Categories
Antivaccine nonsense Bad science Medicine

Paxlovid is NOT “#Pfizermectin”

Pfizer recently announced that its new drug Paxlovid was 89% effective in preventing hospitalization due to COVID-19 and is seeking emergency use authorization for it. Antivaxxers claim that ivermectin targets the same protease and is being “suppressed” to protect Pfizer’s profits, even coining the hashtag #Pfizermectin. What’s the real story? Hint: Antivaxxers…exaggerate. And distort.

Recently, there were announcements of drugs that, unlike the “miracle cures” (primarily hydroxychloroquine in 2020 and ivermectin this year) that have been promoted so heavily on social media, actually have evidence for their efficacy against COVID-19. One announcement was about Pfizer’s new drug Paxlovid, which in its clinical trials was 89% effective in preventing hospitalization due to COVID-19 if taken soon after symptoms develop. The other drug announced was Merck’s molnupiravir (trade name to be Lagevrio), which is now available through a clinical trial in the UK. Both drugs are very promising, and the Pfizer drug (a combination of PF-07321332 and ritonavir—more on why it’s a combination later—before it received a trade name), for example, decreased the hospitalization rate from 7% to 0.8% over 28 days in a Phase 2/3 study, a good absolute and relative risk reduction, with no deaths in the drug treatment arm. (It was so good that Pfizer stopped the study, because it would be unethical to continue with such a result in an interim analysis.) As a result, Pfizer has applied for an emergency use authorization for its drug. In an interim analysis of a phase 3 study, the Merck drug demonstrated a 50% reduction in hospitalization, again with no deaths in the treatment arm.

Unsurprisingly, COVID-19 conspiracy theorists and antivaxxers were not pleased. This is why they seem to have come up with one of the sillier claims that I’ve seen thus far, although I must admit that it’s not obvious how silly they are if you don’t have a background in drug development and some specific knowledge about ivermectin and Paxlovid. (That’s rather the point.) Here are a couple of representative Tweets. I could post a whole bunch of them, but will restrain myself:

And also:

There’s even now a Twitter hashtag, #pfizermectin, full of similar claims:

You get the idea behind the conspiracy theory. It’s pretty simple. Both ivermectin and the Pfizer drug are protease inhibitors, but ivermectin is being “suppressed” because Pfizer wants to make huge profits from its drug Paxlovid and ivermectin is a cheap competitor. (Merck’s drug is not a protease inhibitor, but instead works by being incorporated into the new RNA strand being copied to be packaged into the new virus particles being produced, where it, as one scientist put it, causes the coronavirus to “mutate itself to death.”)

As is the case with many COVID-19 conspiracy theories, there is a tiny grain of truth in the comparison of the drugs, but only a very tiny grain that conspiracy theorists seem to view as a whole field of wheat. In this post, I’ll discuss how one has to ignore some very basic pharmacological principles that differentiate the drugs in order to make the leap to the claim that ivermectin is just like Paxlovid, but being “suppressed” because it’s cheap and generic, as opposed to Paxlovid, which will be on patent and, of course, not cheap. In fact, ignoring one principle will do, the same pharmacological principle whose willful misunderstanding led to people claiming that ivermectin is a miracle cure for COVID-19, namely that concentration matters.

Spoiler alert: Ivermectin does inhibit the same protease that PF-07321332 does, but, as is the case for viral replication, it requires a concentration that is not achievable by oral dosing.

How does Paxlovid work?

As the conspiracy theorists point out correctly, Paxlovid belongs to a general class of drugs known as protease inhibitors. Enzymes belonging to the class of proteases break down proteins by specifically cleaving them into smaller peptides, often by recognizing a specific short amino acid sequence. (Indeed, back in my lab days, we used to use a trypsin to digest the proteins that held cells in cell culture to the substrate, so that we could replate them. Trypsin digests only at a very specific amino acid sequence.) There are a wide variety of proteases in nature, including serine proteases, cysteine proteases, metalloproteases, and more, with some working better in acid pH conditions, others in neutral or basic pH. These proteases are ubiquitous, as well, occurring in basically all organisms ranging from procaryotes to humans and are involved in a wide variety of physiological processes. The aforementioned trypsin, for instance, is a digestive enzyme normally found in the proximal small intestine.

It is therefore unsurprising that many viruses use proteases in their life cycles. The most famous of these among the general public is likely the human immunodeficiency virus (HIV), which causes acquired immunodeficiency syndrome (AIDS). It is the HIV protease that is the key target of the protease inhibitor cocktails that revolutionized the treatment of AIDS in the 1990s, changing it from a virtual death sentence to a chronic, manageable disease:

The main purpose of HIV is to copy itself as many times as it can. However, HIV lacks the machinery it needs to reproduce itself. Instead, it injects its genetic material into immune cells in the body called CD4 cells. It then uses these cells as a kind of HIV virus factory.

Protease is an enzyme in the body that’s important for HIV replication. Protease inhibitor drugs block the action of protease enzymes. This prevents protease enzymes from doing their part in allowing HIV to multiply, interrupting the HIV life cycle as a result. This can stop the virus from multiplying.

There are, of course, now a number of protease inhibitors approved for the use in treating HIV/AIDS, such as atazanavir, fosamprenavir, ritonavir, and others. In any event, protease inhibitors are the mainstays for the HIV/AIDS treatment known as HAART (highly active antiretroviral therapy), which usually consists of three or more medications to treat HIV, mixing protease inhibitors with other antiretroviral drugs. (Yes, some COVID-19 conspiracy theorists are noting that protease inhibitors are used to treat AIDS as well, and then circling back to an older—several months!—conspiracy theory that COVID-19 vaccines make you more susceptible to AIDS. (They don’t.)

