Ibuprofen

Ibuprofen
Systematic (IUPAC) name
(RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid
Clinical data
Trade names Advil, Brufen, Motrin, Nurofen, and others
AHFS/Drugs.com monograph
MedlinePlus a682159
Licence data US FDA:link
  • AU: C
  • US: C (Risk not ruled out)
  • D (US) at ≥30 weeks of gestation, due to the potential for premature closure or patent ductus arteriosus
Oral, rectal, topical, and intravenous
Pharmacokinetic data
Bioavailability 87–100% (oral), 87% (rectal)[1]
Protein binding 98%[1]
Metabolism Hepatic (CYP2C9)[1]
Onset of action 30 minutes[2]
Half-life 1.3-3 hours[1]
Excretion Urine (95%)[1][3]
Identifiers
15687-27-1 Yes
C01EB16 G02CC01 M01AE01 M02AA13
PubChem CID 3672
IUPHAR ligand 2713
DrugBank DB01050 Yes
ChemSpider 3544 Yes
UNII WK2XYI10QM Yes
KEGG D00126 Yes
ChEBI CHEBI:5855 Yes
ChEMBL CHEMBL521 Yes
PDB ligand ID IBP (PDBe, RCSB PDB)
Chemical data
Formula C13H18O2
206.29 g/mol
Physical data
Density 1.03 g/ml g/cm3
Melting point 75 to 78 °C (167 to 172 °F)
Boiling point 157 °C (315 °F)
 Yes (what is this?)  (verify)

Ibuprofen (/ˈaɪbjuːproʊfɛn/ or /aɪbjuːˈproʊfən/ EYE-bew-PROH-fən; from isobutylphenylpropanoic acid) is a nonsteroidal anti-inflammatory drug (NSAID) derivative of propionic acid used for relieving pain, helping with fever and reducing inflammation.[4][5][6] About 60% of people improve with any given NSAID and it is recommended that if one does not work that another should be tried.[7] Ibuprofen might be considered a weaker anti-inflammatory than other NSAIDs.[7]

Compared to other NSAIDs it may have fewer side effects such as gastrointestinal bleeding.[7] At low doses it does not appear to increase the risk of myocardial infarction; however, at higher doses it may.[7] It may result in worsened asthma.[7]

Like other NSAIDs, it works by inhibiting the synthesis of prostaglandins, which are fat-like molecules derived from arachidonic acid, which are involved in mediating inflammation (swelling), pain, and fever. It achieves this effect on prostaglandin synthesis by inhibiting cyclooxygenase, an enzyme that is present in various tissues of the body.

It was originally made and patented in 1961, by the research arm of Boots Company led by Stewart Adams and marketed as Brufen.[8] Ibuprofen is now available under a variety of trade names, with the most notable being Advil, Motrin, and Nurofen.[8][9][10][11][12] Its discovery was the result of research during the 1950s and 1960s to find a safer alternative to aspirin.[8][12] It was later marketed, in 1966, as a prescription drug in the United Kingdom, then the United States in 1974.[8][12] Later in 1983 and 1984, it became the first NSAID (other than aspirin) to be available over the counter (OTC) in these two countries.[8][12] It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[13]

Medical uses

200-mg ibuprofen tablets

Ibuprofen is used primarily for fever (including postimmunisation fever), mild-to-moderate pain (including pain relief after surgery), painful menstruation, osteoarthritis, dental pain, headaches and pain from kidney stones. It is used for inflammatory diseases such as juvenile idiopathic arthritis and rheumatoid arthritis.[14][15] It is also used for pericarditis and patent ductus arteriosus.[16]

Ibuprofen lysine

In Europe, Australia, and New Zealand, ibuprofen lysine (the lysine salt of ibuprofen, sometimes called "ibuprofen lysinate" even though the lysine is in cationic form) is licensed for treatment of the same conditions as ibuprofen. The lysine salt increases water solubility, allowing intravenous use, and is indicated for closure of a patent ductus arteriosus in premature infants weighing between 500 and 1,500 grams (1 and 3 lb), who are no more than 32 weeks gestational age when usual medical management (e.g., fluid restriction, diuretics, respiratory support, etc.) is not effective.[17]

