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New MS Drug Targets Oxidative Stress, Increases Glutathione

Discussion in 'Other Health News and Research' started by MishMash, Sep 6, 2012.

  1. MishMash

    MishMash

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    Some CFS researchers and patients have been taking the subject of oxidative stress and down-regulation of the glutathione very seriously for years now. I must admit, I was not one of them. Seemed a little too speculative, one of many imaginative theories out there, not clear evidence. But....maybe I was wrong.

    Looks like Biogen's next billion-dollar baby is a drug called BG-12. And guess what? It works by targeting oxidative stress's damaging effects on the neurons, and it positively effects the glutathione in the patient. This is the result of years of testing, many millions of dollars, and several laborious rounds of trials.

    Just read the first line in Biogen's release, then read the findings of CFS/ oxidative stress research. It's almost the same, word for word:

    http://www.ncbi.nlm.nih.gov/pubmed/22267202

    The results from their phase III, study showed it to be quite beneficial in preventing relapses in MS patients. Many MS patients will tell you that it is not the ehancing lesions that are important in the treatment of this disease; it is finding a way of staving off the relapses. Because the relapses not only show neurological symptoms, but fatigue, intolerance to exercise, cognitive impairment also. Very similar to what we have.

    I was wondering if this is something Cort might ask our researchers about, as a possible new treatment modality. I would be very interest if they saw any parallels. We have seen possible off-label success with RTX so maybe this might work too.
     
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  2. Marco

    Marco Grrrrrrr!

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    Lately I've come around to the view that oxidative stress may underlie a whole range of neuroinflammatory/neurodegenerative conditions and that diagnostic labels are fairly arbitrary with any individual's symptoms being determined by a combination of genetic predisposition; developmental stage; environmental stressors and perhaps gender.
     
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  3. Emootje

    Emootje Senior Member

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    That reminds me, still got a bottle of Psorex...
     
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  4. richvank

    richvank Senior Member

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    Hi, MishMash.

    Thanks for posting this. I can't say that I understand this very well, but it sounds somewhat like what is claimed for ASEA, i.e. influencing redox signalling molecules.

    Another thing I'm reminded of is that carnitine fumarate has been helpful for a lot of people, based on Amy Yasko's recommendation and also Freddd's. I don't know if the fumarate in that supplement is acting like the methylfumarate in the drug, though. Could be a whole 'nother thing. And I suspect that the carnitine is a big part of the benefit of carnitine fumarate, too.

    I would say that there is no question that oxidative stress and glutathione depletion are major factors in ME/CFS, based on published research and our own lab testing.

    I think it will be very interesting to see how this drug works out. Up to now, I think the pharmaceutical companies have ignored emphasizing oxidative stress to the docs, because they haven't had drugs that would help with it. Only antioxidants, which aren't patentable and have a much lower rate of return, because of the resulting competition.

    One thing I wonder is whether this drug will work when there is a partial methylation cycle block. In theory, I guess that if this drug could raise the glutathione level enough, it would overcome the functional B12 deficiency, and that might overcome the partial methylation cycle block, if there was still enough folate available to the cells.

    Anyway, I guess time will tell.

    Thanks again for posting it.

    Best regards,

    Rich
     
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  5. Legolas

    Legolas

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  6. Sallysblooms

    Sallysblooms P.O.T.S. now SO MUCH BETTER!

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    Supplements and diet can help nerves heal. Pharm. always want to make money with the same thing we can already do.
     
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  7. MishMash

    MishMash

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    Very interesting. I had no idea Biogen's latest wonder drug is just a tweaked OTC supplement. And it is already considered superior to Copaxone, the injectible that poor MS patients have been stabbing themselves with for years. The cost of Copaxone is in the five digits per year, for apparently very little benefit. I wonder how many tens of thousands Biogen will charge for this drug. If it actually works, very few of us will be able to afford it.
     
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  8. voner

    voner Senior Member

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  9. voner

    voner Senior Member

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    Here is a more recent paper on dimethyl fumarate .

    http://www.jneuroinflammation.com/content/pdf/1742-2094-9-163.pdf


    Abstract
    Background: Neuronal degeneration in multiple sclerosis has been linked to oxidative stress. Dimethyl fumarate is a promising novel oral therapeutic option shown to reduce disease activity and progression in patients with relapsing-remitting multiple sclerosis. These effects are presumed to originate from a combination of immunomodulatory and neuroprotective mechanisms. We aimed to clarify whether neuroprotective concentrations of dimethyl fumarate have immunomodulatory effects.

