Chronic inflammation is an underlying etiological factor in carcinogenesis; NSAIDs and their chemically-modified NO-releasing prodrugs (NO-NSAIDs) are promising chemopreventive agents. Head-to-head comparison between two NO-aspirins possessing different NO-donor groups: an organic nitrate (NCX-4016, NO-ASA) or N-diazeniumdiolate (CVM-01, NONO-ASA) as anti-ulcerogenic, analgesic, anti-inflammatory, and anti-pyretic agents. All drugs were administered orally at equimolar doses. Anti-ulcerogenic: 6h post-administration, number/size of hemorrhagic lesions in stomachs from euthanized animals were counted. Tissue samples were frozen for PGE2, SOD, and MDA determination. Anti-inflammatory: 1h after drug administration, the volume of carrageenan-induced rat paw edemas was measured for 6h. Anti-pyretic: 1h after dosing, fever was induced by LPS (ip) and body core temperatures measured for 5h. Analgesic: time-dependent analgesic effect of prodrugs was evaluated by carrageenan-induced hyperalgesia. Drugs were administered 30 min after carrageenan. NCX-4016 and CVM-01 were better analgesic and anti-inflammatory agents compared to aspirin, but equipotent to each other. Despite a drastic reduction of PGE2 in stomach tissue, both prodrugs were devoid of gastric side effects. Lipid peroxidation induced by aspirin was higher than that observed by prodrugs. SOD activity induced by both prodrugs was similar, but about 2-fold higher than that induced by aspirin. CVM-01 is as effective as NCX-4016 in anti-inflammatory, analgesic, and anti-pyretic assays in vivo, and it showed an equivalent safety profile in stomach. These results underscore the use of N-diazeniumdiolate moieties in drug design.
- The American Society for Pharmacology and Experimental Therapeutics