Ibuprofen: pharmacology, efficacy and safety

Abstract

Objectives

This review attempts to bring together information from a large number of recent studies on the clinical uses, safety and pharmacological properties of ibuprofen. Ibuprofen is widely used in many countries for the relief of symptoms of pain, inflammation and fever. The evidence for modes of action of ibuprofen are considered in relation to its actions in controlling inflammation, pain and fever, as well as the adverse effects of the drug.

Summary of outcomes

At low doses (800–1,200 mg day−1) which in many countries are approved for non-prescription (over-the-counter) sale ibuprofen has a good safety profile comparable with paracetamol. Its analgesic activity is linked to its anti-inflammatory effects and is related to reduction in the ex vivo production in blood of cyclo-oxygenase (COX)-1 and COX-2 derived prostanoids. Higher prescription doses (circa 1,800–2,400 mg day−1) are employed long-term for the treatment of rheumatic and other more severe musculo-skeletal conditions. Recent evidence from large-scale clinical trials with the newer coxibs, where ibuprofen was as a comparator, have confirmed earlier studies which have shown that ibuprofen has comparable therapeutic benefits with coxibs and other NSAIDs. For long-term usage (6+ months) there are greater numbers of drop-outs due to reduced effectiveness of therapy, a feature which is common with NSAIDs. Spontaneous reports of adverse events and adverse drug reactions (ADRs) in clinical trails from long-term coxib comparator studies, as well as in epidemiological studies, shows that ibuprofen has relatively low risks for gastro-intestinal (GI), hepato-renal and other, rarer, ADRs compared with other NSAIDs and coxibs. A slightly higher risk of cardiovascular (CV) events has been reported in some, but not all studies, but the risks are in general lower than with some coxibs and diclofenac. The possibility that ibuprofen may interfere with the anti-platelet effects of aspirin, though arguably of low grade or significance, has given rise to caution on its use in patients that are at risk for CV conditions that take aspirin for preventing these conditions. Paediatric use of ibuprofen is reviewed and the main results are that the drug is relatively safe and effective as a treatment of acute pain and fever. It is probably more effective than paracetamol as an antipyretic.

Conclusions

This assessment of the safety and benefits of ibuprofen can be summarized thus: (1) Ibuprofen at OTC doses has low possibilities of serious GI events, and little prospect of developing renal and associated CV events. Ibuprofen OTC does not represent a risk for developing liver injury especially the irreversible liver damage observed with paracetamol and the occasional liver reactions from aspirin. (2) The pharmacokinetic properties of ibuprofen, especially the short plasma half-life of elimination, lack of development of pathologically related metabolites (e.g. covalent modification of liver proteins by the quinine–imine metabolite of paracetamol or irreversible acetylation of biomolecules by aspirin) are support for the view that these pharmacokinetic and notably metabolic effects of ibuprofen favour its low toxic potential. (3) The multiple actions of ibuprofen in controlling inflammation combine with moderate inhibition of COX-1 and COX-2 and low residence time of the drug in the body may account for the low GI, CV and renal risks from ibuprofen, especially at OTC doses.

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Abbreviations

ADME:

Absorption, distribution, metabolism and elimination

AEs:

Adverse events

AUC:

Area-under-the curve (plasma concentration)

CV:

Cardiovascular

CoA:

Coenzyme A

COX-1:

Cyclo-oxygenase-1

COX-2:

Cyclo-oxygenase-2

Coxibs:

COX-2 selective NSAIDs (a sub-group of NSAIDs)

Cl/F:

Clearance (fractional)

C max :

Maximal plasma concentration

CNS:

Central nervous system

Cp:

Plasma concentration

CYP:

Cytochrome P450

GI:

Gastrointestinal

K el :

Elimination rate

NOS:

Nitric oxide synthase (iNOS, inducible eNOS, endothelial, nNOS, neuronal)

NSAIDs:

Non-steroidal anti-inflammatory drugs

NS-NSAIDs:

Non-selective NSAIDs, i.e. those with approximately equivalent COX-1 and COX-2 inhibitory effects

OR:

Odds ratios

OTC:

Over-the-counter, non-prescription

PMNs:

Polymorphonuclear leucocyte

Rac-:

Racemic

tNSAIDs:

traditional NSAIDs, e.g. aspirin, ibuprofen, naproxen

t 1/2 :

Half-time of elimination

T max :

Time of maximal concentration

UDP:

Uridine diphosphate

V D :

Volume of distribution

References

  1. Aabakken L, Dybdahl JH, Eidsaunet W, Haaland A, Larsen S, Osnes M (1989) Optimal assessment of gastrointestinal side effects induced by non-steroidal anti-inflammatory drugs. Endoscopic lesions, faecal blood loss, and symptoms not necessarily correlated, as observed after naproxen and oxindanac in healthy volunteers. Scand J Gastroenterol 24:1007–1013

    CAS  PubMed  Article  Google Scholar 

  2. Aeberhard EE, Henderson SA, Arabolos NS, Griscavage JM, Castro FE, Barrett CT, Ignarro LJ (1995) Nonsteroidal anti-inflammatory drugs inhibit expression of the inducible nitric oxide synthase gene. Biochem Biophys Res Commun 208:1053–1059

    CAS  PubMed  Article  Google Scholar 

  3. Aiba T, Tse MM, Lin ET, Koizumi T (1999) Effect of dosage form on stereoisomeric inversion of ibuprofen in volunteers. Biol Pharm Bull 22:616–622

    CAS  PubMed  Google Scholar 

  4. Akbulut H, Celik I, Ayar A, Vural P, Canbaz M (2005) Ibuprofen reduces plasma nitrite/nitrate levels in a rabbit model of endotoxin shock. Neuro Endocrinol Lett 26:407–412

    CAS  PubMed  Google Scholar 

  5. Albert KS, Gernaat CM (1984) Pharmacokinetics of ibuprofen. Am J Med 77(1A):40–46

    CAS  PubMed  Google Scholar 

  6. Altman RD (1984) Review of ibuprofen for osteoarthritis. Am J Med 77(1A):10–18

    CAS  PubMed  Google Scholar 

  7. Amdekar YK, Desai RZ (1985) Antipyretic activity of ibuprofen and paracetamol in children with pyrexia. Br J Clin Pract 39:140–143

    CAS  PubMed  Google Scholar 

  8. American College of Rheumatology, Hotline (2005) The Safety of COX-2 Inhibitors. Deliberations from the February 16–18, 2005, FDA Meeting. www.rheumatology.org/publications/hotline/0305COX2.asp?aud+mem [accessed 16/01/2007]

  9. Angst MS, Clark JD, Carvalho B, Tingle M, Schmelz M, Yeomans DC (2008) Cytokine profile in human skin in response to experimental inflammation, noxious stimulation, and administration of a COX-inhibitor: a microdialysis study. Pain 139:15–27

    CAS  PubMed  Article  Google Scholar 

  10. Annequin D, Tourniaire B (2005) Migraine and headache in childhood. Arch Pediatr 2:624–629

    Article  Google Scholar 

  11. Anonymous (2006) Pharmaceutical J 277:321

  12. Ansell BM (1973) Ibuprofen in the management of Still’s disease. Practitioner 211:659–663

    CAS  PubMed  Google Scholar 

  13. Ansell BM (1983) The medical management of chronic arthritis in childhood. Ann Acad Med Singapore 12:168–173

    CAS  PubMed  Google Scholar 

  14. Antman EM, Bennett JS, Daugherty A, Furberg C, Roberts H, Taubert KA, American Heart Association (2007) Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation 115:1634–1642

    PubMed  Article  Google Scholar 

  15. Arnaud A (1995) Allergy and intolerance to nonsteroidal anti-inflammatory agents. Clin Rev Allergy Immunol 13:245–251

    CAS  PubMed  Google Scholar 

  16. Arora S, Wagner JG, Herbert M (2007) Myth: parenteral ketorolac provides more effective analgesia than oral ibuprofen. CJEM 9:30–32

    PubMed  Google Scholar 

  17. Arranz I, Martin-Suarez A, Lanao JM, Mora F, Vazquez C, Escribano A, Juste M, Mercader J, Ripoll E (2003) Population pharmacokinetics of high dose ibuprofen in cystic fibrosis. Arch Dis Child 88:1128–1130

    CAS  PubMed  Article  Google Scholar 

  18. Arroyo M, Lanas A (2006) NSAID-induced gastrointestinal damage. Minerva Gastroenterol Dietol 52:249–259

    CAS  PubMed  Google Scholar 

  19. Asanuma M, Nishibayashi-Asanuma S, Miyazaki I, Kohno M, Ogawa N (2001) Neuroprotective effects of non-steroidal anti-inflammatory drugs by direct scavenging of nitric oxide radicals. J Neurochem 76:1895–1904

    CAS  PubMed  Article  Google Scholar 

  20. Ashraf E, Cooper S, Kellstein D, Jayawardena S (2001) Safety profile of non-prescription ibuprofen in the elderly osteoarthritic patient: a meta-analysis. Inflammopharmacology 9:35–41

    CAS  Article  Google Scholar 

  21. Ashraf E, Ford L, Geetha R, Cooper S (1999) Safety profile of ibuprofen suspension in young children. Inflammopharmacology 7:219–225

    CAS  PubMed  Article  Google Scholar 

  22. Autret-Leca E (2003) A general overview of the use of ibuprofen in paediatrics. Int J Clin Pract Suppl (135):9–12

  23. Autret E, Breart G, Jonville AP, Courcier S, Lassale C, Goehrs JM (1994) Comparative efficacy and tolerance of ibuprofen syrup and acetaminophen syrup in children with pyrexia associated with infectious diseases and treated with antibiotics. Eur J Clin Pharmacol 46:197–201

    CAS  PubMed  Google Scholar 

  24. Autret E, Reboul-Marty J, Henry-Launois B, Laborde C, Courcier S, Goehrs JM, Languillat G, Launois R (1997) Evaluation of ibuprofen versus aspirin and paracetamol on efficacy and comfort in children with fever. Eur J Clin Pharmacol 51:367–371

    CAS  PubMed  Article  Google Scholar 

  25. Averbuch M, Katzper M (2000) A search for sex differences in response to analgesia. Arch Intern Med 160:3424–3428

    CAS  PubMed  Article  Google Scholar 

  26. Badin C, Chambrier C, Anouifi A, Boucaud C, Bouletreau P (1997) Non-steroidal anti-inflammatory agents and angiotensin converting enzyme inhibitor: a dangerous combination during postoperative period. Ann Fr Anesth Reanim 16:55–57

    Google Scholar 

  27. Bancos S, Bernard MP, Topham DJ, Phipps RP (2009) Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells. J Cell Immunol 258:18–28

    CAS  Article  Google Scholar 

  28. Bannwarth B, Berenbaum F (2005) Clinical pharmacology of lumiracoxib, a second-generation cyclooxygenase 2 selective inhibitor. Expert Opin Investig Drugs 14:521–533

    CAS  PubMed  Article  Google Scholar 

  29. Bannwarth B, Bérenbaum F (2007) Lumiracoxib in the management of osteoarthritis and acute pain. Expert Opin Pharmacother 8:1551–1564

    CAS  PubMed  Article  Google Scholar 

  30. Bannwarth B, Lapicque F, Pehourcq F, Gillet P, Schaeverbeke T, Laborde C, Dehais J, Gaucher A, Netter P (1995) Stereoselective disposition of ibuprofen enantiomers in human cerebrospinal fluid. Br J Clin Pharmacol 40:266–269

    CAS  PubMed  Google Scholar 

  31. Barclay L (2005) Platelet function may normalize by 24 hours after last ibuprofen dose. Medscape Medical News. www.medscape.com/viewarticle/502566?src=mp [accessed 15/04/2005]

  32. Beaver W (2003) Review of the analgesic efficacy of ibuprofen. Intl J Clin Pract S135:13–17

    Google Scholar 

  33. Bennett WM (1997) Drug interactions and consequences of sodium restriction. Am J Clin Nutr 65:678S–681S

    CAS  PubMed  Google Scholar 

  34. Bergmann JF, Chassany O, Geneve J, Abiteboul M, Caulin C, Segrestaa JM (1992) Enodoscopic evaluation of the effect of ketoprofen, ibuprofen and aspirin on the gastroduodenal mucosa. Eur J Clin Pharmacol 42:685–688

    CAS  PubMed  Article  Google Scholar 

  35. Bernhardt MK, Southard KA, Batterson KD, Logan HL, Baker KA, Jakobsen JR (2001) The effect of preemptive and/or postoperative ibuprofen therapy for orthodontic pain. Am J Orthod Dentofacial Orthop 120:20–27

    CAS  PubMed  Article  Google Scholar 

  36. Bertin L, Pons G, d’Athis P, Lasfargues G, Maudelonde C, Duhamel JF, Olive G (1991) Randomized, double-blind, multicenter, controlled trial of ibuprofen versus acetaminophen (paracetamol) and placebo for treatment of symptoms of tonsillitis and pharyngitis in children. J Pediatr 119:811–814

    CAS  PubMed  Article  Google Scholar 

  37. Bertin L, Pons G, d’Athis P, Duhamel JF, Maudelonde C, Lasfargues G, Guillot M, Marsac A, Debregeas B, Olive G (1996) A randomized, double-blind, multicentre controlled trial of ibuprofen versus acetaminophen and placebo for symptoms of acute otitis media in children. Fundam Clin Pharmacol 10:387–392

    CAS  PubMed  Article  Google Scholar 

  38. Bigby M, Stern R (1985) Cutaneous reactions to nonsteroidal anti-inflammatory drugs. A review. J Am Acad Dermatol 12:866–876

    CAS  Article  Google Scholar 

  39. Bird SE, Williams K, Kula K (2007) Preoperative acetaminophen vs ibuprofen for control of pain after orthodontic separator placement. Am J Orthod Dentofacial Orthop 132(4):504–510

    PubMed  Article  Google Scholar 

  40. Biskupiak JE, Brixner DI, Howard K, Oderda GM (2006) Gastrointestinal complications of over-the-counter nonsteroidal anti-inflammatory drugs. J Pain Palliat Care Pharmacother 20:7–14

    PubMed  Article  Google Scholar 

  41. Bjarnason I (2007) Ibuprofen and gastrointestinal safety: a dose-duration-dependent phenomena. J R Soc Med 100(Suppl 48):10–13

    Google Scholar 

  42. Bjarnason I, Bissoli F, Conforti A, Maiden L, Moore N, Moretti U, Rainsford KD, Takeuchi K, Velo GP (2005) Adverse reactions and their mechanisms from nimesulide. In: Rainsford KD (ed) Nimesulide. Actions and uses. Birkhäuser, Basel, pp 315–415

    Google Scholar 

  43. Bjarnason I, Scarpignato C, Takeuchi K, Rainsford KD (2007) Determinants of the short-term gastric damage caused by NSAIDs in man. Aliment Pharmacol Ther 26:95–106

    CAS  PubMed  Google Scholar 

  44. Björkman R, Hallman KM, Hedner J, Hedner T, Henning M (1996) Nonsteroidal antiinflammatory drug modulation of behavioral responses to intrathecal N-methyl-d-aspartate, but not to substance P and amino-methyl-isoxazole-propionic acid in the rat. J Clin Pharmacol 36(Suppl 12):20S–26S

    PubMed  Google Scholar 

  45. Blain H, Boileau C, Lapicque F, Nédélec E, Loeuille D, Guillaume C, Gaucher A, Jeandel C, Netter P, Jouzeau JY (2002) Limitation of the in vitro whole blood assay for predicting the COX selectivity of NSAIDs in clinical use. Br J Clin Pharmacol 53:255–265

    CAS  PubMed  Article  Google Scholar 

  46. Bliddal H, Rosetzsky A, Schlichting P, Weidner MS, Andersen LA, Ibfelt HH, Christensen K, Jensen ON, Barslev J (2000) A randomized, placebo-controlled, cross-over study of ginger extracts and ibuprofen in osteoarthritis. Osteoarthr Cartil 8:9–12

    CAS  PubMed  Article  Google Scholar 

  47. Blot WJ, McLaughlin JK (2000) Over the counter non-steroidal anti-inflammatory drugs and risk of gastrointestinal bleeding. J Epidemiol Biostat 5:137–142

    CAS  PubMed  Google Scholar 

  48. Boardman PL, Nuki G, Hart FD (1967) Ibuprofen in the treatment of rheumatoid arthritis and osteo-arthritis. Ann Rheum Dis 26:560–561

    CAS  PubMed  Article  Google Scholar 

  49. Body R, Potier K (2004) Best evidence topic report. Non-steroidal anti-inflammatory drugs and exacerbations of asthma in children. Emerg Med J 21:713–714

    PubMed  Article  Google Scholar 

  50. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ, VIGOR Study Group (2000) Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR study group. N Engl J Med 343:1520–1528

    CAS  PubMed  Article  Google Scholar 

  51. Boneberg EM, Zou M-H, Ullrich V (1996) Inhibition of cyclooxygenase-1 and -2 by R(−) and S(+)-ibuprofen. J Clin Pharmacol 36:16S–19S

    CAS  PubMed  Google Scholar 

  52. Boureau F (1998) Multicentre study of the efficacy of ibuprofen compared with paracetamol in throat pain associated with tonsillitis. In: Rainsford KD, Powanda MC (eds) Safety and efficacy of non-prescription (OTC) analgesics and NSAIDs. Kluwer, Dordrecht, pp 119–121

    Google Scholar 

  53. Boureau F, Schneid H, Zeghari N, Wall R, Bourgeois P (2004) The IPSO study: ibuprofen, paracetamol study in osteoarthritis. A randomised comparative clinical study comparing the efficacy and safety of ibuprofen and paracetamol analgesic treatment of osteoarthritis of the knee or hip. Ann Rheum Dis 63:1028–1034

    CAS  PubMed  Article  Google Scholar 

  54. Bradley JD, Brandt KD, Katz BP, Kalasinski LA, Ryan SI (1991) Comparison of an anti-inflammatory dose of ibuprofen, an analgesic dose of ibuprofen and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Engl J Med 325:87–91

    CAS  PubMed  Google Scholar 

  55. Bradley JD, Brandt KD, Katz BP, Kalasinski LA, Ryan SI (1992) Treatment of knee osteoarthritis: relationship of clinical features of joint inflammation to the response to a nonsteroidal anti-inflammatory drug or pure analgesic. J Rheumatol 19:1950–1954

    CAS  PubMed  Google Scholar 

  56. Bradley JD, Katz BP, Brandt KD (2001) Severity of knee pain does not predict a better response to an anti-inflammatory dose of ibuprofen than to analgesic therapy in patients with osteoarthritis. J Rheumatol 28:1073–1076

    CAS  PubMed  Google Scholar 

  57. Bradley RL, Ellis PE, Thomas P, Bellis H, Ireland AJ, Sandy JR (2007) A randomized clinical trial comparing the efficacy of ibuprofen and paracetamol in the control of orthodontic pain. Am J Orthod Dentofacial Orthop 132:511–517

    PubMed  Article  Google Scholar 

  58. Brater DC (1998) Renal safety of ibuprofen: pharmacokinetic aspects. In: Rainsford KD, Powanda MC (eds) Safety and efficacy of non-prescription (OTC) analgesics and NSAIDs. Kluwer, Dordrecht, pp 73–76

    Google Scholar 

  59. Breyer M (1999) Editorial. COX2 selective NSAIDs and renal function: gain without pain? Kidney Int 55:738–739

    CAS  PubMed  Article  Google Scholar 

  60. Beyth RJ, Shorr RI (1999) Epidemiology of adverse drug reactions in the elderly by drug class. Drugs Aging 14:231–239

    CAS  PubMed  Article  Google Scholar 

  61. Brocks D, Jamali F (1999) The pharmacokinetics of ibuprofen in humans and animals. In: Rainsford KD (ed) Ibuprofen. A critical bibliographic review. Taylor & Francis, London, pp 89–142

    Google Scholar 

  62. Brooks CD, Schlagel CA, Sekhar NC, Sobota JT (1973) Tolerance and pharmacology of ibuprofen. Curr Ther Res Clin Exp 15:180–190

    CAS  PubMed  Google Scholar 

  63. Brooks P, Emery P, Evans JF, Fenner H, Hawkey CJ, Patrono C, Smolen J, Breedveld F, Day R, Dougados M, Ehrich EW, Gijon-Baños J, Kvien TK, Van Rijswijk MH, Warner T, Zeidler H (1999) Interpreting the clinical significance of the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2. Rheumatology (Oxford) 38:779–788

    CAS  Article  Google Scholar 

  64. Brown RD, Wilson JT, Kearns GL, Eichler VF, Johnson VA, Bertrand KM (1992) Single-dose pharmacokinetics of ibuprofen and acetaminophen in febrile children. J Clin Pharmacol 32(3):231–241

    CAS  PubMed  Google Scholar 

  65. Brune K, Fenner H, Kurowski M, Lanz R, Members of the SPALA Group (1992) Adverse reactions to NSAIDs: consecutive evaluation of 30, 000 patients in rheumatology. In: Rainsford KD, Velo GP (eds) Side-effects of anti-inflammatory drugs 3. Kluwer, Dordrecht, pp 33–42

    Google Scholar 

  66. Buchanan WW (1990) Implications of NSAID therapy in elderly patients. J Rheumatol 17:29–32

    Google Scholar 

  67. Buchanan WW, Kean WP (2002) Osteoarthritis: clinical therapeutic trials and treatment. Inflammopharmacology 10:79–155

    CAS  Article  Google Scholar 

  68. Buckler JW, Hall JE, Rees JA, Sheldrake FE, Miller AC (1975) The tolerance and acceptability of ibuprofen (‘Brufen’) in the elderly patient. Curr Med Res Opin 3:558

    Google Scholar 

  69. Burian M, Geisslinger G (2005) COX-dependent mechanisms involved in the antinociceptive action of NSAIDs at central and peripheral sites. Pharmacol Therap 107:139–154

    CAS  Article  Google Scholar 

  70. Cameron RG, Feuer G, de la Iglesia FA (eds) (1996) Drug-induced hepatotoxicity. Handbook of experimental pharmacology, vol 121. Springer, Berlin

  71. Carmichael J, Shankel SW (1985) Effects of non-steroidal anti-inflammatory drugs on prostaglandins and renal function. Am J Med 78:992–1000

    CAS  PubMed  Article  Google Scholar 

  72. Castellani S, Ungar A, LaCava G, Cantini C, Stefanile C, Camaiti A, Messeri G, Coppo M, Vallotti B, DiSerio C, Brocchi A, Masotti G (1997) Renal adaptation to stress: a possible role of endothelin release and prostaglandin modulation in human subjects. J Lab Clin Med 129:462–469

    CAS  PubMed  Article  Google Scholar 

  73. Castillo M, Lam YW, Dooley MA, Stahl E, Smith PC (1995) Disposition and covalent binding of ibuprofen and its acyl glucuronide in the elderly. Clin Pharmacol Ther 57:636–644

    CAS  PubMed  Article  Google Scholar 

  74. Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, Vyas SN, FitzGerald GA (2001) Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 345:1809–1817

    CAS  PubMed  Article  Google Scholar 

  75. Cazanave S, Vadrot N, Tinel M, Berson A, Lettéron P, Larosche I, Descatoire V, Feldmann G, Robin MA, Pessayre D (2008) Ibuprofen administration attenuates serum TNF-alpha levels, hepatic glutathione depletion, hepatic apoptosis and mouse mortality after Fas stimulation. Toxicol Appl Pharmacol 231:336–343

    CAS  PubMed  Article  Google Scholar 

  76. Chan SCH, Shum DKY, Tipoe GL, Mak JCW, Leung ETM, Ip MSM (2008) Upregulation of ICAM-1 expression in bronchial epithelial cells by airway secretions in bronchiectasis. Resp Med 102:287–298

    Article  Google Scholar 

  77. Chang CY, Schiano TD (2007) Review article: drug hepatotoxicity. Aliment Pharmacol Ther 25:1135–1151

    CAS  PubMed  Article  Google Scholar 

  78. Chen CY, Chen CS (1995) Stereoselective disposition of ibuprofen in patients with compromised renal haemodynamics. Br J Clin Pharmacol 40:67–72

    CAS  PubMed  Google Scholar 

  79. Chen CY, Pang VF, Chen SS (1994) Assessment of ibuprofen-asociated nephrotoxicity in renal dysfunction. J Pharmacol Exp Ther 270:1307

    CAS  PubMed  Google Scholar 

  80. Cheng H, Rogers JD, Demetriades JL, Holland SD, Seibold JR, Depuy E (1994) Pharmacokinetics and bioinversion of ibuprofen enantiomers in humans. Pharm Res 11:824–830.

    Google Scholar 

  81. Cheruvallath VK, Riley CM, Narayanan SR, Lindenbaum S, Perrin JH (1997) A quantitative circular dichroic investigation of the binding of the enantiomers of ibuprofen and naproxen to human serum albumin. J Pharm Biomed Anal 15:1719–1724

    CAS  PubMed  Article  Google Scholar 

  82. Cheung R, Krishnaswami S, Kowalski K (2007) Analgesic efficacy of celecoxib in postoperative oral surgery pain: a single-dose, two-center, randomized, double-blind, active- and placebo-controlled study. Clin Ther 29(Suppl):2498–2510

    CAS  PubMed  Article  Google Scholar 

  83. Clark E, Plint AC, Correll R, Gaboury I, Passi B (2007) A randomized, controlled trial of acetaminophen, ibuprofen, and codeine for acute pain relief in children with musculoskeletal trauma. Pediatrics 119:460–467 Erratum in: Pediatrics 119(6):1271

    PubMed  Article  Google Scholar 

  84. Cook ME, Wallin JD, Thakur VD, Kadowitz PJ, McNamara DB, Garcia MM, Lipani JA, Poland M (1997) Comparative effects of nabumetone, sulindac, and ibuprofen on renal function. J Rheumatol 24:1137–1144

    CAS  PubMed  Google Scholar 

  85. Costa D, Moutinho L, Lima JLFC, Fernandes E (2006) Antioxidant activity and inhibition of human neutrophil oxidative burst by arylpropionic acid non-steroidal anti-inflammatory drugs. Biol Pharmaceut Bull 29:1659–1670

    CAS  Article  Google Scholar 

  86. Cox SR, Gall EP, Forbes KK, Gresham M, Goris G (1991) Pharmacokinetics of the R(−) and S(+) enantiomers of ibuprofen in the serum and synovial fluid of arthritis patients. J Clin Pharmacol 31:88–94

    CAS  PubMed  Google Scholar 

  87. Crocetti M, Moghbeli N, Serwint J (2001) Fever phobia revisited: have parental misconceptions about fever changed in 20 years? Pediatrics 107:1241–1246

    CAS  PubMed  Article  Google Scholar 

  88. Cryer B, Berlin RG, Cooper SA, Hsu C, Wason S (2005) Double-blind, randomized, parallel, placebo-controlled study of ibuprofen effects on thromboxane B2 concentrations in aspirin-treated healthy adult volunteers. Clin Ther 27:185–191

    CAS  PubMed  Article  Google Scholar 

  89. Curtis JP, Krumholz HM (2004) The case for an adverse interaction between aspirin and non-steroidal anti-inflammatory drugs: is it time to believe the hype? J Am Coll Cardiol 43:991–993

    CAS  PubMed  Article  Google Scholar 

  90. Curtis JP, Wang Y, Portnay EL, Masoudi FA, Havranek EP, Krumholz HM (2003) Aspirin, ibuprofen, and mortality after myocardial infarction: retrospective cohort study. Br Med J 327:1322–1323

    Article  Google Scholar 

  91. Cryer B, Feldman M (1998) Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med 104:413–421

    CAS  PubMed  Article  Google Scholar 

  92. Cuvellier JC, Joriot S, Auvin S, Vallée L (2005) Traitement médicamenteux de l’accès migraineux chez l’enfant. [Pharmacologic treatment of acute migraine attack in children]. Arch Pediatr 12(3):316–325

    CAS  PubMed  Article  Google Scholar 

  93. Czaykowski D, Fratarcangelo P, Rosefsky J (1994) Evaluation of the antipyretic efficacy of single-dose ibuprofen suspension campared to acetaminophen elixir in febrile children. Pediatric Res 35:A141

    Google Scholar 

  94. Dalton JD Jr, Schweinle JE (2006) Randomized controlled noninferiority trial to compare extended release acetaminophen and ibuprofen for the treatment of ankle sprains. Ann Emerg Med 48:615–623

    PubMed  Article  Google Scholar 

  95. Damen L, Bruijn JK, Verhagen AP, Berger MY, Passchier J, Koes BW (2005) Symptomatic treatment of migraine in children: a systematic review of medication trials. Pediatrics 116:e295–e302

    PubMed  Article  Google Scholar 

  96. Dawood MY, Khan-Dawood FS (2007) Clinical efficacy and differential inhibition of menstrual fluid prostaglandin F2alpha in a randomized, double-blind, crossover treatment with placebo, acetaminophen, and ibuprofen in primary dysmenorrhea. Am J Obstet Gynecol 196:35.e1–35.e5

    Article  CAS  Google Scholar 

  97. Day RO, Graham GG, Williams KM (1988) Pharmacokinetics of non-steroidal anti-inflammatory drugs. Baillieres Clin Rheumatol 2(2):363–393

    CAS  PubMed  Article  Google Scholar 

  98. Day R, Morrison B, Luza A, Castaneda O, Strusberg A, Nahir M, Helgetveit KB, Kress B, Daniels B, Bolognese J, Krupa D, Seidenberg B, Ehrich E (2000) A randomized trial of the efficacy and tolerability of the COX-2 inhibitor rofecoxib vs ibuprofen in patients with osteoarthritis. Arch Intern Med 160:1781–1787

    CAS  PubMed  Article  Google Scholar 

  99. DeArmond B, Francisco CA, Lin JS, Huang FY, Halladay S, Bartziek RD, Skare KL (1995) Safety profile of over-the-counter naproxen sodium. Clin Ther 17:587–601

    CAS  PubMed  Article  Google Scholar 

  100. Debley JS, Carter ER, Gibson RL, Rosenfeld M, Redding GJ (2005) The prevalence of ibuprofen-sensitive asthma in children: a randomized controlled bronchoprovocation challenge study. J Pediatr 147:233–238

    PubMed  Article  Google Scholar 

  101. Deodhar SD, Dick WC, Hodgkinson R, Buchanan WW (1973) Measurement of clinical response to anti-inflammatory drug therapy in rheumatoid arthritis. Q J Med 166:387–401 New Series

