Vol. 287, Issue 3, 969-974, December 1998

Differential Contribution of R and S Isomers in Ketoprofen Anti-inflammatory Activity: Role of Cytokine Modulation¹

Pietro Ghezzi, Gabriella Melillo, Cristina Meazza, Silvano Sacco, Luigi Pellegrini, Cinzia Asti, Stefano Porzio, Antonello Marullo, Vilma Sabbatini, Gianfranco Caselli and Riccardo Bertini

Neuroimmunology Laboratory (P.G., C.M., S.S.), Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy; Consorzio Biolaq (S.P.), L'Aquila, Italy; and Department of Pharmacology (G.M., L.P., C.A., A.M., V.S., G.C., R.B.), Dompé S.p.A. Research Center, L'Aquila, Italy

Among nonsteroidal anti-inflammatory drugs (NSAIDs), 2-arylpropionic acids exist as a racemic mixture of its enantiomeric forms, with S-enantiomers primarily responsible for inhibition of prostaglandin synthesis and of inflammatory events. The aim of this study was to compare the anti-inflammatory effects of R- and S-ketoprofen in vitro and in vivo. S-Ketoprofen efficiently inhibited carrageenan-induced edema formation, but it could also amplify the LPS-induced production of the inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1), in close correlation with its ability to inhibit prostaglandin synthesis. Because these inflammatory cytokines are among the factors involved in carrageenan-induced inflammation and also are possibly involved in gastric damage, enhanced cytokine production could partially mask the analgesic effect of S-ketoprofen, and it can be associated with the clinical evidence of its gastric toxicity. On the other hand, R-ketoprofen contributes to the overall activity of the racemate, by playing the main role in ketoprofen-induced analgesia. Unlike the S-isomer, R-ketoprofen did not induce a significant increase of cytokine production even at cyclooxygenase-blocking concentrations. It is concluded that the R-isomer directly contributes to the anti-inflammatory effects of ketoprofen, being more analgesic, and because it does not amplify inflammatory cytokine production.