Guest post by Rud Istvan,
In the 3/19 Wuhan virus briefing with the FDA, team Trump made much of the possibilities for two therapeutic candidates, chloroquine and remdesivir. Having now done informed basic research on both, I found their stories intrinsically interesting, while enabling an early assessment of their chances of success. Hence this hopeful guest post.
Background
Wuhan coronavirus is an enveloped positive sense single strand RNA virus, meaning its core genetic RNA code is just one long chain coding directly for several proteins, surrounded first by a protective viral protein capsid coat, and then a lipid membrane ‘envelope’ from which project so called “E” (for envelope) and “S” (for spike) proteins. The S protein is what the virus uses to bind to and then invade the lung’s epithelial cells in order to hijack those cell’s reproductive machinery to make copies of itself using its RNA polymerase, itself encoded in about 2/3 of the core viral genetics. The newly assembled virions that then bud out to infect new cells also eventually kill the infected epithelial cell. Covid 19 disease is caused both by the death of those cells and the immune system’s eventual response to the infection.
The S spikes are also the reason this virus class is named corona, because the spikes make it look under SEM like the virus is wearing a crown.
Chloroquine
These are actually two closely related anti-malarials, hydroxychloroquine (the small French trial) and chloroquine phosphate (the larger Chinese trial). Both were developed in the 1950’s, and interestingly the main use now is to treat rheumatoid arthritis rather than malaria (which evolved resistance).
The discovery that certain classes of anti-malarials also affect rheumatoid arthritis (RA) was made quite by accident in 1951 by an asute doctor treating malaria in an RA patient. The problem then was the side effects of chronic RA use made them unacceptable for RA. The chloroquines were developed expressly as ‘milder’ side effect anti-malarials, and in the mid to late 1950’s there were a number of papers (I reviewed several for this post) reporting good RA safety and efficacy leading to global approvals for that indication.
The mechanism of chloroquine action on RA has long been well known. It increases a cell’s lysosomal pH. (Lysosomes are membrane bound cellular organelles [think tiny balloons inside the cell floating at a lower pH in the higher pH cytosol] containing about 50 enzymes, discovered and named in 1955.) This in turn changes their ‘leaked’ enzyme balance into the cytosol, which then inhibits the cell’s RA tissue antigen signaling, which in turn reduces the immune system’s attack on the RA tissue, slowing (but usually not stopping) progression of RA tissue damage.
The reason the Chinese and then the French thought to use chloroquine against Wuhan coronavirus is this same mechanism of action, albeit with different sequelae. The viral S protein binds to the epithelial cell wall’s angiotensin-converting enzyme 2 (ACE2) receptor. Raising lysosomal pH changes (via indirect enzymatic action) the ‘shape’ of ACE2 enough that the S protein cannot bind to it, thus preventing cell infection. Chloroquine changes the cell ‘lock’ so the viral ‘key’ doesn’t work. Does not undo damage from infected cells, nor prevent an infected person from shedding existing viable virus, but does stop the spread in an infected person’s body—a promising therapeutic for those testing positive.
Since safety is well known (the main side affect is retinopathy [vision problems] in 25% of patients over 50 that resolves [slowly] after discontinuation), the main FDA legal issue (FDCA Act of 1906 as amended) issue is to determine dosing and duration for this new indication. But for starters, the standard RA 250mg once a day generic cheap pill should suffice for emergency use authorization (EUA). As a ‘Big Pharma’ goodwill gesture, today (3/19) Bayer announced it donated 3 million 250mg chloroquine phosphate pills to the US to get started.
Remdesivir
This is a novel antiviral from Gilead that has a somewhat checkered past. It was originally developed for Ebola, where in African trials a few years ago it was shown reasonably safe but not very effective. It did, however, show efficacy against SARS and MERS in vitro. And, importantly, the NEJM reported a positive case outcome in Seattle patient zero under a compassionate use exception. The patient had visited Wuhan, returned to Seattle, began displaying symptoms, and was hospitalized on symptom day 3. By symptom day 8 X-ray showed clear lower respiratory tract viral pneumonia (diagnostic ‘ground glass’) and supplemental oxygen was started. Patient worsened, and intravenous antibiotics were started day 9. Patient worsened (proving viral pneumonia), so attending physicians consulted with FDA then had Gilead rush the experimental drug by air, with intravenous treatment starting day 10. Patient improved in 24 hours, was saved, and has since been discharged. For those interested, there is this NEJM case report providing a very hopeful proof of principle.
The reason Gilead tested it against SARS and MERS even though those two episodes died out naturally has to do with Remdesivir’s novel mechanism of action. The ‘drug’ is just an analog of the amino acid adenosine, one of the 20 amino acid (only, in all life on Earth, proving a common genetic ancestor) building blocks the viral polymerase uses to ‘assemble’ new copies of the viral RNA genetic code. The polymerase does not recognize the small difference between adenosine and the analog. Flood an infected cell with enough remdesivir molecules, and the polymerase will eventually grab one and add it to the ‘building’ RNA copy. Remdesivir is enough different that the polymerase is then blocked from adding any more amino acids to the RNA chain, so viral replication halts. Neat very basic molecular genetics provided at a basic science 101 level.
What Gilead scientists recognized was that the RNA code for Ebola RNA polymerase was very similar to SARS and MERS RNA polymerase, hence the in vitro testing. And when the Chinese first published the roughly 30,000 base RNA code for Wuhan coronavirus in January, it was evident immediately that it was another good RNA polymerase match, so they started immediate in vitro testing once viral samples were in hand.
Aside from price (Gilead is infamous for its Hep C cure that ‘only’ costs about $100,000 per treated patient), and scaled up availability (none yet, same issue that killed my 3 of 4 EUA for a persistent hand sanitizer in the 2009 swine flu pandemic), there are questions about dosing and treatment timing. There is some thought that remdesivir may not be useful past symptom day 10 or 11, typically when a patient worsens to need an ICU ventilator. The concern logic is simple. Remdesivir blocks virion replication in an infected cell, but not its spread to newly infected cells by virions from previously infected cells. So basically a quantity/quality argument saying eventually blocking further spread when you already need a ventilator for viral pneumonia is futile. Those clinical questions are why China is conducting a double blind (drug/placebo) trial on ~790 patients in Beijing and Gilead is conducting an unblinded smaller trial in the US, starting in Nebraska with Diamond Princess patients. The first results from both will be available sometime in April.
Further observations
Neither chloroquine nor remdesivir are just luck. The rapidity of their development against Wuhan virus reflects the enormously powerful insights that molecular genetics and molecular biology and their associated tools (sequencing, PCR, oligomer synthesis, protein structure) now bring to science and medicine. To echo the contrasts to climate science in my first post on Wuhan, this is as if we actually had now the computational power to avoid parameterization in climate models. Climatologists do not, but virologists do.
Chloroquine probably works, as AW previously posted. It would solve this pandemic’s key issue, progression to viral pneumonia requiring ICU ventilation. New York’s Governor Cuomo said yesterday that he has been told that without ‘bending the curve’ based on Italy, New York will require 27000 ventilators in a few weeks when the state only has 3000. Invoking the Defense Procurement Act cannot solve that mismatch in time without a ‘bent curve’ achieved via social distancing, frequent hand washing, and avoiding touching the mouth, nose, and eyes. All three are difficult but not impossible. Ambassador Dr. Birx is pretty clear about the dire consequences of Millennials ignoring these basic common sense recommendations during Spring Break this week in Florida. Here in ground zero Fort Lauderdale, our public beaches are closed, and the closure is policed.
But chloroquine still has the same Wuhan issue illustrated by its previous use for malaria–evolving resistance. RNA viruses like Wuhan coronavirus mutate rapidly (explained in my first post on this topic). The most conserved protein is necessarily the RNA polymerase. We know this from influenza, where it is the hemagglutinin and neuraminidase envelope proteins (equivalent to Wuhan S) that mutate so the annual vaccine is never ‘right’. Chloroquine may well be effective now, but if Wuhan coronavirus becomes endemic (now likely given its spread in Africa and Southeast Asia), then it is not a long-term solution like a vaccine. But it will probably buy the precious time to get a vaccine.
