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International Journal of Molecular... Dec 2022The mechanism of acetaminophen (APAP) analgesia is at least partially unknown. Previously, we showed that the APAP metabolite N-acetyl-p-benzoquinone imine (NAPQI)...
The mechanism of acetaminophen (APAP) analgesia is at least partially unknown. Previously, we showed that the APAP metabolite N-acetyl-p-benzoquinone imine (NAPQI) activated Kv7 channels in neurons in vitro, and this activation of Kv7 channels dampened neuronal firing. Here, the effect of the Kv7 channel blocker XE991 on APAP-induced analgesia was investigated in vivo. APAP had no effect on naive animals. Induction of inflammation with λ-carrageenan lowered mechanical and thermal thresholds. Systemic treatment with APAP reduced mechanical hyperalgesia, and co-application of XE991 reduced APAP's analgesic effect on mechanical pain. In a second experiment, the analgesic effect of systemic APAP was not antagonized by intrathecal XE991 application. Analysis of liver samples revealed APAP and glutathione-coupled APAP indicative of metabolization. However, there were no relevant levels of these metabolites in cerebrospinal fluid, suggesting no relevant APAP metabolite formation in the CNS. In summary, the results support an analgesic action of APAP by activating Kv7 channels at a peripheral site through formation of the metabolite NAPQI.
Topics: Animals; Acetaminophen; Analgesics, Non-Narcotic; Imines; Analgesics; Liver
PubMed: 36614094
DOI: 10.3390/ijms24010650 -
Environmental Science and Pollution... Aug 2018Currently, analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) are classified as one of the most emerging group of xenobiotics and have been detected in various... (Review)
Review
Currently, analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) are classified as one of the most emerging group of xenobiotics and have been detected in various natural matrices. Among them, monocyclic paracetamol and ibuprofen, widely used to treat mild and moderate pain are the most popular. Since long-term adverse effects of these xenobiotics and their biological and pharmacokinetic activity especially at environmentally relevant concentrations are better understood, degradation of such contaminants has become a major concern. Moreover, to date, conventional wastewater treatment plants (WWTPs) are not fully adapted to remove that kind of micropollutants. Bioremediation processes, which utilize bacterial strains with increased degradation abilities, seem to be a promising alternative to the chemical methods used so far. Nevertheless, despite the wide prevalence of paracetamol and ibuprofen in the environment, toxicity and mechanism of their microbial degradation as well as genetic background of these processes remain not fully characterized. In this review, we described the current state of knowledge about toxicity and biodegradation mechanisms of paracetamol and ibuprofen and provided bioinformatics analysis concerning the genetic bases of these xenobiotics decomposition.
Topics: Acetaminophen; Aquatic Organisms; Biodegradation, Environmental; Biofilms; Genetic Background; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Ibuprofen; Wastewater; Water Pollutants, Chemical; Water Purification
PubMed: 29923050
DOI: 10.1007/s11356-018-2517-x -
BMJ (Clinical Research Ed.) Mar 2015
Topics: Acetaminophen; Analgesics, Non-Narcotic; Back Pain; Humans; Osteoarthritis
PubMed: 25828857
DOI: 10.1136/bmj.h1352 -
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 -
The Cochrane Database of Systematic... 2004Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually preferred for simple analgesics such as paracetamol for rheumatoid arthritis. It is not clear, however, whether... (Review)
Review
BACKGROUND
Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually preferred for simple analgesics such as paracetamol for rheumatoid arthritis. It is not clear, however, whether the trade-offs between benefits and harms of NSAIDs are preferable to those of paracetamol (paracetamol is also called acetaminophen).
OBJECTIVES
To compare the benefits and harms of paracetamol with NSAIDs in patients with rheumatoid arthritis.
SEARCH STRATEGY
Medline Silverplatter, Embase databases were searched up until Sept 2002. Reference lists of identified articles were also searched.
SELECTION CRITERIA
Randomised double-blind studies comparing paracetamol with an NSAID.
