Viral Facts

[Chipper6]

[quote]
Also of note, whatever you think of the anecdotal or early reports (from small studies) of hydroxychloriquine, the most plausible mechanism for any possible effect is that it reduces the expression of the ACE2 receptor.
[/quote]Thanks Doctor.

What do you think of the following theories?

1. Hydroxychloroquine is an ionophore, which allows zinc to enter cells more easily. (Zinc has been shown to inhibit coronavirus RNA polymerase activity in vitro.
2. Hydroxychloroquine might also affect the pH inside the cell, which might also inhibit the replication of the enzyme.

[Jrinne]

[quote]

Also of note, whatever you think of the anecdotal or early reports (from small studies) of hydroxychloriquine, the most plausible mechanism for any possible effect is that it reduces the expression of the ACE2 receptor.
[/quote]Thanks Doctor.

What do you think of the following theories?

1. Hydroxychloroquine is an ionophore, which allows zinc to enter cells more easily. (Zinc has been shown to inhibit coronavirus RNA polymerase activity in vitro.
2. Hydroxychloroquine might also affect the pH inside the cell, which might also inhibit the replication of the enzyme.

Chaim,

I do not have an opinion on these possible mechanisms.

Best,

Jim

[Chipper6]

At least three studies and clinical trials (including one with a control group) have reported good results using zinc in conjunction with Hydroxychloroquine.

On the other hand, anecdotally a number of doctors have reported that they have not had success with Hydroxychloroquine, especially in patients who were already in bad shape. I have reason to believe that zinc was not administered. I also saw a study that showed little or no benefit to using HCQ, but that too was without zinc.

I don’t have a medical degree, but I do have some experience analyzing data. This experience leads me to believe that the combination of zinc together with HCQ should be prioritized for further study.

[Sterling]

The way the dots are being connected with the possible implications of zinc and its possible ionophores having curative powers I find incredibly intriguing. If this turns out to be effective it might open up a lot of exploration on the mechanisms at play. I only wonder if anyone will fund research. It seems that some prostate cancer patients are already using the same idea to induce apoptosis in cancer cells. The other possible zinc ionophores that come up in their discussions are clioquinol, quercetin (found in apples and red onions), and epigallocatechin-gallate (found in green tea). Maybe this is one reason why catechin rich foods when eaten together have been observed to seemingly complement each other e.g. cocoa (zinc) and green tea (EGCG). This is all speculation though and I’d put it in another thread if there was a more pertinent one.

[Jrinne]

Just interesting. I have no predictions about the results. Especially, since a definitive answer is likely to come from this large study. Results expected this summer which is unheard of for a study like this.

It is of note that Remdesivir is an IV medication and Gilead Sciences has no plans for making a pill that could be used as prophylaxis or early treatment.

I would like to add this caution. Nisser mentioned prolongation of the QT interval. This risk is greater when azithromycin (Z-Pak) is added. From the FDA: “Use with caution ……during concomitant administration with QT interval prolonging drugs such as azithromycin and some other antibacterial drugs.”

The article is behind a Medscape paywall (or signup at least) so a link will not be helpful:

[i]"In perhaps the fastest-moving, large prophylaxis trial, researchers at Duke University are leading a $50 million collaboration across hundreds of American health care systems, which will test 15,000 volunteers. Half the health care workers will take hydroxychloroquine, and half a placebo. Other drugs could be added to the study if they prove promising for preventing or lessening infection, says Adrian Hernandez, the trial’s principle investigator.

The trial is being launched by PCORnet®, the National Patient-Centered Clinical Research Network, a network of health care systems that have come together over the last few years to plan and conduct research trials. Although the collaboration predates COVID-19 by nearly five years, this is precisely the kind of situation it was designed to address, says Hernandez, adding that he hopes the network will soon be able to test COVID-19 vaccine candidates as well."[/i]

Lopinavir and Ritonavir prophylaxis also being tested in France:

“In France, researchers are running a trial with 1,200 health care workers to test prophylactic use of hydroxychloroquine or a combination of two HIV drugs, Lopinavir and Ritonavir, which failed as a treatment in people with severe COVID-19 infections but may work as prevention. It is expected to take 6 months.”

[InspectorSector]

https://abc11.com/amp/coronavirus-drug-covid-19-malaria-hydroxychloroquine/6079864/

[Chipper6]

Fascinating.

There is a growing body of thought that some of the disease process in some Covid-19 is related to tiny blood clots. These tiny clots (microthrombi) mean there is reduced blood flow to the air sacs in the lung, and so they have problems oxygenating their blood.

This theory is borne out by the fact that autopsies of Covid-9 bodies have found a high percentage of pulmonary hemorrhaging. That’s weird. And also small thrombi in the periphery of the parenchyma! This might also explain why heart disease is such a risk factor in Covid-19 patients.

…

[Jrinne]

Fascinating.

There is a growing body of thought that some of the disease process in some Covid-19 is related to tiny blood clots. These tiny clots (microthrombi) mean there is reduced blood flow to the air sacs in the lung, and so they have problems oxygenating their blood.

