The DOI matches its Crossref record; 250 of the 251 references it cites were found in a registry or an index; 35 of the 163 sources its claims cite were checked for support.
Paracetamol: New Vistas of an Old Drug
Open accessAbstract
Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB(1) receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB(1) receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB(1) receptor agonist, completely prevents the analgesic activity of paracetamol. Thus, paracetamol acts as a pro-drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB(1) agonists are being introduced for pain treatment, it comes out that an indirect cannabino-mimetic had been extensively used (and sometimes overused) for more than a century.
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Claims the paper makes
51 No full text of the sources · 14 Partly supported · 10 Supported · 6 Sources not found · 6 Not checked yet · 5 No basis given · 4 Supported so far · 3 Not supported · 2 Own interpretation · 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
“However, the actual contribution of these activities of AM404 to the analgesic effect of paracetamol seems negligible.”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 254 A. BERTOLINI ET AL.
What the sources say
- Disputedcites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. sourceExperimental — accuracy not yet measured
The Results report that AM404 inhibits COX-1, COX-2, and prostaglandin E2 formation. The discussion accompanying Fig. 5 connects an analgesic dose of acetaminophen to likely local COX inhibition in the brain, rather than suggesting that this activity contributes negligibly to analgesia. The paper does not quantify that contribution. (LLM, conf=0.76)
Checked by a reasoning model — may be wrong.
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.
- Disputed
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
“Paracetamol must be considered as a safe alternative to NSAIDs for the relief of mildto-moderate pain in elderly patients, in patients with kidney disease (144), hypertension (56,93,104,110,166,184,185,225), congestive heart failure (81,85,98,139,157).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 264 A. BERTOLINI ET AL.
What the sources say
- Disputedcites [144] 144. Mitic-Zlatkovic M, Stefanovic V. Acute effects of acetaminophen on renal function and urinary excretion of some proteins and enzymes in patients with kidney disease. Ren Fail 1999;21:525-532. sourceExperimental — accuracy not yet measured
Citation (144) is attached specifically to the recommendation for patients with kidney disease. The Discussion (page unavailable) instead reports kidney-damage markers after a 2 g dose in such patients and urges caution in their use of acetaminophen. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
- Not checked — no full text of the sourcecites [56] 56. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease. Part 2. Short-term reductions in blood pressure: Overview of randomised drug trials in their epidemiological context. Lancet 1990;335:827-838. source
- Not checked — no full text of the sourcecites [93] 93. Gurwitz JH, Avorn J, Bohn RL, et al. Initiation of antihypertensive treatment during nonsteroidal anti-in- flammatory drug therapy. JAMA 1994;272:781-786. 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.
- Disputed
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB 1 receptors”
- Also stated in: § INTRODUCTION · boosted
“the analgesic activity of paracetamol involves a completely unforeseen mechanism, i.e., the potentiation of the cannabinoid/vanilloid tone in the brain and in dorsal root ganglia (102).”
§ Paracetamol: New Vistas of an Old Drug > ABSTRACT
What the sources say
- Not matchedcites Zygmunt and colleagues
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites Bertolini and colleagues
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. sourceExperimental — accuracy not yet measured
The Abstract reports that paracetamol is converted in the nervous system to AM404, which acts on the endocannabinoid system and is a ligand at CB1 receptors. The discussion following Fig. 5 suggests that AM404 may activate that system, but says its contribution to paracetamol’s effects can only be hypothesized; it does not establish that indirect CB1 activation causes the analgesic effect. (LLM, conf=0.88)
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.
- Rests on an assumption: The cannabinoid mechanism of paracetamol analgesia observed in rats applies to humans.
- Also stated in: § INTRODUCTION · boosted
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Such a peroxide-dependent inhibition of COX might explain why paracetamol is not active at sites of inflammation, where peroxides concentration is high, while being active in the brain, where peroxides concentration is very low.”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 253
What the sources say
- Not checked — no full text of the sourcecites [94] 94. Hanel AM, Lands WE. Modification of anti-inflammatory drug effectiveness by ambient lipid peroxides. Biochem Pharmacol 1982;31:3307-3311. source
- Partly supportedcites [32] 32. Boutaud O, Aronoff DM, Richardson JH, et al. Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H 2 synthases. Proc Natl Acad Sci USA 2002;99:7130-7135. sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) proposes that hydroperoxides in inflammatory cells could attenuate paracetamol’s action and account for its lack of anti-inflammatory effect. It also links paracetamol’s activity in endothelial cells to brain pyrexia, but does not state that peroxide levels in the brain are very low or establish that contrast with inflammatory sites. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [155] 155. Ouellet M, Percival MD. Mechanism of acetaminophen inhibition of cyclooxygenase isoforms. Arch Bio- chem Biophys 2001;387:273-280. 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.
Every source the paper cites for this claim was checked and supports it.
In the paper
“In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine”
- Also stated in: § CNS Drug Reviews, Vol. 12, No. 3-4, 2006 254 A. BERTOLINI ET AL. · plain
“paracetamol, following deacetylation to its primary amine (p-aminophenol) is conjugated with arachidonic acid in the brain and spinal cord to form AM404.”
- Also stated in: § CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 257 · plain
“in brain, spinal cord, and dorsal root ganglia of rats, paracetamol, following deacetylation (mainly in the liver) to p-aminophenol, is conjugated by enzyme fatty acid amide hydrolase (FAAH) with arachidonic acid to form N-arachidonoyl-phenolamine (AM404) (102).”
§ Paracetamol: New Vistas of an Old Drug > ABSTRACT
What the sources say
- Supportedcites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. source
The Results (page not provided) identify p-aminophenol and AM404 in rat brain after acetaminophen administration and detect AM404 in the spinal cord. The Results’ Fig. 1 caption states the proposed sequence: acetaminophen forms p-aminophenol, which is conjugated with arachidonic acid to form AM404. (LLM, conf=0.94)
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.
- Also stated in: § CNS Drug Reviews, Vol. 12, No. 3-4, 2006 254 A. BERTOLINI ET AL. · plain
Every source the paper cites for this claim was checked and supports it.
In the paper
“The involved enzyme is fatty acid amide hydrolase.”
- Also stated in: § CNS Drug Reviews, Vol. 12, No. 3-4, 2006 254 A. BERTOLINI ET AL. · plain
“The involved enzyme is fatty acid amide hydrolase (FAAH)”
§ Paracetamol: New Vistas of an Old Drug > ABSTRACT
What the sources say
- Supportedcites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. source
The Results report that purified rat FAAH formed AM404 when incubated with p-aminophenol and arachidonic acid. The Discussion also states that purified FAAH synthesized AM404 from those substrates, directly supporting the enzyme identification. (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.
