2016 paper in PNAS "SARS-like WIV1-CoV poised for human emergence"
thanks Zhengli-Li Shi of Wuhan Institute of Virology for bat CoV
sequences and plasmid of WIV1-CoV spike protein
Newsletter published on April 11, 2020
(1) COVID-19 starves your body of oxygen by binding to the heme groups
in hemoglobin in your red blood cells
(2) 85 COVID Patients at Dr Brownstein's Center for Holistic Medicine:
Zero Hospitalizations and No Deaths
(3) Remdesivir & Chloroquine effectively inhibit Covid-19 vitro; authors
include Zhengli Shi, director of P4 lab at Wuhan Institute of Virology
(4) 2016 paper in PNAS "SARS-like WIV1-CoV poised for human emergence"
thanks Zhengli-Li Shi of Wuhan Institute of Virology for bat CoV
sequences and plasmid of WIV1-CoV spike protein
(5) Nature issues an apology for linking COVID19 to Wuhan
(6) & (7) Marine LePen on Didier Raoult and HCQ
(8) Alain Soral on the Politics of the Coronavirus
(9) New drugs EIDD-1931, EIDD-2801 for Covid-19
(10) EIDD-2801 could become the first pill for COVID-19 - Scientific
American
(1) COVID-19 starves your body of oxygen by binding to the heme groups
in hemoglobin in your red blood cells
From: Andrew S MacGregor <ama18870@bigpond.net.au>
The original post, at medium.com, was deleted by that site.
Covid-19 had us all fooled, but now we might have finally found its secret
libertymavenstock
Medium
Sun, 05 Apr 2020 18:54 UTC
In the last 3-5 days, a mountain of anecdotal evidence has come out of
NYC, Italy, Spain, etc. about COVID-19 and characteristics of patients
who get seriously ill. It's not only piling up but now leading to a
general field-level consensus backed up by a few previously little-known
studies that we've had it all wrong the whole time. Well, a few had some
things eerily correct (cough Trump cough), especially with
Hydroxychloroquine with Azithromicin, but we'll get to that in a minute.
There is no 'pneumonia' nor ARDS. At least not the ARDS with established
treatment protocols and procedures we're familiar with. Ventilators are
not only the wrong solution, but high pressure intubation can actually
wind up causing more damage than without, not to mention complications
from tracheal scarring and ulcers given the duration of intubation often
required... They may still have a use in the immediate future for
patients too far to bring back with this newfound knowledge, but moving
forward a new treatment protocol needs to be established so we stop
treating patients for the wrong disease.
The past 48 hours or so have seen a huge revelation: COVID-19 causes
prolonged and progressive hypoxia (starving your body of oxygen) by
binding to the heme groups in hemoglobin in your red blood cells. People
are simply desaturating (losing o2 in their blood), and that's what
eventually leads to organ failures that kill them, not any form of ARDS
or pneumonia. All the damage to the lungs you see in CT scans are from
the release of oxidative iron from the hemes, this overwhelms the
natural defenses against pulmonary oxidative stress and causes that
nice, always-bilateral ground glass opacity in the lungs. Patients
returning for re-hospitalization days or weeks after recovery suffering
from apparent delayed post-hypoxic leukoencephalopathy strengthen the
notion COVID-19 patients are suffering from hypoxia despite no signs of
respiratory 'tire out' or fatigue. Here's the breakdown of the whole
process, including some ELI5-level cliff notes. Much has been simplified
just to keep it digestible and layman-friendly.
Your red blood cells carry oxygen from your lungs to all your organs and
the rest of your body. Red blood cells can do this thanks to hemoglobin,
which is a protein consisting of four "hemes". Hemes have a special kind
of iron ion, which is normally quite toxic in its free form, locked away
in its center with a porphyrin acting as it's 'container'. In this way,
the iron ion can be 'caged' and carried around safely by the hemoglobin,
but used to bind to oxygen when it gets to your lungs.
When the red blood cell gets to the alveoli, or the little sacs in your
lungs where all the gas exchange happens, that special little iron ion
can flip between FE2+ and FE3+ states with electron exchange and bond to
some oxygen, then it goes off on its little merry way to deliver o2
elsewhere.
Here's where COVID-19 comes in. Its glycoproteins bond to the heme, and
in doing so that special and toxic oxidative iron ion is "disassociated"
(released). It's basically let out of the cage and now freely roaming
around on its own. This is bad for two reasons:
1) Without the iron ion, hemoglobin can no longer bind to oxygen. Once
all the hemoglobin is impaired, the red blood cell is essentially turned
into a Freightliner truck cab with no trailer and no ability to store
its cargo.. it is useless and just running around with COVID-19 virus
attached to its porphyrin. All these useless trucks running around not
delivering oxygen is what starts to lead to desaturation, or watching
the patient's spo2 levels drop. It is INCORRECT to assume traditional
ARDS and in doing so, you're treating the WRONG DISEASE. Think of it a
lot like carbon monoxide poisoning, in which CO is bound to the
hemoglobin, making it unable to carry oxygen. In those cases,
ventilators aren't treating the root cause; the patient's lungs aren't
'tiring out', they're pumping just fine. The red blood cells just can't
carry o2, end of story. Only in this case, unlike CO poisoning in which
eventually the CO can break off, the affected hemoglobin is permanently
stripped of its ability to carry o2 because it has lost its iron ion.
