6 ms·

When working with biological systems, most of the time your acceptable error margin is between 10-25%. There are a few compounds (like fentanyl or LSD) where th

When working with biological systems, most of the time your acceptable error margin is between 10-25%. There are a few compounds (like fentanyl or LSD) where the dosages are so small and the compound so potent that 10-25% makes a difference but for the majority, precision isn't that critical. The ones where it does matter are tightly controlled and clinically applied by a professional with active monitoring. The only drugs that weren't within 10% of their original concentrations, according to the study, were amphetamines and aspirin. I can't think of any uses off the top of my head for those two where even 25% would make much of a difference to outcomes - amphetamines are mostly used as general purpose stimulants or to treat ADD and aspirin is not the blood thinner of choice for life and death situations. With amphetamines especially, what you eat and small factors like blood pH can have a massive impact on their effectiveness so we're already talking 10-20% differences day by day, let alone person to person.

JohnJamesRambo 9y ago
And to add into that, dosage studies are rarely adequately done for most drugs. The dose we take is often a best guess and may be twice or more than we need, so 10% is even more inconsequential.
- criley2 9y ago
  This is completely wrong. Dosage studies happens between Phase 2 and Phase 3 trials (and Phase 4 "post marketing" too) and are the most expensive, longest and most scientific process that arguably any business engages in in the entire world. Phase 1 is a safety test in healthy ~men. These seek to find the maximum dose before adverse effects appear in the healthiest humans. Phase 2 is a safety/dosage test in a much larger and varied sample. We know dose ranges and begin testing them for efficacy in a varied population. Phase 3 is the big one. It's a randomized, controlled, double blind test of SPECIFIC dosages in SPECIFIC target populations to scientifically prove efficacy over placebo. The dose we take is not a "BEST GUESS" It is the result of a billion dollars of scientific study and that PRECISE NME (new molecular entity) has been studied, at that PRECISE dose, in a target population, for it's effectiveness, and it must be better than existing-treatments and better than placebo. It should be highlighted that this process takes on average 10 years, costs $1 billion dollars, and has a success rate (success meaning FDA approval) of about 1 in 10,000 attempts (hence the price tag). Source: Drugs: From Discovery to Approval, Second Edition http://onlinelibrary.wiley.com/book/10.1002/9780470403587 http://onlinelibrary.wiley.com/book/10.1002/9780470403587
  - maxerickson 9y ago
    Do all 10,000 attempts go through all the testing? Or are many weeded out before $1 billion has been spent?
    - civilitty 9y ago
      The $1 billion dollar cost per drug is risk adjusted, so it includes all failed attempts at clinical trials and compounds that didn't make it through pre-trial screening. Edit: The $1 billion number is meaningless outside the context of large pharmaceutical companies. The cost for phase 3 trials is in the tens or hundreds of millions of dollars so the floor is a wide range and there have been instances of companies getting incredibly lucky and developing a drug for much less than a full billion.
  - PixelB 9y ago
    Sounds like you don't know what you are talking about. Your source is a book written with heavy influence by the Pharmaceutical industry to justify the obscene costs of their drugs, making billions in profits off of sick, poor people. You are the one who is completely wrong. The dosages most certainly do start out with a "best guess" in the pre-clinical phase. For any given drug we would guess at the doses based on our calculations, and give a range on either end. If we thought the effective dose would be 1 mg/kg, we would run an LD50 of doses much higher than that, 10mg/kg, 100mg/kg. Sometimes our guesses would be wrong, and the low dose animals would die as a result. After figuring out a safe dose, we would then split it further into different dosing groups to test the effectiveness of the compound. Most people in the field are underpaid, overworked, and do sloppy work Please talk to someone who has actually worked in the Pharma research field, they will tell you most of what they do is just guessing.. why do you think only 1 in 10,000 make it through? It's all a guess until the end, and even then we're often not sure. Look at anti-depressants. We still don't know how a lot of those work but prescribe them to millions of people regardless. How do you think they determined the dose when they don't know how the drug works?
    - gph 9y ago
