As someone who worked in toxicology, this is absolutely a false statement. This molecule is a covalent binder - it basically attaches itself permanently to proteins. It absolutely could have effects long after the free molecule is metabolized and excreted. The molecule is designed to be selective for the Covid protease but off-target effects are inevitable.

Do I think that is likely? No, because the FDA isn’t stupid and screens for obvious toxicity in cell cultures and lab animals and only then is testing humans allowed. Then those are screened before approval.

Of course the risk isn’t 0%, but it’s pretty low and if you’re at chance of dying or Covid it’s a pretty small risk relatively speaking.

> this is absolutely a false statement. This molecule is a covalent binder

That's why I said if, I know nothing about the molecule.

But you're giving statements out like you know everything about it, and the fact you said if has no relation with the fact it binds to proteins

Unless it were to change something in the body while it was still active, and those changes didn't show any signs for a long time.

I'm just playing devil's advocate, but it doesn't seem impossible.

I guess my question is what is probable rather than possible or is that a risk that's even addressable to any reasonable degree

Well, nothing's impossible really.

Prions are "just" proteins that should get broken down by the body. But they don't, and they cause ‎Creutzfeldt-Jakob in over 10 years after ingesting.

It's a good thing we're all here on HN to question the safety of novel pharmaceuticals. If we weren't, maybe nobody would, and we'd all just be putting prions into ourselves.

If you have something specific about this particular molecule to talk about vis a vis safety, that's an interesting comment to make. But "aspirin is a molecule but so is Mad Cow Disease so we had better be careful about new drugs" is just about the most boring, banal comment you can make. Drugs: can they be unsafe??? We'll have more at 11!

We need more Derek Lowe-type drug safety discussion here, and a lot less of whatever this is.

Are you suggesting that every new molecule should be treated as if it were a prion?

I'm suggesting that sometimes a very small amount of a substance can cause catastrophic effects a decade later. That's why we do testing before we release drugs.

And Pfizer isn't the hero here, they never have been.

https://corporatewatch.org/pfizer-six-scandals-to-remember/

This list doesn't even include Celebrex.

1986: Pfizer had to withdraw an artificial heart valve from the market after defects led to it being implicated in over 300 deaths. The US Food and Drug Administration (FDA) withdrew its approval for the product in 1986 and Pfizer agreed to pay hundreds of millions of dollars in compensation after multiple lawsuits were brought against it.

2003: Pfizer has long been condemned for profiteering from AIDS drugs. In 2003 for example, it walked away from a licencing deal for its Rescriptor drug that would have made it cheaper for poorer countries.

2011: Pfizer was forced to pay compensation to families of children killed in the controversial Trovan drug trial. During the worst meningitis epidemic seen in Africa, in 1996, Pfizer ran a trial in Nigeria their new drug Trovan. Five of the 100 children who took Trovan died and it caused liver damage, while it caused lifelong disabilities in those who survived. But another group of 100 children were given the conventional “gold standard” meningitis antibiotic as a “control” group for comparison. Six of them also tragically died because, the families said, Pfizer had given them less than the recommended level of the conventional antibiotic in order to make Trovan look more effective.

2012: Pfizer had to pay around $1billion to settle lawsuits claiming its Prempro drug caused breast cancer. Prempro was used in hormone replacement therapy, usually for women going through the menopause. The settlements came after six years of trials and hardship for the women affected.

2013: Pfizer paid out $273 million to settle over 2,000 cases in the US that accused its smoking treatment drug Chantix of provoking suicidal and homicidal thoughts, self harm and severe psychological disorders. Pfizer was also accused of improperly excluding patients with a history of depression or other mental disturbances from trials for the drug. Later, in 2017, a coroner in Australia ruled that the drug had contributed to a man’s suicide. The man’s mother campaigned to change the label on the drug.

2020: Pfizer reached an agreement with thousands of customers of its depo-testosterone drug in 2018 after they sued it for increasing the likelihood of numerous issues, including heart attacks.

There is nothing here that suggests that:

>very small amount of a substance can cause catastrophic effects a decade later.

