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 o f its carboxylic acid metabolite on cyclooxygenase and lipoxygenase pa thways was evaluated by in vitro incubation with synovial tissue. Tiss ue specimens obtained at surgery in rheumatoid arthitis (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 tyro de control for OA: LTC(4) to 71-33%, 6-keto-PGF(1a) to 37-20%, PGE(2) to 29-6%. For RA: LTC(4) to 56-22%, 6-keto-PGF(1a) to 43-22%, PGE(2) t o 57-32%. Similarly, its metabolite (10(-7), 10(-5) M) decreased relea se in OA: LTC(4) to 99 and 60%, PGE(2) to 42 and 20%, 6-keto-PGF(1a) t o 54 and 25%. In RA: LTC(4) to 81 and 45%, PGE(2) to 61 and 30%, 6-ket o-PGF(1a) to 46 and 18%. Significance (p<0.05) was achieved for all bu t 1 group (LTC(4), metabolite at 10(-7) M vs tyrode). In summary a mar ked and dose dependent decrease of LT and PG release was obtained when incubating the dual inhibitor tepoxalin and its active carboxylic aci d metabolite with synovial tissue at doses expected to be reached in t he joint during therapy.