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British Journal of Clinical Pharmacology Mar 2016Paracetamol protein adducts (PPA) are a biomarker of paracetamol exposure. PPA are quantified as paracetamol-cysteine (APAP-CYS), and concentrations above 1.1 μmol... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Paracetamol protein adducts (PPA) are a biomarker of paracetamol exposure. PPA are quantified as paracetamol-cysteine (APAP-CYS), and concentrations above 1.1 μmol l(-1) have been suggested as a marker of paracetamol-induced hepatotoxicity. However, there is little information on the range of concentrations observed during prolonged therapeutic dosing.
AIM
The aim of the present study was to describe the concentration of PPA in the serum of subjects taking therapeutic doses of paracetamol for at least 16 days.
METHODS
Preplanned secondary aim of a prospective randomized controlled (placebo vs. 4g day(-1) paracetamol) trial. We measured subjects' serum PPA concentrations every 3 days for a minimum of 16 days. We also measured concentrations on study days 1-3 and 16-25 in subsets of patients. PPA were quantified as APAP-CYS after gel filtration and protein digestion using liquid chromatography/mass spectrometry.
RESULTS
Ninety per cent of subjects had detectable PPA after five doses. Median APAP-CYS concentrations in paracetamol-treated subjects increased to a plateau of 0.1 μmol l(-1) on day 7, where they remained. The highest concentration measured was 1.1 μmol l(-1) and two subjects never had detectable PPA levels. PPA were detected in the serum of 78% of subjects 9 days after their final dose.
CONCLUSIONS
PPA are detectable in the vast majority of subjects taking therapeutic doses of paracetamol. While most have concentrations well below the threshold associated with hepatotoxicity, concentrations may approach 1.1 μmol l(-1) in rare cases. Adducts are detectable after a few doses and can persist for over a week after dosing is stopped.
Topics: Acetaminophen; Adolescent; Adult; Aged; Analgesics, Non-Narcotic; Biomarkers; Cysteine; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Young Adult
PubMed: 26584404
DOI: 10.1111/bcp.12831 -
Therapie 1978
Review
Topics: Acetaminophen; Acute Disease; Analgesics; Anemia, Hemolytic; Animals; Biotransformation; Blood Coagulation Disorders; Chemical Phenomena; Chemical and Drug Induced Liver Injury; Chemistry; Guinea Pigs; Humans; Intestinal Absorption; Kidney; Kinetics; Liver; Methemoglobinemia; Rabbits; Rats; Solubility; Tissue Distribution
PubMed: 369026
DOI: No ID Found -
Drug Safety 1992Paracetamol (acetaminophen) poisoning accounts for almost a third of admissions to our district poisons unit, and is the commonest cause of death in such patients.... (Review)
Review
Paracetamol (acetaminophen) poisoning accounts for almost a third of admissions to our district poisons unit, and is the commonest cause of death in such patients. Antidotal treatment may be effective up to 10h after overdose with oral methionine or up to 24h with acetylcysteine (not 15h as previously suggested for the latter). Patients taking paracetamol overdose while also receiving drugs which induce hepatic enzymes are more susceptible to liver damage, and antidotal treatment may be necessary at lower plasma paracetamol concentrations (50% of the normal treatment line). As survival following liver transplantation is now increasing, it is important to identify early prognostic indicators in fulminant hepatic failure, so that those patients with a high chance of fatal outcome can be considered for transplantation. Useful indicators are the presence of acidosis, marked prolongation of prothrombin time or a continued rise in prothrombin time on day 4 after the overdose. There is no evidence that paracetamol or acetylcysteine are teratogenic in pregnancy. Delays in administering acetylcysteine after paracetamol poisoning in pregnancy have been shown to increase the risk of spontaneous abortion and fetal death. Thus, acetylcysteine should be started as early as possible where treatment is indicated.
Topics: Acetaminophen; Antidotes; Chemical and Drug Induced Liver Injury; Drug Overdose; Enzyme Induction; Female; Humans; Liver Diseases; Liver Transplantation; Pregnancy; Pregnancy Complications
PubMed: 1503665
DOI: 10.2165/00002018-199207030-00002 -
British Journal of Clinical Pharmacology Nov 2015The antiviral agent favipiravir is likely to be co-prescribed with acetaminophen (paracetamol). The present study evaluated the possiblility of a pharmacokinetic...
AIMS
The antiviral agent favipiravir is likely to be co-prescribed with acetaminophen (paracetamol). The present study evaluated the possiblility of a pharmacokinetic interaction between favipiravir and acetaminophen, in vitro and in vivo.
