Biomarkers for cardiovascular side-effects induced by cox-2 inhibitory compounds

Abstract

Cardiovascular tissue mRNA expression profiles in monkeys treated with coxibs was analyzed. Genomic data indicated that the animals showing vasculitis exhibit a specific mRNA expression pattern. The pattern includes gene expression changes involved in blood and endothelial cell (EC) activation, interaction of blood cells with EC, activation of INFγ pathway, and release of pro-inflammatory cytokines and chemo-attractants. These results provide direct evidence of minimal vasculitis together with corresponding genomic signature and peripheral biomarkers for minimal vasculatis. These results also suggest that treatment might triggers/aggravate a clinically latent cardiovascular disorder in the context of an endothelium tropic viral infection and/or an autoimmune vascular disorder. The histopathological examination revealed marginal vascular changes consistent with the genomic findings. Measurement of soluble proteins present in serum and plasma using a multiplex assay were in line with the genomic results, showing the increased level of INFγ inducible proteins, increased expression of CXCL10 chemokine was confirmed by an ELISA both in serum and plasma. Use of these peripheral biomarkers allows a safe usage of cox-2 inhibitory compounds in clinics and selection of cox-2 inhibitory follow-up compounds with no cardiovascular toxicity. These data together with biochemical and histopathological findings suggest that the specific cox2 inhibitor may exaggerate host immune response during some specific viral infections with endothelial tropism, or subjacent vascular autoimmune disorders.

Description

FIELD OF THE INVENTION[0001]The invention relates generally to the in vivo testing of the efficacy of a compound or composition, and particularly to the testing and biologically functionalizing of cox-2 inhibitory compounds (coxibs) by activity in vivo.BACKGROUND OF THE INVENTION[0002]Use of cox-2 specific inhibitory compounds (coxibs) and some NSAIDs has been associated with an increased risk of cardiovascular events in human including deep venous thrombosis, myocardial infarction, stroke, and sudden death. The current hypothesis is that some of anti-inflammatory compounds inhibit PGI2 synthesis but not TxA synthesis, altering the homeostatic balance towards the pro-coagulative / pro-trombotic pathways. Fitzgerald G A. N Engl J Med. 351(17):1709-11 (Oct. 21, 2004). It has been reported that some of anti-inflammatory compounds, mainly cox-2 inhibitors, inhibit PGI2 synthesis only, resulting in altered homeostatic balance towards the pro-coagulative pathways which in rare cases might l...

AI Technical Summary

Benefits of technology

[0009]In one aspect of the invention, the data of the present invention identifies another pathway than the PGI2 synthesis pathway that may be one of the main triggering factors leading to the observed adverse cardiovascular events in human. Alteration in this pathway can be easily monitored in preclinical and clinical studies to avoid such cardiovascular side effects upon cox-2 and/or NSAIDs treatments. B...

Problems solved by technology

The overall genomic findings show that Cox-2/PGE2 inhibition results in strong and uncontrolled induction of INFγ regulated chemo-attracta...

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