NO-NSAIDs: from inflammatory mediators to clinical readouts.
Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase (COX)-2 selective inhibitors (COXIBs) are widely used drugs. However, their use is hampered by gastrointestinal, cardiovascular and renal side effects. Nitric oxide (NO)-releasing NSAIDs, NO-NSAID, are a new class of anti-inflammatory and analgesic drugs generated by adding a nitroxybutyl or a nitrosothiol moiety to the parent NSAID via a short-chain ester linkage. While efficacy of nitrosothiol-NSAIDs still awaits investigation, nitroxybutyl-NO-NSAIDs have been extensively studied in humans. The combination of balanced inhibition of the two main COX isoforms with release of NO confers to NO-NSAIDs reduced gastrointestinal and cardiorenal toxicity. It is suggested that the NO, which is released as the compounds are broken down, may counteract the consequences of the NSAID-induced decrease in gastric mucosal prostaglandins. Recent clinical trials with NO-NSAIDs have provided data consistent with pre-clinical observations.
Fiorucci
Stefano
S
University of Perugia, Italy. fiorucci@unipg.it
Antonelli
Elisabetta
E
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D001241:Aspirin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D001777:Blood Coagulation; D002318:Cardiovascular Diseases / Q000209:etiology; D002634:Chemotaxis, Leukocyte; D002986:Clinical Trials as Topic; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007962:Leukocytes / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009288:Naproxen / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D009566:Nitrates / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D009569:Nitric Oxide / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; C488176:N-acetyl-S-(alpha-methyl-4-(2-methylpropyl)benzeneacetyl)cysteine 4-(nitrooxy)butyl ester; D009566:Nitrates; C111751:naproxen-n-butyl nitrate; D009569:Nitric Oxide; D009288:Naproxen; D052247:Nitric Oxide Synthase Type II; C102148:nitroaspirin; D001241:Aspirin