Monday, 1 January 2018

Drug for a cocktail before bedtime?


Melatonin, agomelatin, imipramine, amitriptyline or something different?

As I can see, many patients take 20mg of melatonin before bedtime.

However, as written in CUSPND
"Agomelatine’s circulating half-life in humans is ~2hours versus 30 to 40 minutes for melatonin. This is a significant advantage of agomelatine. Further complicating the use of melatonin would be the variable and generally poor absorption after oral administration. Agomelatine penetrates the blood-brain barrier."

This study (https://www.ncbi.nlm.nih.gov/pubmed/28500556) compared agomelatine and other drugs and concluded that the most effective for glioblastoma - imipramine or amitriptyline.

However, here (https://www.ncbi.nlm.nih.gov/pubmed/27480195) on the contrary it is reported "that imipramine and tranylcypromine reduced the cytotoxic efficacy of temozolomide under some oxygen conditions while fluoxetine did not demonstrate such effects".

So which of these drugs should be added to the cocktail before bedtime?




16 comments:

  1. Richard Kast (author of the CUSP9 protocols) first introduced agomelatine into CUSP-ND. I agree with his assessment that it is likely superior to melatonin for the reasons listed. The main advantage of melatonin is that it can be purchased without a prescription.

    The study you linked to comparing the effects of various antidepressants is one that I would glance at, check which drug concentrations were being used, and then probably not even bother reading once I've seen they are testing these drugs at 10 micromolar, unless they can back up the observations in vivo. Plasma concentrations of these drugs is in the hundreds of nanomolar range, with free plasma concentrations in the single digit or tens of nanomolar range. While micromolar levels of these drugs have been achieved in human or animal brains, the unbound fraction of these drugs in the brain is typically well under 1%. This is the same problem with most in vitro work: the drug concentrations showing effects in vitro are often far from achievable in vivo. In vitro work usually has to be taken with some huge boulders of salt.

    There is some in vivo evidence for imipramine in a genetically engineered mouse model:
    https://www.ncbi.nlm.nih.gov/pubmed/26412325

    And a mouse model showing efficacy of fluoxetine:
    https://www.ncbi.nlm.nih.gov/pubmed/25671301

    CUSP-ND includes both agomelatine and fluoxetine, but this cocktail hasn't been tried in humans.





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    Replies
    1. Stephen, would you advise against agomelatine then?
      My dad is currently taking 10 mg of melatonin at bedtime but I've been considering agomelatine lately and wondering if it would be a smart and better choice.

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    2. My mother began taking agomelatine 25mg to sleep. Now she drinks 50mg before bed.

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    3. I would not advise against agomelatine. As I mentioned, agomelatine may be superior to melatonin for the reasons quoted in the post.

      The description of agomelatine within the CUSP-ND document can be found here:

      http://www.anticanceralliance.com/cusp-nd/ (click on the "Science" tab)

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    4. I know, I know, I’ve read the CUSP-ND protocol and it’s what made me consider agomelatine. I was just asking because of your last “warning” about not have been tested in humans.
      So... should I dump melatonin and go for agomelatine? It makes perfect sense from a theoretical point of view and I’m really tempted...

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    5. I wasn't trying to warn anyone off agomelatine, I was just noting that the entire CUSP-ND protocol has not been tried in humans before, the way CUSP-9 has.

      Agomelatine is worth a try if you can get the prescription.

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    6. Thank you Stephen, I'm sorry if I misunderstood what you said.
      I guess what I really wanted to know was if I would be losing any advantage of melatonin by giving agomelatine instead. And since we're talking about this, how much should I start with? TIA

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    7. Both melatonin and agomelatine are potent agonists of both MT1 and MT2 receptors, and molecule for molecule, agomelatine looks like it is a somewhat more potent agonist especially at MT2. Agomelatine also has superior pharmacokinetics versus melatonin, although there may be special formulations of melatonin (prolonged-release melatonin) with better bioavilability and longer half-life versus agomelatine. I don't have a strong opinion on using agomelatine versus a prolonged-release form of melatonin. Agomelatine also has 5-HT2C serotonin receptor antagonist activity, but I don't know if that has any implications on glioma biology.

      For agomelatine dosing I would follow the guidelines given by the EMA, starting with 25 mg once daily at bedtime and increasing to 50 mg once daily after a week or two.

      http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000915/WC500046227.pdf (see under "posology and method of administration"

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    8. Once again, thank you very much for your answer Stephen!

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  2. Mitochondria Transcription Factor A: A Putative Target for the Effect of Melatonin on U87MG Malignant Glioma Cell Line.
    2018 https://www.ncbi.nlm.nih.gov/pubmed/29747444

    "Our results confirm the hypothesis, and also show that melatonin reduced the expression of other mitochondrial transcription factors mRNA (TFB1M and TFB2M) and interfered with mtDNA transcription. Moreover, melatonin delayed cell cycle progression and potentiated the reduction of cell survival due to treatment with the chemotherapeutic agent temozolomide. In conclusion, elucidating the effect of melatonin on TFAM expression should help to understand the signaling pathways involved in glioblastoma progression, and melatonin could be potentially applied in the treatment of this type of brain tumor."

