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Combo Metformin And Syrosingopine!!!! Looks Awesome!

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John Pizzuto
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@jcancom

I can't find a link to the full article, but a partial says they were mental patients, with high diastolic pressure, most of them with readings over 100.

Does it give a max dose in g/kg?


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Daniel
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@gge

Thanks a lot for your kind, clear and balanced response. We are all so busy, but allocating time every now and then to address such topics is extremely valuable for all of us. Sharing our thoughts and experience on how to best fight this war in such a balanced way it's very constructive. 


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Daniel
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Jcancom
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JohnnyP, it is frustrating! They are trying to conserve paper or something; most of the relevant details are not included in the article. Hopefully in the modern era of research they will just back up the truck and upload whatever is on their hard drive to a databank. There is no reason to agglomerate data when one can simply provide all the data points.

The article notes that the patients were seen every 2-4 weeks with a 3 visit placebo lead in and then there was a 3 visit treatment phase at the highest attained dose (titrated up?). There is no mention of mg/kg though it is noted that there were 2 women in the trial.

Of the 41 on 6-12 mg per day 31 had a control DP >100, and 10 had  a DP of 90-99. Of those with 90-99 7 of 10 saw a reduction of 0-9 mm Hg, while 11 of 31 saw a 10-19 mm Hg reduction and 8 of 31 saw 0-9 mm Hg. So roughly, there was an equilibration of BP reduction  as a function of initial hypertensive status. Confusingly they also noted that the 90-99 on the 6-12 mg dose per day actually saw their mean BP increase ( explained by suggesting that this hypertension was related to atherosclerosis).

The dosages in this study are starting to move upwards. The patients received treatment over a period of at least a month or two and the side effects did not appear excessive (sedation 14%, nasal congestion 11%, nervousness 7%, headache 5%, GI 3%, nightmares 1%) n=56

There were several other clinical studies I read for syro, though these were mostly on the lower range of <= 4 mg per day ( e.g. 1 mg *4 per day). Yet, one of the articles noted that dosing actually has went up to 20 mg per day in some of the research. The side effects noted would not appear to indicate serious pathology from syro dosing. One thing I did consider was whether catecholamines could be given to override the anti-hypertensive effects. For our purposes depleting catecholamines and thus creating a  hypertensive effect is  a side effect and not a therapeutic outcome; it would be funny if we could just override the side effects by overriding the mechanism of syro while keeping the MCT1/4 effects. Basically all gain, no pain. Not sure whether it would work that way, though it would be nice to know. A trick like that might even allow for a widening of the therapeutic index of the treatment. ( It is possible that such a catecholamine replacement strategy was actually done during the (pre)clinical research stages). I would also love to see a relevant formulation of syro. Something like a chitosan formulation would move you down to microgram scale dosing and much less side effects.      

In an earlier post on this thread D noted a quote from another forum which suggested that even 1 mg dosing syro might be adequate. The pharmacokinetics of syro are very unclear; from what I have seen online it would appear that such research was not conducted (which seems highly surprising, though perhaps in line with the research guidelines of the 1940s-1950s). It is reassuring that up to 12 mg syro dosing appears to have been safe. Metronomic dosing is what we are interested in and metronomic dosing is exactly what you need in hypertension. It wasn't obvious to me that syro would be safe for all cell types over all-day multiple dosing as what would be needed for syro, though apparently it is. One could certainly be concerned that some cell types would not appreciate the shut-down of MCT4 and to some extent MCT1.

GgE's caution is greatly appreciated. It is unclear to me what might happen if a strong MCT1 inhibitor were to be added on top of the syro met combo.  Given the power and the established safety of the two drugs, staying with the published protocol certainly has merit.

Even still I have investigated phenformin and there are many aspects of it that are of interest. For example, phenformin and metformin are cationic in the physiological environment. I would like to know more about this! This could explain the discrepancy we have noted concerning metformin's measured concentration in humans and its actually effectiveness. With cations, actual mitochondrial concentrations can be upwards of 1000 times higher than in plasma. Phenformin is much much more able to enter the cell than metformin and is in fact why the risk of lactic acidosis is so much higher.  

