Of Quinine And Chloroquine

Guest Post by Willis Eschenbach

After all the people saying we shouldn’t take chloroquine because of the side effects, let me take the opportunity to say some words about that curious drug.

I moved to the Solomon Islands, north of Australia near the Equator, in 1984. I ended up living and working there for nine years. The Solomons host all four kinds of malaria—Plasmodium falciparum, P. ovale, P. malariae, and P. vivax. Unlike most parts of the world, at the time the four kinds of malaria in the Solomons were not chloroquine-resistant.

malaria mosquito.png

So I took chloroquine prophylactically once a week to prevent the disease. 500 mg (300 mg base), one pill every seven days.

After I’d been there maybe three years, I thought “I don’t want to take this forever. If I get malaria, I’ll cure it, that’s what medicine is for”. So after having taken well over 100 doses of chloroquine, I gave it up.

Of course, after stopping chloroquine, I got malaria. It is a most curious and devious houseguest. Malaria has a bunch of forms, all with different shapes and different abilities, and it changes form like we change shirts. When it hits your bloodstream, it streaks for your liver as fast as it can. Along the way, it is shedding parts of its skin layer. These skin bits occupy and distract a large number of antibodies, which recognize enemies by their skin surfaces. This allows more of the malaria parasites to make it to the liver. When it gets to the liver, it changes form.

After living for a bit in the liver in that new form, it changes form again and goes back out into your bloodstream and gets inside the red blood cells. Where, of course, it changes into another form.

Unlike the other forms, this latest form can reproduce. It starts to produce thousands and thousands of descendants, which eventually rupture the red blood cells and re-emerge into your bloodstream.

Until that point, you don’t even know the tiny criminals have invaded your corporeal mansion. But when they rupture the red blood cells, your body gets the full-blown malarial crisis, shaking and sweating, chills and fever at once. I’d always thought stories about people’s teeth chattering in sickness from the chills were exaggerations.

I was very wrong.

Now, at the time we were living on a 280 acre (110 ha) coral atoll island called Liapari Island, way out in the outback. Here’s the island, on the right …

liapari island.png

The Solomon Islands are in the middle of nowhere, north of Australia below the equator. Western Province in the Solomon Islands, with the Western Province capital at Gizo Island, is even more nowhere. And Liapari Island, 17 miles (27 km) by water from Gizo, is the very heart of nowhere.

Fortunately, my gorgeous ex-fiancee is a family nurse practitioner. The doctors there advised quinine. So she took the company outboard skiff, drove it seventeen miles to Gizo, and brought back the quinine. I took the prescribed dose. Horribly bitter pills.

Well, I’m here to say that the damn quinine cure is far worse than the disease. It adds bad pain and weakness on top of chills and fever. I recall that at one point it took me about thirty seconds of hard work just to sit up in the bed. When I laid down, I thought “I can’t be that weak! I just can’t be! It can’t take that long just to sit up!”

So I tried it again.

45 seconds that second time. Crazy weakness and pain. I’d never felt anything like the combination of malaria and quinine, and I definitely don’t recommend it no matter how bored you are.

After that, I never took quinine again. I would take its chemical cousin, chloroquine, instead. But this time I was taking it curatively, not preventatively. It was not fun in the high doses, but it beat the malaria back, and it was much more tolerable than quinine.

Finally, after suffering a couple more bouts of malaria over the next couple years, my mad mate Mike told me that when you feel malaria coming on, and you can definitely can feel it coming on, to take three weekly doses at once (1500 mg, or 900 mg of base), then the same thing 24 hours later, then the same thing on the third day. He swore it fended off the malaria.

So I started using his plan, and I never got full-blown malaria again. Just take nine weeks worth of chloroquine in three days, it aborts the onset of the chills and fever, no problem.

In addition, at the time, I knew dozens and dozens of expatriates in the Solomons and maybe half or more of them used chloroquine for either prophylaxis or cure of malaria.

In summary: yes, as with any medicine, some people suffer side effects from chloroquine. But it is widely tolerated. In addition, it’s cheap because it’s been used since the 1930s, so it’s been off-patent for decades, and the side effects are well known

Do we know scientifically if it works for COVID-19? Nope. But I’ll guarantee you that if I get the ‘rona, I will take chloroquine and azithromycin and zinc. Nothing to lose, everything to gain, and Fauci is both mad and destructive to argue against it.

And to close out the story of the madcap transformations of the malaria parasite, we left it swimming in our bloodstream after rupturing the red blood cells. From there, a mosquito removes it from your body with its magic hypodermic needle, and it moves into the mosquito’s stomach where … yes, you guessed it, it transforms itself once again into a new kind of malarious being. And when the mosquito bites another person, it injects that form into your bloodstream, whereupon it starts racing for their liver to start the cycle again.

There is one final oddity of this most odd of life forms. Sometimes, P. falciparum vivax malaria can … yep, you got it … change into yet another form. It does this in the liver, and after changing forms it promptly falls asleep for maybe a year. Or two. Or more. This form goes by the absolutely wonderful name of a “hypnozoite”, after Hypnos, the Greek god of sleep. Hypnozoites are the source of the world-famous recurrence of malaria years, occasionally decades, after leaving the malarial zones.

When one of the hypnozoites wakes up after a two-year nap, I assume it stretches, yawns, looks at the other still-sleeping hypnozoites, and of course, it being malaria and all, just for fun it changes form. No longer a hypnozoite, it jumps into the bloodstream, reproduces inside the red blood cells until they burst … and that is how after I’d left the Solomons and had been living in Fiji for a couple of years, I suddenly felt that awful familiar feeling.

And being an honest man I must confess, at that moment I said very bad words. Not only that, but I engaged in needless and ultimately pointless vituperation, casting unpleasant but extremely satisfying aspersions as to the ancestry of the whole tribe of mosquitoes and malaria in all their evil blood-sucking cell-destroying forms.

I had been convinced at the time that I was done with malaria, but nooo … my main medical squeeze had to go hunt for chloroquine, there’s no malaria in Fiji. And once I got cured of the immediate malarial relapse, I took another drug that in theory kills the remaining hypnozoites, and me and malaria, we parted ways for good. At least I sure hope so.

And that’s my story of chloroquine and the reason why I say that anyone who gets the virus should at least try it. 

My best to all, stay well, wash hands, don’t invite any strange bats to dinner, don’t touch your face, or your bat’s face for that matter, wear a mask, avoid crowds, you know the plan …

w.

PS- Regarding schools as centers of infection, the Solomons uses the British system of boarding schools. Grade school kids go from their villages to the local boarding school, which is often on another island, where they spend the entire semester.

And we always had to gird our loins and break out the mosquito repellent when the kids all returned at semester break, because invariably they brought a surfeit of malaria back with them …

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Marinus
April 12, 2020 2:34 am

Scientists have found what is causing the severe Covid-19 lung problems and how to prevent this:

https://www.radboudumc.nl/en/nieuws/2020/radboudumc-researchers-publish-new-insights-into-covid-19

icisil
Reply to  Marinus
April 12, 2020 5:25 am

Yep, there it is. Severe immune system overeaction due to ACE/ACE2 imbalance that causes ALI and pulmonary microvascular thrombosis.

ACE and ACE2 act in a counter-regulatory manner: ACE promotes inflammatory response, ACE2 promotes counter-inflammatory response.

ACE inhibitor (ACEi) and ARB meds inhibit ACE expression, but not ACE2 expression. Thus inflammatory response is lowered in people on these meds.

ACE2 expression decreases when cells with ACE2 expression are infected with Corona-chan. Counter-inflammatory response is lowered.

ACE expression increases in hospital patients on ACEi/ARB meds because those treatments are stopped upon hospital admittance. Inflammatory response is elevated.

Also, ACEi decrease PAI-1 production. PAI-1 inhibits tPA, which breaks down blood clots, preventing thrombosis. So stopping ACEi treatment in hospital patients increases risk of thrombosis.

And that’s what k!lls most patients on day 10-14: pulmonary microvascular thrombosis.

Two obvious, possible treatments: don’t stop ACEi/ARB meds in infected patients, and take an anti-coagulant.

ACEi/ARB treatments aren’t the only thing that elevate ACE2 expression. Basically any insult/injury to the lungs does so, like heavy chronic air pollution and smoking,

ren
Reply to  icisil
April 12, 2020 8:50 am

Without ACE2 acting as a guardian to inactivate the ligands of B1, the lung environment is prone for local vascular leakage leading to angioedema. Angioedema is likely a feature already early in disease, and might explain the typical CT scans and the feeling of people that they drown. In some patients, this is followed by a clinical worsening of disease around day 9 due to the formation antibodies directed against the spike (S)-antigen of the corona-virus that binds to ACE2 that could contribute to disease by enhancement of local immune cell influx and proinflammatory cytokines leading to damage.
https://www.preprints.org/manuscript/202004.0023/v1

kribaez
Reply to  icisil
April 12, 2020 1:39 pm

Smoking elevates ACE2 expression? This runs counter to many years of research.
Please explain why current smokers are grossly under-represented in COVID-19 serious cases in China, where well over 50% of the male population smokes, but only 8% of hospitalised patients were smokers. The CDC ran a comorbidity study based on US data, where they found that of ca 18,000 patients, just 22 current smokers were hospitalised of which just 5 patients were admitted to ICU. USA generally has about a 14% current smoker population. Go figure. Evidence-based science?

