Sunday 21 January 2018

Improvement of the ketogenic diet


In many studies, it has been shown that a ketogenic diet can be a useful supplement in the treatment of glioblastoma. I would like to discuss the improvement of this diet on the basis of recent research.

1. Ketogenic diet + α-lipoic acid and hydroxycitrate
2017 https://www.ncbi.nlm.nih.gov/pubmed/28122260
"To decrease anabolism, glucose uptake should be reduced (ketogenic diet). To increase catabolism, the oxidative phosphorylation should be restored. Treatment with a combination of α-lipoic acid and hydroxycitrate has been shown to be effective in multiple animal models."

2016 http://crescopublications.org/pdf/CROOA/CROOA-2-019.pdf
"Combination of Metabolic Treatment of Aggressive Primary Brain Tumour
and Multiple Metastases of the Brain"
"We report the cases of 12 patients with advanced brain tumor. They were all treated with
conventional treatment and a combination of sodium R lipoate (800 mgbid), hydroxycitrate at 500 mg tid and low-dose naltrexone at 5 mg at bedtime. Eight patients had primary brain tumour (n=8 including five glioblastomas) four patients had multiple brain metastases."

2. Ketogenic diet + Fenofibrate ?
2016 https://www.ncbi.nlm.nih.gov/pubmed/26869992
"Our results reveal a new, intriguing aspect of cancer cell biology and highlight the benefits of fenofibrate as a supplement to both canonical and dietary (ketogenic) therapeutic approaches against glioblastoma."
2015 https://www.ncbi.nlm.nih.gov/pubmed/26172294
"Given that fenofibrate is a widely used non-toxic drug, we suggest its use in patients with glioblastoma multiforme (GBM)."
2017 https://www.ncbi.nlm.nih.gov/pubmed/28459367
"...the lipid-lowering agent fenofibrate...have potential to lower synthesis or effects of G(M)-CSF and thus deprive a glioblastoma of some of the growth promoting contributions of bone marrow and G(M)-CSF.
It's strange, but in this blog I did not find any information about Fenofibrate. So is it necessary to add it to the ketogenic diet?

3. Ketogenic diet + Inhibition of glutamine metabolism ?
2017 https://www.ncbi.nlm.nih.gov/pubmed/28720668
"Inhibition of glutamine metabolism slows the in vitro and in vivo growth of GLNHigh GBM cultures despite metabolic adaptation to nutrient availability, in particular by increasing pyruvate shuttling into mitochondria."
"...the pleiotropic metabolic inhibitor EGCG, targeting glutamine metabolism, specifically reduces tumor proliferation, in vitro and in vivo, of mesenchymal GLNHigh cells."
How can the findings of this study be used? Only EGCG can not inhibit glutamine metabolism. Maybe there are more options?

4. Ketogenic diet + Specialized medium-chain triglycerides (MCT) ?
2016 http://clincancerres.aacrjournals.org/content/22/10/2482
"MCTs were specifically chosen based on carbon chain lengths (C8:C10::97%:3%), which allow them to rapidly diffuse from the gastrointestinal tract into the hepatic portal system and travel directly to the liver where they are converted into ketone bodies."

5. What other ideas can you offer to enhance the effect of a ketogenic diet?

31 comments:

  1. About inhibiting glutamine - we are using sulfasalazine (1-1,5g every 8 hours) right now and (subjectively) it works very well for us. There is a few publications on that option on pubmed.

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    Replies
    1. Sulfasalazine inhibits the glutamate-cystine exchanger. This exchanger (system xc, catalytic subunit xCT encoded by the SLC7A11 gene) allows GBM cells to take in more cystine for manufacturing glutathione in order to better deal with oxidative stress. The result is a buildup of glutamate around the tumor which aids tumor invasion and contributes to seizures.
      The purpose of sulfasalazine is therefore not the same as the one discussed in this study, but somewhere more than half of GBMs have high expression of SLC7A11 and in these cases one gram per day of sulfasalazine could be beneficial. SLC7A11 is also one of the resistance mechanisms to CBD (cannabidiol) therapy in mouse studies.

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    2. Recently published is such an interesting article:
      "Combination Therapy with Sulfasalazine and Valproic Acid Promotes Human Glioblastoma Cell Death Through Imbalance of the Intracellular Oxidative Response."
      2018 Jan 19. https://www.ncbi.nlm.nih.gov/pubmed/29349577

      Delete

  2. From various pharmacokinetic studies of fenofibrate:
    "No unchanged fenofibrate is detected in the plasma following oral administration" "Fenofibrate is metabolized in several stages. First, the carboxyl ester moiety is cleaved by hydrolysis, resulting in fenofibric acid, the main pharmacologically active compound"

    After standard single doses of fenofibrate, peak plasma concentrations of fenofibric acid are around 14 micromolar, however 99% of this is bound to plasma proteins (see DrugBank), leaving on the order of 140 nanomolar free fenofibric acid in the plasma.

