Coronavirus Epidemic Update 34: US Cases Surge, Chloroquine & Zinc Treatment Combo, Italy Lockdown

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kram welcome to another MedCram kovat
19 update we see here that the total recovered is sixteen times that of the
total deaths and we can see here that the active cases are once again starting
to come back up again that’s because of the activity outside of China in terms
of today March 10th we can see that there’s a number of cases in multiple
countries all over the world and of course the news from yesterday is that
Italy has decided to extend its lockdown to not just the north of Italy but to
all of Italy in terms of yesterday in Spain the number of cases have
essentially doubled with 557 new cases and that seems to be a new hot spot I can tell you as of yesterday I was
able to get a lab test out of a commercial test company that I needed to
have done in a patient in the emergency room so I’m hoping that that is going to
increase dramatically here in the next week or so we’ve talked about zinc here
a couple of updates ago but the story is not done it’s kind of
an exciting story that gives me some cautious optimism in terms of kovat 19
but to understand this better we’ve got to go back and look at the molecular
biology of the cell once again here is the nucleus of the cell and the nucleus
of the cell is the DNA the DNA is a double-stranded string of nucleotides
which are the codes those codes are transcribed using RNA polymerase into
RNA that RNA then goes out of the nucleus gets a 5 prime cap and gets a 3
prime poly a tail and it’s ready for ribosomes to come on to read that code
and that code is then translated into the code of amino acids which amino acid
after amino acid will turn into a polypeptide which turns into a protein
and proteins are how the cell gets things done so it moves by proteins
actin and myosin it can bind oxygen through hemoglobin it can do cellular
metabolism all of those enzymes in glycolysis in the citric acid cycle all
those things that you learned in biochemistry those are all enzymes those
are all proteins so that’s the normal situation now enter coronavirus
coronavirus has its own genome it is made out of RNA and that RNA just
happens to have a five-prime head and a poly a tail so when it pops into the
cytosol it’s going to be read by those same ribosomes that can’t tell the
difference except this time instead of making a
that’s useful to your cell this RNA that comes out of the virus is going to make
something called a RNA dependent RNA polymerase and it’s this enzyme right
here that is going to read from the three prime m to the five prime end of
the viral RNA and replicate it so this RNA dependent RNA polymerase makes more
viral genomes it’s also known as replicase for that reason and there’s
something that has been shown to inhibit this replicase and that is zinc zinc
will shut down RNA dependent RNA polymerase or replicase and so that is
what we learned the problem is how do you get zinc inside the cell the problem
with zinc is that it’s an ion it’s a 2 plus ion and ions cannot get through the
cellular membrane unless there’s a transporter that allows it to come in in
fact the way that they tested this in the paper is with an Iona 4 which allows
the zinc to come into the cell so they could see that the activity of this RNA
dependent RNA polymerase was reduced this is the paper zinc inhibits
coronavirus RNA polymerase activity in vitro and zinc ionophores blocked the
replication of these viruses in cell culture when they looked at the SARS cub
virus that was the one that was seen back in 2002 as the zinc concentration
inside the cell went up you can see that the byproduct of the RNA dependent RNA
polymerase went down down down clearly demonstrating that zinc intracellularly
is going to block this very important enzyme of the virus well that’s great
we’ve got zinc that’s gonna block it but how we get zinc inside the cell it’s one
thing to say that you’re gonna take zinc supplements but how do those zinc
supplements first of all get absorbed into your body in
the blood into the extracellular space and then finally how are you gonna get
that zinc from the extracellular space into the intracellular space in the
cytosol where it needs to work on these infected cells and these viral proteins
well that’s another thing altogether what you need is some sort of ionophore
or some sort of gated mechanism to open and to allow that zinc to come into the
cell increasing the concentration of zinc into the cell so it can block Rd RP
well enter this paper that was pointed out by some of you commenting
chloroquine is a zinc ionna for this paper was published back in 2014 and the
point of this paper was something completely different they weren’t
thinking about coronavirus they probably didn’t even know perhaps that zinc
blocks RNA dependent RNA polymerase what they were looking at here is that zinc