- Also stated in: § CNS Drug Reviews, Vol. 12, No. 3-4, 2006 254 A. BERTOLINI ET AL. · plain
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
“paracetamol is able to inhibit COX, provided that the ambient concentration of peroxides is kept low (94)”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 253
What the sources say
- Not checked — no full text of the sourcecites [94] 94. Hanel AM, Lands WE. Modification of anti-inflammatory drug effectiveness by ambient lipid peroxides. Biochem Pharmacol 1982;31:3307-3311. source
- Supportedcites [32] 32. Boutaud O, Aronoff DM, Richardson JH, et al. Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H 2 synthases. Proc Natl Acad Sci USA 2002;99:7130-7135. source
The Discussion reports that added hydroperoxides reverse acetaminophen’s inhibition of PGHS (COX) activity, while the passage on the study’s rationale says lowering peroxide concentration enhances that inhibition. These passages support the citing sentence’s low-peroxide condition. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [155] 155. Ouellet M, Percival MD. Mechanism of acetaminophen inhibition of cyclooxygenase isoforms. Arch Bio- chem Biophys 2001;387:273-280. 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.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“other findings suggested that spinal and supraspinal antinociception induced by high doses of paracetamol involves brain opioid systems (100).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 253
What the sources say
- Partly supportedcites [100] 100. Herrero JF, Headly PM. Reversal by naloxone of the spinal antinociceptive actions of a systemically ad- ministered NSAIDs. Br J Pharmacol 1996;118:968-972. sourceExperimental — accuracy not yet measured
The paper’s conclusion (p. 968) supports an opioid-mediated spinal antinociceptive effect, but specifically for flunixin in spinalized rats with peripheral inflammation. It does not address high-dose paracetamol, supraspinal antinociception, or brain opioid systems. (LLM, conf=0.84)
hedgeddirect- 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
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“in brain regions with high expression of FAAH, both TRPV1 and CB 1 receptors are also found (mesencephalic trigeminal nucleus, primary sensory neurons) (12,77,140).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 254 A. BERTOLINI ET AL.
What the sources say
- Not checked — no full text of the sourcecites [12] 12. Bae YC, Oh JM, Hwang SJ, et al. Expression of vanilloid receptor TRPV1 in the rat trigeminal sensory nuclei. J Comp Neurol 2004;478:62-71. source
- Not checked — no full text of the sourcecites [77] 77. Egertova M, Cravatt BF, Elphick MR. Comparative analysis of fatty acid amide hydrolase and CB 1 cannabi- noid receptor expression in the mouse brain: Evidence of a widespread role for fatty acid amide hydrolase in regulation of endocannabinoid signalling. Neuroscience 2003;119:481-496. source
- Partly supportedcites [140] 140. Mezey E, Toth ZE, Cortright DN, et al. Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human. Proc Natl Acad Sci USA 2000;97:3655-3660. sourceExperimental — accuracy not yet measured
The Results and Discussion (page not available) place VR1, also called TRPV1, in brain regions and trigeminal-related structures. Our copy does not report FAAH expression or CB1 receptors, so it does not establish that both receptors occur in regions with high FAAH expression. (LLM, conf=0.87)
plaincorrelational- 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
“The formation of AM404 is dose-dependent.”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 257
What the sources say
- Supportedcites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. source
The Discussion explicitly states that formation of AM404 is dose-dependent. Table I in the Results shows increasing AM404 levels in rat brain after increasing doses of acetaminophen or p-aminophenol. (LLM, conf=0.95)
plaincorrelational- 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
- It may state two separate claims as one. 41
- Probably not a substantial claim. 7
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
“moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol.”
§ Paracetamol: New Vistas of an Old Drug > ABSTRACT
What the sources say
- Disputedcites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. sourceExperimental — accuracy not yet measured
The Results report that AM404 inhibits isolated COX-1 and COX-2, supporting the inhibition component. But the discussion following Fig. 5 says that, after an acetaminophen dose commonly used to induce analgesia in rodents, higher local brain concentrations of AM404 are likely and could inhibit COX. That is contrary to the claim that COX-inhibiting concentrations are probably unattainable at analgesic doses; the paper does not directly demonstrate COX inhibition in the brain. (LLM, conf=0.85)
Checked by a reasoning model — may be wrong.
hedgeddirect- 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.
- Disputed
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids”
- Also stated in: § CNS Drug Reviews, Vol. 12, No. 3-4, 2006 254 A. BERTOLINI ET AL. · boosted
“AM404 is a potent activator of vanilloid subtype 1 receptors (TRPV1) (235), and an inhibitor of the cellular anandamide uptake (anandamide membrane transporter, AMT), which leads to increased levels of endogenous cannabinoids”
§ Paracetamol: New Vistas of an Old Drug > ABSTRACT
What the sources say
- Not checked — no full text of the sourcecites [235] 235. Zygmunt PM, Chuang H, Movahed P, et al. The anandamide transport inhibitor AM404 activates vanilloid receptors. Eur J Pharmacol 2000;396:39-42. source
- Not checked — no full text of the sourcecites [19] 19. Beltramo M, Stella N, Calignano A, Lin SY, et al. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 1997;277:1094-1097. source
- Partly supportedcites [66] 66. De Petrocellis, Bisogno T, Davis JB, et al. Overlap between the ligand recognition properties of the ananda- mide transporter and the VR1 vanilloid receptor: Inhibitors of anandamide uptake with negligible capsai- cin-like activity. FEBS Lett 2000;483:52-56. sourceExperimental — accuracy not yet measured
The Abstract (page unavailable) reports that AM404 activates VR1/TRPV1 and inhibits cellular anandamide transport. The Introduction describes anandamide uptake as part of the process that terminates its activity, but the paper does not show that AM404 increases endogenous cannabinoid levels. (LLM, conf=0.86)
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.
- Also stated in: § CNS Drug Reviews, Vol. 12, No. 3-4, 2006 254 A. BERTOLINI ET AL. · boosted
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“TRPV1 (and also cannabinoid CB 1 ) receptors are present in pain and thermoregulatory pathways (66,111,165,209,210,216).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 254 A. BERTOLINI ET AL.
What the sources say
- Partly supportedcites [66] 66. De Petrocellis, Bisogno T, Davis JB, et al. Overlap between the ligand recognition properties of the ananda- mide transporter and the VR1 vanilloid receptor: Inhibitors of anandamide uptake with negligible capsai- cin-like activity. FEBS Lett 2000;483:52-56. sourceExperimental — accuracy not yet measured
The Introduction reports that VR1 (TRPV1) and CB1 occur in some of the same brain regions, including the hypothalamus, and that VR1 occurs in dorsal root sensory neurons. It does not establish that both receptors are present in pain and thermoregulatory pathways specifically. Page numbers were not available in our copy. (LLM, conf=0.78)
- Partly supportedcites [111] sourceExperimental — accuracy not yet measured
The Introduction (page not available) places TRPV1 in neurons that transmit noxious heat and pain signals. The paper does not establish that TRPV1 or CB1 is present in thermoregulatory pathways; CB1 appears only in the title of another work in the References. Thermal pain sensation is not the same as thermoregulation. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [165] 165. Piomelli D, Giuffrida A, Calignano A, Rodriguez de Fonseca F. The endocannabinoid system as a target for therapeutic drugs. Trends Pharmacol Sci 2000;21:218-224. 166. 103. Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med 1993;153:477-484. source
plaincorrelational- 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.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Thus, paracetamol would act as a pro-drug, with the active metabolite (AM404) being formed in the brain through conjugation of the deacetylated derivative of paracetamol (p-aminophenol) with arachidonic acid, by the action of fatty acid amide hydrolase (FAAH).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 254 A. BERTOLINI ET AL.
