Smothering the Fire - Disulfiram going to human trials for COVID-19

I've been touting this drug since March. I'm glad the fine folks at Harvard caught up. Just like it did with SARS, MERS, Disulfiram inhibits the cytokine storm. Really promising news.

Maybe they will listen to me about how lauric acid greatly reduces the Covid-19 cell from attaching to a host in the first place. Fuck people, we have the meds and supplements already to end this pandemic.

https://hms.harvard.edu/news/smothering-fire

Drug prevents runaway inflammatory cell death in mice, could relate to COVID-19

By ALICE McCARTHY | Boston Children'sMay 8, 2020*Research

Inflammation is the alarm system by which cells first respond to potential danger, but in excess, inflammation can be fatal.

In COVID-19, for example, overactive inflammation has led to severe complications and even death for many hospitalized patients.

Research in mice led by Harvard Medical School and Boston Children’s Hospital now reveals that the FDA-approved drug disulfiram, commonly used for treating alcoholism, blocks a key gatekeeper protein involved in inflammation.

Activation of the gatekeeper protein,*gasdermin D, is the final common step in the process of inflammatory cell death, or pyroptosis, and the resulting release of inflammatory cytokines seen in many serious conditions, including sepsis.

Sepsis is the leading cause of death in children in the world and contributes to*about a third of deaths in hospitalized adults.

The researchers report May 4 in*Nature Immunology*that mice treated with disulfiram did not develop fatal sepsis, compared with untreated animals.

The findings offer hope for diseases that involve runaway inflammation, although it remains to be seen whether the results can be replicated in people.

“This research discovery is coincidentally very timely today because most people think that the clinical deterioration of COVID-19 patients is mediated by a cytokine storm, or excessive release of inflammatory molecules,”*explained*Judy Lieberman, professor of pediatrics at HMS and chair of cellular and molecular medicine at Boston Children's.

Lieberman is co-senior investigator of the study together with*Hao Wu, professor of biological chemistry and molecular biology in the Blavatnik Institute at HMS*and the Asa and Patricia Springer Professor of Structural Biology at Boston Children's.

“Even though there has been a lot of interest, there have not been any*bona fidegasdermin D inhibitors,” said Wu. “We screened thousands of compounds and found that the one that worked best—disulfiram—is already on the market, is inexpensive, has a 70-year history of drug safety and could be repurposed pretty quickly.”

Cascade to inflammation

When an invading virus or bacterium enters a cell, it triggers inflammation, unleashing a cascade of events.

One key event is called pyroptosis, a "fiery" or inflammatory cell death. In pyroptosis, the cell’s membrane literally explodes, releasing inflammatory molecules such as interleukin-1, which causes fever.

In a*paper published in*Nature*in 2016, Lieberman and Wu discovered that gasdermin D forms membrane pores. When these pores open, inflammatory molecules spill out of the cell, causing pyroptosis.

Too much inflammation contributes to human diseases, including sepsis, inflammatory bowel disease, gout, type II diabetes, cardiovascular disease and Alzheimer’s disease and is the hallmark of rare inflammatory genetic diseases.

“We knew that gasdermin D is the gatekeeper of the pathway leading to pyroptosis and spillage of inflammatory cytokines,” said Wu. “If we could find a compound that would inhibit this particular step, that could be an attractive drug target to prevent pyroptosis when it was not needed.”

Quieting pyroptosis

Jun Jacob Hu, HMS research fellow in biological chemistry and molecular pharmacology in the Wu lab,*screened more than 3,700 small molecules looking for gasdermin D inhibitors.

He found just 22 active compounds. Disulfiram was at the top of the list. *

Next, the team studied mice sick with sepsis.

They observed that disulfiram blocked pyroptosis and its explosive release of inflammatory molecules. Mice treated with disulfiram survived, while those not receiving the drug died from sepsis within one day.

"There have been hundreds of clinical trials looking for drugs to stop sepsis and the overwhelming inflammatory response without success,” said Lieberman.

“We hope that with this new discovery—inhibiting gasdermin D that is in a critical location in the inflammatory pathway—we could actually have a therapy that might work,” Lieberman said.

