Acetaminophen hepatotoxicity: the first
J Toxicol Clin Toxicol 2002;40(1):3-20
critical understanding of the literature makes it clear that therapeutic doses
of acetaminophen either alone or in the presence of inducers do not produce toxicity.
While the community of clinical toxicologists is small, it needs to be more aggressive
in making sure that physicians from other specialties and non-clinical toxicology
colleagues understand the significance and implications of this science."
Brok J, Buckley N, Gluud C.
for paracetamol (acetaminophen) overdoses (Cochrane Review).
Cochrane Database Syst Rev 2002;(3):CD003328
be given to patients with paracetamol overdose. No N-acetylcysteine regime has
been shown to be more effective than any other." [Abstract]
New developments in the therapy of intoxications.
Toxicol Lett 2002 Feb 28;127(1-3):299-305
"Multiple dose activated charcoal
and urinary alkalinization, commonly used to enhance the elimination of some poisons,
have limited usefulness. While these 'old' and more general methods of 'detoxification'
have thus failed in most cases to improve or change patient outcome, the use of
more specific antidotes, tailored to the exact cause of intoxication is to be
considered. Very few antidotes, however, are used on a consistent basis in the
management of poisoned victims. The indiscriminate use of antidotes may even be
harmful to the patient and incur an inordinate expense. In addition to the commonly
known antidotes N-acetylcysteine (acetaminophen, paracetamol), naloxone (opioids)
and flumazenil (benzodiazepines), new antidotes include fomepizole to treat ethylene
glycol and methanol poisoning and Crotalidae Polyvalent Immune Fab (Ovine) for
pit viper envenomation." [Abstract]
GG, Parikh CR.
Acetaminophen toxicity: suicidal vs. accidental.
Crit Care 2002 Apr;6(2):155-9
"Acetaminophen toxicity, which can lead
to hepatotoxicity, is a burden on our health care system and contributes significantly
to intensive care unit admissions and cost of hospitalization. The aim of our
study was to determine the epidemiology of various types of acetaminophen poisoning
and analyze their outcome compared with their admission characteristics."
M, Gavrilov V.
Deliberate self-poisoning in adolescents.
Isr Med Assoc J 2002 Apr;4(4):252-4
"We evaluated 324 cases of adolescent
self-poisoners aged 12-18 years (mean +/- SD 14.8 +/- 1.5 years). The female/male
ratio was 8:1. Most of the patients were attending school and lived in urban areas.
Oral ingestion was the only route of intake; 84.5% of the patients ingested drugs
and 10.5% non-medicinal compounds. The drug most commonly taken was acetaminophen."
R, Uren Z, Baker A, Majeed A.
Trends in suicide from drug overdose
in the elderly in England and Wales, 1993-1999.
Int J Geriatr
Psychiatry 2002 May;17(5):416-21
"Drugs most commonly used in overdose
were (in order) paracetamol (and related compounds), benzodiazepines, antidepressants,
and opiates." [Abstract]
R, Chiang WK, Reilly R.
Utility of acetaminophen screening in unsuspected
Vet Hum Toxicol 2002 Jun;44(3):171-3
"Although the overall risk of unsuspected acetaminophen toxicity in suicidal
ingestions is small, the definite risk in this treatable entity warrants universal
APAP screening in all suicidal ingestions." [Abstract]
FV, Ott P, Christensen E, Bondesen S.
The value of plasma acetaminophen
half-life in antidote-treated acetaminophen overdosage.
Clin Pharmacol Ther 2002 Apr;71(4):221-5 [Abstract]
Buckley NA, Srinivasan J.
Should a lower
treatment line be used when treating paracetamol poisoning in patients with chronic
alcoholism?: a case for.
Drug Saf 2002;25(9):619-24 [Abstract]
Dargan PI, Jones AL.
Should a lower treatment line be used
when treating paracetamol poisoning in patients with chronic alcoholism?: a case
Drug Saf 2002;25(9):625-32 [Abstract]
P, Kalhorn TF, Slattery JT.
Selective mitochondrial glutathione
depletion by ethanol enhances acetaminophen toxicity in rat liver.
Hepatology 2002 Aug;36(2):326-35
"In conclusion, 10-day ethanol feeding
enhances APAP toxicity through CYP2E1 induction, whereas 6-week ethanol feeding
potentiates APAP hepatotoxicity by inducing CYP2E1 and selectively depleting mitochondrial
Synergetic signaling for apoptosis in vitro by ethanol and acetaminophen.
Alcohol 2002 Jun;27(2):89-98 [Abstract]
Treating fever in children: paracetamol or ibuprofen?