may help some of these cancer cells basically eat themselves in the
lysosomes which are sort of trash compactors of the cell and that by
giving chloroquine you could have these cancer cells disappear well in doing
that research they found out something that’s very interesting to us because of
that finding and this research came out of the University of Oklahoma and some
institutions in China so this is what they used chloroquine diphosphates
here’s the structure of that compound and this chloroquine is a medication
that has been around for decades that is used to treat malaria it’s not under
patent and it’s pretty dirt cheap and widely available however you do need a
prescription to use this and it doesn’t come without side effects what they show
is that they were able to detect intracellular zinc by checking its
fluorescence here on the x-axis we have increasing concentrations of chloroquine
and the white bars represents those cells that were bathed in only five
micro molar solution of zinc chloride and the black was in ten times that
amount at 50 micro concentration of zinc chloride and what
you can see here is that in the normal situation if you’re able to get some
zinc into the cells this is the amount of zinc you’ll see inside the cells so
this is the amount of concentration outside the cell this is the amount of
zinc you see inside the cell and let’s just look at this same concentration 5
micro molar when you bathed the cells in chloroquine you can see how much this
intracellular sink concentration goes up in fact if you look at the amount of
zinc inside the cell by just adding a small amount of chloroquine here at 10
micromolar we would get more zinc inside the cell than if we increase the
concentration of zinc outside the cell tenfold
that’s how powerfully chloroquine will increase intracellular zinc
concentration now remember this is chloroquine this is a medication that’s
been used by millions of people already with known side effects and it’s pretty
well tolerated here’s another example from the article here we have the
control group the 5 micro molar of zinc chloride and then what we do is we
multiply that extracellular zinc concentration tenfold so it’s now 50
micro molar and so this would be the equivalent of just saturating the
extracellular fluid compartment with zinc and see if it tries to get into the
cell which is what you’re trying to do when you take a zinc lozenge essentially
and you can see there’s hardly any effect it’s minimal and that’s because
zinc is a ion it’s a positively charged ion and positively charged ions will not
get into the cell unless there is a gate that allows it to go in and there is
gates that allow it to come in that’s how it’s very tightly regulated but
chloroquine activates those gates and so you can see this is at 50 micro moles of
zinc chloride we can go back to the 5 micro moles here but just adding 300
micro moles of chloroquine lights this thing up like a Christmas tree and you
can see here if we go to 50 again it lights up even more
but the biggest effect is not the jump in the zinc concentration it’s opening
those gates that allows you to get the zinc into the cell and presumably when
that zinc gets into the cell it’s gonna block that viral enzyme and in the
discussion we’ve got the conclusion of the matter the conclusion that
chloroquine is a zinc ion of four is based on the detection of significantly
elevated intracellular zinc levels when both zinc and chloroquine were added to
the cell culture medium so the question is is this being used and to that I turn
to Korea biomedical review physicians work out treatment guidelines for
coronavirus notice that this is published here on the 13th of February
when they were starting to see an uptick in their cases in Korea and the article
goes on to say Korean physicians treating the patients infected with the
new corona virus kovat 19 have established the treatment guidelines for
the unprecedented iris the key guidelines are the following if patients
are young and healthy then they will be observed if more than 10 days have
passed since the onset of the illness they’ll continue to watch them but
notice what happens if the patients are old have underlying conditions or sick
and have symptoms they say here for antiviral treatment the doctors
recommend lopen of air and retina ver this is basically the medication Calitri
which is an HIV medication and they recommend two tablets twice a day or
they can use chloroquine 500 milligrams per day orally in Korea chloroquine is
not available so they use a very close relative of chloroquine which is
hydroxychloroquine and that’s at 400 milligrams orally per day now the reason
why you would not want to use both is because they interact with each other in
a negative way in terms of prolonging the QT interval for those of you who
don’t know what the QT interval is this is a measurement of electrical
