5 ms·

And why not just regular old ketamine instead of a dangerous, untested new derivative? The whole system is broken beyond repair.

La1n 7y ago
It is being tested and it's not a "dangerous, untested new derivative", it's a enantiomer of ketamine, it's literally 50% of the molecules in ketamine. And why don't we just use normal ketamine, why test any new drug, to see if it works better than what we had before.
- SomeOldThrow 7y ago
  > it's a enantiomer of ketamine, it's literally 50% of the molecules in ketamine I’m not a biologist or a chemist. Why does this imply the chemical is as safe? What is the benefit? It seems like a blatant patent grab to bypass the low profit margins of ketamine. Is there evidence otherwise?
  - badamp 7y ago
    The short answer is it can be both (ie safe, beneficial and effectively a patent grab). It is also unlikely that an enantiopure chemical is less safe then it’s racemic counterpart and not unlikely that it is beneficial (this is not without precedent... this is also chemistry 101 and I don’t feel this is the forum for it)... The doubt is not so much the safety but is the benefit of the enantiopure version worth the cost.
    - tempguy9999 7y ago
      Per my comment above, thalidomide is a clear exception. This stands even if the chirality changes within the body.
      - rocqua 7y ago
        That was an example on the other direction. A pure chirality was safe, but a racemic mixture was dangerous. Here we know the racemic mixture is safe, which strongly suggests that either chirality in isolation is also safe.
        Nasrudith 7y ago
        And to make in the previous worse it would apparently "autobalance" and flip to chirality which meant that even if they 100% isolated it at great expense is why we never saw "rebranded Thalimoide but isolated to be all morning sickness drug no birth defects". I don't know enough details to tell how long it took and if it could even be used safely under ludicrously impractical assumptions like "if you it freshly isolated in bulk and take it within five seconds it would be safe but expire in an hour".
        tempguy9999 7y ago
        I think it flipped when in the body, so however long the shelf life was, it still wouldn't matter. Incidentally, and AIUI, the body has a tagging system for unwanted proteins. Once tagged, the proteins are removed. Thalidomide tagged the proteins the were specific to embryonic limb formation, and the body duly cleared them, leading to the infamous result. Again AIUI.
  - skissane 7y ago
    Not a biologist or chemist either, but I'll try to give my layperson understanding: basically, many molecules exist in two different versions which are mirror images of each other (enantiomers). Most drugs are actually an equal mixture of both enantiomers (called a racemic mixture), but often only one of the enantiomers has the desired drug effect, and the other doesn't actually do anything. It is possible to create a drug which has only the effective enantiomer; usually, a pure dose of the effective enantiomer will be effective at half the dose as the racemic mixture. Medically, there are some advantages – both forms need to be metabolised by the liver, so being able to use half the dose to get the same effect gives the liver less work to do, which can reduce the risk of drug-induced liver injury. If the racemic mixture is already being widely used, then the risk of the pure effective enantiomer is likely to be low, since it is basically