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General Ohio University Discussion/Alumni Events Topic
Topic: A review of Scientific Studies of various antivirals
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L.C.
8/2/2020 6:46 PM
I was surprised to read the statement in an AP article today that:
https://apnews.com/80130998284858a7b73c997e76677137
[quote=ap]...Scientific studies have shown hydroxychloroquine can do more harm than good when used to treat symptoms of COVID-19.[/OUTER_QUOTE]
I was under the impression that studies were mixed, but I hadn't really looked at them for awhile, so I thought, why not review what the scientific studies today tell us about all the suggested antivirals, including HCQ, Ivermectin, Remsdesiver, and favapiravir, plus any others that I find along the way? So, I'll start with HCQ, since it seems to be the hot subject recently.

Before I start, let me point out that the virus goes through multiple stages. It starts by entering your body, taking over cells, and replicating. Once it has replicated enough, symptoms begin to appear, and it starts sending out viruses to the outside world, looking for the next host. Antivirals, when they work, are effective at blocking replication of the virus. Given the cycle of the virus, they would be effective primarily if given early, during the key replication stage. They are going to be less effective, if they do anything at all, if given late.

Now to HCQ. It is normally a malaria drug, and has a long track record as an extremely safe medicine, and millions of doses of it are taken every year for the treatment and prevention of malaria. It often causes nausea, and it has a side effect of what is known as QT prolongation, which affects the cycles of the heart. As a result, it is not given to people with known heart problems.

Unfortunately, one of the known effects of Covid19 is that it attacks the heart. By the time patients have a sufficiently advanced case that they are in the hospital, there is a significant possibility of heart involvement. Therefore, if given to Covid patients in the hospital, there is much more risk than if given early, and extreme caution should be used, and probably it should not be used at all.

As a result of the general rule that antivirals should be given early, plus the fact that there is a risk of heart involvement in advanced cases, I'm only going to look at the studies related to HCQ where HCQ is given early, and the studies where it is given as a preventative measure (even earlier). In both cases, HCQ should be safe, and if HCQ is effective, it should do well in these tests.

Here is my source for all the studies for HCQ:
https://c19study.com /

Here is a list of all the studies listed as "Early"
17-Mar Gautret et al., Int. J. of Antimicrobial Agents - France, Positive benefit
https://www.mediterranee-infection.com/wp-content/uploads...

11-Apr Gautret et al., Travel Medicine and Infectious D - France, Positive benefit
https://www.sciencedirect.com/science/article/pii/S147789...

15-Apr Esper et al., Prevent Senior Institute - Brazil, Positive benefit
https://www.dropbox.com/s/5qm58cd4fneeci2/2020.04.15%20jo...

24-Apr Ashraf et al, COVID-19 in Iran, - Iran, Positive benefit
https://www.researchgate.net/publication/341197843_COVID-...

30-Apr Meo et al.,Efficacy of ch loroquine and hydroxych loroquine - Saudi Arabia, Positive benefit
https://www.europeanreview.org/article/21038

5-May Million et al., Early Treatment of COVID-19 Patients With Hydroxychloroquine - France, positive benefit
https://pubmed.ncbi.nlm.nih.gov/32387409 /

18-May Ahmad et al, Doxycycline and Hydroxychloroquine as Treatment - New York, Positive Benefit
https://www.medrxiv.org/content/10.1101/2020.05.18.200669...

27-May Risch, American Journal of Epidemiology, Early Outpatient Treatment of Symptomatic, High-Risk Covid-19 - Meta study, showed significant outpatient efficicy
https://academic.oup.com/aje/article/doi/10.1093/aje/kwaa...

31-May Guérin et al, zithromycin and Hydroxych loroquine Accelerate Recovery of Outpatients - Positive Benefit

6-June Million et al., Clinical Efficacy of Ch loroquine derivatives - Meta Study, HCQ effective
https://www.preprints.org/manuscript/202005.0486/v1

10-June Otea et al, A short therapeutic regimen based on hydroxychloroquine - Positive Benefit

22-June Chen et al, Efficacy and safety of chloroquine or HCQ - Xiamen, Positive Benefit
https://www.medrxiv.org/content/10.1101/2020.06.19.201360...

25-June Lagier et al, Outcomes of 3,737 COVID-19 patients, France, Positive Outcome
https://www.sciencedirect.com/science/article/pii/S147789...

3-July Scholz et al, COVID-19 Outpatients – Early Risk-Stratified Treatment - Positive Benefit
https://www.preprints.org/manuscript/202007.0025/v1

9-July Raoult et al, Hydroxych loroquine and Azithromycin as a Treatment - Updated Meta Study, Positive benefit
https://www.mediterranee-infection.com/wp-content/uploads...

16-July Mitjà et al., Hydroxych loroquine for Early Treatment - Spain, showed no difference
https://academic.oup.com/cid/article/doi/10.1093/cid/ciaa...

