User:Gregchristie1982/Sandbox
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Routes of administration | Oral, rectal, intravenous |
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Pharmacokinetic data | |
Bioavailability | almost 100% |
Metabolism | 90 to 95% Hepatic |
Elimination half-life | 1–4 hours |
Excretion | Renal |
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Formula | C8H9NO2 |
Molar mass | 151.169 g/mol g·mol−1 |
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Paracetamol (INN) (/ˌpærəˈsiːtəmɒl, -ˈsɛtə-/) or acetaminophen (USAN) is a widely used over-the-counter analgesic (pain reliever) and antipyretic (fever reducer). It is commonly used for the relief of fever, headaches, and other minor aches and pains, and is a major ingredient in numerous cold and flu remedies. In combination with non-steroidal anti-inflammatory drugs (NSAIDs) or opioid analgesics, paracetamol is used also in the management of more severe pain (such as cancer pain).[1]
While generally safe for human use at recommended doses, acute overdoses of paracetamol can cause potentially fatal liver damage and, in rare individuals, a normal dose can do the same; the risk is heightened by alcoholism. Paracetamol toxicity 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.[2][3][4][5] In 2008 a study conducted in 31 countries on over 200,000 children indicates that infants who are given paracetamol may be at an increased risk of developing asthma as children.[6]
Paracetamol is derived from coal tar, and is therefore part of the class of drugs known as “aniline analgesics”; it is the only such drug still in use today.[7] It is the active metabolite of phenacetin, once popular as an analgesic and antipyretic in its own right, but unlike phenacetin and its combinations, paracetamol is not considered carcinogenic at therapeutic doses.[8] The words acetaminophen and paracetamol both come from chemical names for the compound: para-acetylaminophenol and para-acetylaminophenol. In some contexts, it is simply abbreviated as APAP, for N-acetyl-para-aminophenol.
History
[edit]Acetanilide was the first aniline derivative serendipitously found to possess analgesic as well as antipyretic proprieties, and was quickly introduced into medical practice under the name of Antifebrin by A. Cahn and P. Hepp in 1886.[9] But its unacceptable toxic effects, the most alarming being cyanosis due to methemoglobinemia, prompted the search for less toxic aniline derivatives.[7] Harmon Northrop Morse had already synthesized paracetamol via the reduction of p-nitrophenol with tin in glacial acetic acid in 1878,[10] but it wasn't until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on patients.[7] In 1893 von Mering published a paper reporting on the clinical results of paracetamol with phenacetin, another aniline derivative.[11] Von Mering claimed that, unlike phenacetin, paracetamol had a slight tendency to produce methemoglobinemia. Paracetamol was then quickly discarded in favor of phenacetin. The sales of phenacetin established Bayer as leading pharmaceutical company.[12] Overshadowed in part by aspirin, introduced into medicine by Heinrich Dreser in 1899, phenacetin was popular for many decades, particularly in widely advertised over-the-counter “headache mixtures,” usually containing phenacetin, an aminopyrine derivative or aspirin, caffeine, and sometimes a barbiturate.[7]
Von Mering's claims remained essentially unchallenged for a century, until two teams of researchers from the United States analyzed the metabolism of acetanilide and paracetamol.[12] In 1947 D. Lester and L.A. Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood,[13] and in a subsequent study they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia.[14] In three papers published in the September 1948 issue of the Journal of Pharmacology and Experimental Therapeutics, Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed using more specific methods that paracetamol was the major metabolite of acetanilide in human blood, and established it was a just as efficacious analgesic as its precursor.[15][16][17] They also suggested that methemoglobinemia is produced in humans mainly by another metabolite, phenylhydroxylamine. A followup paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol.[18] This led to a "rediscovery" of paracetamol.[7] It has been suggested that contamination of paracetamol with 4-aminophenol, the substance from it was sythesized by von Mering, may be the cause for his spurious findings.[12]
![](http://up.wiki.x.io/wikipedia/commons/thumb/2/2a/Axelrod.jpg/200px-Axelrod.jpg)
