/ Corona - Antiviral's ... in the short term.

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StuPoo2 23 Mar 2020

Why aren't they rolling out the antivirals en mass in the short term?

I know it won't do anything to affect transmission but surely its the obvious next step while we wait for a vaccine.

Chloroquine has been around for yonks.  I took it my teens in Africa as an anti-malarial ... its no longer recommended, for that purpose, due in effectiveness.  

It costs nothing to produce.  Side effects are well known.  The initial research suggests it may be effective.

What are they waiting for?

https://www.nature.com/articles/s41422-020-0282-0

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stp 23 Mar 2020
In reply to StuPoo2:

I read that one of the Asian countries, South Korea maybe, were using it combination with zinc.

I imagine, if they're even aware of it, it will probably be difficult to scale up to the necessary degree in a short time.

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StuPoo2 23 Mar 2020
In reply to stp:

Looks like I'm late the antiviral party ... heaps out there on it already.

https://www.google.com/search?q=Chloroquine&rlz=1C1GGRV_enGB766GB766&oq=Chloroquine&aqs=chrome..69i57j69i61j69i60j69i61.3854j0j7&sourceid=chrome&ie=UTF-8 

Naively, I guess I'm asking why they aren't preventatively issuing us all with broad spectrum antivirals?

Chloroquine £5.99 online:

https://www.simpleonlinepharmacy.co.uk/online-doctor/malaria-tablets/chloroquine/

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StuPoo2 23 Mar 2020
In reply to stp:

hah!  Every UK pharmacy is out of stock already ... 

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tcashmore 23 Mar 2020
In reply to StuPoo2:

Like you, I was thinking along the same lines and getting a bit frustrated at the perceived lack of action.  I found this article which was very informative:

https://www.sciencemag.org/news/2020/03/who-launches-global-megatrial-four-most-promising-coronavirus-treatments

It seems there may be some risk, when in the cycle of the infection to use it.  The only thing worse than no remedy is to have a bad remedy that causes more problems than it solves!  Therefore, they need to trial it and understand how, when , who, if to use it.

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Doug 23 Mar 2020
In reply to StuPoo2:

There have been several articles in about possible treatments (including Chloroquine)  in the French press, eg https://www.lemonde.fr/sciences/article/2020/03/17/sars-cov-2-des-pistes-de-traitements_6033381_1650684.html 

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wbo2 23 Mar 2020
In reply to StuPoo2: I believe it's inconclusive.  If you say it works people will not comply with other measures and if it then doesn't you aren't back at square 1 - you're in a very bad position.

I still have some boxes personally but I'd wait on something more reliable

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Dave Garnett 23 Mar 2020
In reply to StuPoo2:

> Why aren't they rolling out the antivirals en mass in the short term?

Because chloroquine is quite poisonous and there is, as yet, little real evidence it works in vivo.

https://www.bbc.co.uk/news/51980731

And also, I'd be quite sceptical about anything that both Donald Trump and Elon Musk are convinced is a no-brainer, despite knowing next to nothing about it. 

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StuPoo2 23 Mar 2020
In reply to wbo2:

Fair comment and wasn't the making the case for it to be used a substitute for social distancing.  Firm believer that 3/4 weeks of extreme social distancing/complete lock down (like the French and Spanish are doing) would put this down and we'd be in the position China now finds itself .. i.e. starting to think about opening back up for business.  I stand to be convinced that the UK is able/willing to lock down in the manner needed to hammer this down into the ground and buy us the time necessary to scale up ready to fight it properly down the road.

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StuPoo2 23 Mar 2020
In reply to Dave Garnett:

> Because chloroquine is quite poisonous and there is, as yet, little real evidence it works in vivo.

That was the point of the link in the original post.  Inhibition vs cytoxivity ... at doses low enough not to be toxic ... it is showing signs of being effective.  

https://www.nature.com/articles/s41422-020-0282-0

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StuPoo2 23 Mar 2020
In reply to Dave Garnett:

And another, albeit non-randomized, study from the French reporting similar results.

https://www.sciencedirect.com/science/article/pii/S0924857920300996

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Neil Williams 23 Mar 2020
In reply to Dave Garnett:

How poisonous it is depends on how much you have, and that depends on how much is needed.  It's still sold pretty much openly[1] as an antimalarial.  It's not nice stuff, but in antimalarial prophylaxis levels of dose it isn't *that* bad.

There are now trials in progress and I expect they will be accelerated as quickly as safely feasible.

[1] Technically by prescription, but you can get it online by making up a trip you're going on.  Note that I do NOT suggest people do this; it should be used for this purpose under medical supervision, and if it is found to be acceptable we want the NHS to be able to get hold of ALL of it in the UK.

