Remdesivir for Covid-19 Treatment!

Why among so many drugs Remdesivir has so far been among the top candidates for treating COVID-19?

What attributes of Remdesivir makes it a good medication for treatment of COVID-19?

What is the mechanism of action of Remdesivir?

What are the most dreaded side effects of Remdesivir?

What Remdesivir-related concepts will most likely show-up on your COMLEX and USMLE Exams?

Beneatha:  I recently heard that the FDA has approved the emergency use of a drug that has reduced the recovery time of hospitalized COVID-19 patients by, I guess, four days. The drug…is…ram…rem…I always have a hard time pronouncing it! It’s Rom-something!

Dr. E: Remdesivir! Just say “Ram desire!” or “RUM desire!” and everyone will know what you’re referring to!

Beneatha: Wow! You gave such an awesome lead for my mnemonic!

Pina COLADA (click)! Puerto RICO! Pineapple and Rum-Desire! Rum Desire! Rem desire! Rem.desi.vir!

Pina Colada!

 Dr. E: Awesome!

Beneatha: How do patients take RUM-desire! RUM-desivir! For how long do they have to take it? Also, what does it mean that it reduces the recovery of patients by four days?

Dr. E: First, I want you to know that frontline medical professionals from across the globe have already pitched in their observations regarding the hospital-in-and-out-days of their patients to establish an average hospital stay for symptomatic COVID-19 patients. Originally, there were mixed reports suggesting anywhere from 4 to 24 days for the duration of COVID-19 illness. That was, in part, due to the original shock that rattled the medical community and resulted in outpours of speculations based on small number of anecdotal observations into the common global grapevine. As the number of cases kept rising and more streamlined information became available the average predicted symptomatic duration of the disease was narrowed to 14 to 16 days. To make it easily comprehensible, let us settle on “15 days”! For this reason, we can assume that “the symptomatic days” or “hospitalization days” for the COVID patients is 15 days. Secondly, patients who participated in the accelerated research that led to acceptance of Remdesivir for COVID treatment were admitted to the hospital with an extremely high index of COVID-19’s diagnostic suspicion! The result of the study that was a placebo-controlled study, showed that Remdesivir reduces the severity of symptoms and lessens the recovery time by 4 days. That is, it reduces the total hospitalization time for each patient to about 11 days.

For your other question, the most common protocol for Remdesivir’s application is once daily, intravenously, for 10 days!

Beneatha: Does my rum, piña colada, do this to all patients? Dr. E I hope that you don’t mind me repeating my mnemonic out loud! It just helps me to remember it better!

Dr. E: Repeating your mnemonics out loud!  That’s perfectly alright! For your other question, you must have known our dictum byheart now! Nothing happens in all-or-none manner in medicine!

Remdesivir is not a cure! It helps with the recovery time or it reduces the severity of the disease in most hospitalized COVID-19 patients!

Beneatha: If it’s not a cure and it only reduces the severity, then why is there so much fuss about it?

Dr. E: Put yourself in the shoes of hospitalized COVID-19 patients whose lives are hanging by a thread. If you see death hanging around the corner—wouldn’t you go for whatever medication your attending doc prescribes for you–even if it only bumps up your livelihood by just a notch? Under life-and-death circumstances, you have no other choice but to put your life in the hands of your attending healthcare providers in the emergency rooms. All you have to trust is that they are the only ones who’ve so far had the firsthand experience of dealing with COVID-19, and they know what maneuvers and what medications will improve the survival odds of their patients.

Beneatha: How did it even occur to anyone’s mind to use…REM…DESI…VIR… among so many other drugs for the COVID-19 virus? OMG, I don’t believe it, I just said REMDESIVIR with no problem!

Dr. E: Actually, the preface of Remdesivir’s story is somewhat similar to the hydroxychloroquine’s that we covered at one our recent meetings! In both cases, the precedent was established by the SARS epidemic in China, back in 2002 to 2003. As you may hopefully recall from our conversation, SARS virus that is also known as SARS-CoV or SARS-CoV-1, structurally and functionally bears much similarities to SARS-CoV-2, the causative agent of COVID-19. Both viruses are nasty coronas that have learned how to jump from bats to humans. If you recall, SARS-CoV-1 and SARS-CoV-2 are collectively known as beta-coronaviruses. This is to differentiates them from the classic and benign human corona virus that we’ve known for quite a long time as one of the main viral causes of common cold.

We just said that nasty human-killer coronas are beta-coronas. That is, their genre is beta! Of course, beta reminds us of “bad” because they are bad for humans! 

