Inhibition of eicosanoid release from synovial organ culture by incubation with tepoxalin and its acid metabolite.
The pharmacological profile of a novel dual inhibitor, tepoxalin and of its carboxylic acid metabolite on cyclooxygenase and lipoxygenase pathways was evaluated by in vitro incubation with synovial tissue. Tissue specimens obtained at surgery in rheumatoid arthritis (RA, n = 10) or osteoarthritis (OA, n = 11) patients were incubated. Tepoxalin (10(-7), 10(-6), 10(-5) M) decreased eicosanoid release calculated in % of tyrode control for OA: LTC4 to 71-33%, 6-keto-PGF1a to 37-20%, PGE2 to 29-6%. For RA: LTC4 to 56-22%, 6-keto-PGF1a to 43-22%, PGE2 to 57-32%. Similarly, its metabolite (10(-7), 10(-5)M) decreased release in OA: LTC4 to 99 and 60%, PGE2 to 42 and 20%, 6-keto-PGF1a to 54 and 25%. In RA:LTC4 to 81 and 45%, PGE2 to 61 and 30%, 6-keto-PGF1a to 46 and 18%. Significance (P < 0.05) was achieved for all but 1 group (LTC4 metabolite at 10(-7)M vs tyrode). In summary a marked and dose dependent decrease of LT and PG release was obtained when incubating the dual inhibitor tepoxalin and its active carboxylic acid metabolite with synovial tissue at doses expected to be reached in the joint during therapy.
Willburger
R E
RE
Dept. of Orthopaedic Surgery, St. Josef-Hospital, Ruhr University, Bochum, Germany.
Wittenberg
R H
RH
Kleemeyer
K S
KS
Hoos
R
R
Brunner-Ferber
F L
FL
Peskar
B A
BA
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001172:Arthritis, Rheumatoid; D002118:Calcium / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism*; D006801:Humans; D017997:Leukotriene C4 / Q000378:metabolism; D009924:Organ Culture Techniques; D010003:Osteoarthritis; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology*; D013583:Synovial Membrane / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015777:Eicosanoids; D011720:Pyrazoles; D017997:Leukotriene C4; D015121:6-Ketoprostaglandin F1 alpha; D015232:Dinoprostone; D002118:Calcium; C073135:tepoxalin