Bernard Terlain

Reaction of inflammation inhibitors with chemically and electrochemically generated hydroxyl radicals

Hydroxyl radicals were generated by chemical or electrochemical Fenton reactions and reacted with inflammation inhibitors. Similar reactivities are observed with all the drugs under examination. The hydroxylation of Ketoprofen leads to the known metabolites.

RP 54745, a potential antirheumatic compound. I. Inhibitor of macrophage stimulation and interleukin-1 production

RP 54745 is an amino-dithiole-one compound found to be active at micromolar concentration on the metabolism of stimulated macrophages, for example, the hexose monophosphate pathway (HMP) and the exocytosis of lysosomal enzymes. LPS-induced interleukin-1 (IL-1) production by murine peritoneal macrophages was also diminished by this compoundin vitro as well asin vivo. This effect was confirmed at the mRNA level; at the concentration of 3×10−6M, the IL-1α and β mRNA signals were inhibited, whereas the TNFα mRNA signal was only slightly lessened. These observations were confirmedin vivo, with a dose of RP 54745 of 25 mg kg−1. These results led us to consider that RP 54745 might influence certain cells and cytokines implicated in the regulation of the immune system, the disfunctioning of which can lead to inflammatory disorders or autoimmune pathologies.

RP 54745, a potential antirheumatic compound. II.In vivo properties in different animal models

The results obtained with RP 54745, an amino-dithiole-one compound, on stimulated macrophages, revealing inhibition of the hexose monophosphate pathway (HMP), of the exocytosis of lysosomal enzymes and of the production of interleukin-1 (IL-1), by the compoundin vitro as well asin vivo, suggested that RP 54745 might influence cells and cytokines implicated in the regulation of the immune system, the disfunctioning of which can lead to inflammatory disorders or autoimmune pathologies. RP 54745 was effective at moderate oral doses (around 5 mg kg−1) in different mouse models of induced arthritis and in the MRL/lpr mice, genetically predisposed to develop an autoimmune pathology including arthritic disorders. The clinical status of the MRL mice, and several of their disturbed biochemical and immunological parameters, improved after a 3-month treatment with RP 54745. This activity of RP 54745 makes it a very attractive antirheumatic compound and a potentially effective treatment in pathologies where IL-1 production is exacerbated.