Fatal toxicity of chloroquine or hydroxychloroquine with metformin in mice [pdf](biorxiv.org)
biorxiv.org
Fatal toxicity of chloroquine or hydroxychloroquine with metformin in mice [pdf]
https://www.biorxiv.org/content/10.1101/2020.03.31.018556v1.full.pdf
29 comments
Ouch... Nasty stuff. I had no idea. Thanks for explaining all this in plain English because that paper is Chinese to me :)
The half lives of these medications are very long, 30+ days I believe. This makes a large dose for a short number of days more reasonable than at first glance.
But the recommendation is for a high dose once or twice a day for a week +, which can easily add up.
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“Only work in vitro” and the fact it’s actively used around the world in vivo contradict.
Also can you cite the solid research showing hydroxychloroquine + arithromycin failing for covid-19?
Also can you cite the solid research showing hydroxychloroquine + arithromycin failing for covid-19?
I mean specifically with regards to treating covid-19, not for other purposes. Sorry if that wasn’t clear. I didn’t say there’s a study that says hydroxychloroquine combined with arithromycin is an ineffective combination, but that unless there’s a scientific reason to assume something will increase the effectiveness of such a possibly lethal drug without exacerbating its negative side effects then there is no reason to start with the assumption that it is safe.
Keep in mind that the lack of rigor in the current pre-peer review literature coming out means that you have to take everything into account and with a grain of salt. For example, a drug showing effectiveness might have been with a mild case that started with a low viral load and wouldn’t have progressed any way (this is just an example, I’m not saying that is the case). Since the therapeutic index is so low, you can’t just dial up the dosage to treat severe cases that actually require pharmaceutical intervention, because it’s a non-starter.
Keep in mind that the lack of rigor in the current pre-peer review literature coming out means that you have to take everything into account and with a grain of salt. For example, a drug showing effectiveness might have been with a mild case that started with a low viral load and wouldn’t have progressed any way (this is just an example, I’m not saying that is the case). Since the therapeutic index is so low, you can’t just dial up the dosage to treat severe cases that actually require pharmaceutical intervention, because it’s a non-starter.
Can you cite it not working for covid-19 in vivo? From what I've found there are early stage trials showing success, plus a few larger anecdotal populations showing bigger success, but nothing that scientifically definitively concludes either way.
Yes, there simply hasn’t been enough time for proper studies to have been made one way or the other [0]. The only “study” showing in vivo efficacy is pretty much a bunch of bunk and has huge issues. It did not report on actual treatment outcomes but only on nasal swab results without a control arm, never mind that covid-19 has been demonstrated to move from upper respiratory down into the lungs in most cases that progress to pneumonia or respiratory distress anyway (so a nasal swab says nothing and can come back negative while the patient is dying of respiratory failure).
[0]: https://www.cebm.net/covid-19/chloroquine-and-hydroxychloroq...
[0]: https://www.cebm.net/covid-19/chloroquine-and-hydroxychloroq...
That means your claim that it “only works in vitro” is false, though. The right claim would be “we don’t know yet”.
Also you do a lot of work to make it sound like a foregone conclusion it doesn’t work (appeals to authority in “anyone paying attention”).
The problem is there is now a lot of anecdotal evidence of it working from good sources (teams of doctors on frontlines from around the world). So really you can’t appeal to anyone paying attention.
Also you do a lot of work to make it sound like a foregone conclusion it doesn’t work (appeals to authority in “anyone paying attention”).
The problem is there is now a lot of anecdotal evidence of it working from good sources (teams of doctors on frontlines from around the world). So really you can’t appeal to anyone paying attention.
Yes, so far as we know.
OK, so this is a little sobering for someone on 200 mg/day hydroxychloroquine for rheumatoid arthritis. And they were thinking about doubling that, until I complained that it made me feel brain dead. But then, the naproxen that I've been taking for decades is damaging my kidneys. And hurting all the time sucks.
But anyway, I see that metformin is used to treat type 2 diabetes mellitus. And I vaguely recall that the incidence of that disorder has been increasing dramatically. So this is arguably a key red flag for hydroxychloroquine in COVID-19. But not for me, fortunately.
