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GgE
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09/05/2020 1:54 am  
Posted by: @jpizzuto

I will ask Shirley's oncologist for Piqray and empagliflozin

Posted by: @jpizzuto

I think that's the one Dr. Lewis Cantley mentioned in the video I linked above.

I see. I may have missed it. I remember he said there are 3 approved already and I got the impression that any of them would do the job of getting rid of the blood glucose. I may be wrong.

I see additional anti-cancer potential with Canagliffozin (if Shirley can tolerate it) because "like biguanides, Canagliflozin inhibits mitochondrial respiration and cellular proliferation"; "clinically relevant concentrations of Canagliflozin, but not Dapagliflozin, potently suppress proliferation and clonogenic survival of cancer cells alone and in combination with cytotoxic therapies." and "We found that canagliflozin, but not dapagliflozin or empagliflozin, exhibited an off-target, and thus SGLT2-independent adverse effect, characterized by the dual inhibition of glutamate dehydrogenase (GDH) and complex I of the mitochondrial electron transport chain (ETC) at pharmacologically relevant concentrations. This combined ETC and GDH inhibition obstructed glutamine input into the tricarboxylic acid (TCA) cycle (i.e. glutamine anaplerosis). As proliferating cells are much more dependent on anaplerosis, this dual inhibition explains why canagliflozin is significantly more toxic for proliferating than for quiescent cells and considerably more potent than classical ETC inhibitors. Thus, our findings demonstrate that canagliflozin interferes with essential energy pathways in glutamine-dependent human cells. This offers a novel mechanistic explanation for the nephrotoxicity reported in patients with increased regenerative cell proliferation, e.g., observed subsequent to acute kidney injury or in chronic kidney disease.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034684/

Have you started it? If so, how is Shirley tolerating it?


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John Pizzuto
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09/05/2020 7:44 am  

@gge

You come up with some really good papers.  Are you an oncologist or cancer researcher, etc?

We are waiting for the biopsy appointment.  I'll ask them to check for the PI3K gene mutation, to see if Piqray will work.

I've been told no visitors due to the Corona virus, so I may not be able to ask about it.  Probably best to put it in writing anyway.


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GgE
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09/05/2020 8:02 am  
Posted by: @jpizzuto

Are you an oncologist or cancer researcher, etc?

We are waiting for the biopsy appointment.  I'll ask them to check for the PI3K gene mutation, to see if Piqray will work.

Just aficionado. Thanks.

I would take some NSAID before and after the biopsy to prevent further spread as a percentage of the biopsies cause. Ketorolac and Etodolac seem to be good ones. You said you had diclofenac. That might do it. Check Daniel's page on this subject and Harvard Prof. Vika's video for more detailed info.

You may want to ask them to check her hormonal receptor status also. If she is ER+ and/or PR+, HER2- and has a PI3K mutation then I think that Piqray + Faslodex offers about 80% chance of stopping the progression or better response (stabilization, shrinkage...) for the 1st 6 months after starting the treatment.

Also, if she responds this drug combo will likely extend her median progression-free survival by about 11 months. This is not overall survival but the time until progression resumes. At that time there may be some better drug in the market that gives her another couple years, and so on.

Good luck.


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John Pizzuto
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10/05/2020 12:22 am  

@gge

I don't think I have that one, but I'll check.  I have a box full of pills she's not taking.  🙂

She takes Meloxicam (15mg) as needed, if the Percosets aren't doing it for her.  I see it's also a NSAID.

I watched a video last year about taking an NSAID before breast surgery, to reduce the chance of it spreading. 

I did a search on youtube but couldn't find it.  I think Daniel has a link to it somewhere.

I took a screen shot of your suggestion about receptor status, and will get it to the biopsy radiologist.

Thanks very much.

OMG, so many "I's", I sound like a former president.  🙂


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GgE
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John Pizzuto
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10/05/2020 8:47 pm  

Daniel:

One of your pages had a link to a video about taking an NSAID before surgery, to reduce the chance of activating metastasis.  I have searched for it but can't find it.  Could you help, please?  Thanks very much.


