Advances in Therapy

, Volume 29, Issue 2, pp 79–98

5-Lipoxygenase Metabolic Contributions to NSAID-Induced Organ Toxicity

Open Access


Cyclooxygenase (COX)-1, COX-2, and 5-lipoxygenase (5-LOX) enzymes produce effectors of pain and inflammation in osteoarthritis (OA) and many other diseases. All three enzymes play a key role in the metabolism of arachidonic acid (AA) to inflammatory fatty acids, which contribute to the deterioration of cartilage. AA is derived from both phospholipase A2 (PLA2) conversion of cell membrane phospholipids and dietary consumption of omega-6 fatty acids. Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the COX enzymes, but show no anti-5-LOX activity to prevent the formation of leukotrienes (LTs). Cysteinyl LTs, such as LTC4, LTD4, LTE4, and leukoattractive LTB4 accumulate in several organs of mammals in response to NSAID consumption. Elevated 5-LOX-mediated AA metabolism may contribute to the side-effect profile observed for NSAIDs in OA. Current therapeutics under development, so-called “dual inhibitors” of COX and 5-LOX, show improved side-effect profiles and may represent a new option in the management of OA.


arachidonic acid cyclooxygenase flavocoxid leukotrienes licofelone 5-lipoxygenase NSAIDs prostacyclin prostaglandin tepoxalin thromboxane 


  1. 1.
    Hallstrand TS, Henderson WR. An update on the role of leukotrienes in asthma. Curr Opin Allergy Clin Immunol. 2010;10:60–66.PubMedCrossRefGoogle Scholar
  2. 2.
    Chari S, Clark-Loeser L, Shupack J, Washenik K. A role for leukotriene antagonists in atopic dermatitis?. Am J Clin Dermatol. 2001;2:1–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Peters-Golden M, Gleason MM, Togias A. Cysteinyl leukotrienes: multi-functional mediators in allergic rhinitis. Clin Exp Allergy. 2006;36:689–703.PubMedCrossRefGoogle Scholar
  4. 4.
    Mathis S, Jala VR, Haribabu B. Role of leukotriene B4 receptors in rheumatoid arthritis.. Autoimmun Rev. 2007;7:12–17.PubMedCrossRefGoogle Scholar
  5. 5.
    Back M. Leukotriene signaling in atherosclerosis and ischemia. Cardiovasc Drugs Ther. 2009;23:41–48.PubMedCrossRefGoogle Scholar
  6. 6.
    Wang D, Dubois RN. Eicosanoids and cancer. Nat Rev Cancer. 2010;10:181–193.PubMedCrossRefGoogle Scholar
  7. 7.
    Rossi A, Cuzzocrea S, Sautebin L. Involvement of leukotriene pathway in the pathogenesis of ischemia-reperfusion injury and septic and nonseptic shock. Curr Vasc Pharmacol. 2009;7:185–197.PubMedCrossRefGoogle Scholar
  8. 8.
    Henderson WR. The role of leukotrienes in inflammation. Ann Intern Med. 1994;121:684–697.PubMedGoogle Scholar
  9. 9.
    Peters-Golden M, Henderson WR Jr. Leukotrienes. N Engl J Med. 2007;357:1841–1854.PubMedCrossRefGoogle Scholar
  10. 10.
    Sánchez-Borges M, Caballero-Fonseca F, Capriles-Hulett A, Gonzalez-Aveledo L. Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs: an update. Pharmaceuticals. 2010;3:10–18.CrossRefGoogle Scholar
  11. 11.
    Brash AR. Arachidonic acid as a bioactive molecule. J Clin Invest. 2001;107:1339–1345.PubMedCrossRefGoogle Scholar
  12. 12.
    Smith WL, DeWitt DL, Garavito RM. Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem. 2000;69:145–182.PubMedCrossRefGoogle Scholar
  13. 13.
    Spencer AG, Woods JW, Arakawa T, Singer II, Smith WL. Subcellular localization of prostaglandin endoperoxide H synthases-1 and -2 by immunoelectron microscopy. J Biol Chem. 1998;273:9886–9893.PubMedCrossRefGoogle Scholar
  14. 14.
    Bolego C, Buccellati C, Prada A, Gaion RM, Folco G, Sala A. Critical role of COX-1 in prostacyclin production by human endothelial cells under modification of hydroperoxide tone. FASEB J. 2009;23:605–612.PubMedCrossRefGoogle Scholar
  15. 15.
    Ruan CH, So SP, Ruan KH. Inducible COX-2 dominates over COX-1 in prostacyclin biosynthesis: mechanisms of COX-2 inhibitor risk to heart disease. Life Sci. 2011;88:24–30.PubMedCrossRefGoogle Scholar
  16. 16.
    Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000;343:1520–1528.PubMedCrossRefGoogle Scholar
  17. 17.
    Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA. 2000;284:1247–1255.PubMedCrossRefGoogle Scholar
  18. 18.
    Chan FK, Lanas A, Scheiman J, Berger MF, Nguyen H, Goldstein JL. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomized trial. Lancet. 2010;376:173–179.PubMedCrossRefGoogle Scholar
  19. 19.
    Chaiamnuay S, Allison JJ, Curtis JR. Risks versus benefits of cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs. Am J Health Syst Pharm. 2006;63:1837–1851.PubMedCrossRefGoogle Scholar
  20. 20.
    Jüni P, Dieppe P. Older people should NOT be prescribed “coxibs” in place of conventional NSAIDs. Age Ageing. 2004;33:100–104.PubMedCrossRefGoogle Scholar
  21. 21.
