Hard News by Russell Brown

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Hard News: Has Iran found an effective Covid-19 treatment?

25 Responses

  • Hilary Stace,

    There seems to be some interesting work happening in Cuba too.

    Wgtn • Since Jun 2008 • 3213 posts Report Reply

  • Bart Janssen,

    Interesting results.
    TLDR entirely reasonable that these drugs work
    also science funding is good

    It's highly likely any effective treatment protocol will involve a nucleotide analog for reasons noted in the main post.
    It's worth noting treatments for viral diseases are uncommon because the immune system handles viruses very very well.
    That means most treatment attempts are likely to come after the immune system has done it's job.
    For viral diseases where for one reason or another you can't wait for the immune system we rely on vaccines - again essentially relying in the immune system.

    Where neither of those options are available the treatments focus on bits of biology that are different between the virus and the host - that usually means targeting the enzymes that replicate the viral genome or process the viral protein. Both of which use mechanisms that are not present in humans and hence are reasonable targets for drugs (since they won't kill the host).

    One of the best targets is the genome replication enzymes because they do something that is very uncommon in humans - convert RNA into DNA - this means the viral enzyme that does that can be blocked without harming the host. Nucletotide analogs are king amongst these. Cold sore creams, real ones not the fake homeopathic ones, contain acyclovir which is a nucleotide analog that kills herpes virus.

    The problem is most of these nucleotide analogs are cheap to make and many of them cure the disease so no long term treatment is required. That's why big pharma don't bother with them - because the profit is piss poor.

    This is another reason why you should harass your local MP into funding government funded research - because that's the money that funds people like Siouxsie Wiles.

    Auckland • Since Nov 2006 • 4458 posts Report Reply

  • Moz,

    That sounds like excellent news, especially the manufacturing ability we already have and thus the price... assuming the trials work out.

    One can only imagine how this will play out politically.

    Sydney, West Island • Since Nov 2006 • 1229 posts Report Reply

  • Ian Dalziel,

    Interesting to note there is evidence of a blood clotting problems with Covid-19, so anything that was aimed at a Haemorrhagic virus like Ebola might not work so well…
    I still can’t get my head around what the endgame of a virus is – seemingly it is just ‘code’ that hijacks an actual living cell to make duplicates of itself, in a parasitic way, but overwhelming the host seems counterproductive unless it has a purely disruptive intent – kind of like ‘Stuxnet’
    Bart can probably clear this up for me – he must have looked into Mosaic and other planet viruses.

    Nice to hear you on The Panel Russell, presenting some sanity to that strange little sonic opinion bubble…

    <aside> I heard Mai Chen the other day – and I’d always thought she was waay smarter than Kellyanne Conway, but she trotted out that "This is Covid-19, not Covid 1" line – sigh…
    ( I am always stunned by the stuff Wallace Chapman has no idea about as well) </aside>

    Christchurch • Since Dec 2006 • 7939 posts Report Reply

  • Ian Dalziel, in reply to Moz,

    assuming the trials work out.

    Trump will leading the trials on 'injecting disinfectant' and 'shining UV light into his dark interior' - I wait for those results with bated breath...

    Christchurch • Since Dec 2006 • 7939 posts Report Reply

  • linger, in reply to Ian Dalziel,

    overwhelming the host seems counterproductive

    unless it can find other hosts easily in the time that takes to happen – as with this virus.
    Individual viruses are parasitic on individual cells; a virus doesn’t have any vested interest in the survival of any host organism as a whole, as long as it continues to be replicated in other cells, in other organisms.

    Additionally, what "overwhelms the host" is not the virus per se but rather the body's immune response to the virus, which differs from individual to individual. A fatal virus eventually selects for a population of host organisms that are better able to spread it without being overwhelmed.

    Tokyo • Since Apr 2007 • 1922 posts Report Reply

  • Pietro C, in reply to Bart Janssen,

    One of the best targets is the genome replication enzymes because they do something that is very uncommon in humans - convert RNA into DNA

    The SARS-CoV-2 genome is not converted to DNA during viral replication. It's RNA to RNA.

    ... this means the viral enzyme that does that can be blocked without harming the host. Nucletotide analogs are king amongst these.

    These drugs are analogues of nucleosides that are also extensively used by our cells, so they clearly don't just inhibit anything that happens to bind nucleosides. It's not immediately obvious why some of them inhibit viral enzymes and not enzymes our cells use.

    This recent article reviews a few different nucleoside inhibitors with respect to SARS-CoV-2, although doesn't mention the ones in the article above. It's technical.

    Since Apr 2020 • 1 posts Report Reply

  • dr. notakiwi hall,

    Is anyone able to access the actual results of the trial and have they been peer reviewed? Two pieces of food for thought - 1. the validity of the hypothesis of testing and repurposing Hep C drugs into covid 19 may be supported in overlap of the drug target in SARS-CoV-2 (and perhaps some biologists out there could do an alignment of the variation between those targets in hepatitis vs SARS-CoV-2 to help gauge this) but 2. the rubber would truly have to meet the road in the conduct and results of the trial to determine just how promising this research is, irrespective of the validity of the hypothesis.