    Google Scholar 

  102. Derry C, Derry S, Moore RA, McQuay HJ (2009) Single dose oral ibuprofen for acutepostoperative pain in adults. Cochrane Database Syst Rev 8(3):CD001548

    Google Scholar 

  103. Desai PR, Sriskandan S (2003) Hypothermia in a child secondary to ibuprofen. Arch Dis Child 88:87–88

    CAS  PubMed  Article  Google Scholar 

  104. de Weck AL, Gamboa PM, Esparza R, Sanz ML (2006) Hypersensitivity to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Curr Pharm Des 12:3347–3358

    PubMed  Article  Google Scholar 

  105. Dieppe PA, Harkness JAL, Higgs ER (1989) Osteoarthritis. In: Wall PD, Melzack R (eds) Textbook of Pain, 2nd edn. Churchill-Livingstone, Edinburgh, pp 306–326

    Google Scholar 

  106. Díez-Domingo J, Planelles MV, Baldo JM, Ballester A, Nunez F, Jubert A, Domínguez Granados R (1998) Ibuprofen prophylaxis fro adverse reactions to diphtheria-tetanus-pertussis vaccination: A randomised trial. Curr Ther Res – Clin Expt 59:588–597

    Google Scholar 

  107. Ding G, Liu Y, Sun J, Takeuchi Y, Toda T, Hayakawa T, Fukushima S, Kishimoto S, Lin W, Inotsume N (2007) Effect of absorption rate on pharmacokinetics of ibuprofen in relation to chiral inversion in humans. J Pharm Pharmacol 59:1509–1513

    PubMed  Article  CAS  Google Scholar 

  108. Dionne RA (1998) Evaluation and analgesic mechanisms and NSAIDs for acute pain using the oral surgery model. In: Rainsford KD, Powanda MC (eds) Safety and efficacy of non-prescription (OTC) analgesics and NSAIDs. Kluwer, Dordrecht, pp 105–117

    Google Scholar 

  109. Dionne RA, Cooper SA (1999) Use of ibuprofen in dentistry. In: Rainsford KD (ed) Ibuprofen. A Critical bibliographic review. Taylor & Francis, London, pp 409–430

    Google Scholar 

  110. Dionne RA, McCullagh L (1998) Enhanced analgesia and suppression of plasma β-endorphin by the S(+)-isomer of ibuprofen. Clin Pharmacol Ther 63:694–701

    CAS  PubMed  Article  Google Scholar 

  111. Długosz CK, Chater RW, Engle JP (2006) Appropriate use of nonprescription analgesics in pediatric patients. J Pediatr Health Care 20:316–325

    PubMed  Article  Google Scholar 

  112. Dong JQ, Ni L, Scott CS, Retsch-Bogart GZ, Smith PC (2000) Pharmacokinetics of ibuprofen enantiomers in children with cystic fibrosis. J Clin Pharmacol 40(8):861–868

    CAS  PubMed  Article  Google Scholar 

  113. Downing A, Jacobsen J, Sorensen HT, McLaughlin JK, Johnsen SP (2006) Risk of hospitalization for angio-oedema among users of newer COX-2 selective inhibitors and other nonsteroidal anti-inflammatory drugs. Br J Clin Pharmacol 62:496–501

    CAS  PubMed  Article  Google Scholar 

  114. Doyle G, Furey S, Berlin R, Cooper S, Jayawardena S, Ashraf E, Baird L (1999) Gastrointestinal safety and tolerance of ibuprofen at maximum over-the-counter dose. Aliment Pharmacol Ther 13:897–906

    CAS  PubMed  Article  Google Scholar 

  115. Doyle G, Jayawardena S, Ashraf E, Cooper SA (2002) Efficacy and tolerability of nonprescription ibuprofen versus celecoxib for dental pain. J Clin Pharmacol 42:912–919

    CAS  PubMed  Article  Google Scholar 

  116. Dunn MJ, Scharschmidt L, Zambraski E (1984) Mechanisms of nephrotoxicity if non-steroidal anti-inflammatory drugs. Arch Toxicol 7:328–337

    CAS  Google Scholar 

  117. Eccles R (2006) Efficacy and safety of over-the-counter analgesics in the treatment of common cold and flu. J Clin Pharm Ther 31:309–319

    CAS  PubMed  Article  Google Scholar 

  118. Edwards JE, Moore RA, McQuay HJ (2004) Individual patient meta-analysis of single-dose rofecoxib in postoperative pain. BMC Anesthesiol 4:1–10

    Article  Google Scholar 

  119. Eller MG, Wright C, Della-Coletta AA III (1989) Absorption kinetics of rectally and orally administered ibuprofen. Biopharm Drug Disp 10:269–278

    CAS  Article  Google Scholar 

  120. Ellison J, Dager W (2007) Recent FDA warning of the concomitant use of aspirin and ibuprofen and the effects on platelet aggregation. Prev Cardiol 10:61–63

    CAS  PubMed  Article  Google Scholar 

  121. Eustace N, Hare B (2007) Use of nonsteroidal anti-inflammatory drugs in infants. A survey of members of the Association of Paediatric Anaesthetists of Great Britain and Ireland. Paediatr Anaesth 17:464–469

    PubMed  Article  Google Scholar 

  122. Evans AM, Nation RL, Sansom LN, Bochner F, Somogyi AA (1990) The relationship between the pharmacokinetics of ibuprofen enantiomers and the dose of racemic ibuprofen in humans. Biopharm Drug Dispos 11:507–518

    CAS  PubMed  Article  Google Scholar 

  123. Farkouh ME, Kirshner H, Harrington RA, Ruland S, Verheugt FWA, Schnitzer TJ, Burmester GR, Mysler E, Hochberg MC, Doherty M, Ehrsam E, Gitton X, Krammer G, Mellein B, Gimona A, Matchaba P, Hawkey CJ, Chesebro JH (2004) Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet 364:675–684

    CAS  PubMed  Article  Google Scholar 

  124. Farkouh ME, Greenberg JD, Jeger RV, Ramanathan K, Verheugt FWA, Chesebro JH, Kirshner H, Hochman JS, Lay CL, Mellein B, Matchaba PT, Fuster V, Abramson SB (2009) Cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib. Ann Rheum Dis 66:764–770

    Article  CAS  Google Scholar 

  125. Farquhar WB, Kenney WL (1999) Age and renal prostaglandin inhibition during exercise and heat stress. J Appl Physiol 86:1936–1943

    CAS  PubMed  Google Scholar 

  126. Farquhar WB, Morgan AL, Zambraski EJ, Kenney WL (1999) Effects of acetaminophen and ibuprofen on renal function in the stressed kidney. J Appl Physiol 86:598–604

    CAS  PubMed  Google Scholar 

  127. Fendrick AM, Pan DE, Johnson GE (2008) OTC analgesics and drug interactions:clinical implications. Osteopath Med Prim Care 2:2–6

    PubMed  Article  Google Scholar 

  128. Florence AT, Attwood D (1998) Physicochemical principles in pharmacy, 3rd edn. Macmillan Press, Houndmills Basingstoke, pp 441–446

    Google Scholar 

  129. Fowler CJ, Naidu PS, Lichtman A, Onnis V (2009) The case for the development of novel analgesic agents targeting both fatty acid amide hydrolase and either cyclooxygenase or TRPV1. Br J Pharmacol 156:412–419

    CAS  PubMed  Article  Google Scholar 

  130. Freis JF, Williams CA, Bloch DA (1991) The relative toxicity of nonsteroidal antiinflammatory drugs. Arth Rheum 34:1353–1360

    Google Scholar 

  131. Friedman H, Seckman C, Lanza F, Royer G, Perry K, Francom S (1990) Clinical pharmacology of predisintegrated ibuprofen 800 mg tablets: an endoscopic and pharmacokinetic study. J Clin Pharmacol 30:57–63

    CAS  PubMed  Google Scholar 

  132. Furey SA, Vargas R, McMahon FG (1993) Renovascular effects of non-prescription ibuprofen in elderly hypertensive patients with mild renal impairment. Pharmacotherapy 13:143–148

    CAS  PubMed  Google Scholar 

  133. Furst DE (1992) Toxicity of antirheumatic medications in children with juvenile arthritis. J Rheumatol Suppl 33:11–15

    CAS  PubMed  Google Scholar 

  134. Gallo JM, Gall EP, Gillespie WR, Albert KS, Perrier D (1986) Ibuprofen kinetics inplasma and synovial fluid of arthritic patients. J Clin Pharmacol 26(1):65–70

    CAS  PubMed  Google Scholar 

  135. Gallego-Sandin S, Novalbos J, Rosado A, Gisbert JP, Galvez-Mugica M-A, Garcia AG, Pajares JM, Abad-Santos F (2004) Effect of ibuprofen on cyclooxygenase and nitric oxide synthase of gastric mucosa: correlation with endoscopic lesions and adverse reactions. Dig Dis Sci 49:1538–1544

    CAS  PubMed  Article  Google Scholar 

  136. Galzin M, Brunet P, Burtey S, Dussol B, Berland Y (1997) Tubular necrosis after non-steroidal anti-inflammatory agents and acute alcoholic intoxication. Nephrologie 18:113–115

    CAS  PubMed  Google Scholar 

  137. Garcia-Rodriguez LA, Hernandez-Diaz S (2001) The risk of upper gastrointestinal complications associated with nonsteroidal anti-inflammatory drugs, glucocorticoids, acetaminophen, and combinations of these agents. Arthritis Res 3:98–101

    CAS  PubMed  Article  Google Scholar 

  138. Garcia Rodriguez LA, Varas-Lorenzo C, Maguire A, Gonzalez-Perez A (2004) Nonsteroidal antiinflammatory drugs and the risk of myocardial infarction in the general population. Circulation 109:3000–3006

    CAS  PubMed  Article  Google Scholar 

  139. Gaziano JM, Gibson CM (2006) Potential for drug-drug interactions in patients taking analgesics for mild-to-moderate pain and low-dose aspirin for cardioprotection. Am J Cardiol 97(9A):23–29

    PubMed  Article  Google Scholar 

  140. Geisslinger G, Dietzel K, Bezler H, Nuernberg B, Brune K (1989) Therapeutically relevant differences in the pharmacokinetical and pharmaceutical behavior of ibuprofen lysinate as compared to ibuprofen acid. Int J Clin Pharmacol Ther Toxicol 27:324–328

    CAS  PubMed  Google Scholar 

  141. Geisslinger G, Schuster O, Stock KP, Loew D, Bach GL, Brune K (1990) Pharmacokinetics of S(+)- and R(−)-ibuprofen in volunteers and first clinical experience of S(+)-ibuprofen in rheumatoid arthritis. Eur J Clin Pharmacol 38:493–497

    CAS  PubMed  Article  Google Scholar 

  142. Geisslinger G, Stock KP, Loew D, Bach GL, Brune K (1993) Variability in the stereoselective disposition of ibuprofen in patients with rheumatoid arthritis. Br J Clin Pharmacol 35:603–607

    CAS  PubMed  Google Scholar 

  143. Géraud G, Lantéri-Minet M, Lucas C, Valade D, French Society for the Study of Migraine Headache (SFEMC) (2004) French guidelines for the diagnosis and management of migraine in adults and children. Clin Ther. 26:1305–1318

    PubMed  Article  Google Scholar 

  144. Geusens P, Lems W (2008) Efficacy and tolerability of lumiracoxib, a highly selective cyclo-oxygenase-2 (COX2) inhibitor, in the management of pain and osteoarthritis. Ther Clin Risk Manag 4:337–344

    CAS  PubMed  Google Scholar 

  145. Giannini EH, Brewer EJ, Miller ML, Gibbas D, Passo MH, Hoyeraal HM, Bernstein B, Person DA, Fink CW (1990) Ibuprofen suspension in the treatment of juvenile rheumatoid arthritis. Pediatric rheumatology collaborative study group. J Pediatr 117:645–652

    CAS  PubMed  Article  Google Scholar 

  146. Gierse JK, Koboldt CM, Walker MC, Seibert K, Isakson PC (1999) Kinetic basis for selective inhibition of cyclo-oxygenases. Biochem J 339:607–614

    CAS  PubMed  Article  Google Scholar 

  147. Glass RC, Swannell AJ (1978) Concentrations of ibuprofen in serum and synovial fluid from patients with arthritis. Br J Clin Pharmacol 6:453P–454P

    CAS  PubMed  Google Scholar 

  148. Glowka FK (2000) Stereoselective pharmacokinetics of ibuprofen and its lysinate from suppositories in rabbits. Int J Pharm 199:159–166

    CAS  PubMed  Article  Google Scholar 

  149. Gomez PF, Pillinger MH, Attur M, Marjanovic N, Dave M, Park J, Bingham CO III, Al-Mussair H, Abramson SB (2005) Resolution of inflammation: Prostaglandin E2 dissociates nuclear trafficking of individual NF-κB subunits (p65, p50) in stimulated rheumatoid synovial fibroblasts. J Immunol 175:6924–6930

    CAS  PubMed  Google Scholar 

  150. Graham GG, Hicks M (2004) Pharmacokinetics and metabolism of paracetamol (acetaminophen). In: Rainsford KD (ed) Aspirin and related drugs. Taylor & Francis, London, pp 182–213

    Google Scholar 

  151. Graham GG, Williams KM (2004) Metabolism and pharmacokinetics of ibuprofen. In: Rainsford KD (ed) Aspirin and related drugs. Taylor & Francis, London, pp 157–180

    Google Scholar 

  152. Graham GG, Roberts MS, Day RO, Rainsford KD (2004) Pharmacokinetics and metabolism of the salicylates. In: Rainsford KD (ed) Aspirin and related drugs. Taylor & Francis, London, pp 97–155

    Google Scholar 

  153. Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, Shoor S, Ray WA (2005) Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 365:475–481

    CAS  PubMed  Google Scholar 

  154. Grennan DM, Ferry DG, Ashworth ME, Kenny RE, Mackinnon M (1979) The aspirin-ibuprofen interaction in rheumatoid arthritis. Br J Clin Pharmacol 8:497–503

    CAS  PubMed  Google Scholar 

  155. Griffin MR (1998) Epidemiology of nonsteroidal anti-inflammatory drug-associated gastrointestinal injury. Am J Med 104(3A):23S–29S

    CAS  PubMed  Article  Google Scholar 

  156. Griffin MR, Yared A, Ray WA (2000) Nonsteroidal anti-inflammatory drugs and acute renal failure in elderly persons. Am J Epidemiol 15:488–496

    Google Scholar 

  157. Grimes DA, Hubacher D, Lopez LM, Schulz KF (2006) Non-steroidal anti-inflammatory drugs for heavy bleeding or pain associated with intrauterine-device use. Cochrane Database Syst Rev 18(4):CD006034

    Google Scholar 

  158. Gurwitz JH, Everitt DE, Monane M, Glynn RJ, Choodnovskiy I, Beaudet MP, Avorn J (1996) The impact of ibuprofen on the efficacy of antihypertensive treatment with hydrochlorothiazide in elderly persons. J Gerontol A Biol Sci Med Sci 51:M74–M79

    CAS  PubMed  Google Scholar 

  159. Haas M, Moolenaar F, Meijer DK, Jong PE, de Zeeuw D (1998) Renal targeting of a non-steroidal anti-inflammatory drug: effects on renal prostaglandin synthesis in the rat. Clin Sci 95:603–609

    CAS  PubMed  Article  Google Scholar 

  160. Haase W, Fischer M (1991) Statistical meta-analysis of multicenter clinical studies of ibuprofen with regard to cohort size. Z Rheumatol 50(Suppl 1):77–83

