Impact on the bowel of amtolmetin guacyl, a new gastroprotective non-steroidal anti-inflammatory drug.
Amtolmetin guacyl (MED15) is a new non-steroidal anti-inflammatory drug (NSAID) which shares anti-inflammatory, analgesic and antipyretic activity with the other drugs of the NSAID family but which shows, unexpectedly, strong gastroprotective activity similar to misoprostol. This effect has been attributed to the presence in its molecule of a vanillic moiety responsible for stimulation of capsaicin receptors present throughout the length of the gastrointestinal tract. MED15 shows antispasmodic activity in the bowel against a number of agonists and compares favourably with reference compounds. In in vivo indomethacin-induced rat ileitis, MED15 heals better than 5-aminosalicylic acid and sulfasalazine, as well as down-regulating intestinal wall myeloperoxidase content. In acetic acid-induced colitis in the rat, levels of malondialdehyde were found to be more markedly reduced with MED15 than with 5-aminosalicylic acid. In contrast with the effect in the stomach, MED15 protective effect in the bowel appears to be unrelated to nitric oxide (NO) production. The MED15 enteroprotective effect is related to stimulation of intestinal capsaicin receptors as demonstrated by the loss of protective effect in the presence of capsazepine, a specific receptor antagonist of capsaicin. In conclusion, following the favourable results obtained in animal models and notwithstanding the pharmacological effects typical of an NSAID, MED15 may rationally be proposed for the treatment of various human colitis conditions and Crohn's disease.
Tubaro
Ezio
E
Research Laboratories, Medosan Ricerca S.r.l., Via Cancelleria, 12, 00040 Albano Laziale, Rome, Italy. medosan.r@flashnet.it
Belogi
Luisella
L
Mezzadri
Carla Maria
CM
Bettelli
Enzo
E
D019342:Acetic Acid; D000636:Aminosalicylic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D006168:Guinea Pigs; D007079:Ileitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007213:Indomethacin; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009195:Peroxidase / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012460:Sulfasalazine / Q000494:pharmacology / Q000627:therapeutic use; D014456:Ulcer / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology
D000636:Aminosalicylic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011758:Pyrroles; C065762:ST 679; D009569:Nitric Oxide; D012460:Sulfasalazine; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D019342:Acetic Acid; D005998:Glycine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin