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Can Existing Drugs Treat COVID-19? From Viagra to Thalidomide to Cough Syrup

As the number of cases of COVID-19 continues to mount, so do entries at clinicaltrials.gov for potential treatments, reaching into the existing pharmacopeia for repurposing candidates.

Clinical trials for COVID-19 treatments range from 10 people to nearly 600, and most are happening in China. But a caveat: ClinicalTrials.gov is a clearinghouse of proposals, not requiring approval. The entries are from all over the world.

Normally – and these are far from normal times – a clinical trial is optimally designed to assess the safety and efficacy of a new treatment on two groups of people, one taking the drug, the other a placebo. Or, in a crossover design, participants take courses of both treatment and placebo at different times but don’t know which is when.

The standard, scientific approach to evaluating drugs takes time. Lots of it. And right now, people are hesitant to sign up for a clinical trial knowing that they face a 50:50 chance of being assigned to a placebo group.

The world can’t wait for clinical trial results, and so information is getting out in other ways. Although the medical and scientific journals have been terrific at getting new information out ASAP, social media has at the same time provided a conduit for what may become a tidal wave of misinformation. Just yesterday, for example, a meme circulated claiming that a gargle with salt water and vinegar would simply wash away the hardy SARS-CoV-2 coronavirus.

Dr. Anthony Fauci, director of the NIAID

Dr. Anthony Fauci Weighs in On Treatments Using Existing Drugs

When Dr. Fauci, director of the National Institute of Allergy and Infectious Disease and unofficial guru of the pandemic in the US, spoke to the media via webinar on March 18 about the challenges of finding treatments, he began with a warning for people not to resort to do-it-yourself remedies, especially repurposing drugs on their own. He used the anti-malarial drug chloroquin as an example because several clinical trials are evaluating it. “I think so much is out there on social media and in medical letters and reports that are not reviewed that people are going to start using it anyhow. Hopefully a program will make it accessible at the same time that it is being studied.”

Misinformation propagates about more commonly used drugs too. Consider ibuprofen.

Dr. Fauci and others say there isn’t definitive data on the value or danger of ibuprofen, yet it made headlines despite the uncertainty. “I suspect there was discussion off-the-cuff that turned into letters that turned into social media and there is no idea where the information comes from,” he said. Dr. Fauci suspects that people were thinking about the link between influenza and taking aspirin causing the neurological Reye’s syndrome in kids, and someone somehow made the leap to NSAIDs like ibuprofen. “To bring down temperature, use Tylenol,” he advises until firm data point one way or the other.

A possible role of ACE inhibitors is especially confusing. These widely-used hypertension drugs block receptors on lung cells that are similar to the receptors where SARS-CoV-2 binds and enters. Do they help, serving as decoys for the virus? Dr. Fauci said  that it could be just the opposite, pointing to data from Italy. There, he noted, 99% of people who died from the virus had an underlying condition, and 75% of them had hypertension.

“Putting the dots together,” Dr. Fauci said, given the high quality of health care in Italy, “why should someone who has hypertension well controlled have a much greater chance of dying than someone with any other type of underlying condition?” He ventures an hypothesis: perhaps ACE inhibitors boost the number of receptors for the virus. Ongoing natural history studies from Italy will help to figure this out, he added. Meanwhile, people with hypertension should ask their cardiologists for advice.

Perusing ClinicalTrials.gov

For a snapshot of efforts to find pre-existing approaches for COVID-19, I went through all 100+ entries and grouped the treatments. Most are festooned with a blue rectangle around the word “NEW.” The proposals were obviously filed quickly, because most of them haven’t filled in the field for rationale. So I’ve guessed on the logic for a few.

I’ve roughly organized the entries by technology: Chinese herbs, recombinant DNA, monoclonal antibodies, nucleotide/side inhibitors, immune modulators, and several interesting others.

CHINESE HERBS

Huaier granule is an elixir from a mushroom, Trametes robiniophila murr, that grows on hardwood tree trunks. It purportedly stops cancer cells and blood vessel lining cells from dividing, and has been part of Chinese medicine for 1600 years. The clinical trial, set to end in September, has enrolled 550 people diagnosed with mild COVID-19 and otherwise healthy. They’ll take a granular preparation by mouth 3 times a day for 2 weeks. The trial is randomized and the researchers will assess mortality.

Tetrandrine is an alkaloid isolated from the root of Stephania tetrandra, a vine that grows in China and Taiwan. It treats silicosis, autoimmune disorders, inflammatory lung diseases, cardiovascular diseases, hypertension, and cancer. For COVID-19, tetrandrine decreases proliferation of fibroblasts, which might alleviate or slow lung damage (fibrosis). It’s given in tablets.