    Findings: We determined time- and concentration-dependent effects of dimethyl fumarate and its metabolite monomethyl fumarate on viability in a model of endogenous neuronal oxidative stress and clarified the mechanism of action by quantitating cellular glutathione content and recycling, nuclear translocation of transcription factors, and the expression of antioxidant genes. We compared this with changes in the cytokine profiles released by stimulated splenocytes measured by ELISPOT technology and analyzed the interactions between neuronal and immune cells and neuronal function and viability in cell death assays and multi-electrode arrays. Our observations show that dimethyl fumarate causes short-lived oxidative stress, which leads to increased levels and nuclear localization of the transcription factor nuclear factor erythroid 2-related factor 2 and a subsequent increase in glutathione synthesis and recycling in neuronal cells. Concentrations that were cytoprotective in neuronal cells had no negative effects on viability of splenocytes but suppressed the production of proinflammatory cytokines in cultures from C57BL/6 and SJL mice and had no effects on neuronal activity in multi-electrode arrays.

    Conclusions: These results suggest that immunomodulatory concentrations of dimethyl fumarate can reduce oxidative stress without altering neuronal network activity.

    Keywords: Dimethyl fumarate, Oxidative stress, Neuroprotection, Neuromodulation
     
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  10. Snow Leopard

    Snow Leopard Hibernating

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  11. Legolas

    Legolas

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    It is (still) for sale in the Netherlands under the brand name Psorinovo. Which is enteric coated slow release DMF.
    Most people with psoriasis seem to be helped by it. It's even covered by some insurances.

    for the non European people; yes the Netherlands are a EU country;)
     
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  12. AFCFS

    AFCFS Senior Member

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    I look at this with some optimism, but also some skepticism. I know the whole ball of wax is not as simple as I am inferring, but it sounds like the end-result of DMF/BG-12 is the same as OTC N-Acetylcysteine (NAC).
    The Conclusions sounded familiar, just replacing the DMF with NAC.

    Suppression of human immunodeficiency virus expression in chronically infected monocytic cells by glutathione, glutathione ester, and N-acetylcysteine.

    Phytochemical induction of cell cycle arrest by glutathione oxidation and reversal by N-acetylcysteine in human colon carcinomacarcinoma cells

    N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action, with snippet:

    Like many therapies, the clinical origins of NAC are far removed from its current use in psychiatry. Whereas the mechanisms of NAC are only beginning to be understood, it is likely that NAC is exerting benefits beyond being a precursor to the antioxidant, glutathione, modulating glutamatergic, neurotropic and inflammatory pathways.

    And then a bit of a tie-in (actually citing the first article I linked from above): Can a Drug for Psoriasis and MS Help Protect the Brain From HIV's Toxicity? but, one thing here,perhaps of interest, is to notice the dosing: "The dose of NAC used was about 4,400 mg daily." I find it interesting at several levels, because my pdod had initially suggested 2400 mg of NAC for brain/psych health, but many may see these doses as high. But it does beg the question anything else is too low. Here is a more in-depth perspective http://www.sfrbm.org/frs/ErcalNAC.pdf

    Vitacost N-Acetyl Cysteine (NAC) -- 600 mg - 240 Capsules is $17.95 (I get mine from Amazon because it is easier to checkout for me - one less online account). The thing I consider humorous, if not informative, is Medicinal Nutraceutics NAC statement:

    A Word About Quality
    Most dietary supplement manufacturers purchase n-acetylcysteine from Chinese sources. Medicinal Nutraceutics purchases amino acids only from Ajnimoto of Japan the world’s recognized leader in the science and manufacturer of amino acids. 95% of all NAC comes from China and is processed from either human hair or duck feathers. Our NAC is produced through enzymatic reaction with organic materials. We pay at least 33% more for this superior grade n-acetylcysteine than we would the more common material from China.

    Medicinal Nutraceutics NAC n-acetylcysteine -- 500 mg - 60 Capsules is $15.05, so while they pay 33% more for their NAC, they charge about a 400% markup. - Will stick with hair or duck feathers.
     
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  13. MishMash

    MishMash

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    In a post above, Dr. Van Konnynenburg wondered if the maker, Biogen, did something to tweak the compound. To make it more effective in the methylation cycle than the OTC drugs. The science of oxidative stress and glutathione depletion was already laid out there, so the company would not have to be starting from scratch.

    I didn't know about the connection between HIV and DMF. Very interesting. More evidence of a neuro-protective effect.

     
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  14. AFCFS

    AFCFS Senior Member

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    Seven Surprising Facts About Biogen-Idec’s Developmental ‘Blockbuster’ for Multiple Sclerosis
    ..... maybe another 200 years for CFS?
    .....
    (bold added for emphasis)
     
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  15. jimells

    jimells Senior Member

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    AFCFS thanks for this.

