ML 3000 reduces gastric prostaglandin synthesis without causing mucosal injury.
In this study we characterized the effects of a novel anti-inflammatory drug, ML 3000 ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine- 5-yl]-acetic acid), on the gastric mucosa and attempted to determine the mechanism responsible for its apparent stomach-sparing properties. Acute gastric damaging properties of ML 3000 versus indomethacin were examined in the rat, while chronic-type gastric ulcer was examined in the rabbit. At doses of up to 100 mg/kg p.o., ML 3000 did not produce significant acute gastric injury, while indomethacin at 5-20 mg/kg p.o. caused mucosal necrosis and bleeding. ML 3000 significantly inhibited gastric and blood prostaglandin E2 synthesis, with the higher doses tested (30 and 100 mg/kg) producing comparable effects to that seen with indomethacin at 10 or 20 mg/kg. Gastric and blood leukotriene B4 synthesis were not significantly affected by either drug. While indomethacin caused a significant increase in leukocyte adherence to mesenteric venules, ML 3000 did not. When administered repeatedly to rabbits, diclofenac caused penetrating ulcer formation in the gastric antrum of the majority of the animals. ML 3000 did not produce any detectable damage at doses of 10 or 30 mg/kg, but an ulcer was observed in one of five rabbits given the 100 mg/kg dose. Prior administration of ML 3000 (10-100 mg/kg) did not significantly affect the extent of gastric damage induced by subsequent oral administration of ethanol. These studies demonstrate that ML 3000 spares the gastric mucosa despite significantly suppressing gastric prostaglandin synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Wallace
J L
JL
Gastrointestinal Research Group, Faculty of Medicine, University of Calgary, Alberta, Canada.
Carter
L
L
McKnight
W
W
Tries
S
S
Laufer
S
S
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D011453:Prostaglandins / Q000096:biosynthesis*; D011758:Pyrroles / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced
D000085:Acetates; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D011453:Prostaglandins; D011758:Pyrroles; C088092:licofelone