Hu is co-first author of the paper along with Xing Liu of HMS, Boston Children's and the Chinese Academy of Sciences.

COVID-19 studies planned

The team is now looking to apply these findings to the new coronavirus.

“Because COVID-19 can produce an inflammatory syndrome that is very similar to sepsis, we wonder whether disulfiram can be used to treat severely ill COVID-19 patients,” said Wu.

“We know from a recent report that disulfiram also inhibits a coronavirus protease, one of the essential proteins of the virus causing COVID-19,” she said.

Plans are already in place to study pyroptosis and coronavirus. The ultimate goal is to start a clinical trial with disulfiram in COVID-19 patients.

“The truth is that gasdermin D contributes to so much pathology in the body that we think an effective gasdermin D inhibitor like disulfiram could open up many therapeutic possibilities,” said Lieberman.

This study was supported in part by the US National Institutes of Health (grants DP1HD087988, R01Al139914, R01AI123265, R01AI142642, R01AI145274, R01AI141386, R01HL092020 and P01HL095489), National Natural Science Foundation of China (grant 31972897), Chinese Academy of Sciences (grant ZDBS-LY-SM008), Shanghai Municipal Science and Technology (grant no. 2019SHZDZX02) Shanghai Science and Technology Committee (grant 19QA1409800) and Flight Attendant Medical Research Institute (CIA123008).

Adapted from a post on Discoveries, the Boston Children's research and clinical innovation blog.

Disulfiram is the most promising drug to date against Lyme and other tick borne pathogens. Not bad for a $19 box of 90 tabs at 250mg. I'll be starting this soon for my chronic TBI which I've had 30+ years. I've tried everything else and finally have hope. No doctor turned me on to this. Years of research and stumbled on it a year ago or so. Thank you doctors, CDC, big pharma for absolutely nothing.
Might want to get some fellas, when this goes public after the trials prove what this drug can do, it'll be near impossible to get

Thousands of compounds tested and only Disulfiram gets the green light for human trials. But carry on and fight

Who makes this stuff, hh?

Michelangelo said:

Who makes this stuff, hh?

Click to expand...

It's been around forever. It's what hydroxychloroquine was supposed to accomplish. It's dirt cheap but in short supply in the states. It completely stops the immune system overeating in it's tract. It's a simple drug (not antibiotic), but devastating against shifty pathogens.

And originally developed for alcoholics to quit drinking

Just started Disulfiram for Lyme, Bartonella, Babesia, Rocky Mountain Spotted Fever and a few others I can't spell. Still also taking monolaurin. I'm ready to roll around in this pussy virus and see what's what. Fucking pussies.

Disulfiram (DSF) is finally going to human trials... The CDC is a fucking joke. They knew DSF worked well on SARS and MERS but are too busy trying to make their dollars with a vaccine. DSF costs like 10 cents per dose. Fuck you big Pharma, the CDC, NAID and most of all.. fuck you Fauci. You cost the lives of many around the world.

The current in silico study provide evidence that FDA-approved, DSF could potentially be develop into new antiviral agents for the treatment of COVID-19. Here we provide in silico data to show that the catalytic Cys145 of SARS-CoV-2mp could be blocked and inactivated by DSF and its thiol-reactive derivatives metabolites.


The use of DSF as antiviral against COVID-19 is promising for many reasons: Upon ingestion, one fifth of the administered dose is active even after one week and hence classified as a long-lasting drug (Clayton & Clayton, 1981). This is of particular interest to avoid long administration periods. The pharmacokinetics studies of DSF indicate that a relatively small fraction of the compound is excreted in urine after 6 h of administration (5-20%) and maintaining a half-life of 6 h in the plasma (Ellenhorn, 1987). While the rest is transformed to other metabolites: MeDDTC-SO; MeDDTC-SO[SUB]2[/SUB]; MeDTC-SO; and MeDTC-SO[SUB]2[/SUB] (Zaldívar-Machorro et al., 2011). Therefore, the administration of DSF, produces six other thiol-reactive species that could additionally reacts with Cys thiol groups. We docked these metabolic products of DSF in SARS-CoV-2 main protease 3CL[SUP]pro[/SUP] (Figure 4).

