At a lower bound estimate of 30-60x the case fatality rate of flu and some unexplained reinfection mechanism, 'it's just the flu bro' is getting really disingenuous.
A simple way to explain this to simple minded people is: ever heard of international travel and massive sports events being cancelled, and armies getting mobilised because of just the flu? No? That's because that's not what this is.
Poster made it clear that the drug is untested an experimental, but ultimately each individual is responsible for their own wellbeing and should be aware of last-ditch options if things get dire.
unexplained and more importantly totally unproven.
It certainly is more dangerous than the flu but if you're not weak or old taking some random untested drugs recommended on an internet forum by someone who has no idea what he's talking about is most likely more risky than just following health organisations recommendations.
> unexplained and more importantly totally unproven.
What do you mean unproven? There are reinfection cases with incredibly low latencies being reported all over the globe. A handful of reports might be written off as misunderstandings or outliers but there are multiple reports per day from reputable sources. Reinfection is certainly a factor, the only question is by what mechanism.
> just following health organisations recommendations
You mean like the CDC which is being actively dismantled while the president of the US goes on national TV and calls their messaging fake news?
The health of every individual is ultimately in their own hands. Being informed of everything pertinent to their health including experimental last-ditch treatments is in everyone's interest. Don't look to authorities to babysit you through a pandemic, especially not in poor countries or USA. By hitting the downvote button on the grandparent comment, you're electing to censor it in some sort of misguided do-gooding effort, inspite of HN guidelines.
Patients only get retested after they appear to have recovered. That means their symptoms have subsided.
You can get super pedantic with semantics and call it a false negative, which might be technically true if the virus subsides but has the ability to persist - which is one of the potential mechanisms for reinfection, but has not been confirmed.
But none of that changes the fact that people are getting reinfected and sometimes dropping dead after appearing to have recovered by all measures. This is clearly different to 'it's just the flu bro'.
I haven't seen any serious source talking about reinfections.
> Does a 29 year old healthy male sound weak or old?
You're statistically very very very very unlikely to die of it if you're young and healthy, just like the regular flu, but of course some people will still die from it, just like some people get cancer at 20. https://www.worldometers.info/coronavirus/coronavirus-age-se...
> The health of every individual is ultimately in their own hands.
Then go ahead and tell people to inject random chemicals in their body, if you don't have the honesty to lay out all the facts people like us will lay them out for you.
> By hitting the downvote button on the grandparent comment,
I probably up/downvoted less than 5 comments in my life, and you're not one of them.
> estimate of 30-60x the case fatality rate of flu
so what do you call comparing cfr of a novel disease that so far has often went unreported, had a small sample size, is often misdiagnosed with pneumonia or the common flu and has no immunization, with another where people at risk get vaccinations and there's large statistical data coming from decades of modern countries tracking strains efficiently?
no, comparing cfrs is disingenuous.
not to say that this disease isn't severe, but enough already with the flu multipliers. it's bullshit and is not making any point across.
yeah but people will look up the figures, figure out the statistics are misleading, and be even more entrenched in their 'just the flu' assumption.
there needs to be a better way and I think "your elders' and your friends elders' are vaccinated against the flu, not this and are gonna catch it from you and 30%^ of them straight up dies" seems a better angle and more solid against argumentation.
A few medicines of note here:
Ace inhibitors are a well known treatment that reduces blood pressure.
However, there are two different types of medicine undergoing clinical trials:
Lopinavir/Ritonavir (tradename KALETRA) - a HIV medicine has shown promise
and
chloroquine - a 60+ year old anti-malaria medicine
Personally, i ordered chloroquine - well known safety profile. I won't wait for docs to discuss prescribing it if i get any symptoms. I may even take it for preventative use. I also have sequenced my DNA (full genome), and checked if I have any mutations that are know to increase production of ACE2 - increasing susceptibility to acquiring covid-19:
I dont think chloroquine has 3% morbidity. And if you are a higher risk individual, the math towards chloroquine improve. By dosing in a controlled ramp-up way, you can better mitigate many known side effects such as psychosis - identify earlier and most cases resolve when treatment is ceased.
