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Top 5 Most PROMISING drugs for Covid 

By  Dr. Mike Hansen

Most PROMISING drugs for Covid – As of right now, mid-April 2020, there is no evidence from randomized clinical trials (RCTs) that any drug improves outcomes in patients with either suspected or confirmed COVID-19. This also applies to anti-COVID19 drugs as prophylaxis.

To understand how effective and safe a drug is, you have to know what kind of study is being done for finding the Most PROMISING drugs for Covid. So I will give you a little cheat sheet right now to help you with that.

The King of all studies is Randomized controlled trials because it compares the effect of treatment versus “no treatment” (or a different treatment). They can also show what happens if you opt not to have the treatment or diagnostic test.

In RCTs, participants are randomly assigned to one of two or more groups. Then one group receives the new drug A, for example, while the other group receives the conventional drug B or a placebo (dummy drug).

Things like the appearance and taste of the drug and the placebo should be as similar as possible. Ideally, the assignment to the various groups is done “double-blinded,”

When neither the study participants nor their doctors know who is in which group, it reduces the chances of bias in the study.

So aRCT, if done properly, determines if there is a cause-and-effect relationship with a particular drug.

All other types of studies, such as cohort studies, case-control studies, observational studies, might provide medical insight, but they don’t give you a cause and effect when it comes to treatment.

Keep in mind, the following drugs in this video (Most PROMISING drugs for Covid) that I discuss, I based on what we already know about the virus, what we already know about the human body, and pharmacology, anecdotal experience, and the studies that have been done so far.

Based on clinical trials, only time will tell which of these drugs will actually work for COVID and which of them will be safe to use. But right now, those drugs are just like the Most PROMISING drugs for Covid.

Now that we got that out of the way, let’s look at what drugs seem the most promising, in no particular order.

As of right now, there are about 300 active clinical trials for COVID. To understand how these drugs work, we have to understand how the virus attacks to understand its weak points and destroy that sunfish.

That’s why if you haven’t done so already, I highly recommend you watch my previous video, called “how covid kills some people, but not others,” because that way, you’ll have a better understanding of how and why these drugs work.

To simplify things, the SARS-CoV-2, which is a single-stranded RNA-enveloped virus, has a spike (S) protein that binds to theACE2 receptor of certain cells in the body.

receptor binding | Most PROMISING drugs for Coronavirus

Following receptor binding, the virus enters the cell

Once inside the cell, viral proteins are made by the cells’ machinery.

Once the virus replicates itself inside the cell, it bursts out and attacks more of the same type II alveolar cells.

Now to the drugs that can potentially stomp out this virus…

Currently300, clinical trials are going on; 29 of them are placebo-controlled trials, which are the best kinds of trials.

Let’s start with the most talked-about ones in the media.

Chloroquine and Hydroxychloroquine (Most PROMISING drugs for Covid)

They treat malaria, lupus, rheumatoid arthritis.

They appear to inhibit viral entry into cells by altering the host receptors and something called endosome acidification… which, in English, means it might alter the cell’s ability to engulf the virus.

These drugs also seem to work by quelling the cytokine storm and inhibiting autophagy.

Auto means self. And phagy means to eat. Soautophagy means the cell eats itself out. Yes, that’s what the cells in your body sometimes do. Please don’t judge them. Sometimes cells do this when they are infected or when they get too old to function out with the old and in with the new.

Chloroquine and Hydroxychloroquine have been shown to inhibit SARS-CoV-2 in vitro (in a test tube). But that’s in a test tube. There are no high-quality studies that have shown efficacy for SARS, MERS, or COVID.

A news briefing from China reported chloroquine was successfully used to treat a series of more than 100 COVID-19 cases, resulting in improved findings on chest x-ray and improved viral clearance, and reduced disease progression.

However, the clinical trial design and outcomes data have not yet been published for peer review, so these claims cant be validated.

Without validation, anyone could claim anything works, including snake oil.

“Silver solution would be effective.”

Recently In France, there was an open-label nonrandomized study of 36 patients (20 in the hydroxychloroquine group and 16 in the control group), meaning both the researchers and the patients knew who was getting the drug.