What the sources say
- Supportedcites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. source
The Results report that purified FAAH forms AM404 from p-aminophenol and arachidonic acid, and that AM404 was not detected in the brains of FAAH-deficient mice given acetaminophen. The paper identifies AM404 as a bioactive metabolite of acetaminophen in the nervous system, supporting the pro-drug characterization. Page numbers are unavailable in our copy. (LLM, conf=0.93)
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.
- Rests on an assumption: The cannabinoid mechanism of paracetamol analgesia observed in rats applies to humans.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“While the peak disturbance in liver function occurs 2 to 4 days after a paracetamol overdose, renal impairment, if it develops, becomes more evident after 1 week and returns to normal about 2 to 3 weeks after ingestion (55,61).”
§ Paracetamol: New Vistas of an Old Drug > TOXICOLOGY
What the sources say
- Partly supportedcites [55] 55. Cobden I, Record CO, Ward MK, Kerr DNS. Paracetamol-induced acute renal failure in the absence of ful- minant liver damage. Br Med J 1982;284:21-22. sourceExperimental — accuracy not yet measured
The Case reports section says renal failure was generally most evident one week after ingestion, compared with two to four days for liver damage. It does not say that renal function returned to normal about two to three weeks after ingestion; the table reports periods of oliguria, not a general time to normal renal function. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [61] 61. Curry RW, Robinson JD, Sughrue MJ. Acute renal failure after acetaminophen ingestion. JAMA 1982;247:1012-1014. 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.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Zygmunt and colleagues have shown that AM404 concentration-dependently inhibits both COX-1 and COX-2, as well as LPS-induced prostaglandin E 2 formation in macrophages.”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 254 A. BERTOLINI ET AL.
What the sources say
- Supportedcites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. source
The Results section states that AM404 concentration-dependently inhibited isolated COX-1 and COX-2 activity and LPS-induced prostaglandin E2 formation in RAW264.7 macrophages. The Fig. 5 caption describes the enzyme assays and macrophage experiment. (LLM, conf=0.95)
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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This novel metabolic pathway (fatty acid conjugation) is of crucial functional importance because it generates the active metabolite of paracetamol.It is negligible, however, in the overall biotrasformation of the drug.”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 257
What the sources say
- Partly supportedcites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. sourceExperimental — accuracy not yet measured
The Abstract and Results identify AM404 as a bioactive metabolite formed from paracetamol by fatty acid conjugation in the nervous system. The Discussion reports AM404 in rat brain but not liver or blood; it does not quantify this pathway's share of overall drug metabolism. The paper also says AM404's contribution to paracetamol's effects in humans remains hypothetical, so calling it *the* active metabolite overstates the finding. (LLM, conf=0.87)
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.
- Rests on an assumption: The cannabinoid mechanism of paracetamol analgesia observed in rats applies to humans.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“At analgesic doses of paracetamol, AM404 that is formed in rat brain regions expressing high levels of FAAH, can indirectly activate CB 1 receptors and directly activate TRPV1 receptors (66,102,235).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 254 A. BERTOLINI ET AL.
What the sources say
- Partly supportedcites [66] 66. De Petrocellis, Bisogno T, Davis JB, et al. Overlap between the ligand recognition properties of the ananda- mide transporter and the VR1 vanilloid receptor: Inhibitors of anandamide uptake with negligible capsai- cin-like activity. FEBS Lett 2000;483:52-56. sourceExperimental — accuracy not yet measured
The Results and discussion (page not available) show that AM404 inhibits anandamide uptake and directly activates the human VR1 receptor, now called TRPV1. The Introduction explains that anandamide is a CB1 agonist, which is consistent with an indirect CB1 mechanism. The paper does not establish that paracetamol produces AM404 in FAAH-rich rat brain regions, or that these receptor effects occur at analgesic doses. (LLM, conf=0.87)
- Partly supportedcites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. sourceExperimental — accuracy not yet measured
The discussion following Fig. 5 reports AM404 in rat brain after an analgesic acetaminophen dose and describes AM404 as a TRPV1 activator. The paper also links AM404’s inhibition of anandamide uptake to increased endocannabinoids, supporting indirect CB1 activation. But it says formation at higher concentrations in FAAH-rich brain regions is likely, rather than demonstrating formation in those specific regions. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [235] 235. Zygmunt PM, Chuang H, Movahed P, et al. The anandamide transport inhibitor AM404 activates vanilloid receptors. Eur J Pharmacol 2000;396:39-42. 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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“At this concentration AM404 activates both rat (102,235) and human (66) TRPV1 receptors, while significant COX-1 and COX-2 inhibition and prostaglandin E 2 formation reduction are obtained at micromolar concentrations (102).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 254 A. BERTOLINI ET AL.
What the sources say
- Partly supportedcites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. sourceExperimental — accuracy not yet measured
The discussion states that AM404 activates rat and human TRPV1 at concentrations above 10 nM. The Results and Fig. 5 caption report concentration-dependent COX-1/COX-2 inhibition and reduced PGE2 formation, but the available text does not establish that significant effects require micromolar AM404 concentrations. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [235] 235. Zygmunt PM, Chuang H, Movahed P, et al. The anandamide transport inhibitor AM404 activates vanilloid receptors. Eur J Pharmacol 2000;396:39-42. source
- Partly supportedcites [66] 66. De Petrocellis, Bisogno T, Davis JB, et al. Overlap between the ligand recognition properties of the ananda- mide transporter and the VR1 vanilloid receptor: Inhibitors of anandamide uptake with negligible capsai- cin-like activity. FEBS Lett 2000;483:52-56. sourceExperimental — accuracy not yet measured
The Results and discussion section reports that AM404 potently activates human VR1, supporting the human-receptor part of the claim. The passages do not establish activation of rat VR1 at roughly 10 nM, and a search of our copy found no COX-1, COX-2, or prostaglandin E2 result to support the micromolar comparison. Page numbers were not available in the indexed passages. (LLM, conf=0.83)
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
Every source the paper cites for this claim was checked and supports it.