Paracetamol was first marketed in the United States in 1953 by Sterling-Winthrop Co., which promoted it as preferable to aspirin since it was safe to take for children and people with ulcers.[12] The best known brand today for paracetamol in the United States, Tylenol, was established in 1955 when McNeil Laboratories started selling paracetamol as a pain and fever reliever for children, under the brand name Tylenol Children's Elixir—the word "tylenol" was a contraction of para-acetylaminophenol.[19] In 1956, 500 mg tablets of paracetamol went on sale in the United Kingdom under the trade name Panadol, produced by Frederick Stearns & Co, a subsidiary of Sterling Drug Inc. Panadol was originally available only by prescription, for the relief of pain and fever, and was advertised as being "gentle to the stomach," since other analgesic agents of the time contained aspirin, a known stomach irritant.[citation needed] In 1963, paracetamol was added to the British Pharmacopoeia, and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents.[20] Concerns about paracetamol's safety delayed its widespread acceptance until the 1970s, but in the 1980s paracetamol sales exceeded those of aspirin in many countries, including the United Kingdom. This was accompanied by the commercial demise of phenacetin, blamed as the cause of analgesic nephropathy, hematological toxicity, and liability for abuse due to psychotropic effects.[7]
The U.S. patent on paracetamol has long expired, and generic versions of the drug are widely available under the Drug Price Competition and Patent Term Restoration Act of 1984, although certain Tylenol preparations were protected until 2007. U.S. patent 6,126,967 filed September 3, 1998 was granted for "Extended release acetaminophen particles".[21]
Structure and reactivity
[edit]![](http://up.wiki.x.io/wikipedia/commons/thumb/7/7e/Polar-surface-area.png/220px-Polar-surface-area.png)
Paracetamol consists of a benzene ring core, substituted by one hydroxyl group and the nitrogen atom of an amide group in the para (1,4) pattern. The amide group is acetamide (ethanamide). It is an extensively conjugated system, as the lone pair on the hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, the p orbital on the carbonyl carbon, and the lone pair on the carbonyl oxygen are all conjugated. The presence of two activating groups also make the benzene ring highly reactive toward electrophilic aromatic substitution. As the substituents are ortho,para-directing and para with respect to each other, all positions on the ring are more or less equally activated. The conjugation also greatly reduces the basicity of the oxygens and the nitrogen, while making the hydroxyl acidic through delocalisation of charge developed on the phenoxide anion.
Synthesis
[edit]Compared with many other drugs, paracetamol is much easier to synthesize, because it lacks stereocenters. As a result, there is no need to design a stereo-selective synthesis.
Paracetamol may be easily prepared in the laboratory by nitrating phenol with sodium nitrate, separating the desired p-nitrophenol from the ortho- byproduct, and reducing the nitro group with sodium borohydride. The resultant p-aminophenol is then acetylated with acetic anhydride.[22]
Phenol is strongly activating, thus the nitration of phenol requires only mild conditions, compared with e.g. the nitration of benzene.
Available forms
[edit]![]() | This section may require copy editing for rambling. (January 2009) |
![](http://up.wiki.x.io/wikipedia/commons/thumb/1/12/Panadol_suppositories.jpg/220px-Panadol_suppositories.jpg)
Panadol, which is marketed in Europe, Africa, Asia, Central America, and Australasia, is the most widely available brand, sold in over 80 countries. In North America, paracetamol is sold in generic form (usually labeled as acetaminophen) or under a number of trade names, for instance, Tylenol (McNeil-PPC, Inc.), Anacin-3, Tempra, and Datril. While there is brand named paracetamol available in the UK (e.g. Panadol), unbranded or generic paracetamol is more commonly sold.
In some formulations, paracetamol is combined with the opioid codeine, sometimes referred to as co-codamol (BAN). In the United States and Canada, this is marketed under the name of Tylenol #1/2/3/4, which contain 8-10 mg, 15 mg, 30 mg, and 60 mg of codeine, respectively. In the U.S., this combination is available only by prescription, while the lowest-strength preparation is over-the-counter in Canada, and, in other countries, other strengths may be available over the counter. There are generic forms of these combinations as well. In the UK and in many other countries, this combination is marketed under the names of Tylex CD and Panadeine. Other names include Captin, Disprol, Dymadon, Fensum, Hedex, Mexalen, Nofedol, Paralen, Pediapirin, Perfalgan, and Solpadeine. Paracetamol is also combined with other opioids such as dihydrocodeine, referred to as co-dydramol (BAN), oxycodone or hydrocodone, marketed in the U.S. as Percocet and Vicodin, respectively. Another very commonly used analgesic combination includes paracetamol in combination with propoxyphene napsylate, sold under the brand name Darvocet. A combination of paracetamol, codeine, and the calmative doxylamine succinate is marketed as Syndol or Mersyndol.