Adverse effects

Adverse effects include: nausea, dyspepsia, gastrointestinal ulceration/bleeding, raised liver enzymes, diarrhea, constipation, nosebleed, headache, dizziness, rash, salt and fluid retention, and hypertension.[15]

Infrequent adverse effects include: esophageal ulceration, heart failure, hyperkalemia, renal impairment, confusion, and bronchospasm.[15] Ibuprofen can exacerbate asthma, sometimes fatally.[18]

Ibuprofen may be quantified in blood, plasma, or serum to demonstrate the presence of the drug in a person having experienced an anaphylactic reaction, confirm a diagnosis of poisoning in hospitalized patients, or assist in a medicolegal death investigation. A monograph relating ibuprofen plasma concentration, time since ingestion, and risk of developing renal toxicity in overdose patients has been published.[19]

Cardiovascular risk

Along with several other NSAIDs, chronic ibuprofen use has been found correlated with risk of hypertension[20] and myocardial infarction (heart attack),[21] particularly among those chronically using high doses. In older hypertensive patients treated with hydrochlorothiazide, ibuprofen at a high daily dose was found to significantly increase systolic blood pressure.[22]

Skin

Along with other NSAIDs, ibuprofen has been associated with the onset of bullous pemphigoid or pemphigoid-like blistering.[23] As with other NSAIDs, ibuprofen has been reported to be a photosensitising agent,[24] but it is considered a weak photosensitising agent compared to other members of the 2-arylpropionic acid class. Like other NSAIDs, ibuprofen is an extremely rare cause of the autoimmune disease Stevens-Johnson syndrome (SJS).[25][26]

Interactions

Drinking alcohol when taking ibuprofen may increase risk of stomach bleeding.[27]

According to the US Food and Drug Administration, "ibuprofen can interfere with the antiplatelet effect of low-dose aspirin, potentially rendering aspirin less effective when used for cardioprotection and stroke prevention." Allowing sufficient time between doses of ibuprofen and immediate-release (IR) aspirin can avoid this problem. The recommended elapsed time between a dose of ibuprofen and a dose of aspirin depends on which is taken first. It would be 30 minutes or more for ibuprofen taken after IR aspirin, and 8 hours or more for ibuprofen taken before IR aspirin. However, this timing cannot be recommended for enteric-coated aspirin. But, if ibuprofen is taken only occasionally without the recommended timing, the reduction of the cardioprotection and stroke prevention of a daily aspirin regimen is minimal.[28]

Overdose

Ibuprofen overdose has become common since it was licensed for OTC use. Many overdose experiences are reported in the medical literature, although the frequency of life-threatening complications from ibuprofen overdose is low.[29] Human response in cases of overdose ranges from absence of symptoms to fatal outcome despite intensive-care treatment. Most symptoms are an excess of the pharmacological action of ibuprofen, and include abdominal pain, nausea, vomiting, drowsiness, dizziness, headache, tinnitus, and nystagmus. Rarely, more severe symptoms, such as gastrointestinal bleeding, seizures, metabolic acidosis, hyperkalaemia, hypotension, bradycardia, tachycardia, atrial fibrillation, coma, hepatic dysfunction, acute renal failure, cyanosis, respiratory depression, and cardiac arrest have been reported.[30] The severity of symptoms varies with the ingested dose and the time elapsed; however, individual sensitivity also plays an important role. Generally, the symptoms observed with an overdose of ibuprofen are similar to the symptoms caused by overdoses of other NSAIDs.

Correlation between severity of symptoms and measured ibuprofen plasma levels is weak. Toxic effects are unlikely at doses below 100 mg/kg, but can be severe above 400 mg/kg (around 150 tablets of 200-mg units for an average man);[31] however, large doses do not indicate the clinical course is likely to be lethal.[32] A precise lethal dose is difficult to determine, as it may vary with age, weight, and concomitant diseases of the individual person.