18-July Skipper et al., Hydroxych loroquine in Nonhospitalized Adults = Internet study in US/Canada, Did not significantly reduce hospitalization, death
https://www.acpjournals.org/doi/10.7326/M20-4207

21-July Risch, Response to: “Early Outpatient Treatment of Symptomatic - Updated his earlier meta analysis, still shows postive benefit
https://academic.oup.com/aje/article/doi/10.1093/aje/kwaa...

So, it seems that while the studies of HCQ given to hospitalized patients are mixed, some showing benfits, others showing harm, the same is not true of studies where it is given early to outpatients with mild symptoms. Almost all studies show a benefit. The only two showing no benefit were the two released on 16-July.

I'm not going to list them all, but if you go through all the research papers related to PrEP (Pre Exposure Prophylaxis) and PEP (Post Exposure Prophylaxis) they are both all postive, except for ones that are extremely small.
https://c19study.com /

I'm confused now. If virutally all of the studies show that HCQ works when given early (before exposure, shortly after exposure, or after diagnosis), why is there only negative publicity about it? Are there any studies I missed, that shows it doesn't work when given early? Sure, I understand that if you wait until the virus has replicated, and there is likely heart involvement, HCQ is probably a bad idea, but that's not what we're even talking about.
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Bobcat Love's Sense of Shame
8/2/2020 8:28 PM
Far from an expert here, so all this post is doing is a little bit of research and making my best attempt at an interpretation. So take it with a grain of salt.

I remembered your previously sharing mixed results on hydroxychloroquine and have been surprised at the (relatively) quick about face in the medical community, Trump Administration (at least some of it, if not its namesake), and FDA.

I thought this seems to be a pretty thorough and well-sourced assessment of why the scientific community seems to have largely turned the page on hydroxychloroquine: https://www.sciencenews.org/article/covid-19-coronavirus-...

Going through it, some interesting things that stand out.

1. There have been over 350 studies of hydroxychloroquine -- far more than any other drug. I'm not sure how they break down between 'early intervention' and 'post-symptom, but that there are so many studies at least indicates that the medical community has a lot of data to go on.

2. Given that Hydroxychloroquine can be deadly for patients with more advanced symptoms, it strikes me that to justify its use as a preventative measure for those early in their diagnosis, the data would have to be extremely positive. Otherwise, aren't you introducing potential risk for little gain?

3. The Iran study you linked to is a "Preprint." That means it's been published prior to peer review.

4. The Saudi study didn't involve the study of any patients, only the review of other studies, all completed prior to March 28. Their conclusion isn't that Hydroxychloroquine necessarily has a positive impact, but rather "It is reasonable, given the hypothetical benefit of these two drugs, that they are now being tested in clinical trials to assess their effectiveness to combat this global health crisis."

5. Several of the studies you cite are retroactive analysis. Those aren't without merit, but also aren't without issue, largely because they lack any sort of control population. The article I linked to above addresses this.

6. Likewise, the May 18th New York study simply compares the results of Hydroxychloroquine use in 54 seniors in New York to the rates of death in a senior facility in Washington state. The study is unable to give any consideration to the treatments used in Washington State. Also important to note this is a Preprint and hasn't been peer reviewed.

7. The New England Journal of Medicine's study includes a much larger sample and found no gain for early patients: https://www.nejm.org/doi/full/10.1056/NEJMoa2019014

8. Unless I'm missing something, the July 21 study you mention isn't a study that involved patients. Instead, it was an analysis of two of the prior studies you referenced.

From what I can gather, it seems that there was real reason for optimism early on involving hydroxychloroquine, which is likely why Trump jumped on it so quickly. However, the studies were small and somewhat haphazard given the urgency of the moment, and as larger studies have been completed, the results haven't kept pace. Largely, it seems to me that the conclusion of big chunks of the medical community is 'no negative impact, no positive impact.'

But again, not an expert. Just my reading of what I came across after reading your post and trying to see if I could figure out the answer to any of your questions.
Last Edited: 8/2/2020 8:28:19 PM by Bobcat Love's Sense of Shame
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L.C.
8/3/2020 9:28 AM
First, thank you for the detailed reply. I appreciate your time in helping me to grasp this issue. There is so much politicization that it's hard to really get an unbiased view of the science, and it's the science that is important, not the politics.

Bobcat Love's Sense of Shame wrote:expand_more
...
I thought this seems to be a pretty thorough and well-sourced assessment of why the scientific community seems to have largely turned the page on hydroxychloroquine: https://www.sciencenews.org/article/covid-19-coronavirus-... ...[/quote]
This link was especially helpful, as it goes into the science of why HCQ might, or might not, be helpful. If the furin cleavage site is giving the Coronavirus a way of bypassing the process that HCQ is blocking, that is a strong indicator that HCQ may not help much, even if given early.

One thing that stood out to me was this quote:
... Although study after study has demonstrated no benefit of hydroxychloroquine for treating people with serious coronavirus infections, some people, including President Donald Trump, still insist the drug has merit. ...

