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