Wednesday, April 8, 2020

Hydroxychloroquine may not be the "magic bullet" it's cracked up to be

We've seen a lot of politically divisive controversy about hydroxychloroquine (HCQ) and its purported effectiveness against the COVID-19 virus.  The arguments in its favor have been based on very small trials, and are hotly disputed.  I must admit, on the face of news reports alone, it looks very promising . . . but when one digs deeper, there are all sorts of potential and actual complications.

Derek Lowe writes the widely-respected and -referenced chemistry blog "In The Pipeline".  We've encountered him in these pages before.  He's written a very thorough and useful analysis of what we know about HCQ, and the potential dangers it represents.  It's a bit technical in parts, but very informative.  Here are a few excerpts.

There are a couple of other things that need to be noted. One is that hydroxychloroquine itself actually lowers the activity of the innate immune system; that’s why people take it for lupus and for rheumatoid arthritis. Many people are saying that perhaps it will work best if taken early in the course of infection, but this effect ... should be kept in mind. Another potentially important point is raised in this preprint – which, it has to be said, is not human data but mouse toxicology. But with that in mind, the authors report what looks like a bad interaction in that species between HCQ and metformin. And by “bad”, I mean about 30% mortality. If this translates at all to humans, it could be bad news, because (as mentioned above) diabetics look like a high-risk group and many patients may well have been taking metformin when they present at the hospital. We need more information on this. An investigational drug combination that showed this effect in mice would not move forward in the normal course of things.

. . .

It’s no wonder that this work has set off so many arguments: statistically, it’s like a funhouse mirror. Here, though, is where some of the folks pinging me on Twitter and sending me emails tend to get more worked up, especially to that point about anecdotal data. I can see where they’re coming from: if you haven’t done this stuff, you can look at a report of people responding to such a treatment and figure that the answer is here – right here, and anyone who doesn’t see it must have some ulterior motives in ignoring what’s in front of their face. But that’s not how it works.

It’s weird and startling, though, if you haven’t had the opportunity to go back through clinical research (and even patient treatment) and seen how many things looked like they worked and really didn’t. It happens again and again. Alzheimer’s drugs, obesity drugs, cardiovascular drugs, osteoporosis drugs: over and over there have been what looked like positive results that evaporated on closer inspection. After you’ve experienced this a few times, you take the lesson to heart that the only way to be sure about these things is to run sufficiently powered controlled trials. No short cuts, no gut feelings – just data.

. . .

My job as a researcher has not to been to raise people’s hopes without data in hand, my job has been to try to produce such data so as to raise hopes with some reason to do so. When I see something to be hopeful about, I’ll say so, and when I think people are getting ahead of what we know, I’ll say that, too. Go back to the first things I wrote about the hydroxychloroquine/azithromycin work: I called it “potentially very interesting” and called for more data to see if it was real. That’s where I still am. Raising hopes just for the sake of raising hopes is not where I am, though, and in fact I find that whole idea to be cruel. We’re going to defeat this virus, this epidemic, by being as hard-nosed as we can be about collecting real data on real-world outcomes as quickly as efficiently as we can, not by talking vaguely about miracle cures and isn’t it something and wouldn’t it be great. You’ll need to go somewhere else for that. Try Dr. Oz, he’s good at that crap. I’ll stick to what I’m good at here.

There's more at the link.

I take Mr. Lowe's point about metformin very seriously.  A very large proportion of the middle-aged and older population in this country (and, I understand, in Europe) are prescribed metformin.  It's pretty much the standard treatment for pre-diabetic patients, and even those who are full-fledged diabetic if their condition is not severe enough to require insulin injections.  If HCQ interacts so poorly with it, it's no wonder that some physicians are seriously questioning the (very limited) investigations so far into its use against COVID-19.  From what Mr. Lowe reports, that could potentially worsen the condition - or even lead to the death - of up to a third of your patients.  Not an optimal outcome . . .

Part of the problem of public perception of the HCQ question is that too many of us expect - even demand - an instant cure from medical science.  We've grown too used to the thought that modern medicine can do anything.  It can't, of course.  As a pastor, I've spent too many hours at the bedsides and with the families of terminally ill patients to be in any doubt about that.  However, since the advent of antibiotics and other so-called "wonder drugs", public expectation has grown out of line with reality.  The coronavirus pandemic is likely to reset that optimistic fallacy.  (I remember my father describing how penicillin was regarded with almost holy awe during World War II, as it was the first medication that could bring severely injured men back from the brink of death by treating their wound infections, etc.  He said some of his fellow servicemen even demanded penicillin to treat ingrown toenails or dandruff, so convinced were they that it was a miracle medication that could cure anything.)

