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infiltrates, cartilage destruction and bone apposition in mice treated with the two highest doses of Org 2140070. Altogether these results demonstrate that the antiinflammatory in vivo efficacy of Org 214007-0 is as good as or even better than that of prednisolone. In the same chronic disease model we wanted to test whether the partial activity of Org 214007-0 on induction of gene expression and its improved TI, as observed in vitro, would be sustained in vivo. Evaluation of the gene expression profiles induced by prednisolone in different tissues and at different time points after the last dosing of compound in a CIA experiment indicated that muscle tissue collected 2.5 hours after dosing provided representative and robust gene expression data. Therefore, muscle tissue was collected from arthritic mice that were treated for 3 weeks with either vehicle only or with dosages of Org 2140070 and prednisolone that were equally effective in inhibiting arthritis. Besides these groups of mice, one group of healthy mice was included. Collected tissue was used to isolate mRNA for microarray analysis. The top 25 genes that were at least 2-fold up-regulated by either Org 214007-0 or prednisolone in comparison to vehicle treated mice are shown in 5 Org 214007-0, a SGRM with Improved TI Cells/Assay A THP-1 rep ind B THP-1 rep Stim I/T I/T Read m.a. m.a. MCP-1 Param Max. eff. Max. eff, IC50 Max. eff. THP-1: Microarray analysis of mRNA isolated from THP-1 cells incubated for 6 hours with either 1 mM prednisolone or 1 mM Org 214007-0 without or with IFNc /TNFa , The mean percentage repression or induction of genes compared to that by prednisolone is indicated. B) THP-1 rep: Repression of gene expression in THP-1 cells. I/T MCP-1, IL-6, IL-8 = TNFa /IFNc induced MCP-1, IL-6 or IL-8 release. C) THP-1 ind: Induction of FK506 binding protein 51, glucocorticoid induced leucine zipper and dual specificity phosphatase 1 in THP-1 cells. D) hWB rep: Inhibition of LPS-induced TNFa release or PMA/anti-CD28 induced IL-5 release by primary human whole blood cells and hWB ind: enhancement of PMA/ anti-CD28/compound induced G-CSF release by primary human whole blood cells. E) CASM3C rep: Inhibition of MCP-1 release of coronary artery smooth muscle cells stimulated with a cytokine mixture of IL-1b, IFNc and TFNa by 1 mM prednisolone or 1 mM Org 214007-0. CASM3C ind: Induction of serum T0070907 site amyloid A of the cells mentioned above by 1 mM prednisolone or 1 M Org 214007-0. F) HDF3CGF rep: inhibition of matrix metalloproteinase release of human neonatal foreskin fibroblasts stimulated with the cytokine mixture mentioned above plus required growth factors. HDF3CGF ind: Activation of plasminogen activator inhibitor-1 by cells mentioned above by 1 mM prednisolone or 1 mM Org 214007-0. G) CIA mus.: Microarray analysis of mRNA isolated from muscle cells isolated at day 21, 2.5 hours after the final oral administration of either 1.5 mg/kg prednisolone or 0.3 mg/ kg Org 214007-0 in the mouse CIA experiment. The mean percentage repression or induction of genes compared to that by prednisolone is indicated. IC50 or EC50 values represent the mean concentration of compound required 10884520 to resp. inhibit or effect the response to 50%. Maximal efficacy is expressed as the mean relative maximal effect compared to the maximal effect by prednisolone. A relative therapeutic index is calculated by the ratio 15647369 of % maximal efficacy in repression and % maximal efficacy in induction of genes by Org 214007

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Author: calcimimeticagent