In the paper
“Efficacy then decreases in a stepwise fashion with further delays, and there is no benefit if NAC administration is started more than 15 h after the overdose (167).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 263
What the sources say
- Supportedcites [167] 167. Prescott LF, Illingworth RN, Critchley JAH. Intravenous N-acetyl-cysteine: The treatment of choice for paracetamol poisoning. Br Med J 1979;2:1097-1100. source
The Liver Damage section reports a stepwise rise in severe liver damage as treatment was delayed beyond eight hours. The Discussion states that treatment after 15 hours was ineffective, matching the cited claim. (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 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
“However, several observations suggest that NAC has other mechanisms of action that are effective also after NAPQI formation and binding: enhancement of oxygen delivery and utilization (70,96,204).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 263
What the sources say
- Not checked — no full text of the sourcecites [70] 70. Devlin J, Ellis AE, McPeake J, et al. N-Acetylcysteine improves indocyanine green extraction and oxygen transport during hepatic dysfunction. Crit Care Med 1997;25:236-242. source
- Supportedcites [96] 96. Harrison PM, Wendon JA, Gimson AES, et al. Improvement by acetylcysteine of hemodynamics and oxy- gen transport in fulminant hepatic failure. N Engl J Med 1991;324:1852-1857. source
The Results (p. 1) report increased oxygen delivery and consumption after acetylcysteine in patients with acetaminophen-induced fulminant hepatic failure. The introduction (p. 1) distinguishes this late use, after severe liver damage has developed, from early glutathione-replenishing treatment; the Discussion (p. 4) proposes improved oxygen transport as an explanation for benefit at that stage. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [204] 204. Spies CD, Reinhart K, Witt I, et al. Influence of N-acetylcysteine on indirect indicators of tissue oxygen- ation in septic shock patients. Crit Care Med 1994;22:1738-1746. source
hedgeddirect- 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 support only part of this claim — read each source’s verdict below.
In the paper
“Depletion of glutathione in airway epithelial lining fluid by paracetamol metabolites has been suggested as the possible cause (192).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 263
What the sources say
- Partly supportedcites [192] 192. Shaheen SO, Sterne JA, Songhurst CE, et al. Frequent paracetamol use and asthma in adults. Thorax 2000;55:266-270. sourceExperimental — accuracy not yet measured
The Discussion proposes that frequent paracetamol use could contribute to asthma morbidity by depleting glutathione in airway epithelial lining fluid. However, the paper attributes depletion by a reactive paracetamol metabolite to the liver; it does not establish that metabolites deplete glutathione in airway lining fluid. (LLM, conf=0.86)
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“It can also antagonize the platelet inhibition induced by low dose aspirin and lessens its cardioprotective effect (46).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 264 A. BERTOLINI ET AL.
What the sources say
- Partly supportedcites [46] 46. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of as- pirin. N Engl J Med 2001;345:1809-1817. sourceExperimental — accuracy not yet measured
The Discussion reports that multiple daily doses of ibuprofen competitively inhibit low-dose aspirin’s sustained antiplatelet effect. It says this may limit aspirin’s cardioprotection, but does not demonstrate a reduction in cardiovascular events; it also reports no such interaction for diclofenac or rofecoxib. (LLM, conf=0.86)
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.
- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Paracetamol is indicated for mild-to-moderate pain, such as that caused by headaches, cold, flu, muscle aches, sprains, backache (including low back pain) (4), dysmenorrhea, minor arthritis pain, toothaches.”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 264 A. BERTOLINI ET AL.
What the sources say
- Could not verifycites [4] 4. Airaksinen O, Brox JI, Cedraschi C. European guidelines for the management of chronic non-specific low back pain. Eur Spine J 2006;15(Suppl 2):S192-S300. sourceExperimental — accuracy not yet measured
Citation (4) is attached to backache, including low back pain, rather than to the other listed conditions. The Subjects (indications) section mentions paracetamol but says no trials compared it with NSAIDs in chronic low back pain; the Pharmacological approaches section calls for trials of its effectiveness. Neither passage establishes that paracetamol is indicated for backache or low back pain. (LLM, conf=0.73)
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.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Renal damage is also produced by chronic use of paracetamol; in a case-control study involving 1,077 subjects who frequently took paracetamol, a dose-dependent relationship between heavier paracetamol use and an increased risk of end-stage renal disease was demonstrated (160).”
§ Paracetamol: New Vistas of an Old Drug > TOXICOLOGY
What the sources say
- Partly supportedcites [160] 160. Perneger TV, Whelton, Klag MJ. Risk of kidney failure associated with use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs. N Engl J Med 1994;331:1675-1679. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
boosteddirectn = 1,077- 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.
- Partly supported
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
“Cannabinoids also produce their antinociceptive effect by descending spinal inhibition, CB 1 receptors being almost exclusively involved.”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 254 A. BERTOLINI ET AL.
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 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
“while paracetamol is a weak inhibitor of prostaglandin synthesis in broken cell systems, therapeutic concentrations of paracetamol inhibit prostaglandin synthesis in intact cells in vitro when the levels of arachidonic acid are low.”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 253
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
“It is generally accepted that the two systemic effects of paracetamol of therapeutic significance are analgesia and antipyresis, while its antiinflammatory and antirheumatic activities are negligible (39,54,177).”
§ Paracetamol: New Vistas of an Old Drug > PHARMACOLOGICAL EFFECTS
What the sources say
- Not matchedcites [39] 39. Bruton L, Lazo J, Parker K. Goodman & Gilman's the Pharmacological Basis of Therapeutics, 11 th Edition. New York: McGraw-Hill, 2006.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites [54] 54. Clissold SP. Paracetamol and phenacetin. Drugs 1986;32(Suppl 4):46-59. source
- Not matchedcites [177] 177. Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology, 5 th Edition. Kidlington, Oxford: Elsevier Ltd, 2003.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boosted- 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.
- Not matched
None of the sources cited for this claim have been checked yet.
In the paper
“At 1,000 mg paracetamol reaches its ceiling effect in adults.Further increase in the dose does not increase analgesic activity (196,232), but does increase toxicity.”
§ Paracetamol: New Vistas of an Old Drug > PHARMACOLOGICAL EFFECTS
What the sources say
- Not checked — no full text of the sourcecites [196] 196. Skoglund LA, Skjelbred P, Fyllingen G. Analgesic efficacy of acetaminophen 1000 mg, acetaminophen 2000 mg, and the combination of acetaminophen 1000 mg and codeine phosphate 60 mg versus placebo in acute postoperative pain. Pharmacotherapy 1991;11:364-369. source
- Not matchedcites [232] 232. Woodbury DM. Analgesics and Antipyretics. In: Goodman LS and Gilman A, Eds., The Pharmacological Basis of Therapeutics, 3 rd edition. New York: The Macmillan Company, 1965:312-344 233. 105. Young CR, Mazure CM. Fulminant hepatic failure from acetaminophen in an anorexic patient treated with carbamazepine [Letter]. J Clin Psychiatry 1998;59:622.
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.
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
“Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration.”
- Also stated in: § INTRODUCTION · plain
“Unlike opiates, it is ineffective in pain arising from smooth muscle spasm in hollow viscera and has no depressant effect on respiration.”
§ Paracetamol: New Vistas of an Old Drug > ABSTRACT
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.