Br J Community Nurs 2002 Jun;7(6):316-20
"Eight randomized controlled
trials that reported temperature differences at time-points between 1 and 6 hours
after administration were identified. Statistical meta-analysis showed no clear
benefit for one drug over another 1 hour after administration. However, by 6 hours
after administration ibuprofen was clearly superior resulting in a mean temperature
0.58 degrees C lower than paracetamol. Both drugs appeared well tolerated and
no evidence of difference in short-term adverse effects was observed. Both drugs
are effective antipyretics but the longer action of ibuprofen may make it preferable
in some circumstances." [Abstract]
CA, Turner JA, Marshall HM, Cardenas DD.
Treatments for chronic
pain associated with spinal cord injuries: many are tried, few are helpful.
Clin J Pain 2002 May-Jun;18(3):154-63
"Respondents reported multiple
pain treatments (range of 0-14 and median of 4 in sample 1; range of 0-16 and
median of 4 in sample 2). The most commonly reported treatments were oral medications
and physical therapy. Medication types most commonly reported were nonsteroidal
anti-inflammatory drugs (NSAIDs), acetaminophen, and opioids. The treatments rated
as most helpful were opioid medications, physical therapy, and diazepam therapy,
and those rated as least helpful were spinal cord stimulation, counseling or psychotherapy,
administration of acetaminophen, and administration of amitriptyline. Alternative
treatments reported as most helpful were massage therapy and use of marijuana.
Acupuncture was tried by many but was rated as only moderately helpful."
Anikwue R, Huffman JW, Martin ZL, Welch SP.
Decrease in efficacy and potency of nonsteroidal anti-inflammatory drugs
by chronic delta(9)-tetrahydrocannabinol administration.
J Pharmacol Exp Ther 2002 Oct;303(1):340-6
"When NSAIDs (p.o.) were administered,
the ED(50) values were as follows: 23 mg/kg aspirin, 3 mg/kg indomethacin, 5 mg/kg
celecoxib, 3 mg/kg ketorolac, 57 mg/kg acetaminophen (32.3-99.8), and 0.8 mg/kg
diclofenac (0.1-4.9). In animals given chronic Delta(9)-THC, only diclofenac and
acetaminophen were active. Conversely, chronic methanandamide (i.p.) did not alter
the antinociceptive effects of the NSAIDs. Neither the CB1 or CB2 antagonist blocked
the effects of the NSAIDs. The effects of chronic arachadonic acid, ethanolamine,
and anandamide could not be evaluated. In summary, our data indicate that chronic
Delta(9)-THC alters the cyclooxygenase system. Alternatively, the data suggest
that this alteration is not due to chronic endogenous cannabinoid release. Based
upon these data, we hypothesize that human subjects who are chronic users of Delta(9)-THC
may not respond to analgesic treatment with the above NSAIDs." [Abstract]
N. V. Chandrasekharan, Hu Dai, K. Lamar Turepu
Roos, Nathan K. Evanson, Joshua Tomsik, Terry S. Elton, and Daniel L. Simmons
COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and
other analgesic/antipyretic drugs: Cloning, structure, and expression PNAS
published September 19, 2002, 10.1073/pnas.162468699
"Comparison of canine
COX-3 activity with murine COX-1 and -2 demonstrates that this enzyme is selectively
inhibited by analgesic/antipyretic drugs such as acetaminophen, phenacetin, antipyrine,
and dipyrone, and is potently inhibited by some nonsteroidal antiinflammatory
drugs. Thus, inhibition of COX-3 could represent a primary central mechanism by
which these drugs decrease pain and possibly fever." [Abstract]
Pierce RH, Franklin CC, Campbell
JS, Tonge RP, Chen W, Fausto N, Nelson SD, Bruschi SA.
model for acetaminophen-induced hepatocyte death in vivo.
Biochem Pharmacol 2002 Aug 1;64(3):413-24
"Overdose of the popular, and
relatively safe, analgesic acetaminophen (N-acetyl-p-aminophenol, APAP, paracetamol)
can produce a fatal centrilobular liver injury. APAP-induced cell death was investigated
in a differentiated, transforming growth factor alpha (TGFalpha)-overexpressing,
hepatocyte cell line and found to occur at concentrations, and over time frames,
relevant to clinical overdose situations. Coordinated multiorganellar collapse
was evident during APAP-induced cytotoxicity with widespread, yet selective, protein
degradation events in vitro. Cellular proteasomal activity was inhibited with
APAP treatment but not with the comparatively nonhepatotoxic APAP regioisomer,
N-acetyl-m-aminophenol (AMAP). Low concentrations of the proteasome-directed inhibitor
MG132 (N-carbobenzoxyl-Leu-Leu-Leucinal) increased chromatin condensation and
cellular stress responses preferentially in AMAP-treated cultures, suggesting
a contribution of the proteasome in APAP- but not AMAP-mediated cell death. APAP-specific
alterations to mitochondria were observed morphologically with evidence of mitochondrial
proliferation in vitro. Biochemical alterations to cellular proteolytic events
were also found in vivo, including APAP- or AMAP-mediated inhibition of caspase-3
processing. These results indicate that, although retaining some attributes of
apoptosis, both APAP- and AMAP-mediated cell death have additional distinctive
features consistent with longer term necrosis."
D, Cohen I, Vieira HL, Poncet D, Boya P, Castedo M, Vadrot N, Belzacq AS, Fau
D, Brenner C, Feldmann G, Kroemer G.
transition as a novel principle of hepatorenal toxicity in vivo.
Apoptosis 2002 Oct;7(5):395-405
acute poisoning was also attenuated by CsA and GSH, both in vitro and in vivo.
Altogether these data indicate that PTPC-mediated MMP may determine the hepatorenal
toxicity of xenobiotics in vivo."
Y, Kondo T, Ohshima T, Fujiwara H, Iwakura Y, Mukaida N.
involvement of IFN-gamma in the pathogenesis of acetaminophen-induced acute liver
FASEB J 2002 Aug;16(10):1227-36
mice survived with reduced serum transaminase elevation and attenuated hepatic
necrosis, leukocyte infiltration, and hepatocyte apoptosis. The gene expression
of all molecules was significantly attenuated in IFN-gamma-deficient mice. Administration
of an anti-IFN-gamma neutralizing antibody even 2 or 8 h after APAP challenge
to wild-type mice alleviated APAP-induced liver injury, and all mice survived.
Thus, IFN-gamma is responsible for APAP-induced liver injury by mediating leukocyte
infiltration, hepatocyte apoptosis, and NO production as well as cytokine and
chemokine production. Moreover, immunoneutralization of IFN-gamma may be therapeutically
effective for developing APAP-induced liver injury." [Abstract]
Schmidt LE, Dalhoff K.
is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity.
Hepatology 2002 Sep;36(3):659-65 [Abstract]
H, Matsumaru K, Feng G, Kaplowitz N.
Reduced glutathione depletion
causes necrosis and sensitization to tumor necrosis factor-alpha-induced apoptosis
in cultured mouse hepatocytes.
Hepatology 2002 Jul;36(1):55-64
"A combination of antioxidants, vitamin E, and butylated hydroxytoluene (BHT)
markedly inhibited necrosis induced by APAP or DEM alone, but the sensitization
to TNF-alpha-induced apoptosis was unaffected." [Abstract]
H, Brittingham JA, Laskin DL.
Differential induction of heme oxygenase-1
in macrophages and hepatocytes during acetaminophen-induced hepatotoxicity in
the rat: effects of hemin and biliverdin.
Pharmacol 2002 Jun 1;181(2):106-15
"Pretreatment of rats with hemin was
found to prevent acetaminophen-induced hepatotoxicity, as measured histologically
and biochemically by decreased serum transaminase levels. This was correlated
with more rapid increases in expression of hepatic ferritin and MnSOD. Heme metabolism
via HO-1 generates biliverdin, which is rapidly converted to bilirubin by biliverdin
reductase. Pretreatment of rats with biliverdin (40 micromol/kg, ip) was also
found to block acetaminophen-induced injury. These data suggest that HO-1 is an
important component of antioxidant defense during acetaminophen-induced hepatotoxicity."
TR, Jaeschke H.
Acetaminophen-induced inhibition of Fas receptor-mediated
liver cell apoptosis: mitochondrial dysfunction versus glutathione depletion.
Toxicol Appl Pharmacol 2002 Jun 1;181(2):133-41 [Abstract]
FN, DeMaster EG, Shoeman DW, Nagasawa HT.
suppression of hepatic AdoMet synthetase activity is attenuated by prodrugs of
Toxicol Lett 2002 Jun 7;132(1):1-8 [Abstract]
M, Reilly TP, Elkahloun AG, George JW, Pohl LR.
inhibitory factor in drug-induced liver injury: a role in susceptibility and stress
Biochem Biophys Res Commun 2002 Jun 7;294(2):225-30
"The decreased hepatic injury in MIF-/- mice correlated with a reduction
in mRNA levels of interferon-gamma and a significant increase in heat shock protein
expression, but was unrelated to the APAP-protein adduct formation in the liver.
These findings support MIF as a critical pro-toxicant signal in drug-induced liver
injury with potentially important and novel effects on heat shock protein responsiveness."
R, Kusunoki N, Matsuzaki T, Hashimoto S, Kawai S.
drugs induce apoptosis in association with activation of peroxisome proliferator-activated
receptor gamma in rheumatoid synovial cells.
Exp Ther 2002 Jul;302(1):18-25 [Abstract]