This theory is borne out by the fact that autopsies of Covid-9 bodies have found a high percentage of pulmonary hemorrhaging. That’s weird. And also small thrombi in the periphery of the parenchyma! This might also explain why heart disease is such a risk factor in Covid-19 patients.

…

Chaim,

I think you are right about this being a problem for COVID-19 patients. I think you are probably referring to disseminated intravascular coagulation (DIC).

Paradoxically, these people develop bleeding problems as all of their clotting factors get used up creating intravascular clots. The problem is devastating. It carries a terrible prognosis and is not limited to COVID-19 patients. So I had a healthy fear of this problem even before I heard of COVID-19.

I do not have full access to this journal article but here is a copy of the “take home message:”

[i]"TAKE-HOME MESSAGE

The authors of this retrospective analysis evaluated coagulation parameters in 183 patients admitted with the severe novel coronavirus COVID-19. Median age at admission was 54 years, and 71.4% of non-survivors developed overt disseminated intravascular coagulation (DIC), with a median time from admission to DIC of 4 days. Only 0.6% of survivors developed DIC. On admission, non-surviving patients presented with higher D-dimer levels, prolonged PT, and aPTT compared with surviving patients.
In patients with COVID-19 infection, the development of coagulopathy and overt DIC appears to be associated with a high mortality rate. Larger analyses confirming these findings and investigating both the pathophysiology and impact of correction of coagulopathy on mortality are warranted."[/i]
– Curtis Lachowiez, MD

[Chipper6]

Doc,

Here are the autopsy reports.

In what may be related news, there is a small but growing group of physicians who believe that ventilators are not the best treatment for the ARDS (Acute Respiratory Distress Syndrome) seen in Covid-19 patients.

from here :

I posed the following question on Twitter: “What is the mortality rate for [COVID-19] patients who require mechanical ventilation?” and received answers ranging from 25% to 70% from people who have personal knowledge of outcomes in their hospitals.

Probably the best published information we have so far is from the Intensive Care National Audit and Research Center (ICNARC) in the UK. Of 165 patients admitted to ICUs, 79 (48%) died. Of the 98 patients who received advanced respiratory support—defined as invasive ventilation, BPAP or CPAP via endotracheal tube, or tracheostomy, or extracorporeal respiratory support—66% died.

Compare that to the 36% mortality rate of non-COVID patients receiving advanced respiratory support reported to ICNARC from 2017 to 2019.

An article in The Guardian said this about the ICNARC study, “The high death rate raises questions about how effective critical care will be in saving the lives of people struck down by the disease.”

[Sterling]

In what may be related news, there is a small but growing group of physicians who believe that ventilators are not the best treatment for the ARDS (Acute Respiratory Distress Syndrome) seen in Covid-19 patients.

from here :

I posed the following question on Twitter: “What is the mortality rate for [COVID-19] patients who require mechanical ventilation?” and received answers ranging from 25% to 70% from people who have personal knowledge of outcomes in their hospitals.

Probably the best published information we have so far is from the Intensive Care National Audit and Research Center (ICNARC) in the UK. Of 165 patients admitted to ICUs, 79 (48%) died. Of the 98 patients who received advanced respiratory support—defined as invasive ventilation, BPAP or CPAP via endotracheal tube, or tracheostomy, or extracorporeal respiratory support—66% died.

Compare that to the 36% mortality rate of non-COVID patients receiving advanced respiratory support reported to ICNARC from 2017 to 2019.

An article in The Guardian said this about the ICNARC study, “The high death rate raises questions about how effective critical care will be in saving the lives of people struck down by the disease.”

In relation to the above, an article from the NY Times: What Doctors on the Front Lines Wish They’d Known a Month Ago

Some patients, by taking oxygen and rolling onto their sides or on their bellies, have quickly returned to normal levels. The tactic is called proning.

Doctors at Montefiore Medical Center in the Bronx and Mount Sinai Medical Center in Manhattan have described it on Twitter; a flier is posted next to beds at Elmhurst Hospital Center in Queens as a guide for patients on how often to turn themselves.

At Lincoln Hospital in the Bronx, Dr. Nicholas Caputo followed 50 patients who arrived with low oxygen levels between 69 and 85 percent (95 is normal). After five minutes of proning, they had improved to a mean of 94 percent. Over the next 24 hours, nearly three-quarters were able to avoid intubation; 13 needed ventilators. Proning does not seem to work as well in older patients, a number of doctors said.

[nisser]

Media is so good at sensationalizing. Proning is nothing new; it’s a common ICU technique to recruit sick lung tissue. I’m sure it was tried day 1 everywhere.

[Jrinne]

Media is so good at sensationalizing. Proning is nothing new; it’s a common ICU technique to recruit sick lung tissue. I’m sure it was tried day 1 everywhere.

Hi Nisser,

Yes! Certainly not new for patients already on a ventilator.

Here is a meta-analysis of 2,129 patients (already on a respirator or intubated) with acute respiratory distress syndrome from 2017: Prone Position for Acute Respiratory Distress Syndrome. A Systematic Review and Meta-Analysis.