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Daniel
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John Pizzuto
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11/05/2020 12:15 am  

@daniel

Thank you, Daniel!


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GgE
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11/05/2020 2:18 am  
Posted by: @jpizzuto

video about taking an NSAID before surgery, to reduce the chance of activating metastasis.

This one probably. https://www.youtube.com/watch?v=H8zVrYEW8vE


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John Pizzuto
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11/05/2020 2:43 am  

@gge

Yes, that's it.  He mentioned an IV of Ketorolac, I think?

How does 15mg Meloxicam/day rate?  Right now she only takes it as needed.  Would she need to take it, say 5 days before the biopsy, and 5 days after?

Towards the end of the video, he suggested taking it whenever a new treatment is started.


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GgE
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11/05/2020 3:43 am  

I can't recall the guidelines but I'd start taking it 5 to 7 days before any surgery and continue taking it until a few days after the wounds are healed. Of course, a core needle biopsy heals much faster than surgery so maybe 3 or 4 days after would be enough to avoid that any cells loosened up by the biopsy settle anywhere.


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Shivani Desai
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15/05/2020 4:23 pm  

@adifer our 7 year old is also fighting DIPG. Are you able to advise if you are still on Metformin + Syrosingopine and if you believe it is beneficial? We have H3.3k27m. 

 

Thanks

Shivani

This post was modified 2 months ago by Daniel

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GgE
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26/05/2020 3:03 am  
Posted by: @jpizzuto

I'll ask them to check for the PI3K gene mutation, to see if Piqray will work.

Did you get the test? In addition to the PIK3CA mutation you may want to check the hormonal status of her cancer (ER, PR and AR) as well as her PTEN and ESR1 because they may affect how well she will respond; and her PD-L1 to have an idea of her chances to respond to immunotherapy.


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John Pizzuto
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26/05/2020 4:35 am  

No, we are still waiting for the appointment for biopsy.  Originally, it was going to be taken from the liver, but the surgeon has changed his mind.  I think it will be from a tumor that is outside the lungs.

We have been approved for Piqray, but they told us we can't get it until the Verzenio stops working.


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toobs1234
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27/05/2020 12:03 am  

Diflunisal+Syrosingopine+Metformin

The Syrosingopine/Metformin strategy is really interesting, but I have serious doubts about whether we can achieve the plasma levels of syrosingopine necessary to get a result from the double therapy. The Metformin I'm less worried about because that has been shown to accumulate in mitochondria, especially of the prostate, which is my area of focus. Meaningful increases of intracellular lactate start at around 10uM of syro in wild type HAP1 cells in 2018 paper: see Fig 2 https://www.cell.com/cell-reports/pdf/S2211-1247(18)31806-0.pdf

We don't know much about the pharmacodynamics of Syrosingopine, but it seems unlikely to me that we can actually achieve 10uM safely at home. In their 2016 in vivo experiment, they injected the mice with 7.5mg/kg. The equivalent injected dose would be around 50mg. Who knows what the equivalent oral dose would be, but it's for sure much higher than the levels used for treatment of high blood pressure.

However, the same level of intracellular lactate accumulation as for the wild type cells HAP1 was achieved with only 50nM in MCT1 knockout cells. This led me to look for MCT1 inhibitors that are easily available, with a good safety profile, and that can achieve meaningful inhibition of MCT1 with known-to-be-safe oral doses. There are lots of MCT1 inhibitors, but after days and days of research, the only candidate I found that meets the above criteria is Diflunisal.

- Diflunisal is a non-competitive MCT1 inhibitor

- At 0.8mM, Diflusinal is highly synergistic In Vitro with Diclofenac (0.1mM), an MCT4 inhibitor, and Metformin (1mM). As an aside, although Diclofenac is readily available and cheap, you're never going to achieve 1mM with Diclofenac.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224440/

- After 7 days of dosing at 500mg twice daily, the mean trough plasma level of Diflunisal was 0.34mM

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2125.1977.tb04511.x

- The official max daily dose is 1500mg per day

This find has me enthusiastic about syro again. Although some tumors have low levels of MCT1 activation, many don't. Prostate cancer for instance often has activated MCT1 and MCT4.

