|
|
call loadScript javascripts\jsmol\core\package.js call loadScript javascripts\jsmol\core\core.z.js -- required by ClazzNode call loadScript javascripts\jsmol\J\awtjs2d\WebOutputChannel.js Jmol JavaScript applet jmolApplet0_object__057083164552466__ initializing getValue debug = null getValue logLevel = null getValue allowjavascript = null AppletRegistry.checkIn(jmolApplet0_object__057083164552466__) call loadScript javascripts\jsmol\core\corestate.z.js viewerOptions: { "name":"jmolApplet0_object","applet":true,"documentBase":"https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:46195","platform":"J.awtjs2d.Platform","fullName":"jmolApplet0_object__057083164552466__","display":"jmolApplet0_canvas2d","signedApplet":"true","appletReadyCallback":"Jmol._readyCallback","statusListener":"[J.appletjs.Jmol.MyStatusListener object]","codeBase":"https://www.ebi.ac.uk/chebi/javascripts/jsmol/","syncId":"057083164552466","bgcolor":"#000" } (C) 2012 Jmol Development Jmol Version: 13.2.7 $Date: 2013-10-01 11:35:15 -0500 (Tue, 01 Oct 2013) $ java.vendor: j2s java.version: 0.0 os.name: j2s Access: ALL memory: 0.0/0.0 processors available: 1 useCommandThread: false appletId:jmolApplet0_object (signed) starting HoverWatcher_1 getValue emulate = null defaults = "Jmol" getValue boxbgcolor = null getValue bgcolor = #000 backgroundColor = "#000" getValue ANIMFRAMECallback = null getValue APPLETREADYCallback = Jmol._readyCallback APPLETREADYCallback = "Jmol._readyCallback" getValue ATOMMOVEDCallback = null getValue CLICKCallback = null getValue ECHOCallback = null getValue ERRORCallback = null getValue EVALCallback = null getValue HOVERCallback = null getValue LOADSTRUCTCallback = null getValue MEASURECallback = null getValue MESSAGECallback = null getValue MINIMIZATIONCallback = null getValue PICKCallback = null getValue RESIZECallback = null getValue SCRIPTCallback = null getValue SYNCCallback = null getValue STRUCTUREMODIFIEDCallback = null getValue doTranslate = null language=en_US getValue popupMenu = null getValue script = null Jmol applet jmolApplet0_object__057083164552466__ ready call loadScript javascripts\jsmol\core\corescript.z.js call loadScript javascripts\jsmol\J\script\FileLoadThread.js starting QueueThread0_2 script 1 started starting HoverWatcher_3 starting HoverWatcher_4 The Resolver thinks Mol Mrv0541 10231312483D starting HoverWatcher_5 Time for openFile( Mrv0541 10231312483D 20 20 0 0 0 0 999 V2000 2.1555 2.6099 -1.0828 C 0 0 0 0 0 0 0 0 0 0 0 0 1.1056 1.6272 -1.1876 C 0 0 0 0 0 0 0 0 0 0 0 0 0.0871 1.9245 -1.8016 O 0 0 0 0 0 0 0 0 0 0 0 0 1.2324 0.4588 -0.6237 N 0 0 0 0 0 0 0 0 0 0 0 0 0.2656 -0.2718 -0.0653 C 0 0 0 0 0 0 0 0 0 0 0 0 0.3402 -1.6834 -0.0940 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.7005 -2.4692 0.4432 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.8213 -1.8510 1.0336 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.7663 -2.5317 1.5014 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.8882 -0.4485 1.1052 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.8474 0.3269 0.5728 C 0 0 0 0 0 0 0 0 0 0 0 0 2.3823 2.7880 -0.0296 H 0 0 0 0 0 0 0 0 0 0 0 0 1.8641 3.5695 -1.5185 H 0 0 0 0 0 0 0 0 0 0 0 0 3.0555 2.2622 -1.5901 H 0 0 0 0 0 0 0 0 0 0 0 0 2.0960 0.0970 -0.6045 H 0 0 0 0 0 0 0 0 0 0 0 0 1.1431 -2.1545 -0.5200 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.6411 -3.4896 0.3972 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.4605 -2.1276 1.8645 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.6874 0.0197 1.5392 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.9147 