RECOMBINANT DNA

The first modern biotechnology, recombinant DNA isolates and mass-produces the gene encoding a human protein in single cells growing in culture, such as bacterial cells or white blood cells. The first recombinant drug was human insulin. Herbert Boyer and Stanley Cohen pioneered the technology in 1973, and today it is the source of several dozen drugs.

Recombinant interferon is a candidate in several clinical trials for COVID-19. It is a type of immune system biochemical called a cytokine that takes part in cell-to-cell signaling. Interferon puts the brakes on other coronaviruses growing in cell culture.

Another recombinant DNA strategy was to supply copies of the receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (rhACE2), but a ClinicalTrials.gov listing was taken down a few days ago. So stay tuned.

MONOCLONAL ANTIBODIES

The generic name for a drug derived using monoclonal antibody technology ends in “mab.”

The blue circles are viruses infecting the first US case of COVID-19. (CDC)

A “MAb” is a single antibody type that targets a specific molecule on a pathogen or cancer cell’s surface, possibly shuttling in a toxin to kill it. MAb technology debuted in 1975, invented by Georges J.F. Köhler and César Milstein. A few existing MAb-base drugs are being tried against the novel coronavirus:

  • Actemra (tocilizumab) dampens the immune response in people with rheumatoid arthritis. Will it help to quell the out-of-control outpouring of immune system biochemicals, called a “cytokine storm,” that ends most battles against COVID-19?
  • Soliris (Eculizumab) controls the immune response in two rare conditions. It lowers outpouring of complement, another class of immune system biochemical that promotes inflammation.
  • Bevacizumab is a cancer drug that inhibits blood vessel extension (an angiogenesis inhibitor). It’s being tested to see if it has an effect on shortness of breath (dyspnea), severe pneumonia, and pulmonary lesions in COVID-19.

ANTIVIRALS

A drug that ends in “vir” is a nucleotide or nucleoside analog, which means that it mimics a DNA or RNA “letter” and interferes with viral replication. (A nucleotide is a base, sugar, and phosphate; a nucleoside is just a base and a sugar.) A few existing antivirals, some on the market for other indications, one in development, have emerged as COVID-19 candidates:

  • Lopinavir/Ritonavir treat HIV infection. But a study from China published in yesterday’s New England Journal of Medicine that treated 99 patients with 100 controls found “no benefit.”
  • Remdesivir treats Ebola and Marburg hemorrhagic fevers.
  • Favipiravir, aka Avigan and T-705, has been in development at Fujifilm Toyama Chemical in Japan since 2014 to treat several RNA viruses, including influenza. Tested on 340 COVID-19 non-severe patients, half receiving the drug and half not, favipiravir shortened the time for viral clearance from 11 days to 4, and improved lung function in 91% of participants compared to 62% not given the drug.

STEM CELLS

Several clinical trials are testing mesenchymal stem cells, which are multi-potential and multi-purpose. They usually come from bone marrow, but one trial is getting them from dental pulp and two others from umbilical cord blood. The stem cells are being sent in to coronavirus-ravaged lungs to try to heal damage.

IMMUNOMODULATORS

The role of the immune defense in COVID-19 is a complex, ever-changing matter of balance. Immunosuppressed individuals are at elevated risk of infection, yet people who die from it often undergo cytokine storms, succumbing to an overzealous immune response that can rapidly lead to sepsis.

Existing drugs that alter immune function in clinical trials include the multiple sclerosis drug  Fingolimod  to tackle COVID-19 pneumonia and PD-1 blockers used to treat cancer to treat cytokine storms.

TRADITIONAL INFECTION TREATMENTS

Corticosteroids (methylprednisolone in particular) are being tested to treat COVID-19 pneumonia, as well as vitamin C infusions to quell inflammation and cytokine storms, which it has done in severe influenza. One trial is looking at the tuberculosis drug carrimycin and several at chloroquin.

DRUG COMBOS

One clinical trial is comparing four drugs:

  • Bromhexine hydrochloride, the main ingredient in Robitussin
  • Arbidol, an influenza drug
  • Recombinant human interferon in a nasal spray
  • Favipiravir tablets

Another clinical trial, in Thailand, is testing “various combinations of” two anti-virals, the malaria treatment chloroquin, and a protease inhibitor.

INTERESTING OTHERS

Viagra (sildenafil) is being tested on 10 people of both sexes for likelihood of remission or progression. The drug’s ability to dilate blood vessels may help fight lung inflammation in COVID-19.

