Anthony I. Stern

Protective effect of sucralfate against aspirin-induced damage to the human gastric mucosa

Sucralfate, an agent that heals peptic ulcers in humans, has been shown to reduce aspirin-induced gastric mucosal damage in experimental animals. It has been suggested that the protective effect of sucralfate is due to stimulation of local prostaglandin production. The purpose of this study was to establish whether sucralfate was capable of reducing aspirin-induced gastric damage in humans. The effect of 1 g of sucralfate or identical placebo was studied in random order in eight healthy subjects. To determine if the effect of sucralfate was related to local prostaglandin synthesis, a second series of studies was performed in which prostaglandin production was inhibited with indomethacin 50 mg given orally eight hours before sucralfate. In each subject, all studies were performed at least one week apart. Following an overnight fast, upper gastrointestinal endoscopy was performed, with sucralfate or placebo given orally 30 minutes before ingestion of 1,200 mg of soluble aspirin in 50 ml of water. Both endoscopist and subject were unaware of the test agent. Ninety minutes after aspirin ingestion, endoscopy was again performed and gastric mucosal lesions were counted and graded to derive an erosion score. Results are expressed as mean +/- SEM. Aspirin produced endoscopic changes (score of 2.75 +/- 0.49) that were significantly (p less than 0.05) inhibited by sucralfate (score of 1.13 +/- 0.44). The protective effect of sucralfate was abolished by pretreatment with indomethacin (scores of 2.88 +/- 0.55 and 1.88 +/- 0.40, respectively). These results demonstrate that sucralfate significantly protects the human gastric mucosa against the acute damaging effects of aspirin. This effect is abolished by indomethacin, suggesting that the protective action of sucralfate on the gastric mucosa of humans may be related to stimulation of endogenous prostaglandins.

Protective Effect of Acetaminophen Against Aspirin- and Ethanol-Induced Damage to the Human Gastric Mucosa

Aspirin and ethanol damage the gastric mucosa in humans, whereas acetaminophen does not. Acetaminophen increases prostacyclin activity in animals and thus may increase endogenous prostaglandin synthesis. The effect of acetaminophen was examined in five healthy subjects after intragastric aspirin or ethanol. Hydrogen and sodium ion fluxes were measured in the pylorus-occluded stomach that prevents duodenogastric reflux and gastric fluid losses. Studies were in random order and on 8 separate days. Potential difference was measured throughout and mucosal erosions were endoscopically quantitated (endoscopist masked, no premedication). The isoosmolar test solution (200 ml, 100 mM HC1, 54 mM mannitol, [14C]polyethylene glycol) was instilled into the stomach and removed 15 min later for four 15-min periods. Either aspirin (1300 mg) or ethanol (20% vol/vol) was added to the test solution only during the second 15 min. Acetaminophen (2600 mg) was given orally 1 h before aspirin or ethanol administration. To determine if the effect of acetaminophen was related to prostaglandin synthesis, prostaglandin production was inhibited with indomethacin (50 mg orally 12 h and 1 h before acetaminophen). Aspirin and ethanol alone each produced significant changes in net hydrogen and sodium fluxes, potential difference, and endoscopic changes. Acetaminophen significantly inhibited hydrogen ion flux, change in potential difference, and endoscopic damage; however, it did not totally abolish these changes. The protective effect of acetaminophen was abolished by pretreatment with indomethacin, suggesting that the effect of acetaminophen is likely to be prostaglandin-mediated. Indomethacin alone was without effect. These results demonstrate that oral acetaminophen protects the human gastric mucosa against the damaging effects of aspirin and ethanol.

Pancreatic polypeptide. Release following surgery for duodenal ulcer disease.

The pancreatic polypeptide (PP) response to food has been measured by radioimmunoassay in patients with duodenal ulcer and 3 months following proximal gastric vagotomy (PGV), 18 and 49 months following truncal vagotomy and pyloroplasty (TV), 35 months following Billroth II gastrectomy (BII), and 35 months following truncal vagotomy and antrectomy (TV&A). Basal PP levels and those in response to food were similar in DU and PGV, but these values were significantly higher than those 18 months or 49 months after TV, or after BII and TV&A. The responses in the latter four groups were similar and in particular, the levels 18 and 49 months after TV were the same. These results indicate that the release of PP by food in unoperated patients consists of two phases, a primary phase which requires both intact vagi and an intact stomach and a secondary phase which also depends on vagal innervation and normal gastric anatomy. Disturbances in vagal innervation or gastric integrity lead to profound changes in PP release which may be due to interruption of neural arcs or loss of gastric hormones. Unlike others, we have been unable to document a return of PP secretion towards normality with time after TV.The pancreatic polypeptide (PP) response to food has been measured by radioimmunoassay in patients with duodenal ulcer and 3 months following proximal gastric vagotomy (PGV), 18 and 49 months following truncal vagotomy and pyloroplasty (TV), 35 months following Billroth II gastrectomy (BII), and 35 months following truncal vagotomy and antrectomy (TV&A). Basal PP levels and those in response to food were similar in DU and PGV, but these values were significantly higher than those 18 months or 49 months after TV, or after BII and TV&A. The responses in the latter four groups were similar and in particular, the levels 18 and 49 months after TV were the same. These results indicate that the release of PP by food in unoperated patients consists of two phases, a primary phase which requires both intact vagi and an intact stomach and a secondary phase which also depends on vagal innervation and normal gastric anatomy. Disturbances in vagal innervation or gastric integrity lead to profound changes in PP release which may be due to interruption of neural arcs or loss of gastric hormones. Unlike others, we have been unable to document a return of PP secretion towards normality with time after TV.

