Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs

Annals of the Rheumatic Diseases

Volumn 62, Issue 6, 2003, Pages 501-509

  Martel Pelletier, J ^a   Lajeunesse, D ^a   Reboul, P ^a   Pelletier, J P ^a  

^a NOTRE DAME HOSPITAL   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

3 AMINO 1 (3 TRIFLUOROMETHYLPHENYL) 2 PYRAZOLINE; ACETYLSALICYLIC ACID; ARACHIDONATE 5 LIPOXYGENASE; CELECOXIB; CYCLOOXYGENASE 1; CYCLOOXYGENASE 2; DEXAMETHASONE; ER 34122; INDOMETACIN; LEUKOTRIENE; LEUKOTRIENE B4; LEUKOTRIENE C4; LEUKOTRIENE D4; LEUKOTRIENE E4; LICOFELONE; LIPOXIN; LIPOXIN A; LIPOXIN B; LIPOXYGENASE INHIBITOR; NAPROXEN; NONSTEROID ANTIINFLAMMATORY AGENT; PROSTACYCLIN; PROSTAGLANDIN SYNTHASE INHIBITOR; SF F 86002; TEPOXALIN; UNCLASSIFIED DRUG;

ANTIINFLAMMATORY ACTIVITY; ARTHRITIS; CLINICAL TRIAL; DRUG EFFECT; DRUG EFFICACY; ENZYME ACTIVITY; ENZYME INHIBITION; GASTROINTESTINAL MUCOSA; GASTROINTESTINAL SYMPTOM; HUMAN; INFLAMMATION; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; STOMACH ULCER; THROMBOSIS;

ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ARACHIDONATE 5-LIPOXYGENASE; CYCLOOXYGENASE INHIBITORS; DRUG SYNERGISM; HUMANS; INFLAMMATION; LEUKOTRIENES; LIPOXYGENASE INHIBITORS; PROSTAGLANDIN-ENDOPEROXIDE SYNTHASES;

EID: 0038147318     PISSN: 00034967     EISSN: None     Source Type: Journal    
DOI: 10.1136/ard.62.6.501     Document Type: Review

References (102)

1. Furst DE. Pharmacology and efficacy of cyclooxygenase (COX) inhibitors. Am J Med 1999;107(suppl):18-26S.
2. Miller TA. Protective effects of prostaglandins against gastric mucosal damage: current knowledge and proposed mechanisms. Am J Physiol 1983;245:G601-23.
3. Schlondorff D. Renal complications of nonsteroidal anti-inflammatory drugs. Kidney Int 1993;44:643-53.
4. Smith WL, Garavito RM, DeWitt DL. Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2. J Biol Chem 1996;271:33157-60.
5. Jouzeau JY, Terlain B, Abid A, Nedelec E, Netter P. Cyclo-oxygenase isoenzymes. How recent findings affect thinking about nonsteroidal anti-inflammatory drugs. Drugs 1997;53:563-82.
6. Fu JY, Masferrer JL, Seibert K, Raz A, Needleman P. The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J Biol Chem 1990;265:16737-40.
7. Maslinska D, Kaliszek A, Opertowska J, Toborowicz J, Deregowski K, Szukiewicz D. Constitutive expression of cyclooxygenase-2 (COX-2) in developing brain. A. Choroid plexus in human fetuses. Folia Neuropathol 1999;37:287-91.
8. Komhoff M, Wang JL, Cheng HF, Langenbach R, McKanna JA, Harris RC, et al. Cyclooxygenase-2-selective inhibitors impair glomerulogenesis and renal cortical development. Kidney Int 2000;57:414-22.
9. Belvisi MG, Saunders M, Yacoub M, Mitchell JA. Expression of cyclo-oxygenase-2 in human airway smooth muscle is associated with profound reductions in cell growth. Br J Pharmacol 1998;125:1102-8.
10. Sousa A, Pfister R, Christie PE, Lane SJ, Nasser SM, Schmitz-Schumann M, et al. Enhanced expression of cyclo-oxygenase isoenzyme 2 (COX-2) in asthmatic airways and its cellular distribution in aspirin-sensitive asthma. Thorax 1997;52:940-5.