    Fiorucci S, Distrutti E, de Lima OM, et al. Relative contribution of acetylated cyclo-oxygenase (COX)-2 and 5-lipooxygenase (LOX) in regulating gastric mucosal integrity and adaptation to aspirin. FASEB J. 2003;17:1171–1173.PubMedGoogle Scholar
  22. 22.
    Bunting S, Moncada S, Vane JR. The prostacyclinthromboxane A2 balance: pathophysiological and theraputic implications. Br Med Bull. 1983;39:271–276.PubMedGoogle Scholar
  23. 23.
    Davidge ST. Prostaglandin H synthase and vascular function. Circ Res. 2001;89:650–660.PubMedCrossRefGoogle Scholar
  24. 24.
    Grosser T, Fries S, Fitzgerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest. 2006;116:4–15.PubMedCrossRefGoogle Scholar
  25. 25.
    Antman EM, DeMets D, Loscalzo J. Cyclooxygenase inhibition and cardiovascular risk. Circulation. 2005;112:759–770.PubMedCrossRefGoogle Scholar
  26. 26.
    Bolli R, Shinmura K, Tang XL, et al. Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning. Cardiovasc Res. 2002;55:506–519.PubMedCrossRefGoogle Scholar
  27. 27.
    Dai W, Kloner RA. Relationship between cyclooxygenase-2 inhibition and thrombogenesis. J Cardiovasc Pharmacol Ther. 2004;9:51–59.PubMedCrossRefGoogle Scholar
  28. 28.
    Guo Y, Bao W, Wu WJ, Shinmura K, Tang XL, Bolli R. Evidence for an essential role of cyclooxygenase-2 as a mediator of the late phase of ischemic preconditioning in mice. Basic Res Cardiol. 2000;95:479–484.PubMedCrossRefGoogle Scholar
  29. 29.
    Caldwell B, Aldington S, Weatherall M, Shirtcliffe P, Beasley R. Risk of cardiovascular events and celecoxib: a systematic review and meta-analysis. J R Soc Med. 2006;99:132–140.PubMedCrossRefGoogle Scholar
  30. 30.
    Targum SL. Consultation NDA 21-042, S-007. Review of cardiovascular safety database. Rofecoxib (MK-0966). US Food and Drugs Administration. Available at: Accessed October 4, 2011.
  31. 31.
    Bresalier RS, Sandler RS, Quan H, et al. Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352:1092–1102. Published correction appears in N Eng J Med. 2006;355:221.PubMedCrossRefGoogle Scholar
  32. 32.
    Merck and Co. Inc. Merck announces voluntary worldwide withdrawal of Vioxx (news release; September 30, 2004). Available at: Accessed November 2, 2006.
  33. 33.
    Herman M. Cardiovascular risk associate with nonsteroidal anti-inflammatory drugs. Curr Rheumatol Reports. 2009;11:31–35.CrossRefGoogle Scholar
  34. 34.
    Schjerning Olsen AM, Fosbøl EL, Lindhardsen J, et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation. 2011;123:2226–2235.PubMedCrossRefGoogle Scholar
  35. 35.
    Harris RC. Cyclooxygenase-2 in the kidney. J Am Soc Nephrol. 2000;11:2387–2394.PubMedGoogle Scholar
  36. 36.
    Whelton A, Hamilton CW. Nonsteroidal anti-inflammatory drugs: effects on kidney function. J Clin Pharmacol. 1991;31:588–598.PubMedGoogle Scholar
  37. 37.
    Whelton A, Schulman G, Wallemark C, et al. Effects of celecoxib and naproxen on renal function in the elderly. Arch Intern Med. 2000;160:1465–1470.PubMedCrossRefGoogle Scholar
  38. 38.
    Whelton A, Fort JG, SUCCESS VI Study Group, et al. Cyclooxygenase-2-specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Am J Ther. 2001;8:85–95.PubMedCrossRefGoogle Scholar
  39. 39.
    Deray G. Renal and cardiovascular effects of nonsteroidal anti-inflammatories and selective cox 2 inhibitors. Presse Med. 2004;33:483–489.PubMedCrossRefGoogle Scholar
  40. 40.
    Bavry AA, Khaliq A, Gong Y, Handberg EM, Cooper-Dehoff RM, Pepine CJ. Harmful effects of NSAIDs among patients with hypertension and coronary artery disease. Am J Med. 2011;124:614–620.PubMedCrossRefGoogle Scholar
  41. 41.
    Chen SH, Fahmi H, Shi Q, Benderdour M. Regulation of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase-activating protein/5-lipoxygenase by 4-hydroxynonenal in human osteoarthritic chondrocytes. Arthritis Res Ther. 2010;12:R21.PubMedCrossRefGoogle Scholar
  42. 42.
    Seuter S, Vaisanen S, Radmark O, Carlberg C, Steinhilber D. Functional characterization of vitamin D responding regions in the human 5-lipoxygenase gene. Biochim Biophys Acta. 2007;1771:864–872.PubMedGoogle Scholar
  43. 43.
    Peters-Golden M, Brock TG. 5-Lipoxygenase and FLAP. Prostaglandins Leukot Essent Fatty Acids. 2003;69:99–109.PubMedCrossRefGoogle Scholar
  44. 44.
    Suzuki YJ, Forman HJ, Sevanian A. Oxidants as stimulators of signal transduction. Free Radical Biol Med. 1996;22:269–285.CrossRefGoogle Scholar
  45. 45.
    Bonizzi G, Piette J, Schoonbroodt S, et al. Reactive oxygen intermediate-dependent NF-κB activation by interleukin-1β requires 5-lipoxygenase or NADPH oxidase activity. Mol Cell Biol. 1999;19:1950–1960PubMedGoogle Scholar
  46. 46.
