Differential contribution of R and S isomers in ketoprofen anti-inflammatory activity: role of cytokine modulation.
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.
Ghezzi
P
P
Neuroimmunology Laboratory, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Melillo
G
G
Meazza
C
C
Sacco
S
S
Pellegrini
L
L
Asti
C
C
Porzio
S
S
Marullo
A
A
Sabbatini
V
V
Caselli
G
G
Bertini
R
R
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
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D002351:Carrageenan; D007660:Ketoprofen; D015232:Dinoprostone