1.3435 0.6607 H 0 0 0 0 0 0 0 0 0 0 0 0 1 2 1 0 0 0 0 2 3 2 0 0 0 0 2 4 1 0 0 0 0 4 5 1 0 0 0 0 5 6 4 0 0 0 0 5 11 4 0 0 0 0 6 7 4 0 0 0 0 7 8 4 0 0 0 0 8 9 1 0 0 0 0 8 10 4 0 0 0 0 10 11 4 0 0 0 0 1 12 1 0 0 0 0 1 13 1 0 0 0 0 1 14 1 0 0 0 0 4 15 1 0 0 0 0 6 16 1 0 0 0 0 7 17 1 0 0 0 0 9 18 1 0 0 0 0 10 19 1 0 0 0 0 11 20 1 0 0 0 0 M END): 17 ms reading 20 atoms ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false 1 model in this collection. Use getProperty "modelInfo" or getProperty "auxiliaryInfo" to inspect them. Default Van der Waals type for model set to Babel 20 atoms created ModelSet: not autobonding; use forceAutobond=true to force automatic bond creation Script completed Jmol script terminated
|
| Paracetamol, or acetaminophen, is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain. It is a widely available over-the-counter drug sold under various brand names, including Tylenol and Panadol.
Paracetamol relieves pain in both acute mild migraine and episodic tension headache. At a standard dose, paracetamol slightly reduces fever; it is inferior to ibuprofen in that respect, and the benefits of its use for fever are unclear, particularly in the context of fever of viral origins. The aspirin/paracetamol/caffeine combination also helps with both conditions where the pain is mild and is recommended as a first-line treatment for them. Paracetamol is effective for post-surgical pain, but it is inferior to ibuprofen. The paracetamol/ibuprofen combination provides further increase in potency and is superior to either drug alone. The pain relief paracetamol provides in osteoarthritis is small and clinically insignificant. The evidence in its favor for the use in low back pain, cancer pain, and neuropathic pain is insufficient.
In the short term, paracetamol is safe and effective when used as directed. Short term adverse effects are uncommon and similar to ibuprofen, but paracetamol is typically safer than nonsteroidal anti-inflammatory drugs (NSAIDs) for long-term use. Paracetamol is also often used in patients who cannot tolerate NSAIDs like ibuprofen. Chronic consumption of paracetamol may result in a drop in hemoglobin level, indicating possible gastrointestinal bleeding, and abnormal liver function tests. The recommended maximum daily dose for an adult is three to four grams. Higher doses may lead to toxicity, including liver failure. Paracetamol poisoning is the foremost cause of acute liver failure in the Western world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand.
Paracetamol was first made in 1878 by Harmon Northrop Morse or possibly in 1852 by Charles Frédéric Gerhardt. It is the most commonly used medication for pain and fever in both the United States and Europe. It is on the World Health Organization's List of Essential Medicines. Paracetamol is available as a generic medication, with brand names including Tylenol and Panadol among others. In 2022, it was the 114th most commonly prescribed medication in the United States, with more than 5 million prescriptions.
|
|
Read full article at Wikipedia
|
| InChI=1S/C8H9NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5,11H,1H3,(H,9,10) |
| RZVAJINKPMORJF-UHFFFAOYSA-N |
|
|
environmental contaminant
Any minor or unwanted substance introduced into the environment that can have undesired effects.
|
|
|
cyclooxygenase 2 inhibitor
A cyclooxygenase inhibitor that interferes with the action of cyclooxygenase 2.
cyclooxygenase 1 inhibitor
A cyclooxygenase inhibitor that interferes with the action of cyclooxygenase 1.