Medication failure modes are either short-term acute and found in test quickly, like Trovan example; or where long-term ingestion causes problems.

All of your examples are one of those two.

Are there any authorized or approved drugs that are taken over a short-term (say less than a month) that have been shown to cause long-term death?

This immediately jumped to mind (Contergan):

https://en.wikipedia.org/wiki/Thalidomide_scandal

    The total number of people affected by the use of thalidomide during the mother's pregnancy is estimated at more than 10,000, of whom approximately 40 percent died at or shortly after the time of birth. Those who survived had limb, eye, urinary tract, and heart defects [...] The severity and location of the deformities depended on how many days into the pregnancy the mother was before beginning treatment; thalidomide taken on the 20th day of pregnancy caused central brain damage, day 21 would damage the eyes, day 22 the ears and face, day 24 the arms, and leg damage would occur if taken up to day 28. Thalidomide did not damage the fetus if taken after 42 days' gestation.

So ~280 days for a pregnancy, minu 21-41 still leaves way more than half a year after taking the drug for when death occurred. And I wouldn't say the non-lethal effects are to be dismissed. If you ask me they're way up there for making sure something like that doesn't happen again. The system today (hopefully) is better than back then. And yes, personally I think it's a good thing when the approval process for drugs assumes that "every new molecule should be treated as if it were a prion".

It is perhaps worth mentioning that our ability to detect compounds that are mutagenic or teratogenic, or are likely to cause developmental abnormalities, has improved dramatically in the past 60 years, as has the stringency of drug testing. I'm not an expert, but I can certainly imagine that some of the animal testing that goes on today before a drug is approved is designed to identify problems in offspring. (The problem with thalidomide was not that its problems could not have been identified even 60 years ago; the problem was that the testing was not done or was suppressed.)

So the previous poster's question about drugs given for a short time causing long delayed effects and approved in the last 20 years stands. If a drug is not a mutagen, it is harder to imagine how it could have a long-term effect.

No idea how I missed this for three days, I'm sorry.

I absolutely agree that they could have tested for certain things but didn't. It's a product of its time in that sense:

    One reason for the initially unobserved side effects of the drug and the subsequent approval in West Germany was that at that time drugs did not have to be tested for teratogenic effects. They were tested on rodents only, as was usual at the time

(side note, not to start a flame war on that, but this is a prime example of what happens thanks to regulation but not market forces) While a lot has improved in that regard through regulation, one thing that sticks out is how similar some of this is to how things are still happening in much more recent times:

    While initially considered safe, the drug was responsible for teratogenic deformities in children born after their mothers used it during pregnancies, prior to the third trimester. In November 1961, thalidomide was taken off the market due to massive pressure from the press and public

Purdue pharma and Oxycontin come to mind. I wasn't even aware of this one until I just tried to find something else I vaguely remembered for you via a quick Google: https://www.reuters.com/investigates/special-report/usa-cour...

I doubly apply to medications that can potentially eff your one body/mind you have up for good what I practice in software development and try to teach my teams: assumptions make an ass out of you and me.

     If a drug is not a mutagen, it is harder to imagine how it could have a long-term effect. 

Harder, sure. I'm not a doctor, pharmacologist or anything like that. But I doubt that somehow doctors, pharmacologists, chemists et al are somehow immune to making assumptions. Test the hell out of this stuff. Check the "impossible" things and sometimes you will find that the "impossible" really just wasn't impossible, we just didn't think of something or didn't know about it yet. It's why general regression testing in an area can very easily find bugs. "But that's impossible, how's that related?" Well, I also can't tell you, it doesn't make immediate sense to me either but you will surely find out once you start debugging this and figure out how you broke that other downstream system, two steps removed from your change.

The OP suggested that one-off drugs rarely had long-term side effects. Thalidomide was raised as a counter example (an expectant mother might take it only once). Oxycontin is not a counter-example; the long term side effects (as opposed to short-term overdose) require dosing over an extended period.