Remdesivir may be a longer-term therapeutic solution, because it tricks the conserved RNA polymerase. But its cost and efficacy remain to be determined.
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I recently read a report that the University of Minnesota was testing the blood pressure drug losartan against Covid19.
Maybe that’s why there’s a shortage of it? My pharmacy can’t get any. My doctor had to change my BP med.
Grumpy Bill March 20, 2020 at 5:41 pm
Losartan, made in China. Or Indian. There have been recalls on a number of batches over the last year or so. Not the case now. Indian has stopped all medical exports. China has threatened to, and may have.
There are some pill factories in Porta Rico that were knocked out by the hurricanes 2017. There is talk of getting them open again
michael
That was pretty much what I thought. Just became curious after reading Mark W’s post.
Hello Istvan,
What’s the chance the World, and especially Italy take China to curt over the delay of the warning?
The communist party new it in late November or early December but had no problem to sign a MoU with Italy to triple the direct fly/week between China and Italy. That was signed in early January!! Then a 1000s of Chinese tourist, buseniss pearson and relatives of the local Chinese community rushed in unchecked.
———–
Gee, it’s as if the ChiCom regime wanted to infect the West.
Well: Didn’t China send propaganda videos to Italy to get them to hug on Chinese people to prove they were not racist –before the Covid 19 ramp in Italy? I can provide links to articles and videos. I am pretty sure this is not a conspiracy theory…
Trojan horse?
Here’s the video. I tell you, it had me stunned… and melts my heart. But, on another level… ugh!
https://www.youtube.com/watch?v=mNMdg4morQs
If anyone can tell me it was not what helped cause Italy’s invitation of the WuHan virus, I would honestly like to know.
” mario lento
March 20, 2020 at 7:13 pm
Here’s the video. I tell you, it had me stunned… and melts my heart. But, on another level… ugh!
https://www.youtube.com/watch?v=mNMdg4morQs
If anyone can tell me it was not what helped cause Italy’s invitation of the WuHan virus, I would honestly like to know.”
Oh dear, you find Italy’s R0
Rud,
Thank you for stressing the reservoir of high quality scientific knowledge assembled by the medical profession over the years; and more, for pointing to the lack of such among climate researchers.
In my ideal world, groups of scientists like medical, chemical, botanical, geological etc. would benefit from this “professionalism” displayed by medical, which long has been the most closed shop of the professions. It is also one that has examinations for continued or more specialised membership, also legislated permissions to conduct forms of research denied to others (like surgeons cutting people with scalpels).
The other professions have been less selective about membership. Almost anyone can self-name as a climate specialist, not so for medical.
Perhaps amusingly, some of the bloggers here are contributing personal medical observations as if they were medical professionals, without stating authorisation. This causes a difficulty when reading the comments of bloggers because one does not know who to believe most.
Rud, you correctly laid out your standing from the start as a benefit to readers. Myself, a Science graduate with Chemistry emphasis, but little formal work on medical topics.
In summary, I wish for more medical-style professionalism in other scientific sub-disciplines. Among other benefits, less of the blatant advertising advocacy that we see in climate research. Geoff S
Cheers for injecting some data and sanity into the discussion.
The nonsense being pushed around by anti-vaxxers and what not is getting ridiculous.
Around 1966, working for CSIRO, we sampled a natural legume Neptunia amplexicaulis that was causing sheep deaths in N-W Queensland. We extracted the toxin and confirmed that its mechanism involved substitution of Selenium for Sulphur in an amino acid. Neptunia was an sccumulator plant. Others are known and for more elements than Se. We later investigated some accumulators for help in mineral exploration using biogeochemistry.
Just for interest, John. Geoff S
That is interesting to this metallurgical engineer! Thanks, Geoff!
A very good estimate of what happens:
http://www.cidrap.umn.edu/news-perspective/2020/03/ecdc-covid-19-not-containable-set-overwhelm-hospitals
J.-P. D.
I believe this is going to sink Trump in the election. It seems obvious to me that even though he correctly shut down the flights into this country early on, he failed to get testing ramped up in this country. And now the cases are going up dramatically. This could have been more easily thwarted had our Government got test kits out much quicker. Compared to South Koreas actions and apparent success, it is obvious that the US government has failed us once again.
Go Home, “Go Home”.
Clever, James.
But it may soon be obvious that Trump and the US government failed to act as swiftly as South Korea to recognize the threat and to get something done about it.
I could never vote D, so this concerns me quite a bit.
re: “But it may soon be obvious that Trump and …”
Nonsense; literally: “the writing of a child.” I will defer to MarkW and others on the other points.
Every country in the world dropped the ball on this, or so one could argue if so inclined.
It makes as much sense as arguing we should have had treatments lined up and stocked on the shelves in case this virus ever appeared.
Recall what was happening at that time in the US?
Impeachment was 24-7.
Is the President a virologist, or epidemiologist?
Does he have 200/20 Amazing Kreskin precognition?
Is it obvious ahead of time which of the “experts” at the CDC or any other of the extensive public health entities in the US are more qualified to be cleaning bed pans that the advising a leader of a large country on the proper response to an emerging infectious disease?
How many countries forbade anyone who had been to China from entering, as of one second past being alerted a new virus had emerged in Wuhan?
That, plus complete closure of the border and a strict policy of zero admittance from the rest of the world, was the only policy that had a single chance of containing this outbreak by the time China got around to telling anyone what was going on.
The virus was likely widespread in Wuhan by mid- and possibly early-December, if not before.
How many flights in and out of that city to the rest of the world in that time?
Who exactly brought the virus to each of the hundreds of thousands of people around the world who now have it, and when? No one has any idea.
Testing would not have preventing anything, because the only way to know to test anyone is when they show up in an emergency room with viral pneumonia. Even then it could be anything.
But by that time it is far too late to trace contacts and contain even that one single lineage of viral propagation. There are several days to as much as two weeks perhaps of latency, in which no symptoms are experienced, and yet a person may be contagious. Then it takes several days to as much as a week before some get to the stage of seeking medical care: We do not run to a hospital when we have a cold or the flu…at least most do not.Some do not even call in sick from work, and in fact many employers offer no sick time, and may even react badly if someone tries to call in sick.
And only then might an alert caregiver administer a test, if they were available, and if that one patient was distinguishable for the many people who get sick in every town every day.
And all that time, the person who infected the patient considered in this example, is infecting others, as is any persons infected by the patient prior to his/her going to a hospital.
And many are getting and spreading the virus with no symptoms whatsoever.
Zero. This group seems to be the majority in fact.
And that is only a partial rundown of the futility and illogic of what you are suggesting…that the President might have somehow been the first man in history to stop an emerging global pandemic in it’s tracks before anyone ever knew a serious threat existed, let alone had any clue what to do about it, or even to identify it in real time.
The nature of this virus makes it increasingly clear, to me anyway, that this die was cast before the person who caught the index infected animal, and brought it to the Wuhan market, ever did so. It was likely cast when, some 20 to 70 years ago, this viral strain evolved in some bat somewhere and passed it to the ancestor of that index animal.
The particulars of a cryptic infection, that has a long latency period, a high proportion of asymptomatic carriers, a high incidence of serious disease in those that do get sick, and is highly transmissible…means that it was always impossible, in my analysis, to catch this in time to do anything about it.
The lesson here is…leave wild animals alone. Do not catch them, do not touch them, do not eat them, and do not bring them into a crowded city and put them in a cage in a crowded food market…EVER!
Let this be the last time this disaster befalls us.
There are plenty more viruses out there, and plenty of other potential disasters.
There has been far too large a number of instances of this exact type of zoonosis in just the past two decades, for anyone to think it will not happen over and over again, as long as people do the sorts of things that led to SARS, Ebola, MERS, and many many others, and now this one.
It is far beyond ludicrous to suggest, let alone believe, one person with no background in any relevant discipline might have prevented such an outcome.
If it was Trump’s fault in the US, whose fault was in everywhere else where they took less decisive actions than he did?