Philip Mulholland
Reply to  kribaez
April 12, 2020 2:26 pm

Nicotine?

icisil
Reply to  kribaez
April 12, 2020 6:24 pm

A recent USC study found ACE2 expression was significantly higher in smokers’ lung tissue. What many years of research are you referring to?

I’ve not seen any reliable data from China regarding smoking habits of patients. One study I saw had a column for smoking, but the data were missing. Please link to the study you describe. Also please link to the CDC study. China has 3-5 times as many smokers as the US, so it is a much more significant issue there.

kribaez
Reply to  icisil
April 13, 2020 1:14 am

icisil,

CDC comorbidity study:- https://www.cdc.gov/mmwr/volumes/69/wr/mm6913e2.htm?s_cid=mm6913e2_w

China study:- https://www.qeios.com/read/article/554
and https://www.ejinme.com/article/S0953-6205(20)30110-2/fulltext

The first looks at the likelihood of being hospitalised with COVID-19 if you are a smoker, relative to the population of smokers in the general population. The second addresses a different question – the likelihood of developing severe symptoms as a smoker, if you have already been hospitalised with COVID-19. Note the various references to the impact of smoking on ACE2 receptor activity.

Here is a further study suggesting that smoking dowregulates ACE2:- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295500/

kribaez
Reply to  icisil
April 13, 2020 5:52 am

Trying again with less links.
China study:- https://www.qeios.com/read/article/554
and https://www.ejinme.com/article/S0953-6205(20)30110-2/fulltext

The first looks at the likelihood of being hospitalised with COVID-19 if you are a smoker, relative to the population of smokers in the general population. The second addresses a different question – the likelihood of developing severe symptoms as a smoker, if you have already been hospitalised with COVID-19. Note the various references to the impact of smoking on ACE2 receptor activity.

kribaez
Reply to  icisil
April 13, 2020 5:55 am

…more

CDC comorbidity study:- https://www.cdc.gov/mmwr/volumes/69/wr/mm6913e2.htm?s_cid=mm6913e2_w

One of multiple studies suggesting that smoking dowregulates ACE2:- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295500/

Lena Hulden
April 12, 2020 3:08 am

Willis!
Nice story but: Plasmodium falciparum does not have hypnozoites. You have mixed up with P. vivax. P. ovale are now been divided into two species. Your picture is not an Anopheles mosquito (the genus that can transmit malaria). An anopheline has long palps.

ren
April 12, 2020 3:27 am

Numerous cases of acute and chronic pulmonary conditions are accompanied by extravasation of erythrocytes to the lower respiratory tract (lung hemorrhage). These pathological events are frequently associated with marked leukocyte influx and an increase in inflammatory markers [1–7]. In cases of moderate to intense hemolysis that succeed hemorrhagic events, the scavenging of free heme by blood-derived hemopexin or albumin collapses, leading to the accumulation of free heme in the extracellular milieu [3]. It has been previously reported that high expression of haptoglobin, the major protein responsible for the removal of free hemoglobin, reduces tissue injury associated to blood exposure [1]. Accordingly, the induction of heme oxygenase-1 (HO-1) can promote cytoprotective responses in some models of lung injury [8–10]. This stress-inducible enzyme controls the deleterious effect of large amounts of free heme, catabolizing this porfirin in biliverdin, carbon monoxide, and free iron, which are addressed, both directly and indirectly, as cytoprotective agents [10]. These observations support the hypothesis that free heme may be involved in the onset and/or amplification of pulmonary inflammatory responses.
https://www.hindawi.com/journals/mi/2013/946878/

ren
Reply to  ren
April 12, 2020 8:28 am

Under oxidative stress however, some hemoproteins, e.g. hemoglobin, can release their heme prosthetic groups.[34][35] The non-protein-bound (free) heme produced in this manner becomes highly cytotoxic, most probably due to the iron atom contained within its protoporphyrin IX ring, which can act as a Fenton’s reagent to catalyze in an unfettered manner the production of free radicals.[36] It catalyzes the oxidation and aggregation of protein, the formation of cytotoxic lipid peroxide via lipid peroxidation and damages DNA through oxidative stress. Due to its lipophilic properties, it impairs lipid bilayers in organelles such as mitochondria and nuclei.[37] These properties of free heme can sensitize a variety of cell types to undergo programmed cell death in response to pro-inflammatory agonists, a deleterious effect that plays an important role in the pathogenesis of certain inflammatory diseases such as malaria[38] and sepsis.
https://en.wikipedia.org/wiki/Heme

April 12, 2020 4:07 am

It’s too early for the tornado season, but the furious unseasonal winds sweeping the USA arise from a different source – the unprecedented flurry of cash filled brown envelopes from US pharmaceutical giants like Gilead (balm – shmarm! there’s cash in Gilead!!) violently opposing the use of off-patent drugs like hydroxycloroquine against cv19, and furiously lobbying for adoption of their own top dollar wanna-be blockbusters.

Fauci, Trump, everyone in any position of influence needs to get to their storm shelter quick or be swept off their feet by that storm of cash filled envelopes like a mail-owl message from Hogwarts in a Harry Potter movie.

This is how America works. No crisis can be missed as an opportunity to create a fortune-making monopoly. Gilead and their rival-comrades will sweep into their Swiss bank accounts the lion’s share of the multi-trillion stimulus package due to the simple rule of medicine in the land of the phree – the more expensive the better! And blasphemously off-patent generics will receive their public stoning to death as written in the unwritten law.

Reply to  Phil Salmon
April 12, 2020 4:32 am

re: “This is how America works.”

A bit jaded, in fact, quite jaded and an over-simp (simplification). You overlook the age we live in, the internet-of-things age (which adds onto the internet and information ages?). We have the best informed public in the world today, just don’t pay any attention to the ‘majors’ (the MSM), who have lost notable market share the last couple decades. For instance, I mark this as my 23rd year on FreeRepublic.com, for instance, a site that predates most ALL so-called ‘social media’ …

Reply to  Phil Salmon
April 12, 2020 2:12 pm

Jim
Yes perhaps an exaggeration for rhetoric effect.
It’s true the US public are better informed about medicines, you don’t get advertisements for serious drugs directly at the public in Europe the same way you do in the US. In Europe doctors alone decide on drugs so the pharma sales people swarm around them like flies but leave the public alone. Neither BTW do we get the ambulance-chasing adverts every 90 seconds, do you have mesothelioma? etc. (amazing that they’re still milking that one).

April 12, 2020 4:44 am

Willis:

There’s a data set that you might be interested in for further analysis at healthweather.us. It’s provided by Kinsa, a company that makes “smart” thermometers that combines people’s temperatures with their locations via their smart phones, virtually real time. It can estimate what percentage of people showing temperatures above normal and this can be compared with empirically derived trends of flu-like infections as a function of time in the flu season. One cannot specifically see covid-19, but you can see when and where fever-inducing disease occurs.

The amazing thing is that you can see how social distancing has dramatically killed the flu season. The US may be in its healthiest state ever with respect to fever-inducing infections. Remarkable.

richard
April 12, 2020 5:24 am

Some testing has been done. “Their mean age was 43.6 years old
and 492 were male (46.4%)” A problem as corona kills mostly the old and as Oxford university pointed out half the UK has probably had the virus with very few symptoms.

https://www.mediterranee-infection.com/wp-content/uploads/2020/04/Abstract_Raoult_EarlyTrtCovid19_09042020_vD1v.pdf

Philip Mulholland
April 12, 2020 5:41 am

Willis,
Thank you for sharing.
It seems strange to take medicines when you are not ill, but it clearly works. Then we have the problem of the view: “But this is a virus and so why use a drug that targets against an organism?” As you so vividly explain the Plasmodium Sp. parasites are the beasts from hell. How do we really know what part of its life cycle the hydrochloroquinine impacts? As was so clearly stated by a medic on the front line describing his patient’s presentation “You don’t have to follow the protocol – you have to follow the physiology.”

Philip Mulholland
Reply to  Philip Mulholland
April 13, 2020 12:22 am

A comment from my network:
“I was never one for protocols as they end up tablets of stone.”

tty
April 12, 2020 6:33 am

While I can’t vouch for the effect of chloroquine on CoVID-19, I can back Willis on its lack of side effects. My sejours in malarial areas have been shorter than his, but I’ve used chloroquine several times for periods of months at a time without any noticeable side effects. And so have many million others. There can be very few drugs that have been used so long, by so many, with so few problems.