    I don't understand how it can be patented for just one illness. Does this mean if one uses it for psoriasis a license fee must be paid, but when used for other purposes, no fee is required? I know very little about patent issues, but this kinda reminds me of the rampant patent abuse seen in the software industry, which I do know something about.
     
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  16. MishMash

    MishMash

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    AFCFS
    Believe it or not, I actually met the doctor who headed the effort to "discover" BG-12. His name is John Richert, and he was a neurologist at Georgetown University hospital. I'm certain he is a very smart man, he probably received a 4.0 GPA, got a high grade in Organic Chemistry, was head of the honors society in high school. But struck me as a very orthodox and conservative physician. Not the inventing, mad scientist type.

    I think what he did as a developer was be very smart by being basically very simple. Pharmaceutical development in the last few decades has been marked by many blunders, failures, pull backs, and frankly ethical lapses. This is because it is extremely difficult to create a treatment for today's chronic illnesses simply ouf of whole cloth. Biogen decided to skip all that lab nonsense, and they sent out investigators to find old, old compounds that actually do work; then tweak a few atoms to say you discovered something new. No matter what, nobody can say DMF is not truly anti-inflammatory.

    I predict that next Biogen will extract a wonderful compound from Willow tree bark and create an incredible new analgesic. Of course, they'll change a few things to the basic structure to "make it better" and put a patent on it. Then sell it for billions. Aspirin, basically used since the days of the ancient Greeks for pain, will be the next wonder drug.
     
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  17. AFCFS

    AFCFS Senior Member

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    I am not sure about how the patents/licensing work either. I know a similar incidence happened with Namenda (Memantine). I had been looking at this because of its Glutamatergic (NMDA receptor), Serotonergic (5-HT3 receptor), Cholinergic (nicotinic acetylcholine receptor), Dopaminergic (D2 receptor) pharmacology, in hopes that it might be of aid for some brain fog/cognitve issues. it also had a circuitous route to billionaire dollar status:

    Memantine hydrochloride was originally synthesized in 1963 at Eli Lilly & Co as an antidiabetic agent but was found to be ineffective in lowering elevated blood sugar. Merz & Co in Germany took it over and, a decade later, showed its effectiveness in Parkinson disease. In 1989, therapeutic action of memantine was shown to be due to antagonism of N-methyl-D-aspartate receptors (Kornhuber et al 1989), and it was launched in Germany for the treatment of dementia. Further clinical trials were conducted on its use in Alzheimer disease between 1995 and 2000, and the drug was approved in the European Union in 2002. The FDA approved it for the treatment of moderate to severe Alzheimer disease in 2003. It is marketed in the United States under the trade name of “Namenda” (Forest Laboratories).

    ....with global sales of memantine for dementia reaching $2 billion in 2011. Despite this, as a class of drugs, aminoadamantanes have not yet been fully explored by the pharmaceutical industry.

    There are also different accounts of its history and I believe Forest Labs has settle several law suites with other producers (in India) who did not acknowledge the patent. Ballpark price is over $200 a month, but can get it from an oversees pharmacy for less.

    With BG-12 (Seven Surprising Facts About Biogen-Idec’s Developmental ‘Blockbuster’ for Multiple Sclerosis), I believe that is the reason there is the mention of the potential concern:
    It really does not make much sense to a rational human being who has not sold their soul to Big Pharma and I only wonder why they were not able to highjack something like aspirin's Revival as heart drug and charge $100 a pill for it.

    Ultimately it makes something like The Microsoft End User License Agreement (EULA) (link shows translation to plain English) look simple. In the end someone comes out a billionaire, and it is not me.
     
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  18. AFCFS

    AFCFS Senior Member

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    Ha ha ha ... must have been thinking alike there, you posted first while i was still writing.
     
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  19. Basilico

    Basilico Florida

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    Old thread, but I wanted to add to it since I'm starting this drug now.

    So I am diagnosed with MS, though my symptoms are somewhat atypical of MS and more closely aligned with CFS (there is a ton of overlap, so I'm coming to understand that this might not be too unusual). BG-12/dimethylfumarate (brand name Tecfidera) is aimed at people who have relapsing/remitting MS for the purpose of reducing flares. I don't have this form of MS, but I decided to take it solely for the fact that it drastically increases glutathione (plus my neurologist was pushing for me to be on some type of medication). I'm curious to see if my fatigue, memory, orthostatic intolerance, and other weird CFSy symptoms improve.

    I realize that since I'm diagnosed with MS, my experience may not be the same as others, but I'm coming to understand that MS and CFS and many other conditions have more similarities than differences (a dysfunctional immune system, CNS problems, etc...) I've just started the initial low-dose introduction and will be ramping up to the full dose next week.

