CombinatoRx Publishes Data on Selective Amplification of Synergistic Combination Drug Candidate
News Jan 30, 2009
CombinatoRx, Incorporated has announced the publication of new in vivo research in Arthritis Research and Therapy on a systems biology based strategy that selectively amplifies the anti-inflammatory activity of very low dose glucocorticoids in immune cells without modulation of pathways associated with glucocorticoid toxicity.
This research, which was conducted by CombinatoRx scientists, demonstrates that the multi-target mechanism of low dose prednisolone (a glucocorticoid) combined with dipyridamole (a cardiovascular agent) creates a dissociated activity profile with an increased therapeutic window through selective amplification of glucocorticoid-mediated anti-inflammatory signaling.
The combination suppressed release of pro-inflammatory mediators, including TNF-a, IL-6 and others, from human peripheral blood mononuclear cells and mouse macrophages. After 8 weeks of oral dosing in mouse models, the immune-specific amplification of prednisolone’s anti-inflammatory activity by dipyridamole did not extend to glucocorticoid-mediated adverse effects including corticosterone suppression.
“This research demonstrates the utility of a systems biology approach to identifying novel therapeutics that are pathway, or multi-target, focused,” said Alexis Borisy, President and CEO of CombinatoRx. “Earlier attempts by the pharmaceutical industry at steroid dissociation using medicinal chemistry have shown mixed results because the anti-inflammatory activity and adverse effects of glucocorticoids do not break cleanly along mechanistic lines of transcription activation and repression. The systems biology approach leverages multi-target action to amplify glucocorticoid activity selectively within the unique network context of inflammatory cells, rather than attempting to dissect various aspects of glucocorticoid receptor biology.”
By leveraging an organ-on-a-chip model and a bioreactor, four human gut metabolites have been identified that can help explain the enhanced sensitivity of the human colon towards enterohemorrhagic E. coli, which is responsible for more than 100,000 infections per year in the USA alone.READ MORE