Unfortunately the falciparum variety of malaria has become chloroquine resistant in many areas, necessitating a shift to other antimalarials like proguanil (paludrine) and mefloquine (lariam) which have considerably worse side effects. I personally have not suffered anything worse than an upset stomach, but I know people that have had serious neurological problems from mefloquine.

tty
April 12, 2020 6:50 am

By the way Willis, your Fiji relapse was probably due to Plasmodium vivax which is the species normally associated with chronic/relapsing malaria.

Plasmodium vivax was quite common in most of Europe and North America until the late nineteenth century when better housing and living conditions in rural areas gradually eliminated it. Or at least that is what the textbooks mostly say. However DNA studies of old tissue samples now indicate that falciparum also occurred in Europe. So it isn’t really a tropical disease at all.

john
April 12, 2020 8:11 am

There are some interactions regarding Zinc, according to the Mayo Clinic and other good sources.

Interactions

Possible interactions include:

Antibiotics. Using oral zinc while you’re taking quinolone or tetracycline antibiotics can interfere with their ability to fight bacteria. Taking the antibiotic two hours before or four to six hours after taking zinc can minimize this effect.
Penicillamine. Using oral zinc with the rheumatoid arthritis drug penicillamine (Cuprimine, Depen) can reduce the drug’s ability to ease arthritis symptoms. Taking zinc at least two hours before or after taking the drug might minimize this effect.
Thiazide diuretics. These blood pressure drugs increase the amount of zinc lost in urine.

Kevin kilty
April 12, 2020 8:42 am

Willis’s story of quinine and chloroquine is very interesting. In addition to being an antimalarial, the Merck index (or mine does at least) lists it as an antipyretic (at least for veterinary use) and one would think it would relieve chills and fever, but with Willis it did not — people have varying success with medications. Now chloroquine is not listed as an antipyretic, nor is hydroxychloroqine nor any other salt. However, it is in use to treat symptoms of Lupus; and there is at least one reference in the Journ. of the AMA (McCarty, Carrera, jama, 248, 1718, 1982.) of it being used in conjunction with other medicines to treat rheumatoid arthritis. Thus, it appears to have some use to treat immune system dysfunction. Perhaps this has something to do with whatever success it has with COVID-19, but I am a bit disappointed by the results being reported so far.

As Commiebob puts it, it is megacomplicated.

Reply to  Kevin kilty
April 15, 2020 3:26 am

Lupus and RA are autoimmune diseases
They are a result of a hyperactive immune system attacking cells, goodies and organs of the patients own body.
Lupus is very rare.
RA is far more common.
Many RD and lupus patients have used the chloroquine for many years, but it is only one of many treatments and it is not the case that all people with these diseases usevthem.
What the drugs do is reduce symptoms related to inflammation, which is a process that occurs when the immune system is activated.
They also modulate the immune system directly, dialing down the immune response, the immune response that harms these patients by being directed at their own tissues.

Phrasing this by day they treat immune dysfunction without specifying how, might give some the impression the drugs strengthen immune response. They do the opposite.
Patients with severe lupus and RA take much stronger drugs like prednisone or biologics. Biologics are monoclonal antibodies that, in this case, then of specific parts of the immune system by blocking specific cytokines.
Powerful steroids like prednisone and biologics like Remicade or Humira are dangerous because they act to turn of the immune system. Steroids in a general way, biologics in focused and specific ways.

Reply to  Kevin kilty
April 15, 2020 3:36 am

I am reposting to correct a bunch of autocorrect my tablet made.
Lupus and RA are autoimmune diseases
They are a result of a hyperactive immune system attacking cells, tissues, and organs of the patients own body.
Lupus is very rare.
RA is far more common.
Many RA and lupus patients have used the hydroxychloroquine drugs for many years, but it is only one of many treatments they may use, and it is not the case that all people with these diseases use them.
What the drugs do is reduce symptoms related to inflammation, which is a process that occurs when the immune system is activated.
They also modulate the immune system directly, dialing down the immune response, the immune response that harms these patients by being directed at their own tissues.

Phrasing this by saying they treat immune dysfunction, without specifying how, might give some the impression the drugs strengthen immune response. They do the opposite.
Patients with the most severe cases of lupus and RA, take much stronger drugs like prednisone or biologics.
Biologics are monoclonal antibodies that, in this case, turn off specific parts of the immune system by blocking specific cytokines.
Powerful steroids like prednisone and biologics like Remicade or Humira are dangerous because they act to turn of the immune system. Steroids in a general way, biologics in focused and specific ways.
People with autoimmune diseases have an overactive immune system.
They are known to be less likely to get infections, especially if they do not treat or use milder treatments, because they have a strong and activated immune system.

c1ue
April 12, 2020 8:59 am

Willis,
The dosages you mention for preventative malaria use (300mg/week = 2-200 mg hydroxychloroquine pill) are far lower than what Raoult and others are using in their studies. They’re talking about 600 mg/day or even 800 mg/day – specifically: targeting a blood concentration of over 1 mg/L when 2 mg/L may be toxic: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa394/5816960.
The larger doses – basically one time shots to get HCH levels in the blood to some target level – are different than taking 800mg/day for a week or more.

c1ue
Reply to  Willis Eschenbach
April 13, 2020 8:16 am

Thanks for the info.
According to this web site: http://www.rheumaknowledgy.com/hydroxychloroquine-and-chloroquine-phosphate/
1-250 chloroquine phosphate tablet is 150 mg of active ingredient vs. 1-200 mg hydroxchloroquine tablet containing 155 mg of same.
So you were taking basically 3+ tablets for 3 days to stop a new malaria attack.
The same web site notes safe use at different levels: 2 hydroxychloroquine tablets to start then less (5 mg/kg) vs. just 1 chloroquine phosphate tablet (2-3 mg/kg).
It is because of this site, and the previous note, why I wonder what the safe dosage (vs. effective vs. nCOV dosage) for hydroxychloroquine and/or chloroquine phosphate is.

john
April 12, 2020 9:50 am

Willis, I bet you’ll find this eye opening too regarding chronic Lymes Disease.

https://pubmed.ncbi.nlm.nih.gov/14586290/

Frank
April 12, 2020 12:22 pm

Willis: There is no doubt that chloroquine has activity against coronavirus in cell culture, but this activity is at least an order of magnitude weaker (IC50 1-2 uM) than typically for useful anti-virals. (For example, the median cell culture IC50 for Tamiflu is 0.004 and 0.06 uM for Influenza A and B.) In addition to treating malaria, chloroquine is also used to treat rheumatoid arthritis and lupus. That means it has immuno-suppressive activity – which may not be the greatest thing for patients trying to fight off a life-threatening viral infection. I’ve heard that COVID-19 patients who have taken ibuprofen for fever before going to the hospital have a poorer prognosis than those who haven’t. On the other hand, if a “cytokine storm” is drowning a patient’s lungs with fluid, immuno-suppressive activity combined with even modest antiviral activity may be an ideal therapy. During the SARS epidemic, steroidal anti-inflammatory drugs were used to suppress this cytokine storm. When an acquaintance of mine needed an increasing amount of oxygen due to chronic lung inflammation, a steroidal anti-inflammatory drug completely eliminated an need for oxygen within 24 hours(!) and allowed a life-threatening bacterial infection to developed in 48 hours. Azithromycin has no activity against coronaviruses, but can help with bacterial pneumonia. Finally, a very small percentage of people have something called qT prolongation, which puts them at risk for sudden cardiac arrest. A surprising number of older drugs make qT prolongation worse, but this problem wasn’t identified until recently. In a modern hospital, a patient is likely to be given an EKG to detect qT prolongation before chloroquine is administered. If everyone on the planet were given chloroquine to prevent COVID-19, more people might die from sudden cardiac arrest, than might escape death from the virus. We face exactly the same problem if we are rushed into administering a vaccine before its safety has been fully established.

In other words, the decision as to whether chloroquine is likely to help a particular patient is a very complicated one that probably has little to do with its anti-viral activity in cell culture. Doctors working on the front lines with desperately ill patients with a novel disease want to believe that their treatment is keeping their patients alive. When they are free to select patients and endpoints that demonstrate some measure of limited efficacy without a control group, you have a classic recipe for confirmation bias, especially when a combination of two or three drugs with multiple possible mechanisms of action are being used. We will have some reliable information after placebo-controlled double-blind clinical trials with pre-determined endpoints begin to report. Based on its high IC50 in cell culture, I’d be surprised if chloroquine causes a significant drop in viral load in the first few days of therapy and it might even cause an increase due to immunosuppression.

sendergreen
Reply to  Frank
April 12, 2020 1:21 pm

Frank says …

” I’d be surprised if chloroquine causes a significant drop in viral load in the first few days of therapy and it might even cause an increase due to immunosuppression.”