Therapy is largely symptomatic. In cases presenting early, gastric decontamination is recommended. This is achieved using activated charcoal; charcoal adsorbs the drug before it can enter the systemic circulation. Gastric lavage is now rarely used, but can be considered if the amount ingested is potentially life-threatening, and it can be performed within 60 minutes of ingestion. Emesis is not recommended.[33] The majority of ibuprofen ingestions produce only mild effects and the management of overdose is straightforward. Standard measures to maintain normal urine output should be instituted and renal function monitored.[31] Since ibuprofen has acidic properties and is also excreted in the urine, forced alkaline diuresis is theoretically beneficial. However, because ibuprofen is highly protein-bound in the blood, renal excretion of unchanged drug is minimal. Forced alkaline diuresis is, therefore, of limited benefit.[34] Symptomatic therapy for hypotension, gastrointestinal bleeding, acidosis, and renal toxicity may be indicated. On occasion, close monitoring in an intensive-care unit for several days is necessary. A patient who survives the acute intoxication usually experiences no late sequelae.

Miscarriage

A Canadian study published in the Canadian Medical Association Journal of thousands of pregnant woman suggests those taking any type or amount of NSAIDs (including ibuprofen, diclofenac and naproxen) were 2.4 times more likely to miscarry than those not taking the drugs.[35] However, an Israeli study following thousands of women found no increased risk of miscarriage in the group of mothers using NSAIDs.[36]

Mechanism of action

Nonsteroidal anti-inflammatory drugs such as ibuprofen work by inhibiting the COX enzymes, which convert arachidonic acid to prostaglandin H2 (PGH2). PGH2, in turn, is converted by other enzymes to several other prostaglandins (which are mediators of pain, inflammation, and fever) and to thromboxane A2 (which stimulates platelet aggregation, leading to the formation of blood clots).

The exact mechanism of action of ibuprofen is unknown. Ibuprofen is a nonselective inhibitor of cyclooxygenase, an enzyme involved in prostaglandin synthesis via the arachidonic acid pathway. Its pharmacological effects are believed to be due to inhibition of cyclooxygenase-2 (COX-2) which decreases the synthesis of prostaglandins involved in mediating inflammation, pain, fever, and swelling. Antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation. Inhibition of COX-1 is thought to cause some of the side effects of ibuprofen including gastrointestinal ulceration. Ibuprofen is administered as a racemic mixture. The R-enantiomer undergoes extensive interconversion to the S-enantiomer in vivo. The S-enantiomer is believed to be the more pharmacologically active enantiomer.[37]

Like aspirin and indometacin, ibuprofen is a nonselective COX inhibitor, in that it inhibits two isoforms of cyclooxygenase, COX-1 and COX-2. The analgesic, antipyretic, and anti-inflammatory activity of NSAIDs appears to operate mainly through inhibition of COX-2, whereas inhibition of COX-1 would be responsible for unwanted effects on the gastrointestinal tract.[38] However, the role of the individual COX isoforms in the analgesic, anti-inflammatory, and gastric damage effects of NSAIDs is uncertain and different compounds cause different degrees of analgesia and gastric damage.[39]

Physical and chemical properties

It is practically insoluble in water, but very soluble in most organic solvents (ethanol, methanol, acetone and dichloromethane).[6]

Stereochemistry

It is an optically active compound with both S and R-isomers, of which the S (dextrorotatory) isomer is the more biologically active; this isomer has also been isolated and used medically (see dexibuprofen for details).[6]

Ibuprofen is produced industrially as a racemate. The compound, like other 2-arylpropionate derivatives (including ketoprofen, flurbiprofen, naproxen, etc.), does contain a chiral center in the α-position of the propionate moiety. So two enantiomers of ibuprofen occur, with the potential for different biological effects and metabolism for each enantiomer. Indeed, the (S)-(+)-ibuprofen (dexibuprofen) was found to be the active form both in vitro and in vivo.