    Compare this with in vitro studies using 50-100 micromolar of fenofibrate. Perhaps this is why in the second study, they had to inject the fenofibrate directly into the tumor, rather than administer it systemically. None of the preclinical work I've seen on fenofibrate has been sufficiently convincing in my opinion.

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  3. Ketogenic diet + hyperbaric oxygen:

    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065522

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  4. The 110 micromolar concentration of EGCG used in the other study is highly unrealistic, unless you perhaps planned on doing intravenous EGCG injections.

    Maximum plasma concentrations of EGCG after a typical dosing (800 mg) is more on the order of 1 micromolar. Concentrations entering the central nervous system would be much less.

    I don't understand why they would go to the trouble of doing a mouse study, when they pre-treat the cells with high concentrations of EGCG before injecting the cells into the mice. That is not any better than an in vitro study.

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    Replies
    1. This isn't to say I'm opposed to the use of EGCG. There's a more well-designed study showing co-operative effects of EGCG + TMZ in a mouse study, after oral administration of TMZ and EGCG. In this case a completely different mechanism was identified for EGCG: inhibition of GRP78 (which alleviates ER stress and helps cells resist TMZ treatment).

      https://www.ncbi.nlm.nih.gov/pubmed/21257259

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  5. The work done at the University of Florida with the modified diet (with half the fat calories coming from MCT oil) and getting comparable results with the straight ketogenic diet is very interesting.

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  6. 2016 http://crescopublications.org/pdf/CROOA/CROOA-2-019.pdf
    "Combination of Metabolic Treatment of Aggressive Primary Brain Tumour
    and Multiple Metastases of the Brain"
    "We report the cases of 12 patients with advanced brain tumor. They were all treated with
    conventional treatment and a combination of sodium R lipoate (800 mgbid), hydroxycitrate at 500 mg tid and low-dose naltrexone at 5 mg at bedtime. Eight patients had primary brain tumour (n=8 including five glioblastomas) four patients had multiple brain metastases."

    So what is better: α-lipoic acid or R lipoic acid?

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    Replies
    1. 800mg R lipoate twice a day - that's a lot, do not you think so?
      I bought this:
      https://www.iherb.com/pr/Thorne-Research-R-Lipoic-Acid-60-Veggie-Caps/18591

      1 capsule 100 mg. It seems to me that this is a lot - 16 capsules a day!
      What do you think?

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    2. As a hydroxycitrate, I bought this:
      https://www.iherb.com/pr/Jarrow-Formulas-HCActive-Garcinia-Cambogia-Extract-90-Veggie-Caps/56614
      I hope it's not a bad choice.

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    3. R-lipoic is one form of α-lipoic acid. See my comments of the clinical study in the "Metabolic therapy with Sodium R lipoate plus hydroxycitrate" in Chapter 7 of the 2017 version of Treatment Options for GBM...

      http://virtualtrials.com/pdf2017/treatment_options_gbm_2017.pdf

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    4. That is a lot of capsules to take in one day. Is it possible to open up the capsules and empty their contents into a glass of water?

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    5. Thanks for the advice! I'll try.
      Or maybe I'll buy capsules of a larger mass.

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    6. Thank you for reminding me of your book. I read it, everything is written in great detail!

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    7. Does anyone know how to take R-lipoic acid and Hydroxycitrate? Before meals, during meals, after meals? Together or separately? Everywhere is written differently! (

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    8. By the way, such an unpleasant feature of R-lipoic acid is possible.

      2017 https://www.ncbi.nlm.nih.gov/pubmed/28984160
      "Thus, high-dose R-lipoic acid could induce autophagy in platelets through modulating the activity of class III PtdIns3K, which was associated with decreased count of circulating platelets and shortened lifespan of platelets."

      The suggested dose in this study is 800 mg twice daily.
      http://crescopublications.org/pdf/CROOA/CROOA-2-019.pdf
      We started taking this dose and I hope this does not affect the platelets.

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  7. Hi, the alpha lipoic and hydroxicitrate combination can be enhanced by adding Capsaicin supplement. I cannot find the link but it was documented by Laurent Schwartz. Hope this helps.

