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.
In order to understand how effective and safe a drug is, you have to know what kind of study is being done. So I will give a little cheat sheet right now to help you with that.
The King of all studies are Randomized controlled trials, because it compares the effect oftreatment versus “no treatment” (or a different treatment). They can also show what happens if you opt to not 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,”
Its when neither the study participants nor their doctors know who is in which group and this 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, these 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 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.
Only time will tell, based on clinical trials, of which of these drugs will actually work for COVID, and which of them will be safe to use.
Now that we got that out of the way,lets take a look at what drugs seem the most promising, in no particular order.
As of right now, there areabout 300 active clinical trials for COVID. In order to understand how these drugs work, we have to understand how the virus attacks, so that we can understand its weak points, and destroy that sunbish.
That’s why if you haven’t done so already, I highly recommend you watch my previous video, called “how coronavirus kills some people, but not others”, because that way, you’ll have a better understanding of how and why these drugs work.
This is a picture I drew……when I was 4 years old.
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.
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…
There are currently300 clinical trials 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
They treat malaria, lupus, rheumatoid arthritis.
They appear to inhibit viral entry into cells by altering the host receptors, as well as 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 do sometimes. 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.
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, as well as 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 of virologic clearance with hydroxychloroquine. The authors also reported that addition of 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; and there weren’t any clinical or safety outcomes reported.
Because of these reasons, in addition to the concern with 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 also studies in the 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 a lot of doctors are saying, I don’t have very much optimism when it comes to this drug working for COVID-19. Look at what this lung doctor said on social media.
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 from he is seeing, and he said they weren’t looking good.
And just the other day, here are the first meaningful RCTfor these drugs:
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 for now, things are not looking good.
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, of how likely I think either of 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, and that is….
Lopinavir/Ritonavir and Other Antiretrovirals
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)
Anyway, Kaletra has also demonstrated in vitro activity against other coronaviruses, and clinical studies in SARS were associated with reduced mortality and reduced need for a ventilator. This was based on retrospective, observational studies, which are studies that have to 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 day of their illness.
There wasn’t any significant benefit in the patients who got the drug, although delayed treatment was probably a big reason for that. There are more RCTs of lopinavir/ritonavir ongoing, but so far this doesn’t look very promising.
The other downside to this drug is that it hasadverse such as 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 inhibits RNA polymerase, the enzyme the virus uses 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 fusion of the viral envelope. In other words, it inhibits this process…..
Arbidolhas in vitro (in a test tube) data suggesting activity against SARS.
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 now ongoing RCT for this drug, and because of what we see so far, it seems fairly promising. Im 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. Because of the way it inhibits the virus of getting into the cell, that is pretty significant, but it hasn’t been looked in RCT until now. I’ll give it a 5.
Nitazoxanide, a relatively safe drug used for certain parasitic infections, and has in vitro activity against sars-CoV-2, and that’s why it’s now enrolled in RCT now. So other than that, we know very little about when it comes to COVID, so ill rate this one a 5.
Alsoa relatively safe drug used for certain parasitic infections, has significant in vitro activity against SARS-CoV-2 (see my dedicated video I made for ivermectin). But because this drug, as of the time of me recording this video, is not in a RCT, unfortunately. I’ll rate this a 4.
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, when given for a month, upregulated ACE2 receptors in heart and kidneys.
But even if it does upregulate ACE2 receptors in the lung, does that necessarily mean that more viruses will bind to it, and therefore more virus gains entry into more cells, making the infection worse?
We know that just the other coronaviruses in the past, including the 1st SARS virus, actually downregulates the ACE2 receptor upon entering the cell, and the same is widely believed occur with this new SARS-CoV-2.
This downregulation is similar to what happens when HIV infects white blood cells, specifically T cells.
The CCR4 and CCR5 receptors are downregulated by the HIV virus after it enters the cell. Its thought that this downregulation takes place because more virus entering the cell actually overloads the cell, and in doing so, inhibits the cells ability to replicate inside.
So why is it that ACEI and/or ARB have the potential to lessen the severity of COVID-19?
In order to understand why this has such potential, you have to understand that the virus downregulates ACE2 expression on the cell, 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 more pulmonary vasoconstriction. When the pulmonary arteries constrict, that means less blood flow is being sent to the lungs to pick up oxygen. And if this is too severe, patients can have worse disease. This is BAD.
But ACEI block part of this pathway, shifting the balance of this pathway to more Angiotensin 1-7 and angiotensin 1-9 in the lungs, while reducing the amount of angiotensin II in the lungs. This is good.
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.
Examples of ARB are:
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 lets 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 im going to let you in on a little secret that not too many people know about.
Recombinant human Angiotensin Converting Enzyme 2 (rhACE2), which is also known as APN01, was developedfor 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-blindtrials, 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 be used to not only block or reduce viral infection, but also protect the lungs, and possibly other organs from the damaging inflammation. This drug is given through an IV infusion and has already shown safety and tolerability in 89 healthy volunteers and patients with pulmonary arterial hypertension (PAH) and ARDS in previously completed Phase I and Phase II clinical trials.
Gotta give this an 8.
In the first known case of COVID-19 on American soil, in the state of 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?
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.
One of those clinical trials, at a University of Chicago hospital, the word has gotten out from an infectious disease doctor, that they are seeing 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 not so sure about the remdesivir having an impact on 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.
Favipiraviris a generally well-tolerated drug, and is currently available in Japan for the treatment of 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 with respect to its effect on influenza and Ebola, and some RNA viruses. When it comes to SARS-CoV-2, it seems to stop viral replication of SARS-CoV-2.In a prospective, randomized, multicenter study, favipiravir (n = 120) was compared with Arbidol (n = 120) for the treatment of 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.
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, there are drugs that 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, 91% success rate to be exact.But because there was no control group in the study, we cant say conclusively if it works or not. Right now there are several RCTs of of this drug either alone, or in combination, for patients with severe COVID.
Sarilumabis another IL-6 receptor antagonist just like tocilizumab, being studied in a multicenter, double-blind trial for hospitalized patients with severe COVID-19.
Other monoclonal antibody or immunomodulatory drugs 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 sarilumaba 5
Ok so this is technically not a medication, but it’s a treatment none the less, and that is convalescent plasma or hyperimmune immunoglobulins.
It works like this. When someone is infected with COVID-19, and 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 rest of the blood, mainly being red blood cells is used for…blood transfusions, when someone has anemia.
So with the plasma that we collect, that’s what contains the antibodies to the virus, and then we give that to someone who is 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 its 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.
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:
Umifenovir (also known as Arbidol)
I wont include convalescent plasma here because technically its 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.
Dr. Mike Hansen, MD
Internal Medicine | Pulmonary Disease | Critical Care Medicine
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