But anyway, I see that metformin is used to treat type 2 diabetes mellitus. And I vaguely recall that the incidence of that disorder has been increasing dramatically. So this is arguably a key red flag for hydroxychloroquine in COVID-19. But not for me, fortunately.
What do you mean it made you feel brain dead?
By "brain dead", I meant that I had difficulty focusing, and felt somewhat sedated. But then, I take so many drugs now that it's hard to really know which are doing what.
I mean, I could have increased the modafinil dose. But it was easy enough to take hydroxychloroquin at night, and naproxen in the morning. And hopefully my kidneys will be happier, even if my retinas etc are more at risk.
I mean, I could have increased the modafinil dose. But it was easy enough to take hydroxychloroquin at night, and naproxen in the morning. And hopefully my kidneys will be happier, even if my retinas etc are more at risk.
Methotrexate (Sarcoidosis) here, not hydroxychloroquine, both are DMARDs.
"Brain fog" is a more commonly used term, although no doubt people experience different things and would describe them differently. For me, it's a weird feeling of vagueness, and to what extent varies significantly. Sometimes it's hard to focus and do work, but not always. Usually it's just like everything is sort of "passing me by". You wouldn't know talking to me, I function just fine, so maybe it mostly just affects my perception of time and/or memories. It's subtle and weird.
"Brain fog" is a more commonly used term, although no doubt people experience different things and would describe them differently. For me, it's a weird feeling of vagueness, and to what extent varies significantly. Sometimes it's hard to focus and do work, but not always. Usually it's just like everything is sort of "passing me by". You wouldn't know talking to me, I function just fine, so maybe it mostly just affects my perception of time and/or memories. It's subtle and weird.
interesting. do they know why it's happening ?
I'm actually not sure, but it's one of the most common side effects. These are pretty intense drugs. Methotrexate quite literally stops cell division; in much higher doses than I take, it's used to abort nonviable pregnancies.
EDIT: I should probably note that stopping cell division isn't the primary mechanism by which Methotrexate treats Sarcoidosis. You basically take Methotrexate then 24+ hours later counteract it with folic acid. They actually don't know how it works!
In my case it probably doesn't help that "brain fog" is also a side effect of Sarcoidosis itself; I mean that's obviously pretty minor in comparison to the fact if left unchecked it'd destroy my lungs.
EDIT: I should probably note that stopping cell division isn't the primary mechanism by which Methotrexate treats Sarcoidosis. You basically take Methotrexate then 24+ hours later counteract it with folic acid. They actually don't know how it works!
In my case it probably doesn't help that "brain fog" is also a side effect of Sarcoidosis itself; I mean that's obviously pretty minor in comparison to the fact if left unchecked it'd destroy my lungs.
That's really bad news for diabetic mice that have contracted the COVID-19...
As far as humans are concerned - who knows...
As far as humans are concerned - who knows...
Chloroquine COVID19 trial has been discontinued in Sweden due to severe side effect, most notably seizure and vision problems in patients.
Original article: https://www.expressen.se/nyheter/carl-40-fick-kramp-och-syn-...
I expect this will appear in international media soon, if it's true. Note that I don't speak Swedish and I used an online translating tool to read the article.
Original article: https://www.expressen.se/nyheter/carl-40-fick-kramp-och-syn-...
I expect this will appear in international media soon, if it's true. Note that I don't speak Swedish and I used an online translating tool to read the article.
show me a study where the mouse model had negative correlation to the human trial : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746847/ , with relation to diabetic drugs and anti malarials?
Well, keeping track of metformin use would be pretty easy. You could even exclude those using it from trials, unless they signed off after full disclosure.
Is there a public index of candidate treatments, regional success rates and drug interactions?
Edit: https://covid19-druginteractions.org/
PDF page 9 (April 3rd version) lists green for Metformin with all drugs, including CLQ and HCLQ.
Edit: https://covid19-druginteractions.org/
PDF page 9 (April 3rd version) lists green for Metformin with all drugs, including CLQ and HCLQ.
The combination with met form in suggests this has little relevance to the Covid-19 discussion?
The drugs are very old and very well understood and have very modest safety profiles.