To orient you better, there are four genera of coronavirus. These are alpha, beta, gamma, and delta! Do you recall the genre of benign coronas that have been causing our good ol’ common cold for as long as me and you remember? To give you a hint, the most common way of labeling diseases or microbes is based on the time we’ve learned about them. For this reason, it is natural for scientists to identify the most common diseases and the most common pathogens first. Having said all these, what is the genre of classic, and benign common cold corona?

Beneatha: Alpha coronaviruses!

Dr. E: Do you also recall what was the other nasty beta corona that we discussed in conjunction with the hydroxychloroquine? I give you a hint! The name of it starts with the letter “M”!

Beneatha: Isn’t that the one that sounds like Marlboro cigarette!  

Dr. E: Do you mean Marburg?

Beneatha: Yes!

Dr. E: Actually, Marburg is not a corona virus! But I am glad that you brought it up as it has much relevance to our story today. By the way, why did you call it Marlboro? I think you must have a lovely mnemonic in mind for it!    

It was 60’s! A German lab scientist was smoking Marlboro!

Beneatha: Yes, I do! Can I say it?

Dr. E: Please do!

Beneatha: Cigarette is elongated! Marburg is a filamentous and elongated RNA virus belonging to the Filoviridae family. How do I know this? Because “filo” reminds me of filament, and filament means “elongated and cigarette-like”! Actually, the picture of Marburg that I see in my mind include more vivid details! I see a guy in Hamburg, Germany, with a Marlboro cigarette in one of his hands and a juicy hamburger on his other hand! Hamburg reminds me of another city in Germany, Marburg! How did I represent this? I draw an arrow to Marburg from Hamburg! I also associate Marlboro cigarette with mid to late sixties when many people used to be chain-smokers! I also see the picture of a few medical laboratories with Marlboro smoke coming out of their chimneys! Oh, one more thing! I see that the parking lots of those labs are all red because blood is overflowing from windows and doors of the labs on them!

Those labs were covered with blood!
Everywhere was red!
Marburg virus is filamentous!

When I put the details of my pictorial mnemonic together, it tells me that in late 1960’s there was a nasty eruption of hemorrhagic fever as result of Marburg infection in laboratories of a few European cities such as Marburg in Germany, and Belgrade in former, Yugoslavia!

Marburg Mnemonic!

By the way, Dr. E, I have made some notes on Marburg that I found on the website of WHO organization. I can’t recall them clearly, but I know that some of them are especially important. Would you allow me to quickly peek at them on my cell?

Dr. E: Of course, you may! Most of what I’ve have learned, I’ve learned from my own students? You just showed me another memorable way of looking at the Marburg virus! Please go on and tell me the highlights of what you have chatted down.

Beneatha: Actually, I got them from this link on WHO website:

https://www.who.int/csr/disease/marburg/Marburg-fact-sheet-EN-20-Oct-2017.pdf?ua=1

The document says that at the time scientists in those labs were working on African green monkeys that were imported from Uganda. I also have chatted down “Egyptian fruit bats”!

Wait a minute…! OMG, Dr. E! I remember that you told me that COVID-19 virus has jumped from bats to other animals and then like Dracula has turned into a blood-sucking human killer!

I have chatted four words here: Marburg! Bats! Monkeys! Humans! Wow, it seems that the Marburg’s story has so much similarity to COVID’s. At the time…it was…

Beneatha keeps on reading her notes…

A few minutes later!

Beneatha: Dr. E! Should I continue?

Dr. E: Oh, you shattered my daymaring! It was a horrible one! Thank you so much for putting an end to my frightening thoughts!

Beneatha: What did happen? What was your daymare all about?

Dr. E: As you were reading your notes I started thinking “what are the chances that both COVID-19 of Wuhan, and Marburg of Germany and Yugoslavia, were broken out by accident while they were brewing in those laboratories? To what extent is it possible that the two were part of deep state bio-weapon-related projects for annihilation of people in the adversarial countries”? Actually, as I say this, I feel that my heart is pounding again!

SARS, MERS, Ebola, and Marburg! There is something creepy about all of them. They all remind me of Dracula and the fact that they all began in bats and ended up with the humans. They are all contagious and can flip on serious inflammatory cytokine release. All are vicious killers! The genome of all of them seems to be volatile and they show tendencies for mutations and changes.  All four have caused pandemics at their own times! Wow—what are the chances that this may be true!

I must confess that for a long time, I’ve been playing volley-thoughts in my mind with China! It all began with my concerns for intellectual property, and then in the summer of 2019, it was reignited with tension between China and Hong Kong. One day I used to feel happy and the other day mad (click) about China! China good, China bad; China good, China bad; and now I have to reconcile my horrible thoughts of biological weapons!

OKAY! Let us think a little straight! Let’s forget about all these bioweapon thoughts that give us goosebumps for today. Let us leave the story of biological weapons for another occasion. For now, let us get back on our original track again. 

Beneatha: I have heard from a few residents that it is important to know about biological weapons for step and level 1 exams. I am only familiar with anthrax and organophosphates! Dr. E, would it be possible if we can devote one of our future meetings to this?

Dr. E: That sounds like a great idea to me!

Okay you brought up the Marburg virus! I like to give you some credit for thinking about Marburg, because likewise COVID, is transmitted from bats–and more exactly, the African fruit bat, to humans. This disease, however, is more like the Ebola than to COVID-19. The older name of it, Marburg hemorrhagic fever, is more descriptive of its symptoms, such as maculopapular rash, petechiae and purpuras. The most important cause of death from Marburg that bears similarities to COVID-19, is septic shock, disseminated intravascular coagulation, and failure of vital bodily organs. Actually, Marburg is claimed to be the most fatal viral disease. It is claimed that 50% to 85% of the patients who contract it, will die as a result of it. Anyhow, as I said Marburg is not a corona virus, and it is not our concern today!   

Beneatha:  OMG! I always rush it! You asked me the very same question the other day! You asked about another beta-corona! Now, I remember it! I even remember that I googled it at that time, and I came up with MERS–Middle East Respiratory Syndrome!

Dr. E: You’re correct! So why did we go such a long way to talk about COVID-19, SARS, and MERS?

Beneatha: They must be relevant to…OMG, I can say “Remdesivir” without stumbling!

Dr. E: Bravo! Okay, now, what’s the common denominating characteristic of Ebola, Marburg, MERS, SARS, and COVID-19 viruses? They are all single stranded…what!

Beneatha: RNA viruses!

Dr. E: So, what did prompt the use of Remdesivir for COVID-19?

Beneatha: I think it must have been presumed to work on some, if not all of these viruses!

Dr. E: Correct! It was shown in the past that it has antiviral activity against several RNA viruses. It has been tried against SARS, MERS, hepatitis C, respiratory syncytial virus, Ebola, and Marburg viruses. Before I forget, I must add that after some studies it was shown that Remdesivir is ineffective on Ebola, Marburg, and Hep C! Nevertheless, despite this in some scientific circles Remdesivir is still known as the Ebola pills!

One other note, can we treat hepatitis B, that is a DNA virus with Remdesivir? Let me help you with the answer and say “no”!  What type of virus is hepatitis C?

Beneatha: You just said it is an RNA virus, am I missing anything?

Dr. E: No! I just wanted to give you a mnemonic-shock so that you never forget it! So, for now, remember that Remdesivir has been a candidate for treating several nasty viral RNA diseases!

To sum it up; the most promising past research work on remdesivir has been on rhesus monkeys that were inoculated with Ebola. However, on March 20, 2020 it became available for compassionate COVID-19 use in the US. Do you know what do we mean when we say, “compassionate use”?

Let me take the load off your shoulder and answer it myself!

Compassionate use is the use of a new, and FDA UNapproved drug for treating seriously ill patients when no other alternatives are available for them. Also, there is another descriptive term that is often confused with “compassionate drugs”.  This is “investigational drugs”.  These are drugs that are in the testing process but have not yet received approval stamp from US Food and Drug Administration (FDA). These drugs are available only to people who are participating in certain clinical trials. If we use one of these drugs for certain seriously ill patients who are not part of the clinical trial for the drug, it is then referred to as compassionate use for the drug!

Beneatha: Can we short-circuit the course of studies and use a drug that is in clinical trial for certain life-threatening conditions?

Dr. E: Of course, as I said, then, that use of the drug qualifies it as a compassionate use!

Beneatha: Dr. E, I just Googled Remdesivir and saw more history on the Wikipedia. Do you want me to read it?

Dr. E: Just the highlights please!

Beneatha: In January 2020, Gilead, an American biopharmaceutical company that used to work on Remdesivir at the time of Ebola outbreaks, accelerated production of its product in Edmonton, Canada.  On March 17th, 2020, the drug was provisionally approved for use for COVID-19 patients in a serious condition as a result of the outbreak in the Czech Republic. On March 20 of 2020, Donald Trump, the US president announced that Remdesivir was available for “compassionate use” for people with COVID-19.

Dr. E: Well I guess this is enough for us to get a feel for the urgency of producing reasonable amount of Remdesivir in shortest possible time. Can you skim over the mechanism of action of it a little?

Beneatha: Remdesivir is an adenosine nucleotide triphosphate analog, and its active metabolite interferes with the action of viral RNA-dependent RNA polymerase and evades proofreading by the Covid viral exonuclease, or more specifically, exoribonuclease. As a result, there is a decrease in viral RNA production. 

Dr. E: Do you recall a few antivirals that their active forms are triphosphated? Actually, let me help you with this one!

The first one is Acyclovir! This is an anti-herpesviridae, and a guanine analog. It inhibits viral DNA polymerase when activated by viral thymidine kinase. That is viral thymidine kinase converts the acyclovir preform or acyclovir monophosphate to the active form or acyclovir triphosphate. Note that acyclovir monophosphate is similar to GMP (guanosine monophosphate) but it distorts or terminates the function of viral DNA polymerase, and as a result it has antiviral effects..  The other closely related antiviral is ganciclovir that after phosphorylation it becomes effective against cytomegalovirus and Epstein Barr virus infections.

The second one is vidarabine! The triphosphated or activated form of it, that is an adenosine analog, is effective against herpes encephalitis and conjunctivitis.

The third one is Idoxuridine! Idoxuridine and its closely related product, trifluridine, are thymidine analogs. They are converted to active triphosphated form and used topically for Herpes simplex and Vaccinia keratitis treatment.

The fourth one is Ribavirin! It is a guanosine monophosphate analog and decreases synthesis of GTP. The active form of is ribavirin triphosphate, and it interferes with viral mRNA formation. The most common use of it is for respiratory syncytial virus management in infants and young children, and for prophylaxis of influenza A and B.

The final one is zidovudine or azidothymidine that is abbreviated as ZDV, or AZT. This is a thymidine analog, and it is converted to active triphosphated form, and inhibits reverse transcriptase. More specifically this medication is a dideoxynucleoside, and it is incorporated into viral RNA and causes chain termination. AZT is the first-line anti-HIV medication. It is a dideoxynucleotide, or ddNTPs, and it is the protype of nucleoside reverse transcriptase inhibitors or NRTIs! When it is added by a DNA polymerase to a growing nucleotide chain it does not allow formation of phosphodiester bonds, and as a result chain elongation stops. You may like to remember that ddNTPs are nucleotides that lack 3′-hydroxyl group on their deoxyribose sugar and as a result cannot form phosphodiester bonds that are required for chain elongation.

Beneatha: I see a note in Wikipedia that says in some viruses such as the respiratory syncytial virus, Remdesivir stops RNA-dependent RNA polymerases, whereas in Ebola it induces an irreversible chain termination.

Dr. E: Well I guess this is something that you may like to just remember.

From what we just said about those antiviral drugs, mechanism of action of which one, likewise Remdesivir, is related to adenosine?

Beneatha: I know the answer to this! It’s Vidarabine! I think the reason that it is not used against COVID-19 is because Vidarabine only works on DNA viruses!

Dr. E: I agree with you–this is a fair assumption! Now that you are still skimming through that document, can you tell me why they call Remdesivir a delayed chain terminator?

Beneatha: Well…oh…here it is! It say that unlike many other chain terminators, the effects of Remdesivir is not mediated by preventing addition of the next immediate nucleotide, instead there is a delayed effect, and it inhibits addition of  bases, after several  bases are added to the growing RNA chain. So, this is why Remdesivir is called a delayed chain terminator.

I guess this is another important note to remember that the RNA-Dependent RNA Polymerase of MERS-CoV, SARS-CoV-1, and SARS-CoV-2 arrest of RNA synthesis is delayed and happens after three additional nucleotides are incorporated into the growing RNA chain. 

I see here a note on a compound named GS-441524. It seems that Remdesivir’s is metabolized into an active form that is known as GS-441524. This is an adenosine nucleotide analog and interferes with the action of viral RNA-dependent RNA polymerase. As a result, it evades proofreading by viral exoribonuclease. The net results are decreased viral RNA production.

Are we required to remember GS-441524 for the medical board exams?

Dr. E: No rational human being is expected to memorize stupid numbers and names like this one!  Just remember that Remdesivir is an RNA-dependent RNA polymerase inhibitor. I do believe that a more high-yield concept for your exam is to know the side effects of Remdesivir!

Okay here’s an open book question for you; and I will give you two minutes to figure it out! What are the most dreaded side effects of Remdesivir?

Two minutes later…

Beneatha: Respiratory, liver and kidney failure!

Dr. E: You are correct. However, we do need more studies to verify these fatal side effects. They may be related to the cytokine storm and sepsis of COVID-19 that leads to multiorgan failure. I trust that before the next common cold season in the Northern hemisphere, our medical researchers can hopefully figure out these issues much more clearly for us!

Well, I think we’ve had enough for today!  Let’s continue our COVID meds on another occasion.   

Dr. Eftekar (Dr. E) is the founder and head coach of the Center for Conquest of Longevity and Northwestern Medical Review. A unique attribute of Dr. E is his well-rounded academic background that, in addition to the science of medicine, extends over several other disciplines such as physiology of aging and longevity, philosophy of science and medicine, and integrated kinesiology.

Write a comment