    PubMed  Google Scholar 

  161. Hage DS, Noctor TA, Wainer IW (1995) Characterization of the protein binding of chiral drugs by high-performance affinity chromatography. Interactions of R- and S-ibuprofen with human serum albumin. J Chromatogr A 693:23–32

    CAS  PubMed  Article  Google Scholar 

  162. Halsas M, Hietala J, Veski P, Jürjenson H, Marvola M (1999) Morning versus evening dosing of ibuprofen using conventional and time-controlled release formulations. Int J Pharm 189:179–185

    CAS  PubMed  Article  Google Scholar 

  163. Hämäläinen ML, Hoppu K, Valkeila E, Santavuori P (1997) Ibuprofen or acetaminophen for the acute treatment of migraine in children: a double-blind, randomized, placebo-controlled, crossover study. Neurology 48(1):103–107

    PubMed  Google Scholar 

  164. Hamman MA, Thompson GA, Hall SD (1997) Regioselective and stereoselective metabolism of ibuprofen by human cytochrome P450 2C. Biochem Pharmacol 54:33–41

    CAS  PubMed  Article  Google Scholar 

  165. Hardy P, Abran D, Hou X, Lahaie I, Peri KG, Asselin P, Varma DR, Chemtob S (1998) A major role for prostacyclin in nitric oxide-induced ocular vasorelaxation in the piglet. Circ Res 83:721–729

    CAS  PubMed  Google Scholar 

  166. Hargreaves KM, Keiser K (2002) Development of new pain management strategies. J Dent Educ 66:113–121

    PubMed  Google Scholar 

  167. Harris RC, McKanna JA, Akai Y, Jacobson HR, Duboois RN, Breyer MD (1994) Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest 94:2504–2510

    CAS  PubMed  Article  Google Scholar 

  168. Haupt MT, Jastrmski MS, Clemmer TP, Metz CA, Goris GB (1991) Effect of ibuprofen in patients with severe sepsis: a randomized, double-blind, multicentre study. The ibuprofen study group. Crit Care Med 19:1339–1347

    CAS  PubMed  Article  Google Scholar 

  169. Hawton K, Townsend E, Deeks J, Appleby L, Gunnell D, Bennewith O, Cooper J (2001) Effects of legislation restricting pack sizes of paracetamol and salicylate on self poisoning in the United Kingdom: before and after study. Br Med J 322:1203–1207

    CAS  Article  Google Scholar 

  170. Hay AD, Redmond N, Fletcher M (2006) Antipyretic drugs for children. BMJ 333:4–5

    PubMed  Article  Google Scholar 

  171. Hay AD, Redmond NM, Costelloe C, Montgomery AA, Fletcher M, Hollinghurst S, Peters TJ (2009). Paracetamol and ibuprofen for the treatment of fever in children: the PITCH randomised controlled trial. Health Technol Assess. 13(27):iii–iv, ix–x, 1–163

    Google Scholar 

  172. Heard K, Green JL, Bailey JE, Bogden GM, Dart RC (2007) A randomized trial to determine the change in alanine aminotransferase during 10 days of paracetamol (acetaminophen) in subjects who consume moderate amount of alcohol. Aliment Pharmacol Ther 26:283–290

    CAS  PubMed  Article  Google Scholar 

  173. Henry D, McGettigan P (2003) Epidemiology overview of gastrointestinal and renal toxicity of NSAIDs. Intl J Clin Pract S135:43–49

    Google Scholar 

  174. Henry DA, Dobson A, Turner C (1993) Variability in the risk of major gastrointestinal complications from non-aspirin nonsteroidal anti-inflammatory drugs. Gastroenterology 105:1078–1088

    CAS  PubMed  Google Scholar 

  175. Henry D, Lim LL-Y, Garcia Rodriguez LA, Perez Gutthann S, Carson JL, Griffin M, Savage R, Logan R, Moride Y, Hawkey C et al (1996) Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. Br Med J 312:1563–1566

    CAS  Google Scholar 

  176. Henry D, Drew A, Beuzeville S (1998) Adverse drug reactions in the gastrointestinal system attributed to ibuprofen. In: Rainsford KD, Powanda MC (eds) Safety and efficacy of non-prescription (OTC) analgesics and NSAIDs. Kluwer, Dordrecht, pp 19–45

    Google Scholar 

  177. Heremans G, Dehaen F, Rom N, Ramet J, Verboven M, Loeb H (1988) A single-blind parallel group study investigating the antipyretic properties of ibuprofen syrup versus acetylsalicylic acid syrup in febrile children. Br J Clin Pract 42:245–247

    CAS  PubMed  Google Scholar 

  178. Hersh EV, Moore PA, Ross GL (2000a) Over-the-counter analgesics and antipyretics: a critical assessment. Clin Ther 22:500–548

    CAS  PubMed  Article  Google Scholar 

  179. Hersh EV, Levin LM, Cooper SA, Doyle G, Waksman J, Wedell D, Hong D, Secreto SA (2000b) Ibuprofen liquigel for oral surgery pain. Clin Ther 22:1306–1318

    CAS  PubMed  Article  Google Scholar 

  180. Hersh EV, Pinto A, Moore PA (2007) Adverse drug interactions involving common prescription and over-the-counter analgesic agents. Clin Ther 29(Suppl):2477–2497

    CAS  PubMed  Article  Google Scholar 

  181. Higton F (1999) The pharmaceutics of ibuprofen. In: Ibuprofen. A critical bibliographic review. Taylor & Francis, London, pp 53–86

  182. Hinz B, Brune K (2006) Antipyretic analgesics: nonsteroidal anti-inflammatory drugs, selective COX-2 inhibitors, paracetamol and pyrazolinones. In: Starke K (ed) Handbook of experimental pharmacology. Springer, Heidelberg, pp 65–93

    Google Scholar 

  183. Hippisley-Cox J, Coupland C (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. Br Med J 330:1366

    CAS  Article  Google Scholar 

  184. Hippisley-Cox J, Coupland C, Logan R (2005) Risk of adverse gastrointestinal outcomes in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case–control analysis. Br Med J 331:1310–1316

    CAS  Article  Google Scholar 

  185. Hofbauer R, Kaye AD, Moser D, Gmeiner B, Rasse M, Evans AM (2000) Frass M (2000) Stereoselective effects of ibuprofen anantiomers on leukocyte transmigration through endothelial cell monolayers. Inflammopharm 8:326–327

    Google Scholar 

  186. Hoffman M, Gray RG (1982) Ibuprofen-induced meningitis in mixed connective tissue disease. Clin Rheumatol 1:128–130

    CAS  PubMed  Article  Google Scholar 

  187. Hollingworth P (1993) The use of non-steroidal anti-inflammatory drugs in paediatric rheumatic diseases. Br J Rheumatol 32(1):73–77

    CAS  PubMed  Article  Google Scholar 

  188. Holt CI, Hutchins MO, Pileggi R (2005) A real time quantitative PCR analysis and correlation of COX-1 and COX-2 enzymes in inflamed dental pulps following administration of three different NSAIDs. J Endod 31:799–804

    PubMed  Article  Google Scholar 

  189. Hong Y, Gengo FM, Rainka MM, Bates VE, Mager DE (2008) Population pharmacodynamic modelling of aspirin- and ibuporfen-induced inhibition of platelet aggregation in healthy subjects. Clin Pharmacokinet 47:129–137

    CAS  PubMed  Article  Google Scholar 

  190. Huber MA, Terezhalmi GT (2006) The use of COX-2 inhibitors for acute dental pain. J Am Dent Assoc 137:480–487

    CAS  PubMed  Google Scholar 

  191. Hunt RH, Bowen B, Mortensen ER, Simon TJ, James C, Cagliola A, Quan H, Bolognese JA (2000) A randomized trial measuring foecal blood loss after treatment with rofecoxib, ibuprofen, or placebo in healthy subjects. Am J Med 109:201–206

    CAS  PubMed  Article  Google Scholar 

  192. Hynninen VV, Olkkola KT, Leino K, Lundgren S, Neuvonen PJ, Rane A, Valtonen M, Vyyryläinen H, Laine K (2006) Effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of S-(+)- and R-(−)-Ibuprofen. Antimicrob Agents Chemother 50:1967–1972

    CAS  PubMed  Article  Google Scholar 

  193. Ichihara A, Imig JD, Navar LG (1999) Cyclooxygenase-2 modulates afferent arteriolar responses to increases in pressure. Hypertension 34:843–847

    CAS  PubMed  Google Scholar 

  194. Inoue T, Mi Z, Gillesoie DG, Jackson EK (1998) Cyclooxygenase inhibition reveals synergistic action of vasoconstrictors on mesangial cell growth. Eur J Pharmacol 361:285–291

    CAS  PubMed  Article  Google Scholar 

  195. Ishiguro C, Fujita T, Omori T, Fujii Y, Mayama T, Sato T (2008) Assessing the effects of non-steroidal anti-inflammatory drugs on antihypertensive drug therapy using post-marketing surveillance database. J Epidemiol 18:119–124

    PubMed  Article  Google Scholar 

  196. Itoh T, Saura Y, Tsuda Y, Yamada H (1997) Stereoselectivity and enantiomer-enantiomer interactions in the binding of ibuprofen to human serum albumin. Chirality 9(7):643–649

    CAS  PubMed  Article  Google Scholar 

  197. Jackson LA, Dunstan M, Starkovich P, Dunn J, Yu O, Nelson JC, Rees T, Zavitkovsky A (2006) Prophylaxis with acetaminophen or ibuprofen for prevention of local reaction to the fifth diphtheria-tetanus toxoids-acellular pertussis vaccination: a randomized, controlled trial. Pediatrics 117:620–625

    PubMed  Article  Google Scholar 

  198. Jacqz-Aigrain E, Anderson BJ (2006) Pain control: non-steroidal anti-inflammatory agents. Semin Fetal Neonatal Med 11(4):251–259

    PubMed  Article  Google Scholar 

  199. Jamali F, Kunz-Dober CM (1999) Pain-mediated altered absorption and metabolism of ibuprofen: an explanation for decreases serum enantiomer concentration after dental surgery. Br J Clin Pharmacol 47:391–396

    CAS  PubMed  Article  Google Scholar 

  200. Jamali F, Singh NN, Pasutto FM, Russell AS, Coutts RT (1988) Pharmacokinetics of ibuprofen enantiomers in humans following oral administration of tablets with different absorption rates. Pharm Res 5:40–43

    CAS  PubMed  Article  Google Scholar 

  201. Jamali F, Mehvar R, Russell AS, Sattari S, Yakimets WW, Koo J (1992) Human pharmacokinetics of ibuprofen enantiomers following different doses and formulations: intestinal chiral inversion. J Pharm Sci 81:221–225

    CAS  PubMed  Article  Google Scholar 

  202. Jeffrey P, Tucker GT, Bye A, Crewe HK, Wright PA (1991) The site of inversion of R(−)-ibuprofen: studies using rat in situ isolated perfused intestine/liver preparations. J Pharm Pharmacol 43:715–720

    CAS  PubMed  Google Scholar 

  203. Jenkins C, Costello J, Hodge L (2004) Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. Br Med J 328:434

    CAS  Article  Google Scholar 

  204. Jick H, Kaye JA, Russmann S, Jick SS (2006) Nonsteroidal antiinflammatory drugs and acute myocardial infarction in patients with no major risk factors. Pharmacotherapy 26:1379–1387

    CAS  PubMed  Article  Google Scholar 

  205. Johnson AG, Nguyen TV, Day RO (1994) Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med 121:289–300

    CAS  PubMed  Google Scholar 

  206. Jüni P, Rutjes AWS, Dieppe PA (2002) Are selective COX-2 inhibitors superior to traditional nonsteroidal anti-inflammatory drugs. Br Med J 324:1287–1288

    Article  Google Scholar 

  207. Kahn LH, Styrt BA (1997) Necrotizing soft tissue infections reported with nonsteroidal antiinflammatory drugs. Ann Pharmacother 31:1034–1039

    CAS  PubMed  Google Scholar 

  208. Kandoth PW, Joshi MK, Joshi VR, Satoskar RS (1984) Comparative evaluation of antipyretic activity of ibuprofen and aspirin in children with pyrexia of varied aetiology. J Int Med Res 12:292–297

    CAS  PubMed  Google Scholar 

  209. Kanna D, Khanna PP, Durst DE (2005) COX-2 controversy: where are we and where do we go from here? Inflammopharmacology 13:395–402

    Article  Google Scholar 

  210. Kanabar D (2007) Ibuprofen and asthma in paediatric populations: clinical concern or clinical reality? J R Soc Med 100(Suppl 48):15–17

    PubMed  Google Scholar 

  211. Kargman S, Wong E, Greig GM, Falgueyret J-P, Cromlish W, Ethier D, Yergey JA, Riendeau D, Evans JF, Kennedy B, Tagari P, Francis DA, O’Neill GP (1996) Mechanism of selective inhibition of human prostaglandin G/H synthase-1 and -2 in intact cells. Biochem Pharmacol 52:1113–1125

    CAS  PubMed  Article  Google Scholar 

  212. Kauffman RE, Nelson MV (1992) Effect of age on ibuprofen pharmacokinetics and antipyretic response. J Pediatr 121(6):969–973

    CAS  PubMed  Article  Google Scholar 

  213. Kauffman RE, Sawyer LA, Scheinbaum ML (1992) Antipyretic efficacy of ibuprofen vs acetaminophen. Am J Dis Child 146:622–625

    CAS  PubMed  Google Scholar 

  214. Kaufman DW, Kelly JP, Sheehan JE, Laszlo A, Wiholm BE, Alfredsson L, Koft RS, Shapiro S (1993) Nonsteroidal anti-inflammatory drug use in relation to major gastrointestinal bleeding. Clin Pharmacol Ther 53:485–494

    CAS  PubMed  Google Scholar 

  215. Kawai S, Nishida S, Kato M, Furumaya Y, Okamoto R, Koshino T, Mizushima Y (1998) Comparison of cyclooxygenase-1 and -2 inhibitory activities of various nonsteroidal anti-inflammatory drugs using human platelets and synovial cells. Eur J Pharmacol 347:87–94

    CAS  PubMed  Article  Google Scholar 

  216. Kean WF, Buchanan WW (1987) Antirheumatic drug therapy in the elderly: a case of failure to identify the correct issues? J Am Geriatr Soc 35:363–364

    CAS  PubMed  Google Scholar 

  217. Kean WF, Buchanan WW, Rainsford KD (1999) Therapeutics of ibuprofen in rheumatic and other chronic and painful diseases. In: Rainsford KD (ed) Ibuprofen. A critical bibliographic review. Taylor & Francis, London, pp 279–353

    Google Scholar 

  218. Kean WF, Kean R, Buchanan WW (2004) Osteoarthritis: symptoms, signs and source of pain. Inflammopharmacology 12:3–31

    CAS  PubMed  Article  Google Scholar 

  219. Kean WF, Rainsford KD, Kean IRL (2008) Management of chronic musculoskeletal pain in the elderly: opinions on oral medication use. Inflammopharmacology 16:53–75

    CAS  PubMed  Article  Google Scholar 

  220. Kearns GL (1993) Hepatic drug metabolism in cystic fibrosis: recent developments and future directions. Ann Pharmacother 27(1):74–79