If I’m reading this correctly, Thalidomide caused damage to fetal tissue, but didn’t actually kill the parent? This is still an awful burden for the parent, but there’s lots of drugs that are known to cause tissue damage during pregnancy. I believe this is why pregnant people are often excluded from clinical trials.

Yes, it didn't kill the parent. You might have missed the part where it killed 40% of the children at or shortly after birth.

And yes, that's (one reason) why the recommendations for the Covid vaccine were not given for pregnant women at first.

The point wasn't that there are drugs known to be dangerous to pregnant women (mainly the unborn child). The ask was for an approved drug that caused delayed death.

There were definitely so many things going wrong w/ that specific drug but it serves as a really good example for why all these precautions are taken and should be taken and any new drug should not be presumed safe but presumed dangerous and proven to not be harmful. The specific time frames and measures can of course be debated to find a good spot on the spectrum and an active pandemic can influence the choices. The discussion was going in the direction of some posters saying we should assume safe first and the Contergan case very clearly shows why assuming safety is the wrong choice.

I think the ask was actually for an approved drug, taken briefly, that caused a delayed death in the person who was taking it. If we’re going to count prenatal effects, we can come up with thousands of examples. This is why pregnant women are always studied separately.

Let's take that apart:

    Are there any authorized or approved drugs that are taken over a short-term (say less than a month) that have been shown to cause long-term death?


    authorized or approved.

Check. Contergan was approved and used in 46 countries. Notably in East Germany there are no known cases of this, because "thalidomide was rejected by the Central Committee of Experts for the Drug Traffic in the GDR, and was never approved for use."

    taken over a short-term (say less than a month)

Check. As quoted before, taking Contergan past day 42 didn't harm the fetus and deformities seem to have started on day 21. Less than a month.

    cause long-term death

Check. Over the long term (>6 months) it caused death in 40% of the babies born.

Nowhere in there does it say to exclude any drugs than only cause direct death to the taker. Nor do I think should that matter. I do agree that pregnant women are studied separately precisely because the risks there are higher. To quote from the wikipedia article again:

    The Society of Toxicology of Canada was formed after the effects of thalidomide were made public, focusing on toxicology as a discipline separate from pharmacology. The need for the testing and approval of the toxins in certain pharmaceutical drugs became more important after the disaster.

Sure. But that’s not what they meant. Can you name any drug that, when taken over a short course, has had long term detrimental effects to the person taking it?

It's debatable what someone meant or didn't mean, if they don't say it. I tend to go by what someone actually said. Especially on the internet (or writing in general) i.e. people you don't know, whose background you don't know, without intonation etc. There's very little to no information for interpretation.

Now you asked a new question. Fair enough. Unlike the previous question, where Contergan immediately jumped to my mind, for your question nothing jumps to mind. But google helped. I think you wanted to ask a different question, more like what I originally answered to, e.g.:

    Can you name any approved drug that, that when taken over a short course, can over the long term cause the death of the person taking it?

You did ask though:

    Can you name any drug that, when taken over a short course, has had long term detrimental effects to the person taking it?

Yes I can, for example: Heroin. https://en.wikipedia.org/wiki/Heroin

Let's take that apart:

    name any drug

Check. Heroin is a drug. It's even been prescribed as a pain killing opioid.

        The UK Department of Health's Rolleston Committee Report in 1926 established the British approach to diamorphine prescription to users, which was maintained for the next 40 years: dealers were prosecuted, but doctors could prescribe diamorphine to users when withdrawing. In 1964, the Brain Committee recommended that only selected approved doctors working at approved specialized centres be allowed to prescribe diamorphine and cocaine to users. The law was made more restrictive in 1968. Beginning in the 1970s, the emphasis shifted to abstinence and the use of methadone; currently, only a small number of users in the UK are prescribed diamorphine.

    taken over a short term

Check. Heroin is apparently way up there in addictiveness. After a very short period of time, you will be addicted (even if not like some people claim, after the very first use and regardless of dose or your own addiction susceptibility.

    However, contrary to Bayer's advertising as a "non-addictive morphine substitute," heroin would soon have one of the highest rates of addiction among its users.