11. Kawai S. Cyclooxygenase selectivity and the risk of gastro-intestinal complications of various non-steroidal anti-inflammatory drugs: a clinical consideration. Inflamm Res 1998;47(suppl 2):S102-6.
12. Schmassmann A, Peskar BM, Stettler C, Netzer P, Stroff T, Flogerzi B, et al. Effects of inhibition of prostaglandin endoperoxide synthase-2 in chronic gastro-intestinal ulcer models in rats. Br J Pharmacol 1998;123:795-804.
13. Katori M, Majima M. Cyclooxygenase-2: its rich diversity of roles and possible application of its selective inhibitors. Inflamm Res 2000;49:367-92.
14. Zhang X, Schwarz EM, Young DA, Puzas JE, Rosier RN, O'Keefe RJ. Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J Clin Invest 2002;109:1405-15.
15. Simon AM, Manigrasso MB, O'Connor JP. Cyclo-oxygenase 2 function is essential for bone fracture healing. J Bone Miner Res 2002;17:963-76.
16. Li J, Burr DB, Turner CH. Suppression of prostaglandin synthesis with NS-398 has different effects on endocortical and periosteal bone formation induced by mechanical loading. Calcif Tissue Int 2002;70:320-9.
17. Lim H, Paria BC, Das SK, Dinchuk JE, Langenbach R, Trzaskos JM, et al. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell 1997;91:197-208.
18. Davis BJ, Lennard DE, Lee CA, Tiano HF, Morham SG, Wetsel WC, et al. Anovulation in cyclooxygenase-2-deficient mice is restored by prostaglandin E2 and interleukin- 1 beta. Endocrinology 1999;140:2685-95.
19. Breyer MD, Harris RC. Cyclooxygenase 2 and the kidney. Curr Opin Nephrol Hypertens 2001;10:89-98.
20. Stichtenoth DO, Frolich JC. COX-2 and the kidneys. Curr Pharm Des 2000;6:1737-53.
21. Vane JR, Batting RM. New insights into the mode of action of anti-inflammatory drugs. Inflamm Res 1995;44:1-10.
22. McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA 1999;96:272-7.
23. Crofford LJ, Oates JC, McCune WJ, Gupta S, Kaplan MJ, Catella-Lawson F, et al. Thrombasis in patients with connective tissue diseases treated with specific cyclooxygenase 2 inhibitors. A report of four cases. Arthritis Rheum 2000;43;1891-6.
24. FitzGerald GA, Austin S, Egan K, Cheng Y, Pralico D. Cyclo-oxygenase products and atherothrombosis. Ann Med 2000;32:21-6.
25. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345:433-42.
26. Wallace JL, Chapman K, McKnight W. Limited anti-inflammatory efficacy of cyclo-oxygenase-2 inhibition in carrageenan-airpouch inflammation. Br J Pharmacol 1999;126:1200-4.
27. Wallace JL, Bak A, McKnight W, Asfaha S, Sharkey KA, MacNaughton WK. Cyclooxygenase 1 contributes to inflammatory responses in rats and mice: implications for gastrointestinal toxicity. Gastroenterology 1998;115:101-9.
28. Langenbach R, Morham SG, Tiano HF, Loftin CD, Ghanayem BI, Chulada PC, et al. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell 1995;83:483-92.
29. Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby DA. Inducible cydooxygenase may have anti-inflammatory properties. Nat Med 1999;5:698-701.
30. Ballou LR, Blatteis CM, Raghow R. Elucidation of the pathophysiological functions of prostaglandins using cyclooxygenase gene deficient mice. In: Vane JR, Botting RM, eds. Therapeutic roles of selective COX-2 inhibitors. London, UK: William Harvey Press, 2001:128-67.
31. Sala A, Zarini S, Bolla M. Leukotrienes: lipid bioeffectors of inflammatory reactions. Biochemistry (Mosc) 1998;63:84-92.