Also while phenformin does have an unacceptable risk profile (a mortality rate of 1 in 4000!) due to lactic acidosis this relates substantially to the populations studied. In one study of ~300 patients with lactic acidosis existing risk factors included  cardiovascular disease (44%), renal insufficiency (35%), infection (25%). It was also noted that ~10% of the population have an inability to hydrolyse phenformin. Surprisingly, pubmed did not have a modern genetic description of this result even while phenformin continues to be used in several nations and there continues to be mortality associated with its use. One might guess that some of that mortality could be associated with the unhydrolyzability effect.

I also felt somewhat vindicated about my idea expressed earlier that going to beta oxidation would up the NADH crisis. The idea here is that beta-oxidation does not directly create ATP but instead mostly NADH. This is exactly what the syro met strategy is  using to create a crisis in the cancer cells.

"... With gluconeogenesis inhibited by biguanides,
pyruvate accumulates. Oxidation of the fatty acids released
from fat catabolism depletes NAD1 and increases
NADH (17). Inhibition of oxidative phosphorylation by
phenformin impairs the ability of the mitochondria to
generate NAD1 from NADH, further increasing the
NADH/NAD1 ratio (15). The resultant increased
NADH/NAD1 ratio inhibits pyruvate dehydrogenase
and the entry of pyruvate into the Kreb’s cycle (15). ..."

Biguanides seem to create a self-reinforcing metabolic crisis that cancer cells might find difficult to extract themselves from. The articles on the combo did not mention this additional NAD+ depletion that would be underway in the cells. We have concentrated mostly on glycolysis and OXPHOS as metabolic targets; it is encouraging to see that other energy pathways including beta-oxidation and Krebs could also be brought in to add even more stress to the cancer cells.

https://www.ncbi.nlm.nih.gov/pubmed/9848705

 

The syro met research has moved us towards the center of a universe of similar powerful treatments including:

atovaquone https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085139/

Asparate auxotroph in OXPHOS ut https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522278/

Duo combo becomes a triple     https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520007/

phenformin  oxamate/DCA    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897486/

This is tremendously exciting as the potential treatment landscape is greatly expanding before us, giving us the possibility of being able to freely choose a treatment without the implicit coercion that results when choices are greatly constricted.  

 

 


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Jcancom
(@jcancom)
Joined: 4 years ago
Posts: 535
Topic starter  

D, I just noticed. This thread used to have 7 pages: now it's down to 4! What happened?

For quite some time I have been unsure about TRAIL and how it might be used as an anti-cancer strategy. TRAIL is highly anti-cancer specific, though it has had somewhat limited success in the clinic; recent research has found that a 3-BP TRAIL combo is quite synergistic.  

This is very very exciting with what we are seeing with a range of metabolic treatments. We are converging on about 20-30 different base treatments that could be recombined in many many ways. There are quite a number of these dual metabolic approaches that should have substantial efficacy, while avoiding problems that could arise from resistance. I remember a few years ago on the compass thread that if 3-BP were rejected I would have few ideas left. On this forum we have opened up an entire universe of potential with almost endless possibilities.

  

 

 

 

 

 


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Jcancom
(@jcancom)
Joined: 4 years ago
Posts: 535
Topic starter  

JohnnyP, you provided a url for an analytical balance that cost about ~$300. Is that a good price?

This cheap one (~$5) measures down to 0.01g and might have done the trick.

https://www.ebay.com/i/133190626868?_trksid=p11010.c100415.m3733&_trkparms=aid%3D1110001%26algo%3DSPLICE.SIM%26ao%3D1%26asc%3D20150526101403%26meid%3D98752f0fe2b54bbd9edd2e644cc12b76%26pid%3D100415%26rk%3D1%26rkt%3D4%26b%3D1%26sd%3D392097904526%26itm%3D133190626868%26pmt%3D1%26noa%3D1%26pg%3D11010&ul_noapp=true


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Daniel
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@jcancom

Hi J, you see everything 🙂 I changed a setting so that there are 30 comments displayed per page instead of 15 as it was before. I thought this may help us so that we do not have to push many times back and forward to see the comments. 


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Daniel
(@daniel)
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@jcancom

0.01g has a 10mg resolution. But you can find also 0.001g at ~$20. Would be great to have one at 0.1mg resolution.


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GgE
 GgE
(@gge)
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@jcancom

Great analysis and comments, as usual coming from you.

In regards to the pharmacokinetic testing of syrosingopine I understand that it was carried out by CIBA back around 1950 and the product was marketed as Singoserp in 1 mg pills. Novartis has bought CIBA since then. Novartis probably still has all the experimental data collecting dust and considered useless. It would help everyone a lot if anyone can find a way to obtain this data from Novartis.

Phenformin seems to have much stronger effect than metformin because, unlike the latter, it is lipophilic and thus can better penetrate the cell membrane. Phenformin used to be sold to diabetics in Italy by Sanofi as Fenformina but it was pulled off the market also in 2013. I don’t know if it still is for sale anywhere. Its risks are real, although they might be lower for people with healthy kidneys. I read this quote:

“Phenformin was removed from clinical use for type 2 diabetes because of incidence of fatalities from lactic acidosis (Crofford, 1995; Owen et al., 2000), reported in 64 cases per 100,000 patients per year, with patients bearing compromised kidney function at greatest risk”

We might learn more about Phenformin safety and effectiveness against cancer from ongoing studies. If it is as efficacious as in the Basel cell studies then it might return to the market. Then people can decide if the risk from taking it is worth the potential rewards.

Daniel has been unwavering in teaching metabolic treatments to defeat cancer. He just got re-vindicated by this recent mice study that further supports his conviction.

The study found a huge improvement in the response rate to a PD-1 immunotherapy when the mice had their T-cells’ energy levels enhanced by something as simple as creatine at human equivalent dosage. The addition of this simple food supplement prevented the anergy that killer cells experience within the tumor microenvironment that keeps them from destroying the cancer cells.

I think creatine could be a low risk addition to anyone who is undergoing a PD-1 or PD-L1 immunotherapy. Of course they would have to discuss it with their oncologists and make sure the patient would avoid taking it while also taking metformin and/or contrast agents such as Iodine. All three substances are eliminated by the kidneys and they might get damaged by trying to eliminate all of them at the same time.

https://www.sciencedaily.com/releases/2019/10/191018131154.htm?utm_source=feedburner&utm_medium=email&utm_campaign=Feed%3A+sciencedaily%2Fhealth_medicine%2Fcancer+%28Cancer+News+--+ScienceDaily%29&fbclid=IwAR1sJNaYMlAlWMyeUuKqKS9BqOLb5VOffogHJwRJCzK0qJT52ufkeovLVF


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Yudaitheska
(@yudaitheska)
Joined: 2 years ago
Posts: 32
 

@jcancom

Phenformin + oxamate

Golden information* Thanks! 


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John Pizzuto
(@jpizzuto)
Joined: 2 years ago
Posts: 214
 

@jcancom

Yes, the scale I referenced is an excellent value.  Before I ordered it, I was looking at antique beam balance scales for less than $200, until I watched a couple videos on using them.

The digital scale is much easier to set up and use.


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Jcancom
(@jcancom)
Joined: 4 years ago
Posts: 535
Topic starter  

Yud, thank you for your reply; replies can help focus our attention on aspects of posts that might not be fully revealed on first inspection.

For example, I had not fully appreciated the relevance of my suggestion regarding the balance created by the combo. Only on further inspection did the counter-vailing effect of oxamate on phenformin's lactic acidosis risk become known to me. Such a combo could be make a very nice combo indeed: phenformin increases lactate (among other biological effects), while oxamate shuts down lactate production through LDH inhibition.

Phenformin as Glibenclamide is available in Mexico.  

The number of these potentially powerful dual combos is substantial and might be of considerable importance to systemically catalogue.  

D's idea of having the forum for generation discussions that can then migrate to the blog area is brilliant. Basically we can plant many seeds in the forum and then see what grows into towering trees. In this forum area we can work through all the basic points of contention and then the blog area can be reserved for more refined discourse. This would allow for a smoother flow of learning especially for those needing a more compact and easily digestible summary of results. Roughly, the forum can function as our back office (workshop), while the blog could be more the front office.   


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Daniel
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@jcancom

J, you are spot on. As you know, everything started with Cancer Compass. We had so many good discussions there, about 3BP and so many other compounds, but everything was lost in a long thread. It takes forever to go through such a long thread to select and consolidate the valuable points. And we had no place where to consolidate information. Like you nicely said, now we have a front office 🙂

On the same line, I was looking some weeks ago at the Fenbendazole Facebook page. There is a lot of activity there, but the admin of the page found the same issue: a forum with no way to consolidate and structure information leads to loos of valuable info and people asking again and again the same question. As a result, the admin decided to stop the Fenbendazole Facebook page and start a a website similar to this one.


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NA
 NA
(@j)
Joined: 3 years ago
Posts: 531
 

@jcancom

oxamate, another one for the -ate list ? 


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Ray Donnelly
(@ray-donnelly)
Joined: 1 year ago
Posts: 55
 

Hi all,

I just found this site. What took me so long? Thank you for all that you do here. It is truly inspiring and valuable.

I'm Ray, I have stage IV colon cancer (KRAS wild-type, MSS) and have been trough good deal so far (including crowdfunding an operation that I had nearly a year ago).

I've recently started taking syro and metformin. I hope it works as I'm finding chemo increasingly intolerable (and it's not working as well as it used to). I'm also on a ketogenic diet and have been for a while, though I may be eating a bit more meat for my macros I am tracking my ketone and glucose levels and they are good.

Any advice, for example on other things to take would be appreciated. I know far less about this stuff than my condition deserves!

Kind regards,

Ray.


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Manuone
(@manuone)
Joined: 3 years ago
Posts: 142
 

I don't know if "syro" can be a good ally in brain cancer .....
Jcancom thanks for your recommendation makes sense added to high doses of honokiol.
I am configuring several drug calendars and looking to add other molecules and I do not supply so much information .....
"I move in unknown lands"


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Daniel
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@ray-donnelly

Hi Ray,

You are very welcome here!

Please read the earlier discussions on this thread including some ideas I shared on possible ways to improve this treatment approach.

Where do you buy Syrosingopine and what is the dose you are using?

Kind regards,
Daniel

 


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Jcancom
(@jcancom)
Joined: 4 years ago
Posts: 535
Topic starter  

There are a whole bunch of replies that I want to reply to! My inbox is filled up; time to move some items to the out box.

~$300 for an analytical balance down to sub-mg is not a bad price, though I think that I would go with one of the  ~$50 models that get you to mg. It threw me when they measured in grams; milligrams would seem to be a more appropriate unit of measure for these balances.  


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Jcancom
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Joined: 4 years ago
Posts: 535
Topic starter  

Regarding the syro research, from a modern perspective it surprises me how little of the clinical research appears to have reached pubmed. Some of the journals seem to be beyond all of the electronic databases.  From the vantage point of today, one might think that at some point the entire FDA submission for a new drug would be placed into the public domain (all 100,000 pages). The disclosure would essentially be exhaustive.

One interesting angle that I discovered online about syro was that it was involved in litigation in the 1970s. The issue surrounded the use of benzothiadiazine specifaically Hydrochlorothiazide (HCT) when used in combination with syrosingopine and others. So, Singoserp-Esideix contained syro and HCT.

"The therapeutic effectiveness of the benzothiadiazines can be increased by administering them together with one or more other drugs. One widely used benzothiadiazine is HCT."

https://law.justia.com/cases/federal/district-courts/FSupp/508/1118/1483673/

What seemed to have happened was that combining syro and HCT allowed for a further reduction in dose of syro and presumably a further reduction in side effects. This might explain why higher doses of syro were typically not reported in the clinical reports; with the combination they would not be needed.

Dosing up to 12 mg per day probably occurred before they made the combination.

One the Inspire thread the poster who has had a good response to syro + met noted that he was also taking daily aspirin. Sometimes these extra items can be overlooked, though I noticed that aspirin is a complex V OXPHOS inhibitor which might be of relevance with this combo.

Also notable is a doctor in the US is formulating the syro in liposomes. This might amplify effectiveness while reducing side effects.  

With phenformin one would need to be very cautious. It would be best to be under the close watch of a physician. As GgE noted, phenformin is much more lipophilic than metformin and it (as well as metformin) are cationic at physiological pH. All combined phenformin is a much much more powerful drug than metformin (50x, (850x ?). As a cation with a good lipophilic profile it would be dragged into the cell and to the mitochondria to shut off OXPHOS. There are a range of biological features that suggest it could lead to lactic acidosis. The fact that ~10% do not hydrolyze (it does not appear to be known which 10% these might be), and that cancer patients can have a range of noted risk factors associated with phenformin lactic acidosis (such as compromised organ function etc.) would contribute further to the risk. At the same time the cationic quality of phenformin should lead to some tumor specificity ( according to the Nernst equation). Yet, it is not clear whether these implications have been adequately researched to date. One can see that there were several well-considered reasons why the syro combination research has chosen metformin over phenformin.

With phenformin + oxamate, articles mentioned that oxamate cannot be dosed up to an appropriate level for clinical benefit.   

 

 


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Ray Donnelly
(@ray-donnelly)
Joined: 1 year ago
Posts: 55
 

Thank you @daniel,

I also got my syro from StevenK in Thailand and am trying to follow his protocol (3-4mg twice a day .. measured by eye and a fair amount of guesswork currently).

My high precision scales arrive soon. I ordered these: https://www.amazon.co.uk/dp/B01N5DARO0/ref=pe_3187911_189395841_TE_dp_1 .. but I didn't pay the £1,457.96 I see them listed for. I paid close to 1/10th of that price! I must have been very lucky (in this instance at least!). We'll see; let's hope it turns up and let's hope the price drops back to what I paid!

I did read some of your posts, I'm going to add sulforaphane as I saw it mentioned and watched Dr Rhonda Patrick's podcasts on the subject and have ordered broccoli seeds for that (her keto lemon tart recipe is something I plan to eat a lot of too!). I'm also taking aspirin. I need to source slow release metformin next, as a proxy for that I take 500mg 4 times a day.

Would you recommend keto in my situation? Steven mentioned that he isn't doing keto as he didn't do well on it when he tried.

I had thought about going to ChemoTherapia in Turkey and still might, depending on how things go, though that would be expensive and I figure a lot of what they offer I can cobble together myself. I get the results from a PET scan on Tuesday. This scan predates me starting syro (just). My CEA levels have been rising for a few months.

An added difficulty is that I live in Spain and don't speak Spanish very well yet. Still, you've got to try these things, eh? And I do love the natural vitamin D I get here (when chemo allows).

Best regards,

Ray.


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Jcancom
(@jcancom)
Joined: 4 years ago
Posts: 535
Topic starter  

D, creating a better information flow on the site would help direct people to the information that they need. There is such an overwhelming amount of cancer research that we have sorted through. We have reached the point already in which organizing and distilling our current knowledge base is becoming more of a priority. What we need to provide the bottom line to those on the thread concisely (without them having to go through all of the detours that we have taken). The forums are a great place to do all the back office negotiations. Finding the nuggets requires a great deal of sifting; offering visitors a finished copy would be of great help to them.

Basically, what we should try and do is keep the blogs open for more limited commenting that might be of particular importance for those considering the treatments, while most of the pre-production stage commenting might stay on the forums. We could have links between the forum and blog pages to make it easier. Possibly you might even consider "evicting" the posts from the blogs and reposting them on the forums. After a thread has matured enough (for instance, possibly this thread) it could then be advanced to a blog post. One helpful feature would be that much of the leg work would have already been done.

One other organizer feature we might try is to have the forums listed as they are now, by category, but also by number of posts. It is another way of seeing what threads are attracting interest. I suspect a fair number of people on the compass went to the 3-BP simply because of its oversized post counts.

Perhaps having a zip file that could be downloaded that contained the entire contents of this site might also be helpful. There could be ways of extracting knowledge from such a format that might not be possible using only forum software and a browser. One such approach that I have been using on my computer files and I have incorporated to some extend on this site is the use of signifiers. So, for example, on this site I have 4 !!!! and then 1 ! at the end of the title of the current thread. A 5! thread !!!!! Not bad. This is one way of conveying meta information. 

Creating signifiers such as that could be used to help organize information on threads, within threads etc. We could create our own signifier code that would label a treatment idea and then posters could add their ratings to the idea. For example, my idea about the phenformin, oxamate combo could be coded [[[ (phen, oxam) [0, Jcc, S(1,2)?, D(2)? ]]]] . Roughly, [[[ means that it is a treatment idea,  (phen, oxam) identifies the treatment, the 0 gives some idea of where it is in the deliberation process (0 is very preliminary), Jcc (that's me), S(1,2)? (questions it's safety, here the first item phenformin and the second item oxamate)), D (for questioning the dosing feasibility (on the second item (oxam) of the combo).

The complete legend could be provided somewhere and those who wanted to add additional info over and above the legend could do so. The only prerequisite identifier would be "[[[" for a treatment idea which could be searched in a browser, greatly reducing the work load of those wanting a coded summary. What is especially great about this is that anyone could add this to a post anywhere on the forum/blog without there being a need for an upgrade to the software and a page search would pick it up. This could be an extremely efficient way of getting information to people. Instead of people having to read through possibly hundreds of blog/forum pages the information could almost by magic seek them out. It could be of great help. It would be of even greater help if we had a web crawler file of the entire site that could be downloaded and then comprehensively searched. (Possibly the entire website could be placed into a large word pad file that could be searched (?).  

[[[ (syro, met) [3, Jcc, uv ]]]]   Is a rating for the combo (syro met), 3 (of 5 rating), Jcc (Me) uv (upvote).    

It might seem somewhat odd to do this, though it could save an enormous amount of effort for those who need to find the information they need fast.

This idea would be especially helpful on the blog posts because there is pagination that would not hinder these searches. Thus, one might search "[[[" on a 3-BP blog post and be able to immediately search through hundreds of posts to find a summary. Importantly, since the posts are arranged chronologically one could be especially attentive to the most recent posts as such posts would reflect the best appraisal at any given time. Possibly we could order the posts in reverse chronological order? Remove pagination on forum pages as well which would allow for rapid scanning through the forum?  

Having to update a file of treatments (another of my ideas) is simply too much of an effort. Yet, typing a triple [ and a treatment identifier and some fields would not seem overly taxing.

 Suggestion, comments, complaints - please!  


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Daniel
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@ray-donnelly

Dear Ray,

Thank you so much for the details. I guess you now go on this road and hopefully it works. If you need to increase the strength of this combo, you let me know and I will share with you some ideas on that. 

Regarding the ketogenic diet, I am not too much in favour of that but on the other hand there are some visitors of this website (now our friends here) from Spain who are on keto diet for years and are doing well (while using a lot of re purposed drugs). I am amazed by the community from Spain (patients and doctors). This is one of the community that sands out in terms of knowledge and pro-active approach to fight cancer - you may want to try and connect with Marcos and/or Manuel.

Enjoying life and sun is essential and I am glad to hear you are doing that!

Kind regards,
Daniel


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John Pizzuto
(@jpizzuto)
Joined: 2 years ago
Posts: 214
 

@jcancom

Merformin is an MCT-1 inhibitor and is potentiated by syro, which strongly inhibits MCT-4, and MCT-1 weakly.

Phenformin is not an MCT inhibitor so it won't work "in combo" with syro.  You have to inhibit both the MCT-1 and MCT-4 transporters to trap the lactate inside the cell.

I'll have to study the Phenformin paper you referenced above.