Next topic I will look into is the pharmacokinetics of syro. Anyone have any info on that? I know there was some data on Reserpine. Seems like 50nM plasma levels should be doable, though.


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toobs1234
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27/05/2020 12:06 am  
Posted by: @toobs

Diflunisal+Syrosingopine+Metformin

The Syrosingopine/Metformin strategy is really interesting, but I have serious doubts about whether we can achieve the plasma levels of syrosingopine necessary to get a result from the double therapy. The Metformin I'm less worried about because that has been shown to accumulate in mitochondria, especially of the prostate, which is my area of focus. Meaningful increases of intracellular lactate start at around 10uM of syro in wild type HAP1 cells in 2018 paper: see Fig 2 https://www.cell.com/cell-reports/pdf/S2211-1247(18)31806-0.pdf

We don't know much about the pharmacodynamics of Syrosingopine, but it seems unlikely to me that we can actually achieve 10uM safely at home. In their 2016 in vivo experiment, they injected the mice with 7.5mg/kg. The equivalent injected dose would be around 50mg. Who knows what the equivalent oral dose would be, but it's for sure much higher than the levels used for treatment of high blood pressure.

However, the same level of intracellular lactate accumulation as for the wild type cells HAP1 was achieved with only 50nM in MCT1 knockout cells. This led me to look for MCT1 inhibitors that are easily available, with a good safety profile, and that can achieve meaningful inhibition of MCT1 with known-to-be-safe oral doses. There are lots of MCT1 inhibitors, but after days and days of research, the only candidate I found that meets the above criteria is Diflunisal.

- Diflunisal is a non-competitive MCT1 inhibitor

- At 0.8mM, Diflusinal is highly synergistic In Vitro with Diclofenac (0.1mM), an MCT4 inhibitor, and Metformin (1mM). As an aside, although Diclofenac is readily available and cheap, you're never going to achieve 1mM with Diclofenac.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224440/

- After 7 days of dosing at 500mg twice daily, the mean trough plasma level of Diflunisal was 0.34mM

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2125.1977.tb04511.x

- The official max daily dose is 1500mg per day

This find has me enthusiastic about syro again. Although some tumors have low levels of MCT1 activation, many don't. Prostate cancer for instance often has activated MCT1 and MCT4.

Next topic I will look into is the pharmacokinetics of syro. Anyone have any info on that? I know there was some data on Reserpine. Seems like 50nM plasma levels should be doable, though.

unrelated: it would be really nice to be able to edit your posts to correct typos!


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GgE
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27/05/2020 4:20 am  
Posted by: @toobs

This find has me enthusiastic about syro again.

Me too! You may be improving this therapy to the point of making it easy and effective for most patients to follow.

With the help of diflunisal people might be able to use a lower dose of syrosingopine and also reduce the big drops in blood pressure that syro often causes. This is so because diflunisal tends to raise the blood pressure and might compensate it a bit. Big drops in blood pressure is one of the reasons many people quit. They leave people lethargic and mentally confused unless you take a lot of caffeine. People don't like living like this for a long time.

Diflunisal (DOLOBID) is an NSAID that requires a prescription but this should not be too difficult for a cancer patient to get it from his/her doctor. Diflunisal seems to be more efficient and to kill pain for longer time than aspirin or other NSAIDs. And there is a generic form of it so it is not too expensive.

Diclofenac is a drug with multiple effectiveness against cancer, including anti-angiogenesis and immunologic properties.

I searched for the pharmacokinetics of syro but did not find many specifics. They developed this drug around the 1950's when the instruments to detect low drug concentration levels were not very sensitive. I can send you what I got if you ask Dan to put you in touch with me via direct emails.