32. Radmark OP. The molecular biology and regulation of 5-lipoxygenase. Am J Respir Crit Care Med 2000;161(suppl):S11-5.
33. Rouzer CA, Ford-Hutchinson AW, Morton HE, Gillard JW. MK886, a potent and specific leukotriene biosynthesis inhibitor blocks and reverses the membrane association of 5-lipoxygenase in ionophore-challenged leukocytes. J Biol Chem 1990;265:1436-42.
34. Miller DK, Gillard JW, Vickers PJ, Sadowski S, Leveille C, Mancini JA, et al. Identification and isolation of a membrane protein necessary for leukotriene production. Nature 1990;343:278-81.
35. Dixon RA, Diehl RE, Opas E, Rands E, Vickers PJ, Evans JF, et al. Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis. Nature 1990;343:282-4.
36. Penrase JF, Austen KF, Lam BK. Leukotrienes: biosynthetic pathways, release and receptor-mediated actions with relevance to disease states. In: Gallin JL, Snyderman R, eds. Inflammation basic principles and clinical correlates. Philadelphia: Lippicort Williams & Wilkins, 1999:361-72.
37. Bray MA, Ford-Hutchinson AW, Smith MJ. Leukotriene B4: an inflammatory mediator in vivo. Prostaglandins 1981;22:213-22.
38. Smith MJ, Ford-Hutchinson AW, Bray MA. Leukotriene B: a potential mediator of inflammation. J Pharm Pharmacol 1980;32:517-18.
39. Ford-Hutchinson AW, Bray MA, Doig MV, Shipley ME, Smith MJ. Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes. Nature 1980;286:264-5.
40. Lewis RA, Ansten KF, Soberman RJ. Leukotrienes and other products of the 5-lipoxigenase pathway. Biochemistry and relation to pathobiology in human diseases. N Engl J Med 2000;192:439-46.
41. 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.
42. He W, Pelletier JP, Martel-Pelletier J, Laufer S, Di Battista JA. The synthesis of interleukin-1 beta, tumour necrosis factor-α and interstitial collagenase (MMP-1) is eicosanoid dependent in human OA synovial membrane explants: interactions with anti-inflammatory cytokines. J Rheumatol 2002;29:546-53.
43. Sala A, Folco G. Neutrophils, endothelial cells, and cysteinyl leukotrienes: a new approach to neutrophil-clependent inflammation? Biochem Biophys Res Commun 2001;283:1003-6.
44. Sala A, Bolla M, Zarini S, Muller-Peddinghaus R, Folco G. Release of leukotriene A4 versus leukotriene B4 from human polymorphonuclear leukocytes. J Biol Chem 1996;271:17944-8.
45. Sala A, Rossoni G, Buccellati C, Berti F, Folco G, Maclouf J. Formation of sulphidopeptide-leukotrienes by cell-cell interaction causes coronary vasoconstriction in isolated, cell-perfused heart of rabbit. Br J Pharmacol 1993;110:1206-12.
46. Sala A, Aliev GM, Rossoni G, Berti F, Buccellati C, Burnstock G, et al. Morphological and functional changes of coronary vasculature caused by transcellular biosynthesis of sulfidopeptide leukotrienes in isolated heart of rabbit. Blood 1996;87:1824-32.
47. Peskar BM. Role of leukotriene C4 in mucosal damage caused by necrotizing agents and indomethacin in the rat stomach. Gastroenterology 1991;100:619-26.
48. Buccellati C, Rossoni G, Bonazzi A, Berti F, Maclouf J, Folco G, et al. Nitric oxide modulation of transcellular biosynthesis of cys-leukotrienes in rabbit leukocyte-perfused heart. Br J Pharmacol 1997;120:1128-34.
49. Sala A, Rossoni G, Berti F, Buccellati C, Bonazzi A, Maclouf J, et al. Monoclonal anti-CD18 antibody prevents transcellular biosynthesis of cysteinyl leukotrienes in vitro and in vivo and protects against leukotriene-dependent increase in coronary vascular resistance and myocardial stiffness. Circulation 2000;101:1436-40.
50. Rainsford KD. The effects of 5-lipoxygenase inhibitors and leukotriene antagonists on the development of gastric lesions induced by nonsteroidal antiinflammatory drugs in mice. Agents Actions 1987;21:316-19.
