6-ketoprostaglandin-f1-alpha and Gastrointestinal-Hemorrhage

Sucralfate has been shown to prevent the formation of acute gastric lesions induced by nonsteroidal antiinflammatory drugs such as aspirin (ASA) in animals, but little is known about the prevention by this agent of ASA-induced gastric damage in humans. This report describes the effects of sucralfate on mucosal formation of prostaglandins (PG), gastric microbleeding and DNA loss in intact and ASA-challenged stomach. Two groups of 12 healthy volunteers were used in a double-blind, placebo controlled trial to assess the effects of sucralfate 1.0g qid on the stomach in subjects without (group A) and with administration of 2.5g ASA during 2 days (group B). Sucralfate treatment during 4 days significantly reduced spontaneous gastric bleeding and DNA loss in group A and prevented blood loss caused by ASA in group B. The protective effects of sucralfate on spontaneous gastric blood loss were accompanied by increased mucosal biosynthesis and luminal release of PGE2 and 6-keto-PGF1 alpha with decreased release of TXB2. In ASA-treated subjects mucosal generation and luminal release of PG and TXB2 were greatly suppressed and sucralfate treatment did not influence these PGs in spite of the decreased mucosal damage. It is concluded that sucralfate has a potent protective action on spontaneous and ASA-treated gastric bleeding in man and that this protection may be partly due to the increased mucosal biosynthesis of prostaglandins.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aspirin; Clinical Trials as Topic; Dinoprostone; DNA; Double-Blind Method; Gastric Mucosa; Gastrointestinal Hemorrhage; Humans; Male; Prostaglandins; Prostaglandins E; Sucralfate; Thromboxane B2

Many nonsteroidal antiinflammatory drugs have the ability to cause gastrointestinal damage in both animals and man. The aim of the present study was to compare nabumetone, a nonacidic drug, with etodolac on rat gastric mucosal damage and prostanoid synthesis, while concurrently measuring prostanoid production during edema formation in a carrageenan model of paw inflammation. The results showed that both drugs inhibited paw exudate prostaglandin E2 and edema significantly, but they did not inhibit gastric prostanoid production 4 hr after dosing. Gastric damage, however, was observed with etodolac. Additional time-course studies showed that over a 4-hr period, etodolac, unlike nabumetone, markedly inhibited gastric mucosal prostaglandin E2 production, which was associated with gastric erosion formation. Further studies demonstrated that nabumetone did not induce gastrointestinal damage or blood loss when administered to rats in a high antiinflammatory oral dose. In contrast, etodolac produced marked gastrointestinal damage and bleeding, which was evident for up to 48 hr after the dose. It is suggested that nabumetone's favorable gastrointestinal irritancy profile may relate, in part, to its nonacidic nature and to its differential effects on prostanoid production.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Butanones; Cecum; Depression, Chemical; Dinoprostone; Edema; Etodolac; Gastric Mucosa; Gastrointestinal Hemorrhage; Haptoglobins; Hemoglobins; Intestinal Mucosa; Male; Nabumetone; Rats; Rats, Wistar

The effect of nabumetone on rat gastric mucosal cyclooxygenase activity ex-vivo and in-vitro has been compared with that of indomethacin. Nabumetone was less potent and less active in inhibiting the production of gastric mucosal 6-keto-PGF1 alpha compared with indomethacin either ex-vivo or in-vitro. Anti-inflammatory doses of nabumetone failed to enhance bile salt-induced gastric erosion or mucosal permeability to dextran whereas indomethacin significantly enhanced gastric erosion and increased dextran permeability. These results suggest that nabumetone fails to promote gastric damage or increase permeability because of minimal effects on gastric mucosal cyclooxygenase.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bile Acids and Salts; Butanones; Dextrans; Gastric Mucosa; Gastrointestinal Hemorrhage; Indomethacin; Male; Nabumetone; Rats; Rats, Inbred Strains

An experimental study on morniflumate, the beta-morpholinoethyl ester of niflumic acid, was undertaken in the rat to test its gastroprotective and "cytoprotective" properties and to assess its effects on gastric secretion and on the prostaglandin contents in the stomach wall. Morniflumate induced intense and usually dose-dependent inhibition of the gastric hemorrhagic lesions caused by acetylsalicylic acid, indomethacin, diclofenac, ketoprofen, naproxen and phenylbutazone and of the gastric necrotic lesions caused by absolute ethanol, HCl 0.6 mol l-1, NaOH 0.2 mol l-1 and NaCl 25%. Morniflumate also exerted marked inhibition of gastric acid secretion both in normal and in pylorus-ligated rats. The compound raised the concentration of "cytoprotective" prostaglandins in the glandular portion of the stomach but did not reverse the synthesis-block effect of the ulcerogenic nonsteroidal anti-inflammatory drugs whose gastric effects it inhibited.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents; Dinoprostone; Ethanol; Gastric Acid; Gastric Mucosa; Gastrointestinal Hemorrhage; Hydrochloric Acid; Hydrogen-Ion Concentration; Male; Nicotinic Acids; Niflumic Acid; Prostaglandins E; Rats; Sodium Chloride; Sodium Hydroxide