just a more effective form of the already used drug, and the side effect profile should be similar to the existing drug. Chemically, the manufacturing process is more complex, which adds to manufacturing costs; however, the main driver of additional costs is that you can get a new patent for the active enantiomer even after the patent on the racemic mixture is expired. For example, the common SSRI anti-depressant citalopram is the racemic mixture, whereas escitalopram is the S-enantiomer. Similarly, esketamine would be the S-enantiomer of ketamine.
- soulofmischief 7y ago
  A lot of chemicals are "50%" of each other but completely different. That's not how chemistry works. Water is H₂0. Hydrogen peroxide is H₂0₂. I wouldn't substitute one for the other.
  - XMPPwocky 7y ago
    Do you know of any examples where a racemic mixture has an effect dramatically different from what you'd expect from a combination of the enantiomers' effects?
    - kellerbw 7y ago
      Thalidomide. One enantiomer is a great morning sickness drug, the other causes catastrophic birth defects.
      - refurb 7y ago
        Thalidomide interconverts in the body. There is no difference between the enantiomers in the human body (there is in a petri dish).
    - tempguy9999 7y ago
      I'm not sure I understand the question[0] fully but thalidomide? https://en.wikipedia.org/wiki/Thalidomide https://en.wikipedia.org/wiki/Thalidomide "Thalidomide is provided as a racemic mixture of two enantiomers; while there are reports that only one of the enantiomers may cause birth defects, the body converts each enantiomer into the other through mechanisms that are not well understood." [0] because a racemic mixture (https://en.wikipedia.org/wiki/Racemates https://en.wikipedia.org/wiki/Racemates) is a 50/50 mix of enantiomers: "In chemistry, a racemic mixture, or racemate [...] has equal amounts of left- and right-handed enantiomers of a chiral molecule" so if you took a racemic mixture surely you'd be getting a combination of the enantiomers' effects?
    - soulofmischief 7y ago
      Amphetamine, for one. Levoamphetamine or dextroamphetamine provide two different physiological experiences (think coffee vs meth). The effects profile of racemic amphetamine is markedly different and much easier to handle physiologically than just dextroamphetamine by itself (the most common isomer found in amphetamine prescription products). From a perspective of safety, I don't have any reason to suspect esketamine to be any worse. However from a psychological perspective, we could be talking pretty big differences in some individuals where subtle changes in behavior or thought can have cascading effects on mood. But... that's why we're testing its efficacy, right? It's stupid not to try, and these test subjects are willing. One of the two isomers will be better in some categories. Could be that both together are the way to go. Having only encountered racemic ketamine I can definitely understand its uses in treating depression.
- deleted 7y ago
  [deleted]
gyuserbti 7y ago
It amazes me how the problems with our drug and medical regulation system never come up even when it's staring us in the face. This article is typical, framing it as a problem with pharm companies rather than with the regulatory system. Between stuff like this, the opioid crisis, and cannabis deregulation, it should be obvious how broken and monopolistic the system is (referring to the FDA, DEA, and medical licensure system).