- Also stated in: § INTRODUCTION · plain
In the paper
“a splice variant of COX-1, derived from the same gene, was characterized in dog brain which was sensitive to inhibition with paracetamol (48); it was designated COX-3 (48)”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 253
What the sources say
- Not checked — no full text of the sourcecites [48] 48. Chandrasekharan NV, Dai H, Roos KL, et al. COX-3, a cyclooxygenase-1 variant inhibited by acetamino- phen and other analgesic/antipyretic drugs: Cloning, structure, and expression. Proc Natl Acad Sci USA 2002;99:13926-13931. source
plaindirect- 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
“Thus, it has been suggested that the effects of paracetamol may be due to selective inhibition of COX-2 dependent pathways that are proceeding at low rates (90).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 253
What the sources say
- Not checked — no full text of the sourcecites [90] 90. Graham GG, Scott KF. Mechanism of action of paracetamol. Am J Ther 2005;12:46-55. 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.
Probably not a substantial claim.
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
“Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects.”
- Also stated in: § INTRODUCTION · plain
“unlike NSAIDs paracetamol does not produce gastrointestinal damage or untoward cardiorenal effects.”
§ Paracetamol: New Vistas of an Old Drug > ABSTRACT
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: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
- Also stated in: § INTRODUCTION · plain
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
“cannabinoids produce analgesia either in animal models of pain (both acute pain and tonic pain) or in clinical painful conditions (for reviews see: 161,221), and endogenous cannabinoids are tonically released to participate in the control of basal nociceptive threshold (137).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 254 A. BERTOLINI ET AL.
What the sources say
- Not checked — no full text of the sourcecites [161] 161. Pertwee RG. Cannabinoid receptors and pain. Prog Neurobiol 2001;63:569-611. source
- Not checked — no full text of the sourcecites [221] 221. Walker JM, Huang SM. Cannabinoid analgesia. Pharmacol Ther 2002;95:127-135. source
- Not checked — no full text of the sourcecites [137] 137. Meng ID, Manning BH, Martin WJ, et al. An analgesia circuit activated by cannabinoids. Nature 1998;395: 381-383. 138. 101. Meredith TJ, Goulding R. Paracetamol. Postgrad Med J 1980;56:459-73. 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-induced antinociception in rats is associated with a decrease of dynorphin A levels in the frontal cortex, and is prevented by blockade of k-opioid receptors (186).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 253
What the sources say
- Not matchedcites [186] 186. Sandrini M, Romualdi P, Vitale G, et al. The effect of a paracetamol and morphine combination on dynor- phin A levels in the rat brain. Biochem Pharmacol 2001;61:1409-1416.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- 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
In the paper
“The analgesic efficacy of paracetamol is equivalent to that of aspirin, while its plasma levels required for the analgesic activity are higher than those needed for the antipyretic activity (18).”
§ Paracetamol: New Vistas of an Old Drug > PHARMACOLOGICAL EFFECTS
What the sources say
- Not checked — no full text of the sourcecites [18] 18. Beck DH, Schenk MR, Hagemann K, et al. The pharmacokinetics and analgesic efficacy of larger dose rec- tal acetaminophen (40 mg/kg) in adults: A double-blinded, randomized study. Anesth Analg 2000;90: 431-436. 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.
In the paper
“while COX-3 might be active in canines, its low expression level and the unfavorable kinetics indicate unlikely clinical relevance.In rodents and humans COX-3 encodes proteins with completely different amino acid sequences than COX-1 or COX-2 and without COX activity”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 253
What the sources say
- Not checked — no full text of the sourcecites [112] 112. Kis B, Snipes JA, Busija DW. Acetaminophen and the COX-3 puzzle: Sorting out facts, fictions and uncer- tainties. J Pharmacol Exp Ther 2005;315:1-7. source
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.
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
“Kidney is the second target organ of paracetamol toxicity: renal dysfunction occurs in about 25% of cases with significant hepatotoxicity (63,172) and in more than 50% of those with hepatic failure (128,230).”
§ Paracetamol: New Vistas of an Old Drug > TOXICOLOGY
What the sources say
- Not checked — no full text of the sourcecites [63] 63. Davenport A, Finn R. Paracetamol (acetaminophen) poisoning resulting in acute renal failure without hepa- tic coma. Nephron 1988;50:55-56. source
- Not checked — no full text of the sourcecites [172] 172. Prescott LF. Analgesic nephropathy. Drugs 1982;23:75-149. source
- Not checked — no full text of the sourcecites [128] 128. Makin AJ, Williams R. The current management of paracetamol overdosage. Br J Clin Prac 1994;48: 144-148. source
plaincorrelational- 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 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 therapeutic paracetamol dose is 10-15 mg/kg, therefore the therapeutic index is ~10).”
§ Paracetamol: New Vistas of an Old Drug > TOXICOLOGY
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 claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Overall mortality in alcohol-paracetamol syndrome is about 20%, and exceeds 75%, if acute liver failure develops (16,75,120,129).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 259
What the sources say
- Not checked — no full text of the sourcecites [16] 16. Barker JD Jr, de Carle DJ, Anuras S. Chronic excessive acetaminophen use and liver damage. Ann Intern Med 1977;87:299-301. source
- Not checked — no full text of the sourcecites [75] 75. Draganov P, Durrence H, Cox C, et al. Alcohol-acetaminophen syndrome. Postgrad Med 2000;107: 189-195. source
- Not checked — no full text of the sourcecites [120] 120. Licht H, Seeff LB, Zimmerman HJ. Apparent potentiation of acetaminophen hepatotoxicity by alcohol [Letter]. Ann Intern Med 1980;92:511. source
plaincorrelational- 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
“Coadministration of paracetamol with zidovudine may result in neutropenia or hepatotoxicity (180);”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 259
What the sources say
- Not checked — no full text of the sourcecites [180] 180. Richman DD, Fischl MA, Grieco MH, et al. The toxicity of azidothymidine (AZT) in the treatment of pa- tients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med 1987; 317:192-197. source
hedgedconditional- 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 claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Serious hepatotoxicity or death after acute paracetamol overdose has been reported in children, but is extremely rare (11,122,181), particularly in children under 5 years of age.”
§ Paracetamol: New Vistas of an Old Drug > TOXICOLOGY
What the sources say
- Not checked — no full text of the sourcecites [11] 11. Arena JM, Rourk MHJ, Sibrack CD. Acetaminophen: Report of an unusual poisoning. Pediatrics 1978;61:68-72. source
- Not checked — no full text of the sourcecites [122] 122. Lieh-Lai MW, Sarnaik AP, Newton JF, et al. Metabolism and pharmacokinetics of acetaminophen in a se- verely poisoned young child. J Pediatr 1984;105:125-128. source
- Not checked — no full text of the sourcecites [181] 181. Rumack BH, Peterson RG. Acetaminophen overdose: Incidence, diagnosis and management in 416 pa- tients. Pediatrics 1978;62(Suppl):898-903. 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
“These novel findings explain the mechanism of action of paracetamol and may provide an explanation of the observation that paracetamol inhibits prostaglandin production in the brain (84).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 254 A. BERTOLINI ET AL.
