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‘Tylenol Lite’ – Will a Safer New Ineffective Painkiller Change a Harmful Previous One?

‘Tylenol Lite’ – Will a Safer New Ineffective Painkiller Change a Harmful Previous One?

2023-03-28 14:16:19

There may be an pressing want for analysis within the space of ache administration. For the reason that Nineties, when aspirin and heroin have been found, there was agonizingly little progress on this area. Some would argue that introducing Tylenol (acetaminophen, paracetamol, APAP, others) in 1950 represents progress. I’d argue with them. As I wrote in a overview of the drug’s professionals and (principally cons) (See Tylenol Isn’t So Safe, But At Least It Works, Right?), there are valuable few painful circumstances for which the drug works, and plenty of extra the place it doesn’t. It might be one factor if the drug had even a modest impact however was typically protected to take. However that is false (See Is Tylenol ‘By Far The Most Dangerous Drug Ever Made?‘)

Nonetheless, Johnson & Johnson’s Tylenol analog, JNJ-10450232 (1), now present process medical trials, is being touted as a a lot safer different to Tylenol. Are they onto one thing? Let’s look. 

Determine 1. The chemical constructions of acetaminophen and JNJ-10450232. Good luck discovering the latter (2).

Discovering a safer Tylenol-like drug ought to not be troublesome. It is because acetaminophen itself just isn’t poisonous; however the drug undergoes oxidation by the liver, and its metabolite NAPQI is very hepatotoxic (Determine 1). It’s NAPQI that destroys the liver. A comparible drug that doesn’t endure this oxidation would undoubtedly be safer.

Determine 1. Acetaminophen undergoes speedy oxidation within the liver, forming a poisonous metabolite accountable for the drug’s toxicity. The pink arrow signifies the reactive carbon that undergoes reactions with biomolecules (particularly people who include a thiol (-SH) group, inflicting extreme liver injury.

Acetaminophen overdose is the main trigger for calls to Poison Management Facilities (>100,000/12 months) and accounts for greater than 56,000 emergency room visits, 2,600 hospitalizations, and an estimated 458 deaths resulting from acute liver failure every year. (3)

Supply: Hepatology, 2004 Jul;40(1):6-9. , DOI: 10.1002/hep.20293

Is that this progress?

JNJ-10450232 is mentioned in a paper printed within the journal Regulatory Toxicology and Pharmacology. The article is a bit sparse on particulars, so we should make a number of assumptions. The paper’s first sentence just isn’t encouraging [emphasis mine].

JNJ-10450232 (NTM-006) is a brand new molecular entity that includes structural similarities to acetaminophen and gives comparable analgesia in animals and people with out inflicting the hepatotoxicity related to acetaminophen overdose in preclinical fashions. 

Supply: Kuffner, et. al., Regulatory Toxicology and Pharmacology, Volume 134, October 2022, 105236. 

Properly, that is not an important begin. J&J succeeded in fixing one of many two issues with acetaminophen – its toxicity. Sadly, “comparable analgesia” sort of blows up the security answer because it does not matter how protected a drug is that if it does not work. In a way, JNJ-10450232 may be seen as a “safer placebo.”

Improved security

At single doses as excessive as 6,000 mg – twice the really useful day by day most of Tylenol – JNJ-10450232 had a half-life of 8-10 hours (that is good), and no dose-limiting toxicity was noticed (additionally good). The one widespread facet impact was a pores and skin rash. The best multiple-day dose studied – 2,500 mg twice day by day for eight days was not problematic. The medical toxicology profile of JNJ-10450232 is clearly superior to that of Tylenol. One shouldn’t take 5,000 mg of Tylenol day by day for eight days. 

Why the improved security? I can solely guess that JNJ-10450232 just isn’t a substrate for CYP2E1, the first liver enzyme accountable for changing Tylenol to NAPQI, the poisonous metabolite, maybe due to the scale of the pyrazole group.

However does it work? (emphasis mine)

There is no such thing as a manner I can take a look at this drug, particularly with out extra full information, and discover any cause to be optimistic.

JNJ-10450232 (NTM-006) is a brand new molecular entity that has structural similarities to acetaminophen (Fig. 1). In rodent pharmacology fashions, it reveals related antinociceptive [pain blocking] and antipyretic [fever reducing] results to that of acetaminophen and reveals potential to have an extended period of motion.

Supply: Kuffner, et. al., Regulatory Toxicology and Pharmacology, Volume 134, October 2022, 105236. 

Listed here are a number of quotes exhibiting why the above assertion is discouraging. 

Nonetheless, on this community meta-analysis, probably the most exceptional result’s that paracetamol doesn’t appear to confer any demonstrable impact or profit in osteoarthritis, at any dose. This discovering just isn’t completely surprising. Paracetamol has been available on the market for so long as most of us bear in mind. Its efficacy has by no means been correctly established or quantified in continual ailments and might be not as nice as many would consider. Its security can also be questioned, not simply in overdose. Is recommending it because the common first-line analgesic in osteoarthritis nonetheless tenable?

Dr. Nicholas Moore Division of pharmacology,College of Bordeaux France  The Lancet, VOLUME 387, ISSUE 10033, P2065-2066, MAY 21, 2016, DOI:


“It’s an old drug, obsolete, and should be avoided altogether.” 

Kay Brune, a professor of pharmacology and toxicology at Germany’s Friedrich-Alexander College

See Also


The addition of 1 g of IV acetaminophen to 1 mg of IV hydromorphone offered neither clinically significant nor statistically superior analgesia than hydromorphone alone.

Bijur, et. al., Tutorial Emergency Medication, 20 February 2020

Lastly, from ACSH buddy Dr. Aric Hausknecht, a New York neurologist and ache administration doctor:

In my medical expertise, acetaminophen is a second-tier remedy for delicate to reasonable ache. NSAIDs are first-tier however are contraindicated or not well-tolerated by some sufferers. Acetaminophen has very restricted utility for reasonable to extreme ache, continual ache or neuropathic ache. Moreover, the quick half life limits and potential hepatotoxicity are limitations.

Though these opinions don’t signify an undisputed or unbiased consensus on Tylenol’s utility or shortcomings, they shouldn’t be dismissed. Thousand of ache sufferers have discovered Tylenol to be ineffective. Many have written to me saying simply this. It might appear that Neumentum (that is the place the title NTM-006 comes from), the corporate that licensed JNJ-10450232 from J&J, might remorse this choice. Are individuals actually going to need to spend X (X = many) of {dollars} on a brand new prescription drug that may allow them to take extra of the same drugs that does not work any higher. 

I simply do not see it. 


(1) NTM-006 is the title given by Neumentum, the corporate that licensed JNJ-10450232 from J&J. I want them luck. They’re gonna want it.

(2) Typically, it’s practically inconceivable to discover a drug’s chemical construction, even one in medical trials. Firms might preserve the construction secret to keep away from attracting opponents that may modify the drug’s formulation to allow them to launch a copycat program. This was no exception. I spent hours searching for the rattling factor and eventually discovered it in a patent. (And the JNJ quantity is not particularly named within the patent; I needed to infer it from the claims.) Ever attempt studying a patent? Here is a snippet of what I needed to undergo to lastly discover the rattling issues. These experiencing suicidal ideation ought to skip this.

(3) Whereas 458 deaths might not appear to be a big quantity, that is deceptive. It’s the quantity of fifty,000 emergency room visits that’s extra telling. If caught in time, Tylenol poisoning may be efficiently handled by an antidote known as N-acetylcysteine. If not for the antidote, the variety of deaths can be a lot larger.

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