I would agree that it has no merit for serious cases. Once a patient is in the hospital, it is not the right drug. The question to me is whether it has merit to take it either before you have been exposed (PrEP), after you have been exposed, but before you test positive (PEP), or after you develop symptoms, but before you need to be hospitalized (Early). Those are the only studies that have shown positive results, though the science of how it enters the cell may indicate that it was a placebo effect that was leading to the positive results, since many of those studies were not double blind.


...Given that Hydroxychloroquine can be deadly for patients with more advanced symptoms, it strikes me that to justify its use as a preventative measure for those early in their diagnosis, the data would have to be extremely positive. Otherwise, aren't you introducing potential risk for little gain? ...

HCQ has a very good safety profile. Millions of doses are given to people every year to treat lupus, arthritis, and malaria, and to prevent malaria, with no cases of death from it. However, it is well established that it should not be given to people with existing heart problems. Patients who have, say, been exposed, but who have no symptoms, have no heart problems from Covid. Patients who are in the hospital because they have have severe symptoms very well may have heart involvement. I'm not a doctor, but I don't think HCQ adds much risk to patients if given at exposure, as opposed to at hospitalization.

...
7. The New England Journal of Medicine's study includes a much larger sample and found no gain for early patients: https://www.nejm.org/doi/full/10.1056/NEJMoa2019014 ...

This appears to be a very high quality study, and was well randomized, and has clear results. My only comment is that while they characterize it as "early", they average time from onset of studies to inclusion in the study was 7 days. To me that is "late".

...
From what I can gather, it seems that there was real reason for optimism early on involving hydroxychloroquine, which is likely why Trump jumped on it so quickly. However, the studies were small and somewhat haphazard given the urgency of the moment, and as larger studies have been completed, the results haven't kept pace. Largely, it seems to me that the conclusion of big chunks of the medical community is 'no negative impact, no positive impact.'

But again, not an expert. Just my reading of what I came across after reading your post and trying to see if I could figure out the answer to any of your questions.

And I appreciate your hard work. It certainly helps to clarify why some believe that there is no benefit, especially the first article, going into the in vitro studies which show that why it might not work. If it is true that HCQ does not block replication at all, it's unlikely to be effective if given at any stage.

Upon further reflection, probably the best studies are the ones looking at HCQ either for PrEP or PEP. In both cases the drug would clearly be "early", and they are all most likley double blind. Do those people have less cases? Are they more mild?

That article also gave me another potential antiviral to look into, camostat mesylate. I'll add that to my list. The next drug I'm going to look at is Ivermectin, another very inexpensive drug that is used for worming horses and for head lice, but which also has a history of being potentially useful as an antiviral.

Edit - Dr. Risch, who wrote two of the papers (which were meta analyses, i.e. examinations of the data from other studies) that I gave links for in the first post, wrote this op-ed:
https://www.newsweek.com/key-defeating-covid-19-already-e...
[quote=Dr. Risch]...the drug has not been used properly in many studies. Hydroxychloroquine has shown major success when used early in high-risk people but, as one would expect for an antiviral, much less success when used late in the disease course.
...
In fact, as inexpensive, oral and widely available medications, and a nutritional supplement, the combination of hydroxychloroquine, azithromycin or doxycycline, and zinc are well-suited for early treatment in the outpatient setting. The combination should be prescribed in high-risk patients immediately upon clinical suspicion of COVID-19 disease, without waiting for results of testing. Delays in waiting before starting the medications can reduce their efficacy.
Last Edited: 8/3/2020 2:40:00 PM by L.C.
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L.C.
8/5/2020 10:26 AM
Is Ivermectin, a generic drug used for head lice, and for worming horses, and that costs perhaps $2 a dose, a wonder drug?
https://www.nature.com/articles/s41429-020-0336-z
Ivermectin has been used for several years to treat many infectious diseases in mammals. It has a good safety profile with low adverse effects when orally prescribed. Ivermectin was identified in late 1970s and first approved for animal use in 1981. Its potential use in humans was confirmed a few years later. Subsequently, William C. Campbell and Satoshi Ōmura who discovered and developed this medication received the 2015 Nobel Prize in Physiology or Medicine [1,2,3].

Studies revealed that ivermectin as a broad-spectrum drug with high lipid solubility possesses numerous effects on parasites, [1, 3] nematodes, arthropods, flavivirus, mycobacteria, and mammals through a variety of mechanisms. In addition to having antiparasitic and antiviral effects, this drug also causes immunomodulation in the host. Studies have shown its effect on inhibiting the proliferation of cancer cells, as well as regulating glucose and cholesterol in animals. Despite diverse effects of this medication, many of its underlying mechanisms are not yet known [4]. Of note, some of these effects may be secondary to toxic effects on cells (Fig. 1).

In vitro, Ivermectin kills virtually all Covid19 in 48 hours.