Also https://web.archive.org/web/20100213101818/http://www.drugre... which curiously notes that nicotine is even more addictive than heroin. I'll not mention nicotine further here though, because the detrimental effect come from the other substances usually taken with it when ingested via tobacco as far as I am aware (tar).

    long term detrimental effects to the person taking it

Check. Detrimental effects of heroin are numerous. And given it's addictive very fast, even side effects that only turn up later, I would definitely include.

    Common side effects include respiratory depression (decreased breathing), dry mouth, drowsiness, impaired mental function, constipation, and addiction.[12] Side effects of use by injection can include abscesses, infected heart valves, blood-borne infections, and pneumonia.[12] After a history of long-term use, opioid withdrawal symptoms can begin within hours of the last use.

Not to mention the constant possibility of overdosing. Meaning death. The ultimate detrimental effect.

I commend your ability to think outside the box, bringing up pregnancy and addiction as answers to the asked question.

So I’ll ask a third time, hoping that perhaps finally I can get you to the original asker’s intention:

Can you name any drug that when taken for only a short period of time, like this Covid drug surely would be, and is non addictive like this Covid drug surely is not, is harmful in the long term to the person who took it (assuming they are not pregnant as all of the people who would be allowed to take it would not be)?

While I do like this discussion I also wonder why addictive substances have to be excluded. I understand that you would like have the answer to the question be "no I don't". We can find all sorts exclusions and find a narrow path to an answer that says "no no, all drugs are always safe, see, if you only take them for a month you won't mysteriously die from exactly this 20 years from now". And while that is most probably true (and if it were true, probably hard to prove), the real answer to the question is: Yes, there medications that even if taken for a short period of time will be detrimental and harmful to you over the long term and heroin or morphine are perfect examples of this.

Remember all those war movies? I remember watching Vietnam war movies as a kid and one of the things I remember best is the use of morphine as _the_ field medicine.

Now we can argue that, especially in those times, it might be better to give a soldier that just lost a limb in the battlefield morphine than not to. It doesn't change the fact that

https://www.onceasoldier.org/veteran-ptsd-and-opioid-addicti...

    The VA and other reports acknowledge that physicians need better training to manage opioid treatment for veterans. Between 2001 and 2009, for example, the percentage of veterans receiving pain management with prescription narcotics increased from 17 percent to 24 percent. The number of opioid prescriptions written by military physicians more than quadrupled during that time.

Full credit to you for this. My only quibble is that "narrow" should be "wide". But all of the rest of your points have been enjoyable to think about and hold a lot of important truth. I believe at the heart of it you have a concern for humans and their welfare that is to be rejoiced and encouraged. I hope you have a good weekend!

This "how did the vaccines get approved so quickly" thing has to be one of the most asked- and- answered questions of the entire pandemic. The basic delivery platform for the vaccines had already been in human trials before the pandemic. We've also been doing rapid development of vaccines for many, many years to combat things like influenza. Coronaviruses had already been well studied, and we had dry-runs for vaccine design with SARS and MERS.

You can just do a Google search to read about 1,000 articles about how the vaccines got approved as quickly as they did. You don't need to ask your friend who works at Gilead. Not for nothing: their clinical trials would probably go a lot faster with a global pandemic lighting a fire under them.

We've administered these vaccines to almost four billion people. "COVID vaccines are dangerous" has become an extraordinary claim, demanding extraordinary evidence. There are people who sincerely believe that aspirin is dangerous, and yeast, and "mycotoxins" on coffee beans, and on and on. We're not required to take these arguments seriously on faith.

You broke the site guidelines badly with this, and we ban accounts that do that. Please don't do this again.

If you'd please review https://news.ycombinator.com/newsguidelines.html and stick to the rules when posting here, we'd appreciate it.

Dan, you're protecting tptacek from criticism which is absolute bullshit. I very fairly criticized his lack of reading comprehension, and the fact he's not an expert in anything except for security. What he accused me of in his comments was worse and protecting him is bullshit.