What the sources say
- Not checked — no full text of the sourcecites [84] 84. Flower RJ, Vane JR. Inhibition of prostaglandin synthetase in brain explains the anti-pyretic activity of pa- racetamol (4-acetamidophenol). Nature 1972;240:410-411. 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.
- Rests on an assumption: The cannabinoid mechanism of paracetamol analgesia observed in rats applies to humans.
In the paper
“There have been no reports of acute toxicity in healthy adults ingesting a single dose of paracetamol below 125 mg/kg; historical data suggest that toxicity generally occurs only above 150 mg/kg (176)”
§ Paracetamol: New Vistas of an Old Drug > TOXICOLOGY
What the sources say
- Not checked — no full text of the sourcecites [176] 176. Prescott LF. Paracetamol overdosage. Pharmacological considerations and clinical management. Drugs 1983;25:290-314. source
hedged- 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 claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“While chronic ethanol increases risk from acute paracetamol dosing (121,189,214) on the basis of induced P450 paracetamol metabolism, and consequent increased formation of NAPQI, or decreased glutathione supply or hepatic regeneration power (118), acute ethanol coadministration with paracetamol may be somewhat hepatoprotective (212,214) presumably by competitive inhibition of P450 paracetamol”
§ Paracetamol: New Vistas of an Old Drug > TOXICOLOGY
What the sources say
- Not checked — no full text of the sourcecites [121] 121. Lieber CS, Lasker JM, Alderman J, et al. The microsomal ethanol oxidizing system and its interaction with other drugs, carcinogens, and vitamins. Ann NY Acad Sci 1987;492:11-24. source
- Not checked — no full text of the sourcecites [189] 189. Seeff LB, Cuccherini BA, Zimmerman HJ, et al. Acetaminophen hepatotoxicity in alcoholics. A thera- peutic misadventure. Ann Intern Med 1986;104:309-404. source
- Not checked — no full text of the sourcecites [214] 214. Tredger JM, Smith HM, Read RB, Williams R. Effects of ethanol ingestion on the metabolism of a hepato- toxic dose of paracetamol in mice. Xenobiotica 1986;16:661-670. 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
“In most countries, paracetamol is the most used analgesic-antipyretic drug in children (21,158,179).”
§ Paracetamol: New Vistas of an Old Drug > THERAPEUTIC USES
What the sources say
- Not checked — no full text of the sourcecites [21] 21. Bentley E, Mackie IC. Trends in prescriptions of paracetamol for children. Br Med J 1995;311:362. source
- Not checked — no full text of the sourcecites [158] 158. Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Pediatr 2005;164: 552-558. source
- Not checked — no full text of the sourcecites [179] 179. Riano-Galan I, Gonzalez M, Sanchez SG, et al. Opinion de los pediatras sobre el dolor infantil. An Esp Pediatr 1998;49:587-593.
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
“The first symptoms after paracetamol overdose may be those of hepatic injury, which develops many hours after the ingestion, when antidotal therapy is already less effective (26).”
§ Paracetamol: New Vistas of an Old Drug > TOXICOLOGY
What the sources say
- Not matchedcites [26] 26. Bizovi KE, Smilkstein MJ. Acetaminophen. In: Golfrank LR, Howland MA, Flomenbaum NE, Hoffman RS, Lewin NA, Nelson RS, Eds. Goldfrank's Toxicologic Emergencies, 7 th Edition. New York: McGraw- Hill, 2002;480-501.
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: 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 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 such patients, NSAIDs, for their mechanism of action, may worsen the renal and cardiovascular function, besides causing gastrointestinal damage (23,85,227,228,229).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 264 A. BERTOLINI ET AL.
What the sources say
- Not checked — no full text of the sourcecites [23] 23. Bertolini A, Ottani A, Sandrini M. Selective COX-2 inhibitors and dual acting anti-inflammatory drugs: Critical remarks. Curr Med Chem 2002;9:1033-1043. source
- Not checked — no full text of the sourcecites [85] 85. Gaziano JM, Gibson CM. Potential for drug-drug interactions in patients taking analgesics for mild-to- moderate pain and low-dose aspirin for cardioprotection. Am J Cardiol 2006;97(Suppl 9A):23E-29E. source
- Not checked — no full text of the sourcecites [227] 227. Whelton A. Clinical implications of nonopioid analgesia for relief of mild-to-moderate pain in patients with or at risk for cardiovascular disease. Am J Cardiol 2006;97(Suppl 9A):3E-9E. 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.
None of the sources cited for this claim have been checked yet.
In the paper
“The dose of 1,000 mg was effective for up to 5 h after oral surgery (134), although pain relief was maximal at 1 to 2 h after administration (22), and was shown to be an effective treatment for extraction of impacted third molars and for various other oral surgeries, including difficult extractions, alveolectomy, multiple extractions, apicoectomy, biopsy, and deep gingival curettage (135,196).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 264 A. BERTOLINI ET AL.
What the sources say
- Not matchedcites [134] 134. Mehlisch DR, Frakes LA. A controlled comparative evaluation of acetaminophen and aspirin in the treatment of postoperative pain. Clin Ther 1984;7(1):89-97.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites [22] 22. Bentley KC, Head TW. The additive analgesic efficacy of acetaminophen, 1000 mg, and codeine, 60 mg, in dental pain. Clin Pharmacol Ther 1987;42:634-640. source
- Not checked — no full text of the sourcecites [135] 135. Mehlisch DR. The efficacy of combination analgesic therapy in relieving dental pain. Jada 2002;133: 861-871. 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.
- Not matched
In the paper
“In a mouse model, NAC actually reversed NAPQI oxidation (58), but there is no evidence of such a process in humans.”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 263
What the sources say
- Not checked — no full text of the sourcecites [58] 58. Corcoran GB, Mitchell JR, Vaishnav YN, et al. Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate, N-acetyl-p-benzoquinoneimine. Mol Pharmacol 1980;18:536-542. 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.
In the paper
“The”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 259
What the sources say
- Not matchedcites [26] 26. Bizovi KE, Smilkstein MJ. Acetaminophen. In: Golfrank LR, Howland MA, Flomenbaum NE, Hoffman RS, Lewin NA, Nelson RS, Eds. Goldfrank's Toxicologic Emergencies, 7 th Edition. New York: McGraw- Hill, 2002;480-501.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: fails — The authors may not put it forward as true.
- Checkable: fails — It may be too vague to check 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 authors may not put it forward as true. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
- Not matched
None of the sources cited for this claim have been checked yet.
In the paper
“Paracetamol, at oral doses of 15-20 mg/kg up to every 4 h, is the mainstay of treatment in childhood headache; since rectal absorption is variable, doses up to 45 mg/kg may be required for this route of administration (89,131,223).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 264 A. BERTOLINI ET AL.