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  3. https://www.ncbi.nlm.nih.gov/pubmed/29925764
    http://www.mdpi.com/2305-6320/5/2/58/pdf
    page 10:

    "In contrast, melatonin had a robust anti-proliferative response in both our cell lines—both when used as an individual agent and as pre-treatment to TMZ—consistent with other studies demonstrating the beneficial effects of melatonin combined with other chemotherapeutics and in other cancer types [30,31]. One concern, however, is that the commonly used concentration of melatonin (1 mM) may not actually be physiologically attainable [32,33]. Therefore, we included three different concentrations to address this issue. We observed a synergistic effect from melatonin 1 mM, as well as at the lower concentration of 50 nM. The 50 nM dose closely mimics physiological levels (54 nM) for patients taking melatonin 20 mg orally [34]. Interestingly, melatonin 1 µM did not exert any significant effect, replicating literature reports of antioxidants’ variability of actions [35]. Anti-oxidants, melatonin included, may directly scavenge free radicals in high (mM) concentrations. Conversely, at low (nM) concentrations, melatonin can act through receptors to increase the activity and expression of enzymes. [36–38] Hence, we see increased GPх1 activity at 50 nM, but not at 1 mM."

    This is part of the just published study. Hard to understand( How can this be interpreted?

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    Replies
    1. "One concern, however, is that the commonly used concentration of melatonin (1 mM) may not actually be physiologically attainable"

      May not? The only way I could see this being possible would be with direct intratumoral injection of high dose melatonin. I have no clue how 1 mM became a common concentration to test melatonin at. It's only 10,000 times higher than what is found in the plasma with normal doses taken orally.

      GPx1 stands for glutathione peroxidase 1, an antioxidant enzyme that reduces hydrogen peroxide to water. The last statement is saying the low concentration of melatonin increases activity of this antioxidant enzyme while the high concentration doesn't.

      Most important is that the reasonable concentration of 50 nM melatonin decreased proliferation in the two GBM cell lines (melatonin alone versus control; and melatonin + TMZ versus TMZ alone).

      See also:
      https://www.ncbi.nlm.nih.gov/pubmed/26510398
      Melatonergic system-based two-gene index is prognostic in human gliomas.

      where lower melatonin synthesis in gliomas (TCGA RNAseq data) correlated to poor survival and higher melatonin synthesis correlated to better survival.




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    2. Stephen, thank you very much for your reply!

      After 3 cycles of Lomustine (2 cycles with a low dose of temozolomide and 1 cycle of only lomustine), we are now planning to start 5 days only with temozolomide 200 mg / m2.

      To strengthen temozolomide (in addition to other additives) instead of melatonin I want to use agomelatin. It has a higher affinity for both M1 and M2, with a pKi of about 10 nM, than does the natural ligand and longer half-life - about two hours.

      However, every day my mother takes fluoxetine 40 mg. On the site drugs.com, I do not find the interactions between these two antidepressants, since agomelatine is not cheered by the FDA.

      Agomelatine is 90% metabolized in the liver with cytochrome P450 1A2 (CYP1A2) and 10% with CYP2C9 / 19.
      Fluoxetine is metabolized in the liver by cytochrome P450 isoenzymes, including CYP2D6. Fluoxetine is an inhibitor of CYP3A4.

      So, probably there are no interactions between fluoxetine and agomelatine? At least for 5 days?

      Cmax of Agomelatine in blood plasma is achieved after 1-2 hours.
      Cmax of Fluoxetine in blood plasma is reached after 6-8 hours.
      Cmax of Temozolomide in blood plasma is achieved after 0.5-1.5 h.

      So I think about taking Fluoxetine 40mg for 6 hours before taking Temozolomide and Agomelatine 50mg for 0.5 hours before taking Temozolomide.

      Your opinion?

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    3. Excellent article on the interaction of antidepressants:
      https://www.progressnp.com/article/antidepressant-drug-interactions-evidence-clinical-significance/
      It seems that there are no interactions between agomelatine and fluoxetine.

      I think more about replacing Melatonin with Agomelatine on the days of taking Temozolomide against the background of a constant intake of fluoxetine.

      The synergies between melatonin and temozolomide are indicated by these studies:

      https://www.ncbi.nlm.nih.gov/pubmed/29925764
      "Do Anti-Oxidants Vitamin D3, Melatonin, and Alpha-Lipoic Acid Have Synergistic Effects with Temozolomide on Cultured Glioblastoma Cells?"

      https://www.ncbi.nlm.nih.gov/pubmed/29747444
      "Melatonin delayed cell cycle progression and potentiated the reduction of cell survival due to treatment with the chemotherapeutic agent temozolomide"

      https://www.ncbi.nlm.nih.gov/pubmed/23632480
      "Combinations of melatonin and chemotherapeutic drugs (including temozolomide, current treatment for malignant gliomas) have a synergistic toxic effect on BTSCs and A172 malignant glioma cells."

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    4. You did well to check for pharmacokinetic interactions between agomelatine and fluoxetine (does one drug inhibit or induce the metabolism of another drug?). Other types of interactions are possible. You can look up class interactions (do melatonin receptor agonists interact with SSRI antidepressants) at drugs.com by including ramelteon in your search (which is an FDA approved melatonergic drug).

      Drugs.com gives a moderate interaction rating on this and the generic comment "MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients." There is no specific literature or warnings about combining melatonergic drugs with SSRI antidepressants.

      Regarding the timing of ingestion, the time to Cmax can be used as a rough guideline, but there's more to consider than just that. Some drugs cause downstream effects within cells that may peak hours after their peak plasma levels are reached, so I wouldn't worry about being too precise with the timing.

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    5. Thank you very much, Stephen for your comment and your time, which you give every day to this blog and people who come here for a bit of hope.

      I decided to take agomelatine 1 hour before temozolomide. I hope this does not affect on the bioavailability of temozolomide, since it should be taken on an empty stomach.

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