In this study, there was an improvement in virologic clearance with hydroxychloroquine. The authors also reported that adding azithromycin to hydroxychloroquine in 6 patients resulted in viral clearance compared with hydroxychloroquine monotherapy.

Although that is positive news, this study has some major flaws. One, it was a small sample size. Two, there was the removal of 6 patients in the hydroxychloroquine group from analysis due to early stoppage of treatment resulting from critical illness or intolerance of the medication, and three, there were variable baseline viral loads between hydroxychloroquine monotherapy and combination therapy groups. There weren’t any clinical or safety outcomes reported.

Because of these reasons, in addition to the concern with the potential for cardiac arrhythmias, especially when you have multiple drugs that prolong the QTc interval, which makes people more prone to arrhythmias….

We need more studies on these drugs before we say yes or no.

Currently, there are several RCTs of both chloroquine and hydroxychloroquine examining their role in COVID-19 treatment. There are also studies in work for these drugs to be used as prophylaxis. So only time will tell.

Both of these drugs are relatively well-tolerated, but they do have the potential to cause adverse effects (<10%), like nausea, diarrhea, low blood sugar, psychiatric effects, and damage to the retina part of your eyes. And the use of these in pregnancy is generally considered safe.

But one of the biggest concerns is the potential to cause cardiac toxicity, especially if given in combination with other medications that can prolong the QT interval.

A prolonged QTc interval on the EKG makes someone more vulnerable to having fatal arrhythmias.

This is why getting a baseline EKGprior to starting the drug is important, to look for potential prolonged. This is even more important in critically ill patients who are likely to be getting other meds that prolong the QT interval, such as azithromycin.

Based on what many doctors are saying, I don’t have very much optimism about this drug working for COVID-19. Look at what this lung doctor said on social media.

Francisco J Baraona Tweet

A lot of my colleagues have had poor results as well.

And there was a news special that interviewed a doctor at SUNY Downstate in Brooklyn, NY. They were in one of these clinical trials for HCQ, and they asked him what results in he was seeing, and he said they weren’t looking good.

And just the other day, here are the first meaningful RCTfor these drugs:
https://emcrit.org/pulmcrit/hydroxychloroquine-fail/

Hydroxychloroquine in Patients

This is the first multi-center RCT investigating the use of hydroxychloroquine for COVID-19. 150 patients hospitalized with COVID-19 were randomized in an open-label, although non-blinded fashion.

Hydroxychloroquine had no beneficial effect on the illness (despite using high doses), and it did appear to cause some side effects (mostly diarrhea). There are more studies on hydroxychloroquine coming out soon, but things are not looking good for now.

On a related note, HCQ is also being looked at when given in combination with zinc, so we will see if this has good results in that clinical trial as well.

So we won’t know for sure until we get the results from the rest of the clinical trials, but on a scale of 1-10, how likely I think either HCQ or chloroquine will be effective for COVID? I’m giving it a 2. And speaking of 2, this next medication is actually 2 medications lumped together as one, which is….

Lopinavir/Ritonavir and Other Antiretrovirals (Most PROMISING drugs for Covid)

Kaletra, aka a combination of Lopinavir and ritonavir, was approved for HIV. Speaking of HIV, you know who was instrumental in developing treatments that enable people with HIV to live long and active lives? This badass (Dr. Anthony Fauci)

Dr. Anthony Fauci

Anyway, Kaletra has also demonstrated in vitro activity against other covid viruses, and clinical studies in SARS were associated with reduced mortality and reduced need for a ventilator. This was based on retrospective, observational studies, which must be taken with a grain of salt.

But if it does work, it seems to only work if given during the early phase of infection, during the peak of the viral replication phase, which is the first 7-10 days of infection, and we know already most people don’t develop symptoms until day 5, on average, if they do have symptoms.

There have been recent reports of an open-label RCT comparing 200 patients with COVID-19, but they didn’t get the drug until, on average, day 13 days of their illness.

There wasn’t any significant benefit in the patients who got the drug, although delayed treatment was probably a big reason. There are more RCTs of lopinavir/ritonavir ongoing, but this doesn’t look very promising so far.

