TrumpLyftAlles | 7 points | Jul 09 2020 17:50:07

A Combination of Ivermectin and Doxycycline Possibly Blocks the Viral Entry and Modulate the Innate Immune Response in COVID-19 Patients (India, PDF)

https://chemrxiv.org/articles/preprint/A_Combination_of_Ivermectin_and_Doxycycline_Possibly_Blocks_the_Viral_Entry_and_Modulate_the_Innate_Immune_Response_in_COVID-19_Patients/12630539

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[-] TrumpLyftAlles | 3 points | Jul 09 2020 18:00:06

This is another docking study; the science is beyond me. Great illustrations in the PDF.

It says ivermectin has a "perfect binding" with the COVID-19 spike, which may prevent the virus from entering the cell (not the nucleus!?).

It has "significant binding" with RdRp which may inhibit replication of the virus.

Looking it up: RdRP is an essential protein encoded in the genomes of all RNA-containing viruses with no DNA stage, i.e. of the RNA viruses. It catalyses synthesis of the RNA strand complementary to a given RNA template. The RNA replication process is a two-step mechanism.

Finally, ivermectin has "significant binding affinity" to NSP3, NSP10, NSP15 and NSP16, which may interfere with the virus's actions that disable the immune system.

#Abstract

The current outbreak of the corona virus disease 2019 (COVID-19), has affected almost entire world and become pandemic now. Currently, there is neither any FDA approved drugs nor any vaccines available to control it.

Very recently in Bangladesh, a group of doctors reported astounding success in treating patients suffering from COVID-19 with two commonly used drugs, Ivermectin and Doxycycline. In the current study we have explored the possible mechanism by which these drugs might have worked for the positive response in the COVID19 patients.

To explore the mechanism we have used molecular docking and molecular dynamics simulation approach. Effectiveness of Ivermectin and doxycycline were evaluated against Main Protease (Mpro), Spike (S) protein, Nucleocapsid (N), RNA-dependent RNA polymerase (RdRp, NSP12), ADP Ribose Phosphatase (NSP3), Endoribonuclease (NSP15) and methyltransferase (NSP10-NSP16 complex) of SARS-CoV-2 as well as human angiotensin converting enzyme 2 (ACE2) receptor.

Our study shows that both Ivermectin and doxycycline have significantly bind with SARS-CoV-2 proteins but Ivermectin was better binding than doxycycline. Ivermectin showed a perfect binding site to the Spike-RBD and ACE2 interacting region indicating that it might be interfering in the interaction of spike with ACE2 and preventing the viral entry in to the host cells. Ivermectin also exhibited significant binding affinity with different SARS-CoV-2 structural and non-structural proteins (NSPs) which have diverse functions in virus life cycle. Significant binding of Ivermectin with RdRp indicate its role in the inhibition of the viral replication and ultimately impeding the multiplication of the virus. Ivermectin also possess significant binding affinity with NSP3, NSP10, NSP15 and NSP16 which helps virus in escaping from host immune system.

Molecular dynamics simulation study shows that binding of the Ivermectin with Mpro, Spike, NSP3, NSP16 and ACE2 was quiet stable. Thus, our docking and simulation studies reveal that combination of Ivermectin and doxycycline might be executing the effect by inhibition of viral entry and enhance viral load clearance by targeting various viral functional proteins.

I posted this to /r/science hoping to get a take on this study from someone who understands this stuff.

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[-] thaw4188 | 1 points | Jul 09 2020 21:13:00

Very recently in Bangladesh, a group of doctors reported astounding success in treating patients suffering from COVID-19 with two commonly used drugs, Ivermectin and Doxycycline.

can you find the study/dosing? I am on both

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[-] TrumpLyftAlles | 2 points | Jul 09 2020 21:31:33

From here:

The study patients were divided into two groups including (A) (n=60): Ivermectin 200 µgm/kg single dose and Doxycycline 100 mg BID for 10 days. Note this is very similar to Dr. Tarek Alam’s successful hospital approved protocol study at the Bangladesh Medical College. Group (B) (n=56): Hydroxychloroquine 400mg first day then 200mg BID for 9 days plus Azithromycin 500mg daily for 5 days.

