Esam Z. Dajani

Healing of benign gastric ulcer: A placebo-controlled comparison of two dosage regimens of misoprostol, a synthetic analog of prostaglandin E1

Misoprostol, a synthetic prostaglandin E1 methyl ester analog with gastric antisecretory and cytoprotective properties, prevents the development of acute experimental gastric and duodenal ulcers in various animal models. This study was designed as a multicenter randomized double-blind parallel-group comparison of the effects of two dosage strengths (25 and 100 μg q.i.d.) of orally-administered misoprostol and placebo on the healing of endoscopically-proven benign gastric ulcer in 299 out-patients. Safety was evaluated by comparison of pre- and post-treatment physical examinations, clinical laboratory tests, gastric antral biopsies and monitoring of adverse experiences. A statistically significant difference in gastric ulcer healing rate was seen at eight weeks among the treatment groups in the Intent-to-Treat Cohort: misoprostol 100 μg (62.0%), misoprostol 25 μg (50.0%), placebo (44.7%). The proportion of subjects healed in up to eight weeks of treatment was greatest in the misoprostol 100 μg group in all cohorts. Ulcer pain decreased in all treatment group in successive weeks and there were no statistical differences among any of the three treatment groups. Diarrhea was the most frequently reported adverse experience: misoprostol 100 μg (9.8%), misoprostol 25 μg (7.7%), placebo (1.9%). The diarrhea was mild and self-limiting despite continued use of misoprostol. Overall evaluation of gastric antral biopsies showed no adverse changes in the morphology of the antral mucosa. We conclude that misoprostol 100 μg q.i.d. for up to eight weeks is safe and effective in the treatment of benign gastric ulcer.

Cytoprotection by a synthetic prostaglandin against ethanol-induced gastric mucosal damage A double-blind endoscopic study in human subjects

This randomized, double-blind, placebo-controlled study compared the cytoprotective effects of misoprostol, a synthetic analog of prostaglandin E1, and cimetidine on ethanol-induced gastric mucosal damage. Forty-five healthy male subjects were accepted, following endoscopy to exclude those with upper gastrointestinal disease. Injury to the gastric mucosa was induced by spraying it with 80% ethanol solution. Misoprostol (200 micrograms) intragastrically or cimetidine (300 mg) orally or placebo was administrated before the ethanol challenge. The gastric mucosa was graded using a seven-point endoscopic scale by two endoscopists 15 and 30 min after ethanol instillation. Thirty minutes following the instillation of ethanol, the gastric mucosa of placebo-treated subjects showed marked damage, with an endoscopic score (mean +/- standard deviation) of 5.5 +/- 0.9. Cimetidine partially prevented gastric mucosal damage, with an endoscopic score of 4.5 +/- 1.7 as compared to placebo (p = 0.04). Misoprostol significantly prevented gastric mucosal injury with a mean endoscopic score of 1 +/- 1.7 when compared to placebo (p = 0.0001) and to cimetidine (p = 0.0002). This cytoprotective action of misoprostol may prove to be clinically very important and warrants further investigation.

Impedance planimetric characterization of the distal oesophagus in the Goettingen minipig.

Regional differences in biomechanical properties of the oesophagus were studied in 15 healthy Goettingen minipigs by means of impedance planimetry. The investigation was performed during anaesthesia by stepwise pressure-induced balloon distensions with concomitant measurement of pressure and luminal cross-sectional area (CSA) in the oesophagus 5 and 10 cm above the gastro-oesophageal junction. The circumferential wall tension, circumferential strain and incremental elastic modulus were computed from the measurements of pressure and CSA at steady-state conditions. Probably due to the anaesthesia, only scant peristalsis was recorded and the CSA always reached steady state during the balloon distensions. The CSAs were highest in the distal oesophagus (P < 0.001). At the highest induced pressure, the CSAs were 605 +/- 32 and 453 +/- 29 mm2 (mean +/- SEM) for the locations 5 and 10 cm from the gastro-oesophageal junction. The tension-strain distributions were non-linear and the curve obtained 5 cm above the gastro-oesophageal junction was shifted to the right when compared with the curve obtained from 10 cm above this junction. Fitting of the function tension = exp(a+b strain) to the data gave determination coefficients higher than 0.97 and P values lower than 0.001 for both measuring points. The constant a differed between the two locations in the oesophagus (P < 0.05). In conclusion, the pressure-CSA and the tension-strain distributions differed between the two measuring points suggesting that the elastic properties are different.