Which brings us to PF-07321332.

PF-07321332 is a class of protease inhibitor that targets the 3C-like protease, which is the main protease found in coronaviruses. (Other names for this protease include coronavirus 3C-like protease, Mpro, SARS 3C-like protease, SARS coronavirus 3CL protease, SARS coronavirus main peptidase, SARS coronavirus main protease, SARS-CoV 3CLpro enzyme, SARS-CoV main protease, SARS-CoV Mpro and severe acute respiratory syndrome coronavirus main protease.) This particular protease has long been recognized as a potential drug target for the treatment of coronavirus-induced diseases because it plays a key role in processing the polyproteins translated from the viral RNA into functional viral proteins.

An article from Science explains in lay terms:

Monoclonal antibodies blocking surface proteins of the coronavirus can slow the infection of new cells with SARS-CoV-2, but their application has been hamstrung by cost, availability, and the need to infuse or inject them. In contrast, Pfizer’s ingestible candidate operates inside an infected cell; it blocks enzymes, called proteases, that normally act early in a virus’ life cycle to help it replicate (see graphic, below). Many protease inhibitors are approved for HIV treatment, and Pfizer’s compound has a nearly 20-year history. Pfizer scientists designed a version of the compound back in 2003 to block a protease in the coronavirus that causes severe acute respiratory syndrome (SARS), a cousin of SARS-CoV-2.

And:

As SARS-CoV-2 infects cells, reproduces itself, and spreads, the coronavirus relies on dozens of viral and host proteins to complete its life cycle. Pfizer’s new oral pill inhibits the main viral protease used to create other proteins for the virus. And Merck’s drug inserts a defective RNA building block when the virus uses an enzyme known as a polymerase to copy its genome.

And here’s a visual representation:

And another figure demonstrating how a long SARS-CoV-2 protein is cleaved into smaller structural proteins:

SARS-CoV-2 genome

As Steve discussed last week, the rapid development of these two drugs adds more hope that the pandemic can finally be brought under control and become manageable, given that we have safe and effective vaccines and now drugs that can be used to treat the unvaccinated who become ill or the unfortunate vaccinated people who suffer breakthrough infections and, if real world data resemble clinical trial data, prevent the vast majority of them from dying or even requiring hospitalization.

It also turns out that PF-07321332 has been a long time coming. In the paper reporting the drug as a promising candidate to treat COVID-19:

In effort to identify inhibitors of the SARS-CoV-1 Mpro in response to the 2002 SARS outbreak led to the identification of PF-00835231 (1, Fig. 1) as a potent inhibitor of recombinant SARS-CoV-1 Mpro in a fluorescence resonance energy transfer (FRET)-based substrate cleavage assay (17). PF-00835231 also demonstrated potent inhibition (inhibition constant (Ki) = 0.271 nM) of recombinant SARS-CoV-2 Mpro, which is expected given that the SARS-CoV-1 and -CoV-2 Mpro share 100% sequence homology across their respective substrate binding sites (18).

Unfortunately, potent in vitro activity against a drug’s target does not necessarily translate to a good drug, and PF-00835231 had poor bioavailability. Specifically, it was poorly absorbed when given orally to experimental animals. So, as pharmacologists do when they have a potent drug candidate that isn’t well absorbed, Pfizer scientists started chemically modifying it to improve its oral bioavailability and testing those analogues in vitro for activity against the 3CL, and:

PF-07321332 demonstrated potent inhibition in FRET Mpro assays representing Mpro from all coronavirus types known to infect humans (6, 7, 30), including beta-coronaviruses (SARS-CoV-2, SARS-CoV-1, HKU1, OC43, MERS) as well as alpha-coronaviruses (229E, NL63) (Fig. 3B and table S2). No inhibitory effects were noted against several mammalian cysteine (caspase 2, cathepsin B, cathepsin L), serine (chymotrypsin, elastase, thrombin) and aspartyl (cathepsin D) proteases at the highest concentration tested (100 μM) of PF-07321332 (table S3). This was also the case for HIV-1 protease, a viral aspartyl protease (table S3).

That last part is important, because specificity is important. PF-07321332 would not have been very useful if, in addition to the SARS-CoV-2 protease, it also inhibited human proteases important in a number of processes, such as protein digestion. Such inhibition could have caused a number of undesirable and potentially harmful gastrointestinal side effects. PF-07321332 did not and was therefore deemed a good candidate with good oral bioavailability. It also exhibited potent antiviral activity against SARS-CoV-2 in vitro.

There was still a problem, though. There’s a reason that Paxlovid is a combination drug, containing PF-07321332 with ritonavir, an anti-HIV drug:

Paxlovid is a combination of two different drugs – the HIV drug ritonavir (a capsule) and an experimental drug PF-07321332 (a pill).

Ritonavir protects the body from metabolising PF-07321332. It acts by being broken down by the body first (known as a sacrificial chemical) to ensure enough PF-07321332 reaches the virus intact.