      >It's all a guess until the end, and even then we're often not sure. Look at anti-depressants. We still don't know how a lot of those work but prescribe them to millions of people regardless. How do you think they determined the dose when they don't know how the drug works? We know how antidepressants work, the chemical reaction is well known and can be quantified at different doses. We just don't know why they work because we don't understand why/how the brain works. Pedantic but important difference.
13of40 9y ago
Any idea whether the chemicals they decompose into are ever more harmful than the original?
- pacaro 9y ago
  Aspirin is a bad actor in this regard. It tends to revert back to salicylic acid, which is ok for some specific topical uses, but has potential to be pretty harmful orally. Sniffing an old bottle of aspirin will tell you whether they're still good enough
  - AstralStorm 9y ago
    It's not that harmful if you know what you're dealing with. Have to be careful about liver toxicity and dosage but in a pinch it will work just fine as an antipyretic. It was used before aspirin has been invented.
  - Magnap 9y ago
    For the record, what you're smelling for is acetic acid (vinegar). When aspirin (acetylsalicylic acid) hydrolyzes into salicylic acid, the other product of that reactions is acetic acid, which is what's in vinegar.
    - pacaro 9y ago
      Thanks! It's been 25 years since my last pharmacology class, the details are all getting a bit vague.
sevenfive 9y ago
> There are a few compounds (like fentanyl or LSD) where the dosages are so small and the compound so potent that 10-25% makes a difference but for the majority, precision isn't that critical. Wrong. Therapeutic ratio, not dosage.
- civilitty 9y ago
  Wrong. LSD and fentanyl have polar opposite therapeutic indexes - the therapeutic index is specific to toxicity whereas I'm talking about clinical outcomes in general. There are drugs that have threshold doses below which there is essentially no effect on the patient but aren't toxic until 10-1000x that threshold dose. Fentanyl just happens to have an effective threshold dosage that is dangerously close to its LD50.
  - philipkglass 9y ago
    LSD has an exceptionally wide therapeutic index, but fentanyl's therapeutic index of 270 is pretty good as prescribed drugs go. That's a far wider TI than over the counter painkillers like ibuprofen. Warfarin, a common narrow-therapeutic-index drug, has a TI of ~2.
    - civilitty 9y ago
      Fentanyl's therapeutic index is NOT 270 except when used as an opioid supplement for surgical anesthesia cocktails, where the dosage is less a microgram per kilogram and it's balanced with several other drugs and opioid antagonists. The maximum recommended dose for fentanyl is 50 mcg/kg and that requires ventilation because it is well above the estimated LD50 of 30 mcg/kg. The recommended low dose for fentanyl on its own is 1 mcg/kg so at best we're talking about a therapeutic index of 30. LSD's therapeutic index is unknown because its LD50 has never been established in humans or monkeys and you can't extrapolate from non-primate animals to humans (for example, rats can handle a dose of fentanyl that is a thousand times higher per kg than monkeys can, which is where many of our LD50 estimates come from).
      - 9y ago
jack9 9y ago
Those 122 compounds were also over-representing publicly available products, as opposed to medically regulated compounds. You would need more rigor for a study where the compound efficacy actually mattered to make a general finding, across all classes of drugs. 25% difference in a beta blocker, glycerine, or blood thinner is a fatal change. These drugs are monitored with physical symptoms (metroprolol) and/or regular blood testing (sodium warafin/heparin/lovenox).
DINKDINK 9y ago
>your acceptable error margin is between 10-25% 10-25 percent of....what?
compuguy 9y ago
For the former (Amphetamines, or drugs derived from them), wouldn't the potency reduction of 25% be a big deal?
tripzilch 9y ago
You're talking about the study linked as "2006 study of 122 drugs", right? I can't find amphetamines in the tables or the text, what page is it on? (or was it maybe another paper linked in the article?) I have a prescription for dexamphetamine, but I don't use/need it a lot, so I have some bottles left that are a bit old--not past the expiration date, which appears to be slightly less than 3 years (after the date of the recipe), on the bottle I'm currently looking at. So I was curious about the amphetamines in particular, and if it's just efficacy deteriorating a bit that's fine, because in my personal experience the effect (which is quickly and clearly noticeable) varies easily by 25% already, depending on so many other factors (like what/how much I eat, how well I slept, stuff like that).

