Antiinflammatory effect of tepoxalin: blood and synovial tissue studied in patients with knee arthrosis.

Our aim was to determine the amounts of eicosanoids in blood and synovial tissue of patients with knee arthrosis and to examine the effects of 2 doses of tepoxalin (50 mg twice, 200 mg twice), administered p.o. for 3.5 days. Concentrations of leukotriene B4 (LTB4, LTC4, and thromboxane B2 (TXB2) were measured in blood before and after oral administration of tepoxalin and release of prostaglandin E2 (PGE2), 6-keto-PGF1alpha, and LTC4 was measured in incubation media of synovial tissue, taken at surgery from patients treated with tepoxalin. Radioimmunoassay (RIA) was used to determine the levels of the eicosanoids. LT and TXB2 release was reduced by tepoxalin in both doses used. Under these conditions, PGE2, 6-keto-PGF1alpha, and LTC4 release from synovial tissue was detectable only after stimulation with calcium ionophore A23187. Washed synovial tissue, in which tepoxalin concentrations should be reduced, released higher amounts of all eicosanoids measured than directly incubated synovial tissue did. Pain after tepoxalin administration was significantly reduced. Relevant drug concentrations were detected in plasma and synovial fluid. Tepoxalin was well tolerated and had no marked adverse effects. At 400 mg, tepoxalin is a dual inhibitor of cyclooxygenase (CO) and 5-lipoxygenase (5-LO) in blood and synovial tissue.

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.

In vitro release of prostaglandins and leukotrienes from synovial tissue, cartilage, and bone in degenerative joint diseases.

OBJECTIVE: To determine the major source of eicosanoid release in arthritic joint tissues and to examine the modulation of this release by indomethacin and diclofenac. METHODS: Release of prostaglandin E2 (PGE2), 6-keto-PGF1 alpha, leukotriene B4 (LTB4), and LTC4 was measured in supernatants of synovial tissue, cartilage, and bone incubates from patients with osteoarthritis, active rheumatoid arthritis (RA), inactive RA, and pseudogout. Radioimmunoassay (RIA) was used to determine the levels of the eicosanoids. RESULTS: Addition of the divalent cation ionophore A23187 resulted in significant release of all eicosanoids measured from synovial tissue, but not from cartilage, cortical bone, or cancellous bone. PG release was significantly inhibited by the addition of indomethacin or diclofenac at either 10(-5) moles/liter or 10(-7) moles/liter. The amount of LTC4 released from cartilage and bone was only slightly above the detection limit of the RIA, whereas large amounts were released from synovial tissue. Neither indomethacin nor diclofenac had an effect on LTC4 release. LTC4 release from synovial tissue of patients with inactive RA was significantly decreased in comparison with the levels from synovial tissue of patients with the other joint diseases. There was no significant difference in PG release among patients in the various disease groups. CONCLUSION: Synovial tissue appears to be the major source of eicosanoids in synovial fluid. Indomethacin and diclofenac inhibit the release of PG, but not LT, from various joint tissues.

[Prostaglandin and leukotriene release of synovial tissue in various joint diseases]. / Prostaglandin- und Leukotrienfreisetzung aus Synovialgewebe bei verschiedenen Gelenkerkrankungen.

Synovial tissue from 37 patients suffering from osteoarthritis, chondrocalcinosis, active and inactive rheumatoid arthritis was investigated. The tissue was obtained during knee surgery and immediately incubated in tyrode solution. PGE2, 6-keto-PGF1 alpha, LTB4 and LTC4 were measured by radioimmunoassay. Calcium ionophore A 23187 stimulated the eicosanoid release significantly. This effect was more pronounced with LT than with PG. In the four different joint diseases there was no significant difference in the PG release. The LTC4 release was significantly lower in inactive rheumatoid arthritis as compared to the other joint diseases. For LTB4 this effect was significant only when compared to osteoarthritis. Indomethacin 10(-5) and 10(-7)mol/l inhibited the PG release from synovial tissue in all joint diseases significantly (p less than 0.05), there was no significant effect on the LT release. LT as well as PG are pro-inflammatory mediators. Non-steroidal anti-inflammatory drugs inhibit only the PG release. The remaining LT synthesis might thus be partially responsible for the lack of efficacy of these drugs in some patients.