Please, let us know if you find anything else and if you start using your triple combination. There are many, many people following this forum and hoping that this therapy works.

Posted by: @toobs

Who knows what the equivalent oral dose would be, but it's for sure much higher than the levels used for treatment of high blood pressure.

Daniel posted in these web pages a table that helps to convert animal drug doses to approximated human drug doses. It can be found here:

https://www.researchgate.net/profile/Bai-Yan_Li/post/Studies_in_antidiuretic_papers_show_the_dose_used_for_HCTZ_is_10_mg_kg_in_a_rat_If_I_use_furosemide_then_what_will_be_the_equivalent_dose_for_a_rat/attachment/59d629fec49f478072e9c9a2/AS:[email protected]/download/ACUC42-1.pdf

According to this table the human dose would be about 12 times lower than the mice dose or = 50/12= 4mg which is very easy to take but is apparently insufficient to produce results in adult humans. Pizzuto was taking about twice as much syro and a medium-high metformin dose and they still did not stop the spread as we hoped for. So, your idea might be what it needs to finally work.

Posted by: @toobs

- At 0.8mM, Diflusinal is highly synergistic In Vitro with Diclofenac (0.1mM), an MCT4 inhibitor, and Metformin (1mM). As an aside, although Diclofenac is readily available and cheap, you're never going to achieve 1mM with Diclofenac.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224440/

- After 7 days of dosing at 500mg twice daily, the mean trough plasma level of Diflunisal was 0.34mM

You may add that from the article you linked,

concentrations of 0.8 mM diflunisal alone could inhibit proliferation of AML cell lines and primary blasts but induction of apoptosis was only achieved in combination with low dose diclofenac and metformin.” And that  Diflunisal prolonged intake of 500 mg b.i.d. for 11 days results in mean peak plasma levels of 0.8 mM”

 

Great job!


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toobs1234
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27/05/2020 11:14 am  
Posted by: @gge

According to this table the human dose would be about 12 times lower than the mice dose or = 50/12= 4mg which is very easy to take but is apparently insufficient to produce results in adult humans. Pizzuto was taking about twice as much syro and a medium-high metformin dose and they still did not stop the spread as we hoped for. So, your idea might be what it needs to finally work.

That was one of the parts of my post that I wanted to edit. It's unclear as written. The 50mg is already with the factor of 12 included! 7.5mg/kg/12*80kg=50mg.

I took a look at sources for Diflunisal. Unfortunately it seems that the sale of Diflunisal was recently discontinued here in Europe. Still available in the US, though.


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John Pizzuto
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27/05/2020 11:24 am  

@toobs

6.25 times what we were doing, and intravenous at that.


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Daniel
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27/05/2020 1:05 pm  

@toobs 

Hi Guys,

 

I hope you also saw my old post but still relevant on Diflunisal https://www.cancertreatmentsresearch.com/diflunisal-2/

This is available as intravenous treatment in Europe. Can be bought from the first compunding pharma listed on Suppliers page under News & Others.

Kind regards,
Daniel


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toobs1234
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27/05/2020 2:35 pm  

@daniel

 

Thanks so much Daniel! That's a perfect example of why this resource you've put together is so valuable. I'm 5 months into this journey and just now feeling like I have a handle on it. Without this web site, I could have searched pub med for years and never found these options!


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Daniel
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27/05/2020 2:55 pm  

@toobs

Thank you Toobs. It's true - most of the people don't want to hear about cancer after they have to deal with this (successfully or unsuccessfully), and this is how valuable information is lost. I remained on the war front and accumulated and shared information. And there is a lot more to share. Challenging life but happy with every decision I took, and will stay here as long as I can.