It’s a clever strategy to maximize the efficacy of PF-07321332. CYP3A4 is a P450 enzyme and often considered the most important drug-metabolizing enzyme, among the most abundant of its type in the liver. As noted by Pfizer:

These in vitro studies, which established a predominant role for CYP3A4 in the metabolism of PF-07321332, also presented an opportunity to boost therapeutic concentrations of PF-07321332 in the clinic via co-dosing with the potent CYP3A4 inactivator ritonavir (RTV), which is used as a pharmacokinetic enhancer of several marketed protease inhibitors (e.g., darunavir, lopinavir) that are subject to metabolic clearance via CYP3A4 (35, 36).

Before I move on, I will note that drug companies like Pfizer often have huge libraries of compounds predicted to target certain enzymes based on computer modeling, and we can expect more compounds like this in the future to be tested.

Speaking of computer libraries, let’s contrast Pfizer’s Paxlovid with ivermectin.

“Ivermectin works just like the Pfizer drug!” Not so much.

So where does the claim that Paxlovid is just “repackaged ivermectin” designed to increase pharma profits come from? Again, it reminds me a lot of how ivermectin came to be thought of as a “miracle cure” for COVID-19 based mainly on in vitro studies of its ability to inhibit SARS-CoV-2 replication cell culture. To that end, let’s look at the paper from which I took one of the figures above. Basically, it was a computer modeling study that was used to identify existing compounds that could target 3CLPro, hence the segue I used. The authors used computer modeling to identify potential promising candidates to inhibit 3CLPro and then tested the top “hits” in cell culture. One of the compounds identified by this strategy was ivermectin.

Before I get to this, let me just point out that it was thought that ivermectin inhibited SARS-CoV-2 replication through the inhibition of a different protein, α/β1 importin, something reported a decade ago. This particular protein is involved in the transport of proteins into the nucleus from the cytoplasm. In the case of SARs-CoV-2 infection, the transport of certain proteins into the nucleus is important for completion of its lifecycle. (I won’t go into the details other than that.)

Now here’s the thing. Inhibition of this protein complex by ivermectin and preventing the replication of HIV and the Dengue virus requires fairly high concentrations (at least in terms of drug concentrations). The original Australian paper that examined the ability of ivermectin to inhibit SARS-CoV-2 replication showed similar results. Now the problem. As stated in this review:

As noted, the activity of ivermectin in cell culture has not reproduced in mouse infection models against many of the viruses and has not been clinically proven either, in spite of ivermectin being available globally. This is likely related to the pharmacokinetics and therapeutic safety window for ivermectin. The blood levels of ivermectin at safe therapeutic doses are in the 20–80 ng/ml range [44], while the activity against SARS-CoV2 in cell culture is in the microgram range. Ivermectin is administered orally or topically. If safe formulations or analogs can be derived that can be administered to achieve therapeutic concentrations, ivermectin could be useful as a broad-spectrum antiviral agent.

Even this paper proposing ivermectin as a treatment for COVID-19 notes:

A dose of 12 mg twice daily alone or in combination with other therapy for 5–7 days has been proposed as a safe therapeutic option for mild, moderate or severe cases of Covid-19 infection.10 The time to reach maximum plasma concentration of 20–50 ng/ml, after a dose of 6 or 12 mg, respectively is approximately 4 h.

This was almost certainly the reason that ivermectin doesn’t work against COVID-19 in spite of its activity in vitro against SARS-CoV-2. It requires a concentration 10- to 20-fold higher than is safely achievable in the blood. That’s why the review concluded that maybe an ivermectin analogue that is either more active or can achieve a higher concentration safely in the bloodstream is worth investigating. Ivermectin itself is a crap drug based on that mechanism.

But what about its protease inhibition? It’s the same damned principle. Yes, ivermectin can inhibit 3CLPro in vitro, but it’s the same old story, as has been pointed out:

The papers to which Nick is referring are the Pfizer paper, recently published and no longer a preprint, and the computer modeling paper.

I further note that these efforts to target 3CLPro date back to 2003 during the original SARS epidemic:

To put things in full context, here’s a reminder. Nanomolar (nM, 10-9 mol/L) concentrations are 1,000-fold lower than micromolar (μM, 10-6 mol/L). The idea is the same for 3CLPro as it was for α/β1 importin. The concentrations of ivermectin needed to inhibit 3CLPro are much, much higher than can be safely achieved in the blood and extracellular fluids of human beings with oral dosing, and it that’s what needs to happen for the drug to work in a living, breathing human being. Many are the drugs that show good activity in cell culture but founder when the attempt is made to test them in mice and other laboratory animals. It turns out that this is just one (among many) reasons why drug development is very, very hard and that promising compounds that appear to work well in cell culture fail when tested in animals.

Indeed, let’s just say that a Ki (the concentration producing 50% of maximal inhibition of a target) of 3.1 nM for a target like 3CLPro is the sort of incredibly low Ki that pharmacologists and medicinal chemists dream about when trying to develop a new drug to target a specific enzyme. I myself have fallen victim to the very same problem in my research career so I am very, very aware of this problem. Let’s just say that my drug’s Ki was a lot closer to that of ivermectin than that of PF-07321332. Let’s also say that my drug, like ivermectin, shows a lot of other fairly nonspecific activities that require high concentrations as well and leave it at that. Again, drug development is hard, and promising compounds that work in cell culture often fail for reasons of achievable plasma concentrations and pharmacokinetics, something that anyone who’s done drug development is painfully aware of.

