Gastric toxicity and prostaglandin content in rats dosed with two chemically similar, nonsteroidal anti-inflammatory agents.
Two chemically similar nonsteroidal anti-inflammatory drugs, orpanoxin and F-1067, had almost identical potencies and efficacies as anti-inflammatory (rat paw edema) and analgesic (mouse writhing) agents, but differed markedly in gastrotoxicity. Orpanoxin alone aggravated stomach lesions in rats subjected to pylorus ligation and failed to protect stomachs of rats challenged with indomethacin. The compounds did not differ in their in vitro enzyme inhibition effects, both failing to inhibit 5- and 15-lipoxygenase and both inhibiting prostaglandin synthetase. Extraction of prostaglandins from the gastric mucosa of pylorus-ligated rats revealed, however, that the safer F-1067 depleted prostaglandin 6-keto-F1 alpha less and increased prostaglandin E2 much more than did orpanoxin. A possible causality is suggested.
Brooks
R R
RR
Research and Product Development, Procter & Gamble Pharmaceuticals, Norwich, New York 13815.
Moorehead
T J
TJ
Pong
S F
SF
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000633:toxicity*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D005663:Furans / Q000494:pharmacology / Q000633:toxicity*; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation; D016859:Lipoxygenase Inhibitors; D008297:Male; D010944:Plants / Q000201:enzymology; D011422:Propionates / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012669:Seminal Vesicles / Q000201:enzymology; D012756:Sheep; D013270:Stomach / Q000187:drug effects / Q000473:pathology*; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D016859:Lipoxygenase Inhibitors; D011422:Propionates; C011677:benoxaprofen; C079342:5-(4-chlorophenyl)-2-furanpropionic acid; D015121:6-Ketoprostaglandin F1 alpha; C024876:orpanoxin; D015232:Dinoprostone; D007213:Indomethacin