    Depending upon their clinical endpoints, N = 30 test / 30 placebo may be insufficiently powered to detect differences in the trial outcomes. If for example the key endpoint is death, and the case fatality rate in Iran is 3.5% based upon their most updated cases/deaths rate available online, then it would certainly be challenging to detect significant differences in Ns of 30 (e.g., is 1 death in the placebo group and none in the control group meaningful or interpretable? is that what the actual data are?) and the study is unlikely powered to detect a difference in terms of basic statistics in terms of fatality...would be useful to see what they actually measured and the breakdown of their patients in the trial arms before concluding how promising this research may be.

    Not trying to be a downer here, it could be that the study is indeed promising depending upon what was measured, but it's unlikely a slam dunk by any measure...In God We Trust, all others must bring data.

    usa • Since Apr 2020 • 2 posts Report Reply

  • Russell Brown, in reply to dr. notakiwi hall,

    Not trying to be a downer here, it could be that the study is indeed promising depending upon what was measured, but it’s unlikely a slam dunk by any measure…In God We Trust, all others must bring data.

    Fair enough. Would you agree that it suggests that wider trialling is warranted? That's really what I'm saying here. It seemed to me that a plausible treatment was missing further investigation for other-than-medical reasons.

    Auckland • Since Nov 2006 • 22807 posts Report Reply

  • Moz, in reply to Russell Brown,

    wider trialling is warranted

    I think so, especially given that the Iranians seem to have decided the same. Obviously their ability to conduct trials outside Iran is limited by the war, but that's no reason we shouldn't carry out our own trials.

    Sydney, West Island • Since Nov 2006 • 1229 posts Report Reply

  • dr. notakiwi hall, in reply to Russell Brown,

    Evaluating the data, the purpose and quality of the trial design, and the outcomes are critical to the decision of whether this warrants further testing. Without seeing that, you really can not conclude whether this warrants further investigation or is simply a pipe dream. Many drug programs are terminated after early small trials because they are unsafe, as as example.

    In general, early stage trials are designed to evaluate and establish safety. Given that these are marketed drugs, some of the safety risks may already be discharged - however there’s no guarantee, as news is reporting elsewhere, the same could have been said for hydroxychloroquine which we are now learning may be causing toxicity issues in sick covid-19 patients.

    If the study was appropriately designed to evaluate safety and tolerability (and the results suggest as much), sure it could warrant further study.

    However, we’d need to critically evaluate the study design to make that determination. Given that these drugs could adversely interact, the opposite could also be true: they could lead to significant toxicity and that could potentially be sufficiently concluded...again, based on the study design which we haven’t seen (and what I’m advocating is necessary to have a critical discussion before concluding more studies should be done).

    Another potential thought experiment that would be pretty damning to proceeding: if the trial were designed specifically to enroll patients over >80 where we are seeing fatality rates in the 15% range, and there were no differences in the treatment and placebo group, that might also be enough data to stop or at least give you pause that you might not be on the right track.

    Any which way you slice it, drug development is hard. It’s never as simple as biology or a hypothesis - the study design and flawless execution are required to evaluate what the next step could or should be. Sometimes that data-driven decision is to stop.

    TLDR; be careful on speculating whether there should be more research or additional trials before the design and results are peer-reviewed and published: the results may be untoward even if it seemed like a good idea.

    usa • Since Apr 2020 • 2 posts Report Reply

  • Thomas Lumley,

    I'd actually be less surprised if it was the sofosbuvir having an effect. Like remdesivir, it's a nucleotide analog (a fake RNA base), which you could easily imagine confusing RNA polymerases from a different virus. Daclatasvir, on the other hand, targets a specific site on Hep C's polymerase and since resistance develops easily, it must be fairly fussy about the details of that site.

    Auckland • Since Feb 2013 • 47 posts Report Reply

  • Bart Janssen, in reply to Ian Dalziel,

    I still can’t get my head around what the endgame of a virus is –

    Hi Ian, you can't anthropomorphize this, it's just a virus. It evolved in bats and exists now because it is well adapted to the bat biology. Bats have a very different immune system that allows them to tolerate many more infections with little harm.

    In humans this virus just replicates the same as it did in bats. It doesn't have an endgame or aim. It could wipe out all humans and then die off itself and it wouldn't "know". And it's ancestor would still exist in bats.

    Auckland • Since Nov 2006 • 4458 posts Report Reply

  • Bart Janssen, in reply to Pietro C,

    The SARS-CoV-2 genome is not converted to DNA during viral replication. It’s RNA to RNA.

    Meep right you are. It does still mean the virus uses an RNA template to make the RNA strand which is the unusual step that doesn't really exist in humans.