Unfortunately, apparently ivermectin cultists are not aware of this very basic principle, which is why the drug was promoted based on an Australian cell culture study that in and of itself strongly suggested that the drug was actually not a particular promising COVID-19 treatment based on pharmacokinetic considerations alone with respect to its ability to inhibit viral replication and α/β1 importin. Now they’re doing it again based on a study that shows that ivermectin is not a particularly promising COVID-19 treatment based on pharmacokinetic considerations alone, just this time with a different target, 3CLPro.

Contrary to the conspiracy theory being pushed by cranks, Paxlovid is not just “repackaged” ivermectin, and ivermectin isn’t being “suppressed” to protect the profits of Pfizer. No one, least of all I, denies that large pharmaceutical companies have done some pretty shady things, but “suppressing” ivermectin in favor of the Pfizer and Merck drugs does not appear to be one of them. Ivermectin, although a fantastic drug to treat diseases caused by roundworm infestations, just doesn’t work against COVID-19, and there was never any really compelling reason to suspect that it would. Now here’s hoping that the clinical trial results for PF-07321332 (Paxlovid) and molnupiravir (Lagevrio) hold up in the real world. That would truly be as much of a game-changer as the development of effective and safe vaccines a year ago.

By Orac

Orac is the nom de blog of a humble surgeon/scientist who has an ego just big enough to delude himself that someone, somewhere might actually give a rodent's posterior about his copious verbal meanderings, but just barely small enough to admit to himself that few probably will. That surgeon is otherwise known as David Gorski.

That this particular surgeon has chosen his nom de blog based on a rather cranky and arrogant computer shaped like a clear box of blinking lights that he originally encountered when he became a fan of a 35 year old British SF television show whose special effects were renowned for their BBC/Doctor Who-style low budget look, but whose stories nonetheless resulted in some of the best, most innovative science fiction ever televised, should tell you nearly all that you need to know about Orac. (That, and the length of the preceding sentence.)

DISCLAIMER:: The various written meanderings here are the opinions of Orac and Orac alone, written on his own time. They should never be construed as representing the opinions of any other person or entity, especially Orac's cancer center, department of surgery, medical school, or university. Also note that Orac is nonpartisan; he is more than willing to criticize the statements of anyone, regardless of of political leanings, if that anyone advocates pseudoscience or quackery. Finally, medical commentary is not to be construed in any way as medical advice.

To contact Orac: [email protected]

35 replies on “Paxlovid is NOT “#Pfizermectin””

That this post even has to written shows how problematic the ‘do your own research’ era is, when combined with a lack of relevant knowledge to do the research. It’s another indictment of the education system in general, and the chemistry teachers in particular.

@David: “shows how problematic the ‘do your own research’ era is, when combined with a lack of relevant knowledge to do the research. It’s another indictment of the education system in general”

The very precise problem I see in the K12 education system is that it never actually teaches kids why. Lots of “whats”, and occasional “how” (if barely that). But nothing that explains why we should trust it or why we should care.

I got all the way through junior and high school with (when I could be arsed) A grades (C when I couldn’t). And all of that “larnin’” wasn’t worth to me crap. (Which, by the way, was also all that was left of me after the real world chewed me up.)

What K12 teaches us is how to memorize a collection of “facts” solemnly stated to us by a Serious Authority Figure, and regurgitate all that pablum reliably on a command.

There was no measurable attempt (that I can recall) to show how those facts were arrived at; nothing that would enable us to weigh for ourselves those facts against the myrad other facts told to us by other equally (if not more) impressive authority figures, and thus be able to detect for ourselves which may be useful and which are definitely not. And indeed, at every level of society, from industrial-military complex and political and priest classes down, there are very large numbers of people who like and intend to keep it as that.

Thus “education” is rendered down to a stately facade. The utterly worthless paraded as valuable achievement, worthy of meritorious praise and vacuous reward, as often by those who make their own rich livings selling pigs in a poke, as those who are simply lost. We learn the shapes and weights of everything, yet none of the skills to assess it. Names of kings and years of battles, but no ability to form our own independent insights into why they were fought or what they might have done wrong. Just pre-baked pre-chewed answers to spew which are “Correct”, so we are told.

“Guess the answer we already thought of, son, and you are sure to go far.”

Good party trick. Absolutely piss all use for navigating this real world, with its infinite complexities and eternal ranges of greys. (Which a true paranoiac would say is exactly the point.) Either way, speaking as N=1, it damn near killed me; did leave me for dead. Trashed mind, squandered life. Very salty now, looking back.

Even when high school (belatedly, rarely) attempts to deprogram that mindset, it’s far too little a lifetime too late. Not least because they cannot tell us why they suddenly now want us to attempt forming original conclusions for ourselves, and that it is not the “answer” itself that’s important but the reasoning we employ to reach it. (If they did explain it—if they admitted that what we’d been taught up to that point was almost all wrong, not merely the data itself but the way in which it was communicated and the reasons we’re told that mean we should care—they’d be gutted. As in, like a fish.) Thus it degenerates, like all the rest, to clever mimicry and clapping crowds delighted at our ability to walk on our hindlegs, like a hound. Epistemology, just a word in a dictionary. Let us Google it now.

Luke 4:12 has a fuckload to answer for.

p.s. I’m not surprised higher academia is so screwed up too, considering what it gets as its feed streams. It must be generational by now: Garbage In, Garbage Out.

@has

This is a lot different than your usual comments here and elsewhere. It seems something touched a nerve. Maybe not a good time to disagree, so I’ll just say that I went through the “just learn it” system and I think there’s a lot to be said for it. At least I know a lot of things that I constantly see younger people getting wrong. I learned a lot more in college of course, but high school in my day actually prepared you for college–not by taking AP classes, but by making you rewrite your essays until they were right and grading you separately on content and mechanics instead of giving everybody an A+ for unreadable garbage and saying to the skeptical parent (me) that it was a really “creative idea” or some such.