JohnJamesRambo 9y ago

And to add into that, dosage studies are rarely adequately done for most drugs. The dose we take is often a best guess and may be twice or more than we need, so 10% is even more inconsequential.

criley2 9y ago
This is completely wrong. Dosage studies happens between Phase 2 and Phase 3 trials (and Phase 4 "post marketing" too) and are the most expensive, longest and most scientific process that arguably any business engages in in the entire world. Phase 1 is a safety test in healthy ~men. These seek to find the maximum dose before adverse effects appear in the healthiest humans. Phase 2 is a safety/dosage test in a much larger and varied sample. We know dose ranges and begin testing them for efficacy in a varied population. Phase 3 is the big one. It's a randomized, controlled, double blind test of SPECIFIC dosages in SPECIFIC target populations to scientifically prove efficacy over placebo. The dose we take is not a "BEST GUESS" It is the result of a billion dollars of scientific study and that PRECISE NME (new molecular entity) has been studied, at that PRECISE dose, in a target population, for it's effectiveness, and it must be better than existing-treatments and better than placebo. It should be highlighted that this process takes on average 10 years, costs $1 billion dollars, and has a success rate (success meaning FDA approval) of about 1 in 10,000 attempts (hence the price tag). Source: Drugs: From Discovery to Approval, Second Edition http://onlinelibrary.wiley.com/book/10.1002/9780470403587 http://onlinelibrary.wiley.com/book/10.1002/9780470403587
- maxerickson 9y ago
  Do all 10,000 attempts go through all the testing? Or are many weeded out before $1 billion has been spent?
  - civilitty 9y ago
    The $1 billion dollar cost per drug is risk adjusted, so it includes all failed attempts at clinical trials and compounds that didn't make it through pre-trial screening. Edit: The $1 billion number is meaningless outside the context of large pharmaceutical companies. The cost for phase 3 trials is in the tens or hundreds of millions of dollars so the floor is a wide range and there have been instances of companies getting incredibly lucky and developing a drug for much less than a full billion.
- PixelB 9y ago
  Sounds like you don't know what you are talking about. Your source is a book written with heavy influence by the Pharmaceutical industry to justify the obscene costs of their drugs, making billions in profits off of sick, poor people. You are the one who is completely wrong. The dosages most certainly do start out with a "best guess" in the pre-clinical phase. For any given drug we would guess at the doses based on our calculations, and give a range on either end. If we thought the effective dose would be 1 mg/kg, we would run an LD50 of doses much higher than that, 10mg/kg, 100mg/kg. Sometimes our guesses would be wrong, and the low dose animals would die as a result. After figuring out a safe dose, we would then split it further into different dosing groups to test the effectiveness of the compound. Most people in the field are underpaid, overworked, and do sloppy work Please talk to someone who has actually worked in the Pharma research field, they will tell you most of what they do is just guessing.. why do you think only 1 in 10,000 make it through? It's all a guess until the end, and even then we're often not sure. Look at anti-depressants. We still don't know how a lot of those work but prescribe them to millions of people regardless. How do you think they determined the dose when they don't know how the drug works?
  - gph 9y ago
    >It's all a guess until the end, and even then we're often not sure. Look at anti-depressants. We still don't know how a lot of those work but prescribe them to millions of people regardless. How do you think they determined the dose when they don't know how the drug works? We know how antidepressants work, the chemical reaction is well known and can be quantified at different doses. We just don't know why they work because we don't understand why/how the brain works. Pedantic but important difference.

