The DOI matches its Crossref record; 182 of the 182 references it cites were found in a registry or an index; 30 of the 149 sources its claims cite were checked for support.
Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action
Open accessAbstract
Paracetamol (acetaminophen) is undoubtedly one of the most widely used drugs worldwide. As an over-the-counter medication, paracetamol is the standard and first-line treatment for fever and acute pain and is believed to remain so for many years to come. Despite being in clinical use for over a century, the precise mechanism of action of this familiar drug remains a mystery. The oldest and most prevailing theory on the mechanism of analgesic and antipyretic actions of paracetamol relates to the inhibition of CNS cyclooxygenase (COX) enzyme activities, with conflicting views on the COX isoenzyme/variant targeted by paracetamol and on the nature of the molecular interactions with these enzymes. Paracetamol has been proposed to selectively inhibit COX-2 by working as a reducing agent, despite the fact that in vitro screens demonstrate low potency on the inhibition of COX-1 and COX-2. In vivo data from COX-1 transgenic mice suggest that paracetamol works through inhibition of a COX-1 variant enzyme to mediate its analgesic and particularly thermoregulatory actions (antipyresis and hypothermia). A separate line of research provides evidence on potentiation of the descending inhibitory serotonergic pathway to mediate the analgesic action of paracetamol, but with no evidence of binding to serotonergic molecules. AM404 as a metabolite for paracetamol has been proposed to activate the endocannabinoid and the transient receptor potential vanilloid-1 (TRPV1) systems. The current review gives an update and in some cases challenges the different theories on the pharmacology of paracetamol and raises questions on some of the inadequately explored actions of paracetamol.List of Abbreviations: AM404, N-(4-hydroxyphenyl)-arachidonamide; CB1R, Cannabinoid receptor-1; Cmax, Maximum concentration; CNS, Central nervous system; COX, Cyclooxygenase; CSF, Cerebrospinal fluid; ED50, 50% of maximal effective dose; FAAH, Fatty acid amidohydrolase; IC50, 50% of the maximal inhibitor concentration; LPS, Lipopolysaccharide; NSAIDs, Non-steroidal anti-inflammatory drugs; PGE2, Prostaglandin E2; TRPV1, Transient receptor potential vanilloid-1
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
This review argues that paracetamol remains a first-line analgesic and antipyretic despite more than a century of use, because its molecular mechanism is still unresolved. It weighs competing COX-centered explanations against serotonergic, AM404/endocannabinoid/TRPV1, and COX-1-variant theories, favoring a central COX-1-derived target for analgesia and thermoregulation.
Key findings
- In vitro COX inhibition by paracetamol is weak and inconsistent: one study reported IC30 values of 2.7 µg/ml for COX-1 and 20 µg/ml for COX-2, while another reported COX-2 selectivity with IC50 values of 25.8 µmol/L for COX-2 versus 113.7 µmol/L for COX-1.
- The proposed COX-3/COX-1 variant was inhibited by paracetamol with an IC50 of 460 µM; in the author’s acetic acid writhing model, paracetamol’s analgesia and central PGE2 reduction were lost in COX-1 knockout mice but not COX-2 knockout mice, with ED50 values of 149 mg/kg for iloprost-induced and 172 mg/kg for acetic acid-induced constriction.
- For thermoregulation, paracetamol-induced hypothermia and antipyresis, along with hypothalamic PGE2 reduction, were attenuated in COX-1−/− mice but not COX-2−/− mice; selective COX-1 inhibition with SC560 and COX-2 inhibition with celecoxib did not produce hypothermia.
- AM404 was detected in human CSF in 14 of 26 patients at 5.1–57.4 nmol/L after 1 g intravenous paracetamol, but conversion rates were very low (about 0.009% in CSF and 0.0013% in rat plasma), below concentrations needed for several proposed in vitro targets; serotonergic involvement is indirect because paracetamol does not bind serotonergic receptors.
Methods
- Narrative review synthesizing historical, preclinical, and clinical literature on paracetamol pharmacology, with particular emphasis on the author’s own rodent and cell-based experiments.
- Evidence discussed includes COX-1 and COX-2 knockout mice, acetic acid-induced writhing and iloprost nociception models, LPS-induced fever, body temperature and PGE2 measurements, human CSF/plasma AM404 sampling, and cited randomized trials.