The other downside to this drug is that it has nausea and diarrhea in one-third of patients and can sometimes cause liver damage.

Other retroviral drugs similar to Kaletra are being looked at as well, such as darunavir.

I’m giving this one a 3.

Ribavirin (Most PROMISING drugs for Covid)

Ribavirin inhibits RNA polymerase, the virus’s enzyme, to make copies of its RNA, but its effectiveness against the virus seems fairly weak.

It also has potential harm with adverse effects, including toxicity to the red blood cells and liver, and can cause damage to the fetus of pregnant women.

I give ribavirin a 2.

Umifenovir (also known as Arbidol) is a more promising drug that targets the spike protein/ACE2 interaction and inhibits the fusion of the viral envelope. In other words, it inhibits this process…..

Arbidolhas in vitro (in a test tube) data suggesting activity against SARS.

Clinical Features of 69 Cases with Coronavirus Disease 2019 in Wuhan China

An observational study of 67 patients with COVID-19 showed that treatment with umifenovir for 9 days was associated with lower mortality rates and higher discharge rates from the hospital compared with patients who did not receive the agent.

There are ongoing RCT for this drug, and because of what we see so far, it seems fairly promising—I’m rating this one a 6.

Camostat mesylate is an approved agent in Japan for the treatment of pancreatitis. Interestingly, it also prevents SARS-Cov-2 from entering the cell, based on an in vitro study. It does this by inhibiting the cell’s serine protease, called TMPRSS2. The way it inhibits the virus from getting into the cell is pretty significant, but it hasn’t been looked at in RCT until now. I’ll give it a 5.

Nitazoxanide, a relatively safe drug used for certain parasitic infections, has in vitro activity against sars-CoV-2, and that’s why it’s now enrolled in RCT. So other than that, we know very little about when it comes to COVID, so ill rate this one a 5.

Ivermectin (Most PROMISING drugs for Covid)

Also, a relatively safe drug used for certain parasitic infections has significant in vitro activity against SARS-CoV-2 (see the dedicated video I made for ivermectin). But because this drug, as of the time of me recording this video, is not in aRCT. I’ll rate this a 4.

ACEI (Most PROMISING drugs for Covid)

SARS-CoV-2 uses the ACE2 receptor for entry into the host cell.

This has sparked conversations in the scientific community about whether ACE inhibitors and/or angiotensin receptor blockers potential to treat COVID-19 or possibly worsen the disease.

These drugs might upregulate ACE2 receptors in the lungs, although this is not proven.

In studies in rats, losartan, an ARB, upregulated ACE2 receptors in the heart and kidneys when given for a month.

Regulation of ACE2 in Cardiac Myocytes and Fibroblasts

But even if it does upregulate ACE2 receptors in the lung, does that necessarily mean that more viruses will bind to it. Therefore more virus gains entry into more cells, making the infection worse?

Not necessarily.

We know that just the other covid viruses in the past, including the 1st SARS virus, actually downregulates the ACE2 receptor upon entering the cell. The same is widely believed to occur with this new SARS-CoV-2.

Replication-Dependent-Downregulation-of-Cellular-Angiotensin-Converting-Enzyme-2-Protein-Expression-by-Human-Coronavirus-NL63

This downregulation is similar to what happens when HIV infects white blood cells, specifically T cells.

Down regulation of cell surface CXCR4 by HIV-I

The HIV downregulates the CCR4 and CCR5 receptors after it enters the cell. It is thought that this downregulation takes place because more viruses entering the cell actually overloads the cell, inhibiting the cell’s ability to replicate inside.

So why is it that ACEI and/or ARB has the potential to lessen the severity of COVID-19?

virus downregulates ACE2 expression on the cell

To understand why this has such potential, you must understand that the virus downregulates ACE2 expression once it enters the cell. When there is less ACE2 receptor, that affects the levels of Angiotensin II and Angiotensin 1-7 and Angiotensin 1-9 in the lungs. Too much angiotensin II  and not enough Angiotensin 1-7 and 1-9 in the lungs leads to more inflammation and pulmonary vasoconstriction. When the pulmonary arteries constrict, less blood flow is sent to the lungs to pick up oxygen. And if this is too severe, patients can have the worse disease. This is BAD.