If you decide to go with intravenous Diflunisal:

- high anticancer potential - personal experience + I was in contact with a panc cancer patient who had complete response in maybe 3-4 weeks
- comes with internal bleeding risks
- performed at some clinics in Germany - very expensive but best there if money are not an issue
- otherwise I can share offline information on what is the intravenous treatment protocol we performed 

Kind regards,
Daniel


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GgE
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27/05/2020 9:29 pm  
Posted by: @toobs

That was one of the parts of my post that I wanted to edit. It's unclear as written. The 50mg is already with the factor of 12 included! 7.5mg/kg/12*80kg=50mg.

Posted by: @jpizzuto

6.25 times what we were doing, and intravenous at that.

I love the idea of Diflunisal allowing people to cut down the syro dose and make it more effective and with lesser side effects. But I think that the actual effective dose in humans may be much lower than 50 mg of syro a day. We can figure this out from info already available online.

CALCULATION OF THE SYROSINGOPINE AND METFORMIN DOSAGE

The Basel University European patent application for the syromet invention is here:

https://patents.google.com/patent/EP2663298A1

“Combination of syrosingopine and mitochondrial inhibitors for the treatment of cancer and immunosuppression

The application talks about a 70 kg human so the calculations below are for a 70 kg person.

Calculating human dosage.

1- BASED ON MICE DOSE:

The application reads:

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

So this lowers our syro number for a 70 Kg person to 2/12*70Kg = 11.67 mg a day which is feasible for many people.

The pure metformin dose for 70 kg humans would be 250/12*70= 1,458 mg a day based on the dose the mice were getting.

Now, these were intra-peritoneal injections. Oral ingestion might need to account for the inefficiency of gut absorption.

2- BASED ON HUMAN DOSE RANGES AND RATIO:

From the same syromet patent, and addressing dosage in humans: “Further dosage forms are, for example, ointments, creams, pastes, foams, tinctures, drops, sprays, and dispersions. Examples are capsules containing from about 0.05 g to about 1.0 g combination of syrosingopine and metformin or other biguanides... In the case of an individual having a bodyweight of about 70 kg the daily dose administered is from approximately 0.05 g to approximately 3 g, preferably from approximately 0.25 g to approximately 1.5 g, of a combination of the present invention.

The paragraph “from approximately 0.05 g to approximately 3 g is not very useful because it could theoretically be as high as 2.9 gr of metformin and 100 mg of syro which would be impossible to handle.

But the next one is very important as it sets a much lower “preferable” upper limit: preferably from approximately 0.25 g to approximately 1.5 g, of a combination

This set the maximum combination of both medicines as 1,500 mg, most of which would be metformin. It doesn’t say how much syro would be in that 1.5 gr. But taking the “preferred” ratios stated elsewhere in the patent:

"1 to 10 and 1 to 1′000, preferably between 1 to 100 and 1 to 200, such as a combination of 1 to 130"

The ratio syro to metformin would be between 1/200 and 1/100 or .5% and 1%.

And now the range of each medicine can be culled out by using a little bit of algebra.

The patent states that the “preferable”  maximum combo daily weight stated of 1.5 grams. So, we can write that S+M<1500 mg where S is the daily dose of syro and M the daily dose of metformin.

Taking the maximum weight we can write that S+M­=1,500 mg

Taking the 1% upper range of their proportions we can write: S/M < 1/100 =.01

And taking the lower range of their proportions we can write S/M> 1/200 = .005

If S/M= .005 then S= .005*M and replacing it in the first formula: .005*M+M = 1,500, thus  1.005*M = 1,500

Then M= 1500/1.005 = 1,492.5 mg and therefore S = .005*1,492.5 = 7.46 mg of syro (minimum daily amount)

On the upper end, if S/M= .01 then S= .01*M and replacing it in the first formula:    .01*M+M = 1,500,  1.01*M = 1,500

Thus M= 1,500/1.01 = 1,485.15 mg and S = .01*1,492.5 = 14.85 mg

Therefore, syro would be between 7.46 and 14.85 mg a day and metformin would be between 1,485.15 and 1,492.5 mg a day for an individual having a body weight of about 70 kg

These quantities are stated for capsules in the ap so there would be no need to correct them for injections as in the mice quote above.

