6 ms·

Mapping the off-target effects of every FDA-approved drug in existence

162 points by abhishaike 1y ago

nerdsniper 1y ago
Interestingly, it does not seem to have any controlled substances - even Schedule V drugs like Lyrica (pregabalin). So they've mapped estradiol and estrone, but not testosterone or drostanolone. Also cabergoline and pramipexole, but not amphetamine or methylphenidate.
- Spivak 1y ago
  Is testosterone a controlled substance? But why?
  - BizarroLand 1y ago
    Because it can be dangerous if misused. It's a steroid, so body builders would use it constantly. It's a sex hormone, so people would use it to masculinize themselves and amp up their sex drive, and it's part of the pubertal cycle so children exposed to it pre-puberty can have masculinizing pubertal side effects before their actual puberty starts.
    - Spivak 1y ago
      I'm not saying to sell it over the counter but surely just bring a prescription would be sufficient. I see medspa clinics advertising it to men for its masculinizing effects so it can't be that hard to acquire.
      - BizarroLand 1y ago
        You asked why it was a controlled substance. It's not hard to acquire. Doesn't mean that it's not a controlled substance. And in fact it is sold over the counter in other countries like Mexico. You get a "prescription" from the "on-site pharmacist" who is actually just some person who works the register.
        Spivak 1y ago
        Is that how that works?! I've always wondered what legal trickery they used since Mexico isn't listed on the WHO's list of countries who don't require Rx for antibiotics.
        BizarroLand 1y ago
        Pretty much. I went on vacation and went into a pharmacy out of curiosity, and they had a laminated card of steroids and other drugs you could get with pre-determined prices and no medical examination required.
      - immibis 1y ago
        Wouldn't needing a prescription be... a control?
        leoh 1y ago
        Yes, but the DEA is unrelentingly cranky and likes to tell physicians how to practice medicine despite swearing up and down that they would never, ever do that.
        klooney 1y ago
        California used to have a medical marijuana program where access was supposed to be controlled by requiring licensed physicians to prescribe it. Turns out there's enough disgraced doctors to rubber stamp huge volumes of prescriptions, rendering the control a joke. If the DEA isn't cranky, we go back to pill mills.
        leoh 1y ago
        Not sure what the problem is, except for the DEA again. Have you heard about how alcohol is sold?
        klooney 11mo ago
        If you want to limit the availability of a substance, you can't rely on Responsible Professionals acting as gatekeepers- too many will take the money and run.
        ranger_danger 1y ago
        When people in the (US at least) healthcare industry use the word "control" they are specifically referring to the well-defined "controlled substances". In the context of the legally defined controlled substances or "scheduled drugs", no, needing a prescription does not automatically mean it is a controlled drug. Is a prescription inherently a type of 'control' against who can access certain drugs? Sure, but I don't think anyone was arguing that.
    - terminalshort 1y ago
      Everything can be dangerous if misused
  - Etheryte 1y ago
    All steroids have a very high risk of misuse, it's incredibly easy to get your body addicted one way or another and it's one of those things that's very hard to fix after the fact.
    - Spivak 1y ago
      The addictive component makes sense, does that mean men who are injured and produce less go through withdrawal? Or like men as they age? That sounds miserable.
      - throwaway48476 1y ago
        It means the body stops producing it and won't ever again.
        GenerWork 1y ago
        This is absolutely false. There's thousands of gym bros who've done absolutely stupid cycles with absolutely no post cycle therapy who've recovered and are producing testosterone again.
        the_sleaze_ 1y ago
