Saturday, 1 August 2015

Mebendazole as an anti-cancer agent

Dear all,

I am wondering if someone here is taking mebendazole?

http://www.ncbi.nlm.nih.gov/pubmed/25594199

There is some preclinical data and also a clinical study ongoing...

https://clinicaltrials.gov/ct2/show/NCT01729260?term=Mebendazole&rank=1

Best,
Katja

15 comments:

  1. Mebendazole has looked reasonably effective in several brain tumor mouse models. However mice and humans may have very different metabolism of the drug. In humans, very high doses of mebendazole are likely required to achieve therapeutic concentrations in the plasma. Doses on the order of 100mg/kg/day (a mega-dose) might be required to get enough of the unmetabolized drug in the bloodstream to see any therapeutic benefit. The safety of taking such a high dose in the context of a cocktail with multiple other drugs is unknown.

    http://www.ncbi.nlm.nih.gov/pubmed/7094986

    This paper shows that mebendazole is extensively metabolized in humans with very little unmetabolized drug making it into the bloodstream, even after high doses. I will add this paper to the pharmacokinetics folder of the Brain Tumor Library.

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  2. I could be wrong about mebendazole, but it's not near the top of my list due to its sub-optimal pharmacokinetic profile. On the other hand, it is extremely well-tolerated (probably due to its low bioavailability).

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  3. And finally, I would not add it to a cocktail at the mega-dose referenced above, but start much lower. The high plasma protein binding of mebendazole means that taking it with other drugs with high plasma protein binding could lead to higher levels of free drug in the bloodstream. This could potentially increase both the efficacy of mebendazole, as well as the risk for adverse side-effects.

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  4. Hi Stephen,
    I see you point regarding the bioavailability. We'll see if the clinical studies will show any benefit. There are couple of positive case reports, but not with gliomas.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096024/#ref19

    Best,
    Katja

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  5. My dad uses 200 mg a day, he started today !

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  6. As Chemo/Radio did not work for my GBM4, will be adding membendazole to a list following my second resction next week. It not at the top of my list, but 'worth a punt' in my mind. Favoured by the slightly infamous London Care Oncology Clinic IRRC.

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  7. The clinical trial (Mebendazole+TMZ) was completed, but the results were not published: https://clinicaltrials.gov/ct2/show/NCT01729260

    Perhaps this clinical study would have given some answers, since one of the goals was to determine whether Mebendazole is able to slow the growth of the tumor.

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    Replies
    1. Greg Riggins showed a preliminary Kaplan-Meier survival curve for the patients in this trial receiving over 50 mg/kg/day of mebendazole at the 2016 SNO conference but nothing has been published yet, and I didn't see anything about it at this year's conference.

      Note that 50 mg/kg/day would be about 3 grams or more daily (depending on body weight).

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    2. By the way, the status of the study of Mebendazole + Temozolomide has just been changed to "Active, not recruiting" instead of "Completed". Perhaps this means that there was a reason to continue the study.
      https://clinicaltrials.gov/archive/NCT01729260/2018_01_21/changes

      And about the dose in this study:
      "The mebendazole will be given by mouth three times every day on a 28 day cycle. it's in the form of 500 mg chewable tablets, to be taken with meals."
      Total daily dose: 1500 mg / day! While many in this blog I have seen take about 200mg / day.

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    3. Interesting research on increasing the bioavailability of mebendazole!

      1989 https://www.ncbi.nlm.nih.gov/pubmed/2674643
      "The method of mebendazole administration with sunflower oil, elaborated by the authors, serves to this purpose: drug concentration exceeding the minimal effective one was attained in 86% patients treated with mebendazole and sunflower oil and only in 40% patients treated with the drug alone."

      2012 https://www.ncbi.nlm.nih.gov/pubmed/22661241
      "Enhanced bioavailability and cysticidal effect of three mebendazole-oil preparations in mice infected with secondary cysts of Echinococcus granulosus."

      What conclusions can be drawn from this? Take mebendazole with olive oil, which contains oleic acid?

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    4. All trials go from "recruiting" to "active, not recruiting" when enrollment is complete but data is still being collected (follow-up continues). Status switches to "complete" when follow-up has been completed and all data has been collected (usually at least 2 years of follow-up for all patients).

      200 mg is the dose used for killing intestinal worms and the dose used by Care Oncology Clinic. It's not necessary to get mebendazole into the bloodstream in order to kill intestinal worms, but it is necessary in order to reach tumor cells. So higher doses are required because of the poor bioavailability of mebendazole.

      1500 mg per day was the *starting dose* used in the trial. As I explained above, they eventually escalated the dose to at least 50/mg/kg per day (or 3000 mg per day for a 60 kg adult). Mebendazole even at 1500 mg per day and higher was quite well tolerated - most likely due to the poor bioavailability, so limited plasma levels were reached on lower doses.

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    5. According to the Vermox product monograph put out by Janssen Inc. (Canada) "Dosing with a high-fat meal leads to a modest increase in the bioavailability of mebendazole."

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  8. More about bioavailability of MBZ:

    "Finally, improved efficacy may also be possible through improvements in the bioavailability of MBZ. As touched on previously, there is evidence that the combination of MBZ with cimetidine increases plasma levels of MBZ [12], potentially improving the therapeutic effect. An alternative means of increasing the bioavailability is through the liposomal encapsulation of MBZ. While this approach has not been explored in an oncological context, some work in this area have been done to enhance the anti-parasitic action of MBZ and other benzimidazole anti-helminthics, including one paper that explored the combined effect of a liposomal benzimidazole (albendazole) and cimetidine and reported a very significant increase in therapeutic effect (including a 75–94% reduction in biomass of the hydatid cysts and a significant increase in survival time) in an animal model [37]. It is possible that a similar approach could yield improvements in the anti-cancer effect of MBZ."

    2014
    http://ecancer.org/journal/8/full/443-repurposing-drugs-in-oncology-redo-mebendazole-as-an-anti-cancer-agent.php

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  9. I'm still considering a high dose of Mebendazole. Here's what dear Gregory J. Riggins answered me by e-mail:

    "There is no phase 2 yet and high dose Mebendazole is unproven in humans.

    I cannot give direct patient care advice as I work only in the laboratory. However our published results suggest the Janssen version of Mebendazole is reliable and can be effective in high doses. We only tested one version of this and there are many from different countries but it is probable they are equivalent.

    The version we make is only for FDA approved clinical trials and not for sale. Currently there are no open adult trials with this drug only for children."

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