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Comment by jamesblonde | Hacker News Reader

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:

https://www.nature.com/articles/s41421-020-0147-1

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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.

[1] e.g., https://www.ncbi.nlm.nih.gov/pubmed/15897343

> ACE inhibitors (lisinopril, etc.) are generally though to be enzymatic inhibitors of ACE, not ACE2

Correct. Ace inhibitors have shown no effect on ACE2.

https://www.nrcresearchpress.com/doi/10.1139/y02-021

Some more recent research seem to at least partially contradict this statement and seem to suggest ACE inhibitors do affect ACE2.

https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1440-1681....

https://www.ncbi.nlm.nih.gov/pubmed/15897343

In addition there is also this specific recent Covid19 paper which does cautiously attract attention on this matter.

https://www.nature.com/articles/s41569-020-0360-5

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.

(Sorry for by bad English, not a native speaker)

I thought your English was great. Your post is perfectly readable. :)

I am a native English speaker, and your English was literally flawless.

Your English is fine.

However, your first two papers seem to state ACE inhibitors makes ACE2 worse in terms of COVID-19.

"Losartan increased plasma levels of both Ang II and Ang-(1-7), as well as cardiac ACE2 mRNA and cardiac ACE2 activity"

The last one does nothing except say, "someone should look at it."

upregulation of ACE2 means the mRNA that is responsible for the code to make ACE2 protien is being transcribed.

this does not mean the ACE2 enzyme activity or concentration is increased

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"

should I check in with my cardiologist?

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.

Thank you very much for the info and taking a look at it!

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 english is fine! Better than mine and I have been a native speaker for 32 years!

I think it wasn't ACE inhibitors but sartans (telmisartan losartan, etc.) that were being discussed as possible prophylaxes, potentially via inhaler.

Everyone is welcome to take their own health into their own hands.

Since when? Last time I checked my body my choice does not apply to the vast majority of pharmaceuticals unless a third party approves it.

It is illegal to take them? Or are you merely referring to the fact that it's illegal to sell them?

Since that's the only legal way of acquiring them, yes.

Did you check using a for loop or a while loop?

Consulting with your medical provider so they can deny life saving drugs to you?

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.

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.

Chloroquine isn't a safe medication. Side-effects include irreversible macular degeneration. Check out how many other side-effects there can be:

https://www.drugs.com/sfx/chloroquine-side-effects.html

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.

this is only part of the story.

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.

This makes perfect sense! Thank you!

Might be of interest:

“Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia”

https://www.ncbi.nlm.nih.gov/m/pubmed/32075365/

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.

It's a ghastly beast, I wouldn't recommend anyone take it for fun. It's available cheaply in third world places, so you could probably get it online.

(Doxycycline and other antimalarials are also terrible, just better than getting malaria.)

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?

That's a f###ing bad idea given the current state of knowledge about this infection. Your chance for doing more harm than good is huge.

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.

https://www.ncbi.nlm.nih.gov/pubmed/32150618

This can change your mind

You mean the "in vitro" part?

I mean it's common practice at hospitals now. Using dumbfounded dumb dumb words is dumb bro

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.

Beware of chloroquine, I read somewhere it wasn't all that good for your health.

Sorry I don't remember much, but do some research before you use it.

it is a 70 years old drug with its safety profile well studied.

Yes... well-studied does not mean without drawbacks.

Right now on this day, OP is probably more likely to die from chloroquine administration than from the pandemic.

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.

Statistically, population wide chloroquine prophylaxis would probably cause more problems than is warranted by the COVID-19 threat.

Even if it works, and isn't just wishful thinking / propaganda.

I agree.

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.

Bleach has a well studied safety profile too

Kills cancer, prevents caries

https://bnf.nice.org.uk/drug/chloroquine.html

> Side-effects

> Rare or very rare

> Cardiomyopathy; hallucination; hepatitis

>Frequency not known

> Abdominal pain; agranulocytosis; alopecia; anxiety; atrioventricular block; bone marrow disorders; confusion; corneal deposits; depression; diarrhoea; eye disorders; gastrointestinal disorder; headache; hearing impairment; hypoglycaemia; hypotension; insomnia; interstitial lung disease; movement disorders; myopathy; nausea; neuromyopathy; neutropenia; personality change; photosensitivity reaction; psychotic disorder; QT interval prolongation; seizure; severe cutaneous adverse reactions (SCARs); skin reactions; thrombocytopenia; tinnitus; tongue protrusion; vision disorders; vomiting

This "frequency not known" is listed alphabetically. There's some potentially fatal things in that list.

have you tried reading paracetamol leaflet under the frequency not known paragraph?

Billions of people take paracetamol with no issues at all. That's not true about chloroquine.

Did you buy it from somewhere that can be delivered to the US?

What service did you use to sequence your genome?

Dante labs. They give you the .vcf files, you have to annoy them for the .bam and .fastq files.

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