What the sources say
- Not checked — no full text of the sourcecites [89] 89. Graf WD, Riback PS. Pharmacologic treatment of recurrent pediatric headache. Pediatr Ann 1995;24: 477-484. source
- Not matchedcites [131] 131. McGrath PA, Hillier LM, Eds. The Child With Headache: Diagnosis and Treatment. Seattle: IASP Press, 2001;12.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites [223] 223. Welborn CA. Pediatric migraine. Emerg Med Clin N Am 1997;15:625-636. 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.
In the paper
“NAC can also increase the substrate for non-toxic sulfation, allowing increased metabolism by this route and less metabolism by oxidation to NAPQI (198).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 263
What the sources say
- Not checked — no full text of the sourcecites [198] 198. Slattery JT, Wilson JM, Kalhorn TF, et al. Dose-dependent pharmacokinetics of acetaminophen: Evidence for glutathione depletion in humans. Clin Pharmacol Ther 1987;41:413-418. 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.
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
“Based on large clinical trials, it appears that NAC efficacy is nearly complete as long as it is initiated within 8-10 h of paracetamol overdose (200): there have been no deaths in cases so treated (182).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 263
What the sources say
- Not checked — no full text of the sourcecites [200] 200. Smilkstein MJ, Knapp GL, Kulig KW, et al. Efficacy of oral N-acetylcysteine in the treatment of acetami- nophen overdose: Analysis of the national multicenter study (1976-1985). N Engl J Med 1988;3190: 1557-1562. source
- Not checked — no full text of the sourcecites [182] 182. Rumack BH, Peterson RC, Koch GG, et al. Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med 1981;414:380-385. 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
“These effects include non-specific antioxidant effects, preservation of cerebral blood flow and perfusion in cerebral edema after liver failure (224).”
§ Paracetamol: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 263
What the sources say
- Not checked — no full text of the sourcecites [224] 224. Wendon JA, Harrison PM, Keays R, et al. Cerebral blood flow and metabolism in fulminant liver failure. Hepatology 1994;19:1407-1413. 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.
In the paper
“The obvious implications are that cannabinoids and similarly acting drugs may regulate cognitive functions, modulate food intake, affect both female and male reproduction, provide neuroprotection and be involved in neurodegenerative diseases; pathophysiology of shock; inhibition of fertilized oocyte implantation; inhibition of cancer growth, angiogenesis and metastasis (for a review see ref. 71).”
§ Paracetamol: New Vistas of an Old Drug > CONCLUSIONS
What the sources say
- Not checked — no full text of the sourcecites [71] 71. Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 2004;3:771-84. 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.
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
“The so-called”
§ Paracetamol: New Vistas of an Old Drug > TOXICOLOGY
What the sources say
- Not checked — no full text of the sourcecites [168] 168. Prescott LF, Matthew H. Cysteamine for paracetamol overdosage. Lancet 1974;1:998. source
- Not checked — no full text of the sourcecites [182] 182. Rumack BH, Peterson RC, Koch GG, et al. Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med 1981;414:380-385. source
- Not checked — no full text of the sourcecites [183] 183. Rumack BH, Peterson RG. Acetaminophen poisoning and toxicity. Pediatrics 1975;55:871-876. source
plaincorrelational- 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 authors state this as an assumption.
AM404 is evenly distributed throughout the brain.
“Assuming an even distribution of AM404 in brain”
The paper relies on this without support.
The cannabinoid mechanism of paracetamol analgesia observed in rats applies to humans.
“The blockade of cannabinoid CB 1 receptors has been shown to completely prevent the analgesic activity of paracetamol in rats (154).”
“At analgesic doses of paracetamol, AM404 that is formed in rat brain regions expressing high levels of FAAH, can indirectly activate CB 1 receptors and directly activate TRPV1 receptors (66,102,235).”
The paper relies on this without support.
Paracetamol is safe when taken at appropriate dosage.
“Paracetamol is a safe drug at appropriate dosage.”
The paper relies on this without support.
The mechanism of action of paracetamol had been a mystery of pharmacology for well over a century.
“For well more than a century the mechanism of action of paracetamol (acetaminophen), one of the most commonly used drugs in the world, has been one of the mysteries of pharmacology.”
The paper relies on this without support.
Drinking alcohol while taking paracetamol can enhance CYP2E1-mediated conversion of paracetamol to the hepatotoxic metabolite NAPQI.
“Concurrent use of alcohol and paracetamol may increase the CYP2E1-mediated metabolism of paracetamol to the highly hepatotoxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI).”
The paper relies on this without support.
In people who do not drink alcohol, NAPQI is detoxified by conjugation with glutathione.
“In non-alcoholics, NAPQI is detoxified by conjugation with glutathione.”
The paper relies on this without support.
Paracetamol is the drug of choice for minor-to-moderate non-inflammatory conditions in patients prone to gastric damage, and is preferable to aspirin in patients on anticoagulants or with coagulation disorders.
“Paracetamol is the drug of choice for treating minor-moderate, non-inflammatory conditions in patients who are prone to gastric damage, and is preferable to aspirin in patients receiving anticoagulants or in patients with coagulation disorders.”
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 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: New Vistas of an Old Drug > CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 257
“Glutathione quickly combines with this intermediate, and the resulting complex is then converted to non-toxic cysteine or mercaptate conjugates, which are eliminated in urine (141) (Fig. 2).”
§ Paracetamol: New Vistas of an Old Drug > AM281, N-(morpholin-4-yl)-5-(4-iodophenyl)-1-(2,4-dichlorphenyl)-4-methyl-1H-pyrazole-3-carboxamide; AM404, N-(4-hydroxyphenyl)arachidonylamide; AST,
“Figure: 2 Fig. 2 . Fig.2.Effect of CB 1 receptor-blockade on the analgesic activity of paracetamol (Para) and of a specific CB 1 agonist (HU210)(HU).”
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: New Vistas of an Old Drug > PHARMACOKINETICS
“The therapeutic concentrations range from 5 to 20 mg/mL.”
§ Paracetamol: New Vistas of an Old Drug > PHARMACOKINETICS
“Peak concentrations of paracetamol after recommended oral doses range from 8 to 32 ìg/mL.”
Citations
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Przybyła, G. W., Szychowski, K. A., & Gmiński, J. (2021) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.13392 · Cited by 190
Drug-induced Hypertension: An Unappreciated Cause of Secondary Hypertension
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Acetaminophen Increases Blood Pressure in Patients With Coronary Artery Disease
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“Acetaminophen (or paracetamol), marketed since the 1950s, is an over the counter (OTC) pain and fever medication generally considered “safe” even for use during pregnancy [Bertolini et al., 2006].”
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“indirect activation of cannabinoid CB1 receptors in brain and spinal cord [2,4].”
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“Still, this highly reactive metabolite is conjugated to the nucleophile, reduced glutathione (Bertolini et al. 2006).”
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“In an effort to support a cannabinoid hypothesis, it has been claimed that paracetamol can produce feelings of relaxation, tranquility and instill a feeling of well-being (114, 115).”
BackgroundPeri‐operative use of paracetamol
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“AM404 increases brain endocannabinoid levels by decreasing the re-uptake of anandamide (Bertolini et al., 2006).”