- Main analysis is qualitative comparison of competing mechanistic theories rather than a systematic review, meta-analysis, or new pooled quantitative synthesis.
Limitations
- The paper states that several hypotheses remain inadequately tested, including the lipid hydroperoxide/reducing-agent theory, which it says has not been tested in vivo; it also notes that AM404’s clinical relevance is unclear because most evidence comes from animals.
- Evident from the text: as a narrative review, it does not describe systematic search criteria or formal bias assessment, and its interpretation often favors the author’s COX-1-variant hypothesis.
- Evident from the text: many mechanistic conclusions rely on animal models, knockout mice, or in vitro systems, and some cited clinical findings are indirect or limited.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
58 No full text of the sources · 14 Own interpretation · 13 Partly supported · 7 Supported · 7 Sources not found · 6 Own result · 5 No basis given · 4 Supported so far · 4 Not checked yet · 1 Not supported · 1 Couldn’t confirm · accuracy not yet measured
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Our study reported on a relatively similar conversion rate of plasma paracetamol to AM404 CSF (0.009%) [106].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > AM404 as a metabolite of paracetamol: A new introduction to the paracetamol dilemma
What the sources say
- Disputedcites [106] sourceExperimental — accuracy not yet measured
The Discussion (section 5) reports a conversion rate of 0.0013%, not 0.009%. The Results (section 4) measure AM404 in rat brain tissue, not cerebrospinal fluid (CSF). (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Disputed
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Using functional magnetic resonance imaging in humans, paracetamol was shown to reduce firing within the spinothalamic tract in response to thermal noxious stimulation [26].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Analgesic action of paracetamol
What the sources say
- Partly supportedcites [26] sourceExperimental — accuracy not yet measured
The Results (fMRI results) report reduced pain-related BOLD activation in several brain regions during noxious thermal stimulation after paracetamol. The Discussion suggests this may reflect inhibition of spinothalamic tracts, but the study did not measure firing within those tracts directly. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In addition, the analgesic action of paracetamol was shown not to be linked to inhibition of prostaglandin synthesis in the periphery [21,23,27,28].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Analgesic action of paracetamol
What the sources say
- Not checked — no full text of the sourcecites [21] source
- Not checked — no full text of the sourcecites [23] source
- Partly supportedcites [27] sourceExperimental — accuracy not yet measured
The Discussion reports no significant effect of acetaminophen on PGE2 in gingival crevicular fluid and says this supports the theory that it does not block prostaglandins peripherally. But the Discussion also states that the study did not evaluate pain relief, so it did not directly show that acetaminophen’s analgesic action is independent of peripheral prostaglandin inhibition. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [28] Seppälä E, 1983, Int J Clin Pharmacol Res
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Ex vivo animal studies have detected levels of AM404 in whole brain tissue equating to the low nanomolar range following systemic administration of standard analgesic doses of paracetamol in rats (300 mg.kg -1 ) [85].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > AM404 as a metabolite of paracetamol: A new introduction to the paracetamol dilemma
What the sources say
- Supportedcites [85] source
Table I (Results; page not supplied) reports 10.3 ± 1.9 pmol/g AM404 in rat brain 20 minutes after intraperitoneal administration of 300 mg/kg acetaminophen. The discussion states that levels above 10 pmol/g in whole rat brain correspond to concentrations above 10 nM, assuming even distribution, and describes the dose as commonly used to induce analgesia in rodents. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“nonetheless in 2005 Högestätt identified a new metabolite for paracetamol [85].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > AM404 as a metabolite of paracetamol: A new introduction to the paracetamol dilemma
What the sources say
- Supportedcites [85] source
The paper explicitly states that it identified AM404 as a novel metabolite of acetaminophen (paracetamol) in the nervous system. This supports the claim attributed to Högestätt and colleagues. (LLM, conf=0.95)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“It was shown that when paracetamol-derived metabolite para-aminophenol, formed in the liver, enters the brain it conjugates with arachidonic acid through the action of fatty acid amidohydrolase (FAAH) to form N-(4-hydroxyphenyl)-arachidonamide (AM404).”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > AM404 as a metabolite of paracetamol: A new introduction to the paracetamol dilemma
What the sources say
- Partly supportedcites [85] sourceExperimental — accuracy not yet measured