3% is as good as a number drawn from a hat at this stage of the epidemic, be it drawn from Nature, Cell or whatever.
Also, those 3% assume you are contaminated. You can't compare that to a short-to-medium term run of preventive chloroquine adminstration, which has a rather high incidence of minor side effects.
You are statistically comparing oranges to apples. This behaviour increases your risk of hurting yourself by a large margin compared to simply following WHO recommendations.
I don't disagree with you, actually. Like I said, if you are in a high risk group, the math changes - but I agree that mass preventive chloroquine adminstration would not be a good idea. However, if there is a large outbreak, shortages of chloroquine or you have to wait days/weeks for your doctor to prescribe chloroquine - that is not a place i personally want to be.
On another note, this is a nice thread helping me (and maybe others) inform them about side effects and efficacy of possible treatments.
Everyone is welcome to take their own health into their own hands. However, for others looking to this as advice, please be aware that:
1) ACE inhibitors (lisinopril, etc.) are generally though to be enzymatic inhibitors of ACE, not ACE2 [1]. Also, enzymatic inhibition of the enzyme does not mean that it will prevent a virus from using that protein as an entry mechanism.
2) Chloroquine is an old drug with a well known safety profile, but it is certainly not a "safe" drug-- there are many known side effects including life threatening or severely disabling ones. As an MD, I recommend always consulting with your own medical provider(s) before starting any medications.
I had a talk with 2 cardiologists and their response (this is not medical advice, talk to your cardiologist) was that it would be reasonable at least until further research is completed to for instance switch medication from ACE inhibitors to a Calcium Channel Blocker (such as Lercanidipine). At least until the pandemic gets under control and/or vaccine/treatment is available and validated.
There are very few cons to this safety measure if this can prevent complications. But that's my sole opinion and again, not medical advice. This might be worth at least an inquiry to your cardiologist. Especially if you're over 60.
So, looking at the NIH conclusion, if I'm on a *saratan and read this:
"Selective blockade of either Ang II synthesis or activity induced increases in cardiac ACE2 gene expression and cardiac ACE2 activity, whereas the combination of losartan and lisinopril was associated with elevated cardiac ACE2 activity"
first off drugs that influence the components of the RAS are not childs play, so yes consult your doctor[s] rather than experimenting with dosages.
This is only just starting to see clinical trials, meaning the people involved are under direct physician supervision.
regarding ACE2:
this increased production of ACE2 is an indirect effect of ACE2 disruption.
you have to be careful with these sorts of experiments.
when you block angiotensin II receptors that means there is a reduction of signal for angiotensin II being present.
This angiotensin that would ordinarily be interacting with the ATreceptors is now available for ACE2 to operate upon.
the summary here is that increased enzymatic product doesnt mean the enzyme has been "turbocharged" . If there is an increased ratio of reactants to products this will cause increased concentration of products in total but does not change the intrinsic rate at which the enzyme actually operates.
This looks like a case of substrate concentration dependent equilibrium driving reaction rate.
basically ACE2 is a regulator that converts between angiotensin II <--> angiotensin 1,7
these have opposite effects , angiotensin II is a vaso-constrictor, thus increases blood pressure.
angoitensin 1,7 is a vaso-dialator, thus decreases blood pressure. so there is an equilibrium state of the two established by ACE2. this is something that ACE inhibitors or ARB blockers dont directly influence.
Your GP knows what other drugs you are on (maybe not in your case) and can tell you about counter-indications when combining them. Could easily save your life.
But go ahead, see a witch doctor and a herbalist and take some random medication you read about in the internet.