The body compensates for this lack of o2 carrying capacity and
deliveries by having your kidneys release hormones like erythropoietin,
which tell your bone marrow factories to ramp up production on new red
blood cells with freshly made and fully functioning hemoglobin. This is
the reason you find elevated hemoglobin and decreased blood oxygen
saturation as one of the 3 primary indicators of whether the shit is
about to hit the fan for a particular patient or not.
2) That little iron ion, along with millions of its friends released
from other hemes, are now floating through your blood freely. As I
mentioned before, this type of iron ion is highly reactive and causes
oxidative damage. It turns out that this happens to a limited extent
naturally in our bodies and we have cleanup & defense mechanisms to keep
the balance. The lungs, in particular, have 3 primary defenses to
maintain "iron homeostasis", 2 of which are in the alveoli, those little
sacs in your lungs we talked about earlier. The first of the two are
little macrophages that roam around and scavenge up any free radicals
like this oxidative iron. The second is a lining on the walls (called
the epithelial surface) which has a thin layer of fluid packed with high
levels of antioxidant molecules.. things like abscorbic acid (AKA
Vitamin C) among others. Well, this is usually good enough for naturally
occurring rogue iron ions but with COVID-19 running rampant your body is
now basically like a progressive state letting out all the prisoners out
of the prisons... it's just too much iron and it begins to overwhelm
your lungs' countermeasures, and thus begins the process of pulmonary
oxidative stress. This leads to damage and inflammation, which leads to
all that nasty stuff and damage you see in CT scans of COVID-19 patient
lungs. Ever noticed how it's always bilateral? (both lungs at the same
time) Pneumonia rarely ever does that, but COVID-19 does... EVERY.
SINGLE. TIME. — — — —
Once your body is now running out of control, with all your oxygen
trucks running around without any freight, and tons of this toxic form
of iron floating around in your bloodstream, other defenses kick in.
While your lungs are busy with all this oxidative stress they can't
handle, your organs are being starved of o2 without their constant
stream of deliveries from red blood cell's hemoglobin, and your liver is
attempting to do its best to remove the iron and store it in its 'iron
vault'. Only its getting overwhelmed too. It's starved for oxygen and
fighting a losing battle from all your hemoglobin letting its iron free,
and starts crying out "help, I'm taking damage!" by releasing an enzyme
called alanine aminotransferase (ALT). BOOM, there is your second of 3
primary indicators of whether the shit is about to hit the fan for a
particular patient or not.
Eventually, if the patient's immune system doesn't fight off the virus
in time before their blood oxygen saturation drops too low, ventilator
or no ventilator, organs start shutting down. No fuel, no work. The only
way to even try to keep them going is max oxygen, even a hyperbaric
chamber if one is available on 100% oxygen at multiple atmospheres of
pressure, just to give what's left of their functioning hemoglobin a
chance to carry enough o2 to the organs and keep them alive. Yeah we
don't have nearly enough of those chambers, so some fresh red blood
cells with normal hemoglobin in the form of a transfusion will have to do.
The core point being, treating patients with the iron ions stripped from
their hemoglobin (rendering it abnormally nonfunctional) with ventilator
intubation is futile, unless you're just hoping the patient's immune
system will work its magic in time. The root of the illness needs to be
addressed.
Best case scenario? Treatment regimen early, before symptoms progress
too far. Hydroxychloroquine (more on that in a minute, I promise) with
Azithromicin has shown fantastic, albeit critics keep mentioning
'anecdotal' to describe the mountain, promise and I'll explain why it
does so well next. But forget straight-up plasma with antibodies, that
might work early but if the patient is too far gone they'll need more.
They'll need all the blood: antibodies and red blood cells. No help in
sending over a detachment of ammunition to a soldier already unconscious
and bleeding out on the battlefield, you need to send that ammo along
with some hemoglobin-stimulant-magic so that he can wake up and fire
those shots at the enemy.
The story with Hydroxychloroquine
All that hilariously misguided and counterproductive criticism the media
piled on chloroquine (purely for political reasons) as a viable
treatment will now go down as the biggest Fake News blunder to rule them
all. The media actively engaged their activism to fight 'bad orange man'
at the cost of thousands of lives. Shame on them.
How does chloroquine work? Same way as it does for malaria. You see,
malaria is this little parasite that enters the red blood cells and
starts eating hemoglobin as its food source. The reason chloroquine
works for malaria is the same reason it works for COVID-19 — while not
fully understood, it is suspected to bind to DNA and interfere with the
ability to work magic on hemoglobin. The same mechanism that stops
malaria from getting its hands on hemoglobin and gobbling it up seems to
do the same to COVID-19 (essentially little snippets of DNA in an
envelope) from binding to it. On top of that, Hydroxychloroquine (an
advanced descendant of regular old chloroquine) lowers the pH which can
interfere with the replication of the virus. Again, while the full
details are not known, the entire premise of this potentially 'game
changing' treatment is to prevent hemoglobin from being interfered with,
whether due to malaria or COVID-19.
No longer can the media and armchair pseudo-physicians sit in their
little ivory towers, proclaiming "DUR so stoopid, malaria is bacteria,
COVID-19 is virus, anti-bacteria drug no work on virus!". They never got
the memo that a drug doesn't need to directly act on the pathogen to be
effective. Sometimes it's enough just to stop it from doing what it does
to hemoglobin, regardless of the means it uses to do so.
Anyway, enough of the rant. What's the end result here? First, the
ventilator emergency needs to be re-examined. If you're putting a
patient on a ventilator because they're going into a coma and need
mechanical breathing to stay alive, okay we get it. Give 'em time for
their immune systems to pull through. But if they're conscious, alert,
compliant — keep them on O2. Max it if you have to. If you HAVE to
inevitably ventilate, do it at low pressure but max O2. Don't tear up
their lungs with max PEEP, you're doing more harm to the patient because
you're treating the wrong disease.
