Inhibition of eicosanoid release from synovial organ culture by incubation with tepoxalin and its acid metabolite

Abstract

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 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 tyrode control for OA: LTC₄ to 71−33%, 6-keto-PGF_1a to 37−20%, PGE₂ to 29−6%. For RA: LTC₄ to 56−22%, 6-keto-PGF_a 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-PGF_1a to 54 and 25%. In RA: LTC₄ to 81 and 45%, PGE₂ to 61 and 30%, 6-keto-PGF_1a to 46 and 18%. Significance (p<0.05) was achieved for all but 1 group (LTC₄, metabolite at 10⁻⁷M 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.