He was excoriated by Democrats and the MSM for ending any flights at all, back when he did so in the case of China.
Amnesia on that.
Even after it was plainly obvious a catastrophic disease outbreak was ongoing on Wuhan, other world leaders did nothing…zero, zip, zilch.
Last week when Trump ended flights from Europe, he was castigated by leaders like Merkel, who said she would not be closing any borders…prior to closing her borders the next day.
Europe refused to close the border crossings though the Alps from the outbreak areas in Italy, even long after it was obvious things were very bad there.
After Merkel closed her borders, the EU President, whose name I do not recall (anyone that stupid should be out of a job retroactive to the day she was installed), said it was a bad idea.
The numbers are looking not good.
We have a guy here claiming that because of Trump, we are all but dead here in the US, and him and his will be fine over in Germany.
A look at the numbers makes him a liar and a fool.
Consider the EU has about as many people as the US, and add all the numbers for those places together, and compare it to the US.
Yesterday in Italy 627 new deaths made the tally 4032 total deaths; 5,986 new cases brought that total to 47,021 total cases. In Italy, the total recovered, 5,129, is over 850 less than the new cases in one day.
New cases yesterday (today’s numbers appear not to have posted in all cases):
Germany: 4,528
Spain: 3,494
France: 1,617
Switzerland: 1,393
Austria: 470
Netherlands: 534
Belgium: 462
Norway: 169
Sweden: 200
Denmark: 104
The list goes on and on and on.
And new deaths…look at them!
Germany, 24; Spain, 262; France, 78; Switzerland, 13; Netherlands, 30; Belgium, 16…
(These numbers of new deaths, from places that have adopted chloroquine as treatment of choice many days ago, …is not cheery news, in case no one else noticed or was looking at that. Italy has been using it, and the rest of those places, or at least most of them…)
Total cases per million people for these EU countries, are Italy, 778; Spain, 461; Germany, 237; Switzerland, 649 (!…shoulda closed that border to Italy…WTF were they thinking?); Austria, 294; Netherlands, Norway, Sweden, Denmark…175, 361, 162, 217.
Let’s hope those deaths are not in people who got experimental antivirals.
While I am holding this bucket of cold water, might as well point out that it is very hot in Florida, has been for weeks, most of the past few months in fact have been very mild.
And cases here are spiking, as they are across the southern tier of the US.
Florida, Georgia, Louisiana, Texas, South Carolina, California…large numbers of new infections.
A lot of the rapid increase can be attributed, no doubt, to having more tests done, but this is not the hopeful sign I was considering it might be when i had not thought about it very carefully.
Whatever the numbers are showing now only gives a partial picture of what was happening with regard to new infections a few weeks ago…when people were mostly not doing much to protect themselves.
The past two weeks have been a mad house of throngs of people crowding into stores and standing shoulder to shoulder to get in, check out, etc.
Not to mention similar but worse scenes in airports.
Tens of thousands of international travelers came back to the US last weekend alone. And I suppose it was about the same in most places.
So, it is very likely we aint seen nothing yet, even if there is not one single new infection from this moment forward.
Ditto for the EU and the rest of the world.
And then tropical countries, including those with malaria?
Cases are rising sharply across Africa (where in Nigeria, to name one example, large numbers of people are showing up in ER’s with chloroquine poisoning, after stripping this important medicine from shelves around that country and indeed the world), and in South America and other warm weather locales it is about the same.
Brazil, yesterday 330 new cases, total now 970 (two weeks ago people were remarking the number seemed to be zero in Central and South America), Chile, 92 new, 434 tot; Ecuador 166 new, 426 tot; Saudi Arabia, Qatar, Bahrain…those hot locales are now well into the hundreds of cases and rising fast.
I suspect the places with low numbers have either bad reporting, no testing, or had a late start in having the virus introduced, but it is now spreading apace.
I think places with malaria tend to be places that have relatively little mechanization, low road penetration and travel infrastructure in general, relatively impoverished populations not given to world travel and possibly not a lot within their country. And that is how it spreads…so why would anyone be surprised that places with no roads and little ability for widespread rapid transportation, would have a lower rate of virus transmission.
Rapid travel, far and wide, by many people, in less time than it takes to become too sick to move around, is exactly why we have these pandemics after all.
I am too tired and ill to offer clarifications regarding what are, IMO, the many errors in the virology, pharmacology, and immunology in the headline post.
I will just leave a few links:
In animal models, chloroquine failed to work as it did in cell cultures vs HIV and SARS, and did not block viral replication, but did work as and anti-inflammatory and immune system modulator. (The ability to function as an immune modulator, down regulating immune response, is why it is used against RA.)
But there was success in newborn mice given chloroquine through their mother’s milk when used to block infections of a lethal coronavirus, OC43:
https://www.asbmb.org/asbmb-today/science/020620/could-an-old-malaria-drug-help-fight-the-new-coron
Remdesivir is being badly characterized by most who write about it.
It worked stunningly well against Ebola in vitro, ditto against all filoviruses and about the same in MERS and SARS and Nipah and Hendra.
But like a very long list of new drug candidates, it was not quite as effective in clearing virus from people who were already in the advanced stage of a viral infection. In fact, most substances that kill viruses in a glass dish cell culture either do not work or work only weakly in a human body. One reason is achieving the proper concentration within cells is not so easy in a person as in a dish. Many substances do not spread evenly through the various tissues of the body. Some reach toxic levels in some tissues long before they are present in the target cell populations at sufficient concentration to be effective.
Chloroquine, for example, is 200-700 times more concentrated in the liver, spleen, skin and kidneys that in plasma, and the concentration is for some reason even higher in the tissues of the eye, in particular in melanin containing tissues of the eyes…so more in the iris and choroid than in the retina, sclera, and cornea.
This tendency to concentrate is one of many reasons why some drugs that work just amazingly well in vitro are useless for curing diseases in people. There can even be huge differences between people and various animal models, and even between different demographic groups, and between people who are healthy and who are patients, and for patients who are gravely vs mildly ill.
Drugs that work in the body must concentrate in the target cells at sufficient level to be therapeutic without building up to dangerously toxic level elsewhere, unless such toxicity weighs favorably against the antiviral activity.
The gold standard is all cause mortality.
Remdesivir would have been a blockbuster vs Ebola had there not been two monoclonal antibody drugs that became available at the same time.
With only standard of care, 80-90% of the Ebola patients were dying.
Remdesivir far outperformed the existing “miracle drug” called ZMAPP, lowering the case fatality rate to less than 34% if given soon after Ebola symptoms appeared in human patients.
This was far less than the response seen in animal models of simians infected with filoviruses.
But even when given late in the disease progression, remdesivir saved many more patients than standard of care alone…bringing the CFR down to about 50-53% or so.
The two mAbs were hardly cure-alls, either, even though they outperformed ZMAPP and remdesivir. The lowest CFR seen was with the Regeneron drug, which got survival rates up near 90%…but only if given immediately after a patient was exposed. Patients who had progressed to a later stage of illness had a CFR no better than 30-35%.
Anyone who hopes to understand what we are likely to see with any of these drug’s results needs to know how to interpret these results and put them in context.
Remdesivir worked very well against Ebola.
If it was all there was, it would have been immediately accepted as the new standard of care.
It outperformed the existing SOC significantly.
Also, it must be understood that a lot of people still died, and as far as I know no trial ever was done to see if remdesivir plus a monoclonal antibody might have achieved a cure rate closer to 95 or even 100%.
If I had Ebola…I would want both.
And there is one more point to make with Ebola and remdesivir, also completely overlooked by every other writer I have read on the subject: Remdesivir will work equally well against all the strains of Ebola. There has been a new strain with almost every major outbreak of Ebola.
The monoclonal antibodies will only work against that one exact strain…so when the next outbreak hits, the best drug on the shelf will be remdesivir, with it’s 45-67% cure rate, until a monoclonal antibody can be isolated, manufactured, tested, and then produced in quantity for the new strain…assuming that an effective antibody to the new strain can be isolated.
Virology is not bean bag.