DATA COLLECTION AND ANALYSIS
Decisions on inclusion of trials and data extraction were performed by the two authors independently.
MAIN RESULTS
Four cross-over studies, published between 1968 and 1982, involving 121 patients, and four different NSAIDs were included. The generation of the allocation sequence and the use of methods to conceal the allocation were not described in any of the studies. The studies were double-blind but it was not clear whether the blinding was effective. Methods for collecting adverse effects were not described. The NSAIDs were preferred more often than paracetamol by the patients or the investigator. In the largest trial, 20 out of 54 patients (37%) preferred ibuprofen and 7 out of 54 (13%) paracetamol. Investigators preference (as established by joint tenderness, grip strength and joint circumference) was 17 out of 35 for diclofenac versus 5 out of 35 for paracetamol in another trial. However, because of the weaknessess in the trials, no firm conclusion can be drawn.
REVIEWER'S CONCLUSIONS
When considering the trade off between the benefits and harms of non-steroidal anti-inflammatory drugs and paracetamol/acetaminophen, it is not known whether one is better than the other for rheumatoid arthritis. But people with rheumatoid arthritis and the researchers in the study did prefer non-steroidal anti-inflammatory drugs more than acetaminophen/paracetamol. There is a need for a large trial, with appropriate randomisation, double-blinding, test of the success of the blinding, and with explicit methods to measure and analyse pain and adverse effects.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Humans; Randomized Controlled Trials as Topic
PubMed: 14974037
DOI: 10.1002/14651858.CD003789.pub2 -
The Cochrane Database of Systematic... 2002Paracetamol (acetaminophen) is widely used for treating fever in children. Like ibuprofen, aspirin, and physical methods (such as fanning), paracetamol aims to provide... (Review)
Review
BACKGROUND
Paracetamol (acetaminophen) is widely used for treating fever in children. Like ibuprofen, aspirin, and physical methods (such as fanning), paracetamol aims to provide relief from symptoms and prevent febrile convulsions. Uncertainty exists about the benefits of using it to treat fever in children.
OBJECTIVES
To assess the effects of paracetamol for treating fever in children in relation to fever clearance time, febrile convulsions, and resolution of associated symptoms.
SEARCH STRATEGY
We searched the Cochrane Infectious Diseases Group specialized trials register (November 2001), The Cochrane Controlled Trials Register (The Cochrane Library Issue 4, 2001), MEDLINE (1966 to November 2001), EMBASE (1988 to November 2001), LILACS (2001, 40a Edition CD-ROM), Science Citation Index (November 2001), and reference lists of articles. We also contacted researchers in the field.
SELECTION CRITERIA
Randomized and quasi-randomized trials of children with fever from infections comparing: (1) paracetamol with placebo or no treatment; and (2) paracetamol with physical cooling methods (eg, sponging, bathing, or fanning). The primary outcomes were fever clearance time and febrile convulsion.
DATA COLLECTION AND ANALYSIS
Two reviewers independently extracted data on methods, types of participants, interventions, and outcomes. The meta-analysis was conducted using Relative Risk with 95% confidence intervals for discrete variables, and weighted mean differences for continuous outcomes.
MAIN RESULTS
12 trials (n = 1509 participants) met the inclusion criteria. Outcomes varied between trials. No data were available on the primary outcome. There is insufficient evidence to show whether paracetamol influenced the risk of febrile convulsions. In a meta-analysis of two trials (n = 120), the proportion of children without fever by the second hour after treatment did not differ significantly between those given paracetamol and those sponged (Relative Risk 1.84; confidence interval 0.94 to 3.61, random effects model). The statistical test showed significant heterogeneity between the groups receiving paracetamol or physical methods. No severe adverse events were reported. The number of children with mild adverse events did not differ significantly between paracetamol and placebo, or paracetamol and physical methods, but numbers were small.
REVIEWER'S CONCLUSIONS
Trial evidence that paracetamol has a superior antipyretic effect than placebo is inconclusive. There is limited evidence that there is no difference between the antipyretic effect of paracetamol and physical methods. Data on adverse events in these trials were limited. Establishing standard outcomes will help comparisons between studies and meta-analysis.
