Anti-inflammatory mechanisms of PS3, a new drug candidate with both anti-inflammatory and anti-thrombotic activities
Abstract number: P0456
Alban* S., Becker M., Franz G.
*Christian-Albrechts-University, Germany; University of Regensburg, Germany
Various diseases like atherosclerosis, cardiovascular disease, restenosis after coronary angioplasty, and sepsis are known to include thrombotic as well as inflammatory processes. Therefore, a drug exhibiting both anti-thrombotic and anti-inflammatory activities may be useful for treatment of such diseases. PS3 (PCT Int. Appl. WO 2002036132 (10.05.2002)), a structurally well-defined partial synthetic sulfated polysaccharide (SP) with a MW of 10 kDa, has been shown to exhibit not only anti-thrombin-independent anti-thrombotic, but also anti-inflammatory activity in vivo. The aim of the present study was to elucidate the mechanisms of its anti-inflammatory action. The influence on complement activation was examined using various modifications of the hemolytic assay. The inhibition of the selection-mediated cell adhesion was tested using a static microplate (MP) cell-adhesion assay as well as a flow chamber model. To elucidate interferences with the chemotaxis of PMN and monocytes, a MP assay based on the Boyden chamber was applied. The PMN-elastase inhibitory activity was checked in various assays using either a chromogenic substrate (+/ plasma), elastin or collagen as substrates and in cell-based assays. The binding of PS3 to elastase was analyzed by means of SPC-EAA (sulf. polysaccharide coating-enzyme activity assay). For comparison, unfractionated heparin (UFH) and other SP were included in the study. PS3 proved to be a potent inhibitor of both the classical and alternative complement activation with IC50 80- and 10-fold, respectively, lower than those of UFH. PS3 is superior to UFH in preventing the P- and L-selectin-mediated adhesion of selectin ligand expressing cells (IC50(P) 5 mg mL-1, IC50(L) 10 mg mL-1). But both compounds are inactive in the E-selectin assay. In contrast to UFH, PS3 also inhibits the selectin-mediated cell rolling under flowing conditions. Further, PS3 reduces the chemotaxis of PMN and monocytes induced by zymosan-activated serum (IC50 1.7 mg mL-1), whereas UFH shows only moderate effects. Especially in the physiological substrate and cell-based assays, the elastase inhibition by PS3 is much better than by UFH. In conclusion, PS3 was shown to interfere with several important mechanisms involved in inflammation. Due to its action profile it represents an interesting candidate for therapy of disorders requiring both anti-thrombotic and anti-inflammatory medication and may be an useful alternative to UFH in sepsis patients treated with anti-thrombin.
To cite this abstract use the following format:
Journal of Thrombosis and Haemostasis 2003; 1 Supplement 1 July: abstract number
|Subject:||Inflammation, infection and immunity|
|Back to top|