    Woo CH, Eom YW, Yoo MH, et al. Tumor necrosis factor-α generates reactive oxygen species via a cytosolic phospholipase A2-linked cascade. J Biol Chem. 2000;275:32357–32362.PubMedCrossRefGoogle Scholar
  47. 47.
    Rola-Pleszczynski M. LTB4 and PAF in the cytokine network. Adv Exp Med Biol. 1991;314:205–221.PubMedGoogle Scholar
  48. 48.
    Node K, Huo Y, Ruan X, et al. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science. 1999;285:1276–1290.PubMedCrossRefGoogle Scholar
  49. 49.
    Spector AA, Norris AW. Action of epoxyeicosatrienoic acids on cellular function. Am J Physiol Cell Physiol. 2007;292:C996–C1012.PubMedCrossRefGoogle Scholar
  50. 50.
    Nithipatikom K, Gross GJ. Review article: epoxyeicosatrienoic acids: novel mediators of cardioprotection. J Cardiovasc Pharmacol Ther. 2010;15:112–119.PubMedCrossRefGoogle Scholar
  51. 51.
    Spiecker M, Liao J. Cytochrome P450 epoxygenase CYP2J2 and the risk of coronary artery disease. Trends Cardiovasc Med. 2006;16:204–208.PubMedCrossRefGoogle Scholar
  52. 52.
    Williams JM, Murphy S, Burke M, Roman RJ. 20-Hydroxyeicosatetraeonic acid: a new target for the treatment of hypertension. J Cardiovasc Pharmacol. 2010;56:336–344.PubMedCrossRefGoogle Scholar
  53. 53.
    Serhan CN, Oliw E. Unorthodox routes to prostanoid formation: new twists in cyclooxygenase-initiated pathways. J Clin Invest. 2001;107:1481–1489.PubMedCrossRefGoogle Scholar
  54. 54.
    Ferreri NR, Howland WC, Stevenson DD, Spiegelberg HL. Release of leukotrienes, prostaglandins, and histamine into nasal secretions of aspirin-sensitive asthmatics during reaction to aspirin. Am Rev Respir Dis. 1988;137:847–854.PubMedGoogle Scholar
  55. 55.
    Picado C. Mechanisms of aspirin sensitivity. Curr Allergy Asthma Rep. 2006;6:198–202.PubMedCrossRefGoogle Scholar
  56. 56.
    Cowburn AS, Sladek K, Soja J, et al. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J Clin Invest. 1998;101:834–846.PubMedCrossRefGoogle Scholar
  57. 57.
    Hedman J, Kaprio J, Poussa T, Nieminen MM. Prevalence of asthma, aspirin intolerance, nasal polyposis and chronic obstructive pulmonary disease in a population-based study. Int J Epidemiol. 1999;28:717–722.PubMedCrossRefGoogle Scholar
  58. 58.
    Babu KS, Salvi SS. Aspirin and asthma. Chest. 2000;118:1470–1476.PubMedCrossRefGoogle Scholar
  59. 59.
    Bavbek S, Celik G, Ozer F, Mungan D, Misirligil Z. Safety of selective COX-2 inhibitors in aspirin/nonsteroidal anti-inflammatory drug-intolerant patients: comparison of nimesulide, meloxicam, and rofecoxib. J Asthma. 2004;41:67–75.PubMedCrossRefGoogle Scholar
  60. 60.
    Dahlen B, Szczeklik A, Murray JJ. Celecoxib in patients with asthma and aspirin intolerance. The Celecoxib in Aspirin-Intolerant Asthma Study Group. N Engl J Med. 2001;344:142.PubMedCrossRefGoogle Scholar
  61. 61.
    Celik G, Pasaoglu G, Bavbek S, et al. Tolerability of selective cyclooxygenase inhibitor, celecoxib, in patients with analgesic intolerance. J Asthma. 2005;42:127–131.PubMedCrossRefGoogle Scholar
  62. 62.
    Valero A, Enrique E, Baltasar M, Cisteró A, Martí E, Picado C. Celecoxib in NSAID-induced cutaneous and respiratory adverse reactions. Med Clin (Barc). 2003;121:695–696.CrossRefGoogle Scholar
  63. 63.
    Mastalerz L, Sanak M, Gawlewicz A, Gielicz A, Faber J, Szczeklik A. Different eicosanoid profile of the hypersensitivity reactions triggered by aspirin and celecoxib in a patient with sinusitis, asthma, and urticaria. J Allergy Clin Immunol. 2006;118:957–958.PubMedCrossRefGoogle Scholar
  64. 64.
    Muñoz-Cano R, Bartra J, Vennera MC, Valero A, Picado C. Asthmatic reaction induced by celecoxib in a patient with aspirin-induced asthma. J Investig Allergol Clin Immunol. 2009;19:64–79.Google Scholar
  65. 65.
    Abraham WM, Laufer S, Tries S. The effects of ML 3000 on antigen-induced responses in sheep. Pulm Pharmacol Ther. 1997;10:167–173.PubMedCrossRefGoogle Scholar
  66. 66.
    Morgan SL, Baggott JE, Moreland L, Desomond R, Kendrach A. The safety of flavocoxid, a medical food, in the dietary management of knee osteoarthritis. J Med Food. 2009;12:1143–1148.PubMedCrossRefGoogle Scholar
  67. 67.
    Wallace JL, Ma L. Inflammatory mediators in gastrointestinal defense and injury. Exp Biol Med (Maywood). 2001;226:1003–1015.Google Scholar
  68. 68.
    Peskar BM. Role of leukotrience C4 in mucosal damage caused by necrotizing agents and indomethacin in the rat stomach. Gasteroenterology. 1991;100:619–626.Google Scholar
  69. 69.
