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Modification of acetaminophen to reduce liver toxicity and enhance drug efficacy

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Re: Modification of acetaminophen to reduce liver toxicity and enhance drug efficacy

#131

Post by kranner »

14 wrote: post #32
ItsHarper wrote: post #2

This would be incredibly cool if it works in reality and not just simulation. Remarkable that the author is just 17.

Seeing articles like this is almost hard to read. My kids are very smart but this girl is 1000 times what they are doing. This girl is 1000 times what I am doing. Maybe it is just imposter syndrome but sometimes I read articles like this and think I fell short in life. But I am also top of my peers at work and I am a health care provider and my clients all request me so I know I am doing good. Sometimes I just wonder…

I think the idea that one has to leave a mark on the world before one dies is overrated and not super useful.

First, what would such a mark be like for you? Is it something you could plausibly achieve with all the resources within your reach? Is it well-defined or is it nebulous? Is it likely to remain stable over the time you would require to achieve it, or is it more defined by the whims and fancies of the world which seemingly change every other week now?

Then, even if you did achieve it, how long would it continue to matter to you? Would you remain satisfied with it or could you become habituated to the achievement in a week, month or year and replace it another mark that would then become the one task you must complete before you die? Even if you did remain satisfied with your great achievement, would it really matter to you at the end of your life, or would you completely forget about it in the physical and mental anguish that many people seem to experience at the end of their lives?

And after you are dead, how long would that achievement be remembered before being supplanted in the public eye by something bigger?

And would it really make a difference to you at that point? Whether it remains a grand success for a thousand years or is forgotten in a day, you won't be there to know the difference anyway. It really only matters to you for the brief periods of time in which you're thinking about it right now. During times that you're distracted, tired, enjoying and appreciating something else or are simply asleep, it's hard to believe it matters at all.

If you're happy, healthy, not harming others, making a decent and honourable living, raising kids, I think you're already winning.

If the idea of having to leave a mark is making you unhappy, maybe it's better to just drop the idea.

Re: Modification of acetaminophen to reduce liver toxicity and enhance drug efficacy

#132

Post by pixl97 »

Jolter wrote: post #113
mulderc wrote: post #68

Earlier quoted context omitted.

“56,000 emergency department visits and 2600 hospitalizations, acetaminophen poisoning causes 500 deaths annually in the United States” -Acetaminophen Toxicity Suneil Agrawal; Brian P. Murray; Babak Khazaeni. https://www.ncbi.nlm.nih.gov/books/NBK441917/

That’s a lot. I keep forgetting how many idiots are in the world. Some of those are probably intentional suicide attempts. What’s the maximum number of tablets for one purchase? Sweden has it regulated down to 14, because that’s just enough to not cause permanent damage in a depressed teenager.

Um. I could go to Walmart or Target and buy pounds of it.

Re: Modification of acetaminophen to reduce liver toxicity and enhance drug efficacy

#133

Post by Rastonbury »

amelius wrote: post #127
Rastonbury wrote: post #125

Earlier quoted context omitted.

I take NAC to help with hangovers, I used to get smashing headaches and people would recommend random Korean and japanese 'hangover supplements', I was obviously very skeptical and googled every ingredient to check it is safe. The ones that worked had NAC or gluthanione. Looked into it and bought some and always take it when I drink or have panadol. Have not noticed any other subjective effects Nausea or vomitting is…

> I was obviously very skeptical and googled every ingredient to check it is safe. Did you check if drinking alcohol was safe? ;)

No because I already know the answer to that!

Re: Modification of acetaminophen to reduce liver toxicity and enhance drug efficacy

#134

Post by uselesswords »

foxwolf wrote: post #104

All my life, I've suffered from frequent (as in daily) headaches. I even have a photo of myself from my 10th birthday (or thereabouts), where you can visibly tell from how I'm holding my head that I had a headache. The nature and intensity of my headaches has changed over time. In my 20's I discovered Excedrin (acetaminophen + caffeine) and, surprisingly, it not only worked, but worked very well. One tablet would kil…

disclaimer: Not medical advice. Just an exercise in theory. See a real doctor/neurologist or migrane specialist.