The Results and Fig. 3 show that p-aminophenol and arachidonic acid form AM404 through FAAH-dependent activity in brain preparations. The Discussion says it is *likely* that acetaminophen is converted to p-aminophenol mainly in the liver and that p-aminophenol is converted to AM404 in the brain. The citing sentence presents that proposed liver-to-brain sequence as established rather than inferred; page numbers are unavailable in our copy. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Experiments in which the conversion of p-aminophenol into AM404 has been interrupted using FAAH knockout mice or selective FAAH inhibitors, the analgesic actions of paracetamol were shown to be blocked [89,90,92,93].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > AM404 as a metabolite of paracetamol: A new introduction to the paracetamol dilemma
What the sources say
- Not checked — no full text of the sourcecites [89] Soukupová M, 2010, Neuro Endocrinol Lett
- Not checked — no full text of the sourcecites [90] source
- Not checked — no full text of the sourcecites [92] source
- Partly supportedcites [93] sourceExperimental — accuracy not yet measured
Results §3.3 reports that the FAAH inhibitor URB597 abolished paracetamol-induced mechanical analgesia when administered to the ventrolateral PAG of rats. The paper does not report a FAAH-knockout-mouse experiment, so that part of the attributed claim is unsupported by this source. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Using an antibody that recognizes the intron-1 sequence, we have also been able to detect an intron-1 retaining protein in rodent CNS tissues [23,43,44] (Figure 3).”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Which cyclooxygenase enzyme does paracetamol inhibit?.
What the sources say
- Not checked — no full text of the sourcecites [23] source
- Partly supportedcites [43] sourceExperimental — accuracy not yet measured
The Western blotting section says the authors used an anti-COX-3 antibody, and the Discussion reports detecting COX-3 protein in mouse spinal cord tissue. Our copy does not say that the antibody recognizes an intron-1 sequence or establish that the detected protein retains intron 1. No page number is available for these passages. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [44] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“We were the first to report on the presence of AM404 in human CSF and plasma samples following intravenous administration of 1 g paracetamol (in CSF samples of 14 of 26 patients at concentrations of 5.1-57.4nmol.L -1 ) [101].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > AM404 as a metabolite of paracetamol: A new introduction to the paracetamol dilemma
What the sources say
- Partly supportedcites [101] sourceExperimental — accuracy not yet measured
The Discussion reports that this was the first study to find AM404 in human CSF and plasma after intravenous administration of 1 g paracetamol. It also reports quantifiable AM404 in CSF in 14 of 26 patients, but the stated 5.1–57.4 nmol/L range omits an outlier of 166.8 nmol/L among those measurements. (LLM, conf=0.88)
plainn = 26- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Li et al. (2008) showed that the antipyretic (and hypothermic) actions of paracetamol were not attenuated in COX-1-/-mice in comparison to wild-type mice [128].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Mechanistic research on the antipyretic and hypothermic actions of paracetamol
What the sources say
- Supportedcites [128] source
The Discussion (section 4; page unavailable) states that acetaminophen caused a temperature fall identical in magnitude and duration in wild-type and PGHS-1−/− mice. It also says the groups’ responses were identical for both its antipyretic and hypothermic activity. (LLM, conf=0.94)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
- Probably not a substantial claim. 11
- It may state two separate claims as one. 31
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“AM404 as a metabolite for paracetamol has been proposed to activate the endocannabinoid and the transient receptor potential vanilloid-1 (TRPV1) systems.”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Abstract
What the sources say
- Supportedcites [85] source
The Abstract identifies AM404 as a metabolite formed from acetaminophen (paracetamol) and states that it acts on the endogenous cannabinoid system and is a TRPV1 agonist. The Results also report that AM404 activates TRPV1. No page numbers are provided in our copy. (LLM, conf=0.94)
- Not matchedcites [86][87][88][89][90]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Mallet et al. (2010) showed attenuation of the paracetamol-induced analgesia in the formalin, tail immersion and von Frey tests of nociception in mice lacking FAAH and TRPV1 and that intracerebroventricular administration of the TRPV1 channel antagonist capsazepine to abolish the analgesic action of paracetamol [88].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > AM404 as a metabolite of paracetamol: A new introduction to the paracetamol dilemma
What the sources say
- Supportedcites [88] source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“AM404 has been demonstrated in in vitro studies to inhibit reuptake of anandamide, block TRPV1 and inhibit COX-1 and COX-2 activities [86,98,[102][103][104][105] in the high nanomolar to low micromolar concentration range, well above the concentrations were able to detect in human CSF [101].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > AM404 as a metabolite of paracetamol: A new introduction to the paracetamol dilemma
What the sources say
- Not matchedcites [86,98,[102][103][104][105]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Supportedcites [101] source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
boosteddirectn = 26- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
Every source the paper cites for this claim was checked and supports it.