But ACEI blocks part of this pathway, shifting the balance to more Angiotensin 1-7 and angiotensin 1-9 in the lungs while reducing angiotensin II in the lungs. This is good.

ACEI include:

benazepril which is Lotensin

captopril which is Capoten

enalapril which is Vasotec

fosinoprilwhich is Monopril

lisinopril aka, Prinivil, aka Zestril

and finally, quinapril, aka Accupril

And ARB blocks the AT1R receptor, which binds angiotensin II. This leads to an even more dramatic shift in this pathway, and this is even better because there is even more angiotensin 1-7 and 1-9 in the lungs and even less angiotensin II in the lungs.

For now, medical societies and practice guidelines recommend people continue their ACEI or ARB if they are supposed to be taking it.

ARB (Most PROMISING drugs for Covid)

Examples of ARB are:

Candesartan (Atacand)

Irbesartan (Avapro)

Losartan (Cozaar)

Olmesartan (Benicar)

Telmisartan (Micardis)

Valsartan (Diovan)

Azilsartan (Edarbi)

So to me, I think ARB are more likely to be more effective than ACEI for preventing and/or reducing COVID severity of illness, but let’s see what these clinical trials show. I’m giving ARB an 7. And ACEI a 5.

And what might be better than an ARB?

Well, I will let you in on a little secret that not too many people know about.

Something called…..

Recombinant ACE2 (Most PROMISING drugs for Covid)

Recombinant human Angiotensin-Converting Enzyme 2 (rhACE2), which is also known as APN01, was developed for the treatment of acute respiratory distress syndrome (ARDS) and pulmonary arterial hypertension (PAH). This was before COVID-19. But now that COVID has happened, and what we know about COVID patients with ARDS, this drug is being looked at in randomized, double-blind trials, where they will compare it to placebo in up to 200 patients at different locations in Europe. It has the potential to be the first drug approved to treat COVID-19 that specifically targets the new SARS-CoV-2 virus,”

Treatment with recombinant human ACE2 could block or reduce viral infection and protect the lungs and possibly other organs from damaging inflammation. This drug is given through an IV infusion. Previously completed Phase I and Phase II clinical trials have shown safety and tolerability in 89 healthy volunteers and patients with pulmonary arterial hypertension (PAH) and ARDS.

Gotta give this an 8.

Remdesivir (Most PROMISING drugs for Covid)

In the first known case of COVID-19 on American soil, in Washington, back in January, Remdesivir was given to a hospitalized patient. The patient ended up getting better and was discharged from the hospital. Did the drug help him? Or was it just a coincidence? Who knows?

First Case of 2019 Novel Coronavirus in the United States

What is known is that Remdesivirhas broad-spectrum, potent in vitro activity against several nCoVs, including SARS-CoV-2.

The safety and efficacy of remdesivir are being looked at in clinical trials for COVID-19and the results from these RCTs are highly anticipated.

In one of those clinical trials at a University of Chicago hospital, the word has gotten out from an infectious disease doctor that they see rapid recoveries in most of the COVID patients who received the drug.

One of the patients who recovered from COVID said, “Remdesivir was a miracle.”

But at Mass General Hospital, one of the Havvvad hospitals, they are also involved in the trial. The director of the medical ICU there, Dr. Hibbert, said she was not so sure about the remdesivir impacting COVID patients there.

Gilead’s severe Covid-19 study includes 2,400 participants from over 150 different clinical trial locations across the globe. Its moderate Covid-19 study includes 1,600 patients in 169 multiple locations as well.

In a recent statement, Gilead said: “What we can say at this stage is that we look forward to data from ongoing studies becoming available.”

These results are expected very soon, probably before the end of the month.

As of right now, you cant get the drug unless you are part of a clinical trial. The only other way to get it is through a compassionate use application under specific circumstances.

So this, I have to give a 7.

Favipiravir (Most PROMISING drugs for Covid)

Favipiravir is a generally well-tolerated drug currently available in Japan to treat influenza but not available in the United States.