La1n 7y ago

It is being tested and it's not a "dangerous, untested new derivative", it's a enantiomer of ketamine, it's literally 50% of the molecules in ketamine. And why don't we just use normal ketamine, why test any new drug, to see if it works better than what we had before.

SomeOldThrow 7y ago
> it's a enantiomer of ketamine, it's literally 50% of the molecules in ketamine I’m not a biologist or a chemist. Why does this imply the chemical is as safe? What is the benefit? It seems like a blatant patent grab to bypass the low profit margins of ketamine. Is there evidence otherwise?
- badamp 7y ago
  The short answer is it can be both (ie safe, beneficial and effectively a patent grab). It is also unlikely that an enantiopure chemical is less safe then it’s racemic counterpart and not unlikely that it is beneficial (this is not without precedent... this is also chemistry 101 and I don’t feel this is the forum for it)... The doubt is not so much the safety but is the benefit of the enantiopure version worth the cost.
  - tempguy9999 7y ago
    Per my comment above, thalidomide is a clear exception. This stands even if the chirality changes within the body.
    - rocqua 7y ago
      That was an example on the other direction. A pure chirality was safe, but a racemic mixture was dangerous. Here we know the racemic mixture is safe, which strongly suggests that either chirality in isolation is also safe.
      - Nasrudith 7y ago
        And to make in the previous worse it would apparently "autobalance" and flip to chirality which meant that even if they 100% isolated it at great expense is why we never saw "rebranded Thalimoide but isolated to be all morning sickness drug no birth defects". I don't know enough details to tell how long it took and if it could even be used safely under ludicrously impractical assumptions like "if you it freshly isolated in bulk and take it within five seconds it would be safe but expire in an hour".
        tempguy9999 7y ago
        I think it flipped when in the body, so however long the shelf life was, it still wouldn't matter. Incidentally, and AIUI, the body has a tagging system for unwanted proteins. Once tagged, the proteins are removed. Thalidomide tagged the proteins the were specific to embryonic limb formation, and the body duly cleared them, leading to the infamous result. Again AIUI.
- skissane 7y ago
  Not a biologist or chemist either, but I'll try to give my layperson understanding: basically, many molecules exist in two different versions which are mirror images of each other (enantiomers). Most drugs are actually an equal mixture of both enantiomers (called a racemic mixture), but often only one of the enantiomers has the desired drug effect, and the other doesn't actually do anything. It is possible to create a drug which has only the effective enantiomer; usually, a pure dose of the effective enantiomer will be effective at half the dose as the racemic mixture. Medically, there are some advantages – both forms need to be metabolised by the liver, so being able to use half the dose to get the same effect gives the liver less work to do, which can reduce the risk of drug-induced liver injury. If the racemic mixture is already being widely used, then the risk of the pure effective enantiomer is likely to be low, since it is basically just a more effective form of the already used drug, and the side effect profile should be similar to the existing drug. Chemically, the manufacturing process is more complex, which adds to manufacturing costs; however, the main driver of additional costs is that you can get a new patent for the active enantiomer even after the patent on the racemic mixture is expired. For example, the common SSRI anti-depressant citalopram is the racemic mixture, whereas escitalopram is the S-enantiomer. Similarly, esketamine would be the S-enantiomer of ketamine.
soulofmischief 7y ago
A lot of chemicals are "50%" of each other but completely different. That's not how chemistry works. Water is H₂0. Hydrogen peroxide is H₂0₂. I wouldn't substitute one for the other.
- XMPPwocky 7y ago
  Do you know of any examples where a racemic mixture has an effect dramatically different from what you'd expect from a combination of the enantiomers' effects?
  - kellerbw 7y ago
    Thalidomide. One enantiomer is a great morning sickness drug, the other causes catastrophic birth defects.
    - refurb 7y ago
      Thalidomide interconverts in the body. There is no difference between the enantiomers in the human body (there is in a petri dish).
  - tempguy9999 7y ago
    I'm not sure I understand the question[0] fully but thalidomide? https://en.wikipedia.org/wiki/Thalidomide https://en.wikipedia.org/wiki/Thalidomide "Thalidomide is provided as a racemic mixture of two enantiomers; while there are reports that only one of the enantiomers may cause birth defects, the body converts each enantiomer into the other through mechanisms that are not well understood." [0] because a racemic mixture (https://en.wikipedia.org/wiki/Racemates https://en.wikipedia.org/wiki/Racemates) is a 50/50 mix of enantiomers: "In chemistry, a racemic mixture, or racemate [...] has equal amounts of left- and right-handed enantiomers of a chiral molecule" so if you took a racemic mixture surely you'd be getting a combination of the enantiomers' effects?
  - soulofmischief 7y ago
    Amphetamine, for one. Levoamphetamine or dextroamphetamine provide two different physiological experiences (think coffee vs meth). The effects profile of racemic amphetamine is markedly different and much easier to handle physiologically than just dextroamphetamine by itself (the most common isomer found in amphetamine prescription products). From a perspective of safety, I don't have any reason to suspect esketamine to be any worse. However from a psychological perspective, we could be talking pretty big differences in some individuals where subtle changes in behavior or thought can have cascading effects on mood. But... that's why we're testing its efficacy, right? It's stupid not to try, and these test subjects are willing. One of the two isomers will be better in some categories. Could be that both together are the way to go. Having only encountered racemic ketamine I can definitely understand its uses in treating depression.
deleted 7y ago
[deleted]

gyuserbti 7y ago

It amazes me how the problems with our drug and medical regulation system never come up even when it's staring us in the face. This article is typical, framing it as a problem with pharm companies rather than with the regulatory system. Between stuff like this, the opioid crisis, and cannabis deregulation, it should be obvious how broken and monopolistic the system is (referring to the FDA, DEA, and medical licensure system).