In the paper
“Previously, we showed that the paracetamol-induced hypothermia in normothermic mice and concomitant reduction in brain PGE 2 synthesis (Figure 6) were significantly attenuated in COX-1-/mice in comparison to wild-type mice but not in COX-2-/-mice [22].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Mechanistic research on the antipyretic and hypothermic actions of paracetamol
What the sources say
- Supportedcites [22] source
The Results report that acetaminophen-induced hypothermia was reduced in COX-1 knockout mice, while the reduction in brain PGE2 was abolished. They report no corresponding difference in hypothermia or PGE2 reduction in COX-2 knockout mice compared with wild-type mice. The experiments measured basal body temperature. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These activated vascular endothelial cells respond through the induction of COX-2 (and not COX-1) that produces PGE 2 , which in turn resits the thermostatic control to a higher temperature [112,116,118].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Mechanistic research on the antipyretic and hypothermic actions of paracetamol
What the sources say
- Not checked — no full text of the sourcecites [112] source
- Partly supportedcites [116] Matsumura K, Cao C, Ozaki M, et al. Brain endothelial cells express cyclooxygenase-2 during lipopolysaccharide-induced fever: light and electron microscopic immunocytochemical studies. 1998;18(16):6279–6289. sourceExperimental — accuracy not yet measured
The Abstract and the section “Timing of COX-2 expression and its physiological relevance” report COX-2 induction in brain endothelial cells during LPS-induced fever and propose that it promotes PGE2 production, which acts on CNS neurons to evoke fever. The paper treats endothelial PGE2 production as a hypothesis still requiring confirmation; it does not establish the claimed exclusion of COX-1 or describe a reset of thermostatic control. (LLM, conf=0.87)
- Not checked — no full text of the sourcecites [118] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“The evidence that support the paracetamolinduced hypothermia and indeed the paracetamolinduced antipyresis and analgesia are centrally mediated is supported by a large volume of published literature that spans 6 decades [18][19][20][21][22][23]27,28,96,[131][132][133][134][135], which comes from direct in vivo experiments in which the pharmacological actions of paracetamol are directly correlated”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Mechanistic research on the antipyretic and hypothermic actions of paracetamol
What the sources say
- Could not verifycites [18] Feldberg W, 1972, BrJ Pharmacol sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [19] Yaksh TL, 1993, Agents Actions
- Not checked — no full text of the sourcecites [20] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The reported paracetamol-induced hypothermia in normothermic animals [22,38,135] and humans [140][141][142][143][144][145] is a reversable and nontoxic action that temporally correlates with the pharmacokinetic profile of paracetamol [22,135]”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Mechanistic research on the antipyretic and hypothermic actions of paracetamol
What the sources say
- Partly supportedcites [22] sourceExperimental — accuracy not yet measured
The Results report that hypothermia in mice resolved within 4–5 hours and correlated with acetaminophen plasma concentrations. The Discussion describes human hypothermia as short-lived and generally not presenting serious problems, but also notes concerns about adverse consequences in young children. It does not establish that the effect is nontoxic across animals and humans. (LLM, conf=0.86)
- Partly supportedcites [38] sourceExperimental — accuracy not yet measured
The Discussion (section 4; page unavailable) reports acetaminophen-induced hypothermia in mice and humans and says its duration approximately coincided with the drug’s plasma half-life. It describes the effect as acute, which is consistent with reversibility, but does not establish that the hypothermia is nontoxic. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [135] source
- Not checked yetcites [140] Van Tittelboom T, 1989, Vet Hum Toxicol
- Partly supportedcites [141] sourceExperimental — accuracy not yet measured
The Results (Secondary outcomes) report hypothermia after acetaminophen in 11 children, supporting the human-hypothermia portion of the citation. The Methods (Subjects) specify that these children were febrile, not normothermic. The sentence attaches separate citations to the reversible, nontoxic, pharmacokinetic characterization, so that characterization is not attributed to this source. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“The authors also go on reference Fischer et al. (1981) in which the dose of paracetamol used to study the pharmacokinetics of a toxic dose of paracetamol in mice was 500 mg/kg [157], well above the 200 mg/ kg and 300 mg/kg doses used by us [22,100,135].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Mechanistic research on the antipyretic and hypothermic actions of paracetamol
What the sources say
- Not checked — no full text of the sourcecites [157] Fischer LJ, 1981, J Pharmacol Exp Ther source
- Supportedcites [22] source
The citation to Ayoub et al. is attached to the 200 and 300 mg/kg doses, not the Fischer et al. 500 mg/kg dose. The Results report that Ayoub et al. administered both 200 and 300 mg/kg acetaminophen to mice. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [100] source
- Not checked — no full text of the sourcecites [135] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In contrast, diclofenac, a peripherally active NSAID [46,47], inhibited the acetic acid-induced constriction with an ED 50 value of 16 mg/kg, but had no effects on the ilorpost-induced constriction [23].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Which cyclooxygenase enzyme does paracetamol inhibit?.
