Is this COVID-19 Mouse work going to mess up your MS Trials

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We know that young people generally do OK and that old people don’t. So what is the difference?….well obviously age is one factor or something that accumulates with age. One thing that aging slows down that is relevant to MS, is repair. If you are young, you tend to get relapsing MS and if you are older progressive MS becomes more appararent and this no doubt is in part related to your neurological reserve and capacity to deal with the inflammatory insult. To repair your meylin you have to clear up the demyelination debris and this is done by macrophages.

If you have been following the story as you age your macrophages become less efficient but if you can given them the elixior or youth then they can repair. Importantly it was seen that with caloric restriction or through the use of metformin, it is may be possible to rejuvinate the macrophages and get the macrophages into repair mode. So when do the trials start?

Well probably everything is on hold with the COVID crisis, but I am aware of a number of planned studies for MS.

Now if macrophages are a key part of the protective immune response against SARS-CoV-2 then maybe a swift dose of metformin would make older people younger and give them resiliance against the problems of COVID-19. That was my “idea of the day” yesterday, but then you do some reading. However, we also know that being older and having diabetes is a risk factor for doing badly from COVID-19.

There is a suggestion that chloroquine or hydroxy chlorine, may inhibit SARS-COV-2 replication, possible by facilitating the influx of zinc into infected cells. The Trumpster has got the FDA to green light this and so people will be stashing these drugs in the off-chance of getting COVID-19. Some of these people with have diabetes and will be taking metforim to modify their glucose responses. Therefore, it is interesting that there is a word of warning of the combination of chloroquine and metformin.

Fatal toxicity of chloroquine or hydroxychloroquine with metformin in miceN.V Rajeshkumar, Shinichi Yabuuchi, Shweta G Pai, Anirban Maitra, Manuel Hidalgo, Chi V DangbioRxiv 2020.03.31.018556; doi: https://doi.org/10.1101/2020.03.31.018556.

Guided by the principle of primum non nocere (first do no harm), we report a cautionary note on the potential fatal toxicity of chloroquine (CQ) or hydroxychloroquine (HCQ) in combination with anti-diabetic drug metformin. We observed that the combination of CQ or HCQ and metformin, which were used in our studies as potential anti-cancer drugs, killed 30-40% of mice. While our observations in mice may not translate to toxicity in humans, the reports that CQ or HCQ has anti-COVID-19 activity, the use of CQ resulting in toxicity and at least one death, and the recent Emergency Use Authorization (EUA) for CQ and HCQ by the US Food and Drug Administration (FDA) prompted our report. Here we report the lethality of CQ or HCQ in combination with metformin as a warning of its potential serious clinical toxicity. We hope that our report will be helpful to stimulate pharmacovigilance and monitoring of adverse drug reactions with the use of CQ or HCQ, particularly in combination with metformin.

In this study the looked in cancer mice but also healthy mice with and without T cells and they find that the combination of the anti-malarial drugs and the metformin causes 30-40% of the mice to die. Whilst, the doses were on the high side, these are the doses used to justify the use of metformin as a myelin repair agent and they were scaled to be a human equivalent dosing. Therefore it is a word of warning, that you should not take medicines unless under medical supervision. Maybe there is a lethal interaction in some people. Adverse reactions have been know to scupper trials in MS before as plans to do sodium channel blockers were canned because to disease activity when you stopped drugs (Waxman.Mechanisms of disease: sodium channels and neuroprotection in multiple sclerosis-current status.Nat Clin Pract Neurol. 2008;4:159-69). Now we know the problem and in that instance it would have been rebound and it was not seen in our experiments or in human studies, but it did delay the optic neuritis trial. So now we have this info of metformin and anti-malarial drug being dangerous the question is whether the Neuros interested in doing the metfromin trials take a step side ways to under stand if this is true, because if the MS trials go ahead in the COVID era what happens if someone gets infected. Now it may be that hdroxychloroquine/chloroquine will bite the dust when it comes to anti-COVID virus treatment and therefore I raise the issue, but if you don’t read about these things you could be oblivious and create unneceesary risk.

Likewise I also have to say there has been a trial of the anti-malarials in diabetes and some of the participants were on metformin. Now I can’t get the paper to read to see if there are any unwanted side effects that may be relevant.

Efficacy and safety of hydroxychloroquine in the treatment of type 2 diabetes mellitus: a double blind, randomized comparison with pioglitazone.Pareek A, Chandurkar N, Thomas N, Viswanathan V, Deshpande A, Gupta OP, Shah A, Kakrani A, Bhandari S, Thulasidharan NK, Saboo B, Devaramani S, Vijaykumar NB, Sharma S, Agrawal N, Mahesh M, Kothari K.Curr Med Res Opin. 2014;30(7):1257-66. 

There is also this

Real-World Clinical Effectiveness and Tolerability of Hydroxychloroquine 400 Mg in Uncontrolled Type 2 Diabetes Subjects who are not Willing to Initiate Insulin Therapy (HYQ-Real-World Study).Gupta A. Curr Diabetes Rev. 2019;15(6):510-519. 

In the animal studies one suggestion is that a neurological effect influences heart. Food for thought

We have been making the case that

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6 comments

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  • On the subject of metformin I’ve been wondering for a while: if metformin actually did work for MS, would we have not noticed that already? It’s not like it is that rarely prescribed… Or is it
    a) simply not visible because nobody prescribes it to people who are not (pre)-diabetic so we are lacking an control group on population level?
    b) not doing much when not combined with clemastine?

    Of course, my ideal study would be high efficacy DMT + metformin + clemastine vs DMT alone on patients without metabolic syndrome. Metformin and clemastine vs placebo is a bit dubious in my view – they are cheap enough that combination treatments should be really looked into.

    • Yes you are correct I have heard Prof Coles say that they havent found the data, but surely MSbase and MSregister has the information. there are must be enough people with MS on metformin. I agree that is the three to gether is a sensible approach without the DMT on the bottom it is potentially a wasted opportunity.

  • Efficacy and safety of hydroxychloroquine in the treatment of type 2 diabetes mellitus: a double blind, randomized comparison with pioglitazone
    “Both the treatments were safe and well tolerated”
    Hydroxychloroquine group: hydroxychloroquine 400 mg/day + metformin + glimepiride/gliclazide;
    Pioglitazone group: pioglitazone group: pioglitazone 15 mg/day + metformin + glimepiride/gliclazide.
    Various doses of other drugs
    Serious side effects in Hydroxychloroquine group
    Acute pulmonary edema*- 1 out of 135 patients
    chest pain* – 1 out of 135 patients
    0 in Pioglitazone group
    * serious adverse effect – resulting in death
    The serious AE of death was reported in two patients from the hydroxychloroquine group… neither related to study drug in the investigator’s opinion and possibly explained by the increased underlying cardiovascular risk in type 2 diabetes patients.

    • It is currently being assessed as a potential Covid-19 treatment in the UK but please don’t jump the gun and start self-medicating!!!!! There are already reports of poisoning and deaths from self-medication.

      • A single dose of antibodies drawn from the blood of Covid-19 survivors appears to have improved the symptoms of 10 patients severely ill with the disease, according to new research. As the Press Association reports, the treatment, known as convalescent plasma (CP) therapy, involves using antibody-rich blood plasma of those who have recovered from coronavirus, which can neutralise the bug to fight infection.

        Scientists in China who conducted the preliminary study said no serious adverse reactions were observed after CP transfusion, PA reports. They believe the findings, published in the journal Proceedings of the National Academy of Sciences, suggest that CP therapy might be a safe and promising treatment for severe Covid-19 patients, and add further investigation is needed in controlled clinical trials.

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