non-narcotic analgesic
A drug that has principally analgesic, antipyretic and anti-inflammatory actions. Non-narcotic analgesics do not bind to opioid receptors.
xenobiotic
A xenobiotic (Greek, xenos "foreign"; bios "life") is a compound that is foreign to a living organism. Principal xenobiotics include: drugs, carcinogens and various compounds that have been introduced into the environment by artificial means.
hepatotoxic agent
A role played by a chemical compound exhibiting itself through the ability to induce damage to the liver in animals.
human blood serum metabolite
Any metabolite (endogenous or exogenous) found in human blood serum samples.
cyclooxygenase 3 inhibitor
A cyclooxygenase inhibitor that interferes with the action of cyclooxygenase 3.
ferroptosis inducer
Any substance that induces or promotes ferroptosis (a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides) in organisms.
|
|
|
non-narcotic analgesic
A drug that has principally analgesic, antipyretic and anti-inflammatory actions. Non-narcotic analgesics do not bind to opioid receptors.
antipyretic
A drug that prevents or reduces fever by lowering the body temperature from a raised state. An antipyretic will not affect the normal body temperature if one does not have fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature. The body will then work to lower the temperature and the result is a reduction in fever.
non-steroidal anti-inflammatory drug
An anti-inflammatory drug that is not a steroid. In addition to anti-inflammatory actions, non-steroidal anti-inflammatory drugs have analgesic, antipyretic, and platelet-inhibitory actions. They act by blocking the synthesis of prostaglandins by inhibiting cyclooxygenase, which converts arachidonic acid to cyclic endoperoxides, precursors of prostaglandins.
geroprotector
Any compound that supports healthy aging, slows the biological aging process, or extends lifespan.
|
|
View more via ChEBI Ontology
|
N-(4-hydroxyphenyl)acetamide
|
|
paracetamol
|
KEGG DRUG
|
paracetamol
|
WHO MedNet
|
paracétamol
|
WHO MedNet
|
paracetamolum
|
ChemIDplus
|
|
4'-hydroxyacetanilide
|
ChemIDplus
|
|
4-(Acetylamino)phenol
|
ChemIDplus
|
|
4-acetamidophenol
|
NIST Chemistry WebBook
|
|
4-acetamidophenol
|
UniProt
|
|
Acenol
|
ChemIDplus
|
|
acetaminofén
|
ChemIDplus
|
|
Acetaminofen
|
ChemIDplus
|
|
Acetaminophen
|
KEGG COMPOUND
|
|
acétaminophène
|
ChEBI
|
|
APAP
|
DrugBank
|
|
N-acetyl-p-aminophenol
|
ChEBI
|
|
p-acetamidophenol
|
NIST Chemistry WebBook
|
|
p-acetaminophenol
|
NIST Chemistry WebBook
|
|
p-Acetylaminophenol
|
ChemIDplus
|
|
p-hydroxyacetanilide
|
NIST Chemistry WebBook
|
|
p-hydroxyphenolacetamide
|
NIST Chemistry WebBook
|
|
Paracetamol
|
KEGG COMPOUND
|
|
Panadol
|
ChEBI
|
|
Tylenol
|
KEGG DRUG
|
|
1906
|
ChemSpider
|
|
52
|
DrugCentral
|
|
Acetaminophen
|
Wikipedia
|
|
C06804
|
KEGG COMPOUND
|
|
CPD-7669
|
MetaCyc
|
|
D00217
|
KEGG DRUG
|
|
DB00316
|
DrugBank
|
|
HMDB0001859
|
HMDB
|
|
LSM-5533
|
LINCS
|
|
TYL
|
PDBeChem
|
| View more database links |
|
103-90-2
|
CAS Registry Number
|
KEGG COMPOUND
|
|
103-90-2
|
CAS Registry Number
|
ChemIDplus
|
|
103-90-2
|
CAS Registry Number
|
NIST Chemistry WebBook
|
|
2208089
|
Beilstein Registry Number
|
Beilstein
|
|
2208089
|
Reaxys Registry Number
|
Reaxys
|
Cohen IV, Cirulli ET, Mitchell MW, Jonsson TJ, Yu J, Shah N, Spector TD, Guo L, Venter JC, Telenti A (2018)
Acetaminophen (Paracetamol) Use Modifies the Sulfation of Sex Hormones.