The drugs are very old and very well understood and have very modest safety profiles.
Metformin is one of the most often prescribed drugs, particularly in the older population that might also suffer the most severe complications of covid19. If this is indeed fatal in humans you as a doctor have to be quite sure that you have the correct information on the patient before you attempt to treat with this.
I will also severely limit the scope of people who can be treated this way.
I will also severely limit the scope of people who can be treated this way.
And? There's lots of dangerous drug combinations. That's why doctors ask you a bunch of questions.
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So much effort is going in to the propaganda war against Hydroxychloroquine, it's really terrifying to watch.
""" Guided by the principle ofprimum 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 [1], 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 with metformin.
"""
Maybe just read the introduction instead of writting this kind of complotist nonsense? I know that's not the first thing to read in a usual, well-written scientific paper, but there is a lot of papers about covid19 everyday and clinical papers are weird anyway.
HCQ enters trial testing and if we can reduce the number of trial death due to wrong medicamental interactions, it will probably boost the survival of tested people using HCQ, so even if a conspiracy exist, you should be happy that paper like this exist, no?
A thing i saw that works against a conspiracy against HCQ is that on french and US website, everyone is talking about HCQ, well or not, but a lot of other, poorer countries put their hope on interferon (as i do: i take chlorphetamine and other antihistamin drugs that can cause tachycardia especially in spring/summer, and i have arythmia => i'd like to avoid another drug with heart-related secondary effect, my kidney and may spleen are in perfect condition, i'd rather ruin them)
If i couldn't read spanish, i wouldn't even know about interferon tbh, it's much more promising that HCQ: like HCQ it works in vitro against HIV, but unlike CA that agravate AIDS, interferon works in vivo too. Here an AFP article about interferon and sras-cov2 (spanish, works with google translate: https://factual.afp.com/el-antiviral-cubano-interferon-alfa-...)
Maybe just read the introduction instead of writting this kind of complotist nonsense? I know that's not the first thing to read in a usual, well-written scientific paper, but there is a lot of papers about covid19 everyday and clinical papers are weird anyway.
HCQ enters trial testing and if we can reduce the number of trial death due to wrong medicamental interactions, it will probably boost the survival of tested people using HCQ, so even if a conspiracy exist, you should be happy that paper like this exist, no?
A thing i saw that works against a conspiracy against HCQ is that on french and US website, everyone is talking about HCQ, well or not, but a lot of other, poorer countries put their hope on interferon (as i do: i take chlorphetamine and other antihistamin drugs that can cause tachycardia especially in spring/summer, and i have arythmia => i'd like to avoid another drug with heart-related secondary effect, my kidney and may spleen are in perfect condition, i'd rather ruin them)
If i couldn't read spanish, i wouldn't even know about interferon tbh, it's much more promising that HCQ: like HCQ it works in vitro against HIV, but unlike CA that agravate AIDS, interferon works in vivo too. Here an AFP article about interferon and sras-cov2 (spanish, works with google translate: https://factual.afp.com/el-antiviral-cubano-interferon-alfa-...)
This is a comment I posted to HN three weeks ago, when I was pretty sure (but unfortunately wrong!) that the suggested chloroquine dosage for purportedly treating covid-19 was being reported in the wrong units because it was so high, using only the information in the FDA docs on the chloroquines: https://news.ycombinator.com/item?id=22611041
Choloroquine is very well known to have an extremely low therapeutic index (ratio of fatal dosage to effective dosage) and people (well, non-infant children) have been known to die from just a 1g dose. The recommendation for Covid-19 starts at an order of magnitude higher than the recommended FDA dosage for malarial suppression.
(Pretty much) everything can kill viruses at high enough doses. The question is if it can do it without killing the patient as well, and it is eminently clear from existing, solid research that choloroquine doesn’t fit that bill.
Hydroxychloroquine is better tolerated than chloroquine base, but not that much more to sufficiently matter. It also has its own horrible dangers (including complete blindness from accelerated macular degeneration) that have been well documented at long-term “low” dosages; it is not a stretch to assume they would happen with short term high dosages.
There is a reason these only work in vitro - you don’t have to worry about killing the patient there.