Paracetamol: New Vistas of an Old Drug

In the paper

“moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol.”

What the sources say

• Disputed

  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.

  cites [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

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”

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 supported

  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)

  cites [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

In the paper

“TRPV1 (and also cannabinoid CB 1 ) receptors are present in pain and thermoregulatory pathways (66,111,165,209,210,216).”

What the sources say

• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [111] sourceExperimental — accuracy not yet measured
• ?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

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).”

What the sources say

• Supported

  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)

  cites [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

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).”

What the sources say

• Partly supported

  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)

  cites [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
• ?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

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.”

What the sources say

• Supported

  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)

  cites [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

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.”

What the sources say

• Partly supported

  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)

  cites [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

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).”

What the sources say

• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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
• ?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

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).”

What the sources say

• Partly supported

  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)

  cites [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
• ?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 supported

  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)

  cites [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

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).”

What the sources say

• Supported

  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)

  cites [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

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).”

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
• Supported

  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)

  cites [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
• ?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

In the paper

“Depletion of glutathione in airway epithelial lining fluid by paracetamol metabolites has been suggested as the possible cause (192).”

What the sources say

• Partly supported

  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)

  cites [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

In the paper

“It can also antagonize the platelet inhibition induced by low dose aspirin and lessens its cardioprotective effect (46).”

What the sources say

• Partly supported

  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)

  cites [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

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.”

What the sources say

• ?Could not verify

  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)

  cites [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

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).”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [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

In the paper

“Cannabinoids also produce their antinociceptive effect by descending spinal inhibition, CB 1 receptors being almost exclusively involved.”

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.”

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).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [39] 39. Bruton L, Lazo J, Parker K. Goodman & Gilman's the Pharmacological Basis of Therapeutics, 11 th Edition. New York: McGraw-Hill, 2006.
• ?Not checked — no full text of the sourcecites [54] 54. Clissold SP. Paracetamol and phenacetin. Drugs 1986;32(Suppl 4):46-59. source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [177] 177. Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology, 5 th Edition. Kidlington, Oxford: Elsevier Ltd, 2003.

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.”

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 matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [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.

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.”

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)”

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

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).”

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

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.”

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).”

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

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).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [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.

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).”

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

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”

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

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).”

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

In the paper

“(the therapeutic paracetamol dose is 10-15 mg/kg, therefore the therapeutic index is ~10).”

In the paper

“Overall mortality in alcohol-paracetamol syndrome is about 20%, and exceeds 75%, if acute liver failure develops (16,75,120,129).”

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

In the paper

“Coadministration of paracetamol with zidovudine may result in neutropenia or hepatotoxicity (180);”

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

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.”

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

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).”

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

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)”

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

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”

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

In the paper

“In most countries, paracetamol is the most used analgesic-antipyretic drug in children (21,158,179).”

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.

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).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [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.

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).”

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

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).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [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.
• ?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

In the paper

“In a mouse model, NAC actually reversed NAPQI oxidation (58), but there is no evidence of such a process in humans.”

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

In the paper

“The”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [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.

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).”

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 matched

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  cites [131] 131. McGrath PA, Hillier LM, Eds. The Child With Headache: Diagnosis and Treatment. Seattle: IASP Press, 2001;12.
• ?Not checked — no full text of the sourcecites [223] 223. Welborn CA. Pediatric migraine. Emerg Med Clin N Am 1997;15:625-636. source

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).”

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

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).”

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

In the paper

“These effects include non-specific antioxidant effects, preservation of cerebral blood flow and perfusion in cerebral edema after liver failure (224).”

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

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).”

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

In the paper

“The so-called”

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