    Rainsford KD. Leukotrienes in the pathogenesis of NSAID-induced gastric and intestinal mucosal damage. Agents Actions. 1993;39:C24–C26.PubMedCrossRefGoogle Scholar
  70. 70.
    Rainsford KD. Inhibition by leukotriene inhibitors, and calcium and platelet-activating factor antagonists, of acute gastric and intestinal damage in arthritic rats and in cholinomimetic-treated mice. J Pharm Pharmacol. 1999;51:331–339.PubMedCrossRefGoogle Scholar
  71. 71.
    Laine L, Sloane R, Ferretti M, Cominelli FA. Randomized, double-blind comparison of placebo, etodolac and naproxen on gastrointestinal injury and prostaglandin production. Gastrointest Endosc. 1995;42:428–433.PubMedCrossRefGoogle Scholar
  72. 72.
    Melarange R, Spangler R, Hoult JR. The in vitro effects of 6-methoxy-2-naphthylacetic acid, the active metabolite of nabumetone, on rat gastric mucosal eicosanoid synthesis and metabolism. Prostaglandins Leukot Essent Fatty Acids. 1996;55:195–200.PubMedCrossRefGoogle Scholar
  73. 73.
    Dreyling KW, Hoppe U, Peskar BA, Morgenroth K, Kozuschek W, Peskar BM. Leukotriene synthesis by human gastrointestinal tissues. Biochim Biophys Acta. 1986;878:184–193.PubMedGoogle Scholar
  74. 74.
    Scheiman JM, Tillner A, Pohl T, et al. Reduction of non-steroidal anti-inflammatory drug induced gastric injury and leucocyte endothelial adhesion by octreotide. Gut. 1997;40:720–725.PubMedCrossRefGoogle Scholar
  75. 75.
    Vieth M, Müller H, Stolte M. Can the diagnosis of NSAID-induced or Hp-associated gastric ulceration be predicted from histology? Z Gastroenterol. 2002;40:783–788.PubMedCrossRefGoogle Scholar
  76. 76.
    Taha AS, Dahill S, Morran C, et al. Neutrophils, Helicobacter pylori, and nonsteroidal anti-inflammatory drug ulcers. Gastroenterology. 1999;116:254–258.PubMedCrossRefGoogle Scholar
  77. 77.
    Konturek JW, Dembinski A, Stoll R, Domschke W, Konturek SJ. Mucosal adaptation to aspirin induced gastric damage in humans. Studies on blood flow, gastric mucosal growth, and neutrophil activation. Gut. 1994;35:1197–1204.PubMedCrossRefGoogle Scholar
  78. 78.
    Hudson N, Balsitis M, Everitt S, Hawkey CJ. Enhanced gastric mucosal leukotriene B4 synthesis in patients taking non-steroidal anti-inflammatory drugs. Gut. 1993;34:742–747.PubMedCrossRefGoogle Scholar
  79. 79.
    Kirchner T, Aparicio B, Argentieri DC, Lau CY, Ritchie DM. Effects of tepoxalin, a dual inhibitor of cyclooxygenase/5-lipoxygenase, on events associated with NSAID-induced gastrointestinal inflammation. Prostaglandins Leukot Essent Fatty Acids. 1997;56:417–423.PubMedCrossRefGoogle Scholar
  80. 80.
    Bias P, Buchner A, Klesser B, Laufer S. The gastrointestinal tolerability of the LOX/COX inhibitor, licofelone, is similar to placebo and superior to naproxen therapy in healthy volunteers: results from a randomized, controlled trial. Am J Gastroenterol. 2004;99:611–618.PubMedCrossRefGoogle Scholar
  81. 81.
    Levy RM, Khokhlov A, Kopenkin S, et al. Efficacy and safety of flavocoxid, a novel therapeutic, compared with naproxen, in subjects with osteoarthritis of the knee. Adv Ther. 2010;27:731–742.PubMedCrossRefGoogle Scholar
  82. 82.
    Pillai L, Burnett BP, Levy RM. GOAL: multicenter, open-label, post-marketing study of flavocoxid, a novel dual pathway inhibitor anti-inflammatory agent of botanical origin. Curr Med Res Opin. 2010;26:1055–1063.PubMedCrossRefGoogle Scholar
  83. 83.
    Mehrabian M, Allayee H, Wong J, et al. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ Res. 2002;91:120–126.PubMedCrossRefGoogle Scholar
  84. 84.
    Zhao L, Moos MP, Grabner R, et al. The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm. Nat Med. 2004;10:966–973.PubMedCrossRefGoogle Scholar
  85. 85.
    Spanbroek R, Grabner R, Lotzer K, et al. Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. Proc Natl Acad Sci USA. 2003;100:1238–1243.PubMedCrossRefGoogle Scholar
  86. 86.
    Helgadottir A, Gretarsdottir S, St Clair D, et al. Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population. Am J Hum Genet. 2005;76:505–509.PubMedCrossRefGoogle Scholar
  87. 87.
    Maznyczka A, Braund P, Mangino M, Samani NJ. Arachidonate 5-lipoxygenase (5-LO) promoter genotype and risk of myocardial infarction: a casecontrol study. Atherosclerosis. 2008;199:328–332.PubMedCrossRefGoogle Scholar
  88. 88.
    Dwyer JH, Allayee H, Dwyer KM, et al. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med. 2004;350:29–37.PubMedCrossRefGoogle Scholar
  89. 89.
    Allayee H, Baylin A, Hartiala J, et al. Nutrigenetic association of the 5-lipoxygenase gene with myocardial infarction. Am J Clin Nutr. 2008;88:934–940.PubMedGoogle Scholar
  90. 90.