Note that the first paper that indicated Ivermectin was a useful treatment for Covid was a now-rescinded paper which was based on a "questionable" database from Surgisphere. If you are more interested in reading about the retraction of that paper, and the retraction on an HCQ study:
https://www.theguardian.com/world/2020/jun/04/unreliable-...


Broward County Study shows 40% reduction in mortality from Ivermectin:
https://www.newsmax.com/us/ivermectin-covid/2020/06/09/id... /
https://ecambiomed.com/medrxiv-icon-ivermectin-in-covid-n... /
Unlike HCQ, it seems to also work very effectively in people with advanced cases.
If reviewed successfully, Ivermectin could become the first COVID-19 therapy shown to reduce mortality risk in seriously ill patients in a clinical trial.

A previous therapeutic medication, remdesivir, has already won FDA emergency use authorization. Trials showed remdesivir shortened patients’ hospital stays, but did not show a statistically significant improvement in reducing overall mortality, according to the National Institutes of Health.

Even more impressive, among the most seriously ill patients, 81% of those not treated died, while only 39% of those given Ivermectin died, a reduction of over 50%. The study also suggests, however, that giving it early could be even more effective, as is usually true of antiviral medicines.

Safety of Ivermectin may depend on dose, and on what condition it is being used to treat:
https://heavy.com/news/2020/04/ivermectin-side-effects-co... /

Here is the in vitro study:
https://www.sciencedirect.com/science/article/pii/S016635...

From Bangladesh/China, Ivermectin tests against a control group using the usual standard of care, i.e. against HCQ, with care given early.
https://www.trialsitenews.com/ivermectin-study-reveals-fa... /
https://www.worldhealth.net/news/ivermectin-displaying-pr... /
100% of Ivermectin patients recovered in an average of 5.93 days, versus 96% of the HCQ group in 6.99 days.

This retrospective analysis in Minnesota of who was taking what did not find a benefit from Ivermectin. The study included 73,000 United Healthcare patients with Covid19, but it doesn't say how many of those were taking Ivermectin. Since it is normally used as an anti-parasite drug, and those aren't commonly needed, I expect that the number of patients on Ivermectin was small.:
https://www.startribune.com/university-of-minnesota-s-lar... /

Edit - As anecdotal evidence, Ivermectin has apparently become a common treatment in the Dominican Republic, advocated by Dr. Jose Redondo.
https://www.trialsitenews.com/president-of-dominican-repu... /
[quote=Dr. Redondo]... we started with what is in the standard anti-parasite protocol of 100 to 200 micrograms per kilogram and have progressed that to 400 micrograms per kilogram of bodyweight. We also include it with Azithromycin. Of the 1,300 patients we have treated (early state cases), over 99% have been cured within 8 to 10 days. It has been frankly amazing. It’s truly feels like a gift from above. [/OUTER_QUOTE]

Another anecdotal data point, Lok Nyak Hospital, a Covid only facility in Delhi, has dropped Favipiravir in favor of Ivermectin and Remdesivir. Price and safety seems to have been the motivation, but it seems logical that they are seeing some positive results as well, given that a placebo is even cheaper and safer.
https://www.trialsitenews.com/delhis-covid-19-provider-lo... /

If I find any additional studies, I will add them, but for now, this seems to be all there is on Ivermectin. More, larger studies are needed. There are at least 31 studies under way, including one from Israel due out in September, and a prophylaxis study in Singapore that tested several items, including HCQ and Ivermectin, among others, on 5000 migrant workers which was completed in July, with results not yet out.

Certainly no one should be taking pills intended for horses or dogs, any more than they should be taking aquarium cleaner. This thread is not intended for medical advice, nor for people to self-medicate. It is merely intended to ascertain the status of medical research. Improved treatments are a key for re-opening the economy, and the resumption of normal activities, including sports.

Next up, I will look at go from the inexpensive to the expensive, and look at Remdesivir.
Last Edited: 8/5/2020 1:43:05 PM by L.C.
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L.C.
8/5/2020 8:04 PM
Now we move from the $2 drugs to the $3200 drug. Remdesivir is a patented antiviral drug from Gilead. It faces a unique disadvantage to the other antivirals in addition to price. It can only be administered by IV. Thus, it can't really be given to a patient early, when an antiviral is normally most effective. Instead, it is typically given to hospitalized patients, i.e. "late".

The first study released was a randomized double blind placebo study in Hubei:
https://www.thelancet.com/journals/lancet/article/PIIS014...
It included patients up to 12 days after the onset of symptoms. Remdesivir was not associated with statistically significant clinical benefits. However, there was a slight reduction in time to clinical improvement, among patients who were less than 10 days after symptom onset, though the difference was not statistically significant.

Another, larger study, was announced by Gilead:
https://www.gilead.com/news-and-press/press-room/press-re...

