Ghezzi P, Melillo G, Meazza C, Sacco S, Pellegrini L, Asti C, Porzio S, Marullo A, Sabbatini V, Caselli G, Bertini R
Neuroimmunology Laboratory, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
J Pharmacol Exp Ther. 1998 Dec;287(3):969-74.
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.
在非甾体抗炎药（NSAIDs）中，2-芳基丙酸以其对映体形式的外消旋混合物存在，其中S-对映体主要负责抑制前列腺素合成和炎症反应。本研究的目的是比较R-酮洛芬和S-酮洛芬在体外和体内的抗炎作用。S-酮洛芬能有效抑制角叉菜胶诱导的水肿形成，但它也能放大脂多糖诱导的炎症细胞因子肿瘤坏死因子（TNF）和白细胞介素-1（IL-1）的产生，这与其抑制前列腺素合成的能力密切相关。由于这些炎症细胞因子是参与角叉菜胶诱导炎症的因素之一，也可能参与胃损伤，细胞因子产生的增强可能会部分掩盖S-酮洛芬的镇痛作用，并且可能与其胃毒性的临床证据有关。另一方面，R-酮洛芬通过在酮洛芬诱导的镇痛中起主要作用，对消旋体的整体活性有贡献。与S-异构体不同，即使在环氧化酶阻断浓度下，R-酮洛芬也不会诱导细胞因子产生显著增加。结论是，R-异构体直接有助于酮洛芬的抗炎作用，更具镇痛性，且因为它不会放大炎症细胞因子的产生。