What the sources say
- Not checked — no full text of the sourcecites [23] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Using the acetic acid-induced abdominal constriction model of acute nociceptive pain, we showed that the analgesic action of paracetamol was accompanied by reduction of prostaglandin synthesis in the brain and spinal cord, but not in the peritoneum; effects that were abrogated in COX-1 homozygote knockout mice, but not in COX-2 homozygote knockout mice [23].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Which cyclooxygenase enzyme does paracetamol inhibit?.
What the sources say
- Not checked — no full text of the sourcecites [23] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Using similar experimental approaches to those reported above, we showed that the hypothermic action of paracetamol in mice is not mediated through AM404 and is not dependent on activation of the endocannabinoid or TRPV-1 pathways [100].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > AM404 as a metabolite of paracetamol: A new introduction to the paracetamol dilemma
What the sources say
- Not checked — no full text of the sourcecites [100] source
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In addition, we showed that the hypothermic action of cannabinoid receptor-1 and TRPV-1 agonists is not mediated through the inhibition of prostaglandin synthesis demonstrating parallel rather than interdependent pathways [100].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > AM404 as a metabolite of paracetamol: A new introduction to the paracetamol dilemma
What the sources say
- Not checked — no full text of the sourcecites [100] source
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In the same cell line, paracetamol did not inhibit the catalytic activity induced by the pro-inflammatory stimulus LPS with the intracellular lipid hydroperoxide tone remaining unchanged after the addition of LPS [71].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > 2.1.1.3. Does the lipid hydroproxide theory explain the weak anti-inflammatory actions of paracetamol?
What the sources say
- Not checked — no full text of the sourcecites [71] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“given the fact that paracetamol is able to induce hypothermia and reduce brain PGE 2 synthesis in the absence and presence of fever within 30 minutes after administration (insufficient time for the induction of COX-2)”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Mechanistic research on the antipyretic and hypothermic actions of paracetamol
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“a notion that is supported by the finding that therapeutically administered paracetamol-induced potent hypothermic and anti-pyretic actions in COX-1+/+ mice (with established pyrexia), which were partly lost in COX-1-/-mice.”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Mechanistic research on the antipyretic and hypothermic actions of paracetamol
What the sources say
- Not checked — no full text of the sourcecites [135] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Bashir et al. (2020) attempt to the challenge the notion that the paracetamol-induced hypothermia is mediated through the inhibition of a COX-1 variant (and other COX enzymes including COX-1 and COX-2), but present no data to support this argument [155].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Mechanistic research on the antipyretic and hypothermic actions of paracetamol
What the sources say
- Not checked — no full text of the sourcecites [155] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Paracetamol showed selectivity for inhibition of COX-3 (IC 50 = 460 µM) over COX-1 and COX-2, which was dependent on the concentration of the substrate arachidonic acid suggesting competitive blockage at the active site [36].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Which cyclooxygenase enzyme does paracetamol inhibit?.
What the sources say
- Not checked — no full text of the sourcecites [36] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“A separate line of research provides evidence on potentiation of the descending inhibitory serotonergic pathway to mediate the analgesic action of paracetamol, but with no evidence of binding to serotonergic molecules.”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Abstract
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Its lipid solubility enables it to rapidly penetrate cellular membranes and to also readily cross the blood-brain barrier.”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Analgesic action of paracetamol
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Several reports disputed the expression of a fully functional COX-3 protein in human and rodent tissues as retention of intron-1 in the mRNA sequence introduced a stop codon early in the translational process resulting in a truncated protein with no catalytic activity [37][38][39][40][41].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Which cyclooxygenase enzyme does paracetamol inhibit?.