Paracetamol is commonly used in multi-ingredient preparations for migraine headache, typically including butalbital and paracetamol with or without caffeine, and sometimes containing codeine.
It is commonly administered in tablet, liquid suspension, suppository, intravenous, or intramuscular form. The common adult dose is 500 mg to 1000 mg. The recommended maximum daily dose, for adults, is 4 grams. In recommended doses, paracetamol generally is safe for children and infants, as well as for adults.
Brand Names[23] |
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Aceta, Actimin, Anacin-3, Apacet, Aspirin Free Anacin, Atasol, Banesin, Crocin, Dapa, Datril Extra-Strength, DayQuil, Feverall, Few Drops, Fibi, Fibi plus, Genapap, Genebs, Lekadol, Liquiprin, Neopap, Oraphen-PD, Panadol, Paralen, Phenaphen, Redutemp, Snaplets-FR, Suppap, Tapanol, Tylenol, Valorin, Xcel. |
Mechanism of action
[edit]The mechanism by which paracetamol reduces fever and pain is debated[24] largely because paracetamol reduces the production of prostaglandins (pro-inflammatory chemicals). Aspirin also inhibits the production of prostaglandins, but, unlike aspirin, paracetamol has little anti-inflammatory action. Likewise, whereas aspirin inhibits the production of the pro-clotting chemicals thromboxanes, paracetamol does not. Aspirin is known to inhibit the cyclooxygenase (COX) family of enzymes, and, because of paracetamol's partial similarity of aspirin's action, much research has focused on whether paracetamol also inhibits COX. It is now clear that paracetamol acts via at least two pathways.[25][26][7][27]
The COX family of enzymes are responsible for the metabolism of arachidonic acid to prostaglandin H2, an unstable molecule, which is, in turn, converted to numerous other pro-inflammatory compounds. Classical anti-inflammatories, such as the NSAIDs, block this step. Only when appropriately oxidized is the COX enzyme highly active.[28][29] Paracetamol reduces the oxidized form of the COX enzyme, preventing it from forming pro-inflammatory chemicals.[26][30]
Paracetamol also modulates the endogenous cannabinoid system.[31] Paracetamol is metabolized to AM404, a compound with several actions; most important, it inhibits the uptake of the endogenous cannabinoid/vanilloid anandamide by neurons. Anandamide uptake would result in the activation of the main pain receptor (nociceptor) of the body, the TRPV1 (older name: vanilloid receptor). Furthermore, AM404 inhibits sodium channels, as do the anesthetics lidocaine and procaine.[32] Either of these actions by themselves has been shown to reduce pain, and are a possible mechanism for paracetamol, though it has been demonstrated that, after blocking cannabinoid receptors and hence making any action of cannabinoid reuptake irrelevant, paracetamol loses analgesic effect, suggesting its pain-relieving action is mediated by the endogenous cannabinoid system.[33]
One theory holds that paracetamol works by inhibiting the COX-3 isoform of the COX family of enzymes. This enzyme, when expressed in dogs, shares a strong similarity to the other COX enzymes, produces pro-inflammatory chemicals, and is selectively inhibited by paracetamol.[34] However, some research has suggested that in humans and mice, the COX-3 enzyme is without inflammatory action.[25] Another possibility is that paracetamol blocks cycloxygenase (as in aspirin), but that in an inflammatory environment, where the concentration of peroxides is high, the oxidation state of paracetamol is high which prevents its actions. This would mean that paracetamol has no direct effect at the site of inflammation but instead acts in the CNS to reduce temperature etc where the environment is not oxidative.[34] The exact mechanism by which paracetamol is believed to affect COX-3 is disputed.
Metabolism
[edit]![](http://up.wiki.x.io/wikipedia/commons/thumb/1/12/Paracetamol_metabolism.svg/250px-Paracetamol_metabolism.svg.png)
Paracetamol is metabolised primarily in the liver, into non-toxic products. Three metabolic pathways are notable:
- Glucuronidation is believed to account for 40% to two-thirds of the metabolism of paracetamol.[35]
- Sulfation (sulfate conjugation) may account for 20–40%.[35]
- N-hydroxylation and rearrangement, then GSH conjugation, accounts for less than 15%. The hepatic cytochrome P450 enzyme system metabolizes paracetamol, forming a minor yet significant alkylating metabolite known as NAPQI (N-acetyl-p-benzo-quinone imine).[36] NAPQI is then irreversibly conjugated with the sulfhydryl groups of glutathione.[36]
All three pathways yield final products that are inactive, non-toxic, and eventually excreted by the kidneys. In the third pathway, however, the intermediate product NAPQI is toxic. NAPQI is primarily responsible for the toxic effects of paracetamol (see #Toxicity); this constitutes an excellent example of toxication.