Thalidomide is famous for stunting limbs in children of women who took it during pregnancy in the 1960s, to combat morning sickness. It has been redeemed as a treatment for multiple myeloma and interstitial pulmonary fibrosis, as an antidote for poisoning with the herbicide paraquat, and in treating the 2009 H1N1 influenza.

Thalidomide has anti-inflammatory, anti-fibrotic, anti-angiogenesis, and immune regulation effects, and in COVID-19, may help to control lung inflammation and slow or halt lung damage. In the new clinical trials, researchers are tracking fever, respiratory rate, oxygen saturation, alleviation of cough, and duration of illness.

“Washed” fecal transplant is being tested to treat diarrhea from antibiotics used to treat secondary bacterial infections.

Nitric oxide gas is in a clinical trial on 240 people with COVID-19. In the SARS and MERS epidemics, it shortened time on ventilators.

And finally, antibodies from survivors might provide protection. Next I’ll tackle vaccines.

 

Discussion
  1. Very concluding article, thanks for the info, some of these drugs will give good results and probably the antibodies from survivors are a breakthrough. Viagra would also work on specific cases as to my experience with flu I had positive results using Kamagra a generic version of Viagra I haven’t had coronavirus but as they are a bit similar to flu it might help.

    Reference:
    https://www.kamagra-now.org/kamagra-kamagra-jelly/Kamagra-Now-UK-generic-viagra

  2. Good afternoon, may the scientific community could use or probe the sildenafil drug for the corona virus treatment, originally sildenafil made it for troubles in heart and lung or circulatory system

  3. Dr. Ries, this is really important and I suggest that you submit it to a major medical journal right away! I know of Eric Block’s work on garlic, thought of it immediately when I read your post. Please publish this in a medical journal! Try JAMA, Lancet, NEJM Perspective. I too have wondered about the regional differences.

  4. Is it just me, or does it seem like quite a few drugs that are used to treat different autoimmune problems, are listed here. I could’ve swore that I’ve seen others listed too, and for the same reason.

  5. Okay, thank you. I have submitted it to The Lancet Infectious Diseases.
    I hope the process of evaluation won’t take ages…and that I took the right steps in the submission.

  6. There is such a wide range in the per capita death rate for COVID-19 across nations e.g. Germany versus Italy or Spain. It’s very puzzling. Could it be some genetic flaw in the host genome? Those with the flaw are more likely to be hospitalized and die, and those without it more likely to be mild or asymptomatic? My own hypothesis is that the wide death rate range is related to the presence of archaic human DNA in our genomes, meaning Neanderthal DNA. I hope there are some computational biologists somewhere comparing on a large scale the genome sequences of the asymptomatic (or mild) patients versus the ones that died within a given nation. The results of such a study might shed light on the development of therapeutics or a vaccine.

    A virus like the coronavirus is simply an agent of evolution. It challenges our genomes. Mercilessly, the fittest genomes survive, the flawed perish. If we inherited some flawed immune system regulatory sequences from Neanderthals, then those with the flaw may be the ones who are overwhelming our healthcare systems, especially if they are also elderly or sick to begin with. So, people who say COVID-19 is nothing more than the flu, well, if they don’t carry the flaw, then I guess they’re right.

    Coincidentally, I read somewhere that the people of Northern Italy have the highest percentage of Neanderthal DNA in their genomes.

  7. For the life of me I cannot understand why they would choose those very obscure Chinese Herbs. Why not focus on more traditional plants like elderberry, astragalus, rhodiola and even the cordyceps mushrooms? The answer lies in plant medicines, boosting our immune systems through diet and nutrition and good hygiene…

  8. Well, Henry, all I can say is oh crap. I agree and have the same thoughts, a resistance gene of some sort. But I’d never thought of the Neanderthal connection – I have the highest percentage of Neanderthal ancestors (the metric is ancestors, not specific sequences) it is possible to have and not look like Fred or Wilma Flintstone. I hope you are not right!! I did a webinar with the main Italian doctor, and he said their patient zero, who’d had contact with someone who’d visited Wuhan, was very sociable and partied for weeks while infected and not knowing it because he felt well. Also, multiple generations living together helped spike the mortality rate. But I like your Neanderthal hypothesis. Let me know if I can use your name in my next post. Thank you!

  9. Daniel, should I delete your post on this blog? The journals usually have rules that a submission can’t have been published anywhere at all. Let me know. Papers are being evaluated with incredible speed these days. I hope they take it!

  10. Didn’t see that last week but so many new entries — that is an HIV/AIDS drug in phase 2/3 clinical trials and is indeed being tested and given on a compassionate use basis. Thanks for adding it!