What the sources say
- Not matchedcites [37][38][39][40][41]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Not matched
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“In this report, the authors conclude that the reduction of central nervous system (CNS) PGE 2 synthesis by paracetamol may be mediated through inhibition of a COX enzyme yet to be discovered [33], a notion that has also been predicted by others [34,35].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Which cyclooxygenase enzyme does paracetamol inhibit?.
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“Paracetamol is a moderately lipid-soluble weak organic acid with a pka value of 9.5 and is largely un-ionized over the physiological range of pH [29].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Analgesic action of paracetamol
What the sources say
- Not checked — no full text of the sourcecites [29] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Despite the potent inhibition by paracetamol of brain and spinal cord-derived prostaglandins in in vivo experiments, in vitro screening experiments demonstrated weak inhibitory activities on COX-1 and COX-2 enzymes by paracetamol [33].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Which cyclooxygenase enzyme does paracetamol inhibit?.
What the sources say
- Not checked — no full text of the sourcecites [33] source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The oldest and most prevailing theory on the mechanism of analgesic and antipyretic actions of paracetamol relates to the inhibition of CNS cyclooxygenase (COX) enzyme activities, with conflicting views on the COX isoenzyme/variant targeted by paracetamol and on the nature of the molecular interactions with these enzymes.”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“A standard therapeutic dose of paracetamol produces 80% bioavailability and reaches peak plasma level (Cmax) of 18 mg/L (120 µM) after approximately 120 minutes and a cerebrospinal fluid (CSF) Cmax of 8.8 mg/ml at around 240 minutes [31].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Analgesic action of paracetamol
What the sources say
- Not checked — no full text of the sourcecites [31] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Paracetamol as a reducing agent has been proposed to work by lowering the intracellular lipid hydroperoxide tone driving COX-1 and COX-2 enzymes into the inactive reduced state ultimately reducing prostaglandin synthesis [65].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > 2.1.1.3. Does the lipid hydroproxide theory explain the weak anti-inflammatory actions of paracetamol?
What the sources say
- Not checked — no full text of the sourcecites [65] source
hedgeddirect- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Activation of the descending inhibitory serotonergic pathway by paracetamol has been proposed as a possible mechanism for the analgesic action of paracetamol in humans [72,73] and experimental animals [74][75][76][77].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Activation of the serotonergic descending inhibitory pathway by paracetamol
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In support of a non-TRPV1 mediated action for AM404, in cultured hippocampal slices and microglial cells AM404 was shown to inhibit the LPS-mediated PGE 2 production in a TRPV1 independent manner and was also able to decrease the expression of COX-2 protein [98].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > AM404 as a metabolite of paracetamol: A new introduction to the paracetamol dilemma
What the sources say
- Not checked — no full text of the sourcecites [98] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Activation of this pathway cannot fully explain the mechanism of analgesic action of paracetamol as it was shown that paracetamol did not have affinity for any of the serotonergic receptor types or subtypes or to any of the enzymes involved in the synthesis or degradation of serotonin [84]; hence, this interaction between paracetamol and the descending inhibitory serotonergic system is an indirect”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Activation of the serotonergic descending inhibitory pathway by paracetamol
What the sources say
- Not checked — no full text of the sourcecites [84] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“AM404 as a novel metabolite for paracetamol was shown to activate the endocannabinoid system and to also activate the transient receptor potential vanilloid-1 (TRPV-1) channel, both of which are involved in the modulation of pain signaling and proposed to mediate the analgesic action of paracetamol [86][87][88][89][90].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > AM404 as a metabolite of paracetamol: A new introduction to the paracetamol dilemma
What the sources say
- Not matchedcites [86][87][88][89][90]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We therefore conclude that the target for the paracetamol-induced hypothermia is not COX-1 or COX-2 and is likely to be a variant of COX-1.”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Mechanistic research on the antipyretic and hypothermic actions of paracetamol