Regarding the potential for DSF and its metabolites to form covalent derivatives with the SARS-CoV-2 protease, it was recently found that DSF is an inhibitor of the MERS-CoV and SARS-CoV-1 papain-like proteases, through a non-competitive and competitive mechanisms, respectively (Lin et al., 2018). In this same publication, it was observed a time-dependent inactivation of the recombinant enzyme, which was not reversed after removal of the excess of DSF, The residual inhibition observed is through a covalent bonding of DSF, which must involve the thiol group of the catalytic Cys residue, probably forming a covalent adduct with Cys112 (number of SARS-CoV-1 PL[SUP]pro[/SUP]), the latter mechanism deduced from crystallography and docking. Finally, it was argued that the combined use of DSF and 6-thioguanine or mycophenolic acid offers a potential therapeutic use for clinical treatment of these emerging coronavirus infections. The SARS-CoV-1 protease conserves the catalytic residues, and probably the mechanism, of the SARS-CoV-2 enzyme; for this reason, we predict the formation of stable and irreversible 3CL[SUP]pro[/SUP]-inhibitor (DSF and its metabolites) complexes.


https://www.tandfonline.com/doi/full/10.1080/07391102.2020.1764393

[h=1]FDA-approved thiol-reacting drugs that potentially bind into the SARS-CoV-2 main protease, essential for viral replication[/h]

Finally Disulfiram is going to human trials for Covid-19. Has the potential to be very effective and even more so than HCQ and Azithro. One huge problem again though, they are giving patients out the gate 2,000 MG a day. That is way too much. I take 125 MG a day for Lyme and Babesia and it absolutely kicks my ass. My target dose which I hope to achieve in the next three months (already been on it for 3 months) is 400MG a day. I have to get my liver enzymes checked once a week because the drug is harsh on the liver and the dieoff from what it is killing puts even more stress on the liver. Many of these patients receiving the high dose will be hospitalized with liver issues, kidney issues, or psychosis. Once again just like HCQ + Azithromycin trials, this study is set up to fail. Why the fuck are they dosing so high. 500MG of disulfiram a day is high and they are going four times this. Then Fauci will ban the RX of Disulfiram for everything except its original intent, treatment for Alcoholics looking to get off the sauce. This shit is criminal.







https://clinicaltrials.ucsf.edu/trial/NCT04485130

[h=3]Summary[/h]Disulfiram a safe, easily dosed, FDA-approved drug for the treatment of alcohol dependence has been identified to be a potential therapeutic target for SARS-CoV-2 infection. Disulfiram may have both antiviral (inhibiting viral replication via blocking the Mpro protease and zinc ejection) and anti-inflammatory effects (via inhibition of NF-kB-induced and NLRP inflammasome-induced cytokine release) on SARS-CoV-2. We will test disulfiram 2000 mg/day for 3 consecutive days (doses shown to be well tolerated and safe in a recent phase 2b trial) in 60 symptomatic COVID PCR+ individuals in a randomized (1:1) clinical trial evaluating the effect on COVID symptoms severity, SARS-CoV-2 viral load, and biomarkers of inflammation over 31 days.