Ideally, some form of treatment needs to happen to:
Inhibit viral growth and replication. Here plays CHQ+ZPAK+ZINC or other
retroviral therapies being studies. Less virus, less hemoglobin losing
its iron, less severity and damage.
Therapies used for anyone with abnormal hemoglobin or malfunctioning red
blood cells. Blood transfusions. Whatever, I don't know the full breadth
and scope because I'm not a physician. But think along those lines, and
treat the real disease. If you're thinking about giving them plasma with
antibodies, maybe if they're already in bad shape think again and give
them BLOOD with ant ibodies, or at least blood followed by plasma with
antibodies. Now that we know more about how this virus works and affects
our bodies, a whole range of options should open up.
Don't trust China. China is ASSHOE. (disclaimer: not talking about the
people, just talking about the regime). They covered this up and have
caused all kinds of death and carnage, both literal and economic. The
ripples of this pandemic will be felt for decades.
Fini.
(2) 85 COVID Patients at Dr Brownstein's Center for Holistic Medicine:
Zero Hospitalizations and No Deaths
85 COVID Patients at The Center for Holistic Medicine: Zero
Hospitalizations and No Deaths
Apr 09 2020
At my office, the Center for Holistic Medicine (CHM), we have had 85
COVID patients. At this time, no one has been hospitalized, no one has
been diagnosed with pneumonia, and there have been no deaths.
There are five practitioners at CHM: Drs. Brownstein, Ng, Nusbaum, Jenny
Drummond, PA, and Taylor Easson, NP. Since the start of the COVID-19
crisis, I have been asking my partners how their COVID patients are
doing. As of this week, we have had 85 patients either diagnosed with
COVID or suspected COVID. I am pleased to report that our patients are
doing well with this illness. (Note, since new guidelines have come out
stating that any suspected COVID patient can be diagnosed with COVID, I
am lumping COVID and suspected COIVD patients together for this post.)
I first reported to you about COVID on January 26, 2020. That was the
first time I presented our protocol of using vitamins A, C, D, and
iodine not only to support the immune system but also to treat viral
infections. In that post, I also pointed out how important eating a
healthy diet is. The importance of using intravenous nutrient therapy,
especially vitamin C, was mentioned. Finally, I suggested that, with
coronavirus, it would be wise not to get a flu vaccine since the flu
vaccine has been shown to significantly increase the risk of coronavirus
and other flu-like viral infections.
That post seems like a lifetime ago even though it was only 10 weeks
ago. During that time period, my message has not changed. In fact,
after witnessing the results our patients have experienced, I am more
convinced than ever that a holistic approach like I presented above
should be the first-line treatment provided to any COVID patient.
The human body is a true wonder. Given the proper support, it can do
wonders. And, when the body is healthy, it can withstand and overcome an
infectious illness like COVID.
The initial conventional approach to COVID was to encourage people to
wash their hands (a good thing). As things worsened, the only other
conventional idea was to quarantine. When the disease spun out of
control our Government and conventional medicine panicked. They had no
real therapies to help COVID-suffering patients except for supportive
care. Thankfully, a few conventional therapies, like hydroxychloroquine
and azithromycin, have been promoted—though many in conventional
medicine were downplaying it for far too long.
At my office, we were ready. The first 24 years of practicing holistic
medicine was our time to figure out what worked and what did not work
for people suffering from viral infections. That set us up to be ready
for this pandemic.
In my blogs, I encouraged people to take high doses of vitamins A, C, D,
and iodine at the first sign of an illness. In our practice, this was
sufficient for the majority of our COVID patients. I (and my partners)
have no doubt that the vast majority of COVID patients would avoid a
deterioration of their symptoms if they started this protocol at the
onset of symptoms.
However, some became more ill or did not start the oral supplements
early enough into their illness. Those patients needed additional
holistic therapies. These included nebulizing hydrogen peroxide and
iodine along with intravenous nutrient therapies.
To protect our staff and healthy patients, we did not treat sick COVID
patients inside my office. We were gowning up and meeting our patients
at their automobile at the back of our building and administering IVs
and ozone therapies. Some of these patients were very sick. So far, they
all recovered. I have shared some of their stories via a skype interview
on previous blog posts. To watch a few of our patient testimonials go to:
There Is Still Hope Out There (3/28/20): Christopher
There Is Still Hope Out There (3/30/20): Jeremiah
There Is Still Hope Out There (4/05/20): Kendra
I think the end is in sight. We seem to be crossing over the hump of
this dreadful disease. I have no doubt we will be in a much better
position over the coming two weeks.
Folks, I hope the Powers-That-Be learn from this catastrophe. In the
future, we need to focus on supporting the host rather than conventional
medicine’s focus on killing the infectious organism. We do not have a
vaccine or any other conventional therapy that is successful at
destroying COVID. In the future, I can guarantee you there will be other
infectious illnesses that conventional medicine has no treatment to
offer. Instead of waiting for the hail-Mary from conventional medicine,
it is better to be prepared and have your body ready to fight back. This
can be achieved by following my original instructions; eat a healthy
diet, maintain optimal hydration, exercise, and correct nutrient
imbalances with vitamin and mineral supplementation.
