Ibuprofen-arginine generates nitric oxide and has enhanced anti-inflammatory effects.
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.
De Palma
Clara
C
Unit of Clinical Pharmacology, Department of Preclinical Sciences, University of Milano, 20157 Milan, Italy.
Di Paola
Rosanna
R
Perrotta
Cristiana
C
Mazzon
Emanuela
E
Cattaneo
Dario
D
Trabucchi
Emilio
E
Cuzzocrea
Salvatore
S
Clementi
Emilio
E
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
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