we dissolve 100mg Syrosingopine in 50ml solution, and we know that each millilitre solution contains 2mg Syrosingopine. This is an alternative approach for those who do not have extremely sensitive scale as you do, and more convenient when we really want to control well the concentration of a substance that may be dangerous in higher amounts. The only questions is in what solution is soluble the substance we want to dilute. For example, I see Syrosingopine is soluble in DMSO (10 mg Syro/mL of DMSO), ethanol and acetic acid.
The syro is a little clumpy but small grains (perhaps 0.3mg) do break off. Trouble is, the grains stick to the foil and cannot be recovered.
Yes, I had thought of a liquid solution as well, thanks for doing the math. That would solve a lot of problems.
Trouble is, the grains stick to the foil and cannot be recovered.
I would not expect dry grains to stick to the tin foil. Do they stick after you place the oil drops on them? If so, how about using coconut oil which is semi-solid at room temperature? Or using small pieces of polyester tissue, wax paper or another non-stick light material?
Maybe it's better to say the smallest particles cling to the foil, like dust.
I add the oil after I have the desired amount on the foil.
the smallest particles cling to the foil, like dust.
If you dip the scoop in coconut butter, plain butter or anything sticky rather than liquid, I imagine you might "glue" and trap all the dust particles in it, out of the tin foil. Then she can lick the scoop up and get it all, including any dust that might be still stuck to the scoop.
Wow! I just came across this one, it looks impressive. Are they saying that Canagliflozin has single agent anti-cancer effects (See Figure 1). Canagliflozin is going through OXPHOS subunit 1 similar to metformin.
Combine with metformin?
https://www.ncbi.nlm.nih.gov/pubmed/?term=27689018
Very impressive. Metformin only became active against cancer when syro brought down the treatment dose into the effective dose range 15 fold. Yet, Canagliflozin is already in the effective dose range! The guess is that a combination of Canagliflozin and syrosingopine should be fairly effective. The question though is how much treatment leverage dose syro have?
I will wait for a response from the thread before commenting further, though this does look impressive. There are many many phase 3 trials with canagliflozin. Some of them combined with metformin at the patients current dose. That would be amazing! Combination strength OXPHOS subunit 1 inhibition? Some clinical research also mentioned that dosing went up to 300 mg twice per day with Cana; over the dosing range up to 300 mg there was a linear increase in drug concentration (?). Yet, some of the research suggested that older patients should limit to 100 mg Cana per day.
Could anyone find the pharmacokinetic data that talks about concentration? The article I linked to above talked about 5-30 microM Cana from the clinical trials, though I have not been able to find this number. There is so much clinical research with Cana!
Table 1 from url below. They treated with Canagliflozin 300 mg twice per day with an average of 1870 mg of metformin. If there is additive OXPHOS subunit 12 inhibition that could put a large amount of stress on the cancer. Considering that CANA is dosed with extended release, metformin fast release might make more sense (to avoid side effects).
Below article gives some clinical pharmacokinetic numbers:
300 mg BID n=10 CANA at steady state after a month at max gave concentration of 3000 ng/ml
molar mass of Cana 444.5 g/mol
online calculator gives 6.7 micromol CANA
https://www.ncbi.nlm.nih.gov/pubmed/?term=22226086
First article on CANA that I cited above.
"Clinically achievable concentrations of Canagliflozin and Dapagliflozin range from 5 to 30 μM"
Just scanning through the text I saw this:
"SGLT2 is expressed primarily in the early proximal renal tubule and is responsible for most of the glucose reabsorption in the kidneys (2,3). Inhibition of SGLT2 decreases glucose reabsorption in the renal tubule and increases glucose excretion (3,4). Partitioning of glucose out of the body through increased urinary glucose excretion (UGE) directly reduces elevated glucose concentrations and, by loss of calories (since each gram of glucose lost is equivalent to 4 calories), tends to lead to weight loss."
Thank you for finding things to consider, but I don't think that applies to my wife's bone mets, and I'm worried about her weight loss.
One thing to consider is that you could inject glucose and override the glucose reduction.
JohnnyP, I hope this suggestion is helpful to you. Cana seems to have the same anti-cancer mechanism of action as metformin (subunit 1), so it is possible that it would also make a good combination with syrosingopine, though the concerns that you noted would need to be addressed if possible. I wonder given the properties of Cana why the 2016 research used metformin instead?
I wonder given the properties of Cana why the 2016 research used metformin instead?
I am speculating that they may have tried to use drugs that were available to everyone rather than patent-covered drugs. Also, metformin seems to have a longer, more established record of safety. It seems as though Cana has more potentially serious SE.
But the anti-cancer results reported seem to be very impressive. It might be worth the extra risk of using Cana with syro if metformin plus syro does not do the trick; if a person cannot tolerate the metformin dosage necessary; or if a person doesn't have time to wait for syro+metf to work.
