Saturday, 22 August 2015

Anti-Oxidants, there is no evidence that they are of use

Plemel JR, Juzwik CA, Benson CA, Monks M, Harris C, Ploughman M. Over-the-counter anti-oxidant therapies for use in multiple sclerosis: A systematic review.
Mult Scler. 2015 Aug 18. pii: 1352458515601513. [Epub ahead of print] 

BACKGROUND: Anti-oxidant compounds that are found in over-the-counter (OTC) supplements and foods are gaining interest as treatments formultiple sclerosis (MS). They are widely used by patients, sometimes without a clear evidence base.
OBJECTIVE:We conducted a systematic review of animal and clinical research to determine the evidence for the benefits of OTC anti-oxidants in MS.
METHODS:Using predefined criteria, we searched key databases. Two authors scrutinized all studies against inclusion/exclusion criteria, assessed study risk-of-bias and extracted results.
RESULTS: Of the 3507 titles, 145 met criteria and included compounds, α(alpha)-lipoic acid (ALA), anti-oxidant vitamins, Ginkgo biloba, quercetin, resveratrol and epigallocatechin-3-gallate (ECGC). The strongest evidence to support OTC anti-oxidants was for compounds EGCG and ALA in animal models; both consistently showed anti-inflammatory/anti-oxidant effects and reduced neurological impairment. Only vitamin E, Ginkgo biloba and ALA were examined for efficacy in pilot clinical trials with either conflicting evidence or evidence of no benefit.
CONCLUSION:OTC anti-oxidants EGCG and ALA show the most consistent benefit, however only in preclinical studies. There is no evidence that they alter MS relapses or progression. Future work should focus on testing more of these therapies for clinical efficacy before recommending them to MS patients
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You recently asked about doing meta analysis of animal studies to get an idea if they are of use in the translational process.

I answered that perhaps, but you need a critical eye. 

So here we have such a thing and it suggests that animal studies show that some anti-oxidants work but when tried in human trials they fail, as may be anticipated for a nutriceutical 

(I am not saying nutriceuticals have no value, but they are not DMT. Nutriceuticals are unlikely to be trialed properly because there is no money to be made and so studies are small, underpowered and invariably inconclusive). 

Remember there is a publication bias for positive data in animal studies and if you give enough water to animals it will stop their EAE. 

The first question that should be asked is whether the animals got a human equivalent dose of the agent. If it is above the human equivalent dose then the "positive data" are meaningless for the translatability and if the doses are too high they should be excluded from the analysis.

Tooth paste will be immunosuppressive to animals if you give enough of it, just like loud noises are immunosuppressive. It's "the building-site effect" put an animal in a building site and EAE stops.

8 comments:

  1. Small human trials have produced evidence as measured by MRI, time to disability progression, and annual relapse rate of the positive effect some nutraceuticals have in MS. A couple small human trials are listed below for those interested. Also, a clinical trial of Lipoic Acid for SPMS may be of interest to some MSers.

    In the absence of approved DMTs for progressive forms of MS it is little wonder that patients try relatively safe, inexpensive nutraceuticals which may help. We realize large trials in this area are exceedingly unlikely. But that doesn’t mean nutraceuticals have no effect in MS. Overtime, people tend to adopt things which work and reject things which don’t. We can expect that the tens of thousands (probably hundreds of thousands) of MSers using things like alpha lipoic acid, green tea extract, or LDN will cease taking things which don’t work very well, cost a lot, and make them sick. Oops, I may have described most MS meds.

    Yes, dear clinician, evidence that ALA, EGCG, or LDN is effective in MS is weak; but evidence that they are not effective is even weaker. Where is proof that any of these three are harmful or evidence they don’t work? Before anyone starts howling I just wanted to express that as a contrasting mind-set between patient and clinician. Bottom line… a clinician is treatment limited; a patient isn’t.

    For those interested:

    A novel oral nutraceutical formula of omega-3 and omega-6 fatty acids with vitamins (PLP10) in relapsing remitting multiple sclerosis: a randomised, double-blind, placebo-controlled proof-of-concept clinical trial
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641495/?report=classic

    Quote, “Over 2 years, the MRI results supported a PLP10-related positive effect as only 29% from the PLP10 group, in contrast to 67% from the placebo group, developed new or enlarging T2 lesions (57% relative risk reduction). After excluding the patients on natalizumab, there was an increased relative risk reduction (64%) for PLP10 compared with the placebo group, with 29% of patients on PLP10 and 80% on placebo developing new or enlarging T2 lesions.” End Quote

    Epigallocatechin-3-gallate: a useful, effective and safe clinical approach for targeted prevention and individualised treatment of neurological diseases?
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585739/