Production of NAPQI is due primarily to two isoenzymes of cytochrome P450: CYP2E1 and CYP1A2. The P450 gene is highly polymorphic, however, and individual differences in paracetamol toxicity are believed to be due to a third isoenzyme, CYP2D6. Genetic polymorphisms in CYP2D6 may contribute to significantly different rates of production of NAPQI. Furthermore, individuals can be classified as "extensive", "ultrarapid", and "poor" metabolizers (producers of NAPQI), depending on their levels of CYP2D6 expression. Most people are poor metabolizers. Although CYP2D6 metabolises paracetamol into NAPQI to a lesser extent than other P450 enzymes, its activity may contribute to paracetamol toxicity in extensive and ultrarapid metabolisers, and when paracetamol is taken at very large doses.[37] At usual doses in poor metabolizers, NAPQI is quickly detoxified by conjugation.[36] Following overdose, and possibly also in extensive and ultrarapid metabolizers, this detoxification pathway becomes saturated and consequently NAPQI accumulates.
Indications
[edit]WHO recommends that paracetamol be given to children with fever higher than 38.5C.[38]
Comparison with NSAIDs
[edit]Paracetamol, unlike other common analgesics such as aspirin and ibuprofen, has relatively little anti-inflammatory activity, and so it is not considered to be a non-steroidal anti-inflammatory drug (NSAID).
Efficacy
[edit]Regarding comparative efficacy, studies show conflicting results when compared to NSAIDs. A randomized controlled trial of chronic pain from osteoarthritis in adults found similar benefit from paracetamol and ibuprofen.[39] However, a randomized controlled trial of acute musculoskeletal pain in children found that the standard OTC dose of ibuprofen gives greater relief of pain than the standard dose of paracetamol.[40]
Adverse effects
[edit]In recommended doses, paracetamol does not irritate the lining of the stomach, affect blood coagulation as much as NSAIDs, or affect function of the kidneys. However, some studies have shown that high dose-usage (greater than 2,000 mg per day) does increase the risk of upper gastrointestinal complications such as stomach bleeding.[41] Paracetamol is safe in pregnancy, and does not affect the closure of the fetal ductus arteriosus as NSAIDs can.[42] Unlike aspirin, it is safe in children, as paracetamol is not associated with a risk of Reye's syndrome in children with viral illnesses.[43]
Like NSAIDs and unlike opioid analgesics, paracetamol has not been found to cause euphoria or alter mood in any way. While paracetamol and NSAIDs may damage the liver, they do not pose a large risk of addiction, dependence, tolerance, and withdrawal.[citation needed] Paracetamol, particularly in combination with weak opioids, is more likely than NSAIDs to cause rebound headache (medication overuse headache), although less of a risk than ergotamine or triptans used for migraines.[44]
In 2008 the Lancet published the largest study to date on long term side effects of paracetamol in children. Conducted on over 200,000 children in 31 countries, the study determined that use of paracetamol for fever in the first year of life was associated with a 46% increase in the risk of developing asthma symptoms when aged 6–7 years. Higher doses and more regular use of the drug are associated with a greater risk of developing asthma; up to a three-fold increase for heavy use. Furthermore, paracetamol use, both in the first year of life and in children aged 6–7 years, was associated with an increased risk of symptoms of rhinoconjunctivitis and eczema.[6]
Toxicity
[edit]Excessive use of paracetamol can damage multiple organs, especially the liver and kidney. In both organs, toxicity from paracetamol is not from the drug itself but from one of its metabolites, N-acetyl-p-benzoquinoneimine (NAPQI). In the liver, the cytochrome P450 enzymes CYP2E1 and CYP3A4 are primarily responsible for the conversion of paracetamol to NAPQI. In the kidney, cyclooxygenases are the principal route by which paracetamol is converted to NAPQI.[45] Paracetamol overdose leads to the accumulation of NAPQI, which undergoes conjugation with glutathione. Conjugation depletes glutathione, a natural antioxidant. This in combination with direct cellular injury by NAPQI, leads to cell damage and death.[46]