13of40 9y ago

Any idea whether the chemicals they decompose into are ever more harmful than the original?

pacaro 9y ago
Aspirin is a bad actor in this regard. It tends to revert back to salicylic acid, which is ok for some specific topical uses, but has potential to be pretty harmful orally. Sniffing an old bottle of aspirin will tell you whether they're still good enough
- AstralStorm 9y ago
  It's not that harmful if you know what you're dealing with. Have to be careful about liver toxicity and dosage but in a pinch it will work just fine as an antipyretic. It was used before aspirin has been invented.
- Magnap 9y ago
  For the record, what you're smelling for is acetic acid (vinegar). When aspirin (acetylsalicylic acid) hydrolyzes into salicylic acid, the other product of that reactions is acetic acid, which is what's in vinegar.
  - pacaro 9y ago
    Thanks! It's been 25 years since my last pharmacology class, the details are all getting a bit vague.

sevenfive 9y ago

> There are a few compounds (like fentanyl or LSD) where the dosages are so small and the compound so potent that 10-25% makes a difference but for the majority, precision isn't that critical. Wrong. Therapeutic ratio, not dosage.

civilitty 9y ago
Wrong. LSD and fentanyl have polar opposite therapeutic indexes - the therapeutic index is specific to toxicity whereas I'm talking about clinical outcomes in general. There are drugs that have threshold doses below which there is essentially no effect on the patient but aren't toxic until 10-1000x that threshold dose. Fentanyl just happens to have an effective threshold dosage that is dangerously close to its LD50.
- philipkglass 9y ago
  LSD has an exceptionally wide therapeutic index, but fentanyl's therapeutic index of 270 is pretty good as prescribed drugs go. That's a far wider TI than over the counter painkillers like ibuprofen. Warfarin, a common narrow-therapeutic-index drug, has a TI of ~2.
  - civilitty 9y ago
    Fentanyl's therapeutic index is NOT 270 except when used as an opioid supplement for surgical anesthesia cocktails, where the dosage is less a microgram per kilogram and it's balanced with several other drugs and opioid antagonists. The maximum recommended dose for fentanyl is 50 mcg/kg and that requires ventilation because it is well above the estimated LD50 of 30 mcg/kg. The recommended low dose for fentanyl on its own is 1 mcg/kg so at best we're talking about a therapeutic index of 30. LSD's therapeutic index is unknown because its LD50 has never been established in humans or monkeys and you can't extrapolate from non-primate animals to humans (for example, rats can handle a dose of fentanyl that is a thousand times higher per kg than monkeys can, which is where many of our LD50 estimates come from).
    - 9y ago

jack9 9y ago

Those 122 compounds were also over-representing publicly available products, as opposed to medically regulated compounds. You would need more rigor for a study where the compound efficacy actually mattered to make a general finding, across all classes of drugs. 25% difference in a beta blocker, glycerine, or blood thinner is a fatal change. These drugs are monitored with physical symptoms (metroprolol) and/or regular blood testing (sodium warafin/heparin/lovenox).

DINKDINK 9y ago

>your acceptable error margin is between 10-25% 10-25 percent of....what?

compuguy 9y ago

For the former (Amphetamines, or drugs derived from them), wouldn't the potency reduction of 25% be a big deal?

tripzilch 9y ago

You're talking about the study linked as "2006 study of 122 drugs", right? I can't find amphetamines in the tables or the text, what page is it on? (or was it maybe another paper linked in the article?) I have a prescription for dexamphetamine, but I don't use/need it a lot, so I have some bottles left that are a bit old--not past the expiration date, which appears to be slightly less than 3 years (after the date of the recipe), on the bottle I'm currently looking at. So I was curious about the amphetamines in particular, and if it's just efficacy deteriorating a bit that's fine, because in my personal experience the effect (which is quickly and clearly noticeable) varies easily by 25% already, depending on so many other factors (like what/how much I eat, how well I slept, stuff like that).