The stakes are life and death, and nothing works against all viruses all the time in any stage of illness…not by itself anyway, at least nothing I can think of off the top of my head.
Even the best antibiotics do not work perfectly in all people against run-of-the-mill infections.
Antivirals are even more capricious.
Some are allergic, some seem to metabolize drugs differently, or concentrate them in tissues wrong, etc.
“Remdesivir (formerly GS-5734) is a prodrug of a
modified adenine nucleoside analog GS-441524.
Remdesivir undergoes efficient metabolic
conversion in cells and tissues to active nucleoside
triphosphate metabolite that inhibits viral RNA
polymerases, but not host RNA or DNA polymerases.
Remdesivir exhibits a potential for clinical efficacy
against Ebola virus and other filovirus infections based
on the following:
1) Potent in vitro activity in multiple relevant cell types
against multiple Ebola virus isolates, including the
Ebola virus variants isolated during the 2014-16
outbreak in West Africa.
2) Potent and consistent in vitro antiviral activity
against diverse species of the ebolavirus family,
including Zaire, Sudan, and Bundibugyo viruses, as well
as Marburg virus.
3) Preclinical pharmacokinetic profile in non-human
primates and other relevant animal species indicating
high and persistent levels of pharmacologically active
nucleoside triphosphate metabolite in peripheral
blood mononuclear cells (PBMCs); this measurement is
used as a surrogate for drug levels in cells relevant for
Ebola virus infection, supporting once daily
administration.
4) Preclinical safety profile supporting safe clinical
administration at doses potentially active against Ebola
and Marburg virus infections.
5) Clinical safety profile from > 100 human subjects
dosed with intravenous remdesivir supports the
clinical dosing regimen recommended for the
treatment of Ebola. Single and repeated doses of
remdesivir were safely administered in Phase 1 studies
in healthy human subjects, PREVAIL IV study in male
Ebola virus disease (EVD) survivors, as well as during
compassionate use for the treatment and post
exposure prophylaxis of Ebola infection.
6) Potent therapeutic efficacy in Ebola virus-infected
rhesus monkeys, the most relevant in vivo preclinical
model of EVD, at drug exposures that
were well tolerated and can be safely achieved in
humans. The in vivo therapeutic efficacy has been
demonstrated in non-human primates against multiple
Ebola virus variants including Kikwit/1995 and
Makona/2014 as well as against Marburg virus
Angola/2005 infections.
7) Tissue distribution studies in non-human primates
indicate effective penetration and distribution of
remdesivir into immune privileged sites (genital tract,
eye, and to some extent brain) that may represent a
persistent reservoir of Ebola virus. Relatively high
levels of remdesivir metabolites were also detected in
human semen following single and repeated
administration of remdesivir, suggesting potential for
antiviral effect in human genital tract.
8) Sufficient supply of remdesivir drug product is
available in a stable lyophilized formulation that does
not require cold chain for transport and
storage”
And this:
“Consistent antiviral activity against all tested filoviruses
(Ebola Zaire, Sudan, Bundibugyo, and Marburg).
Similar antiviral activity was observed also against
pathogenic coronaviruses (MERS and SARS CoV) and
paramyxoviruses (Nipah and Hendra).”
Gilead, as well as research teams in China, did not need to look at the genome of SARS-Co-V-2 to ramp up production and immediately initiate clinical trials and compassionate use all the way back in January… as they already knew it worked equally well in vitro against a broad swath of related and unrelated viruses groups.
https://www.who.int/ebola/drc-2018/summaries-of-evidence-experimental-therapeutics.pdf?ua=1
A long list of people who are professional biotech analysts have dismissed the chance of remdesivir “working” against COVID-19 patients , on the basis of an erroneous understanding of what was found in the Ebola trials, numerous animal studies against a wide range of viruses, and the same vs a wide swath of viruses in in vitro cell cultures.
But look at what the vast majority of clinicians are saying, and what medical researchers and medical educators are saying.
To some degree, the cat is out of the bag regarding chloroquine, it seems. It has disappeared from shelves and pharmacies around the world, and people with malaria or at risk for it cannot obtain it, people who do not need it are taking it, and some of them are landing in emergency rooms…poisoned.
One whole family in Nigeria.
I would feel terrible if I was the one who told everyone it was safe as can be and, in some cases for some people far and wide, implied or said outright that everyone oughta get some and take it.
https://leadership.ng/2020/03/21/lagos-hospitals-flooded-with-chloroquine-overdose-patients/
one other point about chloroquine and malaria. As has already been stated in most areas of likely malaria this drug is ineffective, but it is of course cheap – so the poor use it in belief that it works.
“Chloroquine (Avloclor) is only effective in a small number of countries, mainly in Central America, and should never be taken to prevent malaria in Africa, South East Asia or South America where the malaria parasite has developed resistance to Chloroquine (Avloclor). ”
https://www.nomadtravel.co.uk/blog/travel-health/which-malaria-tablets-should-i-take
Ghalfrunt,
Yes, all true.
I can expand a bit on this point, with regard to chloroquine and it’s usage vs malaria.
There are two distinct usages for any anti malaria drug: One of them is treating people who have become infected with malaria and are very sick.
The other is for what is known as prophylaxis, which is a big word meaning “something that protects”. From the Latin, ‘pro’ meaning “before” or “prior to” + ‘phulaxis’, “the act of guarding”.
Simply stated, you take a drug if you are going to be somewhere that malaria carrying mosquitoes are or may be present, in order to prevent malaria from getting a toehold in your body if one of those mosquitoes bites you.
The dosage given to use as a protection for people who do not have malaria, is similar to the dose used to cure malaria, but it is given every week instead of every day, so it is a far smaller amount overall.
The dosage taken if you have malaria is in the same range as the dosage required for people taking it for RA, short for Rheumatoid Arthritis (a crippling and incurable autoimmune condition), or other autoimmune disorders of a crippling nature like Lupus Erythematosis, abbreviated to simply Lupus.
Many patients of these disease find they cannot tolerate chloroquine, and many others get great relief from it and take it long term.
It appears the dosage given to Covid patients is similar to these two usages.
The dosage is sometimes given in milligrams, but is probably better stated as milligrams per kilogram of body weight, because the “dosage window” is particularly narrow for this drug.
What the term dosage window refers to is the amount which is therapeutic, in other words the amount at which it acts as a medicine.
Too little will not work, and too much is very toxic.
Every drug which is used as a medicine has a dosage window.
But few have such a narrow range that is effective while not being toxic, as chloroquine.
It is not at all clear that everyone who is giving out what sounds like medical advice is aware of any of this.
For most drugs, accidentally or ignorantly taking two instead of one dose, will not kill anyone. For most drugs a child taking an adult dose will never kill them.
But for this one the amount that can kill a child is not far above the amount used as a medicine for an adult.
Also complicating dosing is that there are two version of drug that are similar in name, hydroxychloroquine, and chloroquine, and they have different dosing and may have different levels of effectiveness.
A large family of related drugs exists, all related to and based on the original natural drug called quinine…but they are not quinine.
Anymore that heroin is opium or even morphine.
(OK, I am seeing futures jump up quite suddenly and the VIX took a dive, but I am not sure why…so I lost my train of thought…
Also saw a report from Barron’s that Gilead has halted compassionate usage program after a flood of requests, an exponential increase, had overwhelmed their system for issuing such approvals. All except pregnant women and children who have “severe manifestations” of COVID 19. But it is increasing what is called the expanded access programs. More on this as I find out what is what)
Anyway, trying to get back to my train of thought is proving elusive.
I was going to give details on why the idea that countries with malaria do not have as much COVID 19 is due to chloroquine is poorly supported at best.
In fact it appears that there was little attempt to confirm the basic conclusion or the premises of the assertion.
Oh Go home, will ya. Test kits had to be developed that worked. Are you saying Trump could have just said, “order the test kits right away” and they go out?
What about the test kits that gave 50% false positives offered from Germany when our test kits just got ready to start shipping?
Meanwhile, regarding S Korea. They did not act like Trump to prevent China from seeding us so here are the stats right now today.