I learned about logic in English, about seeing through TV ads in Science when we learned what soap and detergent realy are and how they work. I learned that my rights stop where others’ begin in American History. Sadly, I learned in Home Ec that I should not be better at tennis (or any sport) than my boyfriend because that would be “unladylike” and “diminish his manhood”, so it wasn’t all perfect in the ’60’s, but I came out of high school with marketable job skills, the ability to express myself in writing, and an understanding of basic biology. Most of all, I was taught to hold those who knew more than I did about things in esteem. I was also taught how to actually research a subject and how to evaluate sources–all without a computer or the internet!

All of the above was expanded in college where I studied the history of science, which while it doesn’t make you a scientist, it does teach you to understand what it is, how it works, and who the people were who brought us out of the Dark Ages into the Enlightenment and beyond.

My kids got some of all that, but with a generous helping of praise for stuff they didn’t do well. They turned out to be good skeptics with heavy supplemental education at home, but the grandkids are, well…that’s another story and it’s definitely a mixed bag. One of them who just started grad school told me that people are no longer to be called “disadvantaged”, but rather they are “oppressed”. I need to send him a certain Monty Python sketch. (Alas, he’ll probably say, “Who?)

“It’s another indictment of the education system in general,”

I don’t know what your bug about the educational system is but your constant harping about things you don’t like, without any support, is getting old.

@ldw56old: Sympathies to you, mate. But if you really don’t want to read angry grousing, a science-based blog about AltMed is perhaps not for you?

FWIW, my own personal K12 grouses are very specific:

Because I am myself a fine product of that system, that taught me I was hot stuff cos I passed some exams. And what a disaster that proved when I stepped up to learn medicine…
Because after I picked up the pieces of what was left of me after that, I ended up working in K12 edu publishing, where I learned more from the people I worked with (including numerous teachers who, it turns out, were far more insightful and intelligent and caring than their classroom personas ever let on) than I ever grasped in school. The “system” doesn’t just squander the kids’ early openness to learning, it fails to do right by the adults as well.

Along that road, I’ve picked up a little about how to learn for myself, and in turn I’ve written educational material in hopes that it helps others to teach themselves too, so I’ve come to an appreciation of the great lifelong advantages of that wonderfully adaptable, general-purpose skill. And now I’m a crusty old sod, if I can’t wave my cane angrily at the kids on the grass then what more am I useful for?

“Sympathies to you, mate. But if you really don’t want to read angry grousing, a science-based blog about AltMed is perhaps not for you?”

Don’t need your sympathies, I’m just fine with grousing when it’s supported with evidence. The ed stuff wasn’t — personal anecdotes are not data.

You missed the point, Supporting evidence is what’s been missing from the constant attacks on education. The views (or anecdotes) of one or two people are not data.

I went through school here in the US as well. Started in a medium-rural system just north of Lansing MI. I was in the last generation of one-room school K-6 kids. It was neither as terrible nor as fantastic as people in the two extremes make it. Ended up with a Ph.D. in statistics and have been teaching/working for almost 40 years.

My anecdote doesn’t provide proof that the education system is great, just as the stories/views you or David post don’t prove that it’s terrible. That’s the point.

“The views (or anecdotes) of one or two people are not data.”

Never the less, I stand as a second ‘anecdote’. Only, my nazi high screwell only made it worse. Not with it, nor next to it, but simply near it. For now.

You think that the Ed system is a success?

What about Tony writing ‘Pfizer’s pill is almost an exact replica of Ivermectin’ shows that the education system is working, or do you need more examples? Do you think that Tony actually checked the structure of the two compounds? What about as people explaining that there is no ‘Covid-19 virus’ etc.?

I think that it is also failing to teach people how much they don’t know. Knowing how to learn on your own is very important – but it only works if you know what you don’t know and how to find good sources.
We have +18 months of this, so there are too many examples to list.

@ldw56old: Sure they’re only anecdotes. A really robust unbiased scientific analysis would be a wonderful thing to have, because then we could test our own casual hypotheses against that, and update them according. But in absence of that, what we gonna do? Not have a personal opinion?

I mean, the whole discussion about COVID, anti-vax, AltMed, AltReich, etc ultimately boils down to: something went sideways in a lot of people’s upbringings. Or maybe it didn’t; and they’re exactly as venal, prejudiced, abusive, et al as they were designed to be. Either way, something is deeply concerning about a lot of people’s [self-]learning processes. And it is a dangerous situation all round; a horrific thought when looking at an advanced and mature civilization. Maybe complacency does breed contempt, and this is how they all ultimately fall?

It is true that anecdotes are not evidence. But they can be a useful starting point for enquiry. That’s not my specialism (and I have other fish to fry besides). I know Denice takes an interest in this sort of stuff; perhaps you do too? In which case you’re welcome to chip in with whatever resources you have, and move the talk onto a more scientific, tested foundation.

“You think that the Ed system is a success?”

Point out where I said that. Saying that it is not an abysmal failure is not the same as saying it is a success. Stop engaging in binary thinking.

“What about Tony writing ‘Pfizer’s pill is almost an exact replica of Ivermectin’ shows that the education system is working, or do you need more examples? Do you think that Tony actually checked the structure of the two compounds? What about as people explaining that there is no ‘Covid-19 virus’ etc.?”