    It’s not immediately obvious why some of them inhibit viral enzymes and not enzymes our cells use.

    The reason is the enzyme that incorporates them is different from any of the host enzymes - that difference is enough to develop an analog that affects one enzyme but not the other. And yes you can make such analogs that are immensely toxic to humans.

    Auckland • Since Nov 2006 • 4458 posts Report Reply

  • George Henderson,

    These drugs are very specific for HCV and don't disrupt host processes to any meaningful extent. But different drug combos are specific for genotype 1 and genotype 3.
    How could this work for a completely different virus?
    Hep C drugs need to reduce viral load to "undetectable" because stealth features of HCV interaction with immune system mean it is a persistent infection which immune cells have little chance of clearing.
    Drugs only need to reduce COVID-19 by a decent amount - the immune system is always working on it and can clear it eventually, the drug just needs to give meaningful help (enough so the immune system needn't over-react would be cool).
    I have other questions about pharmakokinetics - it's easy to get drugs into the liver, because that's where they're detoxified, but the lungs?

    Note that rational drug design software has twice pinpointed the herbal andrographis panniculata, a traditional treatment for viral infections and cough.
    https://www.preprints.org/manuscript/202002.0047/v1
    https://www.sciencedirect.com/science/article/pii/S2211383520302999

    Auckland • Since Apr 2020 • 2 posts Report Reply

  • Russell Brown,

    I missed this at the time I wrote the post, but there’s a team at Columbia university working to develop compounds based on sofosbuvir – with Chinese funding.

    And a modelling study from Egypt suggesting “the effectiveness of Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir as potent drugs against SARS-CoV-2 since they tightly bind to its RdRp.”

    It does seem this is a better avenue than throwing all those resources at hydroxychloroquine trials.

    Auckland • Since Nov 2006 • 22807 posts Report Reply

  • Sacha, in reply to George Henderson,

    a traditional treatment for viral infections and cough

    Are there others that might lower the load enough?

    Ak • Since May 2008 • 19705 posts Report Reply

  • Bart Janssen, in reply to Russell Brown,

    RdRp

    FYI
    RNA dependent RNA polymerase =RdRp
    It's the enzyme that uses the viral RNA template to make viral RNA and is pretty much unique to viruses. There are enzymes that can do this in animals but they are very tightly regulated and quite different from the viral enzymes. that's what makes them such a good target for drug design.

    Just a comment about drug design - it's part science part craft. There are computational methods for guessing what might work if you know the 3D structure. And there are clever screening methods that can find fragments of compounds that you can stick together to get better binding. But there is a huge amount of trial and error involved as well. And when you have something that works in your screen you then need to figure out if it works in cells and mice and humans.

    Auckland • Since Nov 2006 • 4458 posts Report Reply

  • George Henderson, in reply to Sacha,

    Elderberry has some ability to bind ACE2 and another coronavirus site. It looks good so far, is effective for flu of course, but like most of these things only studied in small trials with self-reported outcomes.
    The best evidence I've found is for probiotics, it takes a few months but they can double or triple flu vaccine seroprotection rates in healthy elderly people, and probably reduce the incidence of seasonal colds and flus.

    Auckland • Since Apr 2020 • 2 posts Report Reply

  • linger, in reply to George Henderson,

    I am now picturing a virus covered in little elderberries, though I'm sure that's not how it's supposed to work. The scale is massively wrong for a start...

    Tokyo • Since Apr 2007 • 1922 posts Report Reply

  • John Farrell, in reply to George Henderson,

    Small trials with self reported outcomes? Not interested.

    Dunedin • Since Nov 2006 • 496 posts Report Reply

  • Joe Wylie,

    Robitussin make me feel so fine
    Robitussin and Elderberry wine
    Hey Grandma
    Hey Grandma...

    Moby Grape, Hey Grandma, 1967.


    Robitussin and similar cough remedies offered a cheap recreational altered state experience if you could drink enough of the stuff and keep it down. It was probably mostly due to a dodgy ingredient like pseudoephedrine, so the elderberry wine wouldn't have hurt.

    flat earth • Since Jan 2007 • 4592 posts Report Reply

  • Alfie, in reply to linger,

    I am now picturing a virus covered in little elderberries, though I’m sure that’s not how it’s supposed to work. The scale is massively wrong for a start…

    Nah... we've all seen the graphics and the coronavirus has little stalks sticking out, like upsidedown plungers or badly drawn daleks. Elderberries! Pfft!

    Dunedin • Since May 2014 • 1421 posts Report Reply

  • linger, in reply to Alfie,

    So that’s how it works: the virus spines burst the elderberries, and as a result the virus sites are jammed.

    Tokyo • Since Apr 2007 • 1922 posts Report Reply

  • Alfie, in reply to linger,

    the virus spines burst the elderberries...

    Aha. That explains why the virus is almost always coloured blue in infographics. It's the elderberry juice.

    Dunedin • Since May 2014 • 1421 posts Report Reply

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