It was logical, then, to consider the potential for improving the selectivity and potency of ibuprofen formulations by marketing ibuprofen as a single-enantiomer product (as occurs with naproxen, another NSAID). Further in vivo testing, however, revealed the existence of an isomerase (alpha-methylacyl-CoA racemase), which converted (R)-ibuprofen to the active (S)-enantiomer.[40][41][42]

(R)-ibuprofen
(S)-ibuprofen

History

Ibuprofen was derived from propionic acid by the research arm of Boots Group during the 1960s.[11] It was discovered by Andrew RM Dunlop, with colleagues Stewart Adams, John Nicholson, Vonleigh Simmons, Jeff Wilson, and Colin Burrows, and patented in 1961. Adams initially tested the drug on a hangover.[8] The drug was launched as a treatment for rheumatoid arthritis in the United Kingdom in 1969, and in the United States in 1974. Dr. Adams was subsequently awarded an OBE in 1987. Boots was awarded the Queen's Award for Technical Achievement for the development of the drug in 1987.[8]

Marketing

A bottle of generic ibuprofen

Ibuprofen was made available under prescription in the United Kingdom in 1969, and in the United States in 1974.[43] In the years since, the good tolerability profile, along with extensive experience in the population, as well as in so-called phase-IV trials (postapproval studies), has resulted in the availability of ibuprofen OTC in pharmacies worldwide, as well as in supermarkets and other general retailers. Ibuprofen is its INN, BAN, AAN and USAN approved name.

North America

Ibuprofen is commonly available in the United States up to the FDA's 1984 dose limit OTC, rarely used higher by prescription.[44] In 2009, the first injectable formulation of ibuprofen was approved in the United States, under the trade name Caldolor.[45][46] Ibuprofen was the only parenteral for both pain and fever available in the country prior to the approval of Ofirmev (acetaminophen) injection by the FDA.[47]

UK

In the UK, ibuprofen lysine is marketed as express pain relief, tension headache relief, and more commonly, migraine relief medicine. Usually available in packing of 16 342-mg tablets, the pack is marketed OTC by most superstores and pharmacies as their own branded product including Asda, Tesco, and Superdrug.[48]

Research

Ibuprofen is sometimes used for the treatment of acne, because of its anti-inflammatory properties and has been sold in Japan in topical form for adult acne.[49][50] As with other NSAIDs, ibuprofen may be useful in the treatment of severe orthostatic hypotension (low blood pressure when standing up).[51] In some studies, ibuprofen showed superior results compared to a placebo in the prevention of Alzheimer's disease, when given in low doses over a long time.[52][53]