If you don’t have a holistic doctor, it is past time to find one. At my
office, we are happy to see you or do a telemed appointment. If you are
interested in this please email Ann Salomon at
A holistic doctor can help you achieve your optimal health. Conventional
doctors, on the other hand, are busy diagnosing pathology and
prescribing the drug to treat that diagnosis. The problem with the
conventional model is that the drug prescribed does not promote health
as nearly all drugs poison enzymes and block receptors in the body.
There is a time and a place for drug therapies, but they are well
over-prescribed in the US. The use of many drug therapies leaves the
body depleted of vital nutrients that it will need when confronted with
something like COVID.
As I previously stated, the Center for Holistic Medicine currently has
85 COVID patients who are all doing well and have not been hospitalized.
There were some I was worried about—they kept me up at night. I called
them daily to monitor their progress. Having them increase the frequency
of nebulizing hydrogen peroxide and iodine helped them all. Some of the
sickest were advised to nebulize every hour or two for a short period.
IV therapies and ozone treatments have helped many.
This therapy has worked for helping COVID patients. It is sad that
hospitalized COVID patients are not given the proper nutritional support
when they are admitted. In a perfect world, I would immediately start an
IV of vitamin C and begin nebulizing any hospitalized COVID patient with
hydrogen peroxide and iodine. I am sure that would markedly lower the
need for mechanical ventilation.
Final Thoughts:
Like most holistic therapies, the earlier they are started in a disease
process the better they perform. AT THE FIRST SIGN OF A VIRAL ILLNESS I
ENCOURAGE MY PATIENTS TO START MY VIRAL PROTOCOL OF TAKING VITAMINS A,
C, D AND IODINE. Due to the severity of COVID, I now recommend
starting to nebulize hydrogen peroxide and iodine early into the illness
as well.
Better times are coming. Keep me updated on how you are doing. I will
much more to talk about in relation to COVID. More posts will be coming
soon.
To All Our Health,
~DrB
(3) Remdesivir & Chloroquine effectively inhibit Covid-19 vitro; authors
include Zhengli Shi, director of P4 lab at Wuhan Institute of Virology
But Remdesivir is difficult to manufacture, and expensive; Chloroquine
is cheap - Peter M.
chris lancenet <chrislancenet@gmail.com>
authors: Zhengli Shi's team
Cell Research
Nature Publishing Group
Cell Res. 2020 Mar; 30(3): 269–271.
Published online 2020 Feb 4. doi: 10.1038/s41422-020-0282-0
PMCID: PMC7054408
PMID: 32020029
Remdesivir and chloroquine effectively inhibit the recently emerged
novel coronavirus (2019-nCoV) in vitro Manli Wang,#1 Ruiyuan Cao,#2
Leike Zhang,#1 Xinglou Yang,#1 Jia Liu,1 Mingyue Xu,1 Zhengli Shi,1
Zhihong Hu,corresponding author1 Wu Zhong,corresponding author2 and
Gengfu Xiaocorresponding author1
Dear Editor,
In December 2019, a novel pneumonia caused by a previously unknown
pathogen emerged in Wuhan, a city of 11 million people in central China.
The initial cases were linked to exposures in a seafood market in
Wuhan.1 As of January 27, 2020, the Chinese authorities reported 2835
confirmed cases in mainland China, including 81 deaths. Additionally, 19
confirmed cases were identified in Hong Kong, Macao and Taiwan, and 39
imported cases were identified in Thailand, Japan, South Korea, United
States, Vietnam, Singapore, Nepal, France, Australia and Canada. The
pathogen was soon identified as a novel coronavirus (2019-nCoV), which
is closely related to sever acute respiratory syndrome CoV (SARS-CoV).2
Currently, there is no specific treatment against the new virus.
Therefore, identifying effective antiviral agents to combat the disease
is urgently needed.
An efficient approach to drug discovery is to test whether the existing
antiviral drugs are effective in treating related viral infections. The
2019-nCoV belongs to Betacoronavirus which also contains SARS-CoV and
Middle East respiratory syndrome CoV (MERS-CoV). Several drugs, such as
ribavirin, interferon, lopinavir-ritonavir, corticosteroids, have been
used in patients with SARS or MERS, although the efficacy of some drugs
remains controversial.3 In this study, we evaluated the antiviral
efficiency of five FAD-approved drugs including ribavirin, penciclovir,
nitazoxanide, nafamostat, chloroquine and two well-known broad-spectrum
antiviral drugs remdesivir (GS-5734) and favipiravir (T-705) against a
clinical isolate of 2019-nCoV in vitro.
Standard assays were carried out to measure the effects of these
compounds on the cytotoxicity, virus yield and infection rates of
2019-nCoVs. Firstly, the cytotoxicity of the candidate compounds in Vero
E6 cells (ATCC-1586) was determined by the CCK8 assay. Then, Vero E6
cells were infected with nCoV-2019BetaCoV/Wuhan/WIV04/2
multiplicity of infection (MOI) of 0.05 in the presence of varying
concentrations of the test drugs. DMSO was used in the controls.
Efficacies were evaluated by quantification of viral copy numbers in the
cell supernatant via quantitative real-time RT-PCR (qRT-PCR) and
confirmed with visualization of virus nucleoprotein (NP) expression
through immunofluorescence microscopy at 48 h post infection (p.i.)
(cytopathic effect was not obvious at this time point of infection).
