Long time. The only things that look good are hydroxychloroquine and Indometacin.
Main Point: A colleague just shared a Chinese pre-print that suggests Indometacin may be useful in COVID-19 with a good log kill and blood levels 10x IC50 at standard oral doses. The animals dosed with it recovered faster than the controls and this recovery rate was similar to that of other test animals given convalescent serum. 3/8 control dogs died, 1/9 convalescent serum dogs died, and all the dogs dosed with Indometacin survived.
It may have got lost in the noise but there was an Italian observation about Indometacin working on SARS from back in 2006. I tried to get a high containment lab anywhere to check it without any success.
Anyway, the Chinese have gone 1 step further than in vitro cell culture and found exactly the same as the Italians - Indomethiin appears effective in vivo in dogs against SARS-CoV-2
Yes, not human trials but certainly encouraging with the usual pathway is cell culture, mice, rats, small vertebrates, large vertebrates ( dogs and pigs), primates, humans.
Standard oral doses exceed 10x IC50 as opposed to Hydroxychloroquine where you're looking at only 2x over IC50.
The Chinese don't state a log kill but do say it hit zero @ 48 hours.
The Italians suggested a log kill of 3 (this is Daclatasvir/Ledipasvir strength). For comparison, Sofosbuvir has log kill of 4.5, Ribavirin is 0.5 and Interferon about 1-2 (initially) on HCV.
Both the Italian (2006) and Chinese papers are attached. The Chinese paper is a pre-print but the technical detail looks solid. There is a US co-author FWIW.
Given the runs of various things at our pharmacies, it might be worth getting Indometecin constrained like HCQ as I'd be tipping the mainstream media pick this up soon after it starts to bubble on social media.
I rather suspected you might be out at the tip of the spear with regard to research.
Had not heard anything about Indomethacin as a treatment for Covid 19, so this is very exciting.
Was down with Covid 19 symptoms about 5 weeks ago after a pre-Mardi Gras trip to New Orleans.
Here they were only testing if symptoms were severe enough to warrant hospitalization. My symptoms weren't pleasant, but fortunately resolved on their own. I wouldn't necessarily recommend this for anyone else, but I dealt with the symptoms with 800 mg of Ibuprofen every 4 -6 hours to deal the severe body aches, general inflammation, and fever. I also used an Ventolin HFA inhaler (left over from a bout with pneumonia a couple of years ago) when it felt like I wasn't getting quite enough air.
About 10 days in, I sought out and found Cinchona tablets, and some rather powerful low sugar high quinine tonic water, and perhaps it was placebo effect, but I began to feel better within a very short time after starting the Cinchona and tonic combination.
Thanks once again for the fantastic information, and for taking the time to respond at length. I'll print out the papers and make sure my GP gets them!
Thanks also for saving my life. You're one of a kind, and the world is lucky to have you!
Well, as far as the US Media is concerned, anything BUT Hydroxycloroquine. Gilead has now managed to get Remdesivir emergency approval, and it's being rolled out nationwide.
Not that that's a bad thing at all if it works. It's just disheartening to see effective non-proprietary treatments shoved to the back shelf of public consciousness in favor of what must be a relatively expensive proprietary treatment.
Hydroxychloroquine continues to be widely used, but continues to be panned by the mainstream press as "dangerous" and "snake oil", so people who were once rightfully hopeful have become wary.
It's really unbelievable that one of our political parties has so rabidly politicized the use of a proven and effective treatment that it is being smeared in favor of what looks like a less effective proprietary treatment. Make no mistake, this isn't the so called right we're talking about, and it is stunningly obvious, and equally shameful.
It's rather poetic that NYT is now touting Thorazine as a potential anti-covid panacea. Sort of a modern day NeoFascist "Soma" for the unruly freedom loving masses.