    CAS  PubMed  Google Scholar 

  221. Kearns GL, Reed MD (1989) Clinical pharmacokinetics in infants and children. A reappraisal. Clin Pharmacokinet 17(Suppl 1):29–67

    PubMed  Article  Google Scholar 

  222. Kellstein DE, Waksman JA, Furey SA, Binstok G, Cooper SA (1999) The safety profile of nonprescription ibuprofen in multiple-dose use: a meta-analysis. J Clin Pharmacol 39:520–532

    CAS  PubMed  Google Scholar 

  223. Kelley MT, Walson PD, Edge JH, Cox S, Mortensen ME (1992) Pharmacokinetics and pharmacodynamics of ibuprofen isomers and acetaminophen in febrile children. Clin Pharmacol Ther 52(2):181–189

    CAS  PubMed  Google Scholar 

  224. Kepp DR, Sidelmann UG, Hansen SH (1997) Isolation and characterization of major phase I and II metabolites of ibuprofen. Pharm Res 14:676–680

    CAS  PubMed  Article  Google Scholar 

  225. Kermond S, Fink M, Graham K, Carlin JB, Barnett P (2002) A randomized clinical trial: should the child with transient synovitis of the hip be treated with nonsteroidal anti-inflammatory drugs? Ann Emerg Med 40:294–299

    PubMed  Article  Google Scholar 

  226. Khan KN, Venturini CM, Bunch RT, Brassard JA, Koki AT, Morris DL, Trump BF, Maziasz TJ, Alden CL (1998) Interspecies differences in renal localization of cyclooxygenase isoforms: implications in nonsteroidal anti-inflammatory drug-related nephrotoxicity. Toxicol Pathol 26:612–620

    CAS  PubMed  Article  Google Scholar 

  227. Kidon MI, Kang LW, Chin CW, Hoon LS, See Y, Goh A, Lin JT, Chay OM (2005) Early presentation with angioedema and urticaria in cross-reactive hypersensitivity to nonsteroidal antiinflammatory drugs among young, Asian, atopic children. Pediatrics 116:e675–e680

    PubMed  Article  Google Scholar 

  228. Kimmel SE, Berlin JA, Reilly M, Jaskowiak J, Kishel L, Chittams J, Strom BL (2004) The effects of nonselective non-aspirin non-steroidal anti-inflammatory medications on the risk of nonfatal myocardial infarction and their interaction with aspirin. J Am Coll Cardiol 43:985–990

    CAS  PubMed  Article  Google Scholar 

  229. Kirchheiner J, Brockmöller J (2005) Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther 77:1–16

    CAS  PubMed  Article  Google Scholar 

  230. Kirchheiner J, Meineke I, Freytag G, Meisel C, Roots I, Brockmöller J (2002) Enantiospecific effects of cytochrome P450 2C9 amino acid variants on ibuprofen pharmacokinetics and on the inhibition of cyclooxygenases 1 and 2. Clin Pharmacol Ther 72:62–75

    CAS  PubMed  Article  Google Scholar 

  231. Klippel JH (ed) (1997) Primer on the rheumatic diseases. The Arthritis Foundation, Atlanta, Georgia, pp 316–318

  232. Knights KM, McLean CF, Tonkin AL, Miners JO (1995) Lack of effect of gender and oral contraceptive steroids on the pharmacokinetics of (R)-ibuprofen in humans. Br J Clin Pharmacol 40:153–161

    CAS  PubMed  Google Scholar 

  233. Ko D, Wang Y, Berger AK, Radford MJ, Krumholz HM (2002) Nonsteroidal anti-inflammatory drugs after acute myocardial infarction. Am Heart J 143:475–481

    CAS  PubMed  Article  Google Scholar 

  234. Kokki H, Hendolin H, Maunuksela EL, Vainio J, Nuutinen L (1994) Ibuprofen in the treatment of postoperative pain in small children. A randomized double-blind-placebo controlled parallel group study. Acta Anaesthesiol Scand 38:467–472

    CAS  PubMed  Article  Google Scholar 

  235. Kokki H, Kumpulainen E, Lehtonen M, Laisalmi M, Heikkinen M, Savolainen J, Rautio J (2007) Cerebrospinal fluid distribution of ibuprofen after intravenous administration in children. Pediatrics 120:e1002–e1008

    PubMed  Article  Google Scholar 

  236. Konstan MW, Hoppel CL, Chai BL, Davis PB (1991) Ibuprofen in children with cystic fibrosis: pharmacokinetics and adverse effects. J Pediatr 118(6):956–964

    CAS  PubMed  Article  Google Scholar 

  237. Konstan MW, Byard PJ, Hoppel CL, Davis PB (1995) Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med 332(13):848–854

    CAS  PubMed  Article  Google Scholar 

  238. Kotob A (1985) A comparative study of two dosage levels of ibuprofen syrup in children with pyrexia. J Int Med Res 13:122–126

    CAS  PubMed  Google Scholar 

  239. Kurth T, Glynn RJ, Walker AM, Chan KA, Buring JE, Hennekens CH, Gaziano JM (2003) Inhibition of clinical benefits of aspirin on first myocardial infarction by nonsteroidal antiinflammatory drugs. Circulation 108:1191–1195

    CAS  PubMed  Article  Google Scholar 

  240. Kyllönen M, Olkkola KT, Seppälä T, Ryhänen P (2005) Perioperative pharmacokinetics of ibuprofen enantiomers after rectal administration. Paediatr Anaesth 15(7):566–573

    PubMed  Article  Google Scholar 

  241. Lacroix I, Lapeyre-Mestre M, Bagheri H, Pathak A, Montastruc JL (2004) Nonsteroidal anti-inflammatory drug-induced liver injury: a case–control study in primary care. Fundam Clin Pharmacol 18:201–206

    CAS  PubMed  Article  Google Scholar 

  242. Lagunas L, Bradbury CM, Laszlo A, Hunt CR, Gius D (2004) Indomethacin and ibuprofen induce Hsc70 nuclear localization and activation of the heat shock response in HeLa cells. Biochem Biophys Res Commun 313:863–870

    CAS  PubMed  Article  Google Scholar 

  243. Laine L (2001) Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology 120:594–606

    CAS  PubMed  Article  Google Scholar 

  244. Laine L, Smith R, Min K, Chen C, Dubois RW (2006) Systematic review: the lower gastrointestinal adverse effects of non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther 24:751–767

    CAS  PubMed  Article  Google Scholar 

  245. Lanas A, Garcia-Rodriguez LA, Arroyo MT, Gomollon F, Feu F, Gonzalez-Perez A, Zapata E, Bastida G, Rodrigo L, Santolaria S, Güell M, de Argila CM, Quintero E, Borda F, Pique JM (2006) Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations. Gut 55:1731–1738

    CAS  PubMed  Article  Google Scholar 

  246. Langman MJS, Weil J, Wainwright P, Lawson DH, Rawlins MD, Logan RFA, Murphy M, Vessey MP, Colin-Jones DG (1994) Risk of bleeding peptic ulcers associated with individual non-steroidal anti-inflammatory drugs. Lancet 343:1075–1078

    CAS  PubMed  Article  Google Scholar 

  247. Lanza FL, Royer GL, Nelson RS, Chen TT, Seckman CE, Rack MF (1979) The effects of ibuprofen, indomethacin, aspirin, naproxen, and placebo on the gastric mucosa of normal volunteers. A gastroscopic and photographic study. Dig Dis Sci 24:823–828

    CAS  PubMed  Article  Google Scholar 

  248. Lanza FL, Royer GL, Nelson RS, Chen TT, Seckman CE, Rack MF (1981) A comparative endoscopic evaluation of the damaging effects of nonsteroidal anti-inflammatory agents on the gastric and duodenal mucosa. Am J Gastroenterol 75:17–21

    CAS  PubMed  Google Scholar 

  249. Lanza F, Rack MF, Lynn M, Wolf J, Sanda M (1987) An endoscopic comparison of the effects of etodolac, indomethacin, ibuprofen, naproxen, and placebo on the gastrointestinal mucosa. J Rheumatol 14:338–341

    CAS  PubMed  Google Scholar 

  250. Laporte J-R, Ibanez L, Vidal X, Vendrell L, Leone R (2004) Upper gastrointestinal bleeding associated with the use of NSAIDs. Newer versus older agents. Drug Saf 27:411–420

    CAS  PubMed  Article  Google Scholar 

  251. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, Reisch JS, Schiødt FV, Ostapowicz G, Shakil AO, Lee WM, Acute Liver Failure Study Group (2005) Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 42:1364–1372

    CAS  PubMed  Article  Google Scholar 

  252. Laska EM, Sunshine A, Marrero I, Olson N, Siegel C, McCormick N (1986) The correlation between blood levels of ibuprofen and clinical analgesic response. Clin Pharmacol Ther 40:1–7

    CAS  PubMed  Google Scholar 

  253. Layton D, Marshall V, Boshier A, Friedmann P, Shakir SA (2006) Serious skin reactions and selective COX-2 inhibitors: a case series from prescription-event monitoring in England. Drug Saf 29:687–696

    CAS  PubMed  Article  Google Scholar 

  254. Layton D, Souverein PC, Heerdink ER, Shakir SA, Egberts AC (2008) Evaluation of risk profiles for gastrointestinal and cardiovascular adverse effects in nonselective NSAID and COX-2 inhibitor users: a cohort study using pharmacy dispensing data in The Netherlands. Drug Saf 31:143–158

    CAS  PubMed  Article  Google Scholar 

  255. Leroy S, Mosca A, Landre-Peigne C, Cosson MA, Pons G (2007) Ibuprofen in childhood: evidence-based review of efficacy and safety. Arch Pediatr 14:477–484

    CAS  PubMed  Article  Google Scholar 

  256. Lesko SM (2003) The safety of ibuprofen suspension in children. Int J Clin Pract 50–53, 2003

  257. Lesko SM, Mitchell AA (1995) An assessment of the safety of pediatric ibuprofen. A practitioner-based randomized clinical trial. JAMA 273:929–933

    CAS  PubMed  Article  Google Scholar 

  258. Lesko SM, Mitchell AA (1997) Renal function after short-term ibuprofen use in infants and children. Pediatrics 100:954–957

    CAS  PubMed  Article  Google Scholar 

  259. Lesko SM, Mitchell AA (1999) The safety of acetaminophen and ibuprofen among children younger than two years old. Pediatrics 104(4):e39

    CAS  PubMed  Article  Google Scholar 

  260. Lesko SM, Louik C, Vezina RM, Mitchell AA (2002) Asthma morbidity after the short-term use of ibuprofen in children. Pediatrics 109(2):E20

    PubMed  Article  Google Scholar 

  261. Lesko SM, O’Brien KL, Schwartz B, Vezina R, Mitchell AA (2001) Invasive group A streptococcal infection and nonsteroidal antiinflammatory drug use among children with primary varicella. Pediatrics 107:1108–1115

    CAS  PubMed  Article  Google Scholar 

  262. Lewis D, Ashwal S, Hershey A, Hirtz D, Yonker M, Silberstein S, American Academy of Neurology Quality Standards Subcommittee, Practice Committee of the Child Neurology Society (2004) Practice parameter: pharmacological treatment of migraine headache in children and adolescents: report of the American Academy of Neurology Quality Standards Subcommittee and the Practice Committee of the Child Neurology Society. Neurology 63:2215–2224

    CAS  PubMed  Google Scholar 

  263. Lewis JD, Kimmel SE, Localio AR, Metz DC, Farrar JT, Nessel L, Brensinger C, McGibney K, Strom BL (2005) Risk of serious upper gastrointestinal toxicity with over-the-counter nonaspirin nonsteroidal anti-inflammatory drugs. Gastroenterology 129:1865–1874

    CAS  PubMed  Article  Google Scholar 

  264. Le Parc JM, Van Ganse E, Moore N, Wall R, Schneid H, Verrière F (2002) Comparative tolerability of paracetamol, aspirin and ibuprofen for short-term analgesia in patients with musculoskeletal conditions: results in 4291 patients. Clin Rheumatol 21:28–31

    CAS  PubMed  Article  Google Scholar 

  265. Li G, Treiber G, Maier K, Walker S, Klotz U (1993) Disposition of ibuprofen in patients with liver cirrhosis. Stereochemical considerations. Clin Pharmacokinet 25:154–163

    CAS  PubMed  Article  Google Scholar 

  266. Litalien C, Jacqz-Aigrain E (2001) Risks and benefits of nonsteroidal anti-inflammatory drugs in children: a comparison with paracetamol. Paediatr Drugs 3(11):817–858

    CAS  PubMed  Article  Google Scholar 

  267. López-Rodriguez R, Novalbos J, Gallego-Sandin S, Román-Martinez M, Torrado J, Gisbert JP, Abad-Santos F (2008) Inflluence of CYP2C8 and CYP2C9 polymorphisms on pharmacokinetic and pharmacodynamic parameters of racemic and enantiomeric form of ibuprofen in healthy volunteers. Pharmacol Res 58:77–84

    PubMed  Article  CAS  Google Scholar 

  268. Lugardon S, Lapeyre-Mestre M, Montastruc JL (2004) Upper gastrointestinal adverse drug reactions and cyclo-oxygenase-2 inhibitors (celecoxib and rofecoxib): a case/non-case study from the French Pharmacovigilance Database Eur. J Clin Pharmacol 60:673–677

    CAS  Article  Google Scholar 

  269. MacDonald TM, Wei L (2006) Is there an interaction between the cardiovascular protective effects of low-dose aspirin and ibuprofen? Basic Clin Pharmacol Toxicol 98:275–280

    CAS  PubMed  Article  Google Scholar 

  270. MacDonald TM, Morant SV, Robinson GC, Shield MJ, McGilchrist MM, Murray FE, McDevitt DG (1997) Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study. Br Med J 315:1333–1337

    CAS  Google Scholar 

  271. Mäkela AL, Yrjänä T, Mattila M (1979) Dosage of salicylates for children with juvenile rheumatoid arthritis. A prospective clinical trial with three different preparations of acetylsalicylic acid. Acta Paediatr Scand 68:423–430

    PubMed  Article  Google Scholar 

  272. Mäkelä AL, Lempiainen M, Ylijoki H (1981) Ibuprofen levels in serum and synovial fluid. Scand J Rheumatol Suppl 39:15–17

    PubMed  Article  Google Scholar 

  273. Malmberg AB, Yaksh TL (1992) Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formalin test in the rat. J Pharmacol Exp Ther 263:136–146

    CAS  PubMed  Google Scholar 

  274. Mamdani M, Rochon PA, Juurlink DN, Kopp A, Anderson GM, Naglie G, Austin PC, Laupacis A (2002) Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. Br Med J 325:624–629

    CAS  Article  Google Scholar 

  275. Mann JF, Goerig M, Brune K, Luft FC (1993) Ibuprofen as an over-the-counter drug: is there a risk for renal injury? Clin Nephrol 39:1–6

    CAS  PubMed  Google Scholar 

  276. Marriott SC, Stephenson TJ, Hull D, Pownall R, Smith CM, Butler A (1991) A dose ranging study of ibuprofen suspension as an antipyretic. Arch Dis Child 66:1037–1041

    CAS  PubMed  Article  Google Scholar 

  277. Martindale R (2002) The complete drug reference. Pharmaceutical Press, London

    Google Scholar 

  278. Martínez RV, Reval ID, Campos MD, Terrón JA, Domínguez Ramirez AM, López-Muňoz FJ (2002) Involvment of peripheral cyclooxygenase-1 and cyclooxygenase-2 in inflammatory pain. J Pharm Pharmacol 54:405–412