He came in attacking me twice and you do nothing to his account? He didn't even read my post and then started his rant about the vaccine when I wasn't even talking about the vaccine.

If you're going to threaten with banning, I suggest you do it to everyone fairly, even if he's one of your "favorites". You should be flagging his posts, not mine.

Plus, you flagged my perfectly accurate post on how thalidomide is safe, it's the chiral version of it that causes deformities?

That wasn't a neutral post about thalidomide, it was obviously flamewar fodder, and therefore rightly flagged.

Would you please stop posting like this now? If you keep up this flamewarry/offtopic stuff, we're going to have to ban you. Also, please stop hounding any particular user. That's not in the spirit of the site at all.

https://news.ycombinator.com/newsguidelines.html

There really isn't (on HN, at least) such a thing as 'very fairly criticizing [anyone's] lack of reading comprehension' in those exact terms, it's just a slightly wordier version of 'did you read the article/comment/etc'.

Dan doesn't flag posts, users do.

So 6 out of how many other studies and drugs they've released without scandal?

If we're applying the COVID standard to Pfizer, would their failure rate be greater than or less than COVID's death rate?

If we use the 2% number I've seen around here for COVID's death rate, that means if Pfizer has over 300 drugs, these six scandals are a non-issue because they happen so rarely.

I’m perplexed why you are defending a corporation after such an excellent reply from the above poster ( and I’ve taken the vax).

But l add the death rate according the administration is around 0.5% from the latest stats due to lack of testing.

It's less defending Pfizer and questioning the poster's true motives.

Some people seem determined to do anything except take precautions laid out by infectious disease experts and take medicine specifically for this virus. And they're looking for any excuse to do so.

A diversity of people will have a diversity of risk registers, this is actually healthy for long term stability because mono cultures have associated risks.

No it's about one third of drugs according to a Yale study and it took a median of 4.2 years after the drugs were approved for safety concerns to be apparent.

Again, as someone who worked with toxicology, yeah. The default is every new molecule might be highly toxic and needs to be proven otherwise.

It’s why we don’t look at a molecule and say “oh, that’s not a carcinogen! No need to test”. And the same reason we run hERG tests to make sure drugs don’t give you a fatal arrhythmia (a surprising number of drugs do this and some are still on the market).

So over what time period do you believe we should wait to release a drug to the public? 10 - 25 years after discovery?

Straw man. I never said don’t release the drug or delay it decades, I said “the risk is always there”.

And funny you should say 10-25 years. 10 years is pretty typical from initial molecule discovery to FDA approval.

Sorry to offend.

I was referencing your assertion that all molecules are prions until proven otherwise.

Also, I asked two questions. Next time try answering them before jumping to being an ass.

The post to which you are (nominally) responding was not obnoxious in the least. Your name-calling most definitely is obnoxious. I thought this was an adult forum. Eternal November?

And please show us the words where where the poster claimed that “all molecules are prions”…as you claimed. I can point to your exact words here…look forward to you doing the same.

I'm not an expert, but I think if a molecule is isolated, it is possible to determine whether or not it is a prion. IIRC, prions are basically misfolded protiens that cause other protiens to misfold, like a corrupted file that passes the corruption on to every copy or derived file until the system crashes. But you can examine them before systemic problems show up. And I believe a prion has to be a protien-like molecule. Again, not an expert.

Actually: Yes.

> Prions are "just" proteins

According to whom? You make it sound as if at some point scientists thought that prions were "just proteins", which I'm sure is not true.

I'm not saying new medicine can't have side effects a long time after ingestion.

So we shouldn't introduce any new drugs unless it's been tested for more than 10 years? Seems like a great way to put a complete halt on drug development and have more people die / suffer from preventable diseases.

A recent HN posting would like to remind you that this logic doesn’t work:

https://rxisk.org/post-ssri-sexual-dysfunction-pssd/

There are plenty of drugs with long term effects despite not remaining in the body. Every addictive substance comes to mind, but so do chemotherapies and many other things.

And you're going to take the drug for only about 7-10 days. It's unlikely that such a short exposure will introduce lasting toxicity.