        That's the tag-line but it isn't true. I personally know of several early 20s guys who were between light and heavy cycles all under the supervision of doctors (or at least getting blood tested periodically). All of them have renal issues, kidney issues, adrenal system issues, thyroid issues. Some have heart problems. Not one of them is unscathed.
    - dvaun 1y ago
      Steroid abuse indicates body dysmorphia. There isn’t an addictive property like other abused drugs, unless you’re considering it addictive via its effects on dopamine production. Your body doesn’t become addicted, though. The potential for harm is real if you are not taking it under medical supervision or without proper knowledge of usage, like any other drugs.
  - Aurornis 1y ago
    Taking extra testosterone can be acutely rewarding and stimulating. It has moderate addiction potential. It also creates physical dependence by suppressing your body’s production, resulting in testicular atrophy. Some people who experiment with testosterone discover that it can take months or years to rebound, if they can at all.
  - nerdsniper 1y ago
    Mostly only because legislators had a weird obsession with sports, and decided that was a necessary and reasonable to way to prevent doping in sports.
wizzwizz4 1y ago
EvE Bio dataset and explorer: https://data.evebio.org/ https://data.evebio.org/ Novartis dataset paper: https://doi.org/10.1038/s41467-023-40064-9 https://doi.org/10.1038/s41467-023-40064-9
et2o 1y ago
People have been doing this for literally decades. Check out work by Tattonetti
pfisherman 1y ago
This article kind of grinds my gears. I feel like there is an unstated assumption that people in pharma R&D are idiots and haven’t thought of this stuff. Pharma companies care very much about off target effects. Molecules get screened against tox targets, and a bad tox readout can be a death sentence for an entire program. And you need to look at the toxicity of major metabolites too. One of the major value propositions of non small molecule modalities like biologics is specificity, and alternative metabolism pathways; no need to worry about the CYPs. Another thing they fail to account for is volume of distribution. Does it matter if it hits some receptor only expressed in microglia if it can’t cross the blood brain barrier? Also the reason why off targets for a lot of FDA approved drugs are unknown is because they were approved in the steampunk industrial era. To me this whole article reads like an advertisement for a screening assay.
- abhishaike 1y ago
  >molecules get screened against tox targets sure! i cover this in the essay, the purpose of this dataset is not just toxicity, but repurposing also >toxicity of major metabolites this is planned (and also explicitly mentioned in the article) >no need to worry about CYP’s again, this is about more than just toxicity >volume of distribution i suppose, but this feels like a strange point to raise. this dataset doesnt account for a lot of things, no biological dataset does >advertisement to some degree: it is! but it is also one that is free for academic usage and the only one of its kind accessible to smaller biopharmas
  - pfisherman 1y ago
    My main point of skepticism about repurposing is whether this is giving any of new and actionable information. It seems to be reliant on pre existing target annotations, and qualified targets already have molecules designed for them. Is the off-target effect strong enough to give you a superior molecule? Why not just start by picking a qualified target and committing to designing a better molecule without doing all the off target assay stuff first?
- colingauvin 1y ago
  I work in drug discovery (like for real, I have a DC under my belt, not hypothetical AI protein generation blah blah) and had the opposite experience reading it. We understand so little about most drugs. Dialing out selectivity for a closely related protein was one of the most fun and eye opening experiences of my career. Of course we've thought of all these things. But it's typically fragmented, and oftentimes out of scope. One of the hardest parts of any R&D project is honestly just doing a literature search to the point of exhaustion.
nextworddev 1y ago
This substack has a serious fraud smell