Topics: Acetaminophen; Adolescent; Analgesics, Non-Narcotic; Child; Child, Preschool; Fever; Humans; Infant; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 12076499
DOI: 10.1002/14651858.CD003676 -
Paediatric Drugs Oct 2020Worldwide, > 380 million children and adolescents are overweight or obese, including 41 million children aged < 5 years. Obesity can change the pharmacokinetic... (Review)
Review
Worldwide, > 380 million children and adolescents are overweight or obese, including 41 million children aged < 5 years. Obesity can change the pharmacokinetic properties of drugs by altering their distribution, metabolism, and elimination. Thus, children who are overweight or obese are at increased risk for receiving inappropriate doses of commonly used drugs, which can result in treatment failure, adverse events, and/or drug toxicity. This review analyzes available data on paracetamol dosing for pain and fever in children and adolescents who are overweight or obese to identify gaps and challenges in optimal dosing strategies. Literature searches using Medline, Embase, and ClinicalTrials.gov were conducted to identify English-language articles reporting paracetamol pharmacokinetics, dosing practices, and guidelines in children and adolescents who are overweight or obese. Of 24 relevant studies identified, 20 were specific to overweight/obese individuals and 15 were specific to children and/or adolescents. Data on paracetamol pharmacokinetics in children and adolescents who are overweight or obese are lacking, and there is no high-quality evidence to guide paracetamol prescribing practices in these patients. Adult data have been extrapolated to pediatric populations; however, extrapolation does not address differences in paracetamol metabolism in adults versus children; the efficacy and safety effects of such differences are unknown. Given the growing worldwide prevalence of obesity in children and adolescents and the likelihood that paracetamol use in this population will increase accordingly, obesity-specific pediatric dosing guidelines for paracetamol are urgently needed. High-quality research is necessary to inform such guidelines.
Topics: Acetaminophen; Adolescent; Analgesics, Non-Narcotic; Child; Humans; Overweight
PubMed: 32918268
DOI: 10.1007/s40272-020-00417-z -
British Medical Journal Sep 1970Of 41 cases of acute paracetamol poisoning one died of gastrointestinal haemorrhage and acute massive necrosis of the liver, three became jaundiced, and 13 others had...
Of 41 cases of acute paracetamol poisoning one died of gastrointestinal haemorrhage and acute massive necrosis of the liver, three became jaundiced, and 13 others had biochemical evidence of hepatocellular damage. Liver damage is a toxic effect which is present in most patients who ingest more than 15 g. of paracetamol. One patient with liver damage survived renal failure due to acute tubular necrosis. It is suggested that the renal lesion was also the result of paracetamol overdosage.Profound hypoglycaemia and metabolic acidosis may also complicate severe poisoning. Plasma levels of para-aminophenol fall rapidly, and procedures currently used to enhance the elimination of the drug cannot be expected to prevent development of hepatic damage.
Topics: Acetaminophen; Acidosis; Acute Disease; Acute Kidney Injury; Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Female; Gastrointestinal Hemorrhage; Humans; Hypoglycemia; Jaundice; Male; Poisoning
PubMed: 5311516
DOI: 10.1136/bmj.3.5722.557 -
The Cochrane Database of Systematic... Oct 2008This is an updated version of the original Cochrane review published in Issue 1, 2004 - this original review had been split from a previous title on 'Single dose... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an updated version of the original Cochrane review published in Issue 1, 2004 - this original review had been split from a previous title on 'Single dose paracetamol (acetaminophen) with and without codeine for postoperative pain'. The last version of this review concluded that paracetamol is an effective analgesic for postoperative pain, but additional trials have since been published. This review sought to evaluate the efficacy and safety of paracetamol using current data, and to compare the findings with other analgesics evaluated in the same way.
OBJECTIVES
To assess the efficacy of single dose oral paracetamol for the treatment of acute postoperative pain.