Hope that helps!

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[-] thaw4188 | 2 points | Jul 09 2020 21:33:41

that was very helpful and exactly what I am on

100mg Doxy (every 12 hours first three days as loading, then once a day x 10)

and Iver 200mcg/kg = 12mg for five days

if my viral load and weeks of damage wasn't so bad I'd probably be responding better

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[-] TrumpLyftAlles | 1 points | Jul 09 2020 21:39:32

You've been on 12mg of ivermectin for 5 days without improvement? That's discouraging. :(

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[-] thaw4188 | 2 points | Jul 09 2020 21:08:34

I'm on this combo and unfortunately doesn't quite work guaranteed as a treatment.

I am alive but barely.

Maybe very early on at low viral loads, I didn't start until like 5+ weeks in when already very damaged.

Then again maybe it saved me from death, who knows.

But Doxy is a very tricky antibiotic to take, it loses a lot of potency with ANYTHING like vitamin or mineral present so you have to take it first thing on empty stomach and it can cause esophagus and stomach problems in some people. I find it makes me bloated and burping somehow.

ivermectin is hassle free to take though

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[-] pezo1919 | 1 points | Jul 09 2020 21:40:07

I wish you the best I hope you recover soon. May I ask age/gender/comorb?

How do you know its the way to take doxycycline?

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[-] [deleted] | 1 points | Jul 10 2020 04:27:02

budesonide Doc believes is the silver bullet. https://www.newsmax.com/t/newsmax/article/975952 here is an rct that support it

Use in combo treatments https://www.medpagetoday.com/meetingcoverage/ats/87261

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[-] thaw4188 | 1 points | Jul 11 2020 10:48:33

it is so weird I was just googling Budesonide before I saw your reply

https://clinicaltrials.gov/ct2/results?cond=Covid19&term=Budesonide

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[-] nilaul | 1 points | Jul 11 2020 09:33:08

After 5 weeks your body may have very much got rid of the virus by itself. It's very hard to see what's going on without actual virus load data. Which means the body is in the process of healing itself. Or ivermectin might have saved you from death like you said.

Hows your symptoms?

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[-] TrumpLyftAlles | 1 points | Aug 10 2020 07:15:43

But Doxy is a very tricky antibiotic to take, it loses a lot of potency with ANYTHING like vitamin or mineral present so you have to take it first thing on empty stomach and it can cause esophagus and stomach problems in some people. I find it makes me bloated and burping somehow.

Ugh. Sounds crummy.

Glad you're hanging in there!

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[-] thaw4188 | 1 points | Aug 10 2020 11:25:56

its strange to see this reply you bumped from a month ago, weird to see my state of mind then

sickness-wise I am definitely much better, I've definitely cleared the virus

however the damage is real and terrified it's permanent because it's not improving, my spo2 in the morning when I get up is 90-91 and that is very very bad - to this day I cannot sleep more than four hours at a time or risk my spo2 dropping into the 80s

it's a serious problem and there aren't really any therapies, not not that I could access or afford them anyway

the sooner people take ivermectin when they get sick the better, every day counts, I waited too long (weeks)

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[-] TrumpLyftAlles | 1 points | Aug 10 2020 17:34:36

I am definitely much better, I've definitely cleared the virus

This is very good news! :)

my spo2 in the morning when I get up is 90-91 and that is very very bad

I think you exaggerate how serious it is -- but you are no doubt more expert on that subject that me.

I'm healthy, have 2 02 monitors, and just now got 91 and 94.

Good luck with your 02!

