, Volume 29, Issue 4–6, pp 119–128 | Cite as

In Vitro” Differences among (R) and (S) Enantiomers of Profens in their Activities Related to Articular Pathophysiology

  • A. M. Panico
  • V. Cardile
  • B. Gentile
  • F. Garufi
  • S. Avondo
  • S. Ronsisvalle


An important group of non steroidal antinflammatory drugs (NSAIDs), which have been used for the symptomatic treatment of various forms of arthritis, are the 2-arylpropionic acid derivatives, ‘profens’. By virtue of a chiral carbon atom on the propionic acid side chain, they exist as enantiomeric pairs. Whereas the S (+) enantiomer could be represented as an effective, but unselective COX inhibitor, the R (−) enantiomer could be much less active in this respect. However, recent findings suggest that certain pharmacological effects of profens cannot be attributed exclusively to the S (+) enantiomer. To obtain further insights into the pharmacological effects of profens, this study investigated the influence of pure enantiomers (S), (R), and racemic flurbiprofen and ketoprofen on the production of NO, MMP-3, PGE2, ROS and GAGs, key molecules involved in cartilage destruction. Our results show that (S) flurbiprofen and ketoprofen decrease, at 1- and 10-μM concentrations, the interleukin-1β induced cartilage destruction.

Key words

arthritis chondrocytes profens IL-1β 


  1. 1.
    Bullogh, P. G. 1998. In: Rheumatology, J. H. Klippel and P. A. Dieppe, eds. Mosby-Year Book Europe Limited, London, 7:1–7.8.Google Scholar
  2. 2.
    Blanco, F. J., R. L. Ochs, H. Schwartz, and M. Lotz. 1995. Chondrocyte apoptosis induced by nitric oxide. Am. J. Pathol. 146:75–85.PubMedGoogle Scholar
  3. 3.
    Geng, Y., J. Valbracht, and M. Lotz. 1996. Selective activation of the mitogen-activated protein kinase subgroups c-Jun NH2 terminal kinase and p38 by IL-1 and TNF in human articular chondrocytes. J. Clin. Invest. 98:2425–2430.PubMedCrossRefGoogle Scholar
  4. 4.
    Evans, C. H., and M. Stefanovic-Racic. 1996. Nitric oxide in arthritis. Methods 10:38–42.PubMedCrossRefGoogle Scholar
  5. 5.
    Hassan, M. S., M. M. Mileva, H. S. Dweck, and L. Ronsenfeld. 1998. Nitric oxide products degrade chondroitin sulfates. Nitric Oxide 2:360–365.PubMedCrossRefGoogle Scholar
  6. 6.
    Moncada, S., R. M. Palmer, and E. A. Higgs. 1991. Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol. Rev. 43:109–142.PubMedGoogle Scholar
  7. 7.
    Bernardeau, C., E. Dernis-Labous, H. Blanchard, D. Lamarque, and M. Breban. 2001. Nitric oxide in rheumatology. Jt. Bone Spine 68:457–462.CrossRefGoogle Scholar
  8. 8.
    Nedelec, E., A. Abid, C. Cipolletta, N. Presle, B. Terlani, P. Netter, and J. Y. Jouzeau. 2001. Stimulation of cyclooxygenase-2-activity by nitric oxide-derived species in rat chondrocyte: lack of contribution to loss of cartilage anabolism. Biochem. Pharmacol. 61:965–978.PubMedCrossRefGoogle Scholar
  9. 9.
    Sapolsky, A., H. Kaiser, D. S. Howell, and J. F. Woesser. 1976. Metalloproteinases of human articular cartilage that digest cartilage proteoglycan at neutral and acid. Ph. J. Clin Invest. 58:1030–1041.Google Scholar
  10. 10.
    Smith, C., Y. Zhang, C. M. Koboldt, J. Muhammad, B. S. Zweifel, A. Shaffer, J. Talley, J. L. Mansferr, and K. Siebert. 1998. Pharmacological analysis of cyclooxygenase-1 in inflammation. Proc. Natl. Acad. Sci. USA. 95:13313–13318.PubMedCrossRefGoogle Scholar
  11. 11.
    Henrotin, Y. E., P. Bruckner, and J. P. Pujol. 2003. The role of reactive oxygen species in homeostasis and degradation of cartilage. Osteoarthr. Cartil. 11:747–755.PubMedCrossRefGoogle Scholar
  12. 12.