SEARCH STRATEGY
We searched The Cochrane Library, MEDLINE, EMBASE, the Oxford Pain Relief Database and reference lists of articles to update an existing version of the review in July 2008.
SELECTION CRITERIA
Randomised, double-blind, placebo-controlled clinical trials of paracetamol for acute postoperative pain in adults.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trial quality and extracted data. Area under the "pain relief versus time" curve was used to derive the proportion of participants with paracetamol or placebo experiencing at least 50% pain relief over four to six hours, using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated, with 95% confidence intervals (CI). The proportion of participants using rescue analgesia over a specified time period, and time to use, were sought as measures of duration of analgesia. Information on adverse events and withdrawals was also collected.
MAIN RESULTS
Fifty-one studies, with 5762 participants, were included: 3277 participants were treated with a single oral dose of paracetamol and 2425 with placebo. About half of participants treated with paracetamol at standard doses achieved at least 50% pain relief over four to six hours, compared with about 20% treated with placebo. NNTs for at least 50% pain relief over four to six hours following a single dose of paracetamol were as follows: 500 mg NNT 3.5 (2.7 to 4.8); 600 to 650 mg NNT 4.6 (3.9 to 5.5); 975 to 1000 mg NNT 3.6 (3.4 to 4.0). There was no dose response. Sensitivity analysis showed no significant effect of trial size or quality on this outcome.About half of participants needed additional analgesia over four to six hours, compared with about 70% with placebo. Five people would need to be treated with 1000 mg paracetamol, the most commonly used dose, to prevent one needing rescue medication over four to six hours, who would have needed it with placebo. Adverse event reporting was inconsistent and often incomplete. Reported adverse events were mainly mild and transient, and occurred at similar rates with 1000 mg paracetamol and placebo. No serious adverse events were reported. Withdrawals due to adverse events were uncommon and occurred in both paracetamol and placebo treatment arms.
AUTHORS' CONCLUSIONS
A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events.
Topics: Acetaminophen; Adult; Analgesics, Non-Narcotic; Humans; Pain, Postoperative; Randomized Controlled Trials as Topic
PubMed: 18843665
DOI: 10.1002/14651858.CD004602.pub2 -
Molecules (Basel, Switzerland) Dec 2020Studies carried out by X-ray and thermal analysis confirmed that acetaminophen (paracetamol), declared by the manufacturers as an Active Pharmaceutical Ingredient (API),...
Studies carried out by X-ray and thermal analysis confirmed that acetaminophen (paracetamol), declared by the manufacturers as an Active Pharmaceutical Ingredient (API), was present in all studied medicinal drugs. Positions of diffraction lines (2θ angles) of the studied drugs were consistent with standards for acetaminophen, available in the ICDD PDF database Release 2008. |Δ2θ| values were lower than 0.2°, confirming the authenticity of the studied drugs. Also, the values of interplanar distances for the examined samples were consistent with those present in the ICDD. Presence of acetaminophen crystalising in the monoclinic system (form I) was confirmed. Various line intensities for API were observed in the obtained diffraction patterns, indicating presence of the preferred orientation of the crystallites in the examined samples. Thermal analysis of the studied substances confirmed the results obtained by X-ray analysis. Drugs containing only acetaminophen as an API have melting point close to that of pure acetaminophen. It was found that presence of other active and auxiliary substances affected the shapes and positions of endothermal peaks significantly. A broadening of endothermal peaks and their shift towards lower temperatures were observed accompanying an increase in the contents of additional substances being "impurities" in relation to the API. The results obtained by a combination of the two methods, X-ray powder diffraction (XRPD) and differential scanning calorimetry/thermogravimetry (DSC/TGA), may be useful in determination of abnormalities which can occur in pharmaceutical preparations, e.g., for distinguishing original drugs and forged products, detection of the presence of a proper polymorphic form or too low content of the active substance in the investigated drug.
Topics: Acetaminophen; Calorimetry, Differential Scanning; Pharmaceutical Preparations; Thermogravimetry; X-Ray Diffraction
PubMed: 33322235
DOI: 10.3390/molecules25245909