It works by inhibiting the RNA polymerase, which stops viral replication. Most of favipiravir’s studies were done concerning its effect on influenza, Ebola, and some RNA viruses. When it comes to SARS-CoV-2, it seems to stop the viral replication of SARS-CoV-2.In a prospective, randomized, multicenter study, favipiravir (n = 120) was compared with Arbidol (n = 120) to treat moderate and severe COVID-19 infections. Differences in clinical recovery at day 7 were observed in patients with moderate infections. It was 71% recovery for favipiravir and 55% recovery for Arbidol. And this is why there are more ongoing RCTs for favipiravir.

I give it a 6.

Tocilizumab (Most PROMISING drugs for Covid)

IL-6 is at the center of the cytokine storm that occurs as a result of viral infection. What if, in theory, we can stop IL-6 from triggering the cytokine storm?

Well, some drugs exist that can prevent IL-6 from binding to its receptor, which essentially renders IL-6 useless.

For example, we haveTocilizumab, which is a monoclonal antibody that does exactly that. It’s FDA approved to treat cytokine release syndrome, as well as severe RA.

Tocilizumab has been used in small series of 21 patients with severe COVID-19 disease, with early reports of success, a 91% success rate to be exact. But because there was no control group in the study, we can’t say conclusively if it works or not. Right now, there are several RCTs of this drug, either alone or in combination, for patients with severe COVID.

Sarilumab is another IL-6 receptor antagonist like tocilizumab, studied in a multicenter, double-blind trial for hospitalized patients with severe COVID-19.

Other monoclonal antibodies or immunomodulatory drugs are bevacizumab, fingolimod, and eculizumab.

The downside of these medications, well, they’re several. For one, they’re expensive. Two, they do come with side effects, and one of those is it can make you more prone to developing…..infections. So while it might help fight one infection, such as COVID, it can increase your chances of other infections, such as tuberculosis, hepatitis B, etc.

Based on what we know so far about tocilizumab and sarilumab 5

Immunoglobulin Therapy (Most PROMISING drugs for Covid)

Ok, so this is technically not a medication, but it’s a treatment nonetheless, and that is convalescent plasma or hyperimmune immunoglobulins.

It works like this. When infected with COVID-19, they recover; they then develop antibodies, typically within a few weeks. So these IgM and IgG antibodies are in the bloodstream, and we draw that patient’s blood once they’ve recovered, spin that blood in a centrifuge, and collected only a certain portion of that blood, called the plasma. And in that plasma are the immunoglobulins, meaning IgG and IgM. The blood, mainly red blood cells, is used for…blood transfusions when someone has anemia.

Immunoglobulin Therapy

So with the plasma that we collect, that’s what contains the antibodies to the virus, and then we give that to someone infected with COVID.

They did this for some patients with SARS and MERS and had good results.

Then, in 2009, an observational study of over 90 critically ill patients with H1N1 influenza A, 20 of those patients received convalescent plasma.

What did the results show?

The ones who received the plasma had better survival rates.

In theory, the COVID patients who would most likely benefit from this would be the ones who get the plasma within the first 7 to 10 days of infection, when the amount of virus in the body is at its peak.

As the pool of patients who have recovered from COVID-19 increases globally, more and more people will be able to get the plasma, as long as it’s proven to work in these new clinical trials.

On March 24, 2020, the FDA released guidance for requesting an emergency investigational new drug application and screening donors for convalescent plasma.
https://www.biorxiv.org/content/10.1101/2020.03.11.987958v1.full.pdf

I also want to talk more about Zinc. And Vitamin C. And Diamox (acetazolamide), but this video is getting a little long. So ill make another video for those.

But to summarize what seem to be the top 5 most promising drugs coming down the pike for COVID-19:

rhACE2

ARBs

Remdesivir

Favipiravir

Umifenovir (also known as Arbidol)

I won’t include convalescent plasma here because, technically, it’s not a drug. But I do think it will be effective.

So that’s all for this video. Check out my upcoming videos, which be breaking down zinc, vitamin C, Diamox, meaning acetazolamide, and more topics to get to as well.

Doctor Mike Hansen, MD
Internal Medicine | Pulmonary Disease | Critical Care Medicine

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