The active metabolite of leflunomide, A77 1726, inhibits the production of prostaglandin E2, matrix metalloproteinase 1 and interleukin 6 in human fibroblast‐like synoviocytes

Objectives. To investigate the effects of the active metabolite of leflunomide, A77 1726, on fibroblast‐like synoviocytes. In rheumatoid arthritis (RA) synoviocytes participate in tissue destruction by producing metalloproteinases (MMP), prostaglandin E2 (PGE2) and interleukin (IL) 6, which are involved in extracellular matrix degradation, resorption of the mineral phase and osteoclast‐mediated bone resorption. Methods. Human synoviocytes were stimulated with IL‐1α or tumour necrosis factor α (TNF‐α) in the presence of A77 1726. Culture supernatants were analysed for production of interstitial collagenase (MMP‐1), tissue‐inhibitor of metalloproteinases 1 (TIMP‐1), PGE2 and IL‐6. Total RNA was isolated and analysed for steady‐state levels of MMP‐1, cyclooxygenase‐2 (COX‐2) and IL‐6 mRNA. Results. A77 1726 inhibited the production of PGE2 in synoviocytes activated by TNF‐α and IL‐1α with median inhibitory concentrations (IC50) of 7 and 3 µm respectively. In contrast, MMP‐1 and IL‐6 production was inhibited at high A77 1726 concentrations (> 10 µm), whereas TIMP‐1 was not affected. The inhibition of MMP‐1 and IL‐6 production was due to the known inhibitory effect of A77 1726 on pyrimidine synthesis, as it was reversed by the addition of uridine. This did not apply to PGE2 production, which was inhibited via direct action of A77 1726 on COX‐2, as shown by the increasing amount of substrate (arachidonic acid) in the culture medium. Conclusion. This study shows that some of the beneficial effect of leflunomide in RA patients may be due to the inhibition of PGE2, IL‐6 and MMP‐1 production in synoviocytes. This effect, coupled with its multiple inhibitory effects on T lymphocyte functions, might account for the significant reduction in the rate of disease progression in RA patients treated with leflunomid

Main Properties of the THERAFLEX MB-Plasma System for Pathogen Reduction

Methylene blue (MB) treated plasma has been in clinical use for 18 years. The current THERAFLEX MB-Plasma has a number of improved features compared with the original Springe methodology. This overview embodies: the biochemical characteristics of MB, the mechanism of the technology, toxicology, pathogen reduction capacity, current position in clinical setting and status within Europe. The THERAFLEX MB (TMB) procedure is a robust, well standardised system lending itself to transfusion setting and meets the current guidelines. The pathogen kill power of the TMB system, like the other available technologies, is not limitless, probably in order of 6 log for most enveloped viruses and considerably less for non-enveloped ones. It does not induce either new antigen or grossly reducing the function and life span of active principle in fresh frozen plasma (FFP). The removal of the residual MB at the end of the process has the beneficial effect of reducing potential toxic impacts. Clinical haemovigilance data, so far, indicate that cell-free MB plasma is effective in all therapeutic setting requiring FFP, besides inconsistent thrombotic thrombocytopenia purpura data, without serious side-effects or toxicity. The current system is in continuous improvement e.g. regarding virus reduction range, illumination device, software used, and process integration in the blood bank setting