Title:Nonsteroidal Anti-Inflammatory Drugs: Exploiting Bivalent COXIB/ TP Antagonists for the Control of Cardiovascular Risk
VOLUME: 24 ISSUE: 30
Author(s):Silvia Carnevali, Carola Buccellati , Chiara Bolego , Massimo Bertinaria , G. Enrico Rovati * and Angelo Sala
Affiliation:Department of Pharmacological and Biomolecular Sciences University of Milan, Milan, Department of Pharmacological and Biomolecular Sciences University of Milan, Milan, Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Department of Drug Science and Technology, University of Turin, Turin, Laboratory of Molecular and Eicosanoid Pharmacology, Dept. of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Department of Pharmacological and Biomolecular Sciences University of Milan, Milan
Keywords:Arachidonic acid, cardiovascular risk, COX-2 selective inhibitor, multitarget drug, non steroidal antiinflammatory
drug, thromboxane receptor antagonist.
Abstract:Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are some of the
most widely prescribed or dispensed over the counter analgesics and antipyretics that act
by inhibiting prostaglandins and thromboxane synthesis. After the identification of a second
isoform of COX, the pharmaceutical research focused on developing COX-2-
selective drugs (COXIBs) considered as second generation NSAIDs that would retain the
anti-inflammatory and analgesic activities of traditional NSAID without blunting the gastrointestinal
cytoprotection sustained by COX1-derived products such as PGE2. However,
while several clinical trials confirmed a gastrointestinal safer profile of COXIBs vs unselective
COX inhibitors, increasing evidence for potential cardiovascular risk associated
with COXIBs rapidly emerged. Today, there are no really safe NSAIDs to be used in
chronic pain and anti-inflammatory treatments, as an adequate therapy associated with a
minimal gastrointestinal damage and cardiovascular toxicity is yet to be developed.
Objective: Here, we present evidences that combining the anti-aggregating and antiatherotrombotic
activities of a thromboxane receptor antagonist with the antiinflammatory
activity of a COXIB we could obtain a new multitarget drug providing protection
against the harmful activities mediated by the COXIB component, yet exploiting
its recognized therapeutic advantages as a gastrointestinal-safer anti-inflammatory drug.
We also summarize recent progress achieved in this field of research and possible new
strategies to obtain a new bivalent compound.
Conclusion: This possible third-generation NSAID with a safer pharmacological profile,
will have all the pharmacological characteristics for the long-term therapy of chronic disorders
such as inflammatory diseases or selected forms of cancer.