EBioMedicine 28, 316-323 [PubMed:29398597]
[show Abstract]
BackgroundAcetaminophen (paracetamol) is one of the most common medications used for management of pain in the world. There is lack of consensus about the mechanism of action, and concern about the possibility of adverse effects on reproductive health.MethodsWe first established the metabolome profile that characterizes use of acetaminophen, and we subsequently trained and tested a model that identified metabolomic differences across samples from 455 individuals with and without acetaminophen use. We validated the findings in a European ancestry adult twin cohort of 1880 individuals (TwinsUK), and in a study of 1235 individuals of African American and Hispanic ancestry. We used genomics to elucidate the mechanisms targeted by acetaminophen.FindingsWe identified a distinctive pattern of depletion of sulfated sex hormones with use of acetaminophen across all populations. We used a Mendelian randomization approach to characterize the role of Sulfotransferase Family 2A Member 1 (SULT2A1) as the site of the interaction. Although CYP3A7-CYP3A51P variants also modified levels of some sulfated sex hormones, only acetaminophen use phenocopied the effect of genetic variants of SULT2A1. Overall, acetaminophen use, age, gender and SULT2A1 and CYP3A7-CYP3A51P genetic variants are key determinants of variation in levels of sulfated sex hormones in blood. The effect of taking acetaminophen on sulfated sex hormones was roughly equivalent to the effect of 35years of aging.InterpretationThese findings raise concerns of the impact of acetaminophen use on hormonal homeostasis. In addition, it modifies views on the mechanism of action of acetaminophen in pain management as sulfated sex hormones can function as neurosteroids and modify nociceptive thresholds. | Lee WM (2017)
Acetaminophen (APAP) hepatotoxicity-Isn't it time for APAP to go away?
Journal of hepatology 67, 1324-1331 [PubMed:28734939]
[show Abstract]
Acetaminophen (APAP) is the most commonly used drug for the treatment of pain and fever around the world. At the same time, APAP can cause dose-related hepatocellular necrosis, responsible for nearly 500 deaths annually in the United States (US) alone, as well as 100,000 calls to US Poison Control Centers, 50,000 emergency room visits and 10,000 hospitalisations per year. As an over-the-counter and prescription product (with opioids), APAP toxicity dwarfs all other prescription drugs as a cause of acute liver failure in the US and Europe, but it is not regulated in any significant way. In this review the ongoing controversy surrounding the proper role for this ubiquitous pain reliever: its history, pathogenesis, clinical challenges in recognition and management, and current regulatory status are highlighted. A new solution to a 50-year-old problem is proposed. | Sawaguchi A, Sasaki K, Miyanaga K, Nakayama M, Nagasue M, Shimoda M (2016)
Rapid absorption of diclofenac and acetaminophen after their oral administration to cattle.
The Journal of veterinary medical science 78, 1481-1485 [PubMed:27320817]
[show Abstract]
The oral pharmacokinetics of diclofenac (DF) were evaluated in cattle by analyzing plasma concentration-time data after its intravenous and oral administration in order to propose the oral administration of DF as effective route to avoid long withdraw period. DF was intravenously and orally administered at 1 mg/kg to cattle using a crossover design with a 4-week washout period. Plasma concentrations of DF were determined by a HPLC analysis. The mean absorption time (MAT) and absorption half-life (t1/2ka) were 1.61 ± 0.61 and 1.51 ± 0.38 hr, respectively, and bioavailability was nearly 100%. The oral pharmacokinetics of acetaminophen (AAP) were also evaluated in cattle. Plasma concentrations of AAP were determined by a HPLC analysis. MAT and t1/2ka were 2.85 ± 0.93 and 1.53 ± 0.28 hr, respectively, and bioavailability was approximately 70%. In conclusion, the results of the present study indicate that DF and AAP are rapidly absorbed from the forestomach of cattle. Therefore, the appropriate efficacies of these drugs may be achieved via their oral administration, even in cattle. | Lőrincz T, Jemnitz K, Kardon T, Mandl J, Szarka A (2015)
Ferroptosis is Involved in Acetaminophen Induced Cell Death.
