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.

1 . A method for the detecting the presence of minimal or early vasculitis or other vasculopathies in a subject, comprising the steps of:
 (a) obtaining a sample from a subject to whom a compound or drug, susceptible to induce cardiovascular pathologies has been administered or a subject with a vascular autoimmune disorder;   (b) analysing the sample for the presence of a biomarker of minimal or early vasculitis or other vasculopathies; and   (c) determining whether the subject has minimal or early vasculitis or other vasculopathies based upon the presence of absence of a biomarker of minimal or early vasculitis or other vasculopathies.   
   
   
       2 . A method for predicting compound or drug-induced cardiovascular adverse effects in a subject to whom a cox-2 inhibitory compound or drug has been administered, comprising the steps of:
 (a) obtaining a sample from a subject to whom a cox-2 inhibitory compound or drug has been administered;   (b) analysing the sample for the presence of a biomarker of cardiovascular adverse effects; and   (c) determining whether the subject has cox-2 inhibitor-induced cardiovascular adverse effects based upon the presence of absence of a biomarker of cardiovascular adverse effects.   
   
   
       3 . The use of a cox-2 inhibitory compound in the manufacture of an anti-inflammatory medicament with a reduced risk of cardiovascular toxicity, wherein the use comprises the steps of:
 monitoring the patient to whom the anti-inflammatory medicament has been administered for the presence or absence of biomarkers predictive of cox-2 inhibitor-induced cardiovascular adverse effects.   
   
   
       4 . The method of  claim 3 , wherein cox-2 inhibitory compound is selected from the group consisting of cox-2 specific inhibitors (coxibs), classical NSAIDs, other anti-inflammatory/immunosuppressive/immunomodulatory compounds and direct PGE2, cAMP and PKA inhibitors. 
   
   
       5 . The method of  claim 3 , wherein cox-2 inhibitory compound is selected from the group consisting of COX189 (Lumiracoxib®), refocoxib (Vioxx®), and celecoxib (Celebrex®). 
   
   
       6 . The method of  claim 3 , wherein the cox-2 inhibitory compound is the non specific cox-2 inhibitory compound diclofenac (Voltaren®). 
   
   
       7 . The method of  claim 3 , wherein the biomarker predictive of cox-2 inhibitor-induced cardiovascular adverse effects is an increase in gene expression of a gene selected from the genes listed in TABLE 1. 
   
   
       8 . The method of  claim 3 , wherein the biomarker predictive of cox-2 inhibitor-induced cardiovascular adverse effects is an increase in gene expression of an interferon inducible gene selected from the group consisting of the genes encoding for Toll-like receptors (TLRs), classical and non-classical MHC class I proteins, MHC class II proteins, TcRs, NK receptors, CXCL10, CXCL-9, CXCL 11, MCP-1 (CCL2), Jak1 and Stat1. 
   
   
       9 . The method of  claim 3 , wherein the biomarker predictive of cox-2 inhibitor-induced cardiovascular adverse effects is an increase in gene expression of the gene for a coagulation pathways-related molecule selected from the group consisting of PD-ECGF, coagulation factor II (thrombin) receptor-like 1 and Factor 13 A1. 
   
   
       10 . The method of  claim 3 , wherein the biomarker predictive of cox-2 inhibitor-induced cardiovascular adverse effects is an increase in Cc110 gene expression. 
   
   
       11 . The method of  claim 3 , wherein the biomarker predictive of cox-2 inhibitor-induced cardiovascular adverse effects is an increase in the release of pro-inflammatory cytokines and chemo-attractants. 
   
   
       12 . The method of  claim 3 , wherein the biomarker predictive of cox-2 inhibitor-induced cardiovascular adverse effects is an increase in INFγ inducible proteins. 
   
   
       13 . The method of  claim 3 , wherein the biomarker predictive of cox-2 inhibitor-induced cardiovascular adverse effects is an increase in CXCL10 (IP10) protein levels. 
   
   
       14 . The method of  claim 3 , wherein the biomarker predictive of cox-2 inhibitor-induced cardiovascular adverse effects is an increase in PD-ECGF1 protein. 
   
   
       15 . The method of  claim 3 , wherein the biomarker predictive of cox-2 inhibitor-induced cardiovascular adverse effects is an increase in cPLA2 protein. 
   
   
       16 . The method of  claim 3 , wherein the sample is a tissue sample. 
   
   
       17 . The method of  claim 3 , wherein the sample is a cardiovascular tissue sample. 
   
   
       18 . The method of  claim 3 , wherein the sample is selected from the group consisting of blood, plasma, serum, urine and saliva. 
   
   
       19 . A method for the selection of cox-2 inhibitory compounds without cardiovascular toxicity for use in patients, comprising the steps of:
 (a) administering a cox-2 inhibitory compound to a subject;   (b) monitoring of early changes predictive of cardiovascular adverse effects in patients treated with compounds exhibiting cox-2 inhibition or increasing the production of molecules induced by interferons or by virus infections or vascular autoimmune disorders resulting in pro-coagulative/prothrombotic/endothelium changes;   (c) selecting the cox-2 inhibitory compounds that do not show cardiovascular toxicity for use in patients; and   (d) selection of sub-population of patients to be treated safely by cox-2 inhibitory compounds/drugs   
   
   
       20 . The method of  claim 20 , wherein the subject is a cynomolgous monkey. 
   
   
       21 . A vaccination strategy prior to administration of cox-2 inhibitor to a subject, wherein the vaccination strategy reduces cardiovascular toxicity in the subject to whom the cox-2 inhibitor is administered.