One has to assume that the numbers used in the patent ap refer to pure metformin and pure syrosingopine, excluding the parts of the substance that are not active in the commercially available pills, as well as excipients. This has to be adjusted accordingly.

For example, if one takes the Sustained Release Glucophage SR 750 mg pills, they have 750 mg of its “active ingredient” Metformin Hydrochloride. But when one removes the hydrochloride portion, which is not really active against cancer, it is equivalent to only 585 mg of Metformin as stated on the box. In the case above, if one wants to take 1485 mg of metformin then one would take 1485*750/585 = 1,903 mg of the pills, approximately 2,000 of the standard Glucophage SR.

The lower part of this syrosingopine range can probably be tolerated by a large number of patients unless they suffer from hypo-tension. Some people may need to drink coffee or take caffeine pills to counter the blood pressure drop. But everyone should be monitored by a doctor to make sure there are no complications and to ensure it is working enough to offset the side effects and risks.

3- FINE TUNING THE NUMBERS:

If the ratio 130 is included in the ap as a good faith, valid clue to the optimal combination and not just as a random example, then the range of syro and metf in the above solution could be fine-tuned for the “preferable”  upper limit:

S+M=1500 mg = the maximum combination of both medicines

S/M= 1/130 = .0077

Then S= .0077*M and replacing S in the first formula: .0077*M+M = 1,500,  1.0077*M = 1,500

Thus M= 1500/1.0077 = 1,488.55 mg and S = 1,500-1,488.55 = 11.45 mg

Therefore,  the amount of syro would be 11.45 mg a day and the amount of metformin would be 1,488.55 mg a day at the “preferable” upper dosage for an individual having a body weight of about 70 kg

Now, these are maximum "preferable" amounts (max 1.5 gr a day) so if I weighed 70 kg I would not go above them. People with different weights can prorate these values for their weights.

Unfortunately there seems to be no mentions of minimum doses in the patent ap. If anyone sees anything about it, please let us all know so that we can figure out the lower limits.

Also, doses that are lower than the above but are close enough are probably effective although nothing is said about how low one can go. The patent does not talk about the effectiveness of doses above these limits either.

As an example, for a 45 Kg person (weight ratio 45/70 = .643) the syro would be between 4.80 and 9.55 mg a day and pure metformin would be between 954.74 and 959.46  mg a day equivalent to 1,230 mg of commercial Glucophage SR or approximately 1,250 mg. At the 1 to 130 ratio the syro would 7.36 mg a day and metformin would be 956.93mg a day or approximately 1,250 mg of Glucophage SR.

Everyone is invited to check the patent and to do their own calculations because there may be mistakes above.

4- REALITY CHECK:

Steven K, the guy who posted how he beat his incurable mesothelioma just with syromet after it had resisted standard therapies said he was taking 9 mg of syro a day in 3 takes of 3 mg each and 2,000 mg of Metformin pills a day. So, he seems to be within the above parameters although below the “preferable” level.

Of course one has to remember that every person and every cancer are different and may therefore react differently to the same medication and dose.


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toobs1234
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28/05/2020 1:31 am  

@gge

Interesting! When I first saw the patent numbers you are referring to, I noticed that they roughly corresponded with the practical range of human dosing of both syro and metformin and assumed that the numbers were driven by that rather than any insights on optimal human dosing. Perhaps I was wrong. We also don't know the pharmacokinetics of syro...maybe it has a 28 day half life and 100% absorption? We have now positive (Steve) and negative (Shirley) results. Maybe the difference is the level of MCT1 expression? Or maybe it is gamma enolase.


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GgE
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28/05/2020 5:50 am  

Thank you Johnny and another member who previously posted info in this forum regarding syro dosage from the patent application


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John Pizzuto
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29/05/2020 2:58 am  

@gge

Are we off by a factor of 12, or are we good?