    Carry M, Korley V, Willerson JT, Weigelt L, Ford-Hutchinson AW, Tagari P. Increased urinary leukotriene excretion in patients with cardiac ischemia. In vivo evidence for 5-lipoxygenase activation. Circulation. 1992;85:230–236.PubMedGoogle Scholar
  91. 91.
    Solomon DH, Schneeweiss S, Glynn RJ, et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation. 2004;109:2068–2073.PubMedCrossRefGoogle Scholar
  92. 92.
    Roumie CL, Choma NN, Kaltenbach L, Mitchel EF Jr., Arbogast PG, Griffin MR. Non-aspirin NSAIDs, cyclooxygenase-2 inhibitors and risk for cardiovascular events — stroke, acute myocardial infarction, and death from coronary heart disease. Pharmacoepidemiol Drug Saf. 2009;18:1053–1063.PubMedCrossRefGoogle Scholar
  93. 93.
    Solomon SD, McMurray JJ, Pfeffer MA, et al Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005;352:1071–1080.PubMedCrossRefGoogle Scholar
  94. 94.
    Solomon SD, Pfeffer MA, for the APC and PreSAP Trial Investigators, et al. Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas. Circulation. 2006;114:1028–1035.PubMedCrossRefGoogle Scholar
  95. 95.
    ADAPT Research Group. Cardiovascular and cerebrovascular events in the randomized, controlled Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT). PLoS Clin Trials. 2006;1:e33.CrossRefGoogle Scholar
  96. 96.
    Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal antiinflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086.PubMedCrossRefGoogle Scholar
  97. 97.
    Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclooxygenase-2 inhibitors and traditional nonsteroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomized trials. BMJ. 2006;332:1302–1308.PubMedCrossRefGoogle Scholar
  98. 98.
    Solomon DH. Selective cyclooxygenase 2 inhibitors and cardiovascular events. Arthritis Rheum. 2005;52:1968–1978.PubMedCrossRefGoogle Scholar
  99. 99.
    Sun SY, Wang W, Schultz HD. Activation of cardiac afferents by arachidonic acid: relative contributions of metabolic pathways. Am J Physiol Heart Circ Physiol. 2001;281:H93–H104.PubMedGoogle Scholar
  100. 100.
    Stanke-Labesque F, Devillier P, Bedouch P, Cracowski JL, Chavanon O, Bessard G. Angiotensin II-induced contractions in human internal mammary artery: effects of cyclooxygenase and lipoxygenase inhibition. Cardiovasc Res. 2000;47:376–383.PubMedCrossRefGoogle Scholar
  101. 101.
    Brown PH, Subbaramaiah K, Salmon AP, et al. Combination chemoprevention of HER2/neuinduced breast cancer using a cyclooxygenase-2 inhibitor and a retinoid X receptor-selective retinoid. Cancer Prev Res (Phila). 2008;1:208–214.CrossRefGoogle Scholar
  102. 102.
    Duffield-Lillico AJ, Boyle JO, Zhou XK, et al. Levels of prostaglandin E metabolite and leukotriene E(4) are increased in the urine of smokers: evidence that celecoxib shunts arachidonic acid into the 5-lipoxygenase pathway. Cancer Prev Res (Phila). 2009;2:322–329.CrossRefGoogle Scholar
  103. 103.
    Zhang YY, Walker JL, Huang A, et al. Expression of 5-lipoxygenase in pulmonary artery endothelial cells. Biochem J. 2002;361:267–276.PubMedCrossRefGoogle Scholar
  104. 104.
    Allen S, Dashwood M, Morrison K, Yacoub M. Differential leukotriene constrictor responses in human atherosclerotic coronary arteries. Circulation. 1998;97:2406–2413.PubMedGoogle Scholar
  105. 105.
    Sala A, Aliev GM, Rossoni G, et al. Morphological and functional changes of coronary vasculature caused by transcellular biosynthesis of sulfidopeptide leukotrienes in isolated heart of rabbit. Blood. 1996;87:1824–1832.PubMedGoogle Scholar
  106. 106.
    Vidal C, Gomez-Hernandez A, Sanchez-Galan E, et al. Licofelone, a balanced inhibitor of cyclooxygenase and 5-lipoxygenase, reduces inflammation in a rabbit model of atherosclerosis. J Pharmacol Exp Ther. 2007;320:108–116.PubMedCrossRefGoogle Scholar
  107. 107.
    Vlassara H, Torreggiani M, Post JB, Zheng F, Uribarri J, Striker GE. Role of oxidants/inflammation in declining renal function in chronic kidney disease and normal aging. Kidney Int Suppl. 2009;76:S3–11.CrossRefGoogle Scholar
  108. 108.
    Lauretani F, Semba RD, Bandinelli S, et al. Plasma polyunsaturated fatty acids and the decline of renal function. Clin Chem. 2008;54:475–481.PubMedCrossRefGoogle Scholar
  109. 109.
    Komers R, Epstein M. Cyclooxygenase-2 expression and function in renal pathophysiology. J Hypertens Suppl. 2002;20:S11–15.PubMedCrossRefGoogle Scholar
  110. 110.
    Lefkowith JB. Essential fatty acid deficiency inhibits the in vivo generation of leukotriene B4 and suppresses levels of resident and elicited leukocytes in acute inflammation. J Immunol. 1988;140:228–233.PubMedGoogle Scholar
  111. 111.
    Rifai A, Sakai H, Yagame M. Expression of 5-lipoxygenase and 5-lipoxygenase activation protein in glomerulonephritis. Kidney Int Suppl. 1993;39:S95–99.PubMedGoogle Scholar
  112. 112.