Yeah f**k Gilead the ass-holes
been disseminating the sof/dac stuff & indomethacin info
targeted mostly medical ppl,
im just scared now, essential/expendable worker. thankfully not much face time,
when i hit ICU they'll put me on a trolley in the hallway,"just wait over here" too many comorbidities, too old etc,
Oral sofosbuvir delivers the phosphorylated nucleotide to the liver with great efficacy. It is possible that the nucleoside is released into circulation, and gets phosphorylated in lung AT2 cells. In that case, it might work, assuming sars co v polymerase is sensitive.
I can attest to the gastrointestinal symptoms. Won't go into detail, but it wasn't pleasant and involved frequent and urgent trips to the bathroom. Fortunately those symptoms didn't last long. A bit of nausea, but that didn't last long either. Headaches too, and some chills but mild, and short lived.
Right after that severe backaches, and of all things joint pain in my hands. Not knowing any better, I wondered what the hell was wrong, but it didn't occur to me that all of this was related. The joint pain was bad enough, I thought perhaps I should consider what I was going to do if I had to stop working.
At that point, I began to take high doses of Ibuprofen (600 - 800 mg) to deal with the pain and inflammation. That was probably a lucky choice as it turned out.
Then came the runny nose and itching in my lungs which I initially chalked up to seasonal allergies. Those symptoms progressed to a persistent and annoying dry cough, and occasional shortness of breath which brought out the Albuterol inhaler.
Eventually, but thankfully not frequently I started to cough up stuff that looked like and had the consistency of clear gelatin. Weird!
I can be a bit dense at times. It took several days to dawn on me that I had contracted Covid 19. That's when having done some research on Hydroxychloroquine, I started looking around for the closest available analog - anything that contained a considerable amount of Quinine.
After I'd recovered, I remembered that I still had a 3 month supply of Chlorcyclizine (available 'over the counter' here) I'd purchased back when I was still being treated for Hep C, and wondered if anyone had ever looked into it as an anti-viral for Covid 19.
When Dr James responded with the studies on Indomethacin, I immediately passed the information on to my endocrinologist, and began suggesting in social media posts that others look up the research for themselves. Hopefully it's had some positive impact
Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group (p=0.059) is far more accurately worded:
Results FAILED TO DEMONSTRATE ANY STATISTICALLY SIGNIFICANT survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group (p=0.059)
(despite being n=>1000...)
IF remdesivir delivers any benefit whatsoever it is, at best, in the ballpark of the benefit of ribavirin which, when added to Sofosbuvir and an NS5A is ~ 1% extra SVR12 ie so small you can barely measure it.
In short, remdesivir
is not a potent NUC,
it is not even close to a potent NUC and
even at n > 1000 it has failed to demonstrate any significant benefit.
Compared to a real NUC like sofosbuvir it is complete and utter rubbish, leaving aside the issues that it is IV only and exists only at experimental scale.
Here is a reasonably thorough analysis of the remdesivir trials (credit Dr Andrew Hill)
There are 5 main randomised trials of remdesvir. We need all the results from these 5 clinical trials to be combined. Then we could interpret the overall outcomes in a meaningful way.
When the World Health Organisation review a drug, they always run a systematic review and meta-analysis of all available data.
A: Chinese trial of remdesivir versus placebo showed no benefits (Lancet publication), n=237
1. There is no effect of remdesivir on coronavirus viral load levels - they are the same as the control arm. With 237 patients, this trial show easily have enough statistical power to detect an effect on viral load.
2. Remdesivir was stopped early for adverse events in 12% of patients, versus four (5%) who stopped placebo early.
3. Mortality was 14% for remdesivir versus 13% for placebo.
B: Gilead's trial in severe infection seem to suggest that 5 days of treatment is better than 10 days. What does this tell us about how well the drug works? Why should less treatment show trends for better outcomes?
1. Clinical recovery: 65% for 5 days, 54% for 10 days of treatment
2. Mortality: 8% for 5 days, 11% for 10 days
3. Adverse events leading to discontinuation: 5% for 5 days, 10% for 10 days
C: NIH trial. Why was the clinical endpoint and sample size changed in the middle of the trial? n=1063, unpublished interim analysis.