    PubMed  Article  Google Scholar 

  279. Mascia K, Haselkorn T, Deniz YM, Miller DP, Bleecker ER, Borish L, TENOR Study Group (2005) Aspirin sensitivity and severity of asthma: evidence for irreversible airway obstruction in patients with severe or difficult-to-treat asthma. J Allergy Clin Immunol 116:970–975

    CAS  PubMed  Article  Google Scholar 

  280. Matchaba P, Gitton X, Krammer G, Ehrsam E, Schoor-Sloan V, Olson M, Mellein B, Hoexter G, Orloff J, Garaud J-J (2005) Cardiovascular safety of lumiracoxib: A meta-analysis of all randomized controlled trial ≤1 week and up to one year in duration of patients with osteoarthritis and rheumatoid arthritis. Clin Ther 27:1196–1214

    CAS  PubMed  Article  Google Scholar 

  281. McCrory C, Fitzgerald D (2004) Spinal prostaglandin formation and pain perception following thoracotomy: a role for cyclooxygenase-2. Chest 125:1321–1327

    CAS  PubMed  Article  Google Scholar 

  282. McGettigan P, Platona A, Henry DA (2000) Renal and cardiovascular toxicity of non-steroidal anti-inflammatory drugs. Inflammopharmacology 8:1–18

    CAS  Article  Google Scholar 

  283. McIntyre BA, Philp RB, Inwood MJ (1978) Effect of ibuprofen on platelet function in normal subjects and haemophiliac patients. Clin Pharmacol Ther 24:616–621

    CAS  PubMed  Google Scholar 

  284. McIntyre J, Hull D (1996) Comparing efficacy and tolerability of ibuprofen and paracetamol in fever. Arch Dis Child 74:164–167

    CAS  PubMed  Article  Google Scholar 

  285. McQuay H, Moore A (eds) (1998) An evidence-based resource for pain relief. Oxford University Press, Oxford

  286. McQuay HJ, Moore RA (2006) Dose–response in direct comparisons of different doses of aspirin, ibuprofen and paracetamol (acetaminophen) in analgesic studies. B J Clin Pharmacol 63:271–278

    Article  CAS  Google Scholar 

  287. Menzel JE, Kolarz G (1997) Modulation of nitric oxide synthase activity by ibuprofen. Inflammation 21:451–461

    CAS  PubMed  Article  Google Scholar 

  288. Menzel EJ, Burtscher H, Kolarz G (1999) Inhibition of cytokine production and adhesion molecule expression by ibuprofen is without effect on transendothelial migration of monocytes. Inflammation 23(3):275–286

    CAS  PubMed  Google Scholar 

  289. Milsom I, Minic M, Dawood MY, Akin MD, Spann J, Niland NF, Squire RA (2002) Comparison of the efficacy and safety of nonprescription doses of naproxen and naproxen sodium with ibuprofen, acetaminophen, and placebo in the treatment of primary dysmenorrhea: a pooled analysis of five studies. Clin Ther 24:1384–1400

    CAS  PubMed  Article  Google Scholar 

  290. Mitchell AA, Lesko SM (1995) When a randomised controlled trial is needed to assess drug safety. The case of paediatric ibuprofen. Drug Saf 13:15–24

    CAS  PubMed  Article  Google Scholar 

  291. Mitchell JA, Akasereenont P, Thiemermann C, Flower RJ, Vane JR (1994) Selectivity of nonsteroidal anti-inflammatory drugs as inhibitors of constituitive and inducible cyclooxygenase. Proc Natl Acad Sci USA 90:11693–11697

    Article  Google Scholar 

  292. Miwa LJ, Jones JK (1999) Adverse drug reactions attributed to ibuprofen: effects other that gastrointestinal. In: Rainsford KD (ed) Ibuprofen: a critical bibliographic review. Taylor & Francis, London, pp 499–538

    Google Scholar 

  293. Miyamoto A, Hashiguchi Y, Obi T, Ishiguro S, Nishio A (2007) Ibuprofen or ozagrel increases NO release and l-nitro arginine induces TXA(2) release from cultured porcine basilar arterial endothelial cells. Vascul Pharmacol 46:85–90

    CAS  PubMed  Article  Google Scholar 

  294. Moore N (2007) Ibuprofen: journey form prescription to over-the-counter use. J R Soc Med 100(Suppl 48):2–6

    PubMed  Google Scholar 

  295. Moore PA, Acs G, Hargreaves JA (1985) Postextraction pain relief in children: a clinical trial of liquid analgesics. Int J Clin Pharmacol Ther Toxicol 23:573–577

    CAS  PubMed  Google Scholar 

  296. Moore N, Noblet C, Breemeersch C (1996) Focus on the safety of ibuprofen at the analgesic-antipyretic dose. Therapy 51:458–463

    CAS  Google Scholar 

  297. Moore N, Charlesworth A, Van Ganse E, LeParc JM, Jones JK, Wall R, Schneid H, Verrière F (2003) Risk factors for adverse events in analgesic drug users: results from the PAIN study. Pharmacoepidemiol Drug Saf 12:601–610

    CAS  PubMed  Article  Google Scholar 

  298. Moore N, Le Parc JM, van Ganse E, Wall R, Schneid H, Cairns R (2002) Tolerability of ibuprofen, aspirin and paracetamol for the treatment of cold and flu symptoms and sore throat pain. Int J Clin Pract 56:732–734

    CAS  PubMed  Google Scholar 

  299. Moore A, Derry S, Makinson GT, McQuay HJ (2005) Tolerability and adverse events in clinical trials of celecoxib in osteoarthritis and rheumatoid arthritis: systematic review and meta-analysis of information from company clinical trials reports. Arthritis Res Ther 7:R644–R665

    CAS  PubMed  Article  Google Scholar 

  300. Morgan O, Hawkins L, Edwards N, Dargan P (2007) Paracetamol (acetaminophen) pack size restrictions and poisoning severity: time trends in enquiries to a UK poisons centre. J Clin Pharm Ther 32:449–455

    CAS  PubMed  Article  Google Scholar 

  301. Motola G, Russo F, Mazzeo F, Rinaldi B, Capuano A, Rossi F, Filippelli A (2001) Over-the-counter oral nonsteroidal anti-inflammatory drugs: a pharmacoepidemiologic study in southern Italy. Adv Ther 18:216–222

    CAS  PubMed  Article  Google Scholar 

  302. Morse Z, Tump A, Kevelham E (2006) Ibuprofen as a pre-emptive analgesic is as effective as rofecoxib for mandibular third molar surgery. Odontology 94:59–63

    CAS  PubMed  Article  Google Scholar 

  303. Moore RA, Derry S, McQuay HJ, Paling J (2008) What do we know about communicating risk? A brief review and suggestion for contextualising serious, but rare, risk, and the example of cox-2 selective and non-selective NSAIDs. Arthritis Res Ther 10(1):R20

    PubMed  Article  Google Scholar 

  304. Mounier G, Guy C, Berthoux F, Beynes MN, Ratrema M, Ollagnier M (2006) Severe renal adverse events with arylcarboxylic non-steroidal anti-inflammatory drugs: results on an eight-year French national survey. Therapie 61:255–266

    PubMed  Article  Google Scholar 

  305. Müller P, Koch EMW, Simon B (1995) Schutzwirkung von Ranitidin bei Ibuprofen-Gastroduodenopathie. Arzneim Forsch/Drug Res 45:601–603

    Google Scholar 

  306. Murray MD, Brater DC (1999) Renal effects of ibuprofen. In: Rainsford KD (ed) Ibuprofen. A critical bibliographic review. Taylor & Francis, London, p 459

    Google Scholar 

  307. Myers RP, Li B, Shaheen AA (2007) Emergency department visits for acetaminophen overdose: a Canadian population-based epidemiologic study (1997–2002). CJEM 9(4):267–274

    PubMed  Google Scholar 

  308. Nahata MC, Durrell DE, Powell DA, Gupta N (1991) Pharmacokinetics of ibuprofen in febrile children. Eur J Clin Pharmacol 40(4):427–428

    CAS  PubMed  Article  Google Scholar 

  309. Nahata MC, Powell DA, Durrell DE, Miller MA, Gupta N (1992) Efficacy of ibuprofen in pediatric patients with fever. Int J Clin Pharmacol Ther Toxicol 30(3):94–96

    CAS  PubMed  Google Scholar 

  310. Naldi L, Conforti A, Venegoni M, Troncon MG, Caputi A, Ghiotto E, Cocci A, Moretti U, Velo G, Leone R (1999) Cutaneous reactions to drugs. An analysis of spontaneous reports in four Italian regions. Br J Clin Pharmacol 48:839–846

    CAS  PubMed  Article  Google Scholar 

  311. Neuman M, Nicar M (2007) Apoptosis in ibuprofen-induced Steven-Johnson syndrome. Transl Res 149:254–259

    CAS  PubMed  Article  Google Scholar 

  312. Neupert W, Brugger R, Euchenhofer C, Brune K, Geisslinger G (1997) Effects of ibuprofen enantiomers and its coenzyme A thioesters on human prostaglandin endoperoxide synthases. Br J Pharmacol 122:487–492

    CAS  PubMed  Article  Google Scholar 

  313. Neutel CI, Pless RP (1997) Ibuprofen use in children: a benefit or a risk? Ann Epidemiol 7:437–439

    CAS  PubMed  Article  Google Scholar 

  314. Nieman DC, Henson DA, Dumke CL, Oley K, McAnulty SR, Davis JM, Murphy EA, Utter AC, Lind RH, McAnulty LS, Morrow JD (2006) Ibuprofen use, endotoxaemia, inflammation, and plasma cytokines during ultramarathon competition. Brain Behav Immun 20:578–584

    CAS  PubMed  Article  Google Scholar 

  315. Nørholt SE, Aagaard E, Svensson P, Sindet-Pedersen S (1998) Evaluation of trismus, bite force, and pressure algometry after third molar surgery: a placebo-controlled study of ibuprofen. J Oral Maxillofac Surg 56:420–427

    PubMed  Article  Google Scholar 

  316. Novak D, Lewis JH (2003) Drug-induced liver disease. Curr Opin Gastroenterol 19:203–215

    CAS  PubMed  Article  Google Scholar 

  317. Nurmohamed MT, van Halm VP, Dijkmans BA (2002) Cardiovascular risk profile of antirheumatic agents in patients with osteoarthritis and rheumatoid arthritis. Drugs 62:1599–1609

    CAS  PubMed  Article  Google Scholar 

  318. O’Brien WM (1987) Rare adverse reactions to non-steroidal anti-inflammatory drugs. In: Rainsford KD, Velo GP (eds) Side-effects of anti-inflammatory drugs 3. Kluwer, Dordrecht, pp 73–98

    Google Scholar 

  319. O’Brien W, Bagby GF (1985) Rare adverse reactions to nonsteroidal anti-inflammatory drugs. J Rheumatol 12:1–24

    Google Scholar 

  320. Ostor AJK, Hazleman BL (2005) The murky waters of the coxibs: a review of the current state of play. Inflammopharmacology 13:371–380

    CAS  PubMed  Article  Google Scholar 

  321. Owen-Smith BD, Burry HC (1972) Ibuprofen in the management of osteoarthrosis of the hip. Rheumatol Phys Med 11:281–286

    CAS  PubMed  Article  Google Scholar 

  322. Pachkoria K, Lucena MI, Molokhia M, Cueto R, Carballo AS, Carvajal A, Andrade RJ (2007) Genetic and molecular factors in drug-induced liver injury: a review. Curr Drug Saf 2:97–112

    CAS  PubMed  Article  Google Scholar 

  323. Perez C, Sanchez J, Marmol F, Puig-parellada P, Pouplana R (2007) Reactivity of biologically important NSAID compounds with superoxide (O2 ) nitric oxide (NO) and cyclooxygenase inhibition. QSAR Comb Sci 26:368–377

    CAS  Article  Google Scholar 

  324. Perrott DA, Piira T, Goodenough B, Champion GD (2004) Efficacy and safety of acetaminophen vs ibuprofen for treating children’s pain or fever: a meta-analysis. Arch Pediatr Adolesc Med 158:521–526

    PubMed  Article  Google Scholar 

  325. Peterson GM (2005) Selecting non-prescription analgesics. Am J Therap 12:67–79

    Article  Google Scholar 

  326. Pongbhaesaj P, Yamwong P, Chattanamatta P et al. (2003) Effects of ibuprofen and different doses of aspirin on platelet aggregation. Artheroscl Suppl. 4 : 247 Abstract # 3P-0841

  327. Ponvert C, Scheinmann P (2007) Les reactions allergiques et pseudoallergiques aux antalgiques, antipyrétics et anti-inflammatoires non stéroïdiens. Allergic and pseudoallergic reactions to antalgics, antipyretics and non-steroidal anti-inflammatory drugsAllergic and pseudoallergic reactions to antalgics, antipyretics and non-steroidal anti-inflammatory drugs. Archives Pédaitr 14:507–512

    CAS  Article  Google Scholar 

  328. Pope JE, Anderson JJ, Felson DT (1993) Meta-analysis of the effects of non-steroidal anti-inflammatory drugs on blood pressure. Arch Intern Med 22:477–484

    Article  Google Scholar 

  329. Prescott LF, Martin U (1992) Current status of nephrotoxicity caused by non-steroidal anti-inflammatory drugs. In: Rainsford KD, Velo GP (eds) Side-effects of anti-inflammatory drugs 3. Kluwer, Dordrecht

    Google Scholar 

  330. Psaty BM, Furberg CD (2005) COX-2 inhibitors-lessons in drug safety. N Engl J Med 352:1133–1135

    CAS  PubMed  Article  Google Scholar 

  331. Purcell H (2007) Ibuprofen and cardiovascular safety: where do we stand? J R Soc Med 100(Suppl 48):7–10

    PubMed  Google Scholar 

  332. Quiding H, Grimstad J, Rusten K, Stubhaug A, Bremnes J, Breivik H (1992) Ibuprofen plus codeine, ibuprofen, and placebo in a single- and multidose cross-over comparison for coxarthrosis pain. Pain 50:303–307

    CAS  PubMed  Article  Google Scholar 

  333. Quiralte J, Blanco C, Delgado J, Ortega N, Alcntára M, Castillo R, Anguita JL, Sáenz de San Pedro B, Carrillo T (2007) Challenge-based clinical patterns of 223 Spanish patients with nonsteroidal anti-inflammatory-drug-induced-reactions. J Investig Allergol Clin Immunol 17:182–188

    CAS  PubMed  Google Scholar 

  334. Radack KL, Deck CC, Bloomfield SS (1987) Ibuprofen interferes with the efficacy of antihypertensive drugs. A randomized, double-blind, placebo-controlled trial of ibuprofen compared with acetaminophen. Ann Intern Med 107:628–635

    CAS  PubMed  Google Scholar 

  335. Radford MG, Holley KE, Grande JP, Larson TS, Wagoner RD, Donadio JV, McCarthy JT (1996) Reversible membranous nephropathy associated with the use of nonsteroidal anti-inflammatory drugs. JAMA 276:466–469

    CAS  PubMed  Article  Google Scholar 

  336. Rahme E, Nedjar H (2007) Risks and benefits of COX-2 inhibitors vs non-selective NSAIDs: does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study. Rheumatology 46:435–438

