l-663536 and tenidap

Prostaglandins and leukotrienes differentially regulate the production of interleukin-1 (IL-1) in monocytes. It was, therefore, decided to investigate the effects of some 5-lipoxygenase inhibitors compared with standard IL-1 synthesis inhibitors on the production of IL-1 by human synovial tissue explants in organ culture. Human synovial (from hip/knee arthroplasty) or porcine tibio-tarsal joint synovial explants were incubated in organ culture in Dulbecco's Modified Eagle's Medium + 5% foetal calf serum in the presence of the test compounds or solvents (controls), or media alone for 1-5 days. Total bioactive IL-1 was assayed in the medium (following serial dilution or with polyethylene glycol 8000 added in some assays to remove inhibitors) using the D-10 T-cell bioassay. Some assays of interleukins 1 alpha, 1 beta, 6 or 8 were performed by ELISA. Of the 5-lipoxygenase inhibitors investigated, MK-886(3-(1-(4-chlorobenzyl)-3-tert-butyl-thio-5-isopropylindol-2- yl)-2,2 -dimethyl propanoic acid), L-656,224 ((7-chloro-2-[4-methoxypenyl]methyl)-3 -methyl-5-propyl-4-benzofuranol), PF-5901 and tepoxalin were the most potent inhibitors of IL-1 production. While the PF-5901 was effective at 5-30 microM and tepoxalin was effective at 1-10 microM, the others were the most potent having minimal inhibitory activity in the range of 0.01-0.1 microM. The presumed IL-1-synthesis inhibitors, tenidap and IX-207,887, were inactive at concentrations of 30-50 microM. Leukotriene B4 (1-100 ng/mL-1) added to MK-886 (5 microM)-treated cultures reversed the inhibitory effects of the latter on IL-1, confirming the role of 5-lipoxygenase products in the regulation of IL-1 production. Addition of polyethylene glycol 8000 to MI-886-treated cultures eliminated the inhibitory effects of this drug, suggesting that this drug exerts its effects by promoting production of IL-1 inhibitors. MK-886 also inhibited synovial production of two other pleiotrophic cytokines which it regulates, IL-6 and IL-8. The results suggest that some 5-lipoxygenase inhibitors may be usefully employed in regulating production of those interleukins involved in joint cartilage destruction.

Topics: Animals; Benzofurans; Enzyme-Linked Immunosorbent Assay; Hip Joint; Humans; Hydroxyurea; Indoles; Interleukin-1; Knee Joint; Lipoxygenase Inhibitors; Naphthalenes; Organ Culture Techniques; Oxindoles; Pyrazoles; Quinolines; Structure-Activity Relationship; Swine; Synovial Membrane; Tarsus, Animal; Thiazoles; Thiophenes

To compare the proinflammatory effects of tenidap to those of indomethacin, and to assess the influence of lipoxygenase inhibition with either a leukotriene synthesis inhibitor (L663,536) or tenidap on platelet activating factor (PAF) induced leukocyte adhesion.. Adherent leukocytes, emigrated leukocytes, number of rolling leukocytes/100 microns venule, flux of rolling leukocytes, and leukocyte rolling velocity were quantitated in mesenteric venules (25-35 microns diameter and > 150 microns length) of Sprague-Dawley rats using intravital microscopy. In some experiments, the mesentery was superfused with indomethacin (25 micrograms/ml), tenidap (30 micrograms/ml), or both drugs simultaneously. In other experiments the mesentery was superfused with PAF 100 nM and the effects of treatment with L663,536 (10 mg/kg given orally) or superfusion with tenidap were determined.. Indomethacin significantly increased leukocyte rolling and adhesion. Tenidap did not promote leukocyte-endothelial cell adhesion and blocked the increased leukocyte rolling and adhesion promoted by indomethacin. Both L663,536 and tenidap significantly attenuated PAF induced leukocyte-endothelial cell adhesion.. Tenidap does not exhibit the proinflammatory properties of indomethacin. The reduction of indomethacin or PAF induced leukocyte-endothelial cell adhesion by tenidap appeared to result from its lipoxygenase inhibitory activity. Modulation of leukocyte-endothelial cell adhesion may be a novel mechanism of the antiinflammatory activity of tenidap and may reduce the relative risk of gastric ulceration with tenidap.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Adhesion; Endothelium, Vascular; Indoles; Indomethacin; Leukocytes; Leukotriene Antagonists; Male; Oxindoles; Platelet Activating Factor; Rats; Rats, Sprague-Dawley; Splanchnic Circulation; Venules