Some 68 year old guy living in a mid sized city in Spain where the Government has mandated zero treatment to the aged with severe Covid … what else have they got ? They don’t have six months to two years for trials.

Don’t blame me for on the ground reality. Blame the Chines Communist Government that promised a year or two ago to close down the “wet markets” where this pathogen came from … and didn’t.

Reply to  sendergreen
April 13, 2020 3:16 am

“…what else have they got ?”

Two trials for remdesivir expanded access in Spain:
https://clinicaltrials.gov/ct2/results/map?term=remdesivir&cntry=ES&map=

1.5 million doses, the entire existing inventory on the shelf and in production, to be given away from free:
https://www.gilead.com/stories/articles/an-update-on-covid-19-from-our-chairman-and-ceo

Update letter from O’Day, April 10th:
“Two Phase 3 studies are being run by Gilead in areas with a high prevalence of COVID-19 in the United States, Asia and Europe. One of these is for patients with severe disease and the other studies remdesivir in patients with more moderate symptoms. One of the many questions that these studies aim to answer is whether treatment duration can be shortened from 10 days to 5 days. The severe arm fully enrolled the number of patients it was originally designed for and we have now expanded the study so that thousands more patients can participate, including those on mechanical ventilation.”

https://www.gilead.com/stories/articles/an-open-letter-from-our-chairman-and-ceo-april-10

Many other trials for many other treatments can be found at clinicaltrials.gov.
Here are 16 that come up in search for Spain and Covid:
https://clinicaltrials.gov/ct2/results?cond=COVID&term=&cntry=ES&state=&city=&dist=

Many others can be found with more general search, including one’s for numerous IL-6 blockers and all sorts of other stuff. Here are 440 studies for COVID-19:
https://clinicaltrials.gov/ct2/results?cond=COVID-19

Frank
Reply to  Nicholas McGinley
April 14, 2020 4:20 am

Remdesivir was originally developed for treating Ebola. It works in a monkey model for Ebola, but a patient population, treatment regime and endpoints where efficacy weren’t identified during the 2014-6 Ebola epidemic. Therefore the drug has never been approved for sale, which is probably why Gilead is giving it away for free. The safe shelf life is likely only a few years. Nevertheless, certain doses of the drug were proven to be safe.

Chloroquine and remdesivir are the only known drugs with antiviral activity in cell culture at non-toxic concentrations. Most of the other drugs being tested are intended to deal with the dangerous inflammation or “cytokine storm” that develops in many patients who are hospitalized. The same problem plagued patients with SARS-CoV-1. Some of them were treated with steroidal anti-inflammatory drugs.

Reply to  Frank
April 14, 2020 1:16 pm

One data point regarding the Ebola trials which has been widely overlooked is the disparity between Ebola patients treated with remdesivir (and indeed with any of the four drugs tested) when the treatment was given shortly after exposure to the virus, vs those that were only treated after their condition was greatly deteriorated.
The difference was very large, for all of the drugs, even the MAB’s that were deemed to have “passed” the clinical trial and judged to be effective.
In fact for the most effective drug, the range between the survival rate for those treated early was even wider than for remdesivir and for ZMAPP.
Although it is also true that in all classifications of disease progression, the Regeneron monoclonal antibody was much more effective than either of remdesivir or ZMAPP.

Reply to  Nicholas McGinley
April 14, 2020 9:23 am

You have no idea what you are talking about Frank.

Reply to  Nicholas McGinley
April 14, 2020 11:50 am

“You have no idea what you are talking about Frank.”
This is pertaining to your assertion that, “but a patient population, treatment regime and endpoints where efficacy weren’t identified during the 2014-6 Ebola epidemic.”

There is excellent data from the clinical trials for Remdesivir.
Whatever else can be said about Gilead, the trials they have been involved with are very well designed and run, and data sets are impressive.
If you have never seen the data, that is not the same as it not existing.
I have reviewed much of it here and posted links to much more of it, including the trial protocols used in that Ebola epidemic.

Reply to  Nicholas McGinley
April 14, 2020 11:54 am

And I am sorry I said that to you Frank.
Some of the conversation here has made me more than a little impatient with comments I assess as not completely accurate, but that is no excuse.
I do apoogize.
I am trying not to be antagonistic to anyone, but it seems easier said than done right now.

Frank
Reply to  Nicholas McGinley
April 14, 2020 2:42 pm

Nick: For what it is worth, I worked in drug discovery for more than a decade for an organization where drugs to treat HIV were the largest effort. It is unlikely that we would have taken into the clinic a drug candidate with an IC50 above 1 uM against viral replication in cell culture (and toxicity at 10 uM). Remdesivir, however, has already been shown to be safe for humans at certain dose and can easily to tried in humans. You can see the antiviral activity in cell culture for GS-5734/remdesivir in Table 1 in this article. Notice that it has an IC50 between 0.003 and 0.066 uM against four strains of Ebola and less than 0.1 uM against several other viruses.

https://www.nature.com/articles/srep43395

This potent in vitro activity is what prompted Gilead to take this drug through preclinical studies, Phase I (safety) and Phase II (small efficacy studies) and beginning Phase III studies for Ebola. The only efficacy data in humans I have seen comes from an uncontrolled study where 50% of infected patients survived and it was claimed that the expected mortality rate was 75%. Of course, with more experience, doctors have gotten better at helping Ebola patients survive, patients have been getting professional help earlier, and with time the less lethal viral strains tend to spread the fastest, so Gilead still needs a proper placebo-controlled (or comparator-controlled) clinical trial to prove that the drug is efficacious to gain marketing approval.

Cell culture activity against coronaviruses before the discovery of SARS-CoV-2 can be found in this article:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567817/

Again, there activity at less than 0.1 uM and below and some of this activity is reported in units I am more used to seeing IC90 or IC95 or logs of viral reduction. However the IC50 I have seen for one strain of SARS-CoV-2 is modestly above 1 uM. The other data in this paper illustrate some of the other challenges faced by remdesivir. It is a pro-drug that must survive in the blood long enough to get into the cells susceptible to viral entry, it needs to be converted inside the cell into the free nucleoside monophosphate and converted to the triphosphate, which is the actual species that inhibits the viral RNA polymerase.

There certainly may be other data currently unknown to me that might make me more optimistic. If so, please provide me a link.

Reply to  sendergreen
April 13, 2020 3:22 am

My first attempt to post an answer which I very much hope may be of help to your friend in Spain and anyone else, went to moderation.
I shall repost in smaller bites.
Best of luck to your friend and to you.
I pledge my solidarity with all who are effected anywhere on the Earth.
“…what else have they got ?”

Two trials for remdesivir expanded access in Spain:
https://clinicaltrials.gov/ct2/results/map?term=remdesivir&cntry=ES&map=

Reply to  Nicholas McGinley
April 13, 2020 3:23 am

1.5 million doses, the entire existing inventory on the shelf and in production, to be given away from free:
https://www.gilead.com/stories/articles/an-update-on-covid-19-from-our-chairman-and-ceo

Reply to  Nicholas McGinley
April 13, 2020 3:24 am

Many other trials for many other treatments can be found at clinicaltrials.gov.
Here are 16 that come up in search for Spain and Covid:
https://clinicaltrials.gov/ct2/results?cond=COVID&term=&cntry=ES&state=&city=&dist=

Reply to  Nicholas McGinley
April 13, 2020 3:25 am

Many others can be found with more general search, including one’s for numerous IL-6 blockers and all sorts of other stuff. Here are 440 studies for COVID-19:
https://clinicaltrials.gov/ct2/results?cond=COVID-19

Frank
Reply to  sendergreen
April 14, 2020 2:52 am

Sendergreen wrote: “Some 68 year old guy living in a mid sized city in Spain where the Government has mandated zero treatment to the aged with severe Covid … what else have they got ?”

That 68-year old guy has a 68-old-year old immune system which will eventually get around to clearing a viral inflection if the doctor and hospital can keep him alive long enough – and if his immune system isn’t suppressed by chloroquine. The first rule of medicine is “do no harm”. We may break that rule for terminally ill patients, but entering the hospital at 68 with COVID-19 isn’t a death sentence.

Before we had double-bind placebo controlled clinical trials, that 68-year-old man would have been bled – as George Washington was before he died at 67 with a cold. (5 pints of blood if Wikipedia can be believed). Of course, not all medicines and procedures used before modern clinical trials were performed have been proven to be worthless or dangerous, but many have been.