Among the seven tested drugs, high concentrations of three nucleoside
analogs including ribavirin (half-maximal effective concentration (EC50)
= 109.50 mM, half-cytotoxic concentration (CC50) > 400 mM, selectivity
index (SI) > 3.65), penciclovir (EC50 = 95.96 mM, CC50 > 400 mM, SI >
4.17) and favipiravir (EC50 = 61.88 mM, CC50 > 400 mM, SI > 6.46) were
required to reduce the viral infection (Fig. 1a and
Supplementary information, Fig. S1). However, favipiravir has been shown
to be 100% effective in protecting mice against Ebola virus challenge,
although its EC50 value in Vero E6 cells was as high as 67 mM,4
suggesting further in vivo studies are recommended to evaluate this
antiviral nucleoside. Nafamostat, a potent inhibitor of MERS-CoV, which
prevents membrane fusion, was inhibitive against the 2019-nCoV infection
(EC50 = 22.50 mM, CC50 > 100 mM, SI > 4.44). Nitazoxanide, a commercial
antiprotozoal agent with an antiviral potential against a broad range of
viruses including human and animal coronaviruses, inhibited the
2019-nCoV at a low-micromolar concentration (EC50 = 2.12 mM; CC50 >
35.53 mM; SI > 16.76). Further in vivo evaluation of this drug against
2019-nCoV infection is recommended. Notably, two compounds remdesivir
(EC50 = 0.77 mM; CC50 > 100 mM; SI > 129.87) and chloroquine (EC50 =
1.13 mM; CC50 > 100 mM, SI > 88.50) potently blocked virus infection at
low-micromolar concentration and showed high SI (Fig. 1a, b).
The antiviral activities of the test drugs against 2019-nCoV in vitro. a
Vero E6 cells were infected with 2019-nCoV at an MOI of 0.05 in the
treatment of different doses of the indicated antivirals for 48 h. The
viral yield in the cell supernatant was then quantified by qRT-PCR.
Cytotoxicity of these drugs to Vero E6 cells was measured by CCK-8
assays. The left and right Y-axis of the graphs represent mean %
inhibition of virus yield and cytotoxicity of the drugs, respectively.
The experiments were done in triplicates. b Immunofluorescence
microscopy of virus infection upon treatment of remdesivir and
chloroquine. Virus infection and drug treatment were performed as
mentioned above. At 48 h p.i., the infected cells were fixed, and then
probed with rabbit sera against the NP of a bat SARS-related CoV2 as the
primary antibody and Alexa 488-labeled goat anti-rabbit IgG (1:500;
Abcam) as the secondary antibody, respectively. The nuclei were stained
with Hoechst dye. Bars, 100 mm. c and d Time-of-addition experiment of
remdesivir and chloroquine. For "Full-time" treatment, Vero E6 cells
were pre-treated with the drugs for 1 h, and virus was then added to
allow attachment for 2 h. Afterwards, the virus–drug mixture was
removed, and the cells were cultured with drug-containing medium until
the end of the experiment. For "Entry" treatment, the drugs were added
to the cells for 1 h before viral attachment, and at 2 h p.i., the
virus–drug mixture was replaced with fresh culture medium and maintained
till the end of the experiment. For "Post-entry" experiment, drugs were
added at 2 h p.i., and maintained until the end of the experiment. For
all the experimental groups, cells were infected with 2019-nCoV at an
MOI of 0.05, and virus yield in the infected cell supernatants was
quantified by qRT-PCR c and NP expression in infected cells was analyzed
by Western blot d at 14 h p.i.
Remdesivir has been recently recognized as a promising antiviral drug
against a wide array of RNA viruses (including SARS/MERS-CoV5) infection
in cultured cells, mice and nonhuman primate (NHP) models. It is
currently under clinical development for the treatment of Ebola virus
infection.6 Remdesivir is an adenosine analogue, which incorporates into
nascent viral RNA chains and results in pre-mature termination.7 Our
time-of-addition assay showed remdesivir functioned at a stage post
virus entry (Fig. 1c, d), which is in agreement with its putative
anti-viral mechanism as a nucleotide analogue. Warren et al. showed that
in NHP model, intravenous administration of 10 mg/kg dose of remdesivir
resulted in concomitant persistent levels of its active form in the
blood (10 mM) and conferred 100% protection against Ebola virus
infection.7 Our data showed that EC90 value of remdesivir against
2019-nCoV in Vero E6 cells was 1.76 mM, suggesting its working
concentration is likely to be achieved in NHP. Our preliminary data
(Supplementary information, Fig. S2) showed that remdesivir also
inhibited virus infection efficiently in a human cell line (human liver
cancer Huh-7 cells), which is sensitive to 2019-nCoV.2
Chloroquine, a widely-used anti-malarial and autoimmune disease drug,
has recently been reported as a potential broad-spectrum antiviral
drug.8,9 Chloroquine is known to block virus infection by increasing
endosomal pH required for virus/cell fusion, as well as interfering with
the glycosylation of cellular receptors of SARS-CoV.10 Our
time-of-addition assay demonstrated that chloroquine functioned at both
entry, and at post-entry stages of the 2019-nCoV infection in Vero E6
cells (Fig. 1c, d). Besides its antiviral activity, chloroquine has an
immune-modulating activity, which may synergistically enhance its
antiviral effect in vivo. Chloroquine is widely distributed in the whole
body, including lung, after oral administration. The EC90 value of
chloroquine against the 2019-nCoV in Vero E6 cells was 6.90 mM, which
can be clinically achievable as demonstrated in the plasma of rheumatoid
arthritis patients who received 500 mg administration.11 Chloroquine is
a cheap and a safe drug that has been used for more than 70 years and,
therefore, it is potentially clinically applicable against the 2019-nCoV.