S Korea: Population, 51MM; Deaths 94, cases 8,652. So they have 1.8 deaths per million and 170 cases per million.
US: Population; 330MM; Deaths 256; cases, 19,387. So we have 0.77 deaths per million and 58 case per million.
That’s true now, but give it a week as testing gets ramped up in the USA (because we delayed getting test kits out). Then you will see what I fear right now.
You will find that the mortality rate will continue to drop as detected cases go way up. It’s a bad cold virus… it will spread
Mario,
Only a unethical statistician would hide behind “the rate”.
What counts to humanity is raw numbers of death.
Death. Numbers.
You’re happy with how many deaths, Mario?
How many is good?
When does good become bad, to your way of thinking?
Mario,
Only a unethical statistician would hide behind “the rate”.
What counts to humanity is raw numbers of death.
Death. Numbers.
You’re happy with how many deaths, Mario?
How many is good?
When does good become bad, to your way of thinking?,
Your kind of thinking is dangerous and small minded.
Based on your ridiculous understanding of what I wrote, let me ask you a question.
Do you think the current novel Covid 19 is worse than the Flu?
Because by your logic, the flu is infinitely worse since it kills around 600,000 people every yearand Covid 19 so far has killed just under 13,000. Why is that?
Next time you accuse someone of ill intent, you should think about it.
A lower death rate is good and as you indicate, so far, the mortality rate has been dropping.
As of this morning US 12.4%
Who said anyone was happy, Sam?
What is this crap about “unethical statisticians”, or people hiding behind “rates”.
What exactly are you talking about?
What Mario said was true.
None of this, or any other such discussion, has anything to do with how many are gonna get sick and die.
Would test kits a month or two weeks ago have prevented deaths today, or yesterday, or tomorrow?
I would like to understand how, if anyone believes that to be the case?
How many deaths are you happy with Sam?
To your way of thinking, apparently you can blame a pandemic and thousands of deaths on someone if you do not agree with their understanding of the concept of numerical analysis, is that it?
In that case, I think we have the culprits you are looking for…they are called epidemiologists.
Is this their (the epidemiologists) fault, because they study patterns, numbers, and correlations, and make logical inferences based on data?
When did participating in online discussion become the same as being happy about people dying, “to your way of thinking”?
Is this a blame game for you, Sam?
Are people you disagree with responsible for a virus, while you are smugly free of blame?
Does who one voted for in the last election, determine how many people you can accuse that person of being happy with?
In a world quickly becoming unhinged, to the point it is getting very hard to be surprised, I am astounded by this attack on Mario.
You should be ashamed of yourself, Sam.
Thank goodness for people like you Nicholas McGinley, we are lucky for your amount of thoughtful and informed discourse. Us non medically trained folk are doing our best to put some clarity to our reality.
Thank you!
PS : Sam has obviously been indoctrinated into the plague of simple minded thoughtlessness —inability to understand basic knowledge.
“What counts to humanity is raw numbers of death. Death. Numbers. How many is good?”
Well, since I suspect you’ve never demanded a global shutdown of the economy over the flu (which would definitely lower the death rate), I’d say your “good” number of deaths is between 12k and 60k.
This is why appeals to emotion are fallacious. If “every life matters” and you are “unethical” for caring about the rate, then YOU are unethical for never being outraged about flu deaths.
If you respond with “this isn’t like the flu”, I will take that as admission that you have failed to even begin to understand why you are wrong. A dangerous place to be.
Josh Postema: Hi Josh: I am not sure whom you are referring to with the use of the pronoun “you” in your post “Well, since I suspect you’ve never demanded a global shutdown…”
I assume your comments are for Sam who does not understand how to interpret a string of words larger than 3 or 4 in length and wrote a scornful reply to my factual and non emotional assessment.
Well, that got the hares running.
The point is, Mario, you admit you have no medical background and you are “trying to put some clarity to your reality”. Your reality? What’s that beast when it’s at home?
Does “your reality” understand that 795 people died in Italy last night from your “flue”? Or is it just playing intellectual tiddlywinks on the Internet?
There is no data on the untested. Hence you choose to surmise, project and diminish the reality. Not “your” reality. The reality. Seven hundred and ninety five. Last night.
Comparing this to the flue is an invalid comparison. An irrelevancy.
If you persist in to playing mind- games in an area where you are unqualified, you do no more than demonstrate that you are blind to your bias.
SSam. You’re posts are diluting the value of this page. Every time you write something, it is a pure distraction. Until people become immune to the idea of responding to you, your ilk will never go away.
You need to get a GED first before you start criticizing other people’s credentials.
I believe his remarks are directed at Sam, Mario.
In fact I am sure.
He is pointing out yet more reasons why Sam is not only off base, not only wrong, but he has it backwards in fact.
Engineers know how roads and bridges are designed.
At some point in the calculations, one has to assigned a dollar value to a life saved or lost.
We do not make highways lanes 40 feet wide and put thirty feet of Styrofoam padding on each side of each lane, with traffic going the other way 100 feet away.
How wide should Interstate setbacks be? How close should trees be allowed to encroach? How much is spent on the railings and abutment padding, like those trashcan things full of water where toll plaza concrete dividers start?
The same goes for medicine, but in many more, and more complex ways.
If Standard of Care gives a survival rate of 87%, and a new treatment gives a survival rate of 92 %, but in another cohort the numbers are somewhat different, 83% and 89%, but both cohorts have a rate of severe adverse events in the range of 6% to 12%, including a few fatal ones, and the all cause mortality after 12 month is statistically equivalent, then what do we do?
People who have decided ahead of time what they “know” is true, will have a very hard time accepting a logical decision to turn down a new drug application for such a treatment, ewven though it is logically the correct decision, given that with the drug, 6-12% of people who had an 83-87% chance of being fine a year later, are instead living with a permanent harm. And the same amount of people were still alive a year later…or maybe less, if some of those adverse events were strokes, heart failure, kidney failure, etc.
People who have payed close attention over many years to new drug candidates, how they arrive with promises of great benefit, that have failed clinical trials, or who are aware of how the results are very rarely clear cut and dramatic, know that the only way to have a hope of remaining objective is not to decide ahead of time what is going to work.
We have to let the process work.
IN a well designed and run clinical trial, inclusion and exclusion criteria must be laid out in advance. And endpoints must be clearly delineated.
Clyde has it exactly right when he points out the example of aspirin and Reyes Syndrome.
Other sorts examples might be what happened with a drug like Fen-Phen, or one like Vioxx.
In all of these cases, unexpected harms appeared but only after a period of time had passed.
In the case of aspirin, a drug which might be the most widely used and generally safe medication ever, was found to cause a terrible harm when used in one particular circumstance in one subset of the population: Kids who have the flu. For everyone else it is fine. For kids it is fine, except a certain number of ones who take it for the flu, or certain other viral infections like chicken pox. It is rare, but devastating for those it afflicts.
I was not even talking about any of those sorts of things when I urged caution regarding the safety profile, and also to remain skeptical, but by all means cautiously optimistic, regarding chloroquine.
There are reports from China of a wide array of drugs and combinations that have supposedly “worked” in patients with Covid-19.
We do not want the cheapest, or the newest.
We want quantified results of everything that warrants consideration.
If the value of chloroquine is as an anti-inflammatory, is it the best drug for this purpose?
The interleukin 6 monoclonal antibody drugs sound far more promising to me, if what we are looking for is a way to prevent damage from Cytokine Release Syndrome.
But only trials can answer such questions.
I have seen reports that the sensational press reports have made the clinical trials process very difficult. By having unapproved drugs widely available for compassionate use exceptions, they are having trouble finding people willing to enroll…more and more people are demanding compassionate use of whatever it is they read about.
The Chinese tried many separate treatments, and most of them seemed to say words to the effect of “Hey this is good”.
Kaletra they panned.
Others have said Kaletra seems to work.
The results of all fo the trials may well be difficult to parse.
It seems unlikely we will be seeing a result that is 100% for any particular treatment.