My aging immune system struggled with influenza last winter until I paid a visit to the emergency room. One hit from an inhaler used for asthma made it easier to breath and cleared my head. An antibacterial may have helped me deal with and defeat a touch of pneumonia. These things can be done to your 68-year-old patient. And they had Tamiflu, which is one to two orders of magnitude more potent against viral replication in cell culture than chloroquine is against SARS-CoV, and proven to be safe and effective as shortening the course of flu in a doubled-blind placebo-controlled clinical trial – though such efficacy was only observed when taken within 48 hours of symptoms. (I’d been sick for a week.)

The wet market in Wuhan should have been shut down long ago. Americans and Chinese would be healthier if Prohibition was still in effect, too. The published evidence shows the first patient with Covid-19 was likely a 89-year old man to frail to leave home, who was hospitalized two weeks before anyone from the market. The patients whose viral RNA was sequenced several weeks later were associated with the market. In the case of HIV, the person originally identified as Patient Zero was not. HIV had been in the US for more than a decade before “Patient Zero” and had jumped to humans in Africa a half-century earlier. If the Chinese government allows a full investigation, we may find out more later, including the intermediate host between bats and humans, if there was one. Maybe we will learn that the rumors on social media are correct, and Patient Zero was actual a researcher at the Institute of Virology in Wuhan, but so much fake information is deliberately spread by social media these days that such rumors are meaningless. The bats that harbor many strains of coronavirus are a much bigger problem in Southern China (than in Wuhan) where SARS jumped from bats to civets (and several other species) before reaching humans. Someday we may find that SARS-CoV-2 actually got its start at a wet market in Southern China.

sendergreen
Reply to  Frank
April 14, 2020 10:45 am

Frank :

You even copied it TWICE but somehow missed the phrase ” … in Spain where the Government has mandated zero treatment to the aged with severe Covid … ”

Then go on to explain how they can survive with a myriad of treatments. None of this has surprised those of us who have watched the “Death Culture” grow over the past fifty years from both ends of the trail of human life.

Frank
Reply to  sendergreen
April 15, 2020 7:39 am

sendergreen: My comments were intended to be about whether a 68-year-old man should be treated with chloroquine simply because there is no other medication known to be efficacious. I deeply respect your concern that older patients might not be given the appropriate care (like I received for influenza) and did not intend to criticize that. IMO, we are paying a huge economic price by shutting down much of our economy so that our hospitals have the beds and ICU beds to properly treat every patient who needs help. Some cities are looking for new spaces to treat sick patients, but they may not have the trained medical staff needed to handle them as well as respirators and other equipment. They could even be running out of the drugs that were used to treat me for influenza. It is such a breakdown in civilization that all political leaders fear. I presume, but don’t know, that the Spanish measures you are complaining about are due to their inability to properly treat every patient who needs treatment.

niceguy
Reply to  Frank
April 12, 2020 9:31 pm

“Azithromycin has no activity against coronaviruses”

And you know that, because…?

“We face exactly the same problem if we are rushed into administering a vaccine before its safety has been fully established.”

Yes, and many (most?) real vaccine skeptics are skeptical of both Raoult protocol and of the moral authenticity of the noisy anti Raoult crowd.

Frank
Reply to  niceguy
April 14, 2020 4:01 am

Niceguy: We have assays for anti-viral activity that are run in cell culture (in a petri dish). In the case of SARS-CoV-2, you add the virus to a human derived cell line (such as Vero cells) that express the ACE2 receptor used by the virus to enter the cell and let those cells grow in the presence of various amounts of potential antiviral drug. Then you use PCR to quantify the amount of viral RNA in the culture, and calculate the drug concentration (IC50) needed to reduce viral RNA by 50% compared with a control with no drug. Then you check to see if the drug candidate interfered with the growth of Vero cells. Reducing viral growth by killing the cells they replicate in isn’t a useful mechanism of action. In the case of chloroquine, the IC50 from reducing the growth of Vero Cells is about 10-fold higher than the IC50 for reducing viral RNA.

Azithromycin has no activity against viral replication in such cell culture assays, chloroquine and remdesivir have IC50’s a little above 1 uM. A potent antiviral like Tamiflu and the drugs used to treat HIV have IC50 in cell culture below 0.1 uM.

Azithromycin is active against the bacteria that cause pneumonia. Patients with COVID-19 often develop pneumonia and may benefit from treatment with azithromycin for this reason. Or it may be appropriate to use azithromycin to ensure that a COVID-19 patient who doesn’t yet have detectable pneumonia never adds bacterial pneumonia to his problems.

For what it is worth, I am not a skeptic about vaccines, because they have been proven to be save and effective. However, if you want to give everyone in the country a vaccine against SAR-CoV-2, you can’t test it on only 1,000 volunteers. If one dies, and the same fraction of the population dies from vaccination, you will have killed 330,000 Americans. If none of the 1,000 dies, you might have been lucky and 1 in 1,000 will die in the long run. So cautious doctors will insist that we test the vaccine on 10,000 or 30,000 volunteers before beginning a nationwide vaccination campaign. An impatient administration isn’t going to want to wait this long.

I researched the vaccine for Yellow Fever for a friend who was traveling to the waterfalls on the border of Argentina and Brazil, where Yellow Fever is endemic in monkeys and transferred to humans by mosquitos. The well-charcterized serious side-effect rate for the Yellow Fever vaccine (a weakened strain of Yellow Fever virus) is 2 per 100,000, but rises to 5 per 100,000 for those over 60. What are the chances of getting Yellow Fever if you visit this area for a day or two? The people who live there normally have about a 5 in 100,000 chance of contracting yellow fever during the several month long yellow fever season, but this number is very poorly known. Perhaps it could be as high as 5 in 10,000. The coastal cities of Brazil began getting an epidemic of Yellow Fever when mosquitos were transmitting the disease from one human to another without the involvement of monkeys. They had to vaccinate everyone in their southern coastal cities. Getting yellow fever isn’t a death sentence, but some people do die. My friend was over 60. Should I have recommended the vaccine or not?

I told my paranoid friend that the odds were excellent no matter what choice was made, but I personally wouldn’t get the vaccine (which isn’t normally recommended for those over 60). I said my friend was running far more serious risks than the risk of getting yellow fever or having a reaction to the vaccine. Worry about something more important. Prescient, as it turns out, since the trip also involved a cruise from Argentina to Chile in February of this year.

Reply to  Frank
April 14, 2020 11:45 am

“…you add the virus to a human derived cell line (such as Vero cells)…”
Vero cells are not human derived cells.
They are cells derived from the Kidney of a green monkey.
Many other cells lines used in research are derived from human cells, but they are extraordinary (even for cancer) cancer cell lines like HeLa.
There do seem to be a limited number of cells suitable for cell culture studies that are not of dubious utility as a model for a human being, but Vero and HeLa are not among them.
Just sayin.

Reply to  Frank
April 14, 2020 12:21 pm

BTW, your explanation of the need to parse data regarding clinical trials and vaccines and disease rates and the dangers of those disease, are well made.
It is clear to me that there are a lot of people here and around the country who simply have no experience in knowing how to interpret problematic data of drugs and disease, what good data from a clinical trial looks like vs what we have seen for some of the early chloroquine patient sets.
When one goes to a repository of information such as clinicaltrials.gov and examines some studies and the way protocols are written, how and how much data is collected and collated, and how results are presented, then it is very obvious how trivial, lacking in rigor, and unfit for any purpose of comparison or scientific appraisal of safety and efficacy they are.
The simple act of taking several thousand patients and selecting out some smaller set of them to report on, means that for something like this disease, it is absolutely impossible to infer anything regarding the drugs…except that they are not killing some large percentage of people most of the time.
But they did in Brazil.
Giving the malaria drug to some subset of asymptotic patients suspected of COVID infection, without including detailed descriptions of inclusion and exclusion criteria, all by itself makes the data unscientific and impossible to compare to any other set of patients.
But any method of selecting patients that does not then include a randomized selection of control groups and treatment arms from the same poll means that the data is similarly worthless, not matter how well described or followed the inclusion and exclusion criteria are.
When only 1 to 2% of all infected patients are dying, and the possibility exists that the true number is lower due to not knowing the denominator, it is meaningless to draw a conclusion about the results for some triaged set of patients given a treatment.
Even not having the randomization double blinded has been amply demonstrated to invalidate results. Bias creeps in when caregivers know who is getting what treatment.
Many of the patients who wind up with a bad outcome get very sick almost immediately upon becoming symptomatic.
If these people go to a hospital and are admitted, and the ones who get symptoms that are mild go to a doctor who treats them with a treatment, the ones who see the doctor in a regular office setting have already had the worst off set of patients subtracted, which may in fact contain most of the people who will at some point have a bad outcome.
One can glean this sort of thing when looking at the language employed by the authors of the NEJM article regarding remdesivir compassionate use.
Those people are not directly comparable to any other cohort of patients, strictly speaking from a scientific point of view.
But that does not preclude making some observations and some tentative speculations regarding what that data is telling us. It does for them, but not for us.
Compared to the results published by Raoult, the NEJM data from Gilead is the difference between a clay figurine made by a child and a sculpture from a master artist.
The difference in detail is gigantic.
For actual clinical trial data when we see it, it will be steps above the NEJM data.
It is not just the control groups that make it different, it is the amount, consistency, and quality of all of the data that sets it apart as well.