Ibuprofen has been associated with a lower risk of Parkinson's disease, and may delay or prevent it. Aspirin, other NSAIDs, and paracetamol (acetaminophen) had no effect on the risk for Parkinson's.[54] In March 2011, researchers at Harvard Medical School announced in Neurology that ibuprofen had a neuroprotective effect against the risk of developing Parkinson's disease.[55][56][57] People regularly consuming ibuprofen were reported to have a 38% lower risk of developing Parkinson's disease, but no such effect was found for other pain relievers, such as aspirin and paracetamol. Use of ibuprofen to lower the risk of Parkinson's disease in the general population would not be problem-free, given the possibility of adverse effects on the urinary and digestive systems.[58]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Davies, NM (February 1998). "Clinical pharmacokinetics of ibuprofen. The first 30 years.". Clinical Pharmacokinetics 34 (2): 101–54. doi:10.2165/00003088-199834020-00002. PMID 9515184.
  2. ↑ "ibuprofen". Retrieved 31 January 2015.
  3. ↑ "PRODUCT INFORMATION BRUFEN® TABLETS AND SYRUP" (PDF). TGA eBusiness Services. Abbott Australasia Pty Ltd. 31 July 2012. Retrieved 8 May 2014.
  4. ↑ "TGA Approved Terminology for Medicines – July 1999" (PDF). Therapeutic Goods Administration. Australian Government, Department of Health. July 1999. p. 71. Retrieved 26 June 2014.
  5. ↑ Van Esch, A; Van Steensel-Moll, HA; Steyerberg, EW; Offringa, M; Habbema, JD; Derksen-Lubsen, G (June 1995). "Antipyretic efficacy of ibuprofen and acetaminophen in children with febrile seizures.". Archives of Pediatrics & Adolescent Medicine 149 (6): 632–7. doi:10.1001/archpedi.1995.02170190042007. PMID 7767417.
  6. ↑ 6.0 6.1 6.2 Brayfield, A, ed. (14 January 2014). "Ibuprofen". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 26 June 2014.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 Bnf : march 2014-september 2014. (2014 ed. ed.). London: British Medical Assn. 2014. pp. 686–688. ISBN 0857110861.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 Halford, GM; Lordkipanidzé, M; Watson, SP (2012). "50th anniversary of the discovery of ibuprofen: an interview with Dr Stewart Adams.". Platelets 23 (6): 415–22. doi:10.3109/09537104.2011.632032. PMID 22098129.
  9. ↑ "PubMed Health – Ibuprofen". U.S. National Library of Medicine. 1 October 2010. Retrieved 20 January 2011.
  10. ↑ "Chemistry in your cupboard | Nurofen".
  11. ↑ 11.0 11.1 Adams, SS (April 1992). "The propionic acids: a personal perspective.". Journal of Clinical Pharmacology 32 (4): 317–23. doi:10.1002/j.1552-4604.1992.tb03842.x. PMID 1569234.
  12. ↑ 12.0 12.1 12.2 12.3 Rainsford, KD (April 2003). "Discovery, mechanisms of action and safety of ibuprofen.". International Journal of Clinical Practice. Supplement (135): 3–8. PMID 12723739.
  13. ↑ WHO Model List of Essential Medicines (PDF) (16th ed.). World Health Organization. March 2009. Retrieved 30 March 2011.
  14. ↑ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. pp. 665, 671. ISBN 978-0-85711-084-8.
  15. ↑ 15.0 15.1 15.2 Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  16. ↑ "Ibuprofen". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
  17. ↑ "Neoprofen (ibuprofen lysine) injection. Package insert" (PDF). Ovation Pharmaceuticals.
  18. ↑ Ayres, JG; Fleming, D; Whittington, R (9 May 1987). "Asthma death due to ibuprofen". Lancet 1 (8541): 1082. doi:10.1016/S0140-6736(87)90499-5. PMID 2883408.
  19. ↑ Baselt, R (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, USA: Biomedical Publications. pp. 758–761.
  20. ↑ Forman, JP; Stampfer, MJ; Curhan, GC (September 2005). "Non-narcotic analgesic dose and risk of incident hypertension in US women.". Hypertension 46 (3): 500–7. doi:10.1161/01.HYP.0000177437.07240.70. PMID 16103274.
  21. ↑ Hippisley-Cox, J; Coupland, C (11 June 2005). "Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis.". British Medical Journal 330 (7504): 1366. doi:10.1136/bmj.330.7504.1366. PMC 558288. PMID 15947398.