    Rahman MA, Nakazawa M, Emancipator SN, Dunn MJ. Increased leukotriene B4 synthesis in immune injured rat glomeruli. J Clin Invest. 1988;81:1945–1952.PubMedCrossRefGoogle Scholar
  113. 113.
    Maccarrone M, Taccone-Gallucci M, Meloni C, et al. Activation of 5-lipoxygenase and related cell membrane lipoperoxidation in hemodialysis patients. J Am Soc Nephrol. 1999;10:1991–1996.PubMedGoogle Scholar
  114. 114.
    Noiri E, Yokomizo T, Nakao A, et al. An in vivo approach showing the chemotactic activity of leukotriene B(4) in acute renal ischemic-reperfusion injury. Proc Natl Acad Sci USA. 2000;97:823–828.PubMedCrossRefGoogle Scholar
  115. 115.
    Badr KF. Five-lipoxygenase products in glomerular immune injury. J Am Soc Nephrol. 1992;3:907–915.PubMedGoogle Scholar
  116. 116.
    Petric R, Ford-Hutchinson A. Inhibition of leukotriene biosynthesis improves renal function in experimental glomerulonephritis. J Lipid Mediat Cell Signal. 1995;11:231–240.PubMedCrossRefGoogle Scholar
  117. 117.
    Albrightson CR, Short B, Dytko G, et al. Selective inhibition of 5-lipoxygenase attenuates glomerulonephritis in the rat. Kidney Int. 1994;45:1301–1310.PubMedCrossRefGoogle Scholar
  118. 118.
    Raynauld JP, Martel-Pelletier J, Bias P, et al. Protective effects of licofelone, a 5-lipoxygenase and cyclo-oxygenase inhibitor, versus naproxen on cartilage loss in knee osteoarthritis: a first multicentre clinical trial using quantitative MRI. Ann Rheum Dis. 2009;68:938–947.PubMedCrossRefGoogle Scholar
  119. 119.
    Fusellier M, Desfontis JC, Madec S, et al. Effect of tepoxalin on renal function in healthy dogs receiving an angiotensin-converting enzyme inhibitor. J Vet Pharmacol Ther. 2005;28:581–586.PubMedCrossRefGoogle Scholar
  120. 120.
    Kay-Mugford PA, Grimm KA, Weingarten AJ, Brianceau P, Lockwood P, Cao J. Effect of preoperative administration of tepoxalin on hemostasis and hepatic and renal function in dogs. Vet Ther. 2004;5:120–127.PubMedGoogle Scholar
  121. 121.
    Burnett BP, Silva S, Mesches MH, Jia Q. Safety evaluation of a combination, defined extract of Scutellaria baicalensis and Acacia catechu. J Food Biochem. 2007;31:797–825.CrossRefGoogle Scholar
  122. 122.
    Yimam M, Zhao Y, Ma W, Jia Q, Do SG, Shin JH. 90-Day oral toxicity study of UP446, a combination of defined extracts of Scutellaria baicalensis and Acacia catechu, in rats. Food Chem Toxicol. 2010;48:1202–129.PubMedCrossRefGoogle Scholar
  123. 123.
    Burnett BP, Stenstrom KK, Baarsch MJ, Swafford WS, Ehrenzweig J, Levy RM. A flavonoid mixture, dual inhibitor of cyclooxygenase and 5-lipoxygenase enzymes, shows superiority to glucosamine/chondroitin for pain management in moderate osteoarthritic dogs. Intern J Appl Vet Med. 2009;7:1–12.Google Scholar
  124. 124.
    Levy R, Saikovsky R, Shmidt E, Khokhlov A, Burnett BP. Flavocoxid is as effective as naproxen for managing the signs and symptoms of osteoarthritis of the knee in humans: a short-term randomized, double-blind pilot study. Nutr Res. 2009;29:298–304.PubMedCrossRefGoogle Scholar
  125. 125.
    Shimizu T, Wolfe LS. Arachidonic acid cascade and signal transduction. J Neurochem. 1990;55:1–15.PubMedCrossRefGoogle Scholar
  126. 126.
    Zhou BF, Stamler J, Dennis B, et al. Nutrient intakes of middle-aged men and women in China, Japan, United Kingdom, and United States in the late 1990s: the INTERMAP study. J Hum Hypertens. 2003;17:623–630.PubMedCrossRefGoogle Scholar
  127. 127.
    Plumb MS, Aspden RM. High levels of fat and (n-6) fatty acids in cancellous bone in osteoarthritis. Lipids Health Dis. 2004;3:12.PubMedCrossRefGoogle Scholar
  128. 128.
    Paredes Y, Massicotte F, Pelletier JP, Martel-Pelletier J, Laufer S, Lajeunesse D. Study of the role of leukotriene B4 in abnormal function of human subchondral osteoarthritis osteoblasts: effects of cyclooxygenase and/or 5-lipoxygenase inhibition. Arthritis Rheum. 2002;46:1804–1812.PubMedCrossRefGoogle Scholar
  129. 129.
    Maxis K, Delalandre A, Martel-Pelletier J, Pelletier JP, Duval N, Lajeunesse D. The shunt from the cyclooxygenase to lipoxygenase pathway in human osteoarthritic subchondral osteoblasts is linked with a variable expression of the 5-lipoxygenaseactivating protein. Arthritis Res Ther. 2006;8:R181.PubMedCrossRefGoogle Scholar
  130. 130.
    Anderson GD, Keys KL, De Ciechi PA, Masferrer JL. Combination therapies that inhibit cyclooxygenase-2 and leukotriene synthesis prevent disease in murine collagen induced arthritis. Inflamm Res. 2009;58:109–117.PubMedCrossRefGoogle Scholar
  131. 131.