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- The authors state this as an assumption: Paracetamol reduces body temperature through the induction of hypothermia through inhibition of a constitutively expressed COX-1 variant enzyme.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Blockade of brain PGE 2 synthesis by NSAIDs has been associated with the antipyretic action of these drugs, which has been suggested to be due to inhibition of inducible COX-2 produced by hypothalamic vascular endothelial cells [124,125].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Mechanistic research on the antipyretic and hypothermic actions of paracetamol
What the sources say
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Mice lacking the PGE 2 receptor EP3 [112] or microsomal prostaglandin E synthase-1 enzyme [121,122] were shown to have impaired febrile responses.”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Mechanistic research on the antipyretic and hypothermic actions of paracetamol
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“However, the authors report on a conversion rate of plasma paracetamol to AM404 of only 0.0013%, which would result in low concentrations expected to have negligible pharmacological activities.”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > AM404 as a metabolite of paracetamol: A new introduction to the paracetamol dilemma
What the sources say
- Not checked — no full text of the sourcecites [16] source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“As NSAIDs are believed to induce antipyresis through inhibition of the inducible COX-2 enzyme expressed in hypothalamic vascular endothelial cells [112,127]”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Mechanistic research on the antipyretic and hypothermic actions of paracetamol
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Indeed, the suprachiasmatic nucleus within the anterior medial zone of the hypothalamus is known to be involved in circadian control of sleep-wake cycle and body temperature.”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Is paracetamol a sleep-inducing drug?
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“At therapeutic dose paracetamol is a safe drug, but with a narrow therapeutic window, it is easy to accidently or deliberately over-dose.”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Final remarks and future considerations on paracetamol
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings demonstrate that the paracetamol-induced hypothermia is not mediated by AM404 and does not involve activation of the endocannabinoid or TRPV1 systems.”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Mechanistic research on the antipyretic and hypothermic actions of paracetamol
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Thus, despite being nontoxic to the cells, the concentrations of paracetamol used by these authors are pharmacologically irrelevant and do not represent plasma paracetamol concentrations in humans or rodents [31,135].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Mechanistic research on the antipyretic and hypothermic actions of paracetamol
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The authors state this as an assumption.
Dental inflammatory reactions present low-grade inflammation.
“The notion that paracetamol produces anti-inflammatory actions in such dental inflammatory reactions is based on the assumption that such inflammatory reactions present lowgrade inflammation, an idea that has not been tested thoroughly.”
The paper relies on this without support.
The acetic acid-induced constriction model represents a human model of acute pain that shares similar pathologies to human pain.
“The acetic acid-induced constriction model represents a human model of acute pain that shares similar pathologies to human pain.”
The authors state this as an assumption.
Paracetamol reduces body temperature through the induction of hypothermia through inhibition of a constitutively expressed COX-1 variant enzyme.
“We, therefore, make the assumption that paracetamol reduces body temperature through the induction of hypothermia through inhibition of a constitutively expressed COX-1 variant enzyme [22,135].”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“Altogether, these results indicate that the analgesic action of paracetamol cannot be attributed to the inhibition of central COX, however data from the literature would suggest such an involvement.38”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Final remarks and future considerations on paracetamol
“The antipyretic and inhibitory effect of therapeutically administered paracetamol on hypothalamic PGE 2 synthesis was abolished in COX-1 knockout mice.”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Mechanistic research on the antipyretic and hypothermic actions of paracetamol
“which were partly lost in COX-1-/-mice.Similarly, the reduction of hypothalamic PGE 2 synthesis by therapeutically administered paracetamol was significantly attenuated in COX-1-/-mice”
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > AM404 as a metabolite of paracetamol: A new introduction to the paracetamol dilemma
“AM404 as a novel metabolite for paracetamol was shown to activate the endocannabinoid system and to also activate the transient receptor potential vanilloid-1 (TRPV-1) channel”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > AM404 as a metabolite of paracetamol: A new introduction to the paracetamol dilemma
“AM404 has been demonstrated in in vitro studies to inhibit reuptake of anandamide, block TRPV1 and inhibit COX-1 and COX-2 activities”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Which cyclooxygenase enzyme does paracetamol inhibit?.