162 points by abhishaike 1y ago

Interestingly, it does not seem to have any controlled substances - even Schedule V drugs like Lyrica (pregabalin). So they've mapped estradiol and estrone, but not testosterone or drostanolone. Also cabergoline and pramipexole, but not amphetamine or methylphenidate.

Spivak 1y ago
Is testosterone a controlled substance? But why?
- BizarroLand 1y ago
  Because it can be dangerous if misused. It's a steroid, so body builders would use it constantly. It's a sex hormone, so people would use it to masculinize themselves and amp up their sex drive, and it's part of the pubertal cycle so children exposed to it pre-puberty can have masculinizing pubertal side effects before their actual puberty starts.
  - Spivak 1y ago
    I'm not saying to sell it over the counter but surely just bring a prescription would be sufficient. I see medspa clinics advertising it to men for its masculinizing effects so it can't be that hard to acquire.
    - BizarroLand 1y ago
      You asked why it was a controlled substance. It's not hard to acquire. Doesn't mean that it's not a controlled substance. And in fact it is sold over the counter in other countries like Mexico. You get a "prescription" from the "on-site pharmacist" who is actually just some person who works the register.
      - Spivak 1y ago
        Is that how that works?! I've always wondered what legal trickery they used since Mexico isn't listed on the WHO's list of countries who don't require Rx for antibiotics.
        BizarroLand 1y ago
        Pretty much. I went on vacation and went into a pharmacy out of curiosity, and they had a laminated card of steroids and other drugs you could get with pre-determined prices and no medical examination required.
    - immibis 1y ago
      Wouldn't needing a prescription be... a control?
      - leoh 1y ago
        Yes, but the DEA is unrelentingly cranky and likes to tell physicians how to practice medicine despite swearing up and down that they would never, ever do that.
        klooney 1y ago
        California used to have a medical marijuana program where access was supposed to be controlled by requiring licensed physicians to prescribe it. Turns out there's enough disgraced doctors to rubber stamp huge volumes of prescriptions, rendering the control a joke. If the DEA isn't cranky, we go back to pill mills.
        leoh 1y ago
        Not sure what the problem is, except for the DEA again. Have you heard about how alcohol is sold?
        klooney 11mo ago
        If you want to limit the availability of a substance, you can't rely on Responsible Professionals acting as gatekeepers- too many will take the money and run.
      - ranger_danger 1y ago
        When people in the (US at least) healthcare industry use the word "control" they are specifically referring to the well-defined "controlled substances". In the context of the legally defined controlled substances or "scheduled drugs", no, needing a prescription does not automatically mean it is a controlled drug. Is a prescription inherently a type of 'control' against who can access certain drugs? Sure, but I don't think anyone was arguing that.
  - terminalshort 1y ago
    Everything can be dangerous if misused
- Etheryte 1y ago
  All steroids have a very high risk of misuse, it's incredibly easy to get your body addicted one way or another and it's one of those things that's very hard to fix after the fact.
  - Spivak 1y ago
    The addictive component makes sense, does that mean men who are injured and produce less go through withdrawal? Or like men as they age? That sounds miserable.
    - throwaway48476 1y ago
      It means the body stops producing it and won't ever again.
      - GenerWork 1y ago
        This is absolutely false. There's thousands of gym bros who've done absolutely stupid cycles with absolutely no post cycle therapy who've recovered and are producing testosterone again.
        the_sleaze_ 1y ago
        That's the tag-line but it isn't true. I personally know of several early 20s guys who were between light and heavy cycles all under the supervision of doctors (or at least getting blood tested periodically). All of them have renal issues, kidney issues, adrenal system issues, thyroid issues. Some have heart problems. Not one of them is unscathed.
  - dvaun 1y ago
    Steroid abuse indicates body dysmorphia. There isn’t an addictive property like other abused drugs, unless you’re considering it addictive via its effects on dopamine production. Your body doesn’t become addicted, though. The potential for harm is real if you are not taking it under medical supervision or without proper knowledge of usage, like any other drugs.
- Aurornis 1y ago
  Taking extra testosterone can be acutely rewarding and stimulating. It has moderate addiction potential. It also creates physical dependence by suppressing your body’s production, resulting in testicular atrophy. Some people who experiment with testosterone discover that it can take months or years to rebound, if they can at all.
- nerdsniper 1y ago
  Mostly only because legislators had a weird obsession with sports, and decided that was a necessary and reasonable to way to prevent doping in sports.

wizzwizz4 1y ago

EvE Bio dataset and explorer: https://data.evebio.org/ https://data.evebio.org/ Novartis dataset paper: https://doi.org/10.1038/s41467-023-40064-9 https://doi.org/10.1038/s41467-023-40064-9

et2o 1y ago

People have been doing this for literally decades. Check out work by Tattonetti

pfisherman 1y ago

This article kind of grinds my gears. I feel like there is an unstated assumption that people in pharma R&D are idiots and haven’t thought of this stuff. Pharma companies care very much about off target effects. Molecules get screened against tox targets, and a bad tox readout can be a death sentence for an entire program. And you need to look at the toxicity of major metabolites too. One of the major value propositions of non small molecule modalities like biologics is specificity, and alternative metabolism pathways; no need to worry about the CYPs. Another thing they fail to account for is volume of distribution. Does it matter if it hits some receptor only expressed in microglia if it can’t cross the blood brain barrier? Also the reason why off targets for a lot of FDA approved drugs are unknown is because they were approved in the steampunk industrial era. To me this whole article reads like an advertisement for a screening assay.

abhishaike 1y ago
>molecules get screened against tox targets sure! i cover this in the essay, the purpose of this dataset is not just toxicity, but repurposing also >toxicity of major metabolites this is planned (and also explicitly mentioned in the article) >no need to worry about CYP’s again, this is about more than just toxicity >volume of distribution i suppose, but this feels like a strange point to raise. this dataset doesnt account for a lot of things, no biological dataset does >advertisement to some degree: it is! but it is also one that is free for academic usage and the only one of its kind accessible to smaller biopharmas
- pfisherman 1y ago
  My main point of skepticism about repurposing is whether this is giving any of new and actionable information. It seems to be reliant on pre existing target annotations, and qualified targets already have molecules designed for them. Is the off-target effect strong enough to give you a superior molecule? Why not just start by picking a qualified target and committing to designing a better molecule without doing all the off target assay stuff first?
colingauvin 1y ago
I work in drug discovery (like for real, I have a DC under my belt, not hypothetical AI protein generation blah blah) and had the opposite experience reading it. We understand so little about most drugs. Dialing out selectivity for a closely related protein was one of the most fun and eye opening experiences of my career. Of course we've thought of all these things. But it's typically fragmented, and oftentimes out of scope. One of the hardest parts of any R&D project is honestly just doing a literature search to the point of exhaustion.

nextworddev 1y ago

This substack has a serious fraud smell