    Dingle, J. T. 1999. The effects of NSAID on the matrix of human articular cartilages. Z. Rheumatol. 58:125–129.PubMedCrossRefGoogle Scholar
  13. 13.
    Dingle, J. 1993. Prostaglandins in human cartilage metabolism. J. Lipid. Mediat. 6:303–312.PubMedGoogle Scholar
  14. 14.
    Di Battista, J., S. Dore, J. Martel-Pellettier, and J. P. Pelletier. 1996. Prostaglandin E2 stimulates incorporation of proline into collagenase digestible proteins in human articular chondrocytes: identification of an effector autocrine loop involving insulin-like growth factor I. J. Mol. Cell. Endocrinol. 123:27–35.CrossRefGoogle Scholar
  15. 15.
    Carabaza, A., F. Cabre, E. Rotllan, M. Gomez, M. Gutierrez, M. L. Garcia, and D. Mauleon. 1996. Stereoselective inhibition of inducible cyclooxygenase by chiral nonsteroidal antiinflammatory drugs. J. Clin. Pharmacol. 36:505–512.PubMedGoogle Scholar
  16. 16.
    Morrone, R., G. Nicolosi, A. Patti, and M. Piattelli. 1995. Resolution of racemic flurbiprofen by lipasi-mediated esterification in organic solvent. Tetrahedron: Asymmetry. 6:1773–1778.CrossRefGoogle Scholar
  17. 17.
    Morone, R., M. Piattelli, and G. Nicolosi. 2001. Resolution of racemic acids by irreversible lipasi-catalyzed esterification in organic solvent. Eur. J. Org. Chem. 8:1441–1443.CrossRefGoogle Scholar
  18. 18.
    Mosmann, T. 1983. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods. 65:55–63.PubMedCrossRefGoogle Scholar
  19. 19.
    Green, L. C., D. A. Wagner, J. Glogowski, and D. J. Reis. 1982. Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal. Biochem. 126:131–138.PubMedCrossRefGoogle Scholar
  20. 20.
    Farndale, R. W., C. A. Sayers, and A. J. Barrett. 1989. A direct spectrophotometric microassay for sulphated glycosaminoglycans in cultured cartilage. Connect. Tissue Res. 2:247–248.Google Scholar
  21. 21.
    Stone, J. E., N. Akttar, S. Botchway, and C. A. Pennock. 1994. Interaction of 1,9-dimethylmethylene blue with glycosaminoglycans. Ann. Clin. Biochem. 31:147–152.PubMedGoogle Scholar
  22. 22.
    Renis, M., V. Cardile, M. Palumbo, and A. Russo. 2000. Et-18-OCH3-induced cytotoxicity and DNA damage in rat astrocytes. Int. J. Dev. Neurosci. 18:545–555.PubMedCrossRefGoogle Scholar
  23. 23.
    Dinarello, C. A. 1992. Interleukin-1 and tumor necrosis factor: effector cytokines in autoimmune diseases. Semin. Immunol. 4:133–145.PubMedGoogle Scholar
  24. 24.
    Arend W. P., and J. M. Dayer. 1995. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. Arthritis Rheum. 38:151–160.PubMedGoogle Scholar
  25. 25.
    Henrotin, Y. E., P. Bruckner, and J. P. Pujol. 2003. The role of reactive oxygen species in homeostasis and degradation of cartilage. Osteoarthr. Cartil. 11:747–755.PubMedCrossRefGoogle Scholar
  26. 26.
    Hitchon, C. A., and H. S. El-Gabalawy. 2004. Oxidation in rheumatoid arthritis. Arthritis Res. Ther. 6:265–278.PubMedCrossRefGoogle Scholar
  27. 27.
    Little, C. B., C. R. Flannery, C. E. Hughes, A. Goodship, and B. Caterson. 2005. Cytokine induced metalloproteinase expression and activity does not correlate with focal susceptibility of articular cartilage to degeneration. Osteoarthr. Cartil. 13:162–170.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • A. M. Panico
    • 1
  • V. Cardile
    • 2
  • B. Gentile
    • 1
  • F. Garufi
    • 1
  • S. Avondo
    • 3
  • S. Ronsisvalle
    • 1
  1. 1.Department of Pharmaceutical Sciences, Faculty of PharmacyUniversity of CataniaCataniaItaly
  2. 2.Department of Physiological SciencesUniversity of Catania CataniaItaly
  3. 3.Department di Specialità Medico-chirurgicheUniversity of CataniaCataniaItaly

Personalised recommendations