Hopefully your GP can tell you about counter-indications when combining drugs. There is a lot to stay on top of as so much new research is being done so often. Also, things like pharmacogenetics are often not considered to the extent that they maybe should be. In taking drugs, I'd say do your own research and talk to your GP.
Yeah, prepping is great but you might want to rethink this attitude.
Truth is, we don't know what works and you must realize that many (most?) people publishing in those papers you read don't have your well-being as their first priority.
You defy docs who prescribe, but why not also defy those who attempt to ride the fear wave to publish?
Good point about the incentives behind publishing. That said, it would be nice if educated people could make educated risks, and the general population could learn from their successes and failures. It seems like that would be a lot faster than the current system of getting drugs approved
> I won't wait for docs to discuss prescribing it if i get any symptoms. I may even take it for preventative use.
In addition to what everyone else said, would this even make sense in non-preventative use? By the time you show symptoms, the virus has already had several days to spread around your body. Would disrupting cell entry not be much too late at that point?
Sure, because those cells that are already pressed into virus copy duty won't survive forever. Corona copies, being enveloped viruses, apparently can leave the host cell without killing it, but once self-infection is blocked the remaining recovery should be hardly more a victory lap.
Where did you get Chloroquine from? It appears to be a semi-controlled substance, and most pharmacies won't sell it to you unless you can prove that you're traveling to one of the (very few) places left in the world where it's still an effective anti-malarial.
I also got chloroquine but I think I would use it on my parents or me only if we would be sick for a long time without ER room or something. What's your plan?
why? that's a drug that has been used, and honestly if my parents are 20 days in trouble breathing and ER is full I can't see why not. Other choice is to let them die
It amazes me how people can be most defiant regarding usual care practice and so prompt at accepting the first hypothetical unverified claim that comes their way in an emergency. Truly dumbfounding. And I've been at it for more than 10 years already.
Bro understands the difference between "non-peer-reviewed chinese study over 100 patients" and "lifesaving treatment" bro. Because bro happens to do clinical research for a living, bro.
Let's see what you do when your spouse is dying in your apartment with no medical help and all you have is a box of chloroquine. I truly don't wish this for you.
Jesus! Chloroquine has side effects like hearing damage, damage to the eye, irregular heart rhythm.
It’s a terribly dirty drug.
This medicine may cause heart problems and changes in your heart rhythm. Check with your doctor right away if you have chest pain or tightness, decreased urine output, dilated neck veins, extreme fatigue, swelling of the face, fingers, feet, or lower legs, troubled breathing, or weight gain. You may also feel dizzy or faint, or you may have a fast, pounding, or uneven heartbeat.
This medicine may cause hypoglycemia (low blood sugar), which may be life-threatening. Low blood sugar must be treated before it causes you to pass out (unconsciousness). People feel different symptoms of low blood sugar. It is important that you learn which symptoms you usually have so you can treat it quickly. Talk to your doctor about the best way to treat low blood sugar.
Chloroquine may cause vision problems. It may also make you dizzy or lightheaded. Do not drive or do anything else that could be dangerous until you know how this medicine affects you. . If these reactions are especially bothersome, check with your doctor.
Check with your doctor immediately if blurred vision, difficulty with reading, or any other change in vision occurs during or after treatment. Your doctor may want your eyes be checked by an ophthalmologist (eye doctor).
This medicine may cause extrapyramidal disorders (eg, dystonia, dyskinesia, tongue protrusion, torticollis). Check with your doctor right away if you have the following symptoms after using the medicine: difficulty in speaking, drooling, loss of balance control, muscle trembling, jerking, or stiffness, restlessness, shuffling walk, stiffness of the limbs, twisting movements of the body, or uncontrolled movements, especially of the face, neck, and back.
protease inhibitors are a major part of what was being demonstrated here.
the spike protien docks with the human ACE2 enzyme, that is for certain. this is only one part of the entry process.
after docking the spike protien must be "cut loose" [primed] in order to allow the membrane fusion process to proceed. this cutting occurs at the behest of exocytic serine protease, named [TMPRSS2].
the function of TMPRSS2 is not very clear but it seems to facilitate viral entry of SARS-2, Thus serine protease interaction must be manipulated in addition to interfering with ACE2 docking.