  22. ↑ Gurwitz, JH; Everitt, DE; Monane, M; Glynn, RJ; Choodnovskiy, I; Beaudet, MP; Avorn, J (March 1996). "The impact of ibuprofen on the efficacy of antihypertensive treatment with hydrochlorothiazide in elderly persons.". The Journals of Gerontology. Series A, Biological Sciences and Medical sciences 51 (2): M74–9. doi:10.1093/gerona/51A.2.M74. PMID 8612107.
  23. ↑ Chan, LS (12 June 2014). Hall, R; Vinson, RP; Nunley, JR; Gelfand, JM; Elston, DM, ed. "Bullous Pemphigoid Clinical Presentation". Medscape Reference. United States: WebMD.
  24. ↑ Bergner, T; Przybilla, B (January 1992). "Photosensitization caused by ibuprofen.". Journal of the American Academy of Dermatology 26 (1): 114–6. doi:10.1016/0190-9622(92)70018-b. PMID 1531054.
  25. ↑ Raksha, MP; Marfatia, YS (2008). "Clinical study of cutaneous drug eruptions in 200 patients". Indian J Dermatol Venereol Leprol 74 (1): 80. doi:10.4103/0378-6323.38431. PMID 18193504.
  26. ↑ Ward, KE; Archambault, R; Mersfelder, TL (1 February 2010). "Severe adverse skin reactions to nonsteroidal antiinflammatory drugs: A review of the literature.". American Journal of Health-System Pharmacy 67 (3): 206–13. doi:10.2146/ajhp080603. PMID 20101062.
  27. ↑ "Ibuprofen". Drugs.com.
  28. ↑ "Information for Healthcare Professionals: Concomitant Use of Ibuprofen and Aspirin". U.S. Food and Drug Administration. September 2006. Retrieved 22 November 2010.
  29. ↑ McElwee, NE; Veltri, JC; Bradford, DC; Rollins, DE (June 1990). "A prospective, population-based study of acute ibuprofen overdose: complications are rare and routine serum levels not warranted.". Annals of Emergency Medicine 19 (6): 657–62. doi:10.1016/S0196-0644(05)82471-0. PMID 2188537.
  30. ↑ Vale, JA; Meredith, TJ (January 1986). "Acute poisoning due to non-steroidal anti-inflammatory drugs. Clinical features and management.". Medical Toxicology 1 (1): 12–31. PMID 3537613.
  31. ↑ 31.0 31.1 Volans, G; Hartley, V; McCrea, S; Monaghan, J (March–April 2003). "Non-opioid analgesic poisoning.". Clinical Medicine 3 (2): 119–23. doi:10.7861/clinmedicine.3-2-119. PMID 12737366.
  32. ↑ Seifert, SA; Bronstein, AC; McGuire, T (2000). "Massive ibuprofen ingestion with survival.". Journal of Toxicology. Clinical Toxicology 38 (1): 55–7. doi:10.1081/clt-100100917. PMID 10696926.
  33. ↑ "Position paper: Ipecac syrup.". Journal of Toxicology. Clinical Toxicology 42 (2): 133–143. 2004. doi:10.1081/CLT-120037421. PMID 15214617.
  34. ↑ Hall, AH; Smolinske, SC; Conrad, FL; Wruk, KM; Kulig, KW; Dwelle, TL; Rumack, BH (November 1986). "Ibuprofen overdose: 126 cases.". Annals of Emergency Medicine 15 (11): 1308–13. doi:10.1016/S0196-0644(86)80617-5. PMID 3777588.
  35. ↑ Verma, P; Clark, CA; Spitzer, KA; Laskin, CA; Ray, J; Koren, G (July 2012). "Use of non-aspirin NSAIDs during pregnancy may increase the risk of spontaneous abortion.". Evidence-Based Nursing 15 (3): 76–7. doi:10.1136/ebnurs-2011-100439. PMID 22411163.
  36. ↑ Daniel, S; Koren, G; Lunenfeld, E; Bilenko, N; Ratzon, R; Levy, A (March 2014). "Fetal exposure to nonsteroidal anti-inflammatory drugs and spontaneous abortions.". Canadian Medical Association Journal 186 (5): E177–82. doi:10.1503/cmaj.130605. PMC 3956584. PMID 24491470.
  37. ↑ "Ibuprofen: Pharmacology: Mechanism of Action. Updated on September 16, 2013", DrugBank, Open Data Drug & Drug Target Database, Retrieved on 24 July 2014.
  38. ↑ Rao, P; Knaus, EE (20 September 2008). "Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond.". Journal of Pharmacy & Pharmaceutical Sciences 11 (2): 81s–110s. PMID 19203472.
  39. ↑ Kakuta, H; Zheng, X; Oda, H; Harada, S; Sugimoto, Y; Sasaki, K; Tai, A (24 April 2008). "Cyclooxygenase-1-selective inhibitors are attractive candidates for analgesics that do not cause gastric damage. design and in vitro/in vivo evaluation of a benzamide-type cyclooxygenase-1 selective inhibitor.". Journal of Medicinal Chemistry 51 (8): 2400–11. doi:10.1021/jm701191z. PMID 18363350.