Here is a good controlled study published in the New England Journal of Medicine from 2013 (again of patients already intubated): Prone Positioning in Severe Acute Respiratory Distress Syndrome

Best,

Jim

[Sterling]

Media is so good at sensationalizing. Proning is nothing new; it’s a common ICU technique to recruit sick lung tissue. I’m sure it was tried day 1 everywhere.

Unfortunately not everyone has been able to make it to the hospital. If this is well-known this is the kind of information that needs to be disseminated but for some reason isn’t.

[InspectorSector]

https://www.statnews.com/2020/04/16/early-peek-at-data-on-gilead-coronavirus-drug-suggests-patients-are-responding-to-treatment/

[nisser]

https://emcrit.org/pulmcrit/pulmcrit-eleven-reasons-the-nejm-paper-on-remdesivir-reveals-nothing/

The quality of the paper in NEJM is absolutely shameful; shame on the editors for letting this through. I wouldn’t let this be published in the Journal of Scandinavian potato farming.

[Chipper6]

Ivermectin is showing to be very promising for treatment of Covid 19. 70% reduction in deaths for those treated with it in a study.

The principal outcome was to assess the association of ivermectin administration with survival in COVID-19.

Results:
The cohort (including 704 ivermectin treated and 704 controls) was derived from 169 hospitals across 3 continents with COVID-19 illness. The patients were matched for age, sex, race or ethnicity, comorbidities and a illness severity score (qSOFA). Of those requiring mechanical ventilation fewer patients died in the ivermectin group (7.3% versus 21.3%) and overall death rates were lower with ivermectin (1.4% versus 8.5%; HR 0.20 CI 95% 0.11-0.37, p<0.0001).

Newspaper article
Paper

[Jrinne]

Ivermectin is showing to be very promising for treatment of Covid 19. 70% reduction in deaths for those treated with it in a study.

Thanks Chaim. Very interesting study.

I thought this was a good review of some other medications with varying potential: JAMA Review Article

Best,

Jim

[Chipper6]

[quote]

Ivermectin is showing to be very promising for treatment of Covid 19. 70% reduction in deaths for those treated with it in a study.

Thanks Chaim. Very interesting study.

I thought this was a good review of some other medications with varying potential: JAMA Review Article

Best,

Jim
[/quote]Thanks. I skimmed through it. Interesting. At the risk of sounding like a broken record, why did this review omit zinc from its discussions about findings for the HCQ/azithromycin regimen? It’s almost like there is a bias against minerals and in favor of pharmacological treatments.

As someone who did not have formal training in medicine, but has experience in vetting studies, I love to see all kinds of spaghetti thrown at the wall (assuming there is some putative theory and low risk to the patient), find what sticks with a very open mind, try to figure out why it worked, and then run better studies using the exact same regimen which was reported to have success.

[Sterling]

Don’t know but someone I read who looked at the way zinc supposedly works with HCQ was skeptical about the mechanism put forth. He thought the theory of HCQ acting as an ionophore was dubious because the dosage necessary in his opinion would be too high to work as theorized in real life. He said it was far more likely that HCQ if effective worked by raising the pH of the cell.

But I doubt anyone really knows.

Other drugs have backers willing to fund studies.

What I am curious about is whether South Korea and Malaysia which I have heard it implied were using HCQ and zinc in combination are having success and why we aren’t hearing anything from them. Their death rates are pretty low.

[Chipper6]

Don’t know but someone I read who looked at the way zinc supposedly works with HCQ was skeptical about the mechanism put forth. He thought the theory of HCQ acting as an ionophore was dubious because the dosage necessary in his opinion would be too high to work as theorized in real life. He said it was far more likely that HCQ if effective worked by raising the pH of the cell.

But I doubt anyone really knows.

Other drugs have backers willing to fund studies.

What I am curious about is whether South Korea and Malaysia which I have heard it implied were using HCQ and zinc in combination are having success and why we aren’t hearing anything from them. Their death rates are pretty low.

This is not a knock on medical professionals. I believe that medical professionals as a group are among the smartest and most dedicated people around. But I see this in all disciplines. People focus too much on theories and not on data. My investment results have gone up exponentially once I started building my theories around the data instead of the other way around.

Two of the most successful clinical trials included zinc in the regimen. Yes, those clinical trials had flaws. But the results were so good that even after adjusting for the flaws the results were still extraordinary. Yet, instead of trying to replicate the exact same regimen, I was seeing a lot of studies that took out zinc, or tried using HCQ in patients presenting with ARDS, then reported less than stellar results, and these studies were used to prove that HCQ doesn’t work.

Why not try to replicate exactly what worked using well designed studies?

I believe that at this stage, theory is secondary. Data is first. But I can throw out a theory to explain why HCQ would help zinc. The CEO of the company that did the modern research on Cloroquine says that Cloroquine is metabolized by the same enzyme in the liver as azythromycin. Presumably HCQ is also metabolized by that same enzyme. If so, then the effective dosage of HCQ is amplified when taken in conjunction with azythromycin. This may explain some things.

Let’s build theories around the data and not the other way around.