Post edited at 11:40
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Dave Garnett 23 Mar 2020
In reply to StuPoo2:

> That was the point of the link in the original post.  Inhibition vs cytoxivity ... at doses low enough not to be toxic ... it is showing signs of being effective.  

Yes, maybe, but if you start publicising that chloroquine is some sort of miracle cure, you get people buying it off the internet (so it might or might not be what they think it is) and self-medicating.  In Nigeria there have already been cases of poisoning because of this.

Trump is being characteristically irresponsible here, partly because of his belief that all medicine should be privatised anyway, and partly because, as usual, he's speaking with complete assurance about a subject he hadn't even heard of an hour earlier and can scarcely pronounce. 

Post edited at 12:35
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StuPoo2 23 Mar 2020
In reply to Dave Garnett:

??? What you talking about Dave ???

Read what has been written above.

> Yes, maybe, but if you start publicising that chloroquine is some sort of miracle cure, you get people buying it off the internet (so it might or might not be what they think it is) and self-medicating.  In Nigeria there have already been cases of poisoning because of this.

Where was that written?  I linked to the Nature Research scientific journal (1st link) and Scientific Journal (2nd link) to highlight early days research that points to a possible link between, amongst others, Chloroquine and the ability to fight the coravirus.  In fact, I specifically, said "its the obvious next step while we wait for a vaccine."    In this context, the drugs being talked about here aren't cures ... they would buy us time if they were effective and time is what is needed to give us a fighting chance to build up the ammunition the world needs to fight this.

> Trump is being characteristically irresponsible here, partly because of his belief that all medicine should be privatised anyway, and partly because, as usual, he's speaking with complete assurance about a subject he hadn't even heard of an hour earlier and can scarcely pronounce. 

You brought up Trump Dave.  This thread started on published papers and linked into the WHO's megatrail including Chloroquine:  https://www.sciencemag.org/news/2020/03/who-launches-global-megatrial-four-most-promising-coronavirus-treatments

Cheers

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Deadeye 23 Mar 2020
In reply to StuPoo2:

> What are they waiting for?

Alas many things do stuff in vitro that isn't replicated in vivo... so they are finding out.

> Naively, I guess I'm asking why they aren't preventatively issuing us all with broad spectrum antivirals?

Um, there isn't really such a thing.  Viruses are in many ways more diverse and difficult to tackle than bacteria (although they do benefit from not swapping resistance plasmids).

Corona viruses are single stranded RNA (like rhinoviruses e.g. the ordinary cold) - and capable of recombination unfortunately.  Because viruses hijack much of the host cellular machinery for reproduction, you have to be a bit careful what gets targeted too.  You'll be aware that there isn't a pill for the common cold, despite a fairly obvious market!

Post edited at 17:47
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Roadrunner6 23 Mar 2020
In reply to Deadeye:

We start trials here (US) tomorrow.

its shown success in people but anecdotal evidence. People took it, most got better.

they now need proper controlled trials with more numbers to see. Luckily due to general idiocy we’ve plenty of trial subjects to use..

They then need to produce a dosing protocol. I suspect we are a few weeks off yet at least. But we can give it on compassionate grounds already without it being fully tested.

Post edited at 18:07
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Dave Garnett 23 Mar 2020
In reply to StuPoo2:

> Read what has been written above.

> This thread started on published papers and linked into the WHO's megatrail including

Chloroquine:  https://www.sciencemag.org/news/2020/03/who-launches-global-megatrial-four-most-promising-coronavirus-treatments

Yes, and this is what it says:

Chloroquine and hydroxychloroquine

The available data are thin. The drugs work by decreasing the acidity in endosomes, compartments inside cells that they use to ingest outside material and that some viruses can coopt to enter a cell. But the main entryway for SARS-CoV-2 is a different one, using its so-called spike protein to attach to a receptor on the surface of human cells. Studies in cell culture have suggested chloroquines have some activity against SARS-CoV-2, but the doses needed are usually high—and could cause serious toxicities.

Encouraging cell study results with chloroquines against two other viral diseases, dengue and chikungunya, didn’t pan out in people in randomized clinical trials. And nonhuman primates infected with chikungunya did worse when given chloroquine. “Researchers have tried this drug on virus after virus, and it never works out in humans. The dose needed is just too high,” says Susanne Herold, an expert on pulmonary infections at the University of Giessen.

Results from COVID-19 patients are murky. Chinese researchers who report treating more than 100 patients with chloroquine touted its benefits in a  letter in BioScience, but the data underlying the claim have not been published. All in all, more than 20 COVID-19 studies in China used chloroquine or hydroxychloroquine, WHO notes, but their results have been hard to come by. “WHO is engaging with Chinese colleagues at the mission in Geneva and have received assurances of improved collaboration; however, no data has been shared regarding the chloroquine studies.”