Reply to  Nicholas McGinley
April 14, 2020 12:24 pm

“When one goes to a repository of information such as clinicaltrials.gov and examines some studies and the way protocols are written, how and how much data is collected and collated, and how results are presented, then it is very obvious how trivial, lacking in rigor, and unfit for any purpose of comparison or scientific appraisal of safety and efficacy they are.”

Clarification…how unfit for such the chloroquine data from people like Zelenko and Raoult are.

Frank
April 12, 2020 12:41 pm

Willis: I just ran into some useful information about your thermostat hypothesis. Figure 3 in the paper below shows the diurnal variation in tropical precipitation over land and water. In accord with your hypothesis and personal experience, the least precipitation falls over land at 9:00 am and the greatest between 3:00 pm and 6:00 pm. The difference is huge, about 0.17 mm/h (4 mm/day 1.5 m/y). Over water, however, exactly the opposite pattern is observed with the greatest precipitation at 6:00 am and the least from 6:00-9:00 pm. This difference is smaller, but not trivial, about 0.08 mm/h. This makes perfect since the mixing and larger heat capacity of the ocean prevents it from warming more than 1 degC, while the surface of land can rise more than 10 degC. Interestingly, the paper shows that normal climate models completely fail to reproduce the observed diurnal cycle of precipitation in the tropics. Best wishes.
https://journals.ametsoc.org/doi/pdf/10.1175/BAMS-D-18-0210.1

Reply to  Frank
April 12, 2020 2:05 pm

In accord with your hypothesis and personal experience, the least precipitation falls over land at 9:00 am and the greatest between 3:00 pm and 6:00 pm.

It was exactly so when we lived in Kuantan, Malaysia. Every afternoon for days on end the rain came at almost the same time, we heard it advancing through the jungle toward us giving us a minute or two warning. It was the same water falling every late afternoon, having transpired-evaporated during the day.

April 12, 2020 12:53 pm

“Fauci is both mad and destructive to argue against it.” Please provide a quote.

Did he argue against it, or say it hasn’t been studied adequately?

Reply to  Stuart
April 14, 2020 12:35 pm

There are many people who have no willingness or ability to discern a difference.
They seem to only understand head nodding.
Any response besides for that is taken to be rabid opposition.
Very surprising for people who spot the illogic of such mentality when talking about proponents of CAGW.
They are utterly blind to it when they do the exact same thing, regarding something they have long ago made up their minds about.

old engineer
April 12, 2020 2:58 pm

Willis-

I realize this post is “getting long in the tooth” as they say, but Latitude’s comment April 11,2020 at 5:51pm about Plaquenil being available in Tijuana without a prescription, got me to thinking: could availability of Plaquenil without a prescription have some effect on the case and death rates in various countries? If people can decide on their own whether to take a med, without having to get a doctor’s okay, maybe people would self-medicate with Plaquenil.

I found a website that shows the countries by whether or not a prescription is required:

http://www.motherjones.com/kevin-drum/2012/03/lots-countries-dont-require-prescriptions-oral-contraceptives/

A large number of countries don’t require prescriptions, including South Korea! I also looked at Greece which doesn’t require prescriptions. Since it was right across the Adriatic from Italy, one might expect it to have the same case and death rates as Italy (which does require prescriptions). But that’s not so:

Italy 2586 cases/million pop. 329 deaths/million pop.
Greece: 203 cases/million pop. 9 deaths/ million pop.

Of course there could be all kinds of reasons, but I just found this curious.

Clyde Spencer
April 12, 2020 5:41 pm

old engineer
The article that you link is about oral contraceptives, not HCQ. While HCQ has reportedly been used for abortions in Africa, (as well as suicides), that is not a routine use in first-world countries.

niceguy
Reply to  Clyde Spencer
April 12, 2020 9:19 pm

Because Di-antalvic was often used for suicide in ONE country in Europe, in was banned all over the EU.

(Also, because it wasn’t patented, I believe.)

old engineer
Reply to  Clyde Spencer
April 13, 2020 2:10 pm

Clyde-

Yeah. Noticed that it was for oral contraceptives after my comment. My mistake. Too much in hurry to find the data I wanted. I still wonder about self-medicating though. I haven’t been able to find a site that shows countries that require prescriptions for most drugs, as in the U.S. Mexico is the only country I know of that doesn’t require prescriptions for most (maybe any) drugs.

Reply to  old engineer
April 13, 2020 2:16 pm

” I still wonder about self-medicating though. I haven’t been able to find… ”

Try the following: Any nutrition store will have quercetin supplements. Quercent is a known Zn ionophore. It will drive Zn into cells and has other beneficial effects. Also bump up your D3 and or get some sun if you can. And of course, vitamin C. This is the best we can do, with 100% safety and no need for prescriptions. As well, green tea (I take the extract). I don’t charge for this information, but if you want to start a go-fund-mario page, I will happily accept.

Now If I can get a call back from Red Cross so I can donate my antibodies through plasma…

Reply to  mario lento
April 13, 2020 2:18 pm

TYPO ‘Quercent’ should have been ‘Quercetin’

Clyde Spencer
Reply to  old engineer
April 17, 2020 12:49 pm

o e
I’m not going to take the time to try to run down the citations at the moment because this thread is so old that you may not even read it. However, from my reading, it appears that many drugs are available on the Black Market in Africa. The downside is that many are thought to be counterfeit drugs with no efficacy. It also becomes a situation, not unlike the US, where many illicit drugs are not as represented and often are dangerous.

Tmatsci
April 12, 2020 9:59 pm

Just looked up BCG vaccination and found it was for TB. Got me wondering whether TB exposed persons (i.e with strong antibodies for TB and Positive Mantoux Test but without development of TB) are likely to succumb to Covid-19. I am curious because as a child in the 1950s I had a next door neighbour who had TB of the hip that I used to play with. I tested positive very strongly to the Mantoux test when I was 21 but x-rays showed no lung infection or any indication of such. If there are any studies showing this someone like me could still have antibodies that could be of use for vaccine development. Of course this may not be necessary if the BCG vaccine is also effective.

Ken
April 13, 2020 7:00 am

Dr Didier Raoult who became noted during this crisis by publishing the results of his first small test where he combined hydroxychloroquine with azithromycin as a new Covid-19 treatment has just released the results of his latest test where he has 1061 patients. The most basic result is he saw 5 deaths.
Perhaps we should do some simple math since the “so called experts in the medical profession” still seem to me mathematically challenged.
5 deaths out of 1061 patients is 0.47%
As of today France has recorded 129,654 confirmed cases and 13,832 deaths.
This is a death rate of 10.67% per confirmed case.
Currently the same random population in France shows a death rate that is 22 times as large in the population who was not treated compared to the 1061 in this test that were treated. This incredible result is the definition of statistically significant.
For those asking for a “control group” as some magical requirement for statistical significance in their rigid illogical and unthinking brain, I recommend they use 1061 of the 129,654 confirmed cases which has resulted in the 13,832 dead French who are available in the morgues of France. They represent a truly random group and the only significant difference in their outcome compared to this treated group is they were blocked from a treatment the Chinese and Koreans have been dispensing FOR MONTHS and have published generally positive if not “PERFECT” results.
I personally could not care less if Dr Raoult is arrogant, or labeled a quack by other self important quacks during any previous studies. I only care about results of any useful treatment to reduce the suffering from this deadly virus. This treatment has never been called a cure for this disease, it is a treatment when used early can limit the number of people who eventually DIE. This is not a study on the latest treatment for hair loss, or skin dryness, this is an attempt to have less DEATH. Any fear mongering about a drug which has been safely prescribed for 70 years is the mindless blathering of a fool. I don’t see any indication this drug came close to KILLING 10.67% of the 1061 patients who took if for the short term of this test. We would expect 10.67% of these patients would be DEAD using the average death rate from the rest of France. What is so difficult to understand between 0.47% and 10.67% DEAD.
At this point anyone who is blocking this treatment should be removed due to there being only 2 possible reasons for their obstruction. Either they are grossly incompetent, or they are criminally blocking a viable safe treatment for financial or professional benefit.

Reply to  Ken
April 13, 2020 8:50 am

+1 * 10^100

Reply to  Ken
April 13, 2020 9:14 am

It would be nice if you could provide a clue where to find this report of which you speak.

Reply to  Nicholas McGinley
April 13, 2020 9:38 am

Quarterly NM performance review: Writes well, reads poorly, retains even less …

Reply to  _Jim
April 13, 2020 10:25 am

IOW you have no idea where to find a new report showing results of over 1000 patients from Raoult?
Or you refuse to say?