Then there is the damage. ACE2 sweeps up angiotensins I, and II and converts them into a nonactive form thus regulating the angiotensin pool created by ACE.
when angiotensin II reaches its receptor [ATR] the immediate functional effect is to cause vasoconstriction and increase blood pressure to operational level.
when ACE2 is disrupted from managing the angiotensin II pool
there is an excess of ATR activation and this leads to a pathological state. The space between lung epithelial cells becomes reinforced with extracellular fibres leading to pulmonary sclerosis in addition to widespread cell death in lung tissue.
this is where the concept of ACE inhibitor and ATR blockers come into play. the reduction of angiotensinII and reduction of ATR signalling is thought to be a method of mediating this pathophysiological consequence of initial ACE2 disruption during viral docking process.
the whole picture is to block the virus ability to dock, and block virus ability to initiate the fusion process; And to mediate damages caused by the disruption of the RAS by way of ACE inhibitors and ATR blocking.
that means four points of leverege in this system, require
four drugs minimum and clinical care for patient management.
Consider me skeptical of the practical significance of their findings. IMO, protease inhibitors are a moot point if the they don't also block cell entry via antibody-dependent enhancement (ADE):
ADE has me worried the most. There's some circumstantial evidence that COVID-19 might use ADE. The arguments against it (from claimed medical experts) on reddit was basically "ADE is extremely rare."
If the evidence for/against something is based solely on percentages, you'll get a raised eyebrow from me.
There's enough anecdotal evidence of re-infection that suggest otherwise, although there a wide variety of reasons for that -bad tests, they were never fully recovered in the first place, etc.
SARS is believed to use ADE, and COVID-19 is closely related to SARS.
On the good news-ish side, a MERS vaccine entered into Phase 2 trials at Walter Reed late last year, although I can't find anything about that more recently. MERS is another coronavirus, but doesn't use ADE.
In medicine and biology, evidence IS based on percentages. That's why all these papers that present possible mechanisms with no numbers to back them up are confusing people. You need thousands to hundreds of thousands of datapoints. This is not an exact engineering discipline (yet..) unfortunately.
ACE2 has direct effects on cardiac functiona and is expressed predominantly in vascular endothelial cells of the heart and the kidneys. -wikipedia
ACE2 entry is [betacoronavirus] lineage B clade 1 specific.
----- TMPRSS2 -----
• positive regulation of viral entry into host cell
• protein autoprocessing
• receptor-mediated endocytosis
• proteolysis
• vesicle-mediated transport
• endocytosis
This gene was demonstrated to be up-regulated by androgenic hormones in prostate cancer cells and down-regulated in androgen-independent prostate cancer tissue. The protease domain of this protein is thought to be cleaved and secreted into cell media after autocleavage. The biological function of this gene is unknown. - wikipedia
Interestingly, TMPRSS2 is the same exact pathway used by SARS, murine respirovirus and influenza. So, a blockade or modification of this might be a way to cure the flu as well.
TMPRSS2 entry is found in betacoronavirus lineage B, but not specific to it.
Camostat
CAS: 59721-29-8
Approvals: Japan
$0.10/mg in bulk (2 week lead time), or $1.25/mg in-stock
https://en.wikipedia.org/wiki/Camostat
https://www.adooq.com/camostat-mesylate.html
https://www.medkoo.com/products/11665
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E-64d
CAS: 88321-09-9
LD50 in rats: >100000 mg/kg
$12.5/mg in-stock
https://www.sigmaaldrich.com/catalog/product/sigma/e8640
https://www.apexbt.com/e-64d.html
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Obviously: untested, unknown dosage and not FDA approved. It would need a little DMSO to dissolve both.
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