    Huskisson EC, Berry H, Gishen P, Jubb RW, Whitehead J. Effects of antiinflammatory drugs on the progression of osteoarthritis of the knee. LINK Study Group. Longitudinal Investigation of Nonsteroidal Antiinflammatory Drugs in Knee Osteoarthritis. J Rheumatol. 1995;22:1941–1946.PubMedGoogle Scholar
  132. 132.
    Clausen PA, Flechtenmacher J, Haeuselmann HJ, Kuettner KE, Aydelotte MB, Iyer AP. Evidence of an eicosanoid contribution to IL-1 induction of IL-6 in human articular chondrocytes. Am J Ther. 1996;3:101–108.PubMedCrossRefGoogle Scholar
  133. 133.
    Martel-Pelletier J, Mineau F, Fahmi H, et al. Regulation of the expression of 5-lipoxygenaseactivating protein/5-lipoxygenase and the synthesis of leukotriene B(4) in osteoarthritic chondrocytes: role of transforming growth factor β and eicosanoids. Arthritis Rheum. 2004;50:3925–3933.PubMedCrossRefGoogle Scholar
  134. 134.
    Marcouiller P, Pelletier JP, Guévremont M, et al. Leukotriene and prostaglandin synthesis pathways in osteoarthritic synovial membranes: regulating factors for interleukin 1β synthesis. J Rheumatol. 2005;32:704–712.PubMedGoogle Scholar
  135. 135.
    Charlier C, Michaux C. Dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) as a new strategy to provide safer nonsteroidal anti-inflammatory drugs. Eur J Med Chem. 2003;38:645–659.PubMedCrossRefGoogle Scholar
  136. 136.
    Martel-Pelletier J, Lajeunesse D, Reboul P, Pelletier JP. Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs. Ann Rheum Dis. 2003;62:501–509.PubMedCrossRefGoogle Scholar
  137. 137.
    Pelletier JP, Boileau C, Boily M, et al. The protective effect of licofelone on experimental osteoarthritis is correlated with the downregulation of gene expression and protein synthesis of several major cartilage catabolic factors: MMP-13, cathepsin K and aggrecanases. Arthritis Res Ther. 2005;7:R1091–R1102.PubMedCrossRefGoogle Scholar
  138. 138.
    Gay RE, Neidhart M, Pataky F, Tries S, Laufer S, Gay S. Dual inhibition of 5-lipoxygenase and cyclooxygenases 1 and 2 by ML3000 reduces joint destruction in adjuvant arthritis. J Rheumatol. 2001;28:2060–2065.PubMedGoogle Scholar
  139. 139.
    Boileau C, Martel-Pelletier J, Jouzeau JY, et al. Licofelone (ML-3000), a dual inhibitor of 5-lipoxygenase and cyclooxygenase, reduces the level of cartilage chondrocyte death in vivo in experimental dog osteoarthritis: inhibition of proapoptotic factors. J Rheumatol. 2002;29:1446–1453.PubMedGoogle Scholar
  140. 140.
    Rainsford KD, Ying C, Smith F. Effects of 5-lipoxygenase inhibitors on interleukin production by human synovial tissues in organ culture: comparison with interleukin-1-synthesis inhibitors. J Pharm Pharmacol. 1996;48:46–52.PubMedCrossRefGoogle Scholar
  141. 141.
    Macrory L, Vaughan-Thomas A, Clegg PD, Innes JF. An exploration of the ability of tepoxalin to ameliorate the degradation of articular cartilage in a canine in vitro model. BMC Vet Res. 2009;5:25.PubMedCrossRefGoogle Scholar
  142. 142.
    Raynauld JP, Martel-Pelletier J, Abram F, et al. Analysis of the precision and sensitivity to change of different approaches to assess cartilage loss by quantitative MRI in a longitudinal multicentre clinical trial in patients with knee osteoarthritis. Arthritis Res Ther. 2008;10:R129.PubMedCrossRefGoogle Scholar
  143. 143.
    Klickstein LB, Shapleigh C, Goetzl EJ. Lipoxygenation of arachidonic acid as a source of polymorphonuclear leukocyte chemotactic factors in synovial fluid and tissue in rheumatoid arthritis and spondyloarthritis. J Clin Invest. 1980;66:1166–1170.PubMedCrossRefGoogle Scholar
  144. 144.
    Koshihara, Y, Isono T, Oda H, Karube S, Hayashi Y. Measurement of sulfidopeptide leukotrienes and their metabolism in human synovial fluid of patients with rheumatoid arthritis. Prostaglandins Leukot Essent Fatty Acids. 1988;32:113–119.PubMedGoogle Scholar
  145. 145.
    Nakamura H, Hishinuma T, Suzuki N, et al. Difference in urinary 11-dehydro TXB2 and LTE4 excretion in patients with rheumatoid arthritis. Prostaglandins Leukot Essent Fatty Acids. 2001;65:301–306.PubMedCrossRefGoogle Scholar
  146. 146.
    Edwards SW, Hallett MB. Seeing the wood for the trees: the forgotten role of neutrophils in rheumatoid arthritis. Immunol Today. 1997;18:320–324.PubMedCrossRefGoogle Scholar
  147. 147.
    Chen M, Lam BK, Kanaoka L, et al. Neutrophilderived leukotriene B4 is required for inflammatory arthritis. J Exp Med. 2006;203:837–842.PubMedCrossRefGoogle Scholar
  148. 148.
    Griffiths RJ, Pettipher ER, Koch K, et al. Leukotriene B4 plays a critical role in the progression of collagen-induced arthritis. Proc Natl Acad Sci. USA. 1995;92:517–521.PubMedCrossRefGoogle Scholar
  149. 149.