Researchers in France have published a study in which they treated 20 COVID-19 patients with hydroxychloroquine. They concluded that the drug significantly reduced viral load in nasal swabs. But it was not a randomized controlled trial and it didn’t report clinical outcomes such as deaths. In guidance published on Friday, the U.S. Society of Critical Care Medicine said “there is insufficient evidence to issue a recommendation on the use of chloroquine or hydroxychloroquine in critically ill adults with COVID-19.”

Hydroxychloroquine, in particular, might do more harm than good. The drug has a variety of side effects and can in rare cases harm the heart. Because people with heart conditions are at higher risk of severe COVID-19, that is a concern, says David Smith, an infectious disease physician at the University of California, San Diego. “This is a warning signal, but we still need to do the trial,” he says. What’s more, a rush to use the drug for COVID-19 might make it harder for the people who need it to treat their rheumatoid arthritis or malaria.

It's not impossible that chloroquine might do some good in some cases, but it needs to be properly evaluated before people start self-medicating.  Even if it works therapeutically, it doesn't follow that would work as a prophylactic (or vice versa). Is it working by preventing the full lowering of pH the endosome (but SARS-CoV-2 seems to use protease-dependent endocytosis), or is it working as a zinc ionophore (which seems to account for some of its other antiviral activity)?  Or some other mechanism?

On the plus side, we know it was a widely used anti-malarial, so it isn't stupidly toxic (although considered too toxic for long-term use) and it's widely available and cheap.

Post edited at 20:24
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LeeWood 26 Mar 2020
In reply to StuPoo2:

Just don't try to formulate your own:

https://www.theguardian.com/world/2020/mar/24/coronavirus-cure-kills-man-after-trump-touts-chloroquine-phosphate

It seems to be controversial in the french press - why does it need a six week trial when its already proven safe in other treatments ?

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Neil Williams 26 Mar 2020
In reply to LeeWood:

It's "safe" rather than safe.  It (like most anti-malarials) has some nasty side effects.  Not as bad as Lariam, where if that was the only option I'd rather not go to the place concerned than take it, but certainly up there.

They also need to work out and prove the correct dose.  Too little and it'll be pointless (and the virus might become resistant), too much and those side effects could cause greater issues.

Post edited at 10:23
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DaveHK 26 Mar 2020
In reply to StuPoo2:

When I see chat about something being effective in vitro I always think of this:

https://imgs.xkcd.com/comics/cells_2x.png

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LeeWood 26 Mar 2020
In reply to Neil Williams:

According to Professor Raoult who is at the heart of chloroquine controversy:

'Contrairement à ce que disent certains à la télévision, la Nivaquine (le nom d’un des médicaments conçus à base de chloroquine, NDLR) est plutôt moins toxique que le Doliprane ou l’aspirine prise à forte dose.'

https://gerardbrazon.wordpress.com/2020/03/24/interview-choc-du-professeur-raould-qui-sinscrit-en-faux-sur-le-parisianisme-des-politiciens/

Safer than Doliprane and asprin ! 

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nniff 26 Mar 2020
In reply to StuPoo2:

Mostly, I suppose, because a little knowledge is a dangerous thing

https://www.theguardian.com/world/2020/mar/24/coronavirus-cure-kills-man-after-trump-touts-chloroquine-phosphate

And Trump has less knowledge than most.

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LeeWood 26 Mar 2020
In reply to nniff:

> Mostly, I suppose, because a little knowledge is a dangerous thing

The value of chloroquine is in its formulation. The american who died wasn't using a known medicinal formula - but rather - fishtank cleaner ! what can you expect

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kipper12 26 Mar 2020
In reply to StuPoo2:

Is Covid 19 a retrovirus?  If so, why wouldn’t some of the other antiretrovirals be of any use.  Ive no knowledge at all here, so interested to hear.

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Dave Garnett 26 Mar 2020
In reply to kipper12:

> Is Covid 19 a retrovirus?  If so, why wouldn’t some of the other antiretrovirals be of any use.  Ive no knowledge at all here, so interested to hear.

No,it has an RNA genome but doesn't 'reverse transcribe' this into DNA, or insert it into the host genome when it replicates.  Actually the process looks pretty complicated to someone like me who only ever used dumbed down viruses as gene vectors.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369385/

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cb294 26 Mar 2020
In reply to kipper12:

As DG said, coronavirus replication and transcription seems amazingly bizarre!

Its genome is made from RNA, and is therefore made by a viral RNA polymerase that copies RNA into RNA.

Human polymerases either make RNA from a DNA template, or make a copy of DNA from a DNA template.

Retroviruses possess a  reverse transcriptase that makes DNA from RNA at one point of the life cycle.