They found that patients treated sooner than 10 days after symptoms had better results than patients treated later than that, which is consistent with the Chinese study, and consistent with antivirals in general. They also found that a 5-day course was as effective as a 10-day course.

https://www.nih.gov/news-events/news-releases/peer-review...
https://www.gilead.com/news-and-press/press-room/press-re...
This was a non-placebo study, with open labels, so patients and doctors knew which patients were getting Remdesivir. It showed that more people improved by day 11 with Remdesivir than with standard of care.

Neither of the above studies make any mention of reducing mortality, but I believe that they adjusted their data analysis later to show an improvement in mortality in some cases.

Here's a summary of Remdesivir:
https://bgr.com/2020/06/01/coronavirus-drug-trial-remdesi... /
[quote=bgr]In other words, remdesivir therapy can be helpful, but there’s still no evidence that the drug can prevent complications, which is a key objective for COVID-19 treatments. Even so, access to remdesivir may speed up recovery for some patients. “These study results offer additional encouraging data for remdesivir, showing that if we can intervene earlier in the disease process with a 5-day treatment course, we can significantly improve clinical outcomes for these patients,” Harvard Medical School professor and Brigham and Women’s Hospital infectious disease physician Francisco Marty said in a statement.[/OUTER_QUOTE]

So, that's it - remdesivir can help, but that is especially if it is given early. Unfortunately, it has to be given by IV, so administering it early is problematic.
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L.C.
8/5/2020 8:26 PM
And, then there is favapiravir. Here's an early study comparing it with lopinavir, which found no difference:
https://www.sciencedirect.com/science/article/pii/S209580...

This describes a study comparing it to a Russian antiviral, Umifenovir. It found that patients recovered faster, though a similar number ended up on respirators:
https://www.marca.com/en/lifestyle/2020/04/10/5e90e6c7226...
The article also mentions that Lopinavir and ritonavir were ineffective.

This article describes a study where patients taking favapiravir cleared the virus in 4 days versus 11 days in the control group, but the study size was only 35 on favapiravir and 45 in the control group. The favapiravir group also showed significant improvement in chest imaging: (second article on this page)
https://www.medicalnewstoday.com/articles/anti-flu-drug-e...

Fujifilm has shipped it to 43 countries for further testing:
https://www.cnbc.com/2020/05/04/fujifilms-flu-drug-favipi...

India, in a test on people with mild to moderate cases, reports faster recovery and faster viral clearance.
https://www.newindianexpress.com/nation/2020/jul/23/covid...

More results should be out soon.
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L.C.
8/5/2020 8:35 PM
And that brings us to camostat mesylate, which I found in the link posted above by BLSOS.
https://www.forbes.com/sites/victoriaforster/2020/03/03/t...

The compound is approved in Japan for the treatment of a number of non-infectious conditions in people, such as chronic pancreatitis and postoperative reflux esophagitis.

There appear to be a number of studies underway, but no results yet:
https://www.sciencemag.org/news/2020/04/these-drugs-don-t...
https://clinicaltrials.gov/ct2/show/NCT04321096
https://clinicaltrials.gov/ct2/show/NCT04353284
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L.C.
8/7/2020 3:58 PM
Another antiviral on the horizon is RLF-100, also known as aviptadil. Houston Methodist reports anecdotal evidence that it works:
https://www.click2houston.com/news/local/2020/08/05/houst... /
https://bgr.com/2020/08/03/coronavirus-cure-rlf-100-avipt... /

Clinical trials are under way.

Edit - I guess I should add to this post it's other use.
[Quote=pubmed]...Aviptadil in combination with phentolamine and sexual stimulation, is expected to provide a new and effective alternative for erectile dysfunction (ED) patients that is essentially free of the troublesome side effects and cumbersome delivery methods which limit the use of other pharmacologic preparations. ...[/OUTER_QUOTE]
https://pubmed.ncbi.nlm.nih.gov/11566015 /

Edit2- RLF-100 is granted Expanded Access Protocol/Emergency Use Authorization for use treating respiratory failure in patients with Covid-19. RLF-100 may have two potential benefits. The first is rapid respiratory failure reduction in the most clinically ill patients, and the other is blocking replication of the virus. This authorization if for the former purpose.
Last Edited: 8/10/2020 9:21:51 AM by L.C.
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L.C.
8/10/2020 9:52 AM
So far, we have a drug for malaria, one for worms, and one for ED. How about adding one for heartburn? Famotidine, found in Pepcid, was reported back in May to have had an association with improved survival significantly, and clinical trials were started:
https://www.cnn.com/2020/05/09/health/famotidine-covid-19...
[quote=Dr. Tracey]We don't know if it has any benefit. We really don't. I swear we don't. People are hoping for anything. But we need to do this clinical trial.

It's generic, it's plentiful and it's inexpensive.[/OUTER_QUOTE]

A study released July 27 says Fomotidine is not an effective antiviral, but doesn't rule out that it might help in some other way:
https://www.sciencenews.org/article/coronavirus-covid-19-...