METHODS
The effect of favipivir on the transformation of acetaminophen to its glucuronide and sulfate metabolites was studied using a pooled human hepatic S9 fraction in vitro. The effect of acute and extended adminstration of favipiravir on the pharmacokinetics of acetaminophen and metabolites was evaluated in human volunteers.
RESULTS
Favipiravir inhibited the in vitro formation of acetaminophen sulfate, but not acetaminophen glucuronide. In human volunteers, both acute (1 day) and extended (6 days) administration of favipiravir slightly but significantly increased (by about 20 %) systemic exposure to acetaminophen (total AUC), whereas Cmax was not significantly changed. AUC for acetaminophen glucuronide was increased by 23 to 35 % above control by favipiravir, while AUC for acetaminophen sulfate was reduced by about 20 % compared to control. Urinary excretion of acetaminophen sulfate was likewise reduced to 44 to 65 % of control values during favipiravir co-administration, while excretion of acetaminophen glucuronide increased to 17 to 32 % above control.
CONCLUSION
Favipiravir inhibits acetaminophen sulfate formation in vitro and in vivo. However the increase in systemic exposure to acetaminophen due to favipiravir co-administration, though statistically significant, is small in magnitude and unlikely to be of clinical importance.
Topics: Acetaminophen; Adult; Amides; Analgesics, Non-Narcotic; Antiviral Agents; Drug Interactions; Female; Humans; In Vitro Techniques; Inhibitory Concentration 50; Male; Middle Aged; Pyrazines; Young Adult
PubMed: 25808818
DOI: 10.1111/bcp.12644 -
F1000Research 2020Paracetamol (acetaminophen) is widely used in pregnancy and generally regarded as "safe" by regulatory authorities. Clinically relevant doses of paracetamol were...
Paracetamol (acetaminophen) is widely used in pregnancy and generally regarded as "safe" by regulatory authorities. Clinically relevant doses of paracetamol were administered intraperitoneally to pregnant rats twice daily from embryonic day E15 to 19 (chronic) or as a single dose at E19 (acute). Control samples were from un-treated age-matched animals. At E19, rats were anaesthetised, administered a final paracetamol dose, uteruses were opened and fetuses exposed for sample collection. For RNA sequencing, placentas and fetal brains were removed and flash frozen. Fetal and maternal plasma and cerebrospinal fluid were assayed for α-fetoprotein and interleukin 1β (IL1β). Brains were fixed and examined (immunohistochemistry) for plasma protein distribution. Placental permeability to a small molecule ( C-sucrose) was tested by injection into either mother or individual fetuses; fetal and maternal blood was sampled at regular intervals to 90 minutes. RNA sequencing revealed a large number of genes up- or down-regulated in placentas from acutely or chronically treated animals compared to controls. Most notable was down-regulation of three acute phase plasma proteins (α-fetoprotein, transferrin, transthyretin) in acute and especially chronic experiments and marked up-regulation of immune-related genes, particularly cytokines, again especially in chronically treated dams. IL1β increased in plasma of most fetuses from treated dams but to variable levels and no IL1β was detectable in plasma of control fetuses or any of the dams. Increased placental permeability appeared to be only from fetus to mother for both C-sucrose and α-fetoprotein, but not in the reverse direction. In the fetal brain, gene regulatory changes were less prominent than in the placenta of treated fetuses and did not involve inflammatory-related genes; there was no evidence of increased blood-brain barrier permeability. Results suggest that paracetamol may induce an immune-inflammatory-like response in placenta and more caution should be exercised in use of paracetamol in pregnancy.
Topics: Acetaminophen; Animals; Blood-Brain Barrier; Brain; Female; Gene Expression; Inflammation; Permeability; Placenta; Pregnancy; Rats
PubMed: 32934805
DOI: 10.12688/f1000research.24119.2 -
Social Cognitive and Affective... Sep 2016Simulation theories of empathy hypothesize that empathizing with others' pain shares some common psychological computations with the processing of one's own pain.... (Randomized Controlled Trial)
Randomized Controlled Trial
Simulation theories of empathy hypothesize that empathizing with others' pain shares some common psychological computations with the processing of one's own pain. Support for this perspective has largely relied on functional neuroimaging evidence of an overlap between activations during the experience of physical pain and empathy for other people's pain. Here, we extend the functional overlap perspective to the neurochemical level and test whether a common physical painkiller, acetaminophen (paracetamol), can reduce empathy for another's pain. In two double-blind placebo-controlled experiments, participants rated perceived pain, personal distress and empathic concern in response to reading scenarios about another's physical or social pain, witnessing ostracism in the lab, or visualizing another study participant receiving painful noise blasts. As hypothesized, acetaminophen reduced empathy in response to others' pain. Acetaminophen also reduced the unpleasantness of noise blasts delivered to the participant, which mediated acetaminophen's effects on empathy. Together, these findings suggest that the physical painkiller acetaminophen reduces empathy for pain and provide a new perspective on the neurochemical bases of empathy. Because empathy regulates prosocial and antisocial behavior, these drug-induced reductions in empathy raise concerns about the broader social side effects of acetaminophen, which is taken by almost a quarter of adults in the United States each week.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Double-Blind Method; Empathy; Female; Humans; Male; Noise; Pain; Social Behavior; Social Environment; Young Adult
PubMed: 27217114
DOI: 10.1093/scan/nsw057 -
Molecular Pharmaceutics Dec 2014The analgesic and antipyretic compound acetaminophen (paracetamol) is one of the most used drugs worldwide. Acetaminophen overdose is also the most common cause for...
