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Licofelone: The answer to unmet needs in osteoarthritis therapy?

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Abstract

Licofelone, a competitive inhibitor of cyclooxygenases 1 and 2 and 5-lipoxygenase enzyme, is under clinical evaluation for its effectiveness in the treatment of osteoarthritis (OA). Licofelone decreases the production of both prostaglandins and leukotrienes and has been shown to possess a combination of analgesic or anti-inflammatory effects with a promising gastrotolerability profile. Available clinical data have shown that licofelone is at least as effective as the conventional nonsteroidal anti-inflammatory drugs or coxibs in ameliorating the symptoms of OA, but it may offer the advantage of improved gastrotolerability and fewer or no incidences of worsened peripheral edema. Last, further evidence suggests that it could be a suitable alternative for the long-term treatment of a wide population of patients with OA. The preset review describes the status of licofelone in the treatment of OA.

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References and Recommended Reading

  1. McCarthy GM, Molloy SE: Eicosanoids, osteoarthritis, and crystal deposition diseases. Curr Opin Rheumatol 2005, 17:346–350.

    Article  PubMed  Google Scholar 

  2. Brune K: Safety of anti-inflammatory drugs: new ways of thinking. Rheumatology 2004, 43(Suppl 1):i16–i20.

    Article  PubMed  CAS  Google Scholar 

  3. Celottio F, Durand T: The metabolic effects of inhibitors of lipoxygenase and of cyclooxygenase 1 and 2 are an advancement in the efficacy and safety of antiinflammatory therapy. Prostaglandins Other Lipid Mediat 2003, 71:147–162.

    Article  Google Scholar 

  4. Vane JR, Bakhle YS, Botting RM: Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 1998, 38:97–120.

    Article  PubMed  CAS  Google Scholar 

  5. Warner TD, Mitchell JA: Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J 2004, 18:790–804.

    Article  PubMed  CAS  Google Scholar 

  6. Kis B, Snipes JA, Busija DW: Acetaminophen and the cyclooxygenase-3 puzzle: sorting out facts, fictions, and uncertainties. J Pharmacol Exp Ther 2005, 315:1–7.

    Article  PubMed  CAS  Google Scholar 

  7. Burdan F, Chalas A, Szumilo J: Cyclooxygenase and prostanoids-biological implications. Postepy Hig Med Dosw 2006, 60:129–141.

    Google Scholar 

  8. Bombardier C, Laine L, Reicin A, et al.: VIGOR Study Group. 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.

    Article  PubMed  CAS  Google Scholar 

  9. Center for Drug Evaluation and Research: The benefits and risks of pain relievers. Available at http://www.fda.gov/consumer/updates/pain_relievers.pdf. Accessed December 5, 2007.

  10. Funk CD: Prostaglandins and leukotrienes: advances in eicosanoids biology. Science 2001, 294:1875–1890.

    Article  Google Scholar 

  11. Pelletier JM, 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 Rehum Dis 2003, 62:501–509.

    Article  Google Scholar 

  12. Ding C, Cicuttini F: Licofelone (Merckle). I Drugs 2003, 6:803–808.

    Google Scholar 

  13. de Gaetano G, Donati MD, Cerletti C: Prevention of thrombosis and vascular inflammation: benefits and limitations of selective or combined COX-1, COX-2 and 5-LOX inhibitors. Trends Pharmacol Sci 2003, 24:245–251.

    Article  PubMed  Google Scholar 

  14. Algate DR, Augustin J, Atterson PR, et al.: General pharmacology of [2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid in experimental animals. Arzneimittelforschung 1995, 45:159–165.

    PubMed  CAS  Google Scholar 

  15. Singh VP, Patil CS, Kulkarni SK: Anti-inflammatory effect of licofelone against various inflammatory challenges. Fundam Clin Pharmacol 2006, 20:65–71.

    Article  PubMed  CAS  Google Scholar 

  16. Singh VP, Patil CS, Kulkarni SK: Effect of licofelone against mechanical hyperalgesia and cold allodynia in the rat model of incisional pain. Pharmacol Rep 2005, 57:380–384.

    PubMed  CAS  Google Scholar 

  17. Singh VP, Patil CS, Kulkarni SK: Effect of licofelone against NSAIDs-induced gastrointestinal ulceration and inflammation. Indian J Exp Biol 2005, 43:247–253.

    PubMed  CAS  Google Scholar 

  18. Smith WJ, Garavito RM, DeWitt DL: Prostaglandin endoperoxidase H synthases (cyclooxygenases)-1 and-2. J Biol Chem 1996, 271:33157–33160.

    Article  PubMed  CAS  Google Scholar 

  19. Pelletier JP, Martel-Pelletier J, Howell DS: Etiopathogenesis of osteoarthritis In Arthritis and Allied conditions. A Textbook of Rheumatology. Edited by Koopman WJ. Baltimore: Williams and Wilkins; 2001:2195–2245.

    Google Scholar 

  20. He W, Pelletier JP, Martel-Pelletier J, et al.: The synthesis of interleukin-1beta, tumor necrosis factor-alpha and interstitial collagenase (MMP-1) is eicosanoid dependent in human OA synovial membrane implants: interactions with anti-inflammatory cytokines. J Rheumatol 2002, 29:546–553.

    PubMed  CAS  Google Scholar 

  21. Cheng S, Afif H, Martel-Pelletier J, et al.: Activation of peroxisome proliferator-activated receptor gamma inhibits interleukin-1beta-induced membrane-associated prostaglandin E2 synthase-1 expression in human synovial fibroblasts by interfering with Egr-1. J Biol Chem 2004, 21:22057–22065.