If millions of people have taken Chloroquine for many decades, and done so in places with endemic viral infections, how is it no one noticed that they not only keep people from getting infected with viruses, but cure viral infections?
After all, the benefit to RA and Lupus patients was discerned all the way back in the 1950s.
Counter intuitive results are not at all unheard of in immunology, though.
Back in the latter part of the first decade of this century, clinical trials were conducted on a cyclosporin derivative which was a cyclophilin inhibitor, for use with combination antiviral therapies in the long fight against HCV.
There was also some data that indicated that Hep C patients who underwent antiviral chemotherapy with Interferon Alfa and ribavirin, had a higher rate of successful treatment if they were on one of the immune system inhibitors typically used for RA and other autoimmune disorders. Humira or Remicade I think…cannot recall which one.
There are also specific mutations called single nucleotide polymorphisms, SNPs, which were found to be highly predictive of whether a particular treatment regimen would be likely to work for any specific individual.
One of them, the gene for IL28B, was highly correlated with whether or not interferon plus ribavirin would work for a patient. Other SNPs in the same region are highly predictive of not just who is likely and who is unlikely to respond to a particular therapy, they are predictive of who will become chronically infected and who will clear the virus spontaneously and never need any therapy because their own immune system overcame the infection soon after becoming exposed.
These findings have been subsequently expanded upon immensely.
I am confident that in the very near future, researchers will be able to determine why it is that some proportion of individuals become asymptomatic carriers, and which get sick, which become the most ill, and who is likely to die, or to be cured, by dint of a particular intervention.
It has long been known that when a person is infected by the hepatitis C virus, they may clear the virus or they may become chronically infected, and that for some people, viral clearance was far more likely than others.
Among the factors that were strongly predictive of chronic infection or viral clearance were being female (higher incidence of clearance), being young (higher incidence of clearance), and the size of the infective dose (larger dose gave far higher chance of chronic infection).
It may well be there is something akin to that going on with this virus.
I am certain we will see a surge in our understanding of the complexities of how environmental factors, genetic predispositions, and how such factors as age and overall health of the immune system interact to protect us from viruses and other infectious diseases, with spillover into oncology a near guarantee.
We may get to that singularity yet.
Wow: I have saved this wealth of information so I can digest it later. Much appreciated.
Mario
Oh, here is a good read on the subject of SNPs and such, that I was just touching on:
https://www.researchgate.net/publication/50867065_IL28B_single_nucleotide_polymorphisms_in_the_treatment_of_hepatitis_C
Mario, I appreciate you have difficulty dealing with a pricked ego.
Ad homs are not the solution. Rather, they’re an indication you’re out of ammo.
Confront your reality Mario.
Answer the questions:
1. What is a good number of deaths?
2. What is a bad number of deaths
3. Why do you seek to diminish the death rate for the Chinese corona virus?
And finally, why is the comparison to flu (the mortality rate for which is lessened by the existence of a vaccine) a valid comparison, in your view?
Sam you’re a moron:
Answer the questions:
1. What is a good number of deaths?
0
2. What is a bad number of deaths
>0
3. Why do you seek to diminish the death rate for the Chinese corona virus?
so fewer people can expect to
again: You’re a moron
Mario asserts:
“Sam you’re a moron:
Answer the questions:
1. What is a good number of deaths?
0
2. What is a bad number of deaths
>0
3. Why do you seek to diminish the death rate for the Chinese corona virus?
so fewer people can expect to
again: You’re a moron”
You’re losing it Mario. Calm down ,and take a deep breath.
Your answers to the first two questions are correct, Mario.
The third tells me that you don’t check before shooting your mouth off.
“So fewer people can expect to”…….what, exactly, Mario? Die? Nope, that’s illogical. Get infected? Nope. That doesn’t work either does it, Mario?
So what’s the answer?
The fourth remains unanswered.
Your ad homs provide evidence to the hypothesis that you’re out of ammo.
I hope you don’t design bridges.
Sam, this is a tense and unhappy time for an awful lot of people.
Maybe a little more light, and less heat, eh?
You keep making the claim that we delayed getting the tests out. Yet you fail to provide any evidence that there was anything the government could have done to speed up the rate at which tests were deployed.
Nicholas
Besides the surprises that there are differences in susceptibility correlated with gender and blood type, I think that we have collectively forgotten the role that smoking and persistent air pollution may play.
I see many people here who are so desperate for a quick solution that they have adopted the “Ready, Fire, Aim!” approach with their suggested solutions.
I am concerned at this point that successful treatments are being all but promised.
The language used makes it sound like at this point clinical trials are a formality, as these drugs are shown to be effective.
We also see an undercurrent of belief that the only reason why an old and inexpensive medicine has not been widely adopted is because no one can make money on it.
What it adds up to, in my view, is a situation where an ambiguous but less than stellar result will be disbelieved by many.
Let’s look at the example of remdesivir tested vs Ebola.
A look at the actual results showed something that is fairly common for a antiviral against a awful disease: Some are cured, some are not. And several factors are identified that may influence efficacy, such as initial viral loading, at length of time since symptoms became apparent, etc.
So remdesivir had results far superior to anything that existed prior to the time of the study. Over two thirds of patients getting it were cured if they got it soon after presenting with symptoms.
Patients that were worse off had almost a 50% cure rate.
With no treatment almost 90% of patients in that outbreak were dying, a particular virulent and deadly strain, evidently.
So it saved a lot of people who would have surely died without it.
It was far more efficacious than what had been accepted as the best drug known, called ZMAPP.
But it turned out two other new drugs worked better.
Much better if given soon after symptoms began, under 10% in some cases, but none of the drugs cured everyone.
Even the strongest of the monoclonal antibody drugs were unable to save over 1/3 of people who were in more advanced stages of illness.
So the MAbs, as they are known, outperformed remdesivir…for sure.
But no one looking at that result ought to be able to conclude that remdesivir had no effect.
And yet that is how it has been described by a long list of writers, including some at major scientific publications…in at least one case the very publication that had reported the Ebola results.
This publication seemed to me to go out of their way to be completely inconsistent in how they described the history and prospects of each drug being tested vs corona virus.
Here are the articles i am referring to, first the Ebola article describing how effective remdesivir was:
“In the 41% of trial participants who sought treatment early after infection and had lower levels of Ebola virus in their blood, the two new treatments had astonishing success: Mortality plummeted to 6% in the Regeneron antibody group and to 11% with mAb114. (With ZMapp and remdesivir, mortality rates in people with low viral load were 24% and 33%, respectively.) There is far less hope for patients with a high viral load, however: Even with the best treatment, REGN-EB3, their death rate was 60%.”
https://www.sciencemag.org/news/2019/08/finally-some-good-news-about-ebola-two-new-treatments-dramatically-lower-death-rate
And now a new article in that same publication on a new megatrial organized by WHO, describes the results, summarized above, like this:
“Researchers tested remdesivir last year during the Ebola outbreak in the Democratic Republic of the Congo, along with three other treatments. It did not show any effect. (Two others did.) But the enzyme it targets is similar in other viruses, and in 2017 researchers at the University of North Carolina in Chapel Hill showed in test tube and animal studies that the drug can inhibit the coronaviruses that cause SARS and MERS.”
They say remdesivir DID NOT SHOW ANY EFFECT!
Then they characterized the animal and in vitro studies of it as favorable, when those same animal and in vitro studies vs Ebola gave about the same results in all of the viruses tested against!
This is astoundingly bad reporting, and I really have no idea what to make of it.
Some tentative results that are not quantified, used tiny sample sizes, and do not characterize any viral loading in an objective way, are hyped as if they are proof of efficacy.
A combo with clinical trial results that show no effect are described using some comments made prior to the trials, this in the case of the Ritonavir/lopinavir.
See here:
https://www.sciencemag.org/news/2020/03/who-launches-global-megatrial-four-most-promising-coronavirus-treatments
On the whole this all makes no sense.