Lack of gastric mucosal protection by sucralfate during long-term aspirin ingestion in humans

The ability of sucralfate to prevent gastric mucosal erosions caused by long-term aspirin ingestion was studied in 19 normal human subjects. A placebo-controlled, double-blind, crossover design was used to study the capacity of 4 g sucralfate daily to lessen the noxious effect on gastric mucosa of 3.6 g aspirin daily for 14 days. Gastric mucosal injury was assessed by endoscopic scoring of erosions. There was no significant difference in mean erosion scores or the degree of partial mucosal protection between the two groups. It was concluded that sucralfate lacks a mucosal protection capacity at the dosage studied in human subjects ingesting large doses of aspirin over a two-week period.

Effects of long-term cimetidine on serum gastrin in duodenal ulcer

Basal and food-stimulated gastrin were measured in 16 patients with duodenal ulcer before and during long-term maintenance therapy with 400 mg cimetidine twice daily. Basal gastrin (mean±se) rose significantly from 27.5±3.1 pmol/liter precimetidine to 32.8±2.1, 37.2±2.6, and 38.5±3.3 pmol/liter at 1,3, and 6 months, respectively. The total integrated gastrin response to a protein meal was 1.67±0.18 nmol/liter/120 min pre-, and 2.54±0.35, 3.29±0.3, and 4.36±0.4 nmol/liter/120 min at 1, 3, and 6 months, respectively. These increases were significantly higher at each time period. This study has thus demonstrated a progressive increase in both basal and food-stimulated gastrin during cimetidine therapy, and this increase could theoretically lead to an increase in gastric acid secretion following cessation of cimetidine.

Low-dose antacids and nonsteroidal anti-inflammatory drug-induced gastropathy in humans.

Gastroduodenal injury induced by nonsteroidal anti-inflammatory drugs (NSAIDs) is common. As yet, the ideal means to prevent NSAID-related mucosal injury remains controversial. Antacids are effective agents in treating gastric and duodenal ulcers unrelated to NSAIDs. The aim of this study was to assess the ability of a low-dose antacid to prevent NSAID injury in humans. Fifty healthy human volunteers were studied using a randomized, double-blind, placebo controlled, crossover design. After initial endoscopy, subjects were randomized to either Maalox TC (1 tablet q.i.d., acid neutralizing capacity of 104 mEq/day) or identical placebo while receiving 500 mg of naproxen b.i.d. for 21 days. After this period, a second endoscopy was performed to count antral and duodenal erosions and to evaluate symptoms and compliance with study medications. A 21-day washout period ensued, followed by a third endoscopy to insure a return to endoscopically normal mucosa. Subjects then crossed over into the alternate treatment arm for a further 21 days, followed by a fourth endoscopy to assess erosions. Forty subjects completed the study. Subjects receiving Maalox TC developed a significantly greater number of gastric erosions than did those on placebo. While this result was unforeseen, it is supported by statistical analysis and may have clinical relevance in regard to short-term NSAID therapy.

Pancreatic polypeptide release in gastric ulcer

The pancreatic polypeptide (PP) response to a protein-rich meal has been studied in similarly aged patients with gastric ulcer, duodenal ulcer, and controls. The response of the gastric ulcer patients was significantly lower at all points than that of the duodenal ulcer patients or controls, which were similar to one another. Vagal stimulation is probably the single most important factor in PP release, and it is possible that diminished PP release in the gastric ulcer patients is a reflection of vagal underactivity.The pancreatic polypeptide (PP) response to a protein-rich meal has been studied in similarly aged patients with gastric ulcer, duodenal ulcer, and controls. The response of the gastric ulcer patients was significantly lower at all points than that of the duodenal ulcer patients or controls, which were similar to one another. Vagal stimulation is probably the single most important factor in PP release, and it is possible that diminished PP release in the gastric ulcer patients is a reflection of vagal underactivity.