Comparison between 3-Nitrooxyphenyl acetylsalicylate (NO-ASA) and O2-(acetylsalicyloxymethyl)-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (NONO-ASA) as safe anti-inflammatory, analgesic, antipyretic, antioxidant prodrugs.
Chronic inflammation is an underlying etiological factor in carcinogenesis; nonsteroidal anti-inflammatory drugs (NSAIDs) and their chemically modified NO-releasing prodrugs (NO-NSAIDs) are promising chemopreventive agents. The aim of this study was to conduct a head-to-head comparison between two NO-ASAs possessing different NO donor groups, an organic nitrate [3-nitrooxyphenyl acetylsalicylate (NO-ASA; NCX-4016)] and an N-diazeniumdiolate [NONO-ASA, O(2)- (acetylsalicyloxymethyl)-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (NONO-ASA; CVM-01)], as antiulcerogenic, analgesic, anti-inflammatory, and antipyretic agents. All drugs were administered orally at equimolar doses. For antiulcerogenic study, 6 h after administration, the number and size of hemorrhagic lesions in stomachs from euthanized animals were counted. Tissue samples were frozen for prostaglandin E(2) (PGE(2)), superoxide dismutase (SOD), and malondialdehyde determination. For anti-inflammatory study, 1 h after drug administration, the volume of carrageenan-induced rat paw edemas was measured for 6 h. For antipyretic study, 1 h after dosing, fever was induced by intraperitoneal LPS, and body core temperatures measured for 5 h. For analgesic study, time-dependent analgesic effect of prodrugs was evaluated by carrageenan-induced hyperalgesia. Drugs were administered 30 min after carrageenan. NO-ASA and NONO-ASA were equipotent as analgesic and anti-inflammatory agents but were better than aspirin. Despite a drastic reduction of PGE(2) 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 approximately 2-fold higher than that induced by aspirin. CVM-01 is as effective as NCX-4016 in anti-inflammatory, analgesic, and antipyretic assays in vivo, and it showed an equivalent safety profile in the stomach. These results underscore the use of N-diazeniumdiolate moieties in drug design.
Chattopadhyay
Mitali
M
Department of Physiology and Pharmacology, City University of New York Medical School, 138th St. and Convent Ave., New York, NY 10031, USA.
Velazquez
Carlos A
CA
Pruski
April
A
Nia
Kamran V
KV
Abdellatif
Khaled R
KR
Keefer
Larry K
LK
Kashfi
Khosrow
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D058633:Antipyretics / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001241:Aspirin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004487:Edema / Q000188:drug therapy; D005334:Fever / Q000188:drug therapy; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006930:Hyperalgesia / Q000188:drug therapy; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D015394:Molecular Structure; D011355:Prodrugs / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D058633:Antipyretics; D006834:Hydrazines; C553487:O2-(acetylsalicyloxymethyl)-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate; D011355:Prodrugs; D014409:Tumor Necrosis Factor-alpha; D008315:Malondialdehyde; D013482:Superoxide Dismutase; C102148:nitroaspirin; D015232:Dinoprostone; D001241:Aspirin