Paracetamol hepatotoxicity is, by far, the most common cause of acute liver failure in both the United States and the United Kingdom.[5][47] Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance.[48] Signs and symptoms of paracetamol toxicity may initially be absent or vague. Untreated, overdose can lead to liver failure and death within days. Treatment is aimed at removing the paracetamol from the body and replacing glutathione. Activated charcoal can be used to decrease absorption of paracetamol if the patient presents for treatment soon after the overdose. While the antidote, acetylcysteine, acts as a precursor for glutathione helping the body regenerate enough to prevent damage to the liver, a liver transplant is often required if damage to the liver becomes severe.[2]
Effects on animals
[edit]Paracetamol is extremely toxic to cats, and should not be given to them under any circumstances. Cats lack the necessary glucuronyl transferase enzymes to safely break paracetamol down, and minute portions of a tablet may prove fatal. Initial symptoms include vomiting, salivation and discolouration of the tongue and gums. Unlike an overdose in humans, liver damage is rarely the cause of death; instead, methaemoglobin formation and the production of Heinz bodies in red blood cells inhibit oxygen transport by the blood, causing asphyxiation (methemoglobemia and hemolytic anemia).[49] Treatment with N-acetylcysteine, methylene blue or both is sometimes effective after the ingestion of small doses of paracetamol. Female cats have better survival record.[50]
Although paracetamol is believed to have no significant anti-inflammatory activity, it has been reported to be as effective as aspirin in the treatment of musculoskeletal pain in dogs.[51] A paracetamol-codeine product (trade name Pardale-V)[52] licensed for use in dogs is available on veterinary prescription in the UK.[53] It should be administered to dogs only on veterinary advice. The main effects of toxicity in dogs is liver damage.[54] N-acetylcysteine treatment is efficacious in dogs when administered within a few hours of paracetamol ingestion.[51]
Paracetamol is also lethal to snakes, and has been suggested as chemical control program for the brown tree snake (Boiga irregularis) in Guam.[55]
See also
[edit]Notes and references
[edit]- ^ Control of Pain in Patients with Cancer Sign Guidelines 40Section 6 [1].
- ^ a b Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA (2008). "Guidelines for the management of paracetamol poisoning in Australia and New Zealand—explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres". Med. J. Aust. 188 (5): 296–301. doi:10.5694/j.1326-5377.2008.tb01625.x. PMID 18312195. S2CID 9505802.
{{cite journal}}
: Unknown parameter|month=
ignored (help)CS1 maint: multiple names: authors list (link) - ^ Khashab M, Tector AJ, Kwo PY (2007). "Epidemiology of acute liver failure". Curr Gastroenterol Rep. 9 (1): 66–73. doi:10.1007/s11894-008-0023-x. PMID 17335680. S2CID 30068892.
{{cite journal}}
: Unknown parameter|month=
ignored (help)CS1 maint: multiple names: authors list (link) - ^ Hawkins LC, Edwards JN, Dargan PI (2007). "Impact of restricting paracetamol pack sizes on paracetamol poisoning in the United Kingdom: a review of the literature". Drug Saf. 30 (6): 465–79. doi:10.2165/00002018-200730060-00002. PMID 17536874. S2CID 36435353.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ a b Larson AM, Polson J, Fontana RJ; et al. (2005). "Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study". Hepatology. 42 (6): 1364–72. doi:10.1002/hep.20948. PMID 16317692. S2CID 24758491.
{{cite journal}}
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(help)CS1 maint: multiple names: authors list (link) - ^ a b Beasley, Richard; Clayton, Tadd; Crane, Julian; von Mutius, Erika; Lai, Christopher; Montefort, Stephen; Stewart, Alistair (2008). "Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children aged 6–7 years: analysis from Phase Three of the ISAAC programme". The Lancet. 372 (9643): 1039–1048. doi:10.1016/S0140-6736(08)61445-2. PMID 18805332. Retrieved 2008-09-19.
{{cite journal}}
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ a b c d e f g Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S (2006). "Paracetamol: new vistas of an old drug". CNS Drug Reviews. 12 (3–4): 250–75. doi:10.1111/j.1527-3458.2006.00250.x. PMC 6506194. PMID 17227290.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Bergman K, Müller L, Teigen SW (1996). "The genotoxicity and carcinogenicity of paracetamol: a regulatory (re)view". Mutat Res. 349 (2): 263–88. doi:10.1016/0027-5107(95)00185-9. PMID 8600357.