I would be very suspect of a Medication Overuse Headache (MOH) due what appears to be acute/abortive use of painkiller medication as compared to a prophylactic usage of other drugs. I'll do this exercise mostly ignoring the #1 concern because presumably your doctors would be hyperaware of that.

# Pathways

0. Excedrin is combination of aspirin, acetaminophen, & caffeine.

1. Aspirin --> COX-1 (/2) inhibition --> Reduces Prostacyclin/Prostaglandin/Thromboxane Synthesis --> Decreased inflammation, nociceptor sensitization, pain signaling

2. Acetaminophen --> Central COX Inhibition, possible COX-3 inhibition (splice variant of COX-1) --> Reduces Prostacyclin/Prostaglandin/Thromboxane Synthesis --> Decreased inflammation, nociceptor sensitization, pain signaling

3.a. Acetaminophen --> Metabolized to N-Arachidonoylphenolamine (AM404) --> Inhibition of reuptake of Anadamide (endogenous cannabinoid) --> Increased activation of CB1 receptors

3.b. Acetaminophen --> Metabolized to N-Arachidonoylphenolamine (AM404) --> Transient Receptor Potential Vanilloid (TRPV1) agonist --> active? at periaqueductal (central) gray --> opioid receptors that send descending axons to modulate pain at the level of the dorsal horn of the spinal cord

4. Acetaminophen --> Enhancement of serotonergic descending inhibition (5-HT pathways)

5. Caffeine --> Adenosine anatagonist (nonselective A1, A2A, A2B) --> Inhibition of vasodilation --> Cerebral vasoconstriction

6. Caffeine --> Analgesic Adjuvant --> Enhances availability of aspirin and acetaminophen.

# Thoughts

1. Selective: -COX, +CB1, +TRPV1, +Opioid, -Serotenergic, -Adenosine, -Inflammation, +Vasoconstriction/-Vasodilation

2. Aspirin doesn't work in isolation.

3. Tylenol-3 (acetaminophen) doesn't work in isolation (surprising!!!).

4. Headaches probably not -COX mechanisms

5. Caffeine is likely needed for -adenosine, vasculature effect implicating cerebral vasodilation

6. Densensitization strongly implicates +CB1/+TRPV1 as well as -adenosine, +Sero, +Opioid.

# Concluding Thoughts

0. Need to address MOH, this should be a conversatio with your real doctor.

1. Then for the headache, normal first-line would probably be a TCA prophylaxis such as amitriptyline with bonus target +sero/+opioid. Assuming you've tried this.

2. The failure of your other drugs means you should probably try CGRP Inhibitors to target vascular and pain-signaling effects. Maybe even gepants (acute)

3. Botox could be a consideration in a complex CDH case.

4. Zebras: Ditan/Lasmiditan. I assumed +vasoconstriction, but could be -vasoconstriction which is why non-combination drugs failed. Target 5-HT1F and avoid vasoconstriction for symptomatic relief, but doesn't treat underlying. Probably avoid due to MOH.

# Clarifying questions for your doctor, not me

1. Is your headache pulsatile/throbbing (migrane) or dull, tight, & persistent (tension-type)?

2. Onset characterized by stress (tension-type)?

3. Is it unilateral (migrane) or bilateral (tension-type)?

# What I would do next

1. Make an appointment with a neurologist

2. Before the appointment, make a detailed headache diary (when your headaches start/end, intensity of the pain, location and quality of the pain, associated symptoms (nausea, light senstivity), any potential triggers, what you did to try to relieve the headache and if it worked)

Re: Modification of acetaminophen to reduce liver toxicity and enhance drug efficacy

#135

Post by oliwarner »

raffraffraff wrote: post #116
oliwarner wrote: post #82

Earlier quoted context omitted.

"Therapeutic index" is a strange number to worry about. Those index scores are the balance between efficacy and toxicity. Acetaminophen is an effective analgesic, just toxic in large doses. It's perfect for lower intensity pain. It's non-addictive, doesn't have long term issues like NSAIDs. It's popular for a reason.

My family always had boxes of it around the place when I was growing up. Never really had much use for pain killers. But when I was in my early 20s, no money, not looking at myself, I cracked a tooth in half and it took a few days to see the dentist. It was excruciating. First thing I did, take paracetamol (our name for acetaminophen). It did absolutely nothing. The pain was like a lightning bolt from tooth to brain.…

Neuropathic pain (which dental pain mostly is) is poorly handled.