51. Rainsford KD. Leukotrienes in the pathogenesis of NSAID-induced gastric and intestinal mucosal damage. Agents Actions 1993;39:C24-6.
52. Laufer S. Discovery and development of ML 3000. Inflammopharmacology 2001;9:101-12.
53. Hudson N, Balsitis M, Everitt S, Hawkey CJ. Enhanced gastric mucosal leukotriene B4 synthesis in patients taking non-steroidal anti-inflammatory drugs. Gut 1993;34:742-7.
54. 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;51:135-43.
55. Serhan CN, Levy BD, Clish CB, Gronert K, Chiang N. Lipoxins, aspirin-triggered 15-epi-lipoxin stable analogs and their receptors in anti-inflammation: a window for therapeutic opportunity. Ernst Schering Res Found Workshop 2000:143-85.
56. Serhan CN. Lipoxins and novel aspirin-triggered 15-epi-lipoxins (ATL): a jungle of cell-cell interactions or a therapeutic opportunity? Prostaglandins 1997;53:107-37.
57. Serhan CN, Oliw E. Unorthodox routes to prostanoid formation: new twists in cyclooxygenase-initiated pathways. J Clin Invest 2001;107:1481-9.
58. Serhan CN. Inflammation: basic principles and clinical correlates. Philadelphia: Lippincott Williams & Wilkins. 1999:373-85.
59. Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN. Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol 2001;2:612-19.
60. Gronert K, Gewirtz A, Madara JL, Serhan CN. Identification of a human enterocyte lipoxin A4 receptor that is regulated by interleukin (IL)-13 and interferon gamma and inhibits tumor necrosis factor alpha-induced IL-8 release. J Exp Med 1998;187:1285-94.
61. Sodin-Semrl S, Taddeo B, Tseng D, Varga J, Fiore S. Lipoxin A4 inhibits IL-1 beta-induced IL-6, IL-8, and matrix metalloproteinase-3 production in human synovial fibroblasts and enhances synthesis of tissue inhibitors of metalloproteinases. J Immunol 2000;164:2660-6.
62. Takano T, Fiore S, Maddox JF, Brady HR, Petasis NA, Serhan CN. Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors. J Exp Med 1997;185:1693-704.
63. Clish CB, O'Brien JA, Gronert K, Stahl GL, Petasis NA, Serhan CN. Local and systemic delivery of a stable aspirin-triggered lipoxin prevents neutrophil recruitment in vivo. Proc Natl Acad Sci USA 1999;96:8247-52.
64. Wallace JL, McKnight GW, Keenan CM, Byles NI, MacNaughton WK. Effects of leukotrienes on susceptibility of the rat stomach to damage and investigation of the mechanism of action. Gastroenterology 1990;98:1178-86.
65. Wallace JL, Keenan CM. Leukotriene B4 potentiates colonic ulceration in the rat. Dig Dis Sci 1990;35:622-9.
66. Paredes Y, Massicotte F, Pelletier JP, Martel-Pelletier J, Laufer S, Lajeunesse D. Study of role of leukotriene B4 in abnormal function of human subchondral osteoarthritis osteoblasts. Effects of cyclooxygenase and/or 5-lipoxygenase inhibition. Arthritis Rheum. 2002;46:1804-12.
67. Domoki F, Perciaccante JV, Puskar M, Bari F, Busija DW. Cyclooxygenase-2 inhibitor NS398 preserves neuronal function after hypoxia/ischemia in piglets. Neuroreport 2001;12:4065-8.
68. Liu XH, Kirschenbaum A, Yao S, Lee R, Holland JF, Levine AC. Inhibition of cyclooxygenase-2 suppresses angiogenesis and the growth of prostate cancer in vivo. J Urol 2000;164(3 Pt 1):820-5.
69. Ottino P, Bazan HE. Corneal stimulation of MMP-1, -9 and uPA by platelet-activating factor is mediated by cyclooxygenase-2 metabolites. Curr Eye Res 2001;23:77-85.