To really master COVID-19 is probably going to require a vaccine, and at least one completely new anti-viral treatment or medication.  None of them are yet available.  All we can do right now is try anything and everything, in as controlled and safe a way as possible, and hope for the best.  As the ancient medical principle teaches, "First, do no harm".  HCQ might do no harm, and even a lot of good, to some patients:  but it might harm many others.  It's a dilemma for which there's no immediate answer or solution.



urbane legend said...
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Doug Hornby said...

Mr. Grant.
As this drug has been around for some time, and as it is prescribed for various purposes already, I would suggest that the side effects are well known (or should be). At the end of the day, are these risks from those drugs higher or lower than the risks posed by this virus?
That should be the spoken question, we have yet to hear any answer.
I feel that there is too much money, power, prestige, fame and graft wrapped up in this virus, and a quick solution or assistance in fighting this is not wanted by the political/health/research communities. Cui Bono Sir.

Spin said...

I'm call BS on this one Mr Grant. First off, I agree with Doug in the above comment and second if Metformin was 30% fatal in combination with HCQ them there would be a BIG EFFING WARNING in the literature that comes with the prescription. Thirdly there are only theories on why HCQ works in combo with Zpak and Zinc. Most center on blocking the entry of the virus into host cells, helping zinc absorption to kill the virus tat does get in and the antibacterial to ward off bacterial pneumonia. I've also read that the virus binds with the iron in the blood (like CO) and displacing O2 from the hemeglobin.

If you wanted to scare the population some more after the initial scare you would put out that the virus attacks the testes (the rumour from last week) and other nonsense. Now we get to scare old people to not take the HQC by saing you will die if you take Metformin. All four adults in my house take Metformin.

You should not promote this type of scare crap.

Spin Drift

Peter said...

@Spin: Derek Lowe is hardly the source for "scare crap". He's a very highly respected scientist. If he has reservations, I listen, and so do most professionals I know.

Doug Hornby said...

First do no harm. Excellent, my father is dying, if nothing is done, he will likely pass in a few short days. Use the darn drug cocktail. THAT is less harm than nothing.
And that Sir is my point.
I cannot seem to find where a short term usage does the sort of harm the scientists seem to be afraid of. Can someone enlighten me?
Ok to poison someone to administer an anesthesia, but wrong to use a viable drug alternative? We will never have it perfect. Some kids die of vaccinations every year. We keep vaccinating because the benefit to society is so much better than the risk. To me, same here.

kamas716 said...

There's side effects of taking a drug? I'm completely and totally shocked to find that out. Who could have guessed? /sarc

I mean, really, going to webmd and looking it up would point you to side effects of every known drug, as well as drug interactions. No one should be surprised that it isn't a miracle drug for everyone.

Old NFO said...

Concur with Doug on this one. The drug has been in use for a long time with contraindicated medications are well noted. The French study has continued to expand and is NOT 'anecdotal', and does show that Hydroxychloroquine works on some level. If it comes down to it, I would take the cocktail in a heartbeat in an attempt to save my life. Research is well and good when you have months or years to perfect it, which is NOT the case here. This is a case of good enough, not perfect, as decreed by the lab rats.

Beans said...

I agree with all of you above.

HCQ may have bad interactions at some point.

HCQ has been shown to be rather startlingly beneficial in many cases and has been used as a last resort and been quite successful.


Since, in many cases, HCQ has been used as a drug of last resort, is it any worse to die of HCQ side effects than from Wuhan Corona?

And, generally, when you are in the hospital, the doctors stop many medications, like Metformin, just because they don't want all the non-critical meds reacting to the new meds they are prescribing. So Metformin, various cholesterol meds, some blood pressure meds, even some pain meds are all reduced or removed during the hospital stay.

Is HCQ a wonder drug that you can stick in a sage stick and ward off the demons of Wuhan and cleanse your house of cursed Chinese viruses? No. Is it the best hope we have at this time? Yes.

Perfect is the enemy of Good.

During war (which this may be) it is better to field Good now than Perfect in a year, two years even three.

Perfectly? HCQ is far from perfect. Works on some people, doesn't work on others. But it's what we have now available, and we have a body of knowledge working with it for... 50+ years. Which makes me... curious.

(sounds of keyboard tapping, swearing at Firefox for using Yahoo as their default browser...)

The Wiki article on HCQ says... "Hydroxychloroquine was approved for medical use in the United States in 1955.[2] It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[6] In 2017, it was the 128th-most-prescribed medication in the United States, with more than five million prescriptions."

Hmmm. If it's such a dangerous drug, why is it so highly prescribed? And as much as I don't trust the WHO, it is listed as one of the most effective and safest.

So why now all the bashing of HCQ? Though you and many may trust the good doctor, why is he now coming out against it, when it has been the #1 treatment for malaria and other diseases? What drives his negativity? Actual worries about a drug that's been on market safely for so long, or, in these troubled political times, when everything is political, is he siding with many in the CDC and other hallowed halls of medicine who seem to have, sorry to say, bad, nearly fatal cases of Trump Derangement Syndrome.