If it turns out that chloroquine is only weakly effective and the effects are in the anti inflammatory aspects, it is probably a mistake to waste time when far better drugs for that are available, such as the IL-6 monoclonal antibody drugs that have saved the lives of people undergoing intense cytokine storm, and are safe and approved and in stock in hospitals.
mario lento March 20, 2020 at 6:52 pm
Meanwhile, regarding S Korea. They did not act like Trump to prevent China from seeding us so here are the stats right now today.
S Korea: Population, 51MM; Deaths 94, cases 8,652. So they have 1.8 deaths per million and 170 cases per million.
US: Population; 330MM; Deaths 256; cases, 19,387. So we have 0.77 deaths per million and 58 case per million.
S. Korea acted very aggressively regarding testing, anyone who showed up sick with the virus was tracked for contacts, and those contacts tested and the appropriate quarantine measures taken. Consequently they were able to ‘flatten the curve’ very early, ~300 cases over the last 4 days (number of active cases declining), compared with the US, still in the exponential growth phase, with ~13,000 more cases in the same period.
South Korea did a good job, however, their task was not as difficult. The U.S. obviously has more routes of entry given much larger area and population.
Had the Chinese not hidden this outbreak, the entire world would have been better off.
Importantly the number as a fraction of the population is about way less. Said another way, Korea as a fraction of the population saw it spread there more than 4 times more violently. We have way more people and it spread here way way less per capita. They tailed off and that is yet to be seen here since they got it earlier than the USA. They also used medicine that we are still testing that I think we should speed up, which I think we are.
Look at the statistics I posted again.
How exactly was government supposed to ramp up the production of tests?
Mark and Mario, how did Korea ramp up the tests so fast compared to us???
re: ” how did Korea ramp up the tests so fast compared to us???”
What so-called “testing” do you think they perform? This is _not_ like “CSI” where one swab from inside the mouth provides a suitable ‘sample’ for follow-on lab work (where the processing leads to an eventual ‘result’ used to make the diagnosis.)
Go Home March 20, 2020 at 8:14 pm
You are omitting one important point. We got the test kits out as quick as the Germans.
When the first “kit” which is for 800 tests was being tested in Washington it was found to be defective. All testing was stopped until new ones could be made. Normally the CDC does not have a problem with production runs.
So did a lab worker make a mistake or was it more insidious .
president Trump did not neglect to get the test kits made. The folks making the test kits had a “Boeing” moment.
That should answer your question.
https://www.reuters.com/article/us-china-health-test-kits/u-s-agency-investigating-production-of-faulty-coronavirus-test-kits-idUSKBN20P09Y
People often expect too much from diagnostic tests. They expect them to be infallible when they are not in the real world. We already know that China, which had a big head start on this, abandoned one testing protocol in favor of CT scans. Tests give false positive and false negative results.
There was a problem with the first tests, at least, that the U.S. rolled out. There are questions about a death in South Korea even though the patient tested negative multiple times. Japan’s testing is being questioned with some asking whether there is an “Olympics” bias that leads to few cases being found.
Death is less ambiguous. The low rate of death among German patients is raising suspicion that perhaps too many false positives are occurring, or perhaps the test is good but the actual severity of the illness is low. Hopefully, the latter is true.
Back to China, this article that is in review, suggests a much lower infection fatality rate in Wuhan. https://www.medrxiv.org/content/10.1101/2020.02.12.20022434v2
The truth is between the extremes, somewhere. BTW, one more of the cruse ship passengers succumbed and there are now 8 total deaths from the Diamond Princess. He was a Canadian man in his 70’s.
If sabotage is possible, then AG Barr has an even fuller plate than last month. I’m willing to believe that some Trump haters would be willing to kill old people in order to torpedo his reelection.
I would not put it past them… Hate has no boundaries!
GH, If you are claiming that the Korean government is responsible for the faster production of tests by Korean companies, then please detail how. You are the one making the claim. Support it.
We may be on a closer trajectory to Italy than South Korea.
Go Home uses mealy mouth words like “may”. Evidence does not support anything close to the trajectory in Italy here in the US. Not close. Evidently, you’re just not able to process information. You’re a waste of time.
What trajectory are you writing about?
Our mortality rate has been steadily dropping from about 3% early on (without reporting) to now just over 1%. I submit, that as more counting goes on it will fall far below 1%. Italy on the other hand has been between 8% and 10% which is alarmingly high. Again, we do not know how well the counting is being performed. But you are flat wrong based on any measure.
Another bottleneck is the people collecting the sample, I’m told this is slow process. I understand inow there are enough tests but getting the sample is time consuming due to safety protocol.
Most problems were due to regs and rules by Obama. Tests were only to be developed by CDC and Masks like the 95 could nor be used medically, and on and on.Not sure about director of CDC — though everyone wants a 100% guarantee he seems to be dragging his feet and quite reluctant to get things done
The Obama administration made the CDC the sole provider of viral test kits. But the CDC screwed the pooch and produced faulty kits. Trump rescinded the order, so that private enterprise could make more and valid kiits. That took time.
He also had to overrule FDA regulations.
The administrative deep state is to blame for the lack of and flaws in the early kits.
Go Home
Might it be that the reason that the Asian countries have done a better job of getting testing kits produced quickly is because the western world has forsaken manufacturing for the advantage of cheaper products? That is, Asian countries have now become the world’s experts on rapidly meeting consumer demands.
Rud – any thoughts on angeotensin II blockers (ARBs)?
I take olmesartan-HZT to control hypertension (it does a very good job, at least in my case).
I have seen claims that it could be protective, and claims that the effect could be the reverse.
Since (as I understand it) they block the conversion of angiotensin I into angiotensin II I don’t see it having much effect on the ACE-2 receptors, other than leaving them “unoccupied”, so I could see a negative effect wrt covid-19 infection progression
Original Post focus on the repurposing of the anti-malarial drug function reconfiguring the Wuhan virus’ enzyme receptor, thus allaying viral “docking” for cell entry, could use some context of the drug. For example chloroquine also modulates human immunological aspects; however my poor ability to parse immunology means I’ll only mention it.
What is easier to convey is that chloroquine (& derivatives) allays our cellular process of auto-phagy; akin to cellular housekeeping, it performs interior functions & recycling. Inside cell stations (so to speak) called lyso-somes is where auto-phagy occurs & optimal functioning requires a lower pH than it’s internal cellular surroundings.
As a lyso-some finishes up performing auto-phagy the recyclables it has are released. Viruses pirate recycled bits of membrane from lyso-some auto-phagy to incorporate those into the viral forms that the infected cell proliferated.
Then the formation of the replicated virus is survivable outside that infected cell & can circulate within the human body. Thus, as a consequence of normal human auto-phagy the virus can move to other cells; but the anti-malarial drug chloroquine raises lyso-some pH – thereby inhibiting auto-phagy limiting what the virus needs in order to spread.
maybe True but then would we not expect chloroquine to work on many virus like Ebola and hiv ? Seems this drug may work because of something specific to this virus or this family of viruses.
Hi Stevek, – As I indicated, my comment was skipping immunological aspects. Since you asked about HIV see this research as a sample of the drug’s potential: (2010) “Chloroquine modulates HIv-1-induced plasmacytoid dendritic cell alpha-interferon: implication for T-cell activation”; free full text available on-line .
Clinical trials that have investigated chloroquine for anti-HIV/AIDS activity:
https://clinicaltrials.gov/ct2/results?cond=HIV&term=chloroquine&cntry=&state=&city=&dist=
Summary of a careful review of all of them is very simple: No benefit has ever been found after many trials and many years of looking for a benefit by numerous researchers.
Unfortunately.
Most studies were either terminated or did not even bother to post results.
The ones that did made it very clear that no clincial benefit has been seen.
Here is the same for hydroxychloroquine.
Same result.
The one that compared to aspirin showed little difference between the two.
The others either did not even bother to complete the study or ended it and did not report results.
Looking at these drugs vs every other virus or cancer they have been tested for activity against have failed to show a benefit, with the exception of the well known immunomodulating effect.
But this immunomodulation can be found with many other drugs, many of which have a better safety profile.
https://clinicaltrials.gov/ct2/show/NCT02475915?term=hydroxychloroquine&cond=HIV&draw=2&rank=3
Immunomodulation AND anti-inflammatory effects, I should have said.