  40. ↑ Tracy, TS; Hall, SD (March–April 1992). "Metabolic inversion of (R)-ibuprofen. Epimerization and hydrolysis of ibuprofenyl-coenzyme A.". Drug metabolism and disposition: the biological fate of chemicals 20 (2): 322–7. PMID 1352228.
  41. ↑ Chen, CS; Shieh, WR; Lu, PH; Harriman, S; Chen, CY (12 July 1991). "Metabolic stereoisomeric inversion of ibuprofen in mammals.". Biochimica et Biophysica Acta 1078 (3): 411–7. doi:10.1016/0167-4838(91)90164-U. PMID 1859831.
  42. ↑ Reichel, C; Brugger, R; Bang, H; Geisslinger, G; Brune, K (April 1997). "Molecular cloning and expression of a 2-arylpropionyl-coenzyme A epimerase: a key enzyme in the inversion metabolism of ibuprofen.". Molecular Pharmacology 51 (4): 576–82. PMID 9106621.
  43. ↑ "Written submission to the NDAC meeting on risks of NSAIDs presented by the International Ibuprofen Foundation". International Ibuprofen Foundation. August 2002. Retrieved 20 March 2014.
  44. ↑ "Ibuprofen". U.S. Food and Drug Administration (FDA).
  45. ↑ "Drug Approval Package: Caldolor (Ibuprofen) NDA #022348". U.S. Food and Drug Administration (FDA). 11 March 2010.
  46. ↑ "FDA Approves Injectable Form of Ibuprofen" (Press release). U.S. Food and Drug Administration (FDA). 11 June 2009.
  47. ↑ "FDA Approves Caldolor: Cumberland Pharmaceuticals Announces FDA Approval of Caldolor" (Press release). Drugs.com. 11 June 2009. Retrieved 13 June 2009.
  48. ↑ "Boots Rapid Ibuprofen Lysine 342 mg Tablets – Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Nottingham, UK: THE BOOTS COMPANY PLC. 15 March 2010. Retrieved 26 June 2014.
  49. ↑ Wong, RC; Kang, S; Heezen, JL; Voorhees, JJ; Ellis, CN (December 1984). "Oral ibuprofen and tetracycline for the treatment of acne vulgaris.". Journal of the American Academy of Dermatology 11 (6): 1076–81. doi:10.1016/S0190-9622(84)80192-9. PMID 6239884.
  50. ↑ "In Japan, an OTC ibuprofen ointment (Fukidia) for alleviating adult acne has been launched". Inpharma (Adis) 1 (1530): 18. 25 March 2006. doi:10.2165/00128413-200615300-00043. ISSN 1173-8324.
  51. ↑ Zawada ET, Jr (May 1982). "Renal consequences of nonsteroidal antiinflammatory drugs.". Postgraduate Medicine 71 (5): 223–30. PMID 7041104.
  52. ↑ Townsend, KP; Praticò, D (October 2005). "Novel therapeutic opportunities for Alzheimer's disease: focus on nonsteroidal anti-inflammatory drugs.". FASEB Journal 19 (12): 1592–601. doi:10.1096/fj.04-3620rev. PMID 16195368.
  53. ↑ Vlad, SC; Miller, DR; Kowall, NW; Felson, DT (6 May 2008). "Protective effects of NSAIDs on the development of Alzheimer disease.". Neurology 70 (19): 1672–7. doi:10.1212/01.wnl.0000311269.57716.63. PMC 2758242. PMID 18458226.
  54. ↑ Chen, H; Jacobs, E; Schwarzschild, MA; McCullough, ML; Calle, EE; Thun, MJ; Ascherio, A (December 2005). "Nonsteroidal antiinflammatory drug use and the risk for Parkinson's disease.". Annals of Neurology 58 (6): 963–7. doi:10.1002/ana.20682. PMID 16240369.
  55. ↑ Bower, JH; Ritz, B (8 March 2011). "Is the answer for Parkinson disease already in the medicine cabinet?: Unfortunately not.". Neurology 76 (10): 854–5. doi:10.1212/WNL.0b013e31820f2e7a. PMID 21368280.
  56. ↑ Gao, X; Chen, H; Schwarzschild, MA; Ascherio, A (8 March 2011). "Use of ibuprofen and risk of Parkinson disease.". Neurology 76 (10): 863–9. doi:10.1212/WNL.0b013e31820f2d79. PMC 3059148. PMID 21368281.
  57. ↑ McSharry, C (May 2011). "Parkinson disease: Could over-the-counter treatment protect against Parkinson disease?". Nature Reviews. Neurology 7 (5): 244. doi:10.1038/nrneurol.2011.49. PMID 21555992.
  58. ↑ Gleason, JM; Slezak, JM; Jung, H; Reynolds, K; Van den Eeden, SK; Haque, R; Quinn, VP; Loo, RK; Jacobsen, SJ (April 2011). "Regular nonsteroidal anti-inflammatory drug use and erectile dysfunction". The Journal of Urology 185 (4): 1388–93. doi:10.1016/j.juro.2010.11.092. PMID 21334642.

External links

Wikimedia Commons has media related to Ibuprofen.