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    Replies
    1. Thanks for the offer! By the way, here is the study:

      2012 https://www.ncbi.nlm.nih.gov/pubmed/22797854
      "Tumor regression with a combination of drugs interfering with the tumor metabolism: efficacy of hydroxycitrate, lipoic acid and capsaicin."

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  8. We are also folowwing right now a Ketogenic diet + α-lipoic acid and hydroxycitrate.
    We try to enhance it with callorie restriction and intermittent fasting.
    Alpha-lipoic and hydroxycitrate are listed as Calorie Restriction Mimetics.
    I have read that Curcumin and Resveratrol also act as CRMs so we added that too in our daily intake.

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    Replies
    1. when do you take α-lipoic acid and hydroxycitrate and in what dose?

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  9. 2x300mg ALA(Jarrow) +2x500mg HCY(Solgar) in the morning. Same dose in the evening.

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  10. I was reading in a post that under Glucose restriction, acetate may become the fuel for tumor growth. It was proposed there the use of tocotrienols from Vitamin E as inhibitors.
    I have not decided yet about using Vitamin E as i read mixed opinions so far...

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    Replies
    1. In one study vitamin E had a negative association with survival in brain tumors. The theory was that because vitamin E is lipid soluble, it has an easier time getting into the brain, and its potent antioxidant activity could protect cancer cells from conventional therapy.

      "There is a lack of established scientific research in the field,
      but one possible hypothesis is that the antioxidative effects of vi-
      tamin E may potentially antagonize the therapeutic effects of ra-
      diation therapy by interfering in the oxidative stress-induced
      killing of cancer cells by radiotherapy agents. In the present
      analysis, vitamin E was the only antioxidant shown to have an in-
      creased association with mortality."

      "A possible explanation is that vitamin E, in contrast
      to these other antioxidant compounds, is a lipid-soluble mole-
      cule. Lipid-soluble molecules are more readily able to diffuse
      across the blood-brain barrier and are therefore more likely to
      exert their effects on the brain tissues. Further research is war-
      ranted to confirm the present results."

      Complementary therapy and survival in glioblastoma
      https://www.ncbi.nlm.nih.gov/pubmed/26649185

      I've not seen these observations validated by other studies.

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  11. This article seemed to me interesting:
    2015 https://www.ncbi.nlm.nih.gov/pubmed/26306884
    "Ketosis may promote brain macroautophagy by activating Sirt1 and hypoxia-inducible factor-1."

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  12. A very interesting article is a report on the treatment of a patient with a ketogenic diet and some supplements!

    2018 https://www.frontiersin.org/articles/10.3389/fnut.2018.00020/full

    "In this case report, we describe a favorable therapeutic response to KMT and other treatments targeting metabolism in a 38-year-old man with GBM and metabolic imbalances. KMT is a nutritional anti-neoplastic intervention involving ketogenic or low-glycemic diets for managing malignant gliomas."

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    Replies
    1. Yes interesting. Unfortunately there was no information on IDH1 status available for this patient, all the more necessary due to the younger age of the patient (more likely to have the mutation).

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    2. Hello. Already sent you an email with setting me up as an author. Dont know if you got this. My Boy has rare medulloblastoma. Searchng for CMyc inhibitors and new trials. Will post full story when you’ll add me. Thanks.

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    3. I just added you to the author list. Look for an email with an invite in your inbox or spam folder. You're welcome to post, but I'm not sure if there are any other medulloblastoma caregivers on this blog (I haven't heard of any, most people here are dealing with gliomas). But other medulloblastoma caregivers might see your post through google searches etc.

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  13. Some interesting articles Semyon. Hopefully Keto research will continue to develop and more research will get done.

    For anyone doing Keto I'd strongly suggest getting setup with a blood testing device such as Abbott Precision Xtra, or the possibly the new Keto-Mojo. This is because most of the research points to higher efficacy the deeper you are in ketosis (to a point of course).

    The issue is that the rest of the cells in your body will switch to ketone metabolism before your brain and this glucose sparing behavior means a mildly ketotic state may have little effect on brain cancer. If you get a test meter and work on the diet you find it is actually pretty hard to stay in the 'target zone' and that you have to really fine tune what foods you can/cannot eat, how much you eat, how much you exercise, etc. Its unfortunately a fairly big commitment.

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  14. The role of ketogenic diets in the therapeutic management of adult and paediatric gliomas: a systematic review

    2018 https://www.futuremedicine.com/doi/10.2217/cns-2017-0030
    "the evidence for effectiveness and acceptability of various KDs is insufficient to suggest they have a therapeutic effect in the management of gliomas"

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