If I would have no conventional medical support (and even if I did, as additional treatment), I would place my bets on Elderberry (Sabucus Nigra) for its antiviral properties from anthocyanidins and other components it contains, see for example:
https://www.naturalmedicinejournal.com/blog/elderberry%E2%80%99s-anti-viral-activity-update
The most interesting paragraphs (imo) from the article:
“While elderberry was shown to have inhibitory effect at all stages of influenza infection, it had a significantly stronger effect on the late-stage of infection than at early stage; smaller concentrations (higher dilutions) of elderberry had partial or no inhibitory effect during the early phase but those same concentrations had significant inhibitory effect during the late-phase of infection. Furthermore, the antiviral activity of elderberry on influenza was strongest when used in pre-treatment, during infection and post-infection, rather than when used solely during infection. The study confirmed that elderberry exerts its antiviral activity on influenza through a number of mechanisms of action, including suppressing the entry of the virus into cell, modulating the post-infectious phase, and preventing viral transmission to other cells.”
“No human clinical trials have been published on the prevention of influenza with elderberry, however, black elderberry extract has previously been shown to inhibit human influenza A (H1N1) infection in vitro by binding to H1N1 virions, thereby blocking the ability of the viruses to infect host cells.2 The same study showed elderberry to be effective against 10 strains of influenza virus and compared its effectiveness favorably to the known anti-influenza activities of oseltamivir (Tamiflu) and amantadine.”
“one of the 20 amino acid (only, in all life on Earth, proving a common genetic ancestor)” Or, proving a common Designer.
It’s impossible to “prove” a Designer, which is exactly how the Christian God would want it, otherwise faith would have no value.
OTOH, the use of just 22 out of at least hundreds of amino acids, and almost all of the same chirality, is evidence of common descent.
Descent is a scientific concept, since subject to conformation or falsification by testing predictions based upon the hypothesis. Design is a religious belief, incapable of such tests by experiment or observation.
Behe’s “irreducible complexity” of structures such as bacterial flagella was shown false shortly after he proposed it. A scientist would have tried to find out how such structures evolved. Instead Behe acted like a theologian, leaving it for others to discover how flagella, for instance, evolved.
re: “It’s impossible to “prove” a Designer, which is exactly how the Christian God would want it, otherwise faith would have no value.”
Picking and choosing select evidentiary material; Excluding events, claims made and recorded / documented in the NT?
Jim,
Sorry, but I don’t get your point.
If you think you have testable physical evidence for the existence of the NT God, that would be a major breakthrough after 2000 years of looking.
The concept of God of course changes greatly during the course of the OT, from an anthropomorphic Being Who Personally builds the foundations of the immobile, flat Earth, makes people, talks to and strolls with them, sits on the edge of the world looking down at them, who appear as insects, walks on the firmament operating the levers of the storehouses of the rain and snow, to speaking only from storms and vegetation, finally to see Him is to die.
Q1 is there any indication that elderly Coronavirus patients who are currently on RA medication having less impact from the virus?
Q2 Here in Australia Diabetes is a bigger killer than hypertension. But it is the other way around in Italy. Is it possible that the “mix” of pre-exiting conditions of elderly Italians have just as important as their age?
Good paper, thank you Rud. Lots of big words. 😉
I’m sending a copy to my doctor.
Lots of useful info on Wuhan flu in an article over at medium.com title is evidence over hysteria. Don’t know how to link it https:\medium.com\six-four-six-four. iirc
Burning questions:
After surviving a SARS COV 2 infection, is there a lasting immunity?
How long does the immunity last?
Is there permanent or lasting damage?
The answer to all three, for an individual, is “It depends.”
Statistically, “Yes,” “For survivors, quite a while,” “Usually not.”
I can’t give track odds for the population as a whole – not that I would apply track odds to myself. One can only predict history.
I am posting to philincalifornia because that post would not allow me to respond.
“commented on Hopeful: Summary of Wuhan #Coronavirus Therapies and Potential Cures.
in response to mario lento:
Good for you! That’s why a sample size of 1 is never enough data for true analysis… But whatever you’re doing, keep on doing it… and get sleep unless the pay off is worth it…”
I saw what you did there ……
I thought I was being cute/clever? Please expound sir!
No, it showed up and I responded. Not everyone might have caught your humor.
I did.
Thank you Phil… I should have use a sarc/ or humor tag indeed! Humor is a sign of intellect… and that you and most on this site have.
These are actually two closely related anti-malarials, hydroxychloroquine (the small French trial) and chloroquine phosphate (the larger Chinese trial). Both were developed in the 1950’s,
There is a book, the fever tree which details how quinine from the bark of a tree high in the Andes somehow worked on malaria a protozoan found at low altitudes.
Totally amazing.
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Since safety is well known (the main side affect is retinopathy [vision problems] in 25% of patients over 50 that resolves [slowly] after discontinuation), the main FDA legal issue (FDCA Act of 1906 as amended) issue is to determine dosing and duration for this new indication.
I used Quinine on patients for many years as a treatment for leg cramps, then malaria risk travelers and then restless leg syndrome before the use in RA became known.
As far as I was aware eye problems were rare not 25%, but maybe it is the synthetic drugs??
Quinine is added to some soft drinks, tonic water.
If the Quinine does not work I am sure the gin will help.
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Many thanks for the clear explanation Rudd
It makes no sense to close businesses because people are just as likely and even more likely to catch COVID-19 in a grocery store as anywhere else. How many people touch the produce? No one has proposed closing grocery stores. The mall I go to has little more than 2 stores open, the grocery store and Walmart’s. Almost everything else is closed. Too many people going out of business with this shutdown. South Korea has been testing everybody and mandatory isolating individuals. The problem is that the false negatives are up to 40%. So if South Korea has the same tests I dont understand how they have been able to hold death rate to 1% about the same as Canada. The difference is that South Korea has not closed their economy down like we have. This is madness.
A complication of the flu is most often bacterial pneumonia, which is treated with an antibiotic. Covid-19 causes viral pneumonia quickly.
Quinoline derivatives such as natural quinine, quinidine, and synthetically produced chloroquine are well known for their use in the treatment of malaria. Chloroquine is the big pharma one for mass production reasons so this was the study drug. There is no reason to dismiss natural quinine. It may be more effective we don’t know. It certainly is used in cases where chloroquine has become ineffective due to resistance.
If no antibodies form in the body, then no medicine will help. You need to focus on your own immunity.
Slowly suck the zinc tablets and take high doses of vitamin C.
In the case of infection, you need antioxidants that protect the heart. It’s best to take high doses of coenzyme Q10. This is particularly true for older people.
Israeli scientists: ‘In a few weeks, we will have coronavirus vaccine’ (This article is a week old)
Once the vaccine is developed, it will take at least 90 days to complete the regulatory process and potentially more to enter the marketplace.
https://www.jpost.com/HEALTH-SCIENCE/Israeli-scientists-In-three-weeks-we-will-have-coronavirus-vaccine-619101
The race is on and all prior records will probably be beaten, but this is a long term process. On top of that, whatever vaccine is produced must accommodate mutations to be effective.
https://nextstrain.org/ncov from yirgach on other thread
re: “Once the vaccine is developed, it will take at least 90 days to complete the regulatory process and potentially more to enter the marketplace.”
NOT an inviolate ‘law of nature’ (the ’90 days to complete …’); some ‘countries’ aren’t so encumbered by a ‘regulatory hurdles’ of that kind …
Death rates are falling as positive cases increase dramatically
https://medium.com/six-four-six-nine/evidence-over-hysteria-covid-19-1b767def5894
Great link ! Full of info and graphs.
Readers may be interested in this article on work by Dr Michel Chretien on a potential treatment for Covid.
https://www.macleans.ca/politics/china-kidnapped-two-canadians-what-will-it-take-to-free-them/?utm_source=nl&utm_medium=em&utm_campaign=mme_daily&sfi=3a792db1538c290c6620a758587c5f95
That story is difficult to follow. What are the charges against the two Canadians?