The point you haven’t made (because you haven’t tried) is that the reason he (and by extension all other science deniers, whether related to medicine and vaccines, climate change, …) take that behavior because the education system failed them. Being absolute in assigning these behaviors to one thing (I’m picking on education because that’s what and others are doing) is foolish.

“But in absence of that, what we gonna do? Not have a personal opinion?”

Again, point out where I implied that. But again, what should not be done is say any single item as the reason for the asinine comments made by these people. If the education system were as massive a failure as is being implied it would not have produced the people who post here and with whom you agree.

@ldw56old: Why the hyperbole? I didn’t say that it is a ‘abysmal failure’, but I continue to see the lack of scientific knowledge. There was a time when people knew what they didn’t know, but that time seems to have passed.

But you could be right, maybe the problem isn’t that no one taught them the scientific information needed to understand complicated issues. But the other option is much more problematic – that people don’t want to know or want to believe something else.

The solution to the situation you describe this is much harder, because it can’t be solved by teaching people if they don’t want to learn. And scientific process is based on continued learning and producing more data, that is then used to further learning.

How do you think we should proceed?

“But the other option is much more problematic – that people don’t want to know or want to believe something else.”

True — but that is, IMO, what is the primary driver of this.

“The solution to the situation you describe this is much harder, because it can’t be solved by teaching people if they don’t want to learn. And scientific process is based on continued learning and producing more data, that is then used to further learning.

How do you think we should proceed?”

If I had a good answer to that I’d be rich — or on my way to becoming rich.

@ldw56old: Maybe more information is not enough.

There has been research into ‘inoculating’ people against disinformation (Inoculation theory), to fight our instinct to dismiss facts that don’t fit our negative. If we don’t teach people how to better understand the issues, then we can’t be surprised that they fall for dis-information.

I guess that we come full circle – back to the education system: who can provide this ‘immunity’, if not science teachers?

@David: Not science teachers but educators in general, from parents upwards.

If we don’t teach our kids how to be wrong—and not to be ashamed but to revel in the learning opportunites that affords—how can they learn to be anything more?

“back to the education system: who can provide this ‘immunity’, if not science teachers?”

Don’t discount the results of decades of attacks on science and education in general (primarily by the right for recent history).

This was really helpful, and it’s exactly the kind of thing lay people need the help on.

I’m finding myself wondering if baths of horsepaste are on the horizon next as an antivaccine miracle cure.

@Denice: Seconded.

Very good clear lay-accessible explanation of why Ivermectin, which does possess antiviral properties, falls on the last jump. If the therapeutic window is a negative—if it kills the patient even harder than the disease, it is no damn use as a medicinal product.[1]

I might not follow all the fine technical details (that stuff gets insanely complex fast), but the broad sweep I can grasp no problem. (Perhaps thanks to flunking pre-med, which taught me humility if nothing else.)

By the way, I feel pretty confident that “Always bet against all possible new drugs”, is the best rule-of-thumb default, as most hopefuls do fail, thus the money I pay out on the few that succeed is more than is paid in on the majority that don’t. Thus my own personal skepticism regarding Ivermectin is the exactly same skepticism I hold against ALL newcomers: HCQ, Resdemivir, Paxlovid, et al. I expect ALL to fail, and will be pleasantly surprised if even one does not.

I think that’s the only sensible lay position to hold—or am I wrong? And if I am right in this, why are so many lay people determined to hold another? (Rhetorical question, really: I may not know much about medicine, but dysfunctional personalities? I get that.)

That out the way, a couple things still bug me:

Has anyone posted a good review/metaanalysis of the (if any) Ivermectin studies that weren’t complete crap? (There is so much noise and BS out there, and I don’t have the skills—or patience—to sift through myself, so just wondering if there is a handy Cliff Notes.) IIRC there was an Argentinian study that found a negative, and Oxford’s PRINCIPLE trial [2] which is ongoing. Is it even ethical to proceed with further trials if we already understand it won’t work in-vivo, as the dosage it takes to be effective will poison the patients first? That brings to my mind the [weak] bleach chuggers [3]: who imbibe ClO₂ not as a physical therapy (as they believe) but a psychological crutch [4]. So how much research is too much, and anything more should be shut straight down?
What is the deal with Dr John Campbell? I had a quick squiz the first time his name came up, and he appeared to be legit: retired Dr of Nursing (i.e. a nursing school teacher), who had found some modest fame making YouTube videos about handwashing, masking and such. It doesn’t immediately sound to me like he’d be go-to to assess pharmacological research. No sleight to the man; if he taught nurses that gets mad props in my book. (My old mum is a retired nurse, and about the most decent humane person I have known.) But our gracious host here has the advantage of being not just a medical doctor but a research scientist, and I suspect it’s the latter that really counts here as it means understanding how stuff works from first principles, not just correctly translating a dosage chart. So has he done a John Ioannidis, demonstrating again that a little competence is a dangerous thing?

[1] At least, not for treating COVID. Ivermectin is still extremely effective and appropriate for killing parasites, if only small ones.

[2] https://www.ox.ac.uk/news/2021-06-23-ivermectin-be-investigated-possible-treatment-covid-19-oxford-s-principle-trial

[3] MMS junkies, whose argument is that they know how to drink bleach at a dose that’s high enough to poison bacteria and parasites but low enough not to poison themselves. Even though we already know bleaches are an indiscriminate killer of everything; so won’t even have a negative therapeutic window, just no window at all.