Our findings reveal that remdesivir and chloroquine are highly effective
in the control of 2019-nCoV infection in vitro. Since these compounds
have been used in human patients with a safety track record and shown to
be effective against various ailments, we suggest that they should be
assessed in human patients suffering from the novel coronavirus disease.
Acknowledgements
We thank Xi Wang, Yan Wu, Weijuan Shang, Huanyu Zhang, Yufeng Li,
Hengrui Hu, Xiaming Jiang, Yuan Sun, from Wuhan Institute of Virology
for their essential assistance with this study. We thank Prof. Fei Deng
from National Virus Resource Center, and Tao Du, Jia Wu and Hao Tang
from BSL-3 Laboratory of Wuhan Institute of Virology for their critical
support. We thank Prof. Yanyi Wang and other colleagues of Wuhan
Institute of Virology and Wuhan National Biosafety Laboratory for their
excellent coordination. We thank Dr. Basil Arif for scientific editing
of the manuscript. We thank the anonymous reviewers for their valuable
suggestions. This work was supported in part by grants from the National
Science and Technology Major Projects for "Major New Drugs Innovation
and Development" (directed by Prof. Song Li) (2018ZX09711003), the
National Natural Science Foundation of China (31621061), and the
Emergency Scientific Research Project for 2019-nCoV from Hubei Province
(to Profs. Zhengli Shi and Gengfu Xiao).
Author contributions
G.X., W.Z., Z.H., M.W., R.C., and L.Z. conceived and designed the
experiments. X.Y., J.L., M.X., M.W., R.C., and L.Z. participated in
multiple experiments; G.X., W.Z., Z.H., Z.S., M.W., R.C., and L.Z.
analyzed the data. M.W., L.Z., R.C., and Z.H. wrote the manuscript.
G.X., W.Z., and Z.H. provided the final approval of the manuscript.
The authors declare no competing interests.
These authors contributed equally: Manli Wang, Ruiyuan Cao, Leike Zhang,
Xinglou Yang.
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(4) 2016 paper in PNAS "SARS-like WIV1-CoV poised for human emergence"
thanks Zhengli-Li Shi of Wuhan Institute of Virology for bat CoV
sequences and plasmid of WIV1-CoV spike protein
Zhengli-Li Shi is mentioned in the ACKNOWLEDGMENTS at the end.
From: E (epidemiologist in USA)
Proceedings of the National Academy of Sciences of the USA
SARS-like WIV1-CoV poised for human emergence
Vineet D. Menachery, Boyd L. Yount Jr., Amy C. Sims, Kari Debbink,
Sudhakar S. Agnihothram, Lisa E. Gralinski, Rachel L. Graham, Trevor
Scobey, Jessica A. Plante, Scott R. Royal, Jesica Swanstrom, Timothy P.
Sheahan, Raymond J. Pickles, Davide Corti, Scott H. Randell, Antonio
Lanzavecchia, Wayne A. Marasco, and Ralph S. Baric
PNAS March 15, 2016 113 (11) 3048-3053; first published March 14, 2016
Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New
York, NY, and approved January 6, 2016 (received for review September 4,
2015)
Outbreaks from zoonotic sources represent a threat to both human disease
as well as the global economy. Despite a wealth of metagenomics studies,
methods to leverage these datasets to identify future threats are
underdeveloped. In this study, we describe an approach that combines
existing metagenomics data with reverse genetics to engineer reagents to
evaluate emergence and pathogenic potential of circulating zoonotic
viruses. Focusing on the severe acute respiratory syndrome (SARS)-like
viruses, the results indicate that the WIV1-coronavirus (CoV) cluster
has the ability to directly infect and may undergo limited transmission
in human populations. However, in vivo attenuation suggests additional
adaptation is required for epidemic disease. Importantly, available SARS
monoclonal antibodies offered success in limiting viral infection absent
from available vaccine approaches. Together, the data highlight the
utility of a platform to identify and prioritize prepandemic strains
harbored in animal reservoirs and document the threat posed by WIV1-CoV
for emergence in human populations. [...]
ACKNOWLEDGMENTS. We thank Dr. Zhengli-Li Shi of the Wuhan Institute of
Virology for access to bat CoV sequences and plasmid of WIV1-CoV spike
protein. Research was supported by the National Institute of Allergy and
Infectious Disease and the National Institute of Aging of the NIH under
Awards U19AI109761 and U19AI107810 (to R.S.B.), AI1085524 (to W.A.M.),
and F32AI102561 and K99AG049092 (to V.D.M.). Human airway epithelial
cell cultures were supported by the National Institute of Diabetes and
Di-gestive and Kidney Disease under Award NIH DK065988 (to S.H.R.).
Support for the generation of the mice expressing human ACE2 was
provided by NIH Grants AI076159 and AI079521 (to A.C.S.). ==
(5) Nature issues an apology for linking COVID19 to Wuhan
From: E (epidemiologist in USA)
(6) Marine LePen on Didier Raoult and HCQ
From: leo schmit <leoschmit@yahoo.com>
Subject: Marine LePen
Peter,
In the link below MLP responds to questions of some 'adherents',
including one Q at around 22:00 concerning Dr. Raoult's application of
hydroxyclorine (plaquenil) with antibiotic azithromycine. She points out
that this therapy can only work in an initial stage and she is highly
critical of the authorities who insist to do a clinical review among
those patients who are already hospitalised in a 'grave state of
health', when this therapy cannot be effective.
MLP also has some remarks on her willingness to contribute to the unity
of France and restore the confidence of the people in politics, saying
that the only way to achieve that is when the government stops lying to
its citizens. And more on EU...