Because these enzymes are all related but different, it is in principle possible to design nucleotide analoga that are preferentially used by the viral enzymes and rejected (or corrected) by the human enyzmes, and thus interfere with virus transcription or replication without killing the cell.

The antiretroviral drugs are already known to a) not damage human cells too badly, and b) to be accepted as the real thing by a polymerase that uses RNA as a template. Hence the hope is that these drugs may also interfere with the coronavirus enyzme.

The recently developed anti-Ebola virus drugs may be an even better bet, as they specifically target a (different) RNA dependent RNA polymerase.

CB

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StuPoo2 26 Mar 2020
In reply to nniff:

While I agree with you nniff, ... if you eat too much of practically anything it will kill you.  

https://www.youtube.com/watch?v=IPrndNZ4m6w  (I have no idea where they got their sources from )

Our shared hatred for Trump aside, the reason Chloroquine etc is an important development is because the randomized trails have been completed , and the control groups, and the large population sets etc ... all done.  

There are literally 100's of thousands of compounds proposed but very very few make it to market and stay there.  Chloroquine is one of them.  If they try for a brand new compound ... 12-18 months is typical.

Generally speaking, if Trump spoke less the world would be a better place. 

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Dave Garnett 26 Mar 2020
In reply to LeeWood:

> Safer than Doliprane and asprin ! 

Taken at high doses, with chloroquine presumably at low doses.

It all depends on efficacy.  If it works, it's clearly worth the risk.  If it doesn't, it's not.

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BnB 26 Mar 2020
In reply to StuPoo2:

France has tonight approved Chloroquine as a therapy for CV19

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LeeWood 26 Mar 2020
In reply to Dave Garnett:

> Taken at high doses, with chloroquine presumably at low doses.

> It all depends on efficacy.  If it works, it's clearly worth the risk.  If it doesn't, it's not.

I take it you don't read french - shame. The claims of Prof Raoult are controversial because he declares to have done the necessary research and proved the case. In the lines I cited above he states "In opposition to what certain people say, Nivaquine (a particular formulation of chloroquine) is less toxic than Doliprane or asprin - even taken in strong doses'

The man doesn't appear to be 'fringe' - he's got a reputation to maintain - and cites necessary doses of related drugs - open to scrutiny. 

As others have said - given there is no other viable remedy - it's bizarre they seem to be putting the brakes on. Let's hope latest news follows through - BnB !

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Neil Williams 26 Mar 2020
In reply to BnB:

> France has tonight approved Chloroquine as a therapy for CV19

That's positive, I'd imagine others will follow.

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LeeWood 26 Mar 2020
In reply to BnB:

in french of course :

https://actu17.fr/coronavirus-le-gouvernement-autorise-la-prescription-de-chloroquine-en-traitement-contre-le-covid-19/

Plus de 1 000 cas de Covid-19 dépistés positifs et traités à l’IHU

Depuis qu’il procède systématiquement aux dépistages, l’IHU a détecté et traité plus de 1 000 patients positifs. Tous les cas « de modérés à sévères » ont reçu le traitement préconisé par le professeur Didier Raoult, « avec succès », selon lui. « Je suis sur le terrain, pas devant des statistiques. Ne vous inquiétez pas, ça marche ! », lance-t-il à « ses détracteurs de plateau télé ».

translates:

More than 1000 cases of cv-19 treated with success at the IHU

Since it has systematically begun these diagnostics, the IHU has detected and treated 1000 patients positive. All cases "both moderate and severe" have recieved the treatment prescribed by Raoult - "with success" - according to him. "I am here engaged in this fieldwork, not ahead of the statistics. Don't stress any more - this works!" he retorted to "his TV critics" 

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StuPoo2 27 Mar 2020
In reply to BnB:

Mega!

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Dave Garnett 27 Mar 2020
In reply to LeeWood:

> I take it you don't read french - shame.

My French is pretty rusty but I read 'plutôt moins toxique que le Doliprane ou l’aspirine prise à forte dose.' as rather less toxic than Doliprane or aspirin taken at a high dose.

I bow to your superior French but I read that as the paracetamol or aspirin being at high dose.  You might be right that he meant the Nivaquine but I'm not sure where you get the 'even' (meme) and the em dash from, which do rather change the meaning.

Anyway, as I said, if there's good evidence that it works, it's clearly worth the risk, just as it is when given to treat malaria, if nothing safer is available or effective.

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LeeWood 27 Mar 2020
In reply to Dave Garnett:

You might be right. Perhaps it helps to look at the question posed:

Quid des risques d’effets indésirables graves liés à la prise de chloroquine, notamment à haute dose ?

What are the serious undesirable risks linked to taking chloroquine; notably at hi-dose ?

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