Tuesday, 1 December 2015

verapamil and TMZ

Stephen,
. IF I was to take verapamil with temodal do I need to start the verapamil a few days before starting temodal also if that is correct and once that is established can I take both drugs at the same time? Would it effect the absorption of temodal? I wanted to take them so they are both in the system at peak plasma times. From what I've read the  time to peak plasma concentration for temodal is 1 hour, half life 1.8 and Verapamil immediate release is 1 - 2 hours for  and half life is 2.8 to 7.4 hours Verapamil extended release with food is 12hours to peak plasma concentration and without food 7 hours. as per link below.

I have both immediate release and slow release but not sure how Alan will respond so not sure if we'll end up taking the SR or the immediate release. Do you know what the best time frame to maximise  Verapamil's multidrug resistance effect along with Temodal for both slow release and immediate release would be.
http://www.medsafe.govt.nz/profs/datasheet/v/VerpamilSRtab.pdf

9 comments:

  1. I'm not aware of any deleterious interaction between verapamil and TMZ. If anything, verapamil would improve the absorption of TMZ through P-glycoprotein inhibition in the intestines. However TMZ is probably not a major P-gp substrate so it might make little difference to absorption.

    In terms of chemosensitizing, there may be other mechanisms for verapamil beyond P-gp inhibition.

    Ben took verapamil for the week surrounding the CCNU or BCNU, that is, for a few days before and after chemo. I don't have any strong opinion on this.

    In general, immediate release drugs give a more dramatic plasma spike and decline with a higher Cmax, while extended release gives a more sustained plasma concentration, with a lower Cmax.

    There was a clinical trial done with verapamil in combination with chemo for advanced non-small cell lung cancer. Verapamil was started 24 hours prior to the chemo. It was given at 160 mg three times daily. Survival was better in the verapamil + chemo arm.

    http://www.ncbi.nlm.nih.gov/pubmed/8388231

    You can find in vitro studies showing verapamil increases sensitivity to TMZ, but I have seen no animal or human studies on this.

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  2. Thanks Stephen, very much appreciated,

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  3. "Treatment with specific ion channel blockers was not associated with the risk of GBM but was associated with worse survival in patients with GBM. Copyright © 2016 John Wiley & Sons, Ltd."
    https://www.ncbi.nlm.nih.gov/pubmed/27384764

    What do you think about these results?

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    Replies
    1. The concluding statement is misleading, because they only found a significantly negative association with survival with one of the drugs (amiodarone), but not with verapamil, diltiazem, or digoxin.

      It's hazardous to draw conclusions from epidemiological studies such as this because association does not necessarily equal causation. In any case, verapamil doesn't appear to be implicated or associated with worse survival in this study.

      Amiodarone is listed in the study as being a potassium-channel blocker while diltiazem and verapamil are listed as calcium channel blockers.

      There were also very low numbers of users for some of the drugs: 6 active users of amiodarone and 6 active users of verapamil.

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    2. Thank you Steven, you are very, very helpful and support us in our battle for the lives of our loved ones.

      Your operational explanations are very useful to all of us. I now, together with our doctor, choose a medicine from the group of calcium channel blockers, which will reduce blood pressure less, since my mother has low blood pressure. The doctor suggests diltiazem.

      In a few days my mother should take Lomustin. And I'm looking for any ways to strengthen it. Probably the best choice is disulfiram + copper and a calcium channel blocker?

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    3. Thanks for your kind words Semyon.

      It's important to realize here that verapamil has additional mechanisms besides its activity as a calcium channel blocker. The most recognized mechanism is its activity as a P-glycoprotein (also known as MDR1, gene name ABCB1) inhibitor. P-glycoprotein is one of the drug efflux pumps that allows cells to eject drugs that get into the cell. P-glycoprotein is also highly expressed at the blood-brain barrier.

      Other calcium channel blockers such as diltiazem do not necessarily have anti P-glycoprotein properties as verapamil does. According to this webpage: "Verapamil is a well known P-glycoprotein inhibitor, whereas diltiazem is not known to affect P-glycoprotein and it might be the dual inhibitory effect of verapamil on both CYP3A4 and P-glycoprotein that results in the greater effect on sirolimus levels."

      https://www.pharmaceutical-journal.com/careers-and-jobs/career-feature/p-glycoprotein-why-is-it-significant/11076309.article

      There is also experimental laboratory evidence showing longer survival in mice when verapamil is added to BCNU, in a flank-injected glioma model. I've not seen similar studies with other calcium channel blockers besides verapamil.

      The low blood pressure certainly presents a problem when it comes to anti-hypertensive meds such as verapamil. If you do decide to try it I'd recommending starting on the conservative side with the dosing and monitoring blood pressure closely (you could even looking into getting a home blood pressure monitor). Other classes of drugs, such as angiotensin receptor blockers, also could be useful in GBM, but like verapamil they also lower blood pressure.

      Cold water fish oils containing long-chain omega 3 fatty acids (DHA and EPA) could also help in combination with lomustine, as well as disulfiram, and fish oil is very low risk.
      https://www.ncbi.nlm.nih.gov/pubmed/25526274
      https://www.ncbi.nlm.nih.gov/pubmed/28107189

      With disulfiram of course one needs to strictly avoid alcohol (ethanol) and any product that may contain ethanol. Side effects to watch for include peripheral neuropathy (common), and potential psychological reactions due to its activity as a dopamine beta-hydroxylase (DBH) inhibitor (more rare).


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    4. Reference for verapamil + BCNU in mice.
      https://www.ncbi.nlm.nih.gov/pubmed/2366081

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  4. By the way, I already bought this product "Max DHA":
    http://www.jarrow.com/product/90/Max_DHA

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  5. "In our search for potential cellular mechanisms behind the enhanced cytotoxicity of the combination of DSF and DHA, we assumed that either DHA’s anticancer action is enhanced by DSF, or vice versa, that DSF’s anticancer activity is enhanced by DHA. We discovered that the combination of DHA and DSF indeed leads to a mutual enhancement of their actions in cancer cells, including DHA-induced oxidative response, and DSF-induced suppression of mammosphere formation."
    http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=14702&path[]=46934

    The question is, how is it better to take DHA for the therapeutic effect ...

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