Pathology oncology research : POR 21, 1115-1121 [PubMed:25962350]
[show Abstract]
The recently described form of programmed cell death, ferroptosis can be induced by agents causing GSH depletion or the inhibition of GPX4. Ferroptosis clearly shows distinct morphologic, biochemical and genetic features from apoptosis, necrosis and autophagy. Since NAPQI the highly reactive metabolite of the widely applied analgesic and antipyretic, acetaminophen induces a cell death which can be characterized by GSH depletion, GPX inhibition and caspase independency the involvement of ferroptosis in acetaminophen induced cell death has been investigated. The specific ferroptosis inhibitor ferrostatin-1 failed to elevate the viability of acetaminophen treated HepG2 cells. It should be noticed that these cells do not form NAPQI due to the lack of phase I enzyme expression therefore GSH depletion cannot be observed. However in the case of acetaminophen treated primary mouse hepatocytes the significant elevation of cell viability could be observed upon ferrostatin-1 treatment. Similar to ferrostatin-1 treatment, the addition of the RIP1 kinase inhibitor necrostatin-1 could also elevate the viability of acetaminophen treated primary hepatocytes. Ferrostatin-1 has no influence on the expression of CYP2E1 or on the cellular GSH level which suggest that the protective effect of ferrostatin-1 in APAP induced cell death is not based on the reduced metabolism of APAP to NAPQI or on altered NAPQI conjugation by cellular GSH. Our results suggest that beyond necroptosis and apoptosis a third programmed cell death, ferroptosis is also involved in acetaminophen induced cell death in primary hepatocytes. | Bahrami H, Farrokhpour H (2015)
Corona discharge ionization of paracetamol molecule: peak assignment.
Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy 135, 646-651 [PubMed:25128677]
[show Abstract]
Ionization of paracetamol was investigated using ion mobility spectrometry equipped with a corona discharge ionization source. The measurements were performed in the positive ion mode and three peaks were observed in the ion mobility spectrum. Experimental evidence and theoretical calculations were used to correlate the peaks to related ionic species of paracetamol. Two peaks were attributed to protonated isomers of paracetamol and the other peak was attributed to paracetamol fragment ions formed by dissociation of the N-C bond after protonation of the nitrogen atom. It was observed that three sites of paracetamol compete for protonation and their relative intensities, depending on the sample concentration. The ratio of ion products could be predicted from the internal proton affinity of the protonation sites at each concentration. | Roux A, Xu Y, Heilier JF, Olivier MF, Ezan E, Tabet JC, Junot C (2012)
Annotation of the human adult urinary metabolome and metabolite identification using ultra high performance liquid chromatography coupled to a linear quadrupole ion trap-Orbitrap mass spectrometer.
Analytical chemistry 84, 6429-6437 [PubMed:22770225]
[show Abstract]
Metabolic profiles of biofluids obtained by atmospheric pressure ionization mass spectrometry-based technologies contain hundreds to thousands of features, most of them remaining unknown or at least not characterized in analytical systems. We report here on the annotation of the human adult urinary metabolome and metabolite identification from electrospray ionization mass spectrometry (ESI-MS)-based metabolomics data sets. Features of biological interest were first of all annotated using the ESI-MS database of the laboratory. They were also grouped, thanks to software tools, and annotated using public databases. Metabolite identification was achieved using two complementary approaches: (i) formal identification by matching chromatographic retention times, mass spectra, and also product ion spectra (if required) of metabolites to be characterized in biological data sets to those of reference compounds and (ii) putative identification from biological data thanks to MS/MS experiments for metabolites not available in our chemical library. By these means, 384 metabolites corresponding to 1484 annotated features (659 in negative ion mode and 825 in positive ion mode) were characterized in human urine samples. Of these metabolites, 192 and 66 were formally and putatively identified, respectively, and 54 are reported in human urine for the first time. These lists of features could be used by other laboratories to annotate their ESI-MS metabolomics data sets. | Zhao L, Pickering G (2011)
Paracetamol metabolism and related genetic differences.