    CAS  PubMed  Article  Google Scholar 

  337. Rainsford KD, Schweitzer A, Brune K (1981) Autoradiographic and biochemical observations on the distribution of non-steroid anti-inflammatory drugs. Arch Int Pharmacodyn Ther 250:180–194

    CAS  PubMed  Google Scholar 

  338. Rainsford KD (ed.) (1984) Aspirin and the salicylates. Butterworth, London, Boston

  339. Rainsford KD (1999a) History and development of ibuprofen. In: Rainsford KD (ed) Ibuprofen. A critical bibliographic review. Taylor & Francis, London, pp 3–24

    Google Scholar 

  340. Rainsford KD (1999b) Pharmacology and toxicology of ibuprofen. In: Rainsford KD (ed) Ibuprofen. A critical bibliographic review. Taylor & Francis, London, pp 145–275

    Google Scholar 

  341. Rainsford KD (1999c) Safety and efficacy of non-prescription (OTC) ibuprofen. In: Rainsford, KD (ed) Ibuprofen. A critical bibliographic review. Taylor & Francis, London, pp 357–405

  342. Rainsford KD (2001) The ever-emerging anti-inflammatories. Have there been any real advances? J Physiol (Paris) 95:11–19

    CAS  Article  Google Scholar 

  343. Rainsford KD (2003) Discovery, mechanisms of action and safety of ibuprofen. Intl J Clin Pract S135:3–8

    Google Scholar 

  344. Rainsford KD (2004a) Side effects and toxicology of the salicylates. In: Rainsford KD (ed) Aspirin and related drugs. Taylor & Francis, London, pp 367–554

    Google Scholar 

  345. Rainsford KD (2004b) Inhibitors of eicosanoids. In: Curtis-Prior P (ed) The eicosanoids. Wiley, Chichester, pp 189–210

    Google Scholar 

  346. Rainsford KD (2005a) Introduction—the coxib controversies. Inflammopharmacology 13:331–341

    CAS  PubMed  Article  Google Scholar 

  347. Rainsford KD (ed) (2005b) Nimesulide. Actions and uses. Birkhäuser, Basel

    Google Scholar 

  348. Rainsford KD (1998) Review of published clinical trial data on the adverse reactions from ibuprofen and paracetamol/acetaminophen at OTC dosages. In: Rainsford KD, Powanda MC (eds) Safety and Efficacy of Non-Prescription (OTC) Analgesics and NSAIDs. Kluwer Academic Publishers, Dordrecht, pp 11–18

    Google Scholar 

  349. Rainsford KD (2007) Anti-inflammatory drugs in the 21st century. In: Harris R (ed) Inflammation in the pathogenesis of chronic diseases. The COX-2 Controversy. Springer, Heidelberg, pp 3–27

    Google Scholar 

  350. Rainsford KD, Roberts SC, Brown S (1997) Ibuprofen and paracetamol: relative safety in non-prescription dosages. J Pharm Pharmacol 49:345–376

    CAS  PubMed  Google Scholar 

  351. Rainsford KD, Adesioye J, Dawson S (2001) Relative safety of NSAIDs and analgesics for non-prescription use or in equivalent doses. Inflammopharmacology 8:351–359

    Article  Google Scholar 

  352. Rainsford KD, Kean IRL, Kean WF (2008) Gastro-intestinal complications of anti-rheumatic drugs. In: Font J, Ramos-Casals M, Rhodes J (eds) Handbook of systemic autoimmune diseases, vol 8, Chap 18. Elsevier, Amsterdam, pp 243–275

  353. Rainsford KD, James C, Johnson DM, Stetsko PI, Hill RE, Salena BJ, Hunt RH (1993) Effects of chronic NSAIDs on gastric mucosal injury related to mucosal prostanoids, and plasma drug concentrations in human volunteers. Agents Actions 39 (Special Issue):C21–C23

  354. Re E, Pariente-Khayat A, Gouyet L, Vauzelle-Kervroëdan F, Pons G, D’Athis Ph, Dubois MC, Murat I, Lassale C, Goehrs M, Sainst-Maurice Cl, Olive G (1994) Stereoselective disposition of ibuprofen enantiomers in infants. Br J Clin Pharmacol 38:378–375

  355. Roth SH, Tindall EA, Jain AK, McMahon FG, April PA, Bockow BI, Cohen SB, Fleischmann RM (1993) A controlled study comparing the effects of nabumetone, ibuprofen, and ibuprofen plus misoprostol on the upper gastrointestinal tract mucosa. Arch Intern Med 153:2565–2571

    CAS  PubMed  Article  Google Scholar 

  356. Rodrigues LAG, Jick H (1994) Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet 343:769–772

    Article  Google Scholar 

  357. Rodriguez F, Llinas MT, Moreno C, Salazar FJ (2001) Role of cyclooxygenase-2-derived metabolites and NO in renal response to bradykinin. Hypertens 37:129–134

    CAS  Google Scholar 

  358. Roig F, Llinas MT, Lopez R, Salazar FJ (2002) Role of cyclooxygenase-2 in the prolonged regulation of renal function. Hypertension 40:721–728

    CAS  PubMed  Article  Google Scholar 

  359. Royal College of Paediatrics and Child Health with the Neonatal and Paediatric Pharmacists Group (2003) Medicines for Children

  360. Royer GL, Seckman CE, Schwartz JH, Bennett K (1985) Effects of ibuprofen on normal subjects: clinical and routine and special laboratory assessments. Curr Ther Res 37:412–426

    CAS  Google Scholar 

  361. Rudy AC, Knight PM, Brater DC, Hall SD (1991) Stereoselective metabolism of ibuprofen in humans: administration of R-, S- and racemic ibuprofen. J Pharmacol Exp Ther 259:1133–1139 Erratum in: J Pharmacol Exp Ther 1992; 260(3):1456

    CAS  PubMed  Google Scholar 

  362. Sabaté M, Ibáñez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A, Guarner C, Forné M, Solà R, Castellote J, Rigau J, Laporte JR (2007) Risk of acute liver injury associated with the use of drugs: a multicentre population survey. Aliment Pharmacol Ther 25(12):1401–1409

    PubMed  Article  CAS  Google Scholar 

  363. Sachs CJ (2005) Oral analgesics for acute non-specific pain. Am Family Phys 71:913

    Google Scholar 

  364. Sánchez-Borges M, Capriles-Hulett A, Caballero-Fonseca F (2005) Risk of skin reactions when using ibuprofen-based medicines. Expert Opin Drug Saf 4:837–848

    PubMed  Article  Google Scholar 

  365. Sanchez-Matienzo D, Arana A, Castellsague J, Perez-Gutthann S (2006) Hepatic disorders in patients treated with COX-2 selective inhibitors or nonselective NSAIDs: a case/noncase analysis of spontaneous reports. Clin Ther 28:1123–1132

    CAS  PubMed  Article  Google Scholar 

  366. Sarrell EM, Wielunsky E, Cohen HA (2006) Antipyretic treatment in young children with fever: acetaminophen, ibuprofen, or both alternating in a randomized, double-blind study. Arch Pediatr Adolesc Med 160(2):197–202

    PubMed  Article  Google Scholar 

  367. Schaffer D, Florin T, Eagle C, Marschner I, Singh G, Grobler M, Fenn C, Schou M, Curnow KM (2006) Risk of serious NSAID-related gastrointestinal events during long-term exposure: a systematic review. MJA 185:501–506

    PubMed  Google Scholar 

  368. Schiff M, Minic M (2004) Comparison of the analgesic efficacy and safety of non-prescription doses of naproxen sodium and ibuprofen in the treatment of osteoarthritis of the knee. J Rheumatol 31:1373–1383

    CAS  PubMed  Google Scholar 

  369. Schneeweiss S, Solomon DH, Wang PS, Rassen J, Brookhart MA (2006) Simultaneous assessment of short-term gastrointestinal benefits and cardiovascular risks of selective cyclooxygenase 2 inhibitors and nonselective nonsteroidal antiinflammatory drugs: an instrumental variable analysis. Arthritis Rheum 54:3390–3398

    CAS  PubMed  Article  Google Scholar 

  370. Schneider HT, Nernberg B, Dietzel K, Brune K (1990) Biliary elimination on non-steroidal anti-inflammatory drugs in patients. Br J Clin Pharmacol 29:127–131

    CAS  PubMed  Google Scholar 

  371. Schnitzer TJ, Burmester GR, Mysker E, Hochberg MC, Doherty M, Ehrsam E, Gitton X, Krammer G, Meillein B, Matchaba P, Gimona A, Hawkey CJ (2004) Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 364:665–674

    CAS  PubMed  Article  Google Scholar 

  372. Schoenfeld P (2001) An evidence-based approach to the gastrointestinal safety profile of COX-2 selective anti-inflammatories. Gastroent Clin N Am 30:1027–1044

    CAS  Article  Google Scholar 

  373. Schou S, Nielsen H, Nattestad A, Hillerup S, Ritzau M, Branebjerg PE, Bugge C, Skoglund LA (1998) Analgesic dose–response relationship of ibuprofen 50, 100, 200, and 400 mg after surgical removal of third molars: a single-dose, randomized, placebo-controlled, and double-blind study of 304 patients. J Clin Pharmacol 38:447–454

    CAS  PubMed  Google Scholar 

  374. Schwartz JI, Vandormael K, Malice MP, Kalyani RN, Lasseter KC, Holmes GB, Gertz BJ, Gottesdiener KM, Laurenzi M, Redfern K-J, Brune K (2002) Comparison of rofecoxib, celecoxib, and naproxen on renal function in elderly subjects receiving normal-salt diet. Clin Pharmacol Ther 72:50–61

    CAS  PubMed  Article  Google Scholar 

  375. Scott CS, Retsch-Bogart GZ, Kustra RP, Graham KM, Glasscock BJ, Smith PC (1999) The pharmacokinetics of ibuprofen suspension, chewable tablets, and tablets in children with cystic fibrosis. J Pediatr 134:58–63

    CAS  PubMed  Google Scholar 

  376. Seideman P, Lohrer F, Graham GG, Duncan MW, Williams KM, Day RO (1994) The stereospecific disposition of the enantiomers of ibuprofen in blood, blister and synovial fluid. Br J Clin Pharmacol 38:211–227

    Google Scholar 

  377. Seinelä L, Ahvenainen J (2000) Peptic ulcer in the very old patients. Gerontology 46:271–275

    PubMed  Article  Google Scholar 

  378. Seymour RA, Hawkesford JE, Weldon M, Brewster D (1991) An evaluation of different ibuprofen preparations in the control of postoperative pain after third molar surgery. Br J Clin Pharmacol 31:83–87

    CAS  PubMed  Google Scholar 

  379. Shah AA, Thjodleifsson B, Murray FE, Kay E, Barry M, Sigthorsson G, Gudjonsson H, Oddsson E, Price AB, Fitzgerald DJ, Bjarnason I (2001) Selective inhibition of COX-2 in humans is associated with less gastrointestinal injury: a comparison of nimesulide and naproxen. Gut 48:339–346

    CAS  PubMed  Article  Google Scholar 

  380. Shirley MA, Guan X, Kaiser DG, Halstead GW, Baillie TA (1994) Taurine conjugation of ibuprofen in humans and in rat liver in vitro. Relationship to metabolic chiral inversion. J Pharmacol Exp Ther 269:1166–1175

    CAS  PubMed  Google Scholar 

  381. Sidler J, Frey B, Baerlocher K (1990) A double-blind comparison of ibuprofen and paracetamol in juvenile pyrexia. Br J Clin Pract Suppl 70:22–25

    CAS  PubMed  Google Scholar 

  382. Sikes DH, Agrawal NM, Zhao WW, Kent JD, Recker DP, Verburg KM (2002) Incidence of gastroduodenal ulcers associated with valdecoxib compared with that of ibuprofen and diclofenac in patients with osteoarthritis. Eur J Gastroenterol Hepatol 14:1101–1111

    CAS  PubMed  Article  Google Scholar 

  383. Silvarajan M, Wasse L (1997) Perioperative renal failure associated with preoperative intake of ibuprofen. Am Soc Anestisiol 86:1390–1392

    Google Scholar 

  384. Silver S, Gano D, Gerretsen P (2008) Acute treatment of paediatric migraine: a meta-analysis of efficacy. J Paediatr Child Health 44:3–9

    PubMed  Google Scholar 

  385. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, Burr AM, Zhao WW, Kent JD, Lefkowith JB, Verburg KM, Geis GS (2000) Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. JAMA 284:1247–1255

    CAS  PubMed  Article  Google Scholar 

  386. Singer F, Mayrhofer F, Klein G, Hawel R, Kollenz CJ (2000) Evaluation of the efficacy and dose–response relatioinship of dexibuprofen (S(+)-ibuprofen) in patients with osteoarthritis of the hip and comparison with racemic ibuprofen using the WOMAC osteoarthritis index. Int J Clin Pharmacol Ther 38:15–24

    CAS  PubMed  Google Scholar 

  387. Singh G (2000) Gastrointesstinal complications of prescription and over-the-counter nonsteroidal anti-inflammatory drugs: a view from the ARAMIS database. Arthritis, Rheumatism, and Aging Medical Information System. Am J Ther 7:115–121

    CAS  PubMed  Article  Google Scholar 

  388. Singh G, Ramey DR, Morfeld D, Shi H, Hatoum HT, Fries JF (1996) Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis. A prospective observational cohort study. Arch Intern Med 156:1530–1536

    CAS  PubMed  Article  Google Scholar 

  389. Skeith KJ, Jamali F (1991) Clinical pharmacokinetics of drugs used in juvenile arthritis. Clin Pharmacokinet 21:129–149

    CAS  PubMed  Article  Google Scholar 

  390. Solomon DH, Glynn RJ, Rothman KJ, Schneeweiss S, Setoguchi S, Mogun H, Avorn J, Stürmer T (2008) Subgroup analyses to determine cardiovascular risk associated with nonsteroidal antiinflammatory drugs and coxibs in specific patient groups. Arthritis Rheum 59:1097–1104

    PubMed  Article  Google Scholar 

  391. Sørensen R, Abildstrom SZ, Torp-Pedersen C, Gislason GH (2008) Use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs in high doses increases mortality and risk of reinfarction in patients with prior myocardial infarction. J Cardiovasc Nurs 23:14–19

    PubMed  Google Scholar 

  392. Stagnara J, Vermont J, Dürr F, Ferradji K, Mege L, Duquesne A, Ferley JP, Kassaï B (2005). Parents’ attitudes towards childhood fever. A cross-sectional survey in the Lyon metropolitan area (202 cases). Presse Med 34:1129–1136

    Google Scholar 

  393. Steans A, Manners PJ, Robinson IG (1990) A multicentre, long-term evaluation of the safety and efficacy of ibuprofen syrup in children with juvenile chronic arthritis. Br J Clin Pract 44:172–175

    CAS  PubMed  Google Scholar 

  394. Steen Law SL, Southard KA, Law AS, Logan HL, Jakobsen JR (2000) An evaluation of preoperative ibuprofen for treatment of pain associated with orthodontic separator placement. Am J Orthod Dentofacial Orthop 118:629–635

    CAS  PubMed  Article  Google Scholar 

  395. Stewart WF, Lipton RB (1998) Ibuprofen plus caffeine in the treatement of Migraine. In: Rainsford KD, Powanda MC (eds) Safety and efficacy of non-prescription (OTC) analgesics and NSAIDs. Kluwer Academic Publishers, Dordrecht, pp 123–124