Reply to  Nicholas McGinley
April 13, 2020 11:02 am

NM, it’s in one of my previous posts to; maybe it hasn’t/didn’t or won’t make it through (moderation?) to posting.

It’s BEEN posted before, in this thread even, here: https://wattsupwiththat.com/2020/04/11/of-quinine-and-chloroquine/#comment-2963751

BTW, one can find ALL these reports/dispatchs here: “COVID-19 Therapeutic and Prevention” by Didier Raoult and Dr. Po-Ren Hsueh here:

https://www.sciencedirect.com/journal/international-journal-of-antimicrobial-agents/special-issue/10V3JMBH9GZ

JUST to be complete HERE is a link to the dispatch regarding the 1,061 patients treated by Dr. Raoult and associates:

https://www.mediterranee-infection.com/wp-content/uploads/2020/04/Abstract_Raoult_EarlyTrtCovid19_09042020_vD1v.pdf

Excerpt: Methods
The study was performed at IHU Méditerranée Infection, Marseille, France.

A cohort [test population] of 1061 COVID-19 patients, treated for at least 3 days with the HCQ-AZ combination and a follow-up of at least 9 days was investigated. Endpoints were death, worsening and viral shedding persistence.

For “Findings” read the dispatch.
.

Reply to  Nicholas McGinley
April 13, 2020 12:48 pm

This is in the findings:
“A good clinical outcome and virological cure was obtained in 973 patients within 10 days (91.7%). Prolonged viral carriage at completion of treatment was observed in 47 patients (4.4%) and was associated to a higher viral load at diagnosis (p < 10-2) but viral culture was negative at day 10 and all but one were PCR-cleared at day 15. A poor outcome was observed for 46 patients (4.3%); 10 were transferred to intensive care units, 5 patients died (0.47%) (74-95 years old) and 31 required 10 days of hospitalization or more. Among this group, 25 patients are now cured and 16 are still hospitalized (98% of patients cured so far).”

In other words, it works remarkably well.
The use of the term ‘endpoints’ is quite misleading to us ordinary folks.

Reply to  Dan Pangburn
April 13, 2020 1:42 pm

Also, Dan (and you, too, NM), see this breakdown of pre-existing conditions, and other metrics here of that referenced 1061 patient French study by Dr. Raoult:

https://www.mediterranee-infection.com/wp-content/uploads/2020/04/Table_final_website_IHU_09_04_2020.pdf

Reply to  Nicholas McGinley
April 13, 2020 3:38 pm

I was wondering what dosage was used but haven’t found it. I read some place that too much HCQ (600mg/day for 10 days) causes heart arrhythmias so how little has high probability of working? In the news stuff they show pictures of 200 mg pills. Willis says he took 500 mg once per week to prevent malaria.

It appears that the Trump-haters are OK with thousands of people dying as long as they can spin it to make Trump look bad.

Reply to  Nicholas McGinley
April 13, 2020 11:04 pm
Reply to  Nicholas McGinley
April 13, 2020 11:05 pm

“If no hydroxychloroquine
available, consider chloroquine
base 600 mg (10mg/kg) at
diagnosis and 300mg (5
mg/kg) 12 h later, followed by
300 mg (5 mg/kg) BID up to
Day 5 or chloroquine
phosphate 1000mg at
diagnosis and 500mg 12h
later, followed by 300mg BID
up to day 5.”

Reply to  Nicholas McGinley
April 13, 2020 11:15 pm

Not a word about how they selected or excluded patients.
These where not people that presented at hospitals.
If you consider this scientific, I suppose that is why so many are having problems communicating.
In fact this is a typed sheet of paper.
Anyone could have written that.
No wonder it shows up on zero searches, and appears no where in discussion anyplace except social media.
Show we one place where this appears on something that does not look like a ten year old could have typed it up.
On that there are people that claim they have a cure.
I cannot wait for the day.

Reply to  Nicholas McGinley
April 14, 2020 4:01 am

re: “Not a word about how they selected or excluded patients.”

People (walk-ins) presenting known symptoms, subsequently testing positive as well. Ppl who KNOW something is off, that something has ‘taken ahold’ of them, and have seen no improvement in several days. Ppl who want to return to a state of wellness again. With no “brain” in gear on your end, NM, this gets tedious quite quickly. Do you know what the full set of symptoms are? Raoult and associates operate an infectious-disease medical research and treatment facility in southern France. This is the research institute’s website here: https://www.mediterranee-infection.com/ Mission and objective statement: https://www.mediterranee-infection.com/linstitut/missions-et-objectifs/

Two more questions, have you been through the virology course here yet (it is up to date and mentions the latest corona virus):

Virology Lectures 2020 #1: What is a Virus?
Vincent Racaniello
https://www.youtube.com/watch?v=lj3NhPgOoX4
(A number of videos follow in succession this video.)

and have you read ANY of the papers cataloged, linked here (the page appears to be updated every week or so):

http://clarivate.com.cn/coronavirus-resources/research04.htm\
(Language is Chinese; FlashPeak Slimjet or Chrome browsers will translate.)

Also regarding the following (swerving ever-closer into idiot classification): “Show we one place where this appears on something that does not look like a ten year old could have typed it up.” have you seen the followup table (WHICH) I posted previously in your direction? It lists known pre-existing conditions of patients ion this 1061 patient ‘study’:

Table 1. Baseline characteristics according to clinical and virological outcome of 1061 patients
treated with HCQ + AZ ≥ 3 days at IHU Méditerranée infection Marseille, France with Day 0 between
March 3 and March 31, 2020.
https://www.mediterranee-infection.com/wp-content/uploads/2020/04/Table_final_website_IHU_09_04_2020.pdf

Pls, read more, and retain more. This gets tedious, for all of us, NM.

Reply to  Nicholas McGinley
April 14, 2020 9:29 am

You are off the deep end pal.
You have no idea what anyone who disagrees with you is talking about.
You have abandoned science and are now a rabid take no prisoners advocate for some inane political point of view or illogical obsession with an open question which has been settled beyond all doubt…but only in your mind, not in any way settled in reality.
I do not hope to reason with you or explain anything I think you will comprehend.
I am merely saying so for the record, and in case you have a moment of clarity, in your fevered imagination.
Do not bother including me in your ranting, or answer questions I ask someone else please.

Reply to  Ken
April 13, 2020 2:35 pm

Ken: I applaud your post. And would add, if Zn and Hydroxychloroquine were given earlier rather than later, I suspect the results would be even more amazingly positive.

Clyde Spencer
Reply to  Ken
April 17, 2020 12:57 pm

Ken
You derisively commented, “For those asking for a “control group” as some magical requirement for statistical significance in their rigid illogical and unthinking brain, …”

So, if I take most of the watermelon-flavored jelly beans out of a box, before pouring them into a jar for subsequent sampling, by your reasoning, it shouldn’t effect the outcome of trying to determine the proportions of the different flavors. Now, do you care to comment more on just how you define “unthinking?”

April 13, 2020 7:45 am

Think you know viruses?
Think you know “Virology” –
Want to LEARN more about viruses and Virology?
Below is #1 in a series of lectures by Vincent Racaniello, Ph.D. Columbia University
http://www.virology.ws

Virology Lectures 2020 #1: What is a Virus?
https://www.youtube.com/watch?v=lj3NhPgOoX4
.

April 13, 2020 9:49 am

“The Brazilian study included 81 hospitalized patients, with about half being given a dose of 50 milligrams of chloroquine twice daily for five days. The other participants were prescribed a dose of 600 milligrams for 10 days.

Patients taking higher doses experienced heart arrhythmias, or improper beating of the heart, within three days, according to the study. Eleven patients died by the sixth day of treatment and caused the research on high-dosages to end”
https://thehill.com/policy/international/492460-small-chloroquine-study-stopped-after-irregular-heart-beats-detected-in

Curious George
Reply to  Nicholas McGinley
April 13, 2020 3:07 pm

What a nice study! Give half the patients a sixtuple dose, call it a research, and be surprised!

Reply to  Curious George
April 13, 2020 10:59 pm

What are you talking about?
The dosage was 600 mg.
Are you asserting that some protocols for COVID -19 are based on a dose of only 100mg a day?
In fact, 600 mg is the recommended dosage.

This is the third country, after China and then Sweden, to halt usage of Chloroquine due to toxicity and side effects issues.
Why don’t you get your facts straight?
Obviously you never bothered to look at what dosage is being used anyplace else, or you would never have said anything so dumb.

Frank
Reply to  Nicholas McGinley
April 14, 2020 11:00 am

Nicholas: There is a typo in the article in The Hill. Follow the link in the article to the paper itself.