70. Casado M, Callejas NA, Rodrigo J, Zhao X, Dey SK, Bosca L, et al. Contribution of cyclooxygenase 2 to liver regeneration after partial hepatectomy. FASEB J 2001;15:2016-18.
71. Attiga FA, Fernandez PM, Weeraratna AT, Manyak MJ, Patierno SR. Inhibitors of prostaglandin synthesis inhibit human prostate tumor cell invasiveness and reduce the release of matrix metalloproteinases. Cancer Res 2000;60:4629-37.
72. McMillan RM, Walker ER. Designing therapeutically effective 5-lipoxygenase inhibitors. Trends Pharmacol Sci 1992;13:323-30.
73. Steinhilber D. 5-Lipoxygenase: a target for antiinflammatory drugs revisited. Curr Med Chem 1999;6:71-85.
74. Knapp HR. Reduced allergen-induced nasal congestion and leukotriene synthesis with an orally active 5-lipoxygenase inhibitor. N Engl J Med 1990;323:1745-8.
75. Weinblatt ME, Kremer JM, Coblyn JS, Helfgott S, Maier AL, Petrillo G, et al. Zileuton, a 5-lipoxygenase inhibitor in rheumatoid arthritis. J Rheumatol 1992;19:1537-41.
76. Collawn C, Rubin P, Perez N, Bobadilla J, Cabrera G, Reyes E, et al. Phase II study of the safety and efficacy of a 5-lipoxygenase inhibitor in patients with ulcerative colitis. Am J Gastroenterol 1992;87:342-6.
77. Hawkey CJ, Dube LM, Rountree LV, Linnen PJ, Lancaster JF. A trial of zileuton versus mesalazine or placebo in the maintenance of remission of ulcerative colitis. The European Zileuton Study Group For Ulcerative Colitis. Gastroenterology 1997;12:718-24.
78. Wong S, Lee SJ, Frierson MR 3rd, Proch J, Miskowski TA, Rigby BS, et al. Antiarthritic profile of BF-389 - a novel anti-inflammatory agent with low ulcerogenic liability. Agents Actions 1992;37:90-8.
79. Higgs GA, Mugridge KG, Moncada S, Vane JR. Inhibition of tissue damage by the arachidonate lipoxygenase inhibitor BW755C. Proc Natl Acad Sci USA 1984;81:2890-2. with potent anti-inflammatory activity in an arachidonic acid-induced ear inflammation model. Inflamm Res 1998;47:375-83.
80. Horizoe T, Nagakura N, Chiba K, Shirota H, Shinoda M, Numata H, et al. Effects of ER-34122, a novel dual 5-lipoxygenase/cyclooxygenase inhibitor, on indices of early articular lesion in MRL/MpJ-Ipr/Ipr mice. Inflamm Res 1999;48:432-6.
81. Spurney RF, Ruiz P, Pisetsky DS, Coffman TM. Enhanced renal leukotriene production in murine lupus: role of lipoxygenase metabolites. Kidney Int 1991;39:95-102.
82. Knight EV, Kimball JP, Keenan CM, Smith IL, Wong FA, Barrett DS, et al. Predinical toxicity evaluation of tepoxalin, a dual inhibitor of cyclooxygenase and 5-lipoxygenase, in Sprague-Dawley rats and beagle dogs. Fundam Appl Toxicol 1996;33:38-48.
83. 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;56:417-23.
84. Waldman SA, Vitow C, Osborne B, Gillen L, Argentieri DC, Wong FA, et al. Pharmacokinetics and pharmacodynamics of tepoxalin after single oral dose administration to healthy volunteers. J Clin Pharmacol 1996;36:462-8.
85. Depre M, Van Hecken A, Verbesselt R, Verpooten GA, Arnout J, Brunner F, et al. Biochemical activity, pharmacokinetics and tolerability of tepoxalin, a cyclaoxygenase/5-lipoxygenase inhibitor, in man. Int J Clin Pharmacol Res 1996;16:1-8.