conduction in the myocardium in the heart and if the Qt becomes too
prolonged you can get fatal cardiac arrhythmias in this article they do talk
about the antiviral treatment thing about seven to ten days but it
could be shortened or extended and here is one of the keys that I want to
mention this is all being used empirically we don’t have randomized
controlled trials looking at chloroquine in patients with kovat 19 that being
said there has been some publications interestingly coming out of China which
do tout the efficacy of chloroquine now I have to say at this point that it’s a
little bit interesting that that’s happening from my standpoint and from
the standpoint of somebody who understands what a randomized controlled
trial that’s blinded says because if you are truly doing a blinded study you will
not be able to tell if an intervention is working or not that’s the whole point
of a blinded study and that is to avoid bias for instance if you know that
someone’s getting the intervening choice you might be doing a better job of
taking care of that patient without even knowing it so it’s a little interesting
to hear that there may be some efficacy some improvement in some of these
patients unless it was a unblinded study and if it’s a unblinded study then it
has to be taken with a grain of salt and that’s why we really need a randomized
placebo-controlled double-blind ‘add ideally type of study anyway here is an
article that is indexed expert consensus on chloroquine phosphate for the
treatment of novel coronavirus pneumonia this was published in February 2020 and
says here at previous studies have shown that chloroquine phosphate or
chloroquine had a wide range of antiviral effects including anti
coronavirus here we found that treating the patients diagnosed as novel
coronavirus pneumonia with chloroquine might improve the success rate of
treatment and improve patient outcome in order to guide and regulate the use of
chloroquine in patients with novel coronavirus pneumonia the multicenter
collaboration group developed this expert consensus it is recommended
chloroquine phosphate 500 milligrams twice per day for 10 days for patients
diagnosed as mild moderate and severe cases of coronavirus pneumonia and
without contraindications to chloroquine so interestingly the Koreans
are using according to the literature once a day and the Chinese were using it
twice a day now that is all to say if we look at South Korea numbers and of
course we know that they have extensively tested and this is my
hypothesis if you extensively go out and try to find as many cases as you
possibly can and then you set up a standardized treatment regimen and get
people on that regimen early you can see here that even though Italy and South
Korea have very similar total cases the number of deaths is an order of
magnitude difference the number of serious and critical is more than an
order of magnitude different between them and one has to wonder either the
tip of the iceberg is much much smaller on a very very large iceberg in terms of
Italy or there is some sort of systematic treatment difference between
what is going on in Italy and what is going on in South Korea at this point I
don’t know how widespread chloroquine use is in Italy but it’d be interesting
to find out we’ll end on this where they talk about the trials of coronavirus
data from the drug study showed certain curative effect with fairly good
efficacy Chinese National Center for Biotechnology development deputy head
son Yin Rong said that chloroquine an anti-malarial medication was selected
after several screening rounds of thousands of existing drugs according to
son patients treated with chloroquine demonstrated a better drop in fever
improvement of lung CT images and required a shorter time to recover
compared to parallel groups the percentage of patients with negative
viral nucleic acid tests was also higher with the anti-malarial drug chloroquine
has so far showed no obvious serious adverse reactions in more than 100
participants in the trials so getting back to our idea here of what’s going on
in molecular we’ve got sink here that needs to shut down RNA dependent RNA
polymerase and what we’re saying here is that chloroquine
is gonna somehow open up this ion gate and allow the zinc to come in to block
and shut down viral replication inside of the cells I think that’s exciting
I am cautiously optimistic that this may lead to something but again I have to
stress that we need randomized control trials to prove this many times we come
up with ideas that make sense and look like they should work but the proof is
in the pudding and we need to do the randomized control trial we’ve got a lot
more areas to hit on this coronavirus one of the things that we’re going to
look at is the ACE 2 receptor have a lot of questions about the ACE 2 receptor
we’ll talk about that in upcoming updates

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