I did a search on the body area dosing scheme and found this article:

https://web.ics.purdue.edu/~jfleary/nanomedicine_course_2011/Lecture_9%20Drug%20Delivery/References/Miller-Body%20Surface%20area.pdf

From the article:

"Is the continued use of body surface area based on scientific data and, therefore, rational? The work by Baker et al. (2) in this issue of the Journal suggests no on both counts."


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GgE
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29/05/2020 9:20 am  
Posted by: @jpizzuto

Are we off by a factor of 12, or are we good?

I always think of these conversion values as gross estimators that give you an idea of the human dosage as a starting point, not as an exact value. In other words, to me they mean that a human's therapeutic dose is probably of the order of 12 times smaller than a mouse's, and not just 2 times or 40 times larger. This means that it is around 12 times larger, but can easily be 10 times or 15 times larger.


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toobs1234
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31/05/2020 10:09 pm  

Well I spent a few days trying to find some kind of indication about the pharmacokinetics of Syrosingopine. I didn't find anything definitive, but what little I did find wasn't good news:

- Syro is an analogue of Reserpine. Syro is about 1/5th as effective as Reserpine gram per gram in lowering blood pressure. This could be due to lower oral absorption or the molecule is less effective in reducing hypertention or a combination

https://www.ncbi.nlm.nih.gov/pubmed/?term=14408654

 

- Reserpine has a 50-70% absorption rate, a half life of 5 hours, and a terminal half life of 200 hours

https://www.drugs.com/pro/reserpine.html

 

- Clinical oral versus intramuscular dosing (human):

intramuscular injection: The amount, usually limited by postural hypotension or other symptoms related to the drug's administration, ranged from 1.5 to 6 mg./day and averaged 4.8 mg./day. 

oral dosing: 41 of 56 patients received 6-12 mg per day of syro (average 9.2), 43% of the patients developed side effects, these side effects largely consisted sedation, nasal congestion and nervousness.

so not directly comparable, but around 1:2 ratio

https://www.ahajournals.org/doi/pdf/10.1161/01.RES.9.5.989

https://www.ncbi.nlm.nih.gov/pubmed/?term=14408654

 

- the lethal dose of syro, 50% kill for mice is:

1293mg/kg oral
101mg/kg Intraperitoneal
281mg/kg subcutaneous

The fact that the oral dose is so much higher could imply that oral absorption is low or that absorption is via a diffusion process, which gets saturated at high levels.

https://www.drugfuture.com/toxic/q142-q773.html

 

- the only direct comparison of oral versus injection dosing is for a single human subject. The following chart shows blood pressure under various doses of syro alone and in combination with hydrochlorothiazide:

patient P.G. dose of syro
  3mg oral 6mg oral 3mg subcutaneous
Syro only 210/118   180/120
Syro+Hydrochlorothiazide 199/106 185/110 90/70

the oral dosing is chronic, whereas the injected dose was 4 hours after a single dose.

for equal doses of syro alone, injection is more effective. However, with Hydrochlorothiazide, a 3mg injection is also significantly more effective than a 6mg oral dose.

Although they don't show the data in the paper, the authors say that they 1mg of reserpine injected was about as effective as 3mg of syro injected in terms of lowering blood pressure. However, when orally dosed, the reserpine is significantly more effective. This could well imply that the oral absorption of syro is significantly worse than that of reserpine.

the authors had this to say:

"Our observations suggest that syrosingopine is either poorly absorbed or inactivated in the intestinal tract."

https://www.nejm.org/doi/full/10.1056/NEJM19601208263230 3"> https://sci-hub.tw/https://www.nejm.org/doi/full/10.1056/NEJM196012082632303

 

- there is a paper that looked at oral dosing in dogs, but I couldn't find a copy. Every other animal study I found was injected. If anyone has access to this, it could be interesting...

PLUMMER, A. J.; BARRETT, W. E.; MAXWELL, R. A.; FINOCCHIO, P.; EARL, A. E., AND LUCAS, R. A.: Hypotensive properties of syrosingopine, Su-3118, an ester of methyl reserpate, Arch. internat. de pharmacodyn. 119: 245, 1959.


