title: Non-steroidal anti-inflammatory drug, nabumetone, prevents indometacin-induced gastric damage via inhibition of neutrophil functions.
abstract: Nabumetone is a non-steroidal anti-inflammatory drug (NSAID). It works as a prodrug and is extensively metabolized to an active metabolite, 6-methoxy-2-naphthylacetic acid (6MNA). It is well known that neutrophil infiltration and activation are critical in the pathogenesis of NSAID-induced gastric injury, and nabumetone shows less incidence of gastrointestinal irritancy. We examined the effects of nabumetone on neutrophil activation and on indometacin-induced gastric damage. In the indometacin-induced gastric mucosal injury, rats were treated with indometacin and then nabumetone or 6MNA was orally administered. Nabumetone prevented gastric damage accompanied by the reduction of neutrophil infiltration into gastric mucosa, but such an effect was not observed with 6MNA. Nabumetone reduced the formyl methionyl leucyl phenylalanine (fMLP)-induced respiratory burst of human neutrophils to 30% of the control level in-vitro, but 6MNA did not. In addition, nabumetone prevented the fMLP-induced migration of neutrophils. Nabumetone did not inhibit O2- generation in the xanthine-xanthine oxidase system. These results suggest that nabumetone prevents gastric damage induced by the active metabolite, 6MNA, via the suppression of neutrophil activation in gastric mucosa.
authors.affiliation: Central Research Laboratory, Sanwa Kagaku Kenkyusho Co. Ltd, Mie, Japan. y_ishiwata@mb4.skk-net.com
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Ishiwata
authors.forename: Masayuki
authors.initials: M
authors.lastname: Okamoto
authors.forename: Shoji
authors.initials: S
authors.lastname: Yokochi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyachi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Naito
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D002074:Butanones / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D005753:Gastric Mucosa / Q000187:drug effects*; D007213:Indomethacin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D019255:NADPH Oxidases / Q000187:drug effects / Q000378:metabolism; D000077430:Nabumetone; D009504:Neutrophils / Q000187:drug effects*; D051381:Rats; D011917:Rats, Inbred Lew
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002074:Butanones; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019255:NADPH Oxidases; D000077430:Nabumetone; D007213:Indomethacin