(7) Marine LePen on Didier Raoult and HCQ
From: G in Rouen
She says she is not a medical expert.
She quotes Professor Rault, the initial and principal proponent of this
treatment - a combination of hydroxychloroquine + an antibiotic - as
proposing this medicine at the beginning of an infection to hinder the
build up of the viral load in the patient.
the French govt however is only allowing it to be used on gravely ill
patients and she says this is an incoherent govt policy and wastes the
chance of this treatment being successful since it should be used in the
early stages before the viral load build up
She hopes there will ultimately be an enquiry into this approach of the
government she deplores the deaths of patients in retirement homes who
are dying in the absence of their loved ones (due to very strict
quarantine rules in these homes and implies their outcome might have
been better had the treatment been properly used.
*******************
Just to give you some background. The scientific establishment in France
is very cautious about this treatment since it can have some adverse
side effects. There is a large scale trial underway of several possible
treatments including this drug.
Although chloroquine has been around for a long time as an anti-malarial
(I took it for two years when I worked in Botswana 1975-76), the dosage
is much higher (x2 I have heard mentioned) in Professor Rault's
treatment than the anti-malarial dose.
{but the prophylactic dose, recommended by the Government of India, is
the same as for malaria: 2 x 250mg tablets a week. I am taking that dose
myself; my tablets are 40 years old - Peter M.
}
This treatment was not officially sanctioned in France but there were
doctors who advocated its use as there seemed to be nothing else so
under pressure the govt said it could be used if requested by a patient
but only in a hospital setting in case of adverse side effects. You have
to have a grave case to be admitted to hospital - they are under
enormous strain.
Also Professor Rault it appears to me is a fringe figure in the French
medical establishment - long hair, beard - to some he probably comes
across as a hippie in a white coat, but he does seem to head a
significant medical establishment at Marseille.
by the way did you know that you can turn on subtitles on Youtube and if
you are lucky it is also possible to have the subtitles translated. I
did this last week for a different Youtube video - I had the English
translated into French. I also tried with this one, I obtained the
subtitles but didn't manage to establish the translation. Don't know why
- maybe it doesn't exist. There would be a much higher demand for
English to French translations than the inverse I expect
(8) Alain Soral on the Politics of the Coronavirus
From: Laurent Guyénot <l.guyenot109@orange.fr>
Alain Soral's take on the "Corona hustle" with English ST:
Part 1 : https://youtu.be/UbNoW73OQ48
Part 2 : https://youtu.be/UB-oTrsY2gA
Part 3 : https://youtu.be/63WlysVLDEA
Check also his earlier video on "Environmentalism & New World Order":
And if you like it, subscribe to the New Video Channel ERTV International:
(9) New drugs EIDD-1931, EIDD-2801 for Covid-19
These new medicines are NOT vaccines. These new drugs were developed, in
part, by Ralph Baric, whose lab in North Carolina did gain-of-function
research in 2015, in which an ancestor of Covid-19 was bred. Note item 4
above, where Baric et al thank Zhengli-Li Shi of Wuhan Institute of
Virology for bat CoV sequences and plasmid of WIV1-CoV spike protein.
She participated in that 2015 research at the University of North
Carolina. More details at http://mailstar.net/coronavirus.html - Peter M.
From: E (epidemiologist in USA)
Ralph Baric, PhD, are working with colleagues in the lab of Mark
Denison, MD, Edward Claiborne Stahlman Professor of pediatrics at
Vanderbilt University Medical Center (VUMC), and with George Painter,
PhD, chief executive officer of the nonprofit DRIVE (Drug Innovation
Ventures at Emory) and director of the Emory Institute for Drug
Development (EIDD), where EIDD-2801 was discovered.
The results of the team's most recent study were published online April
6 by the journal Science Translational Medicine. The paper includes data
from cultured human lung cells infected with SARS-CoV-2, as well as mice
infected with the related coronaviruses SARS-CoV and MERS-CoV.
The study found that, when used as a prophylactic, EIDD-2801 can prevent
severe lung injury in infected mice. (EIDD-2801 is an orally available
form of the antiviral compound EIDD-1931; it can be taken as a pill and
can be properly absorbed to travel to the lungs.)
When given as a treatment 12 or 24 hours after infection has begun,
EIDD-2801 can reduce the degree of lung damage and weight loss in mice.
This window of opportunity is expected to be longer in humans, because
the period between coronavirus disease onset and death is generally
extended in humans compared to mice.
"This new drug not only has high potential for treating COVID-19
patients, but also appears effective for the treatment of other serious
coronavirus infections," said senior author Baric.
Compared with other potential COVID-19 treatments that must be
administered intravenously, EIDD-2801 can be delivered by mouth as a
pill. In addition to ease of treatment, this offers a potential
advantage for treating less-ill patients or for prophylaxis — for
example, in a nursing home where many people have been exposed but are
not yet sick.
"We are amazed at the ability of EIDD-1931 and -2801 to inhibit all
tested coronaviruses and the potential for oral treatment of COVID-19.
This work shows the importance of ongoing National Institutes of Health
(NIH) support for collaborative research to develop antivirals for all
pandemic viruses, not just coronaviruses" said Andrea Pruijssers, PhD,
the lead antiviral scientist in the Denison Lab at VUMC.
Denison was senior author of a December 2019 study that first reported
that EIDD-1931 blocked the replication of a broad spectrum of coronaviruses.