Two physicians from Wisconsin proposed using it with celocoxib.
https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3646583
Their sample of 14 patients, with no control group, all recovered. Five of the patients were deemed to have a 98% chance of mortality because of their very high reading of Lactic Acid Dehydrogenase (a measure of damage to your tissues). Not only did 100% survive, they also saw improvements in clinical, biomarker and radiographic outcome measures.

While not an antiviral, this is another potentially useful therapeutic that may improve outcomes.
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L.C.
8/11/2020 9:51 AM
Another target for a potential anti-viral would be Papain-like protease, which is essential for the rapid replication of the virus, and which also blocks the immune system from recognizing it:
https://medicalxpress.com/news/2020-07-covid-anti-viral-s...
https://www.nature.com/articles/s41586-020-2601-5

Known protease inhibitors include disulfiram, lopinavir and ritonavir, but this protease is different than the ones involved in HIV, so there is doubt that the HIV drugs will be effective. Disulfiram (used to treat alcohol dependence) has been reported to inhibit the papain-like protease of MERS and SARS in vitro.
https://www.nature.com/articles/d41573-020-00016-0

Screening 1697 drugs for potentially binding to PLpro, revealed an interesting list, including some drugs previously mentioned in this thread:
https://pubmed.ncbi.nlm.nih.gov/32597315 /
cell protectants: NAD+, quercitin, oxiglutatione
anti-virals: ritonavir, moroxydine, and zanamivir
antimicrobials: doripenem and sulfaguanidine
antacid: famotidine
anti-hypertensive ACE receptor blockers: candesartan, losartan, and valsartan

This article summarizes the various points where antivirals might work, and the fact that the various antivirals don't all attack SARS-CoV2 the same way:
https://biomedpharmajournal.org/vol13no2/active-compounds... /
[quote=biomedpharmajournal]...Coronavirus infects its host with three stages. The first stage is the virus infects its host by attaching the transmembrane spike glycoprotein to host through angiotensin-converting enzyme 2 (ACE2) in the host so that a complex is formed between S-glycoprotein with ACE2 with the help of transmembrane protease, serine 2 (TMPRSS2) produced by host cells.6,7 The next stage is the replication stage using RNA-dependent RNA polymerase (RdRp). Coronaviruses are RNA viruses that use host cells to replicate. Coronavirus uses RdRp to make new RNA copies. The last stage is the maturation stage of virus replication in the host cell using proteases such as 3CLpro (3C-like protease) and PLpro (Papain-like protease).8 Some drugs are known to be able to inhibit these three processes, including arbidol as ACE2 inhibitors; camostat mesylate as TMPRSS2 inhibitors; remdesivir and ribavirin as RdRp inhibitors; Lopinavir and ritonavir as protease inhibitors. ...[/OUTER_QUOTE]
That article goes on to measure the binding energy in vitro of various compounds, including antivirals and medicinal herbs to screen for potential antivirals. Drugs, such as Chloroquine, camostat mesylate, remdesivir, ribivarin, and lopinivir generally bound to a single site, whereas medicinals, such as quercitin, ginger, and curcumin tended to bind to all of them, though not necessarily as strongly.

Note that all of the information in this post are just from drug screenings in vitro. Nothing here involves actual studies where a drug was used to treat patients. Nothing here should be construed that any of the above are effective treatments. Rather, these sorts of screenings are a way to look for potentially useful treatments, which then can be tested to see if they help. The reason I posted it was to show that "antiviral" is a broad term, and that they don't all work the same way. Instead, there are a variety of points of attack. In the real world, some will work better than others.
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Pataskala
8/11/2020 11:06 AM
Russia claims to have a vaccine.

I wouldn't trust it.
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L.C.
8/11/2020 1:06 PM
Pataskala wrote:expand_more
Russia claims to have a vaccine.

I wouldn't trust it.

I believe Russia skipped phase 3 trials. China also has a vaccine that they are giving to all their military personnel, again, skipping phase 3. The Russian and Chinese vaccines use a weakened adenovirus with the spike protein, which is the same technology as the Oxford vaccine. If one works, they may all work.
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Pataskala
8/11/2020 2:26 PM
L.C. wrote:expand_more
Russia claims to have a vaccine.

I wouldn't trust it.

I believe Russia skipped phase 3 trials. China also has a vaccine that they are giving to all their military personnel, again, skipping phase 3. The Russian and Chinese vaccines use a weakened adenovirus with the spike protein, which is the same technology as the Oxford vaccine. If one works, they may all work.
I still wouldn't trust a Russian vaccine. Putin is notorious for poisoning his enemies. We're his enemies. Nuff said.
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L.C.
8/11/2020 3:26 PM
I wasn't suggesting taking his. I was suggesting that his was not much different than the Oxford vaccine. For that matter, it's not impossible that Russia and/or China hacked the Oxford computers. In any case, if his works, and is safe, the Oxford vaccine will likely work and be safe as well.
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L.C.
8/11/2020 10:10 PM
Ivermectin is gaining usage in India:
https://www.trialsitenews.com/tata-main-hospital-picks-up... /
https://www.trialsitenews.com/northern-indian-state-of-ut... /

They found the results to be vastly superior to HCQ and Azithromycin.

