
Fatal toxicity of chloroquine or hydroxychloroquine with metformin in mice [pdf] - Lasso2
https://www.biorxiv.org/content/10.1101/2020.03.31.018556v1.full.pdf
======
ComputerGuru
I don’t see how any of this is coming as a surprise to anyone, or even why
people are bothering (questionable science behind the choloroquine paper
aside, even).

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](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.

~~~
cameldrv
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.

~~~
ComputerGuru
But the recommendation is for a high dose once or twice a day for a week +,
which can easily add up.

------
mirimir
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.

~~~
jeffdavis
What do you mean it made you feel brain dead?

~~~
Benjamin_Dobell
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.

~~~
buboard
interesting. do they know why it's happening ?

~~~
Benjamin_Dobell
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.

------
vsviridov
That's really bad news for diabetic mice that have contracted the COVID-19...

As far as humans are concerned - who knows...

~~~
sabujp
show me a study where the mouse model had negative correlation to the human
trial :
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746847/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746847/)
, with relation to diabetic drugs and anti malarials?

------
walterbell
Is there a public index of candidate treatments, regional success rates and
drug interactions?

Edit:
[https://covid19-druginteractions.org/](https://covid19-druginteractions.org/)

PDF page 9 (April 3rd version) lists green for Metformin with all drugs,
including CLQ and HCLQ.

------
pbreit
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.

~~~
Lasso2
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.

------
tgafpc2
And? There's lots of dangerous drug combinations. That's why doctors ask you a
bunch of questions.

------
vanniv
So much effort is going in to the propaganda war against Hydroxychloroquine,
it's really terrifying to watch.

~~~
orwin
""" 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-...](https://factual.afp.com/el-antiviral-cubano-interferon-alfa-2b-se-
usa-en-china-para-tratar-enfermos-del-nuevo-coronavirus))