    As for the price, yes that is something that is pretty unreasonably outrageous. Full price is something in the neighborhood of $4,500/month. My insurance covers it (though I'm sure they negotiate it down like crazy and probably pay WAY less than that. My co-pay is supposed to be $900/month but Biogen has a co-pay assist program which waives the co-pay, so I am not paying anything at all. I'm not sure how it would work if I didn't have insurance that covered it (Hopefully I won't find out too soon - wouldn't that be a kicker to find something that works but then not be able to afford it!) The price is especially outrageous since this drug has been effectively used in Germany and the Netherlands for 30+ years to treat psoriasis, so it's nothing new.

    There is a supplement that is very similar to dimethylfumarate that is cheap and widely available online. It is not as effective at raising glutathione, but it also has fewer side effects. Dimethylfumate is generally well tolerated and the side effects are not bad compared to other MS drugs.

    My husband (who has CFS) may try this alternate form - I know he has glutathione issues since liposomal glutathione seems to consistently reduce or prevent PEM attacks. I don't think glutathione is THE solution, but I think it has the potential to bring some improvement. If either of us has a positive reaction, I will definitely post more information about our experiences on PR).
     
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  20. Basilico

    Basilico Florida

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    Just posting an update for anyone who might be interested.

    Tecfidera was a bust and I had to stop it about 1.5 weeks ago.

    From what I've read, the people who have good effects from Tecfidera are the ones who have a drop in white blood cell count (but not so low as to cause a problem). The ones who experience no benefit typically see no change in their WBC. After 5 weeks of medication, my WBC was unchanged, though my liver enzymes spiked a bit.

    Initially, I didn't experience any side effects that other people commonly get (flushing, itching, stomach pain/GI problems). The first couple of weeks I felt nothing at all, good or bad.

    Then, I slowly starting feeling worse. My 'normal' fatigue was greatly amplified to the point where I could do none of the tasks that I normally can do with pacing (like grocery shopping, dishes). And I spent a majority of the day trying to wake up or fighting to stay awake and getting off the couch was a struggle. My memory/cognition got noticeably worse (and I thought it was already bad!). My legs began to feel wooden, like dead weights. Walking felt more like shuffling. I also got some extreme muscle spasms that were far more intense and long lasting than what I normally get.

    Then, about 1.5 months into it, I spontaneously developed rashes/hives that covered about 1/2 my body. I was slathering myself in hydrocortisone cream, popping Benadryl, and sometimes it wouldn't help. One night I was up till 2am covered in ice packs to try to lesson the crazy itching.

    So, I stopped taking Tecfidera, and the very next day the extreme exhaustion disappeared (now I just have my regular exhaustion, which by comparison makes me feel like a normal person!) Wooden/dead legs disappeared, walking is back to normal. Muscle spasms drastically reduced to the point where they are not causing discomfort.

    I still have intense rash/hive outbreaks everyday, even 1.5 weeks after stopping medication. I've found that the combo of Benadryl cream and a Benadryl pill is working well to keep it in control. Hopefully, I don't have some kind of long term mast cell activation and it doesn't continue for too much longer otherwise I will have to buy stock in Benedryl.

    I was thinking that since I have a very atypical MS which is more like CFS, this drug might have some potential as mentioned in my previous post, but it was a big disappointment. I'm unclear by which mechanism it made me feel so much worse. I very rarely have any negative reactions to any medicines/supplements, I can generally take extremely high doses of just about anything with no problems, so this experience was very confusing to me. Even the pharmacist I spoke to said most patients have some bad side effects in the beginning and then they taper off - she's never heard of someone starting out fine and developing side effects later on. However, from reading on various MS forums, it does seem that some MS patients do develop side effects/intolerances much later on, so this isn't unheard of.

    Btw, I have no methylation issues...I did a full methylation protocol years ago and discovered that I seem to have no methylation block because I felt exactly the same taking/not taking all the B vitamins. I still occasionally take methylB12 and methylfolate and a general B vitamin just in case, but I never feel anything as a result of taking it. So I don't think that this drug was in any way affected by a methylation issue.



    I developed a bit of psoriasis a few months before starting Tecfidera, and reading that this drug was used to treat psoriasis in Germany and the Netherlands for 30+ years made me look forward to trying it even more. Not only did this stupid drug make me worse, but it didn't even improve my psoriasis! WTF??? Applying topical hydrocortisone continues to be the only thing that helps.

    Oh well, cross this one off the list and on to the next experiment!
     
    Last edited: May 11, 2017
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