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Jcancom
(@jcancom)
Joined: 4 years ago
Posts: 535
Topic starter  

Sorry for the confusion JohnnyP.  I was thinking of the 2016 article. The article noted that a range of OXPHOS inhibitors appeared to be effective. Combination of syrosingopine with these other OXPHOS inhibitors (including phenformin) was proposed to be explored in future research. 

 

Figure 3

Even antimycin and oligomycin were thought promising.

"Antimycin A had an IC50 at ~3 nM with syrosingopine while showing no toxicity at 40 nM. Finally, oligomycin had an IC50 at ~750 pM with syrosingopine while showing no toxicity up to 16 nM in the absence of syrosingopine. Similar titrations for 6.5 cells are shown in fig. S6A."

 

The non-responding cells expressed gamma-enolase.

"Markedly, most of the nonresponsive or poorly responding cell lines express γ-enolase (syrosingopine-metformin responsiveness shown in fig. S7B)"

 

wiki gave pharmacokinetics of phenformin in patients treated with 50 mg per day with max of 0.18 (mm 205.26 g/mol) gives about 1 microM. The IC50 from the article was 30-400 microM. The molarity of phenformin is somewhat below what might be needed. However, this discrepancy was noted elsewhere on this thread and apparently involves a highly technical unresolved question.      

0.000 000 876937 M = ~ 1 microM
https://en.wikipedia.org/wiki/Phenformin

in the presence of syrosingopine and 13-fold with phenformin (IC50 from ~400 to 30 μM)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5182053/

 

From another section of the article, the syrosingopine dosing used by the mice was also somewhat beyond the range attempted in the human clinical trials.

Dosing used below Figure 2 "syrosingopine (7.5 mg/kg body weight) = ~28 mg in humans (50 kg),

, metformin (200 mg/kg), or in combination, ..."   = ~800 mg in humans (though there might be a dosing difference between mice and people with metformin).

The different cell lines had a range of sensitivities to the combination. Interestingly, many of the cell lines were sensitive to the combination; several at low molarities. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5182053/

 

The 2018 article then focused on the MCT-1/4 without much discussion of the previous results with

the other OXPHOS inhibitors (though some phenformin research

https://cancerres.aacrjournals.org/content/75/1/171.long   is noted).

 

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816454/

These are MCT1 and MCT4 scores for lung cancer patients. There are 4 quadrants ( MCT 1/4 high/low) available. Yet, cancer cells are being increasingly confined to specific evolutionary paths as many of the resistance pathways are being blocked off. The red dots represent the patients that would especially benefit from AZD3965 ( high MCT-1, low MT-4). Syrosingopine strongly blocks MCT4; AZD3965 strongly blocks MCT1; 3-Bp enters cells by MCT-1. There are fewer and fewer routes for cancer to successfully escape. There are only a handful of MCTs and they are vitally important for cancer biology.

     

https://www.ncbi.nlm.nih.gov/pubmed/24277449

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302548/

 

While the 2016 article noted the promise of other OXPHOS inhibitors, the 2018 was more concerned with the MCT1/4 behavior in the metformin syrosingopine combination.l


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Jcancom
(@jcancom)
Joined: 4 years ago
Posts: 535
Topic starter  

Ray, there is so much research to consider. It is too much for anyone to manage for themselves. I hope that we can help reduce the complexity for you.  

One approach that you might investigate is metabolically supported chemotherapy. This treatment has been used with great success at the Turkish clinic that you mentioned. If chemotherapy is active, then metabolic stress can have a very large anti-cancer effect. This was seen with one of our thread posters. As can be seen, adding in a few metabolic treatments resulted in a very large and rapid decline in tumor markers. D is pursuing metronomic 2-DG with his foundation.   

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

 

While you will want a more comprehensive strategy possibly involving a few metabolic approaches in parallel, here is one that you might choose to add-in:

https://spiral.imperial.ac.uk:8443/handle/10044/1/65247

Search below url for term "mannose"

https://www.cancertreatmentsresearch.com/drugs-and-supplements-that-block-fermentation-and-help-fight-cancer/

 

This is the url for the forum index. There are a few suggestions for CRC.

https://www.cancertreatmentsresearch.com/community/

We have started to see tentative successes on forum (especially within the last year of so), so it would be helpful to review some of these experiences. 

https://www.cancertreatmentsresearch.com/category/visitor-story/

One of the lessons that I have learned from the site is that vigorous treatment plans are required with cancer. What this actually implies is that treatments that can be better tolerated can be more effective. Taking chemotherapy drug holidays greatly advantages cancer cells.