    Article  Google Scholar 

  22. Pelletier JM, Mineau F, Fahmi H, et al.: Regulation of the expression of 5-Lipoxygenase-activating protein/5-lipoxygenase and the synthesis of leukotriene B4 in osteoarthritic chondrocytes. Arthritis Rheum 2004, 50:3925–3933.

    Article  PubMed  Google Scholar 

  23. Kulkarni SK, Singh VP: Licofelone: a novel analgesic and anti-inflammatory agent. Curr Top Med Chem 2007, 7:251–263.

    Article  PubMed  CAS  Google Scholar 

  24. Gay RE, Neidhart M, Pataky F, et al.: Dual inhibition of 5-lipoxygenase and cyclooxygenases 1 and 2 by ML3000 reduces joint destruction in adjuvant arthritis. J Rheumatol 2001, 28:2060–2065.

    PubMed  CAS  Google Scholar 

  25. Lajeunesse D, Martel-Pelletier J, Fernandes JC, et al.: Treatment with licofelone prevents abnormal subchondreal bone metabolism in experimental dog osteoarthritis. Ann Rheum Dis 2004, 63:78–83.

    Article  PubMed  CAS  Google Scholar 

  26. 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 catabolic factors: MMP-13, cathepsin K and aggrecanases. Arthritis Res Ther 2005, 7:R1091–R1102.

    Article  PubMed  CAS  Google Scholar 

  27. Moreau M, Boileau C, Martel-Pelletier J, et al.: Licofelone reduces progression of structural changes in a canine model of osteoarthritis under curative conditions: effect on protease expression and activity. J Rheumatol 2006, 33:1176–1183.

    PubMed  CAS  Google Scholar 

  28. Moldovan F, Pelletier JP, Hambor J, et al.: Collagenase-3 (matrix metalloprotease 13) is preferentially localized in the deep layer of human arthritic cartilage in situ: in vitro mimicking effect of transferring growth factor beta. Arthritis Rheum 1997, 40:1653–1661.

    Article  PubMed  CAS  Google Scholar 

  29. Hillal G, Martel-Pelletier J, Pelletier JP, et al.: Osteoblast like cells from human subchondreal osteoarthritic bone demonstrate an altered phenotype in vitro: possible role in subchondreal bone sclerosis. Arthritis Rheum 1998, 41:891–899.

    Article  Google Scholar 

  30. Moreau M, Lussier B, Doucet M, et al.: Efficacy of licofelone in dogs with clinical osteoarthritis. Vet Rec 2007, 160:584–588.

    PubMed  CAS  Google Scholar 

  31. Forest Laboratories announces positive results with ML 3000 in early clinical trials [press release]. New York: Forest Laboratories Inc.; March 29, 2000.

  32. Positive ML 3000 clinical trial results announced by EuroAlliance at OARSI meeting in Barcelona [press release]. West Caldwell, NJ: Alfa Wassermann Spa; October 2000.

  33. 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(Suppl):116.

    Google Scholar 

  34. Langman MJ: Adverse effects of conventional non-steroidal anti-inflammatory drugs on the upper gastrointestinal tract. Fundam Clin Pharmacol 2003, 17:393–403.

    Article  PubMed  CAS  Google Scholar 

  35. Singh VP, Patil CS, Kulkarni SK: Effect of licofelone against NSAIDs-induced gastrointestinal ulceration and inflammation. Indian J Exp Biol 2005, 43:247–253.

    PubMed  CAS  Google Scholar 

  36. Smolka AJ, Goldenring JR, Gupta S, Hammond CE: Inhibition of gastric H,K ATPase activity and gastric epithelial cell IL-8 secretion by pyrrolizine derivative ML3000. BMC Gastroenterol 2004, 10:4–10.

    Article  Google Scholar 

  37. Klesser B, Bias P, Buchner A: Licofelone (ML 3000), an inhibitor of COX-1, COX-2, and 5-LOX, has a little or no effect on the gastric mucosa after 4 weeks of treatment [abstract THU0243]. Ann Rheum Dis 2002, 61(Suppl 1):130.

    Google Scholar 

  38. Alvero-Gracia JM: Licofelone-clinical update on a novel LOX/COX inhibitor for the treatment of osteoarthritis. Rhematology 2004, 43(Suppl 1):i21–i25.

    Article  Google Scholar 

  39. Fiorucci S, Distrutti E, de Lima OM, et al.: Relative contribution of acetylated cyclo-oxygenase (COX)-2 and 5-lipoxygenasxe (5-LOX) in regulating gastric mucosal integrity and adaptation to aspirin. FASEB J 2003, 17:1171–1173.

    PubMed  CAS  Google Scholar 

  40. Bias P, Buchner A: Licofelone-an inhibitor of 5-LOX, COX-1 and COX-2 has superior GI tolerability in OA patients compared with naproxen, regardless of low-dose aspirin co-medication, previous ulcer history or H. pylori status [abstract 67]. Arthritis Rheum 2003, 48(Suppl):S72.

    Google Scholar 

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Authors and Affiliations

  1. Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160 014, India

    Shrinivas K. Kulkarni

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  1. Shrinivas K. Kulkarni
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  2. Vijay Pal Singh
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Correspondence to Shrinivas K. Kulkarni.

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Kulkarni, S.K., Singh, V.P. Licofelone: The answer to unmet needs in osteoarthritis therapy?. Curr Rheumatol Rep 10, 43–48 (2008). https://doi.org/10.1007/s11926-008-0008-7

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