title: Identification of a unique nsaid, fluoro-loxoprofen with gastroprotective activity.
abstract: We previously proposed that direct cytotoxicity of NSAIDs due to their membrane permeabilization activity, together with their ability to decrease gastric prostaglandin E(2), contributes to production of gastric lesions. Compared to loxoprofen (LOX), fluoro-loxoprofen (F-LOX) has much lower membrane permeabilization and gastric ulcerogenic activities but similar anti-inflammatory activity. In this study, we examined the mechanism for this low ulcerogenic activity in rats. Compared to LOX, the level of gastric mucosal cell death was lower following administration of F-LOX. However, the gastric level of prostaglandin E(2) was similar in response to treatment with the two NSAIDs. Oral pre-administration of F-LOX conferred protection against the formation of gastric lesions produced by subsequent administration of LOX and orally administered F-LOX resulted in a higher gastric pH value and mucus content. In the presence of a stimulant of gastric acid secretion, the difference in the ulcerogenic activity of F-LOX and LOX was less apparent. Furthermore, an increase in the mucus was observed in gastric cells cultured in the presence of F-LOX in a manner dependent of increase in the cellular level of cAMP. These results suggest that low ulcerogenic activity of F-LOX involves its both low direct cytotoxicity and protective effect against the development of gastric lesions. This protective effect seems to be mediated through an increase in a protective factor (mucus) and a decrease in an aggressive factor (acid).
authors.affiliation: Department of Analytical Chemistry, Faculty of Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Suemasu
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamakawa
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ishihara
authors.forename: Teita
authors.initials: T
authors.lastname: Asano
authors.forename: Kayoko
authors.initials: K
authors.lastname: Tahara
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Tanaka
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Matsui
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Masami
authors.initials: M
authors.lastname: Otsuka
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Tohru
authors.initials: T
authors.lastname: Mizushima
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D002478:Cells, Cultured; D003470:Culture Media; D020287:In Situ Nick-End Labeling; D010666:Phenylpropionates / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003470:Culture Media; D010666:Phenylpropionates; C040656:loxoprofen