It's puzzling, the lack of interest in this drug, considering that every study that has been done has been extremely positive, and that every bit of anecdotal evidence is extremely positive.
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The Optimist
8/14/2020 12:36 PM
Pataskala wrote:expand_more
Russia claims to have a vaccine.

I wouldn't trust it.
If I refuse to take Russia's vaccine, does that make me an anti-vaxxer?

I've said it elsewhere, but I cannot trust any vaccine pushed out anytime soon. From a time standpoint, it's just impossible to do proper testing into any long-term side-effects. The unfortunate reality of the situation...
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L.C.
8/19/2020 10:07 AM
I'm not sure science matters in a politicized world, but studies continue to come out that show HCQ works. This is yet another study where HCQ was given to hospitalized patients, i.e. "late":
https://www.sciencedirect.com/science/article/pii/S092485...
HCQ was particularly effective among patients with (lymphocyte≥1000/mm3 or CRP≥100 mg/L), i.e. early enough that disease progression hadn't depleted the lymphocytes. It would still be better to see HCQ, or any other antiviral, tested early, i.e. on patient who were just diagnosed, far before they present to a hospital.

Meanwhile, Dr. Barody, an Australian gastroenterologist who developed the first cure for the peptic ulcer, is frustrated because his evidence is that Ivermectin is nearly 100% effective, extremely inexpensive, and has an extraordinarily high safety profile, but because it is off patent, no one will fund the research studies to support it's use, so it is only being used in countries like India, Bangladesh, Bolivia, Peru, and Dominican Republic, which have permitted it.
https://www.newsmax.com/health/health-news/australia-iver... /
Here is a systematic review of Ivermectin, recently published in Nature:
https://www.nature.com/articles/s41429-020-0336-z
[quote=nature]...This study presents the possibility that ivermectin could be a useful antiviral agent in several viruses including those with positive-sense single-stranded RNA, in similar fashion. Since significant effectiveness of ivermectin is seen in the early stages of infection in experimental studies, it is proposed that ivermectin administration may be effective in the early stages or prevention. Of course, confirmation of this statement requires human studies and clinical trials.[/OUTER_QUOTE]

Right now, we have a tragic situation, in my opinion. We can identify patients who have Covid19. We can identify which of these are at high risk, due to age and co-morbidities. These patients have about a 15% chance of dying. We have two approved drugs, remdesivir (the fact that it got approved is surprising, since it shows minimal benefit) and dexamethasone. Both are solely to be used in a hospital setting. There are no approved drugs for use in an outpatient setting. Thus, when a doctor has a patient who has Covid19, and who is at high risk, the current standard of care is to send the patient home to eat chicken soup, and wait until they either recover, or they get close to death, at which point they are hospitalized, and treatment can begin (oxygen, drugs, ventilators, etc).

In the meantime, we have drugs with a high safety profile that can be given in an outpatient setting, which in a variety of studies have been shown to be useful when given early. Why is the FDA sitting on it's hands? I really don't care which of these they approve, but I really think that the FDA should do an emergency use authorization of some antiviral regimen that can be given early. It could be HCQ+Azithromycin+zinc. It could be Ivermectin+doxycyline+zinc. It could be favapiravir. But, what makes no sense is not to treat high risk people at all until the virus has replicated to the stage that they need hospitalization. Treating early could not only reduce hospitalizations, and total medical expense, it could also reduce the number of people with severe enough cases that they end up with long term disability. To me, it is inexcusable to just send people home and let the disease progress. Other countries are treating people as soon as they show symptoms. Why does the US have to be last?

In other news, RLF-100 is showing promise for rapid recovery of people with advanced lung problems, and I expect Doctors may soon have another drug in their toolkit for dealing with advanced cases.

Also, Russia has approved it's vaccine for human use, skipping the normal Phase 3 trials. It would seem that Russian Scientists have been giving themselves experimental doses of the vaccine for some time. Did they eliminate the need for Phase 3 trials by doing "challenge trials", where they vaccinated themselves, and then deliberately exposed themselves to the virus to test their immunity? Perhaps. It is considered unethical to do challenge trials in humans because if the challenge fails, there is a risk that someone could die, however it provides much faster information about the effectiveness of a vaccine.
Last Edited: 8/19/2020 10:14:00 AM by L.C.
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L.C.
8/24/2020 2:50 PM
It's not an antiviral, but for those of you on blood pressure medicine, you'll be happy to know that ACE inhibitors and Angiotensin receptor blockers (ARBs), both significantly improve outcomes and reduce the chance of death:
https://link.springer.com/article/10.1007/s11883-020-00880-6
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L.C.
9/7/2020 1:32 PM
A new study goes into the fact that in addition to a potential cytokine store, Covid19 may also trigger what is referred to as a bradykinin storm. Rather than linking to the technical article, in which a supercomputer was used to analyze changes in gene expression which happened in Covid19 patients, to try to figure out what was happening, here's a link to a colorful but knowledgeable doctor explaining it on youtube:
https://www.youtube.com/watch?v=tDbRfur36sE
Dr. Mobeen Syed (aka Dr. Been), uses some amusing illustrations to lighten the material, to make it more understandable, and shows why the bradykinin hypothesis may explain why such things as Zinc, HCQ, and Vitamin D have been so effective, when given early.