This study, announced by Anthony Fauci, shows a slightly lower mortality for remdesivir (8.0%) versus placebo (11.6%), but this is not statistically significant. Remember that in the comparison of 5 versus 10 days of remdesivir, we also had 8% mortality for 5 days of remdesivir, versus 11% for 10 days of treatment. How do we interpret these two non-significant trends in the two trials?
Combined with the Chinese survival data, any difference in survival between remdesivir and placebo will be small and not statistically significant.
This study of 308 patients was suspended for poor recruitment, but no results are available for the people who were actually recruited before April 15th. The website mentions 308 patients. What results are available? When will they be published?
Even if remdesivir does show overall efficacy, there is the question of drug supplies. Will there be enough drug to treat everyone in need? Also the daily IV infusions of remdesivir will be a large burden on healthcare services.
Wow! Did not expect such a detailed response, Doc! You know, when the Remdesivir study results were publicized I remember thinking "what?, is this supposed to be good?" To me, a layman, the numbers looked like a complete and utter failure, yet it was being sold as the next great hope (?). Just didn't make any sense unless one considers the Big Pharma profit motive. Then of course, it makes perfect sense. Sell a "cure" that allegedly takes 11 out of a 14 day disease course to kick in, and at the end of the day ends up killing slightly more old people than it "cures", thereby adding significantly to Gilead's balance sheet, and permanently subtracting long term liabilities from the federal government's burgeoning medicare roles. Win/win right?
Anyway, Physicans here are quietly continuing to prescribe a Hydroxycloroquine, Azythromicin and Zinc cocktail , and in some places life is sort of resembling normal. Not the state I live in though. Still completely locked down, and literally helicoptering Covid patients in from neighboring states to keep the hospitals busy enough, and statistics high enough to justify the lockdown.
The payoff for our local politicos is an attempt to push through universal mail in (unverifiable) election ballots so that they get to put a a heavy thumb on the scale, and stay in power. No kidding!
Meanwhile, small businesses are dropping like flies, unemployment numbers are skyrocketing, and people are literally going insane from boredom and fear. I imagine it's the same everywhere in the world right now.
Long after the virus has largely washed through, people are just now donning masks and gloves and regarding each other as potential illness threats.
This whole thing is utterly insane! Random serological antibody testing is demonstrating in no uncertain terms that the actual rate of infection is many orders of magnitude higher than the official numbers, which is actually a good thing, because it means tat real mortality rates are actually many orders of magnitude lowerthan the official tally, Instead of 3 - 4%, more like 0.3%, or in the neighborhood of common Flu, even without a readily available vaccine.
So called "social distancing" doesn't seem to be making any real difference at all. Tested infection rates after an initial spike remain fairly constant. If you test 1,000 individuals, you're pretty much going to get a fairly standard active infection rate. Test 100,000 for antibodies, and somewhere between 25% sand 40% have already had it and cleared it.
JFK Memorial Hospital, CA, USA
I think hepatitis C meds like Sofosbuvir/Daclatasvir could work. Both are +RNA viruses. Sof has already been proven safe and effective against RNA virus polymerase. The inactive form of Sofosbuvir needs activation by CatA to form the active form of Sofosbuvir GS-461203. The active form can dock in the SARS-CoV-2 polymerase and CatA is found not just in liver cells but also in lung cells so we can expect the active form of Sofosbuvir would work in the lungs.
University of Michighan on Indomethacin, indications, contra-indications
Note Indomethacin not recommended for patients with active GI bleeds as is general for most NSAIDs www.uofmhealth.org/health-library/d00039a1
Fitz I wholly agree with your summation.
“The payoff for our local politicos is an attempt to push through universal mail in (unverifiable) election ballots so that they get to put a a heavy thumb on the scale, and stay in power. No kidding!”
Contracted HCV 1980's
Geno Type 1a
F3 ( doc says once treated I'll be F2 maybe F1)
Meds shipped 6/17/2016 arrived early 7/2016
Viral count - 3,471,080
4 week quantitative bloods: August 17, 2016. I have been diagnosed as <15 (told undetected)
8 week quantitative bloods: September 14th. I have been diagnosed as <15 (told undetected)