“Eligible participants were allocated to receive orally or via nasogastric tube high dose CQ (600mg CQ twice daily for 10 days or total dose 12g); or low dose CQ (450mg for 5 days, twice daily only on the first day, or total dose 2.7g). In addition, all patients received ceftriaxone and azithromycin.”

“Eligible participants were allocated to receive orally or via nasogastric tube high dose CQ (600mg CQ twice daily for 10 days or total dose 12g); or low dose CQ (450mg for 5 days, twice daily only on the first day, or total dose 2.7g). In addition, all patients received ceftriaxone and azithromycin.

“Regarding cardiotoxicity and QTc over time, the variation in the QTc as compared to the baseline ECG increased more on days 2 and 3 in the high-dose CQ arm, with both arms showing more similar QTc variations in the last three days of follow up. Two patients in the high dose CQ arm evolved with ventricular tachycardia before death. This severe type of arrythmia is usually facilitated when QTc is prolonged.”

The high dose arm of the study was discontinued, but the low dose arm is ongoing.

“The fact that in many countries the ‘compassionate use” of CQ or HCQ has already been formally indicated for severe patients , made it UNETHICAL TEO TEST PROPER EFFICACY DUE TO LACK OF A PLACEBO ARM AS A COMPARATOR. Our study aimed to comprehensively evaluate primarily the safety, and secondarily the efficacy of CQ in two different dosages.”

So all of the publicity about the alleged efficacy of CQ from non-placebo controlled double-blind trials has made it impossible the proper clinical trials.

“In a unique pandemic situation, health care PROFESSIONALS have to choose between offering medical assistance and generating a reporting reliable data, a dichotomy that compromises the generation of good quality evidence for clinical management. Global recommendations for COVID-19 are being made BASED ON UNPOWERED STUDIES, however and due to the chaotic urgency, such drugs are being prescribed in a compassionate manner given the severity of the disease. However, CQ, despite being a safe drug used for more than 70 years for malaria, MIGHT BE TOXIC IN THE DOSAGES RECOMMENDED BY CHINESE AUTHORITIES (high dose 10 g for 10 days). Our study raises enough red flags to stop the use of 12 g of CQ … in total in order to avoid more unnecessary deaths.”

“Placebo-controlled studies could still be performed in countries no routinely using the drug. Several ongoing trials have been addressing the early use of CQ, IN WHICH THE ANTI-INFLAMMATORY PROPERTIES COULD BE USEFUL. That information is urgently needed.”

In an earlier comment, I half-jokingly compared treatments whose efficacy and safety hadn’t been established in double-blind, placebo-controlled clinical trial to the old practice of bleeding patients. However, automatic use of CQ with patients with QTc prolongation or other serious heart conditions may be as bad as bleeding. The problem is that doctors treating a patient may not be sure if the heart problems he sees were previously mild, but are being made worse by viral attack on heart tissue (for which there is some evidence), or whether CQ is too risky to use on this patient.

Reply to  Frank
April 14, 2020 1:07 pm

Ah, I see, it was not 50 mg, it was 450 mg in the low dosage arm.
That makes more sense.
I was wondering about that dosage.
Honestly I am sifting through so much material to read I am not taking the time to follow up on every detail of such stories.
What I found noteworthy was the discontinuation, the third I have found in the past day (China, Sweden, and now Brazil. The China doctors in Wuhan seemed to be pouring cold water on the entire idea of these drugs having efficacy, without coming right out and saying so. This is because it is not scientific to do so until there is at least some proof, from a double blind placebo controlled trial, that it is so, no matter how low confidence may be).

I have come across assessments of the size of the set of all people for whom the malaria drugs are not safe. In these assessments, the drugs can only be assumed to be relatively safe in about 90% of the population, given all of the known drug interactions and the number of people who take one of those, the contraindications regarding various medical conditions, and so forth.
So there drugs are unsafe in something like 10% of people in the US, and possibly anywhere.
It is entirely possible that even if they have some therapeutic value, it could well be outweighed by possible harms, and almost certainly will be without careful screening.
Many drugs that are general safe for healthy people, are decidedly unsafe for sick people…and that goes for any sort of drug.
It is just not the same to assume something has the same safety profile in people who are critically ill that it does in healthy people. But even healthy people need to be screened when considering using one of these drugs.

As to the point about not knowing why patients died, who may have done so due to the drugs used for treatment, which were then not recognized as such because it was assumed they were from the disease, I totally agree with your point and that made by several authors.
The danger of not having good data from large and properly designed trials is immense.
And this is one reason why trials typically stretch over a period of many years, and involved several stages of testing and long periods of monitoring.
Many harms do not become apparent for long periods of time. A few months or even a year will not catch many of the well known and recent cases of harms caused by medications.
The gold standard of safety is all cause mortality after some period of time, and the longer the period and the larger the set of patients studied, the better.
One problem, of course, is that “safety” has a different meaning when used in the context of a treatment or cure for a deadly condition or disease. This adds urgency. As does the sheer number of people at risk. But that very urgency and number at risk might cause a discarding of standards that ends up being extremely deleterious to public health in the long run, and may do so even in the short term if standards are simply abandoned.

As an aside, this same concept of long term all cause mortality brings up another shortcoming of simply looking at disease mortality stats in the short term, the binary lived/died question so many are focused intently on.
If there are five to ten cases of viral pneumonia for every death, with most of them walking out of the hospital eventually, this may well not be revealing the true mortality rate, if many of those pneumonia patients have suffered harm which has drastically shortened their life…which I believe will turn out to be the case for people who have viral pneumonia for an extended period but eventually recover enough to be released from the hospital, and declared cured or resolved. Many of these people may be dead within a year or two, or whatever time period one may consider.
Some diseases damage a person permanently in a life shortening way, although they will likely die from something else down the road and not pneumonia or a lung ailment.

Frank
Reply to  Nicholas McGinley
April 15, 2020 10:20 am

Nick: Glad to hear someone here is interested in wanting to know what drugs work – rather than believing they work or don’t work because of what the President or liberal media say. Try reading original sources whenever possible which can often be found by searching google scholar even when published in journals with a paywall. And have some faith in the experts who are advising or making decisions. It a crisis like this one, they may not make all of the correct decisions, but they do have informed reasons for choosing one course over another. You can’t say that for the president or his critics.

The article from the Brazilian doctors was extremely informative. Normally a new drug is shown to have efficacy (and safety in some animal model before it is tried on humans). However any doctor can prescribe an approved drug (ie one believed to be safe enough to use for some condition) for any condition he sees fit (but drug companies are not allowed to encourage the doctor to do so for a new condition by advertising). Normally a drug is tested in a double-blind clinical trial against a placebo – something the French and Chinese doctors didn’t do before publicizing the use of chloroquinine. However, once there is a drug assumed to be useful for treating a disease, it is unethical to conduct a clinical trial and give half of the patients a placebo. The Brazilian doctors cleverly avoided this problem by doing a trial with the same dose of chloroquine as used by others, but for a slightly longer period, and added a comparator arm with a lower dose. This allowed them to unambiguously demonstrate that the high dose of chloroquine had safety issues.

Those seeking to develop a new antibiotic must run double blind clinical trial using an existing antibiotic (not a placebo) as a control, because it would be unethical to withhold a useful treatment from any patient. A new antibiotic can be approved by being as good as an existing antibiotic because resistance is making many antibiotics less effective. Unfortunately, a new (expensive) antibiotic has trouble competing against a cheap older treatment unless no older drugs work for a patient and it takes a few days for lab work to demonstrate efficacy against an infecting antibiotic.

In the case of COVID-19, if chloroquine is assumed to be useful, a clinical trial that tested remdesivir against placebo would be unethical, because that would be withholding useful treatment from a patient. So by prematurely and widely publicizing (and now politicizing) the use of chloroquine, every new clinical trial might need to use chloroquine instead of placebo as the control. This is complicating the scientific challenge of learning what treatments are effective.

Clyde Spencer
Reply to  Frank
April 17, 2020 1:04 pm

Frank
Thank you for your insightful comments.

TomH
April 13, 2020 11:43 am

Providence/Little Company of Mary Medical Center in Torrance, Calif is reportedly giving hydroxychloroquine & azithromycin to all ICU patients diagnosed with the chinese virus
ref: http://www.dailybreeze.com/2020/04/13/coronavirus-patients-recovery-after-20-days-on-ventilator-is-a-miracle-for-family-a-welcome-boost-for-doctors/

April 14, 2020 9:07 am

Per the epidemio pdf, the interim clinical guidance for adult dose for confirmed mild to severe covid-19 is hydroxychloroquine 400 mg at diagnosis, 400 mg 12 h later and 200 mg BID [means twice a day] on days 2-5. Because of the long elimination half-life of the drug (32–50 days), the duration of treatment should not exceed 5 days.

Critical cases (on ventilator) use Remdesivir instead.

Chloroquine is different stuff with worse side effects and different dosage.