It's interesting to note that India appears to be about to pass the US in total cases, but with only about half the deaths. They use antivirals early much more often than in the US, as does Costa Rica, another country with much lower mortality.
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oldkatz
9/7/2020 2:13 PM
L.C. wrote:expand_more
A new study goes into the fact that in addition to a potential cytokine store, Covid19 may also trigger what is referred to as a bradykinin storm. Rather than linking to the technical article, in which a supercomputer was used to analyze changes in gene expression which happened in Covid19 patients, to try to figure out what was happening, here's a link to a colorful but knowledgeable doctor explaining it on youtube:
https://www.youtube.com/watch?v=tDbRfur36sE
Dr. Mobeen Syed (aka Dr. Been), uses some amusing illustrations to lighten the material, to make it more understandable, and shows why the bradykinin hypothesis may explain why such things as Zinc, HCQ, and Vitamin D have been so effective, when given early.

It's interesting to note that India appears to be about to pass the US in total cases, but with only about half the deaths. They use antivirals early much more often than in the US, as does Costa Rica, another country with much lower mortality.
Was about to send that study to you. Should have known you would be on top of it!
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L.C.
9/7/2020 9:56 PM
In the news:
Zagazig University (Egypt) releases results of a study of Ivermectin as a prophylaxis against Covid19. The drug was given to people who had close exposure to family members who were infected, with 203 in the Ivermectin group, and 101 in the control group. They found a statistically significant benefit, but the sample size was small, and the study was not blinded. Also, the study has not been peer reviewed.
https://www.trialsitenews.com/zagazig-university-randomiz... /

An Argentinian study also showed positive results for Ivermectin combined with carrageeneen:
https://www.trialsitenews.com/argentinas-ivercar-ivermect... /
This was also a prophylaxis study. In the control group, 58% of the people were infected. In the Ivermectin/Carrageeneen group, out of 788 people, there were 0 infections.

For what it's worth, Ivermectin is believed to be effective against many other RNA viruses because it binds to Importin Alpha, which viruses use to penetrate the nucleus of the cell.
https://www.sciencedirect.com/science/article/abs/pii/S01...

A new study is out on Remdesivir. Once again, it produced not very positive results. After 5 days, the patients had a statistically significant improvement in status, but comparing patients after 10 days, they did not.
https://www.trialsitenews.com/remdesivir-use-in-multi-nat... /
https://clinicaltrials.gov/ct2/show/NCT04292730

This is consistent with the earlier study, which showed faster recovery, but no improvement in mortality. In fairness, it's not surprising that Remdesivir doesn't work when given late, for the same reason that it's not surprising that HCQ doesn't work when given late. An anti-viral is intended to block replication of the virus. It is going to be most effective the earlier it is given, because the earlier it is given, the less the virus has already replicated. Think of an auto accident. An airbag is going to be effective if you deploy it at the right time, but if you deploy it too late, it's not going to help, and may make things worse.

In my opinion, of all the study types for antivirals, the one I consider the most informative and valuable are the ones where the proposed antiviral is used for prophylaxis. The reason is that in those, you always know exactly the stage of infection where treatment started (none), so things are always equal. You also know that it is not too late, and that the virus has not already replicated and/or irreparably harmed the patient. If an anti-viral works, it will be very effective in prophylaxis; if it is not effective, it will accomplish nothing. Unfortunately for Remdesivir, it wouldn't be appropriate to use for prophylaxis for two reasons. First, it is very expensive, at $3200, so you wouldn't want to give it to everyone who might get exposed. Second, it can only be administered by IV, which makes it only practical to give to hospitalized patients.
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L.C.
9/15/2020 7:26 PM
A systematic review of HCQ shows that it has consistently been shown to be safe and effective when given early, in an outpatient setting prior to hospitalization:
https://thebfd.co.nz/2020/09/12/hydroxychloroquine-is-eff... /

[quote=Chawick Prodromos]HCQ was found consistently effective against Covid-19 when administered early, in the outpatient setting. It was found overall effective. No credible study found worse outcomes with HCQ use. No mortality or other serious safety issue was found.[/OUTER_QUOTE]
Last Edited: 9/15/2020 7:31:11 PM by L.C.
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