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[-] thaw4188 | 2 points | Aug 10 2020 20:35:56

either you are not using them right or you have a problem, they should not be that low (or you are at altitude)

I was at 98+ when well, many people are when rested and measuring sitting still

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[-] TrumpLyftAlles | 1 points | Aug 10 2020 20:41:01

or you have a problem

Could be. I'll ask my MD about it, if/when we ever see each other.

you are not using them right

How could I use them wrong? Different fingers doesn't make a difference. Finger up or finger down, same result.

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[-] thaw4188 | 1 points | Aug 10 2020 20:44:15

does your meter show a perfusion index (PI) to indicate quality of reading?

you've probably been taking lots of zinc which means it's blocking iron absorption, which may mean you are low iron or even anemic which could also give low readings but this is just a guess - they have to be taken many hours apart, I do 12 hours morning/evening routine, zinc morning, iron evening

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[-] TrumpLyftAlles | 1 points | Aug 10 2020 21:12:17

does your meter show a perfusion index (PI) to indicate quality of reading?

Nope, both of them just do 02 and pulse.

they have to be taken many hours apart, I do 12 hours morning/evening routine, zinc morning, iron evening

I get some zinc, in my cubic foot of supplements, but not iron. It's not recommended for old people (I was born during the Truman Administration) because it can lead to heart problems. My Costco "Mature Multi" vitamin for people aged 50+ omits iron, presumably for that reason. IIRC, high iron (ferritin) is associated with a worse course of disease.

Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion.

Maybe 30 years ago I read about a Finnish investigation into why the men in a particular town had an outstandingly low rate of heart attacks. Turns out that the town had a cultural moray about donating blood. They gave a LOT. This correlates with the observation that women get few heart attacks until after they stop menstruating.

I adopted the habit of giving blood regularly, the joke being that was my form of menstruating (I'm male). I have donated in the vicinity of 10 gallons. I used to donate every six weeks at a Red Cross facility, and they tracked my contributions to 8 gallons. They gave me a numbered pin each time I hit another gallon. Then I started donating at a local hospital, which doesn't give me any report about how much I have donated. Doesn't matter, I'm not keeping score.

A good thing about donating is they measure your iron level every time. Mine was never too low to donate. Could be different now, given my ridiculous supplement routine.

I want an app that reads bar codes on supplement bottles, adds up the nutrients, and gives warnings like "You need to add copper because you are taking so much zinc." I'm too lazy/dumb to attempt doing that manually.

I never used pubmed before this pandemic.

Dietary iron intake and risk of death due to cardiovascular diseases: A systematic review and dose-response meta-analysis of prospective cohort studies

Results: We included eight articles (19 studies including 720,427 participants [46,045 deaths due to CVD]) in the meta-analysis. When comparing the highest versus lowest level of dietary heme iron intake, the pooled RR for CVD mortality was 1.19 (95% CI, 1.01-1.39). With a 1-mg/day increase in dietary heme iron intake, the pooled RR for death due to CVD, stroke, coronary heart disease, and myocardial infarction were 1.25 (95% CI, 1.17-1.33), 1.17 (1.04-1.32), 1.25 (0.70-2.22), and 1.17 (0.55-2.50) respectively. The association between dietary iron intake and CVD mortality was linear (pnonlinearity 0.05).

Conclusions: Higher dietary intake of heme iron was associated with a greater risk of CVD mortality. Reducing consumption of heme iron may help to prevent premature death due to CVD.