[4] https://www.youtube.com/watch?v=xSVqLHghLpw

@ has:

I didn’t say that, Dorit did.
However, I take it as an extremely generous compliment to ever be mistaken for her in any manner. I hope it’s not just the letter D.

I’ve seen an analysis or two that suggests that Ivermectin maybe actually does have beneficial outcomes for treatment of patients who have COVID, if and only if they’re in an area of the world where parasitic worms are endemic.

Which, well… that at least has a straightforward mechanism of action.

One last observation (as my link-laden comments wind through moderation): a 10× measurable reduction in hospitalizations is a bloody great result! So what if Paxlovid retails at $500? It’s a fantastic bargain at that. Average cost of a COVID hospitalization in comparison? $20,000!

And, of course, the Ivermectin boosters and the rest of the Alties immediately piss on that result from great height, telling us that greedy Pfizer’s just in it for the money. Which, yes, Pfizer are. But it doesn’t take a paranoiac coke-snorting genius to deduce that the Alties’ outrage is not really because Pfizer is charging that much, but because all of that lucre is channelling into someone else’s pocket instead of landing in their own!

Those who protest the loudest… are Steaming Bullshit Artists. Pissed AF to see treatments which work hit market at last, simply ’cos they’re not in the position to sell them themselves. But happy to flog worthless tat.

For all the grift that Pharma gets up to (and it does), the Alties’ own grift is 10× worse. (And only that much ’cos they’ve not yet figured how to steal more.) At least Pharma’s stuff usually mostly usually works. AltMed is shameless.

@ has November 22, 2021 at 2:47 pm
Has anyone posted a good review/metaanalysis of the (if any) Ivermectin studies that weren’t complete crap?

I cannot remember seeing any but it may exist. You might want to have a look at James Heather’s article in the Atlantic and see if he provides any leads. The Real Scandal About Ivermectin

I think a major problem has been that the meta-analysists took the Elgasser stduy at face value and they may be scrambling to reanalyse their data.

Elgazzar, yes? Will read the Atlantic piece after dinner: it looks to be a slam on shoddy standards in scientific publishing and peer review (which I think we all agree is well justified and much needed) which uses the Ivermectin studies only as its jumping-off point.

Meantime, I did follow the two links to the metastudies that appear in its introduction, and:

The American Journal of Therapeutics metastudy is both glowing and uses the Egypt (Elgazzar) study, so we can immediately discount that. I think it horribly lax that there isn’t even a notice of concern slapped at the top, never mind withdrawing it until that giant honking problem is resolved (which ought to be the right and automatic thing to do). Will they revise it in future—who knows? Whatever, NOT a good look. Trash.
The OFID metastudy has already been reworked to exclude Elgazzar and another dodgy study, and concludes in the abstract: “Ivermectin did not show a statistically significant effect on survival … or hospitalizations …. Ivermectin displayed a borderline significant effect on duration of hospitalization in comparison with standard of care …. There was no significant effect of ivermectin on time to clinical recovery …” So that one’s worth bookmarking, although the Ixx groupies will doubtless scream “bias” for doing so.

Well, yes, that is bias. Bias against bullshit, incompetence, and lies; no matter how much we might wish them to be true. Just cold, hard, thankless, unforgiving facts (or at least the best facts we’ve got unless and until better ones come along). That’s science, and if they don’t like it they can cram their delicate feels up their overstuffed ass.

All of which fits with what Orac and others are saying that while Ixx may be a candidate on paper, it’s useless in practice for treatment of COVID (both in prior plausibility and in-vivo experiment), and that its noisy boosters are at this point running a religion and/or con. And probably know it too.

Many thanks for helpfully answering my dumb questions. We should all have lots more of that! And, just one more:

Is it too late to bring back tar and feathering, do you think?

(Asking on behalf of all the good scientists.)

Since I was named:
Is RI ( ” a science-based blog about AltMed”) really a place to discuss the failings of educational systems?

Why do people accept the lame, unsubstantiated so-called logic of alt med in the first place? Orac and others ( on SBM, Quack Watch, Wikipedia, Rational Wiki, SR) examine what alt med teaches and why people fall for it. A specific section on QW addresses why medical professionals accept woo. We might ask indeed whether studying science at any level -as a child or as an adult – can inoculate people against such nonsense. Critical thinking is a frequent topic here. As is wishful thinking.

Personally , for years ( actually decades), I’ve followed alt med prevaricators “lecture” and “instruct” their audiences through downright confabulation about human biology, health, nutrition and psychology and the bulk of it does not remotely resemble anything I’ve studied formally. If you observe these charlatans, you would learn to whom they speak, as followers call in or write comments: the shocking surprise is that they’re not all illiterate drop outs but people who finished secondary school, college or beyond who MAY live in sophisticated large cities / suburbs and have meaningful careers**. Well known anti-vaxxers ostentatiously display their credentials, universities and degrees as if that ALONE would validate their fantastical claims. Shouldn’t an adult with a college degree at least be able to spot obvious misinformation?

During the pandemic, we have learned how widespread acceptance of glaring untruths and opportunistic maneouverings are and that their motivation might be political or emotional. Orac often discusses how political advocates steer followers towards particular biased positions on medicine, biology and other science based topics ( AGW). in the past decade, psychologists ( US, UK, AUS) have studied just what type of person is most susceptible to conspiracy mongering and how they process information. Perhaps having a certain personality/ profile increases the effects of sub-standard educational training in critical thought, fact checking and source analysis.

