title: Differential contribution of R and S isomers in ketoprofen anti-inflammatory activity: role of cytokine modulation.
abstract: 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.
authors.affiliation: Neuroimmunology Laboratory, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Ghezzi
authors.forename: G
authors.initials: G
authors.lastname: Melillo
authors.forename: C
authors.initials: C
authors.lastname: Meazza
authors.forename: S
authors.initials: S
authors.lastname: Sacco
authors.forename: L
authors.initials: L
authors.lastname: Pellegrini
authors.forename: C
authors.initials: C
authors.lastname: Asti
authors.forename: S
authors.initials: S
authors.lastname: Porzio
authors.forename: A
authors.initials: A
authors.lastname: Marullo
authors.forename: V
authors.initials: V
authors.lastname: Sabbatini
authors.forename: G
authors.initials: G
authors.lastname: Caselli
authors.forename: R
authors.initials: R
authors.lastname: Bertini
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002351:Carrageenan; D016207:Cytokines / Q000096:biosynthesis*; D015232:Dinoprostone / Q000032:analysis; D004487:Edema / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D006168:Guinea Pigs; D006930:Hyperalgesia / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D007660:Ketoprofen / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008297:Male; D013237:Stereoisomerism; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D002351:Carrageenan; D007660:Ketoprofen; D015232:Dinoprostone