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“APAP does not produce gastrointestinal damage or untoward cardiorenal effects (Bertolini et al. 2006), and is contained in many preparations.”
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“GSTs are known to be involved in the in acetaminophen metabolism in mammals ( Bertolini et al. 2006 ), and in plants they play a major role during detoxification of organic pollutants and herbicides (Schroder and Collins 2002; Edwards and Dixon 2004).”
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“This pathway involves deacetylation of paracetamol in the liver producing p-aminophenol that conjugates with arachidonic acid in the brain and in the spinal cord [107,108].”
BackgroundParacetamol metabolism and related genetic differences
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“Deacetylation in the liver leads to para-aminophenol (p-aminophenol, 4-aminophenol), which is conjugated with arachidonic acid in the brain using the fatty acid amide hydrolase enzyme (FAAH) to form N-arachidonoylphenolamine (AM404) (Bertolini et al., 2006).”
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Current etiological comprehension and therapeutic targets of acetaminophen-induced hepatotoxicity
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“Sinatra and colleagues44 conducted a randomized, double-blind, placebo- and active-controlled, single- and repeated-dose, 24-hour study at nine study centers in the United States.”
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“75 Parecoxib COX is the enzyme that acts on arachidonic acid, and then triggers a reaction cascade that eventually forms prostaglandins, which are responsible for inflammation and pain.”
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Drug induced hypertension – An unappreciated cause of secondary hypertension
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“It can be mediated by COX-2 inhibition, by central COX-3 inhibition (Hinz et al., 2008) or by an indirect activation of cannabinoid receptors (Bertolini et al., 2006).”
BackgroundManagement of Chronic Arthritis Pain in the Elderly
Fitzcharles, M., Lussier, D., & Shir, Y. (2010) · Drugs & Aging · doi:10.2165/11536530-000000000-00000 · Cited by 93
Effects of opioid- and non-opioid analgesics on responses to psychosocial stress in humans
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Updates on Multimodal Analgesia for Orthopedic Surgery
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“Despite its wide use, debate exists regarding the analgesic mechanism of action (MoA) of paracetamol.(7) Historically, it was believed that the paracetamol-mediated analgesia stems solely from its cyclooxygenase (COX)dependent inhibitory effect on prostaglandin (PG) synthesis(8); however, it is now evident that the an…”
BackgroundThe Common Pain of Surrealism and Death
Randles, D., Heine, S. J., & Santos, N. (2013) · Psychological Science · doi:10.1177/0956797612464786 · Cited by 82
“When taken orally, Tylenol’s expected time to reach peak absorption is 45 to 60 min, and its ceiling effectiveness in adults occurs at 1,000 mg (Bertolini et al., 2006; Gibb & Anderson, 2008); this is also the maximum recommended single dose.”
BackgroundPrinciples of Burn Pain Management
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Acetaminophen Differentially Enhances Social Behavior and Cortical Cannabinoid Levels in Inbred Mice
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“However, acetaminophen is largely devoid of anti-inflammatory activity (Clissold, 1986; Bertolini et al., 2006; Brunton et al., 2011), which is a hallmark effect of classical COX inhibitors.”
BackgroundPostoperative Pain Management in Pediatric Spinal Fusion Surgery for Idiopathic Scoliosis
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Cyclization-activated Prodrugs
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“have tested this hypothesis on a systematic study of the reactivity of dipeptide esters of paracetamol, 17, as this phenolic drug represents an excellent leaving group in the course of intramolecular aminolysis of the dipeptide esters [23] and is known to originate hepatotoxic metabolites [64].”
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The influence of acetaminophen on repeated sprint cycling performance
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“However, definitive proof that Act directly acts on cyclooxygenase is still lacking (Bertolini et al. 2006), and further research is required to confirm these assumptions.”
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“These findings pave the way for a hypothesis where a paracetamol/AM404/CB1R/brainderived neurotrophic factor-mediated pathway is responsible for the neurobehavioral alterations seen after developmental exposure to paracetamol.”
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Analgesics and Sport Performance: Beyond the Pain‐Modulating Effects
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“In general, paracetamol has been deemed a safe drug when it is consumed within therapeutic dosages [28].”
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Effect of UV light on acetaminophen degradation in the electro-Fenton process
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The Role of Intravenous Acetaminophen in Acute Pain Management: A Case-Illustrated Review
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“It has since become one of the mostly widely used analgesic and antipyretic agents (Bertolini et al., 2006; Kaufman, Kelly, Rosenberg, Anderson, & Mitchell, 2002; Malaise et al., 2007) and is often the firstline therapy of choice for children (Cranswick & Coghlan, 2000).”
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“Alternatively, increasing endogenous cannabinoids such as anandamide leads to analgesia which is mediated via activation of the cannabinoid-1 (CB1) receptor (Bertolini et al., 2006; Hohmann, 2002; Lichtman et al., 2004; Russo et al., 2007b).”
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“At therapeutic doses, paracetamol is metabolized essentially in the liver, via conjugation with glucuronic acid and sulfonate ions; in addition, part of its metabolism can also occur at the level of the intestine and kidneys.(9) A small fraction of paracetamol is metabolized by the cytochrome P450 enzyme system, with…”
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“Acetaminophen (or paracetamol) was first used clinically in 1887 and has been widely marketed from the 1950s [20].”
BackgroundMultimodal analgesia in children
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“They were able to show that blockage of cannabinoid receptor 1 (CB1) completely prevents the analgesic activity of acetaminophen (Bertolini et al. 2006).”
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Metadata
- Authors
- Bertolini, A., Ferrari, A., Ottani, A., Guerzoni, S., Tacchi, R., & Leone, S.
- Affiliations
- University of Modena and Reggio Emilia (IT)
- University of Chieti-Pescara (IT)
- Corresponding author
- Bertolini, Alfio
- Venue
- CNS Drug Reviews
- Publisher
- Wiley
- Published
- 2006-09
- Volume
- 12
- Issue
- 3-4
- Pages
- 250-275
- ISSN
- 1080-563X (ISSN-L)
- 1527-3458
- PMC
- PMC6506194
- OpenAlex
- W1971079627
- Cited by
- 674
- References
- 251
- Citations by year
- 2026: 23 · 2025: 36 · 2024: 36 · 2023: 45 · 2022: 36 · 2021: 48 · 2020: 44 · 2019: 45 · 2018: 42 · 2017: 35 · 2016: 41 · 2015: 46 · 2014: 32 · 2013: 35 · 2012: 35
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- CNS Drug Reviews (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Pharmacology (medical) › Inflammatory mediators and NSAID effects
- Keywords
- paracetamol, analgesic mechanism, CB1 receptor, fatty acid amide hydrolase, TRPV1 receptor, endocannabinoids, cyclooxygenase inhibition, prodrugs, 4-aminophenol
- MeSH terms
- Acetaminophen, Animals, Humans, Pain, Analgesics, Non-Narcotic, History, 19th Century, History, 20th Century, History, 21st Century
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