title: Ibuprofen-arginine generates nitric oxide and has enhanced anti-inflammatory effects.
abstract: Ibuprofen, a chiral non-steroidal anti-inflammatory drug chemically related to fenoprofen and naproxen, has moderate but definite anti-inflammatory, analgesic and antipyretic properties, with considerably less gastrointestinal adverse effect than other drugs in the same family. Currently available in the market are preparations in which bioavailability of ibuprofen is increased by salification with various salts. We have investigated the pharmacological properties of one such salt, ibuprofen-arginine, of biological interest because l-arginine acts as substrate of the nitric oxide (NO) synthesising enzymes. Using epithelial HeLa cells expressing the endothelial NO synthase we show that ibuprofen-arginine releases NO and that this NO protects against the cytotoxic apoptogenic effects of staurosporine. We also found that ibuprofen-arginine is endowed with enhanced anti-inflammatory effects with respect to ibuprofen, as shown by reduced hind paw oedema, neutrophil infiltration and chondrocyte apoptosis in collagen-induced mouse arthritis, a model of chronic inflammation. NO has pleiotropic beneficial effects that may contribute to limit inflammation and anti-inflammatory compounds able to release NO display higher efficacy than the parent drugs in defined clinical settings. Our results open the possibility that NO generation contributes to the enhanced anti-inflammatory effects of ibuprofen-arginine vs. ibuprofen, suggesting co-administration of anti-inflammatory drugs and arginine as an additional way to exploit the beneficial effects of NO.
authors.affiliation: Unit of Clinical Pharmacology, Department of Preclinical Sciences, University of Milano, 20157 Milan, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: De Palma
authors.forename: Rosanna
authors.initials: R
authors.lastname: Di Paola
authors.forename: Cristiana
authors.initials: C
authors.lastname: Perrotta
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Dario
authors.initials: D
authors.lastname: Cattaneo
authors.forename: Emilio
authors.initials: E
authors.lastname: Trabucchi
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Emilio
authors.initials: E
authors.lastname: Clementi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001120:Arginine / Q000494:pharmacology / Q000627:therapeutic use*; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D004338:Drug Combinations; D006367:HeLa Cells; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004338:Drug Combinations; D009569:Nitric Oxide; D001120:Arginine; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D007052:Ibuprofen; C106674:ibuprofen arginine