    Lipoic Acid for Secondary Progressive Multiple Sclerosis (MS)
    https://clinicaltrials.gov/ct2/show/NCT01188811

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    Replies
    1. Well said Anon and I agree with a lot of what you have written.
      There has been a small trial of 500mg per day with CO Q10 in relation to fatigue and depression, which was reported on this blog
      http://multiple-sclerosis-research.blogspot.com/2015/02/coq10-nutriceutical-for-fatgue-and.html
      I am taking CO Q10 in a normal dose of 150mg a day, and while I cannot say that I have seen any "results" per se, I have noted that my general mood and fatigue has been a lot worse in the past than it is now.
      I am also taking LDN, and no miracles there either, but within a few days of staring on the 0.5 mg titration dose my disrupted sleep patterns resolved (the opposite of what most LDN users report!), and my bladder issues settled. So, I have continued to take it and now take 4mg each night. There are many people taking LDN who claim that they have seen no progression in their MRIs - my MRIs have been basically stable since my first one, but I am not going to sing from the rooftops that LDN is responsible for this. Neither of these substances is going to do me any harm, and who knows - they may actually be doing some good, so I will continue with them.

      Re "things which don’t work very well, cost a lot, and make them sick. Oops, I may have described most MS meds". Yup - that was my experience with Rebif - it was worse than the MS, and if I'd stayed on it I probably would have given up the ghost. Life is much better without Rebif, but I must note that it is not that way for everyone and each person must make the decisions that work for them. Personally, I research thoroughly, and work on a fairly simple basis of do not try anything which may cause me harm and only try those things which are known to not cause harm. As a result, I now feel much better than I have done since being diagnosed two years ago - and my MS was slowly ravaging my brain and spinal cord for around 6 years before I even had my first appointment with a neurologist.

      Big Pharma has no interest in anything which will not turn a profit for the shareholders so we will never see trials done with things that are easily accessible and affordable - no matter how much "anecdotal" evidence is produced.

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    2. I think that science is starting to understand mitochondrial dysfunction is a key aspect of the progressive phase of the disease. Looking at what supports this without doing clinical trials is a way to understand what might be beneficial.

      The combination of acetyl-L-carnitine and alpha lipoic acid has positive effects when fed to old rats and the amount was not out of the realm as to what is equivalent to over the counter dosage levels in the combined form.

      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2790461/

      It seems obvious to me that this combination would not have been made available if there was no basis for it. It has done wonders for me anecdotally. Looking at the mechanisms of action of what seems to be happening in progressive MS and looking for treatment to address the issue seems like a logical approach in stead of randomly trialing immunosuppressive drugs in a hope the side effects aren't to severe as the method pharma is pursuing.

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    3. @anon 2:09:00 regarding the high energy demands placed on demyelinated axons and the subsequent mitochondrial dysfunction. This was referenced earlier in this blog. High doses of d-biotin in proressive disease with the goal of preserving axons.
      http://www.sciencedirect.com/science/article/pii/S2211034815000061

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    4. Steve: That's the pilot study, the results of which were so much more exciting than the larger, double blind, placebo controlled one.

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    5. There is a clinical study for EGCG regarding SPMS in Germany. I hope they report results soon.
      https://clinicaltrials.gov/ct2/show/NCT00799890

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  2. In 2011 I was diagnosed with delayed radiation myelopathy from treatment that I had for hodgkins lymphoma in 1990. In 2012 I saw another neuro for a second opinion. He disagreed with the radiation myelopathy theory and said possible MS. Following several more tests he could not give me a MS dx due to not enough evidence.
    If I did have radiation myelopathy I often wondered why I was fine for 20+ years after treatment. Then I read that as we age our natural antioxidants decline allowing free radicals to attack areas that are already weakened (ie the area damaged by the radiation ). This could happen in SPMS were the free radicals attack areas were there had been relapses. My problems started at age 46 which is a similar age to the start of SPMS. Could the increase in Free radicals coupled with the decline in out natural antioxidants be causing the progression. In the same way problems can occur in our skin years after a bad attack of sunburn (excess wrinkles and skin cancer).

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  3. The way I see nutriceuticals is that they can contribute to general health and therefore make a significant difference to one's condition over a long period of time. Some things may or may not slow my MS progression, who knows. But if they do not have any deleterious side effects and are pleasurable and affordable as part of a good diet, such as my daily fix of green tea - why not? (Green tea exctracts on the other hand - no thanks.)

    I don't expect nutriceuticals to "cure" my PPMS, just help me cope a little better, even just psychologically. It always feels better to be trying to do something. But I am sure as hell happy that my neurologist is not saying to me that I should go home, drink green tea with a dash of turmeric and stuff myself full of biotin powder. I am glad that he is frank and honest and I hope that the scientific research into something which we can _know_ works goes on.

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