title: In vitro evaluation of (S)-ibuprofen toxicity on joint cells and explants of cartilage and synovial membrane.
abstract: Intra-articular drug delivery systems (DDSs) are envisaged as interesting alternative to locally release nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen to reduce pain in patients with osteoarthritis. The present study examines the toxicity of (S)-ibuprofen on chondrocytes and synoviocytes isolated from sheep shoulder joint and cultured in monolayers during 72 h, and on joint explants (cartilage and capsule) cultured in mono- or in co-culture for 13 days. (S)-ibuprofen (5 μM up to 1 mM) did not reduce the cell viability and protein content when added on chondrocyte monolayers, while at 1 mM (S)-ibuprofen reduced (by 8%, p=0.01) the synoviocytes viability compared to untreated cells. During co-culture of joint explants, (S)-ibuprofen at 50 μM significantly reduced by 35% the spontaneous release of glycosaminoglycans (GAGs) from cartilage (p=0.0065) whereas in monoculture, (S)-ibuprofen was inactive on GAG metabolism. (S)-ibuprofen at 1 mM significantly reduced cell lysis (lactate dehydrogenase leakage) by 74% during monoculture of capsule explants (p=0.0136) and by 35% during co-culture of explants (p=0.0013). Our findings demonstrate that the active isomer of ibuprofen at micro- and millimolar levels was not toxic for chondrocytes and synoviocytes and may reduce at 1mM the cell lysis during culture of joint explants. The limited toxicity of (S)-ibuprofen at low and high concentration in sheep joint shoulder makes this enantiomer a promising drug candidate for the loading of intra-articular DDS.
authors.affiliation: Occlugel, 24 rue du Faubourg Saint Jacques, 75015 Paris, France. bedouet.occlugel@orange.fr
authors.forename: Laurent
authors.initials: L
authors.lastname: Bédouet
authors.forename: Florentina
authors.initials: F
authors.lastname: Pascale
authors.forename: Michel
authors.initials: M
authors.lastname: Bonneau
authors.forename: Michel
authors.initials: M
authors.lastname: Wassef
authors.forename: Alexandre
authors.initials: A
authors.lastname: Laurent
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D002356:Cartilage / Q000187:drug effects* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D007052:Ibuprofen / Q000633:toxicity*; D007596:Joints; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012756:Sheep; D012782:Shoulder; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D006025:Glycosaminoglycans; D011506:Proteins; D007770:L-Lactate Dehydrogenase; D020782:Matrix Metalloproteinases; D007052:Ibuprofen