This virtual community is trying its best to help those in need, I wish that our efforts will benefit you.

Kind regards, Jcancom


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GgE
 GgE
(@gge)
Joined: 2 years ago
Posts: 240
 

I think D posted that someone had said in another forum that 1 mg of syrosingopine a day was sufficient. If this was said, can anyone please let me know where at? I would like to know what was their basis to say that.

Thanks!


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John Pizzuto
(@jpizzuto)
Joined: 2 years ago
Posts: 214
 

@gge

Look at figure C in the group of graphs posted by J.  Nothing happens until the concentration goes above 10uM.  Figure A  is almost as bad.  We don't know the dose required to achieve 10uM.  I would be afraid of under dosing.

SteveK on the inspire forum takes 4mg twice a day and it took months to see results.


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Ray Donnelly
(@ray-donnelly)
Joined: 1 year ago
Posts: 55
 

Thanks for the very kind welcomes everyone,

I will order this: https://www.amazon.co.uk/gp/product/B073Q3F36T/ref=ox_sc_act_title_1?smid=A39DHN41RGMD64&psc=1

Is there any information on a PMI inhibitor? I worry about stressing out my system with so much 'stuff' going on! I've also been taking LongVida Curcumin for ages now and also Omega-3 fish oil. What are your opinions on matcha tea, beta-carotene and exogenous ketone salts?

Here are some papers I found interesting, I apologize if they've been discussed already (I had a look and didn't find anything):

1. HyperFoods: Machine intelligent mapping of cancer-beating molecules in foods

I love the openness of this paper. They provide so much data and code. It's a really impressive example of open (data) science. *

https://www.nature.com/articles/s41598-019-45349-y

Leading to this list of foods:

https://static-content.springer.com/esm/art%3A10.1038%2Fs41598-019-45349-y/MediaObjects/41598_2019_45349_MOESM1_ESM.pdf

.. tea, carrot, dill, grape .. can we target different cancers with different recommendations? I'd love to create an app for that using this data.

# 2. Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding

Another data oriented paper, again, nice open research. Ouabain and digitoxin do not sound like drugs I would like to try though!

https://www.sciencedirect.com/science/article/pii/S009286741831571X

I hope these links prove interesting to some of you.

 

Kindest regards,

Ray.

 

* I work in this field actually, for Anaconda, Inc. on a software distribution aimed at data science which probably explains the data-science bias in the papers I've linked to!


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Matsim
(@matsim)
Joined: 1 year ago
Posts: 12
 

@gge

Link is that:
https://healthunlocked.com/advanced-prostate-cancer/posts/139563286/antihypertensive-drug-syrosingopine-enhances-metformins-anti-cancer-efficacy.

There are a user ruediger2010, I think from Germany, that states:

I have contact with Dr.Ben Benjamin for his study about Metformin and Syrosingopine.1mg Syrosingopine dayly ist enough combined with Metformin 2x 800 mg to help killing the stammcells of cancer.

For me is very important too about a minimal dosage of both drugs. And which Metformin is better - normal or that one with slow release?

I can't understand how the dosage of StevenK appears. Maybe it's experimental? Firstly I've read in Inspire forum, he started with 3 or 4mg once a day. After couple of months, he wrote that he start to take it 4mg two times a day. What happens in between, to make he to double the dosage?

Sorry for my bad English, it's not my first language.


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Matsim
(@matsim)
Joined: 1 year ago
Posts: 12
 

Oops, sorry. I've make mistake. Now I've read again the post in the Inspire forum and it's seems that StevenK start with 3mg Syrosingopine with 500mg Metformin, but 3 times a day, not once. The he change it to 2x4mg Syrosingopine + 2x1000mg Metformin.


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