  396. Strand V (2007) Are COX-2 inhibitors preferable to non-selective non-steroidal anti-inflammatory drugs in patients with risk of cardiovascular events taking low-dose aspirin? Lancet 370:2138–2151

    CAS  PubMed  Article  Google Scholar 

  397. Strassburg CP, Strassburg A, Kneip S, Barut A, Tukey RH, Rodeck B, Manns MP (2002) Developmental aspects of human hepatic drug glucuronidation in young adults and children. Gut 50:259–265

    CAS  PubMed  Article  Google Scholar 

  398. Stratman NC, Carter DB, Sethy VH (1997) Ibuprofen: effect on inducible nitric oxide synthase. Brain Res Mol Brain Res 50:107–112

    CAS  PubMed  Article  Google Scholar 

  399. Stricker BH Ch. (1992) Drug-induced hepatic injury. Elsevier, Amsterdam

  400. Strom BL, Schinnar R, Bilker WB, Feldman H, Farrar JT, Carson JL (1997) Gastrointestinal tract bleeding associated with naproxen sodium vs ibuprofen. Arch Intern Med 157:2626–2631

    CAS  PubMed  Article  Google Scholar 

  401. Suri A, Grundy BL, Derendorf H (1997) Pharmacokinetics and pharmacodynamics of enantiomers of ibuprofen and flurbiprofen after oral administration. Int J Clin Pharmacol Ther 35:1–8

    CAS  PubMed  Google Scholar 

  402. Suthisisang C, Poolsup N, Kittikulsuth W, Pudchakan P, Wiwatpanich P (2007) Efficacy of low-dose ibuprofen in acute migraine treatment: systematic review and meta-analysis. Ann Pharmacother 41:1782–1791

    CAS  PubMed  Article  Google Scholar 

  403. Suzuki A, Yuen N, Walsh J, Papay J, Hunt CM, Diehl AM (2009) Co-medications that modulate liver injury and repair influence clinical outcome of acetaminophen-associated liver injury. Clin Gastroenterol Hepatol 7:882–888

    PubMed  Article  Google Scholar 

  404. Tegeder I, Pfeilschifter J, Geisslinger G (2001) Cyclooxygenase-independent actions of cyclooxygenase inhibitors. FASEB J 15:2057–2072

    CAS  PubMed  Article  Google Scholar 

  405. Teixeira AVasconcelos, Abrunhosa R, Poças L (1977) Observations on the gastric mucosa of rheumatic patients before and after ibuprofen administration as studied by the pentagastrin test, endoscopy, and light and electron microscopy. Int J Med Res 5:243–252

    CAS  Google Scholar 

  406. Thomsen RW, Riis A, Munk EM, Nørgaard M, Christensen S, Sørensen HT (2006) 30-day mortality after peptic ulcer perforation among users of newer selective COX-2 inhibitors and traditional NSAIDs: a population-based study. Am J Gastroenterol 101:2704–2710

    CAS  PubMed  Article  Google Scholar 

  407. Tolman KG (1998) Hepatotoxicity of non-narcotic analgesics. Am J Med 105:13S–19S

    CAS  PubMed  Article  Google Scholar 

  408. Topol EJ (2004) Failing the public health—rofecoxib, Merck, and the FDA. N Engl J Med 351:1707–1709

    CAS  PubMed  Article  Google Scholar 

  409. Topol EJ (2005) Arthritis medicines and cardiovascular events—“house of coxibs”. J Am Med Assn 293(3):366–368

    CAS  Article  Google Scholar 

  410. Tornio A, Niemi M, Neuvonen PJ, Backman JT (2007) Stereoselective interaction between the CYP2C8 inhibitor gemfibrozil and racemic ibuprofen. Eur J Clin Pharmacol 63:463–469

    CAS  PubMed  Article  Google Scholar 

  411. Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. (2006) Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 25(1):CD004257

    Google Scholar 

  412. Traversa G, Bianchi C, Da Cas R, Abraha I, Menniti-Ippolito F, Venegoni M (2003) Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs. Br Med J 327:18–22

    CAS  Article  Google Scholar 

  413. Trocóniz IF, Armenteros S, Planelles MV, Benítez J, Calvo R, Domínguez R (2000) Pharmacokinetic-Pharmacodynamic Modelling of the antipyretic effect of two oral formulations of ibuprofen. Clin Pharmacokinet 38:505–518

    PubMed  Article  Google Scholar 

  414. Troullos E, Hargreaves KM, Dionne RA (1997) Ibuprofen elevates immunoreactive β-endorphin levels in humans during surgical stress. Clin Pharmacol Ther 62:74–81

    CAS  PubMed  Article  Google Scholar 

  415. Ulinski T, Guigonis V, Dunan O, Bensman A (2004) Acute renal failure after treatment with non-steriodal anti-inflammatory drugs. Eur J Paediatr 163:148–150

    CAS  Article  Google Scholar 

  416. van den Anker JN (2007) Use of ibuprofen in paediatric populations. J R Soc Med 100(Suppl 48):18–22

    PubMed  Google Scholar 

  417. van der Linden MW, van der Bij S, Welsing P, Kuipers EJ, Herings RM (2009) The balance between severe cardiovascular and gastrointestinal events among users of selective and non-selective non-steroidal anti-inflammatory drugs. Ann Rheum Dis 68:668–673

    PubMed  Article  CAS  Google Scholar 

  418. Van Esch A, Van Steensel-Moll HA, Steyerberg EW, Offringa M, Habbema JD, Derksen-Lubsen G (1995) Antipyretic efficacy of ibuprofen and acetaminophen in children with febrile seizures. Arch Pediatr Adolesc Med 149:632–637

    PubMed  Google Scholar 

  419. Van Hoogdalem EJ, de Boer AG, Breimer DD (1991) Pharmacokinetics of rectal drug administration, Part II. Clinical appplications of peripherally acting drugs, and conclusions. Clin Pharmacokinet 21:110–128

    PubMed  Article  Google Scholar 

  420. Van Staa TP, Leufkens HGM, Cooper C (2000) Use of non-steroidal anti-inflammatory drugs and risk of fractures. Bone 27:563–568

    PubMed  Article  Google Scholar 

  421. van Stuijvenberg M, Derksen-Lubsen G, Steyerberg EW, Habbema JD, Moll HA (1998a) Randomized, controlled trial of ibuprofen syrup administered during febrile illnesses to prevent febrile seizure recurrences. Pediatrics 102(5):E51

    PubMed  Article  Google Scholar 

  422. van Stuijvenberg M, Steyerberg EW, Derksen-Lubsen G, Moll HA (1998b) Temperature, age, and recurrence of febrile seizure. Arch Pediatr Adolesc Med 152(12):1170–1175

    PubMed  Google Scholar 

  423. van Stuijvenberg M, de Vos S, Tjiang GC, Steyerberg EW, Derksen-Lubsen G, Moll HA (1999) Parents’ fear regarding fever and febrile seizures. Acta Paediatr 88(6):618–622

    PubMed  Article  Google Scholar 

  424. Vanderhoeven SJ, Lindon JC, Troke J, Nicholson JK, Wilson ID (2006) NMR spectroscopic studies of the transacylation reactivity of ibuprofen 1-beta-)-acyl-glucuronide. J Pharm Biomed Anal 41:1002–1006

    CAS  PubMed  Article  Google Scholar 

  425. Vandivier RW, Eidsath A, Banks SM, Preas HL III, Leighton SB, Godin PJ, Suffredini AF, Danner RL (1999) Down-regulation of nitric oxide production by ibuprofen in human volunteers. J Pharm Exptl Ther 289:1398–1403

    CAS  Google Scholar 

  426. Vauzelle-Kervroëdan F, d’Athis P, Pariente-Khayat A, Debregeas S, Olive G, Pons G (1997) Equivalent antipyretic activity of ibuprofen and paracetamol in febrile children. J Pediatr 131:683–687

    PubMed  Article  Google Scholar 

  427. Vane JR, Botting RM (Eds) (2001) Therapeutic roles of selective COX-2 inhibitors. William Harvey Press, London

  428. Verhagen AP, Damen L, Berger MY, Passchier J, Merlijn V, Koes BW (2006) Is any one analgesic superior for episodic tension-type headache? J Fam Pract 55:1064–1072

    PubMed  Google Scholar 

  429. Vestergaard P, Rejnmark L, Mosekilde L (2006) Fracture risk associated with use of nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, and acetaminophen and the effects of rheumatoid arthritis and osteoarthritis. Calcif Tissue Int 79:84–94

    CAS  PubMed  Article  Google Scholar 

  430. Velo GP, Minuz P, Arosio E, Capuzzo MG, Covi G, Lechi A (1987) Interaction between non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors in man. In: Rainsford KD, Velo GP (eds) Side-Effects of Anti-inflammatory Drugs. Part 1. Clinical and Epidemiological Aspects. MTP Press, Lancaster (UK), pp 195–201

    Google Scholar 

  431. Vij N, Amoako MO, Mazur S, Zeitlin PL (2008) CHOP transcription factor mediates IL-8 signaling in cystic fibrosis bronchial epithelial cells. Am J Respir Cell Mol Biol 38:176–184

    CAS  PubMed  Article  Google Scholar 

  432. Villanueva M, Heckenberger R, Strobach H, Palmer M, Schrör K (1993) Equipotent inhibition by R(−)-, S(+)- and racemic ibuprofen of human polymorphonuclear cell function in vitro. Br J Pharmacol 35:235–242

    CAS  Google Scholar 

  433. Volans G, Fitzpatrick R (1999) Human toxicity of ibuprofen. In: Rainsford KD (ed) Ibuprofen. A critical bibliographic review. Taylor & Francis, London, pp 541–559

    Google Scholar 

  434. Voutilainen M, Sokka T, Juhola M, Färkkilä M, Hannonen P (1998) Scand J Gastroenterol 33:811–816

    CAS  PubMed  Article  Google Scholar 

  435. Vural P, Canbaz M, Akbulut A, Celik I (2002) Effects of ibuprofen on plasma endothelin levels and some vital parameters during endotoxin shock in rabbits. Clin Chim Acta 316:101–108

    CAS  PubMed  Article  Google Scholar 

  436. Walker JS, Carmody JJ (1998) Experimental pain in healthy human subjects: gender differences in nociception and in response to ibuprofen. Anesth Analg 86:1257–1262

    CAS  PubMed  Article  Google Scholar 

  437. Walson PD, Mortensen ME (1989) Pharmacokinetics of common analgesics, anti-inflammatories and antipyretics in children. Clin Pharmacokinet 17(Suppl 1):116–137

    CAS  PubMed  Article  Google Scholar 

  438. Walson PD, Galletta G, Braden NJ, Alexander L (1989) Ibuprofen, acetaminophen, and placebo treatment of febrile children. Clin Pharmacol Ther 46:9–17

    CAS  PubMed  Google Scholar 

  439. Walson PD, Galletta G, Chomilo F, Braden NJ, Sawyer LA, Scheinbaum ML (1992) Comparison of multidose ibuprofen and acetaminophen therapy in febrile children. Am J Dis Child 146(5):626–632

    CAS  PubMed  Google Scholar 

  440. Wanwimolruk S, Brooks PM, Birkett DJ (1983) Protein binding of non-steroidal anti-inflammatory drugs in plasma and synovial fluid of arthritic patients. Br J Clin Pharmacol 15:91–94

    CAS  PubMed  Google Scholar 

  441. Wan Po A (2006) Editorial commentary. Dose–response of minor analgesics in acute pain. B J Clin Pharmacol 63:268–270

    Google Scholar 

  442. Wagener HH, Vögtle-Junkert U (1996) Intrasubject variability in bioequivalence studies illustrated by the example of ibuprofen. Int J Clin Pharmacol Ther 34:21–31

    CAS  PubMed  Google Scholar 

  443. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR (1999) Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci USA 96:7563–7568

    CAS  PubMed  Article  Google Scholar 

  444. Warrington SJ, Halsey A, O’Donnell L (1982) A comparison of gastrointestinal bleeding in healthy volunteers treated with tiaprofenic acid, aspirin or ibuprofen. Rheumatology 7:107–110

    CAS  Google Scholar 

  445. Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW, Harris SC (2006) Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. J Am Med Assn 296:87–93

    CAS  Article  Google Scholar 

  446. Whelton A (1995) Renal effects of over-the-counter analgesics. J Clin Pharmacol 35:454–463

    CAS  PubMed  Google Scholar 

  447. Whelton A, Stout RL, Spilman PS, Klassen DK (1990) Renal effects of ibuprofen, piroxicam, and sullindac in patients with asymptomatic renal failure. A prospective, randomized, crossover comparison. Ann Intern Med 113:481–482

    Google Scholar 

  448. White WB (2007) Cardiovascular effects of the selective cyclooxygenase-2 inhibitors. Subcell Biochem 42:145–158

    PubMed  Article  Google Scholar 

  449. White WB (2008) Defining the problem of treating the patient with hypertension and arthritis pain. Am J Med 122(5 Suppl):S3–S9

    Google Scholar 

  450. Wilson JT, Brown RD, Kearns GL, Eichler VF, Johnson VA, Bertrand KM, Lowe BA (1991) Single-dose, placebo-controlled comparative study of ibuprofen and acetaminophen antipyresis in children. J Pediatr 119:803–811

    CAS  PubMed  Article  Google Scholar 

  451. Williams K, Day R, Knihinicki R, Duffield A (1986) The stereoselective uptake of ibuprofen enantiomers into adipose tissue. Biochem Pharmacol 35(19):3403–3405

    CAS  PubMed  Article  Google Scholar 

  452. Winter B, Mygynd N (2003) Potential benefits of ibuprofen in the treatment of viral respiratory infections. Inflammopharmacol 11:445–453

    Article  Google Scholar 

  453. Wolf K, Castrop H, Hartner A, Goppelt-Strübe M, Hilgers K, Kurtz A (1999) Inhibition of the rennin-angiotensin system upregulates cyclooxygenase-2 expression in the macula densa. Hypertension 34:503–507

    CAS  PubMed  Google Scholar 

  454. Wolfe MM, Lichtenstein DR, Singh G (1999) Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med 340:1888–1899

    CAS  PubMed  Article  Google Scholar 

  455. Zerr DM, Alexander ER, Duchin JS, Koutsky LA, Rubens CE (1999) A case-control study of necrotizing fasciitis during primary varicella. Pediatrics 103:783–790

    CAS  PubMed  Article  Google Scholar 

  456. Zhang DH, Marconi A, Xu ML, Yang CX, Sun GW, Feng XL, Ling CQ, Qin WZ, Uzan G, d’Alessio P (2006) Tripterine inhibits the expression of adhesion molecules in activated endothelial cells. J Leukoc Biol 80:309–319

    CAS  PubMed  Article  Google Scholar 

  457. Zimmerman HJ (2000) Hepatotoxicity. The adverse effects of drugs and other chemicals on the liver, 2nd edn. Lippincott, Williams & Wilkins, Philadelphia

    Google Scholar 

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Correspondence to K. D. Rainsford.

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Rainsford, K.D. Ibuprofen: pharmacology, efficacy and safety. Inflammopharmacol 17, 275–342 (2009). https://doi.org/10.1007/s10787-009-0016-x

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Keywords

  • Ibuprofen
  • Arthritis
  • Pain
  • Anti-inflammatory
  • Analgesia
  • Antipyresis
  • Prostaglandins
  • Non-prostaglandin mechanisms
  • Adverse reactions