These interinstitutional collaborators, supported by an NIH grant
through the University of Alabama at Birmingham, also performed the
preclinical development of remdesivir, another antiviral drug currently
in clinical trials of patients with COVID-19. In the new Science
Translational Medicine paper, Maria Agostini, PhD, a postdoctoral fellow
in the Denison lab, demonstrated that viruses that show resistance to
remdesivir experience higher inhibition from EIDD-1931.
"Viruses that carry remdesivir resistance mutations are actually more
susceptible to EIDD-1931 and vice versa, suggesting that the two drugs
could be combined for greater efficacy and to prevent the emergence of
resistance," said Painter.
Clinical studies of EIDD-2801 in humans are expected to begin later this
spring. If they are successful, the drug could not only be used to limit
the spread of SARS-CoV-2, but also could control future outbreaks of
other emerging coronaviruses.
"With three novel human coronaviruses emerging in the past 20 years, it
is likely that we will continue to see more," said first author Timothy
Sheahan, PhD, a Gillings assistant professor of epidemiology and a
collaborator in the Baric Lab. "EIDD-2801 holds promise to not only
treat COVID-19 patients today, but to treat new coronaviruses that may
emerge in the future."
Contact the Gillings School of Global Public Health communications team
at sphcomm@unc.edu.
(10) EIDD-2801 could become the first pill for COVID-19 - Scientific
American
From: E (epidemiologist in USA)
New Coronavirus Drug Shows Promise in Animal Tests
Slated for human trials, EIDD-2801 could become the first pill for COVID-19
By Michael Waldholz
Scientific American April 7, 2020
An oral medicine was able to hinder the coronavirus behind COVID-19 as
it attempted to replicate itself in human lung cells in test tubes,
scientists reported Monday. It also hampered closely related
coronaviruses from reproducing in mice for several days and improved
their lung functions.*
The drug, called EIDD-2801, interferes with a key mechanism that allows
the SARS-CoV-2 virus to reproduce in high numbers and cause infections,
the researchers explained in the journal Science Translational Medicine.
Human trials have not yet been done, but if the effect is similar in
people, the drug would be the first pill available to help with the
COVID-19 pandemic, which has resulted in more than 1.3 million cases and
about 76,400 deaths worldwide. An oral medication would be a boon,
because it would be easier to give to more people than an intravenous
injection.
The study was done by a team at Emory University, the University of
North Carolina at Chapel Hill and Vanderbilt University Medical Center
in Nashville, Tenn. A company that has licensed the drug, Ridgeback
Biotherapeutics, has just been granted permission from the U.S. Food and
Drug Administration to begin 10 patient trials of the antiviral pill in
the next few months.
The same university collaboration had already found that Gilead
Sciences' experimental medicine remdesivir was effective in shutting
down replication of the coronaviruses that caused the original SARS and
MERS epidemics. Remdesivir has received attention because it entered
clinical trials against SARS-CoV-2 in March, and the first results may
come by late April. The findings announced yesterday indicate that
EIDD-2801 was possibly even more successful in disrupting coronavirus
replication than the Gilead drug. On March 20 the researchers
investigating EIDD-2801, co-led by Tim Sheahan of Chapel Hill, posted
the results of their animal studies on the preprint server bioRxiv while
submitting them for peer review. Given the current COVID-19 crisis, "it
was important to share," says George Painter, a professor of chemistry
and executive director of the Emory Institute for Drug Development,
which first produced the drug.
Back in 2018 Painter and the labs he leads identified EIDD-2801's
activity during a search for a universal influenza medicine. Last
October, before the pandemic hit, the Emory program got $15.9 million
from the National Institute of Allergy and Infectious Diseases to
perform human tests of the drug against the flu virus that was likely to
be circulating later in the year. When SARS-CoV-2 emerged, Painter's
group immediately shifted focus.
EIDD-2801 inhibits the coronavirus's self-copying operations in a manner
that is different from remdesivir. While remdesivir brings that
replication process to a full stop, EIDD-2801 introduces
mutations—mistakes—into the virus's RNA as it makes copies so that the
viral RNA becomes so damaged that it cannot infect cells. Another
feature of the drug is that it is able to work against a host of other
RNA viruses. Thus, it could serve as a multipurpose antiviral, much in
the way some antibiotics can work against a wide variety of bacteria. In
several preclinical studies, researchers from multiple labs have shown
that EIDD-2801 was effective against several strains of influenza, as
well as the viruses for respiratory syncytial virus and the viruses for
chikungunya, Venezuelan equine encephalitis and Eastern equine
encephalitis—all microbes that intermittently pop up in different parts
of the world and produce widespread sickness in their wake.
The compound may be initially beneficial as a "prophylaxis [that] health
care workers can take to prevent an infection," says Wayne Holman,
co-founder of Miami-based Ridgeback Biotherapeutics, which has licensed
the drug from Emory's nonprofit biotech company Drug Innovation Ventures
at Emory (DRIVE). Another potential use of EIDD-2801 might be to protect
uninfected nursing home residents and workers if an outbreak occurs
inside a facility. Holman says the wider goal is to have an oral pill
that can be taken twice a day by patients at home early in the course of
the disease to prevent it from progressing to hospitalization,
mechanical ventilation or death.
In addition to planning clinical trials in the U.S., Ridgeback has also
asked U.K. authorities to start tests there as well. "We've done three
to four years of development work in just the past three to four weeks
in response to the new pandemic," Holman says.
*Editor's Note (4/7/20): This paragraph was edited after posting to
correct the description of the study's findings. Only coronaviruses
related to SARS-CoV-2 were tested in mice, not SARS-CoV-2 itself.
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