    Griffiths RJ, Smith MA, Roach ML, et al. Collagen-induced arthritis is reduced in 5-lipoxygenaseactivating protein-deficient mice. J Exp Med. 1997;185:1123–1129.PubMedCrossRefGoogle Scholar
  150. 150.
    Sperling RI, Benincaso AI, Anderson RJ, Coblyn JS, Austen KF, Weinblatt ME. Acute and chronic suppression of leukotriene B4 synthesis ex vivo in neutrophils from patients with rheumatoid arthritis beginning treatment with methotrexate. Arthritis Rheum. 1992;35:376–384.PubMedCrossRefGoogle Scholar
  151. 151.
    Allendorf DJ, Yan J, Ross GD, et al. C5a-mediated leukotriene B4-amplified neutrophil chemotaxis is essential in tumor immunotherapy facilitated by anti-tumor monoclonal antibody and β-glucan. J Immunol. 2005;174:7050–7056.PubMedGoogle Scholar
  152. 152.
    de Weck AL, Gamboa PM Esparza R, Sanz ML. Hypersensitivity to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Curr Pharm Des. 2006;12:3347–3358.PubMedCrossRefGoogle Scholar
  153. 153.
    Goodman L, Coles TB, Budsberg S. Leukotriene inhibition in small animal medicine. J Vet Pharmacol Ther. 2008;31:387–398.PubMedCrossRefGoogle Scholar
  154. 154.
    Asero R. Leukotriene receptor antagonists may prevent NSAID-induced exacerbations in patients with chronic urticaria. Ann Allergy Asthma Immunol. 2000;85:156–157.PubMedCrossRefGoogle Scholar
  155. 155.
    Faucheron JL, Parc R. Non-steroidal antiinflammatory drug-induced colitis. Int J Colorectal Dis. 1996;11:99–101.PubMedGoogle Scholar
  156. 156.
    Wallace JL, Keenan CM. Leukotriene B4 potentiates colonic ulceration in the rat. Dig Dis Sci. 1990;35:622–629.PubMedCrossRefGoogle Scholar
  157. 157.
    Lanas A. Nonsteroidal antiinflammatory drugs and cyclooxygenase inhibition in the gastrointestinal tract: a trip from peptic ulcer to colon cancer. Am J Med Sci. 2009;338:96–106.PubMedCrossRefGoogle Scholar
  158. 158.
    Rask-Madsen J, Bukhave K, Laursen LS, Lauritsen K. 5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease. Agents Actions. 1992;Spec No:C37-46.Google Scholar
  159. 159.
    Shapiro H, Singer P, Halpern Z, Bruck R. Polyphenols in the treatment of inflammatory bowel disease and acute pancreatitis. Gut. 2007;56:426–435.PubMedCrossRefGoogle Scholar
  160. 160.
    Polito F, Bitto A, Irrera N, et al. Flavocoxid, a dual inhibitor of COX-2 and 5-LOX, reduces pancreatic damage in an experimental model of acute pancreatitis. Brit J Pharmacol. 2010;161:1002–1011.CrossRefGoogle Scholar
  161. 161.
    Fischer L, Hornig M, Pergola C, et al. The molecular mechanism of the inhibition by licofelone of the biosynthesis of 5-lipoxygenase products. Br J Pharmacol. 2007;152:471–480.PubMedCrossRefGoogle Scholar
  162. 162.
    Tries S, Neupert W, Laufer S. The mechanism of action of the new antiinflammatory compound ML3000: inhibition of 5-LOX and COX-1/2. Inflamm Res. 2002;51:135–143.PubMedCrossRefGoogle Scholar
  163. 163.
    Bau B, Gebhard PM, Haag J, Knorr T, Bartnik E, Aigner T. Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro. Arthritis Rheum. 2002;46:2648–2657.PubMedCrossRefGoogle Scholar
  164. 164.
    Tam SS, Lee DH, Wang EY, Munroe DG, Lau CY. Tepoxalin, a novel dual inhibitor of the prostaglandin-H synthase cyclooxygenase and peroxidase activities. J Biol Chem. 1995;270:13948–13955.PubMedCrossRefGoogle Scholar
  165. 165.
    Lee JI, Burckart GJ. Nuclear factor κB: important transcription factor and therapeutic target. J Clin Pharmacol. 1998;38:981–993.PubMedCrossRefGoogle Scholar
  166. 166.
    Altavilla D, Squadrito F, Bitto A, et al. Flavocoxid, a dual inhibitor of cyclooxygenase and 5-lipoxygenase, blunts pro-inflammatory phenotype activation in endotoxin stimulated macrophages. Brit J Pharmacol. 2009;157:1410–1418.CrossRefGoogle Scholar
  167. 167.
    Messina S, Bitto A, Aguennouz M, et al. Flavocoxid inhibits NF-κB, MAPKs and COX/5-LOX pathways and improves muscle function and morphology in mdx mice: a comparison study with methylprednisolone. Exp Neurol. 2009;220:349–358.PubMedCrossRefGoogle Scholar
  168. 168.
    Burnett BP, Bitto A, Sqadrito F, Levy RM, Pillai L. Flavocoxid inhibits phospholipase A2, peroxidase moieties of the cyclooxygenases (COX), 5-lipoxygenase, modifies COX-2 gene expression and acts as an antioxidant. Mediators Inflamm. 2011:385780.Google Scholar

Copyright information

© Springer Healthcare 2012

Authors and Affiliations

  1. 1.Department of Medical Education and Scientific AffairsPrimus Pharmaceuticals, Inc.ScottsdaleUSA
  2. 2.Department of Clinical DevelopmentPrimus Pharmaceuticals, Inc.ScottsdaleUSA

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