Drug metabolism reviews 43, 41-52 [PubMed:21108564]
[show Abstract]
Paracetamol (acetaminophen) is a worldwide used analgesic and antipyretic drug. It is metabolised via several metabolic pathways, including glucuronidation, sulfation, oxidation, hydroxylation, and deacetylation: Hepatic and other organ damage may occur, especially in overdose, because of the accumulation of a toxic metabolite. Intersubject and ethnic differences have been reported in paracetamol metabolism activation, suggesting possible differences in susceptibility to toxicity and in pain alleviation, linked to different pharmacogenetic profiles. This article aims at reviewing, in the literature, the links between paracetamol metabolism and enzyme genotypes in the context of toxic side effects and efficacy of paracetamol in therapeutics. | Lublin A, Isoda F, Patel H, Yen K, Nguyen L, Hajje D, Schwartz M, Mobbs C (2011)
FDA-approved drugs that protect mammalian neurons from glucose toxicity slow aging dependent on cbp and protect against proteotoxicity.
PloS one 6, e27762 [PubMed:22114686]
[show Abstract]
Screening a library of drugs with known safety profiles in humans yielded 30 drugs that reliably protected mammalian neurons against glucose toxicity. Subsequent screening demonstrated that 6 of these 30 drugs increase lifespan in C. elegans: caffeine, ciclopirox olamine, tannic acid, acetaminophen, bacitracin, and baicalein. Every drug significantly reduced the age-dependent acceleration of mortality rate. These protective effects were blocked by RNAi inhibition of cbp-1 in adults only, which also blocks protective effects of dietary restriction. Only 2 drugs, caffeine and tannic acid, exhibited a similar dependency on DAF-16. Caffeine, tannic acid, and bacitracin also reduced pathology in a transgenic model of proteotoxicity associated with Alzheimer's disease. These results further support a key role for glucose toxicity in driving age-related pathologies and for CBP-1 in protection against age-related pathologies. These results also provide novel lead compounds with known safety profiles in human for treatment of age-related diseases, including Alzheimer's disease and diabetic complications. | Pavlicević I, Kuzmanić M, Rumboldt M, Rumboldt Z (2008)
Interaction between antihypertensives and NSAIDs in primary care: a controlled trial.
The Canadian journal of clinical pharmacology = Journal canadien de pharmacologie clinique 15, e372-82 [PubMed:18953082]
[show Abstract]
BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) may increase blood pressure (BP) and blunt the effects of many antihypertensives. It seems that NSAIDs and the antihypertensive drugs differ in their propensity to such an interaction.ObjectivesTo determine the extent of the interaction between two antihypertensives and three NSAIDs.MethodsA prospective clinical trial in a family practice included 88 treated hypertensives aged over 55 years; 39 controls and 49, also taking NSAIDs for osteoarthritis. During this 3-month study, two antihypertensives, lisinopril/hydrochlorothiazide and amlodipine, were compared with three NSAIDs: ibuprofen, acetaminophen, and piroxicam. BP was measured with standard mercury sphygmomanometer and with an automatic device, in standing, sitting, and supine position.ResultsThe average starting blood pressure in the study group was 149.3A+/-9.8/88.6A+/-6.8 mm Hg. In the lisinopril/hydrochlorothiazide subgroup, both ibuprofen and piroxicam elevated systolic BP by 7.7-9.9% (p<0.001), which, during the acetaminophen period, decreased by 6.9-9.4% to 0.3-0.9% above baseline (p<0.001), increasing again by 7.0-7.7% (p<0.001) during the second exposition to these drugs. In the amlodipine subgroup, ibuprofen or piroxicam increased BP by 1.1-1.6% (p>0.290) only, and there were no significant shifts in the follow-up periods. Analogous deviations were observed with both measurement devices, in all the examinee's positions. In the control group, BP did not change appreciably.ConclusionsPiroxicam and ibuprofen markedly blunt the effects of antihypertensive drugs while acetaminophen is almost inert. Lisinopril/hydrochlorothiazide combination is much more affected by this interaction than amlodipine (ClinicalTrials.gov #NCT00631514). | Espinosa Bosch M, Ruiz Sánchez AJ, Sánchez Rojas F, Bosch Ojeda C (2006)
Determination of paracetamol: historical evolution.
Journal of pharmaceutical and biomedical analysis 42, 291-321 [PubMed:16716555]
[show Abstract]
Paracetamol is a common analgesic and antipyretic drug that is used for the relief of fever, headaches and other minor aches and pains. Their determination in pharmaceuticals is of paramount importance, since an overdose of paracetamol can cause fulminating hepatic necrosis and other toxic effects. Many analytical methodologies have been proposed for the determination of paracetamol. The aim of the present study is to evaluate the utility of different techniques for quantification of paracetamol content in pharmaceutical formulations and biological samples. | Wulferink M, González J, Goebel C, Gleichmann E (2001)
T cells ignore aniline, a prohapten, but respond to its reactive metabolites generated by phagocytes: possible implications for the pathogenesis of toxic oil syndrome.
Chemical research in toxicology 14, 389-397 [PubMed:11304127]
[show Abstract]
The most basic arylamine, aniline, belongs to a class of compounds notorious for inducing allergic and autoimmune reactions. In 1981 in Spain, many people succumbed to toxic oil syndrome (TOS), a disease caused by ingestion of cooking oil contaminated with aniline. Indirect evidence points toward an immune pathogenesis of TOS driven by T lymphocytes, but it is unclear to which antigens these cells could react. Here, using the popliteal lymph node (PLN) assay in mice, we analyzed the sensitizing potential of aniline, its metabolites, and some of the aniline-coupled lipids detected in the contaminated cooking oil. Whereas aniline itself and its non-protein-reactive metabolites nitrobenzene, p-aminophenol and N-acetyl-p-aminophenol, failed to elicit PLN responses, its reactive metabolites nitrosobenzene and N-hydroxylaniline did. The aniline-coupled lipids, namely, linoleic anilide and linolenic anilide, and a mixture of fatty acid esters of 3-(N-phenylamino)-1,2-propanediol, all implicated in TOS, induced significant PLN responses, whereas the respective aniline-free lipids, linoleic acid, linolenic acid, and triolein, did not. Hence, the aniline moiety plays a crucial role in the immunogenicity of the aniline-coupled lipids of TOS. PLN responses to the reactive aniline metabolites and the one aniline-coupled lipid that was tested, linolenic anilide, were T-cell-dependent. Secondary PLN responses to nitrosobenzene were detectable not only after priming with nitrosobenzene but, in some experiments, also after priming with linolenic anilide. This suggests that the aniline moiety was cleaved from the aniline-coupled lipid and metabolized to the intermediate nitrosobenzene that generated the prospective neoantigens. Consistent with this, in lymphocyte proliferation tests in vitro, T cells primed to nitrosobenzene reacted in anamnestic fashion to white bone marrow cells (WBMCs) pulsed with aniline. Hence, we propose that aniline is a prohapten that can be metabolized by WBMCs, which form neoantigens that are recognized by T cells. The possible significance of these findings for the pathogenesis of TOS is discussed. | Noriega GO, Ossola JO, Tomaro ML, Batlle AM (2000)
Effect of acetaminophen on heme metabolism in rat liver.
