COVID19 update: a brief look at three possible drugs; Bonus: a brief look at pre-existing conditions in Italy

Yesterday, the Israeli Ministry of Health fast-tracked approval for no fewer than eight experimental therapies for use.

Normally, Phase I, II, and III clinical trials on a drug take a lot of time and effort. But if you are merely repurposing an existing drug for another disease, you can short-circuit a lot of that since you already know safe dosage range and side effects.

These are the three that jumped out at me.

(1) Remdesivir was originally developed by Gilead Science as an anti-ebola drug. It worked against that virus in vitro (i.e. in the lab “test tube”) but not in vivo (i.e. in actual patients). It also worked in vitro against MERS and against the original SARS, so trying it against COVID-19 was worth at least a try.

Which is what was tried as a desperation roll of the dice on an early patient patient in Washington state, with apparently impressive success . Since then, increasing confirmation has been seeping in. Controlled clinical trials are in progress, with results expected next month.

Remdesivir is a so-called “nucleotide analog”. In plain English, it pretends to be a nucleic acid (i.e., a letter in the genetic code), but when the “imposter” is being incorporated in a piece of RNA instead of the real nucleotide, it has no place to attach the next one, and copying stops. Thus, the virus cannot reproduce.

(2) Favipiravir (sold in Japan under the brand name AVIGAN by Toyama Chemicals, a subsidiary of FUJIfilm). This was developed as a broad-spectrum anti-RNA-viral drug. It is an RdRA (RNA-dependent RNA polymerase) inhibitor, i.e., it interferes with the enzyme responsible for copying the viral RNA.

Japanese doctors apparently are using the drug, and China is running clinical trials.

(3) Chloroquine (a 70-year old generic antimalarial), and its close relative hydroxychloroquine, are at first sight the odd duck among the three. It’s obvious why the two above drugs could work, and it appears that they do. But why do we hear a lot about chloroquine these days? Last time I checked, malaria was not even a viral disease?

There is a fairly lucid explanation here of what is going on:

Zn2+ and RdRA discussion about midway through the video

Like for AVIGAN, it’s again about RdRA. Turns out Zn2+ ions latch onto the enzyme and act as an inhibitor. [UPDATE: reference here.] The trouble is getting zinc into the cell. Now in a completely unrelated research project on metallophores as anticancer drugs, it was found that chloroquine is a very good zinc ionophore:

I doubt it is the most effective of the three. On the other hand, chloroquine and its less toxic close relative hydroxychloroquine have been used extensively for decades in areas where malaria is endemic, both for treatment and prophylaxis, so their safety profile and side effects are very well understood. Besides they are very cheap as well. (Report of stocks running out in Western countries: well, these aren’t drugs you routinely stockpile unless you are dealing with malaria all the time… although they have been in some use for lupus and rheumatoid arthritis.) So it apparently has been part of treatment regimes in both Korea (hydroxchloroquine) and China, and it appears to at least some extent in Italy.

Speaking of Italy: yesterday the independent media circulated a report that only 1% of case fatalities in Italy were people without pre-existing conditions. Meanwhile, Bloomberg has picked up the story, and from there I located the original official report (in Italian) on the website of the Italian public health office. This graph is from the Bloomberg report:

and this table (screenshot) comes from the original report

Table 1 from the Italian March 17 report:pre-existing conditions in patients deceased from coronavirus

The Italian names mean, in order, coronary disease, atrial fibrillation, stroke, hypertension, diabetes, dementia, COPD (chronic obstructive pulmonary disease), active cancer in the past 5 years, chronic liver disease, and chronic kidney insufficiency. Needless to say, the statistical risk for ALL of these increases with age, so as patients get older, the percentage of them without any comorbidities will get smaller and smaller.

Stay well, stay safe, and above all, stay calm and rational.

UPDATE: Teva Pharmaceuticals donates 6 million doses of hydroxychloroquine.
And a commenter on Facebook drew my attention to this French clinical trial that just got published (open access PDF here). Especially in combination with azithromycin (presumably for secondary infection prophylaxis), results look very promising.

6 thoughts on “COVID19 update: a brief look at three possible drugs; Bonus: a brief look at pre-existing conditions in Italy

  1. CURES ARE UNDERWAY:  COVID19 update: a brief look at three possible drugs; Bonus: a brief look at p… – The usa report says:

    […] CURES ARE UNDERWAY:  COVID19 update: a brief look at three possible drugs; Bonus: a brief look at pre-existing conditions… […]

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