“Reproduced from Qin et al. 2005 [43].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > References
“43. Ayoub SS, Yazid S, Flower RJ. Increased susceptibility of annexin-A1 null mice to nociceptive pain is indi- cative of a spinal antinociceptive action of annexin- A1. Br J Pharmacol. 2008;154(5):1135-1142.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Brief history of paracetamol
“It was first synthesized by Joseph von Mering in (1893) by reacting p-nitrophenol with tin and glacial acetic acid.”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Brief history of paracetamol
“In the 1880s paracetamol and phenacetin (Figure 1) were found to possess antipyretic and later analgesic activity.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Final remarks and future considerations on paracetamol
“Reproduced from Ayoub and Flower 2019 [130].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > References
“130. Engström RL, Wilhelms DB, Eskilsson A, et al. Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2. Neuropharmacology. 2013;71:124-129.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > Final remarks and future considerations on paracetamol
“Reproduced from Ayoub et al. 2011[72].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > References
“72. Pickering G, Loriot MA, Libert F, et al. Analgesic effect of paracetamol in humans: first evidence of a central serotonergic mechanism. Clin Pharmacol Ther. 2006;79:371-378.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > AM404 as a metabolite of paracetamol: A new introduction to the paracetamol dilemma
“Muramatsu et al. reported on the metabolism of paracetamol to AM404 in rats at doses of paracetamol similar to therapeutic doses in humans [16].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > References
“16. Flower RJ, Vane JR. Inhibition of prostaglandin synthetase in brain explains the anti-pyretic activity of paracetamol (4-acetamidophenol). Nature. 1972;240:410-411.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > AM404 as a metabolite of paracetamol: A new introduction to the paracetamol dilemma
“Our study reported on a relatively similar conversion rate of plasma paracetamol to AM404 CSF (0.009%) [106].”
§ Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action > References
“106. Muramatsu S, Shiraishi S, Miyano K, et al. Metabolism of AM404 from acetaminophen at human therapeutic dosages in the rat brain. Anesth Pain Med. 2016;6(1):e32873. .”
Citations
Cites
Inhibition of Prostaglandin Synthesis as a Mechanism of Action for Aspirin-like Drugs
VANE, J. R. (1971) · Nature New Biology · doi:10.1038/newbio231232a0 · Cited by 8,605
Bombardier, C., Laine, L., Reicin, A. S., Shapiro, D., Burgos‐Vargas, R., Davis, B. R., Day, R. O., Ferraz, M. B., Hawkey, C. J., Hochberg, M. C., et al. (2000) · New England Journal of Medicine · doi:10.1056/nejm200011233432103 · Cited by 4,014
Chandrasekharan, N. V., Dai, H., Roos, K. L. T., Evanson, N. K., Tomsik, J., Elton, T. S., & Simmons, D. L. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.162468699 · Cited by 1,989
Mitchell, J. A., Akarasereenont, P., Thiemermann, C., Flower, R. J., & Vane, J. R. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.24.11693 · Cited by 1,659
Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic.
Masferrer, J. L., Zweifel, B. S., Manning, P. T., Hauser, S. D., Leahy, K. M., Smith, W. G., Isakson, P. C., & Seibert, K. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.8.3228 · Cited by 1,310
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“Moreover, the presence of p-AP in paracetamol samples may not only be a cause of therapeutic failure, but also may pose a safety issue, since p-AP has been shown to be significantly more potent than paracetamol as a nephrotoxicant in animal models [18].”
Background
Metadata
- Authors
- Ayoub, S. S.
- Affiliations
- University of East London (GB)
- Corresponding author
- Ayoub, Samir S
- ORCID
- Ayoub, Samir S
- Venue
- Temperature
- Publisher
- Informa UK Limited
- Published
- 2021-03-16
- Volume
- 8
- Issue
- 4
- Pages
- 351-371
- ISSN
- 2332-8940 (ISSN-L)
- 2332-8959
- PMC
- PMC8654482
- OpenAlex
- W3129333098
- Cited by
- 223
- References
- 178
- Citations by year
- 2026: 59 · 2025: 73 · 2024: 58 · 2023: 22 · 2022: 10 · 2021: 1
- FWCI
- 2.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Temperature (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UEL Research Repository (University of East London) (submittedVersion, cc-by-nc)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Inflammatory mediators and NSAID effects
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Pain Management
- Keywords
- paracetamol, mechanism of action, cyclooxygenase inhibition, cyclooxygenase-1, cyclooxygenase-2, fever reduction, analgesia, descending serotonergic pathways, AM404, endocannabinoid system, TRPV1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-11, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-11 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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