86. Rotondo S, Dell'Elba G, Manarini S, Martelli N, Simone V, Evangelista V, et al. ML 3000, a balanced inhibitor of cyclooxigenase and lipoxygenase, inhibits/polymorphonuclear/platelet leukocyte transcellular metabolism and PMN adhesion and degranulation [abstract]. J Thromb Haemost 2001:P2835.
87. Laufer S, Tries S, Augustin J, Elsasser R, Albrecht W, Guserle R, et al. Acute and chronic anti-inflammatory properties of [2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H- pyrrolizine-5-yl]-acetic acid. Arzneimittelforschung 1995;45:27-32.
88. Reginster JY, Bias P, Buchner A. First clinical results of Licofelone (ML 3000), an inhibitory of COX-1, COX-2 and 5-LOX, for the treatment of osteoarthritis [abstract]. Ann Rheum Dis 2002;61(suppl I):189.
89. Wallace JL, Carter L, McKnight W, Tries S, Laufer S. ML 3000 reduces gastric prostaglandin synthesis without causing mucosal injury. Eur J Pharmacol 1994;271:525-31.
90. Laufer S, Tries S, Augustin J, Dannhardt G. Pharmacological profile of a new pyrrolizine derivative inhibiting the enzymes cyclo-oxygenase and 5-lipoxygenase. Arzneimittelforschung 1994;44:629-36.
91. 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;28:2060-5.
92. Jovanovic DV, Fernandes JC, Martel-Pelletier J, Jolicoeur FC, Reboul P, Laufer S, et al. The in vivo dual inhibition of cyclooxygenase and lipoxygenase by ML-3000 reduces the progression of experimental osteoarthritis. Suppression of collagenase-1 and interleukin-1 beta synthesis. Arthritis Rheum 2001;44:2320-30.
93. Boileau C, Martel-Pelletier J, Jouzeau JY, Netter P, Moldovan F, Laufer S, et al. Licofelone (ML-3000), a dual inhibitor of both 5-lipoxygenase and cyclooxygenases, reduces the level of cartilage chondrocyte death in vivo in experimental dog osteoarthritis: inhibition of pro-apoptotic factors. J Rheumatol 2002;29:1446-53.
94. Notoya K, Jovanovic DV, Reboul P, Martel-Pelletier J, Mineau F, Pelletier JP. The induction of cell death in human osteoarthritis chondrocytes by nitric oxide is related to the production of prostaglandin E2 via the induction of cyclooxygenase-2. J Immunol 2000;165:3402-10.
95. Laufer S, Tries S, Augustin J, Elsasser R, Algate DR, Atterson PR, et al. Gastrointestinal tolerance of [2,2-dimethyl-6-(4-chlorophenyl-7-phenyl-2,3- dihydro-1H-pyrrolizine-5-yl]-acetic acid in the rat. Arzneimittelforschung 1994;44:1329-33.
96. Tries S, Neupert W, Laufer S. ML 3000, a novel anti-inflammatory compound without the potential for causing gastric damage [abstract]. Inflamm Res 2001;50:S203.
97. Fiorucci S, Meli R, Bucci M, Cirino G. Dual inhibitors of cyclooxygenase and 5-lipoxygenase. A new avenue in anti-inflammatory therapy. Biochem Pharmacol 2001;62:1433-8.
98. Klesser B, Bias P, Buchner A, Elsaesser R. Licofelone (ML3000), an inhibitor of COX-1, COX-2 and 5-LOX, has little or no effect on the gastric mucosa after 4 weeks of treatment. Ann Rheum Dis 2002;61:130.
99. Reginster J, Bias P, Buchner A. First clinical results of licofelone (ML3000), an inhibitor of COX-1, COX-2 and 5-LOX, for the treatment of osteoarthritis. Ann Rheum Dis 2002;61:116.
100. Albrecht W, Bias P, Lammerich A, Carre C, Clerch L. Pharmacokinetics, safety and tolerability of licofelone (ML3000) 200 mg b.i.d. given with food in young and elderly healthy volunteers [abstract]. Ann Rheum Dis 2002;61(suppl I):422.
101. Ferreira SHVJR. New aspects of the mode of action of NSAIDs. Annu Rev Pharmacol 1974;14:57-71.
102. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 1971;231:232-5.