[h=3]Official Title[/h]Virologic and Immunologic Response to Disulfiram in Early Symptomatic COVID+ Outpatients
[h=3]Details[/h]The identification of a safe, effective treatment for individuals with early mild-to-moderate symptomatic COVID-19 that prevent progression to more severe disease would have immediate public health implications. A hallmark of severe COVID-19 disease is immune system dysregulation called cytokine storm. Multiple studies have reported that patients with severe disease demonstrate elevated levels of pro-inflammatory cytokines early in disease, and elevated IL-6 plasma concentrations are predictive of poor clinical outcomes in COVID-19. Disulfiram, an FDA-approved drug for the treatment of alcohol dependence disorder is an appealing therapeutic option for COVID-19. It has a good safety profile, easy dosing schedule, and recent data suggesting multiple mechanisms by which disulfiram may act on COVID-19 (both as a direct antiviral agent as well as indirect effects on reducing inflammation). In addition disulfiram has been studied extensively with detailed available pharmacokinetic data; disulfiram has a short half-life ~7.5 hours with >90% of drug eliminated within 3 days post-dose, allowing quick reversal of any potential adverse effects. This is a randomized, placebo-controlled assessment of disulfiram in people with early mild-to-moderate symptomatic COVID-19. Disulfiram 2 grams or a placebo will be administered orally once daily for 3 consecutive days. Sixty (N=30 mild, N= moderate/severe) symptomatic COVID PCR+ participants will be randomized (1:1) to receive active drug versus placebo. Subsequent stratified analyses will be performed based on upper limit of normal hs-CRP, ferritin, D-dimer levels. Drug/placebo will be administered using strict infection control protocols designed to support the study of people with acute COVID-19 infection per the Center for Diseases Control (CDC) guidelines (https://www.cdc.gov/coronavirus/2019-ncov/hcp/disposition-in-home-patients.html).

[h=1]Russia is studying Disulfiram against Covid-19. Fauci remains silent on other treatment options except Remdisivir and his vaccine. Fuck you Fauci.


https://www.hindustantimes.com/worl...-study-says/story-suvtkWAxNU7Lnc5zOic7yJ.html

Alcoholism drug may help in fight against Covid-19, study says
[/h] [h=2]The researchers from National Research University Higher School of Economics (HSE) in Russia noted that the structural elements of the novel coronavirus that are less subject to mutation during its evolution should be chosen as a target for the potential treatment.[/h]
Disulfiram, the medication used to treat alcoholism, may help in the fight against SARS-CoV-2, the virus that causes Covid-19, according to a study.
The researchers from National Research University Higher School of Economics (HSE) in Russia noted that the structural elements of the novel coronavirus that are less subject to mutation during its evolution should be chosen as a target for the potential treatment.
Otherwise, a medication effective against one strain would no longer be effective against another, they said.
The best candidates for this are conservative proteins, such as the SARS-CoV-2 virus main protease M pro, according to the study published in the Mendeleev Communications journal.


In addition to being resistant to mutations, M pro plays a major role in coronavirus replication, which means that its inhibition is able to slow down or even completely stop its reproduction inside the body, the researchers said.
The potential drugs were taken from the database of medications approved by the US Food and Drug Administration (FDA).
The modelling data demonstrated that sulphur-containing drugs show unusually high ligand efficiency at the active centre of SARS-CoV-2 main protease Mpro, but only disulfiram 4 retains stable interactions.


Most commonly used for treating alcoholism, disulfiram fights SARS-CoV-2 in two ways, the researchers said.
First, as previously demonstrated in vitro with SARS and MERS coronaviruses, it is a covalent inhibitor, they said.
It fights Covid-19 symptoms such as the significant decrease in reduced glutathione, which is an important antioxidant, according to the researchers.


This deficiency may lead to severe manifestations of the disease, they said.
The Russian chemists said they were also the first to predict the potential efficiency of neratinib, an irreversible tyrosine kinase inhibitor, against SARS-CoV-2.
According to the researchers, the tests that were performed on July 27, 2020, demonstrated that disulfiram really inhibits M pro in 100 nm concentration, which confirmed the results of the modelling.

Disulfiram is gaining optimism from researchers that it will be effective against covid. If anyone wants additional information, pm me. If human trials go well, it'll be scooped up in a day.

Trump was on the right path of trying to find an already FDA approved drug like an HCQ or Disulfiram but got completely stopped by the FDA at the direction of Fauci. We more than likely already have the solution, we just have to find it and Fauci failed us in every way. He needed to be leading the charge of repurposing drugs that kill covid in vitro. HCQ and disulfiram fall into this category. Human trials are underway.

Why it took 4.5, months to take disulfiram to human trials is an absolute digrace and criminal. Fauci is beyond corrupt

Fauci is in the bag. Trump hates him but hands are tied. Trump gets re-elected Fauci is gone day 1