Post #562: Three rays of light on finding effective anti-viral drugs

Posted on March 19, 2020

An new antiviral drug proven effective in humans

My wife passed this on to me.  As it is not from a US newspaper, I thought it was worth sharing.

The Chinese government has reported identifying antiviral drug that is “clearly effective” for coronavirus (COVID 19).  Link is to the Guardian article is here.  This is billed as a clinical trial, so that seems like the real deal (i.e., randomized controlled clinical trial).

But there is one big caveat.  As with Tamiflu and many other antivirals for acute illness, the drug has to be given early in the course of the disease to be effective.

Let me quote the relevant parts, from the Guardian article, emphasis mine:

Patients who were given the medicine in Shenzhen turned negative for the virus after a median of four days after becoming positive, compared with a median of 11 days for those who were not treated with the drug, public broadcaster NHK said.

In addition, X-rays confirmed improvements in lung condition in about 91% of the patients who were treated with favipiravir, compared to 62% or those without the drug.

Doctors in Japan are using the same drug in clinical studies on coronavirus patients with mild to moderate symptoms, hoping it will prevent the virus from multiplying in patients.

But a Japanese health ministry source suggested the drug was not as effective in people with more severe symptoms. “We’ve given Avigan to 70 to 80 people, but it doesn’t seem to work that well when the virus has already multiplied,” the source told the Mainichi Shimbun.

The same limitations had been identified in studies involving coronavirus patients using a combination of the HIV antiretrovirals lopinavir and ritonavir, the source added.

As clinical trials go, the results for that population — those dosed early — are about as unambiguous as it gets.  No folk medicine there (Post #552).

An old drug that works in vitro (in a test tube).  Not yet proven in humans, but it sure looks like it ought to work.

You can read coverage here.  This drug (hydroxychloroquine) was known to be effective in vitro (in a test tube) against a prior novel coronavirus, SARS.  And now there’s been an in vitro test and it also appears to work against COVID-19.

But this hasn’t yet gone through a clinical trial, so they don’t know if it will actually work in SARS patients.  But it’s a start.  Here’s a link to a report of that research, in Nature.

Somebody must think it’ll work, because Bayer already donated a fairly large volume of it to the US. (That article on Bayer also lists several other drugs that are being considered for use as anti-virals against COVID 19.

The huge advantage here is that, because it’s already a recognized drug in the US, docs can just start using it off-label.  Apparently it has an excellent safety record.  (A precursor drug, chloroquine, by contrast, had issues with poisoning people.)  In theory, the FDA can take its own sweet time about approving it for coronavirus.  It won’t matter.  If physicians see that it appears to be effective, they’ll just use it.

FWIW, from the Nature link above:  The Chinese have added it to their list of drugs approved for use in treating COVID 19.  It sounds like the Chinese approved it because it appears to work in humans, but that’s not clear from the research writeup.  They appear to have seven clinical trials already registered.  The drug also has anti-inflammatory properties (it’s used to treat Lupus, for example), and that will likely be beneficial, to some degree, for limiting the “cytokine storm” (out-of-control immune response) that appears to inflict a lot of damage on patients with COVID 19.

Reading that Nature report, I’d say that looks promising.  In-vitro studies test two things.  First, what concentration of the drug will kill you (the “cytotoxic level”).  Typically, they’ll report the level at which the drug kills half the tissue cells in the test tube.  Second, what concentration will kill the virus, again, typically reporting the concentration required to kill half the virus.

The bigger the first number, and the smaller the second number, the more likely the drug is to be useful.  I.e., if you can actually get it delivered to human tissues in adequate concentration, it’ll kill the virus and not kill the patient.  I’m not sure what the units of measure are, but the toxic dose appears to be about 100 times the dose that kills half the virus.  That’s provides plenty of wiggle room for dosing.

Moreover, one of the big questions for new drugs has already been answered for this one:  Can it get to where it’s needed in the body.  In this case, into the patient’s lung tissue.  And apparently this drug is known to concentrate in certain organs at levels that should be effective in suppressing the virus, at perfectly tolerable dosing levels.

To me, it sure sound like that’ll work just fine.

The reported safe dose rate is 6 mg/kg/day (migs-per-kig per day), so the average adult would need … half a gram a day?  And it’s cheap, to boot.

Golly, that’s like “take two aspirin and call me in the morning.”

I sincerely hope this turns out to work in actual, live patients.  The drug was first synthesized just after WWII.

As a footnote, the Bayer article above cites a small-scale trial with what appears to me to be an almost-unambiguous impact.

 "In France, for instance, a professor conducted a small study of the malaria drug in 24 patients with novel coronavirus infections.  Of those who received the medicine, only 25% tested positive for the virus after 6 days, according to en24. Meanwhile, of those who didn't receive it, 90% tested positive after that timeframe. The French government now plans to run larger studies. "

That last sentence is just killing me.  The French have a cheap, readily-available drug that looks effective, and they’re just going to bide their time until all the evidence is in?  This, in a nutshell, is what I fear most about coronavirus vaccine development.  There’s an economic urgency to all of this that I am afraid the medical establishment just doesn’t give full weight to.

Malaria, a final odd footnote.  One Traditional Chinese Medicine (TCM, see Post #552) herb that showed excellent in-vitro anti-coronavirus activity was sweet wormwood (Artemisia Annua).  That was one of just four such TCM herbs, from a study that looked at more than 200 such plants during the 2003-4 SARS outbreak (Sciencedirect).  The oddity is that the active ingredient in wormwood (artemisinin) is now the preferred anti-malarial drug that has largely replaced hydroxychloroquine for treatment of malaria.

Details:  Here’s a reference to a 2005 summary of TCM herbs considered in 2005 for the SARS outbreak (Nature) , along with the research showing in-vitro effectiveness of wormwood extract in killing the SARS coronavirus (Sciencedirect).  And, again similar to hydroxychloroquine, artemisinin has immunosuppressive properties (Hindawi).

I just think it’s odd that they tested 200 TCM herbs, and of the four with significant anti-SARS activity, one was the basis for the modern treatment of malaria, artemisinin.  And the drug it largely displaced for that purpose is …  hydroxychloroquine.  And both are, as a side benefit, immune system modulators.  Makes me wonder if that’s more than just a coincidence.

Weirder still, you have to wonder whether the grand-daddy of malarial treatments — quinine — has significant anti-viral properties.  And, apparently, it does (reference).  And, more generally, the anti-viral activity of many classes of anti-malarial drugs has already been noted, and their use has been suggested in (e.g.) certain viral infections (abstract via PubMed, or full full article, .pdf).

Maybe I’ll add thujone-free wormwood to my flavonoid regimen (Post #552).  Try saying that three times, fast.

A third new drug with at least a case report of effectiveness

The Nature article above mentions yet a third drug, remdesivir, which they say has proven in vitro effectiveness against COVID 19, has (at least) one case report of effectiveness in treatment in the US, and is currently in a Phase III clinical trial (meaning, it has actually already been tested in humans and found to be effective (Phase II), and now they’re just doing things like fine-tuning the dosing regimen and double-checking that it is effective.)