** THIS BOTHERS ME IMMENSELY- I could go on but I won’t

@Denice: “the shocking surprise is that they’re not all illiterate drop outs but people who finished secondary school, college or beyond who MAY live in sophisticated large cities / suburbs and have meaningful careers”

I do not find this shocking at all. Being intelligent and educated only guarantees you can invent much cleverer ways to fool yourself. (Speaking from experience.)

The cause, I suspect, lies primarily in wants. (I suspect in US that also gets entangled in needs, due to access issues with mainstream healthcare. But that’s secondary.) A lot of extraordinarily privileged westerners seem very much to want an emotional crutch. If not several at once.

Likewise, any correction must grow from personal wants. And the problem there is: you cannot make people speak truth to themselves. They have to want to be rigorously ruthlessly honest, even knowing they personally WON’T like some/most/all of those answers one bit.

Perhaps this also explains our love of the pleasing distractions? As a means of passive-aggressive avoidance: ignore all the big issues by inflating the indulgent trivia to greatest importance. It is so much easier to do. And I get that.

Again, speaking from N=1: where I am now was not a path I took by choice but forced by harsh reality, and only finally, resentfully, conceded once I could no longer deny my sole alternative was to walk off a roof. (And while I may not have personally given a crap whether I lived or died, it wasn’t something I was willing to inflict on anyone else. Empathy’s a real you-know-what; it wasn’t till later I figured how to turn it on/off.) I don’t regret the insight I’ve got nw, but what it cost me to grow it…ugh. I can understand others’ reluctance, even before we factor in dishonorable agendas. Of which there are a lot. But as a long-term species-level survival strategy, “Ignorance is Bliss” must be a deadly trap. But if others don’t want to admit it, what can you do? Other than keep a safe distance and watch.

In the end, I suspect a solution (of sorts) will be forced regardless of who wants it or not. Just add 2–3°C warming and a hundred years from now. These kinds of “wants” will become a luxury that few will be able to afford; superseded by “wants” more familiar to our ancestors 500 years ago. I will be dead and gone by then, and my genome with me, so makes no difference to me directly. Even so, I dearly wish it wouldn’t have to come to that. It genuinely breaks my cold black heart.

“A person is smart. People are dumb, panicky dangerous animals and you know it.” – Agent K, Men in Black

@ has

I just want to say I feel ya, bro. About the problems with education, about the roof, about the climate, about the broken black heart….

I was lucky enough to attend a good (public) high school (St. Louis Park, MN: go Orioles!), that offered electives and AP classes that went into critical thinking (you know, stuff like philosophy…) but more importantly (I now realize) gave me the opportunity to be socialized educationally among a host of very bright inquisitive classmates. After high school. my career goal was actually to become a high school teacher myself, but when I finally got out into student teaching, I just couldn’t deal with how the structure of the system instills intellectual and practical passivity… Or as you say “squanders the kids’ early openness to learning”…

Education is a deep, complicated issue, and quickie global hot takes like David offered at the head of the thread aren’t very helpful — I really wouldn’t put too much on the head of the Chem teachers, or imagine that even the best school could innoculate the Tony’s of the world against their errors. I did wind up as a classroom teacher (university level) anyway, and believe me, just because you teach X doesn’t mean the students actually get it or keep it. Lots of other influences, authorities, agenda etc. intervene, and to quote Paul Simon “a man hears what he wants to hear and disregards the rest”.

I’m not sure there was indeed “a time when people knew what they didn’t know”, but it makes sense that with both increasing globalization, increasing global factors on everyday life of pretty much everybody, and increasing vague awareness of this, that people are increasingly freaked out by what they don’t know, and the ‘natural’ (if somewhat perverse) defense mechanism is to imagine that one does know more, has more control than one actually does.

I don’t think it’s really a matter of knowledge — it strikes me as more than Quixotic to imagine K-12 would teach “the scientific information needed to understand complicated issues”. It’s more a matter of epistemology, of teaching people how to learn. Props to you for trying to foster that in the materials you created. But it goes far deeper even than that, to questions of values, social and cultural contracts, and the like. In practice we need to rely on experts who have specialized knowledge, and identifiying who does and doesn’t qualify as such is difficult for lots of people among all the noise generated by predators…

I shall end these meanderings with an attempt at humor:
“The Merck drug demonstrated a 50% reduction in hospitalization, again with no deaths in the treatment arm.”
Sign me up for ivermercktin then, because I know that if that vax jab doesn’t kill all of me dead, it will at least make my treatment arm shrivel up and fall off at the shoulder!

You make important points and I have to confess that many of the people I was educated alongside don’t seem to have been awake in the same classes that I credit for my own critical thinking–if Facebook is any measure? So, in spite of my lengthy comment above, there has to be more going on than when or where one went to school.

I was always curious and a bookworm who read way above grande level. I actually LIKED school and loved college, and I still read a lot. People say I’m smart, but I always say that I just read a lot. I’m just smart enough to read this blog and humbly accept that even if I can’t grasp all the details in a post like this one, I will be better informed for making the effot.

I think that Tony just repeats the party line. No education will cure that, actually many very well educated people have done same thing.

Want to respond to Orac? Here's your chance. Leave a reply! Just make sure that you've read the Comment Policy (link located in the main menu in the upper right hand corner of the page) first if you're new here!

This site uses Akismet to reduce spam. Learn how your comment data is processed.