I agree, paracetamol isn't perfect for every type of pain. NSAIDs help relieve pressure and can help, and opioids can waffle-stomp most pain but only for a little while and with dire risks of dependency, but for-purpose drugs like gabapentin are usually a lot more effective at blocking even high intensity neuropathic pain. Unlike NSAIDs, you can take them long term without needing a cocktail of PPIs to keep your stomach from imploding, and they're non-addictive.

Re: Modification of acetaminophen to reduce liver toxicity and enhance drug efficacy

#136

Post by shawabawa3 »

atombender wrote: post #121
porphyra wrote: post #43

It's always weird to me that acetaminophen has such a low therapeutic index, like in order to get enough for it to do anything, you're also on the verge of liver failure (especially if you also drink alcohol). Also it just doesn't work super well in my personal experience --- I hardly feel anything when I take it. And yet it's one of the most commonly taken medicines worldwide.

I'm a big fan of it in terms of efficacy; does wonders for headaches as well as joint aches. My concern is about the relatively recent findings about potential Alzheimer risk [1]: > During a median follow-up of 12.3 years, 6407 (3.0%) participants developed new-onset all-cause dementia. Participants who regularly used paracetamol had a significantly higher risk of new-onset all-cause dementia (adjusted HR, 1.18; 95%C…

I'm pretty sure ibuprofens risks are significantly higher than a 10-20% increased risk of dementia, it gives significantly increased risk of strokes iirc

Re: Modification of acetaminophen to reduce liver toxicity and enhance drug efficacy

#138

Post by mulderc »

Jolter wrote: post #113
mulderc wrote: post #68

Earlier quoted context omitted.

“56,000 emergency department visits and 2600 hospitalizations, acetaminophen poisoning causes 500 deaths annually in the United States” -Acetaminophen Toxicity Suneil Agrawal; Brian P. Murray; Babak Khazaeni. https://www.ncbi.nlm.nih.gov/books/NBK441917/

That’s a lot. I keep forgetting how many idiots are in the world. Some of those are probably intentional suicide attempts. What’s the maximum number of tablets for one purchase? Sweden has it regulated down to 14, because that’s just enough to not cause permanent damage in a depressed teenager.

My understanding is it isn’t so much people being idiots but that acetaminophen is in many products making it easy to overdose on when you are sick.

https://www.fda.gov/consumers/consumer-updates/dont-overuse-...

Re: Modification of acetaminophen to reduce liver toxicity and enhance drug efficacy

#139

Post by adamredwoods »

Mizza wrote: post #3

She didn't even break the top 10 in this content: https://www.societyforscience.org/regeneron-sts/2025-student... I'm impressed beyond words by these kids, though I think I'd give her the top prize. Watching my grandfather's final days taken away from him by the effects of morphine has always made me wish so much that we had much more effective non-narcotic painkillers

I'm pro-morphine as a controlled medicine for extreme pain and end-of-life. I've seen it work. I've had it post-surgery.

Fentanyl, my brother claims to be the best. It, too, can work wonders under a controlled environment.

Re: Modification of acetaminophen to reduce liver toxicity and enhance drug efficacy

#140

Post by dreamcompiler »

Ey7NFZ3P0nzAe wrote: post #61
dreamcompiler wrote: post #51

Earlier quoted context omitted.

Two tablets work great for me for headaches but results do vary. The danger zone for liver damage is roughly 14 tablets taken all at once. (Less if you've been drinking.) From what I'm told, acetaminophen overdose is quite an unpleasant way to die.

It's terrible that you are counting in tablets instead of actual amount of acetaminophen

It's not possible to state an absolute toxic dose in milligrams for everybody because it depends on things like your body mass, the preexisting condition of your liver, whether other liver-damaging drugs are on board, etc.

In my case I was talking about 500 mg tablets which are commonly branded in the US as "Extra Strength Tylenol."

The point I was trying to make is that the deadly dose divided by the therapeutic dose for acetaminophen can be as small as 7. This is a much smaller ratio than for most other common over-the-counter drugs. There's not much room for error with acetaminophen.

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