Not that WIKI is the best source, but if you follow the links in the article they do come back to more solid and trustworthy sources.

Beans said...

And in reference to the WHO, did you see where President Trump has halted all funding of them from the US Treasury? Interesting....

Doug Hornby said...

Beans, are you suggesting that there may be a whiff of TDS involved? Just asking, we find it in so many unexpected places.

urbane legend said...
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urbane legend said...

To really master COVID-19 is probably going to require a vaccine, and at least one completely new anti-viral treatment or medication.

There is not yet a vaccine that really conquers the flu. What was it, three years ago, the vaccine produced was for the wrong virus strain? How helpful was that? How confident can we be then that we will ever have a vaccine that conquers COV-19?

I'm with Old NFO here. If my doc suggests drug X may save my life, I will probably ask why do you think so, and after getting a sensible answer, say " Ok, let's do it. " As a matter of fact, I take a drug produced for leprosy to treat something very different.

Beans said...

Doug, I came outright and said it about the leftist medical professionals at the CDC and other learned institutions.

As to the WHO, Trump basically called them a front for the ChiComs. Who are also showing serious signs of TDS.

Will Brown said...

Something I don't see being much considered in this discussion; every story I've read all make the point that hydroxychloroquine only seems to be effective against the pneumonia-like symptoms of COVID-19 when taken with an unidentified dosage level of erythromycin as well as an also unspecified dose of zinc. The combination is what seems to be effective in at least largely reducing the effects of the COVID-19 on the lungs of the humans infected, often in a remarkably short period of time.

I've read nothing that describes what effect, if any, this drug combo has on the heart damage this virus seems to inflict, so obviously there remains much yet to do. Still and all, it seems there is an at least partially effective drug regimen available to treat the worst ravages to victim's ability to breathe on their own without having to resort to much more dangerous treatments like forced-air ventilators. I particularly look for informed commentary on the effect that albeuterol inhaler and nebulizer treatments have on the drug combo's effectiveness, but don't find more than anecdotal evidence of breathing treatments being of some good effect in countering the low oxygenation aspect of infection.

It seems obvious that there are far more treatment options to be considered, far earlier than showing up at an ER with shortness of breath and an elevated temperature. I suggest this is the sort of information that amateur medical researchers could usefully occupy themselves identifying and cataloging in some transparent fashion.

Mike said...

HCL is an old and well-understood drug. Interactions are well documented and may present issues for some portion of the population, but they are not mysterious. There's plenty of literature on how to use it.

Ivermectin is also showing promise as a treatment.

BFR said...

And, while not suggesting that HCQ should not be used for those with diabetes, it is also true that Type 2 diabetes is almost entirely reversible. It is pus-gut fat-ass disease, and anyone who has it could already have taken steps to lower their comorbidity matrix.

Everyone know what causes it, and everyone knows how to prevent it. It is not "a gland problem" (what being a lard-ass was called in the 50's), it is not a "slow-metabolism" (the human body do not make calories from thin air), it is not "hypoglycemia" (said with a slack-jawed stupid look). It is suicide-by-fork.

I remember my mother, who after being told by her MD (BZ's to him) that she needed to lose weight. She expressed consternation as to how. He said Ma'am, did you ever notice how skinny the survivors of (WWII) concentration camps were. She perked up and said "yes, why did that happen..." The Doc looked at her, and with a firm and moderately raised voice said "THEY DID NOT EAT".

Try this one easy step to eliminate ugly fat. (And concomitant multiple disease processes.)

Eat less.

Doug Hornby said...

I often wonder if the "smarter" members of our tribe don't get caught up in the minutia of their work, thereby allowing PERFECT to be the one and only goal, when good enough should be the target.
Your CDC,FDA and a myriad of other government departments slow, hinder and even stop progress. It is the same here in Canada.
As well Sir, if I may be critical, because a scientist is well respected, does not mean that they and their pronouncements cannot be questioned. That is the very basis of science. Without questioning, there is no progress.
Now I must go, read and digest Willis Eschenbach's latest on flattening the curve. It fills my confinement.
Thank you Sir, for being. Important read each morning, and haven't missed a book yet.

tsquared said...

BFR, that may be true for a lot of type II diabetics but I have had it since my late 30's and I have never been above 15% body fat. There is a small percentage of us that it is hereditary regardless of lifestyle choices.

Deejay. said...

I believe we're running out of time. We need a cure before the economy collapses. Too many businesses on the edge of no return.

Beans said...

Willie Brown. The only thing that you can die from directly and require you to be ventilated IS the pneumonia associated with it.

So... HCQ for every instance of Corona-Wuhan-19? No. But for when the person takes a dive for the worse because of the lungs starting drowning? Yes. Most definitely yes.

Unknown said...

Given that the mechanism of death for this disease is the immune system overreacting and flooding the lungs, I can't see "depressing immune system response" as a negative.
Instead of the reason the treatment was tried in the first flipping place.