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GgE
 GgE
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31/05/2020 11:22 pm  
Posted by: @toobs

the authors had this to say:

"Our observations suggest that syrosingopine is either poorly absorbed or inactivated in the intestinal tract."

Thanks for posting so much interesting info on syro. Great job! Is there anything in it that makes you pessimistic about this combo?

I do not worry about syro having low intestinal absorption. Commercial syrosingopine sold as "Singoserp" was made as 1 mg pills was sold for a couple decades to lower blood pressure. It'd not have lasted that much if it was not absorbed and effective. In addition, in our forum, Pizzuto has usually seen his wife's pressure drop quite a bit shortly after oral administration of syro, indicating that it had been absorbed and that it was causing systemic effects. 

I have not found data on syro's half-life in the human body but my guess is that it must not be just a few hours because it accumulates for days and only after 2 weeks you feel the full effects. Unless it is some metabolite or another factor that accumulates rather than the syro itself. The PDR of 1974 stated:

"Dosage and Administration: The suggested initial dose is 1 to 2 tablets (1 to 2 mg) daily in single or divided doses. Some patients may require and tolerate 3 and more tablets daily.

Since the drug has both a gradual onset and prolonged duration of effect, a trial of at least 2 weeks with the starting dose is indicated for proper evaluation of results.

The usual dose for long-term maintenance therapy in most cases is from ½ to 3 tablets (0.5 to 3 mg) daily.

Since the antihypertensive effects of syrosingopine are not immediately apparent, maximal reduction in blood pressure from a given dosage of the combination may not occur for 2 weeks. At this time the dosage should be adjusted to the amount necessary to sustain the desired blood pressure response."

In regards to the oral dosing article you may want to contact a medical library. They may have the original journal in their archives.


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toobs1234
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01/06/2020 1:04 am  

Hi GgE,

I don't want to be negative. I just want to be realistic. There are soooo many research articles that show anti-cancer effects of drugs or natural chemicals, but at concentrations that will never be able to be achieved by us. But then so many people take them hoping they will work.

In the case of Metformin and Syro I am very hopeful. As I said already, I'm not worried about achieving high enough levels of Metformin. Metformin has been shown to accumulate in mitochondria at high levels because of the mitochondrial membrane potential...so even though we will never achieve the plasma concentrations that the researchers used in the papers, I believe those levels or higher should be easily achieved in mitochondria. I did a calculation, which unfortunately I didn't save, which implied that even if 100% of the Metformin dose (5mM as I recall) used in the in vitro experiments was absorbed into the mitochondria, it would still be half as much as the Metformin concentration found in prostate tissue, even though we are lucky to achieve a plasma concentration of Metformin of 50 uM in practice.

In the case of Syro, though, we know almost nothing about the pharmacokinetics. We should be skeptical, though for the simple reason that at one point in time, there were a lot of diabetics with high blood pressure who probably were prescribed both syro and metformin and yet there were no reports of spontaneously disappearing cancer.

The references I listed above are by no means conclusive, but they suggest that syrosingopine does not appear to be well absorbed, to have a long half life, or to accumulate in tissue simply because a one-time 3mg injection significantly outperforms a chronic 6mg daily oral dose.

There is so little we know about syro, so we cannot possibly say for sure. My personal view is that it's not realistic that we can achieve the levels that were used in the research and that appear to be required to have an effect as long as MCT1 is at least partially expressed. It's a big leap for me to assume that because the dosing numbers in the patent are in the normal range of Syro dosing that the authors have unplublished information indicating that these dose levels will work in humans consistently.

Now the saving grace is that the triple combination with an MCT1 inhibitor requires a much lower concentration of syro that in fact may be achievable. There is at least one such inhibitor in development that they showed worked and Diflunisal may in fact also...fingers crossed. Or for those lucky ones with inactive MCT1, the required dose may be easily achievable.

I hope that is useful. Again, I'm not trying to be pessimistic. I just want to realistic.


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