{{cite journal}}
: Unknown parameter|month=
ignored (help)CS1 maint: multiple names: authors list (link) - ^ Chan A, Hepp P. Das Antifebrin, ein neues Fiebermittel. Centralbl Klein Med 1886;7:561–564.
- ^ H. N. Morse (1878). "Ueber eine neue Darstellungsmethode der Acetylamidophenole". Berichte der deutschen chemischen Gesellschaft. 11 (1): 232–233. doi:10.1002/cber.18780110151.
- ^ Von Mering J. Beitrage zur Kenntniss der Antipyretica. Ther Monatsch 1893;7:577–587.
- ^ a b c d Sneader, Walter (2005). Drug Discovery: A History. John Wiley and Sons. p. 439. ISBN 0471899801.
- ^ D. Lester, L.A. Greenberg, Metabolic fate of acetanilide and other aniline derivatives. II. Major metabolites of acetanilide in the blood., J. Pharm. Exp. Ther., 1947; 90: 68
- ^ D. Lester, L.A. Greenberg, Metabolic fate of acetanilide and other aniline derivatives. II. Major metabolites of acetanilide in the blood., J. Pharm. Exp. Ther., 1947; 90: 68
- ^ Brodie BB, Axelrod J (1948). "The estimation of acetanilide and its metabolic products, aniline, N-acetyl p-aminophenol and p-aminophenol (free and total conjugated) in biological fluids and tissues". J Pharmacol Exp Ther. 94 (1): 22–28. PMID 18885610.
- ^ Brodie BB, Axelrod J (1948). "The fate of acetanilide in man" (PDF). J Pharmacol Exp Ther. 94 (1): 29–38. PMID 18885611.
- ^ Frederick B. Flinn, Bernard B. Brodie (1948). "The effect on the pain threshold of N-acetyl p-aminophenol, a product derived in the body from acetanilide". J Pharmacol Exp Ther. 94 (1): 76–77. PMID 18885618.
- ^ Brodie BB, Axelrod J (1949). "The fate of acetophenetidin (phenacetin) in man and methods for the estimation of acetophenitidin and its metabolites in biological material". J Pharmacol Exp Ther. 94 (1): 58–67.
- ^ "A Festival of Analgesics." Chemical Heritage Foundation. 2001. Retrieved on August 17, 2007.
- ^ Milton Silverman, Mia Lydecker, Philip Randolph Lee (1992). Bad Medicine: The Prescription Drug Industry in the Third World. Stanford University Press. pp. 88–90. ISBN 0804716692.
{{cite book}}
: CS1 maint: multiple names: authors list (link) - ^ US patent 6126967, "Extended release acetaminophen particles", issued 2000-10-03
- ^ Ellis, Frank (2002). Paracetamol: a curriculum resource. Cambridge: Royal Society of Chemistry. ISBN 0-85404-375-6.
- ^ Reader's Digest Guide to Drugs and Supplements. Pleasantville, New York; Montreal: Reader's Digest Association, Inc. 2002. ISBN 0-7621-0366-3.
- ^ Rossi, S. (ed.) (2008). Australian Medicines Handbook 2008. Adelaide: Australian Medicines Handbook. p. 30. ISBN 978-0-9757919-6-7.
{{cite book}}
:|author=
has generic name (help) - ^ a b Kis B, Snipes JA, Busija DW (2005). "Acetaminophen and the cyclooxygenase-3 puzzle: sorting out facts, fictions, and uncertainties". J. Pharmacol. Exp. Ther. 315 (1): 1–7. doi:10.1124/jpet.105.085431. PMID 15879007. S2CID 86624308.
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: CS1 maint: multiple names: authors list (link) - ^ a b Aronoff DM, Oates JA, Boutaud O (2006). "New insights into the mechanism of action of acetaminophen: Its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2 synthases". Clin. Pharmacol. Ther. 79 (1): 9–19. doi:10.1016/j.clpt.2005.09.009. hdl:2027.42/109994. PMID 16413237. S2CID 26447377.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Graham GG, Scott KF (2005). "Mechanism of action of paracetamol". American Journal of Therapeutics. 12 (1): 46–55. doi:10.1097/00045391-200501000-00008. PMID 15662292. S2CID 38261222.