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[-] thaw4188 | 1 points | Aug 10 2020 21:18:22

as a lifelong athlete in my 50s I assure you iron is not a health enemy but exactly the opposite, my best performances were when iron levels were at their peak

it all comes down to balance, your red blood cells will become malformed without enough iron and it takes many many weeks to fix because RBC can only be created from bone marrow and are replaced at only 1% per day

oxygen can only be carried throughout the body by healthy RBC

but if you've donated blood recently that would explain your low spo2

you don't really need another but look near the bottom of my long rambling post here for the newest $20 meters that have perfusion index and respiratory rate, they are rather neat, I own several models over the years and the new ones are amazing for the price

u/thaw4188/comments/hhdl98/articles_on_covid19_longterm_damage

ps. those studies showing heme iron mortality rates, think about the fact their source would likely be lots of livestock meat through their lives and all that goes with that

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[-] TrumpLyftAlles | 1 points | Aug 08 2020 23:12:36

Going through the study again, looking for ways that ivermectin may take action against COVID-19:

This is in addition to binding to Importin (IMP) α/β1, so the virus cannot enter the nucleus and interfere with immune functions there, and the possible reduction of blood clots as seen when malaria is treated with ivermectin.

In a sentence:

Possible mechanisms for #ivermectin vs COVID-19 are preventing entry to the cell, preventing entry to the nucleus so immune functions remain intact, interfering with viral replication, preventing the virus from disguising itself so the immune system attacks.

more about NSP16.

From the article, summarized above.

Ivermectin showed a perfect binding site to the Spike-RBD and ACE2 interacting region indicating that it might be interfering in the interaction of spike with ACE2 and preventing the viral entry in to the host cells. I

Significant binding of Ivermectin with RdRp indicate its role in the inhibition of the viral replication and ultimately impeding the multiplication of the virus.

Ivermectin also possess significant binding affinity with NSP3, NSP10, NSP15 and NSP16 which helps virus in escaping from host immune system.

At the same time, Ivermectin has significantly high binding affinity with the viral RNA dependent RNA polymerase (RdRp, NSP12), indicating poor viral genome replication for viral multiplication.

The predicted binding energies of Ivermectin and doxycycline -8.0 and -7.1 kcal/mol for NSP3 whereas -8.5 and -7.1 kcal/mol for PLpro. These observations show that, binding of Ivermectin with NSP3 and PLpro may block its enzymatic activity and thereby prevent SARS-CoV-2 from downregulating the anti-viral interferon response. This may improve viral load clearance by host innate immune system and reduce the extent of viral pathogenesis in COVID-19 patients without any previous memory of the antigen.

The predicted binding energies of Ivermectin and doxycycline -8.0 and -7.1 kcal/mol for NSP3 whereas -8.5 and -7.1 kcal/mol for PLpro. These observations show that, binding of Ivermectin with NSP3 and PLpro may block its enzymatic activity and thereby prevent SARS-CoV-2 from downregulating the anti-viral interferon response. This may improve viral load clearance by host innate immune system and reduce the extent of viral pathogenesis in COVID-19 patients without any previous memory of the antigen.

This indicates that the binding of Ivermectin to the S-Adenosylmethionine binding site will hamper the essential methyl-group transfer and inhibit the methyltransferase activity of NSP16.

The CoVs N protein is a structural protein that forms complexes with viral genome, interacts with the viral membrane protein during virion assembly and plays an important role in enhancing the efficiency of virus transcription and assembly The CoVs N protein is a structural protein that forms complexes with viral genome, interacts with the viral membrane protein during virion assembly and plays an important role in enhancing the efficiency of virus transcription and assembly The CoVs N protein is a structural protein that forms complexes with viral genome, interacts with the viral membrane protein during virion assembly and plays an important role in enhancing the efficiency of virus transcription and assembly. In our study, predicted binding energies of Ivermectin and doxycycline for Nprotein are -8.2 and -6.3 kcal/mol respectively. Altogether binding of Ivermectin with these proteins will hamper their individual function and decreases the viral genome replication, processing of virion packaging and ultimately viral load.

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[-] TrumpLyftAlles | 1 points | Aug 08 2020 23:27:36

Posted the PDF to SCRIBD here:

https://www.scribd.com/document/471836403/A-Combination-of-Ivermectin-and-Doxycycline-Possibly-Blocks-the-Viral-Entry-and-Modulate-the-Innate-Immune-Response-in-COVID-19-Patients

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