Harald Fellier

The analgesic NSAID lornoxicam inhibits cyclooxygenase (COX)-1/-2, inducible nitric oxide synthase (iNOS), and the formation of interleukin (IL)-6 in vitro

Abstract.Objective: To investigate anti-inflammatory effects of lornoxicam in vitro on COX-1/COX-2, on NO formation from iNOS and on the formation of the pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-8.¶Materials and Methods: COX-1 inhibition in intact cells was assessed employing two systems: measurement of aggregation in human washed platelets and assessment of TXB2 formation in HEL cells. COX-2 inhibition was assessed by measuring 6-keto-PGF1α in supernatants of intact cells of LPS-stimulated J774.2 cells (murine) and of Mono Mac 6 cells (human). In whole blood inhibition of COX-1 was performed by measuring TXB2 formation after clotting, and COX-2 inhibition was examined in LPS-stimulated whole blood cultures. The reduction of NO levels as a measure of the inhibition of cellular NO formation was assayed in supernatants of LPS-stimulated RAW 264.7 cells using the Griess reaction. Compound influence on the formation of TNF-α, IL-1β, IL-6, and IL-8 was examined using LPS-stimulated monocytic cells (THP-1) and measurement of cytokine concentrations by specific ELISAs.¶Results: In intact human cells, lornoxicam showed a balanced inhibition of COX-1/-2 exhibiting the lowest IC50 (0.005μM/0.008 μM) of the large panel of NSAIDs tested. Similar results were obtained in the whole blood for COX-1/-2. NO formation was dose-dependently inhibited by lornoxicam (IC50 of 65 μM) whereas piroxicam, diclofenac, ibuprofen, ketorolac and naproxen inhibited the NO formation markedly less. Indomethacin was approximately equipotent with lornoxicam. In stimulated monocytic cells (THP-1), lornoxicam showed a marked inhibition of IL-6 formation (IC50 54 μM) while the formation of TNF-α, IL-1β and IL-8 was only moderately affected.¶Conclusions: Of the panel of NSAIDs tested, lornoxicam was found to be the most potent balanced inhibitor of human COX-1/-2. The equipotent COX-isoenzyme inhibition by lornoxicam is complemented by a marked inhibition of IL-6 production and of iNOS-derived NO formation. The in vitro activities described support the marked anti-inflammatory and analgesic activities of lornoxicam found in animal models as well as in clinical studies.