RE:RE:RE:RE:RE:Keep this in mind LONGs ...There is alot to unpack here so I'll take it one by one.
The "liver history" that you are alluding to is likely the issue with paid participant from the ph1 trial. That individual was polypharmacy trial participants i.e. he was in more than one clinical trial, lied about it, and had a history of cholecystis (reference ~16:30 mark: https://www.youtube.com/watch?v=w_3heP7ol0A).
The current pause is precautionary and purely based on trial design criteria. IF (subjects LTEs) >= 5* (ULN) THEN (pause and investigate). Now that the investigation is completed, heres what was found, and I'll just quote Dan Legualt from his latest interview with Bloom Burton 2022:
"All NSAIDS cause AST and ALT rises in the neighbourhood of 2-4% of people. Tylenol causes 39%, but Tylenol would never be approved today. Historically we've been at about a 9% average and it's too much. We've finally think we've actually figured it out. It's clear that it's coming from reactive oxygen species from naproxen, all NSAIDS cause them and we think it's from the reactive oxygen species. In a small number of people, this 9%, everyone of whom has pre-existing liver damage, but common damage, so it's still something we have to deal with, we can't just exclude them. What is happening, and this is still a hypothesis, but this is pretty considered hypothesis. In the past 2 years, other scientists have discovered, have realized that every cell in our body makes hydrogen sulfide, but the liver specifically makes hydrogen sulfide additionally in the glutathione production process. And the liver uses both glutathione and hydrogen sulfide to protect against, among other things reactive oxygen species. And in the small number of people, over the longer term, we think the liver is essentially saying "wow free lunch!" Free hydrogen sulfide, and they're slowing down their own production of it. So it's not toxic, for these people it's too much of a good thing. And we think that the solution is going to be a sophisticated regimen control and so we're working on that. Yeah, yeah, hydrogen sulfide, there's huge scavenging systems in the body for it, so it dissipates relatively quickly compared to the naproxen which doesn't, so it has those reactive oxygen species. So we think that we're going to solve it now that we understand it. But we don't face it on acute pain."
His quotation captures hits on serveral notes:
1- Management still talks about the chronic indication and a trial will be underway.
2- The elevation is both a time frame issue AND a dose related issue of the moeity itself, blunting endogenous production of H2S in the liver. And thankfully can be easily managed without changing the formula; its the regime dosing.
3- the current drugs on the market such as Tylenol and opioids are the only options for the older adults. Demonstrating how serious the GI issue is compared to elevated liver enzymes. i.e. practitioners will manage a 39% elevation in ALTs instead of managing GI ulcers.
And to augment point #3 further, the average geriatric patient is on at least 3 different drugs in the west. And ALT elevation is common place but managed appropriately by the primary health care provider. So say " LTEs were more concerning than they might first appear" is not accurate from a clinical perspective. It is an issue from an approval standpoint. Refer to my previous post on baricitinib for rheumatoid arthritis as great example of fast tracking because of a clinical need despite horrendous side effects (much worse than "elevated ALTs") https://stockhouse.com/companies/bullboard?symbol=t.ate&postid=34563635
w.r.t. "drug manufacturers cannot promote off-label use without FDA concurrence", it doesnt mean prescribers can't use it off label. Case in point, domperidone, which is given off label for lactation. Used widely for that indication despite FDA stating otherwise (https://www.fda.gov/drugs/investigational-new-drug-ind-application/how-request-domperidone-expanded-access-use) and there numerous examples like this. So I think your "hypothesis" goes against current practices.
The remainder of you comments on Wallace's venture with NO-releasing NSAIDs I cannot speak on because I have not researched adequately myself, but you are welcome to post or DM your references that you found.
Long post but I think it was need to correct much of what you said. Feel free to dissect and we can discuss. However I would appreciate you reference your claims so I can investigate them myself.