Effect of a new non-steroidal anti-inflammatory combination of a histamine H2 antagonist and indomethacin on gastroduodenal mucosal membrane in rat.
The new non-steroidal anti-inflammatory drug (NSAID), N-(3-[3-(piperidinyl-methyl) phenoxy] propyl)-carbamoyl-methylthio]ethyl 1-(p-chlorobenzoyl) 5-methoxy-2-methyl-3-indolyl-acetate (CP 331, CAS 127966-70-5), a compound with a structure of an ester combining indomethacin (IM) and a histamine H2 antagonist, has been reported to have anti-inflammatory, analgesic and antipyretic effects. However, the influence of CP-331 on the gastroduodenal mucosa was not fully investigated. Therefore this study was undertaken to investigate the effect of CP-331 on the gastroduodenal mucosa membrane in rats. After single oral drug administration, the UD50 value (50% ulcerogenic dose) of CP-331 calculated from the incidence rate of gastric ulcer was higher than 1000 mg/kg; that for IM was 5.2 mg/kg. Moreover it was examined whether CP-331 had a preventive effect on NSAID-induced gastric damage. The results showed that the co-administration of CP-331 10-30 mg/kg prevented significantly the acute gastric mucosal injury caused by IM administration (20 mg/kg). CP-331 with anti-inflammatory activity does not cause gastric injury, moreover, because of its preventing and therapeutic effects on the damage to gastric mucous membrane induced by IM, CP-331 might be useful in the treatment of gastropathy caused by NSAID in clinic.
Department of Pharmacology, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
Y
Y
Segawa
T
T
Omata
T
T
Abe
N
N
Tsuzuike
Y
Y
Itokazu
K
K
Yoshida
I
I
Ueda
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000494:pharmacology*; D004386:Duodenum / Q000187:drug effects; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D006635:Histamine H2 Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D007213:Indomethacin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008566:Membranes / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006635:Histamine H2 Antagonists; C069844:CP 331; D007213:Indomethacin