The international journal of biochemistry & cell biology 32, 983-991 [PubMed:11084378]
[show Abstract]
Background and aimsAcetaminophen (APAP) or paracetamol is a hepatotoxic drug through mechanisms involving oxidative stress. To know whether mammalian cells possess inducible pathways for antioxidant defense, we have to study the relationship between heme metabolism and oxidative stress.Methodsfasted female Wistar rats received a single injection of APAP (3.3 mmol kg(-1) body weight) and then were killed at different times. Heme oxygenase-1 (HO), delta-aminolevulinic acid (ALA) synthase, ALA dehydratase, and porphobilinogenase activities, lipid peroxidation, GSH, catalase and glutathione peroxidase, were measured in liver homogenates. The antioxidant properties of bilirubin and S-adenosyl-L-methionine were also evaluated.ResultsAPAP increased lipid peroxidation (115% +/- 6; S.E.M., n=12 over control values) 1 h after treatment. GSH reached a minimum at 3 h (38% +/- 5) increasing thereafter. At the same time antioxidant enzymes reached minimum values (catalase, 5. 6 +/- 0.4 pmol mg(-1) protein, glutathione peroxidase, 0.101 +/- 0.006 U mg(-1) protein). HO induction was observed 6 h after treatment reaching a maximum value of 2.56 +/- 0.12 U mg(-1) protein 15 after injection. ALA synthase (ALA-S) induction occurred after enhancement of HO, reaching a maximum at 18 h (three-fold the control). ALA dehydratase activity was first inhibited (31 +/- 3%) showing a profile similar to that of GSH, while porphobilinogenase activity was not modified along the whole period of the assay. Administration of bilirubin (5 micromol kg(-1) body weight) or S-adenosyl L-methionine (46 micromol kg(-1) body weight) 2 h before APAP treatment entirely prevented the increase in malondialdehyde (MDA) content, the decrease in GSH levels as well as HO and ALA-S induction.ConclusionThis study shows that oxidative stress produced by APAP leads to increase in ALA-S and HO activities, indicating that toxic doses of APAP affect both heme biosynthesis and degradation. | Mauri-Hellweg D, Bettens F, Mauri D, Brander C, Hunziker T, Pichler WJ (1995)
Activation of drug-specific CD4+ and CD8+ T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine.
Journal of immunology (Baltimore, Md. : 1950) 155, 462-472 [PubMed:7602118]
[show Abstract]
To investigate how T cells are involved in hypersensitivity reactions to drugs that become immunogenic after metabolization, e.g., sulfonamides and antiepileptics, we analyzed in vitro the drug-induced activation of CD4+ and CD8+ T cell subsets, cytokine secretion, TCR V beta distribution, and proliferation of T cells from four drug-allergic individuals. In addition, the activation parameters CD25 and HLA-DR were analyzed in vivo on CD4+ and CD8+ T cells from five patients with acute drug allergies, some of them with anticonvulsant hypersensitivity syndrome with hepatitis. Our results show that, in vitro, drug-induced proliferation of PBMC from patients with allergy to sulfamethoxazole, phenytoin, or carbamazepine was specific and dose dependent. CD4+ as well as CD8+ T cells expressed elevated levels of CD25 and HLA-DR molecules after drug stimulation. Drug-activated lymphocytes secreted high amounts of IL-5 and normal or low levels of IL-2, IFN-gamma, IL-4, and TNF-alpha. An enhanced expansion of TCR V beta 17+ T cells 9 days after in vitro stimulation with sulfamethoxazole was observed in one patient with sulfamethoxazole allergy. The drug specificity of the in vitro-activated T cells was confirmed by generation of different sulfamethoxazole specific T cell lines and CD4+ and CD8+ T cell clones. T cell analysis of patients with acute drug allergy to carbamazepine, phenytoin, allopurinol, or paracetamol confirms the in vitro data, because all patients had activated CD4+ or CD8+ T cells in the circulation. Our data clearly show the involvement of drug-specific T cells in drug allergies. |
|
2014-10-29