The analgesic and antipyretic compound acetaminophen (paracetamol) is one of the most used drugs worldwide. Acetaminophen overdose is also the most common cause for acute liver toxicity. Here we show that acetaminophen and many structurally related compounds bind quinone reductase 2 (NQO2) in vitro and in live cells, establishing NQO2 as a novel off-target. NQO2 modulates the levels of acetaminophen derived reactive oxygen species, more specifically superoxide anions, in cultured cells. In humans, NQO2 is highly expressed in liver and kidney, the main sites of acetaminophen toxicity. We suggest that NQO2 mediated superoxide production may function as a novel mechanism augmenting acetaminophen toxicity.
Topics: Acetaminophen; HeLa Cells; Humans; In Vitro Techniques; Kidney; Liver; Quinone Reductases; Reactive Oxygen Species
PubMed: 25313982
DOI: 10.1021/mp5004866 -
American Journal of Health-system... Sep 2006
Topics: Acetaminophen; Alanine Transaminase; Analgesics, Non-Narcotic; Controlled Clinical Trials as Topic; Humans
PubMed: 16914622
DOI: 10.2146/news060006 -
Drug and Therapeutics Bulletin Jun 2018Paracetamol, on its own or in combination with other analgesics, is widely used to treat pain associated with acute and chronic conditions. It is considered safe enough... (Review)
Review
Paracetamol, on its own or in combination with other analgesics, is widely used to treat pain associated with acute and chronic conditions. It is considered safe enough to have a general sales licence (GSL) for use by "adults, elderly and children over 16 years" and has few listed cautions or contraindications.1,2 However, recently the effectiveness and safety of paracetamol for some conditions have been challenged, 3,4 and there are published case reports of liver failure associated with therapeutic doses.5-9 Here, we review the use of paracetamol, its pharmacokinetics, the mechanisms by which it can cause liver damage and consider whether frail older people are at greater risk of adverse effects. We also discuss if dose reduction should be considered in some circumstances.
Topics: Acetaminophen; Age Factors; Aged, 80 and over; Analgesics; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Frail Elderly; Humans; Pain
PubMed: 29903753
DOI: 10.1136/dtb.2018.6.0636 -
Drug Safety 2005The excellent tolerability of therapeutic doses of paracetamol (acetaminophen) is a major factor in the very wide use of the drug. The major problem in the use of... (Review)
Review
The excellent tolerability of therapeutic doses of paracetamol (acetaminophen) is a major factor in the very wide use of the drug. The major problem in the use of paracetamol is its hepatotoxicity after an overdose. Hepatotoxicity has also been reported after therapeutic doses, but critical analysis indicates that most patients with alleged toxicity from therapeutic doses have taken overdoses. Importantly, prospective studies indicate that therapeutic doses of paracetamol are an unlikely cause of hepatotoxicity in patients who ingest moderate to large amounts of alcohol. Controlled clinical trials have found that paracetamol is very well tolerated by the gastrointestinal tract. While variable results have been found in case control studies, most studies have shown no change or a small increase in the relative risk of perforations, ulcer or bleeding in the upper gastrointestinal tract. However, associations between the use of paracetamol and gastrointestinal toxicity, as well as with chronic renal disease and asthma, are very likely to reflect biases in some case control studies. In particular, such biases may be caused by the perceived high tolerability of paracetamol in these diseases. The consequent use of paracetamol in these diseases states then leads to an apparent association between paracetamol and the disease. Despite metabolism of paracetamol to reactive compounds, hypersensitivity reactions are rare, although urticaria occurs in occasional patients. Paracetamol appears to be well tolerated during pregnancy although prospective studies are required.
Topics: Acetaminophen; Chemical and Drug Induced Liver Injury; Humans; Molecular Structure; Treatment Outcome
PubMed: 15733027
DOI: 10.2165/00002018-200528030-00004