  11. Those Neanderthals in Northern Italy and elsewhere must have been quite resilient to all sorts of bugs in the old days with no docs around eventually passing their DNA on through the ages to the folks living today…don’t you think?

    If you trace the genetic heritage back you’d find only the ones who were alive and could procreate passed their DNA on. Furthermore, if the people of Northern Italy are so immunosuppressed why have they not died earlier from other illnesses? Are there heaps of Chinese people and New Yorkers also descendants of the Neanderthals? I’m sure there will also be a bed for you and not only for the elderly.

  12. They should try combining thalidomide and methrotraxate together followed by folic acid.to subside the side affects might be good cure for Corona virus.doesnt hurt to try.

  13. Very unlikely. Anti-hypertensives, however, are highly suspect, as they induce ACE2, the receptor used by CoVs 3-5 fold. Probably, virtually all hypertensives in Italy have BP controlled by these drugs. Per Tony Fauci, all hypertensives should talk to their cardiologist!

  14. Luteolin and silvestrol are natural products that have activity against CoVs and low toxicity. Luteolin is widely available as a supplement. No one will do a trial because not patentable… but in a pinch, i guess I’d try it…

  15. Thanks for posting. Dr. Fauci said in a webinar that they could be dangerous, causing upregulation of the receptors. I truly have no idea. I just advise people, when I’m asked, to ask their cardiologists.

  16. Exactly. I talked to my pulmonologist and mentioned Fauci’s comment she said the angiotensin receptor drugs showed benefit in the previous epidemic and is in a clinical trial. More receptors does not equate to more infectivity. For instance, in HIV, more receptors reduces infectivity. Wait for evidence and don’t discontinue the meds without physician oversight.

  17. Have you heard about liquorice root extract to be researched for covid-19 treatment? There are plenty of works for SARS treatment discontinued after the 2012 outbreak died down. However, there are several virulogists (PhDs from Germany, Austria, Thailand, you can google it) saying that glycyrrhizic acid practically wiped out SARS from cells of infected monkeys. Apparently, people drinking liquorice brew resisted infection even though living with infected families during the epidemic.
    Good summary by the way. Found it translated to Polish already. Regards

  18. I have Gilbert’s syndrome and its linked to UGTA1 gene and I was told by a doctor its very common of descendants of the Mediterranean area…could this the common denominator?

  19. Hi Ricky,

    Why don’t people try to PREVENT Covid-19 virus infection rather than struggling to find solutions to help the victims with full-blown symptoms? I have more than 30 years experience of gargling aspirin (300 mg x 2 tablets) solution 2/3 times per day and it worked very well to prevent flu and other respiratory sickness infected by viruses. One of the relevant medical publications “Antiviral activity of aspirin against RNA viruses of the respiratory tract-an in vitro study” isirv 2017 Jan 11 (1):85-92 by Bernadette Glatthaar-Saalmuller & others supported the aspirin effect. The only difference is my method is “non-invasive” GARGLING rather than consuming aspirin solution which may have many bad side effects. I have more than a dozen publications on this subject which I will like to share.

  20. That’s a great idea, Jeff, thanks for posting. Glad it has worked for you. But, it may be difficult to prevent a pathogen that is novel. Can you please post or send me one of your papers that is a random controlled clinical trial? Thanks! Stay well.

  21. Has there been any consideration for drugs like hizentra that are used for weekend auto immune systems. They would not be able to be mass- produced quickly enough but they could save lives in the critical cases.

  22. I have read the science about this and agree that Luteolin shoud be trialed as it supresses Interleukin 6 (IL-6) and elevated levels of IL-6 is detected in patients with COVID-19 that require intubation and invasive wentilation.
    I too will be taking Luteolin if I become ill along with curcumin which clocks the furin pathway and reduces IL-6 and also quercetin again another furin blocker furin being the know pathway that the coronavirus that causes COVID-19 uses to gain entry to the cell.

  23. Remember that licorice root increases BP , a works like the mineralcoricoid , aldosterone which chronically lowers in stressful times . It is produced in the adrenal cortex.

    Meditation and of course very good nutrition will help among other key strategies .

  24. We don’t yet know what makes one person get sick and another not, so it is very difficult to deduce possible treatments. I understand the frustration, fear, and desperation, but as Dr. Fauci says, we do need those randomized controlled clinical trials to glean useful information from potential treatments.

  25. The central problem is that the immune response is too robust, ending in a cytokine storm. Boosting immunity once someone is already infected is the opposite of what you’d want to do. The immune response is highly complex and interactive, so taking a product that “boosts immunity” doesn’t tell me enough to evaluate whether what it does, precisely, makes any sense.

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