- ^ Ohki S, Ogino N, Yamamoto S, Hayaishi O (1979). "Prostaglandin hydroperoxidase, an integral part of prostaglandin endoperoxide synthetase from bovine vesicular gland microsomes". J. Biol. Chem. 254 (3): 829–36. doi:10.1016/S0021-9258(17)37880-8. PMID 104998.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Harvison PJ, Egan RW, Gale PH, Nelson SD (1986). "Acetaminophen as a cosubstrate and inhibitor of prostaglandin H synthase". Adv. Exp. Med. Biol. Advances in Experimental Medicine and Biology. 197: 739–47. doi:10.1007/978-1-4684-5134-4_68. ISBN 978-1-4684-5136-8. PMID 3094341.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Roberts, L.J II. & Marrow, J.D. "Analgesic-antipyretic and Antiinflammatory Agents and Drugs Employed in the Treatment of Gout" in, "Goodman & Gilman's The Pharmacological Basis of Therapeutics 10th Edition" by Hardman, J.G. & Limbird, L.E. Published by McGraw Hill, 2001, p.687–731.
- ^ Högestätt ED, Jönsson BA, Ermund A; et al. (2005). "Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system". J. Biol. Chem. 280 (36): 31405–12. doi:10.1074/jbc.M501489200. PMID 15987694. S2CID 10837155.
{{cite journal}}
: Explicit use of et al. in:|author=
(help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ Köfalvi A (2008). "Chapter 9: Alternative interacting sites and novel receptors for cannabinoid ligands. In: 'Cannabinoids and the Brain' Springer-Verlag": 131–160. doi:10.1007/978-0-387-74349-3_9.
{{cite journal}}
: Cite journal requires|journal=
(help) - ^ Ottani A, Leone S, Sandrini M, Ferrari A, Bertolini A (2006). "The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors". Eur. J. Pharmacol. 531 (1–3): 280–1. doi:10.1016/j.ejphar.2005.12.015. PMID 16438952.
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: CS1 maint: multiple names: authors list (link) - ^ a b Chandrasekharan NV, Dai H, Roos KL; et al. (2002). "COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression". Proc. Natl. Acad. Sci. U.S.A. 99 (21): 13926–31. doi:10.1073/pnas.162468699. PMC 129799. PMID 12242329.
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(help)CS1 maint: multiple names: authors list (link) - ^ a b Hendrickson, Robert G.; Kenneth E. Bizovi (2006). “Acetaminophen”, in Nelson, Lewis H.; Flomenbaum, Neal; Goldfrank, Lewis R. et al. Goldfrank's toxicologic emergencies, p. 525, New York: McGraw-Hill. Retrieved on January 18, 2009 through Google Book Search.
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- ^ Dong H, Haining RL, Thummel KE, Rettie AE, Nelson SD (2000). "Involvement of human cytochrome P450 2D6 in the bioactivation of acetaminophen". Drug Metab Dispos. 28 (12): 1397–400. PMID 11095574.
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: CS1 maint: multiple names: authors list (link) Free full text - ^ "Baby paracetamol asthma concern". BBC News. 2008-09-19. Retrieved 2008-09-19.
- ^ Bradley JD, Brandt KD, Katz BP, Kalasinski LA, Ryan SI (1991). "Comparison of an antiinflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee". N. Engl. J. Med. 325 (2): 87–91. doi:10.1056/NEJM199107113250203. PMID 2052056.
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ignored (help) - ^ Lesko SM, Mitchell AA (1999). "The safety of acetaminophen and ibuprofen among children younger than two years old". Pediatrics. 104 (4): e39. doi:10.1542/peds.104.4.e39. PMID 10506264. S2CID 3107281.
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB (1973). "Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione". The Journal of Pharmacology and Experimental Therapeutics. 187 (1): 211–7. PMID 4746329.
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ a b Maddison, Jill E. (2002). Small Animal Clinical Pharmacology. Elsevier Health Sciences. pp. 260–261. ISBN 0702025739.
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External links
[edit]- Paracetamol Information Centre
- The Julius Axelrod Papers
- Manning AM. "Acetaminophen Toxicity in Dogs". PetPlace.com. Retrieved 17 January 2009.
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Category:Amides Category:Phenols Category:Analgesics Category:Antipyretics Category:World Health Organization essential medicines
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