Comparative cytoprotective effects against alcohol insult. Misoprostol versus cimetidine.

Misoprostol is a synthetic prostaglandin E1 methyl ester analog that has been shown to possess gastric antisecretory and cytoprotective properties in laboratory animals and in man. The aim of our study was twofold: first, to compare the cytoprotective effects of misoprostol and cimetidine on ethanolinduced gastric mucosal damage; and second, to determine if this cytoprotection was related to the inhibition of gastric acid secretion. A total of 45 healthy adult men aged 20--40 years, were enrolled in this randomized, double-blind, placebo-controlled, parallel-group study. Prior to admission, the following assessments were performed and found to be normal: medical history, physical examination, CBC, urinalysis, and SMA-20. Subjects did not have a history of smoking or analgesic or ethanol use. Each participant received one tablet of cimetidine, 300 mg, or placebo by mouth after an overnight fast. One hour later, esophagogastroduodenoscopy was performed. Only subjects with normal gastric mucosa were treated with misoprostol (200 ~g, dissolved in 40 ml of 0.9% sodium chloride solution containing 0.5% ethanol) or placebo. This solution was sprayed directly onto the mid-gastric body along the greater curvature of the stomach, via a catheter passed through the biopsy channel of

Systemic treatment with recombinant human epidermal growth factor accelerates healing of sclerotherapy-induced esophageal ulcers and prevents esophageal stricture formations in pigs.

Human epidermal growth factor (EGF), a small polypeptide (6 kDa) with mitogenic properties, has been implicated in the protection of gastrointestinal mucosal integrity. The efficacy of EGF in the prevention and healing of sclerotherapy-induced esophageal lesions was investigated in 24 minipigs with surgically induced portal hypertension. In addition, the effect of EGF on intragastric acidity and pharmacokinetics was investigated as possible means to explain its protective mechanism of action. The animals underwent three weekly sessions of sclerotherapy with polidocanol 2% and were concomitantly and for an additional three weeks treated with either placebo or EGF administered paravenously in the esophagus and/or subcutaneously. The subcutaneous treatment with EGF significantly (P<0.05) reduced esophageal stricture and scar formations associated with sclerotherapy. Gastric pH values were significantly (P<0.01) elevated only in animals receiving subcutaneous injections of EGF. Furthermore, the subcutaneous administration of EGF was associated with unexpected prolonged plasma concentration of the peptide. These results suggest a possible clinical value of EGF as an adjunctive treatment with the sclerotherapy.

Misoprostol but not antacid prevents endotoxin-induced gastric mucosal injury

Many of the complications of septic shock are believed to be a consequence of elevated circulating levels of tumor necrosis factor (TNF), which is an important mediator of tissue injury. Prostaglandins (PGs) of the E series have recently been reported to inhibit TNF productionin vitro. We investigated thein vivo effect of misoprostol, a PGE1 analog, on endotoxin-induced gastric mucosal injury and TNF production. For the gastric mucosal injury studies, groups of animals were pretreated with intragastric misoprostol (100 and 200 μg/kg) or with antacid (2 ml/animal of Maalox Plus) 30 min prior to a challenge with intravenousE. coli lipopolysaccharide (LPS) at 5.0 mg/kg. Stomachs were examined 3 hr after LPS. Systemic endotoxin alone induced microscopic edema, vascular congestion, and polymorphonuclear (PMN) infiltration of the gastric mucosa. Pretreatment with misoprostol, but not with antacid, significantly and dose-dependently reduced the gastric mucosal injury. For the TNF studies, groups of rats were given either misoprostol (100 or 200 μg/kg, intragastric), or saline 1 hr prior to LPS challenge. Serum samples were obtained 1.5 hr after LPS challenge. Misoprostol dose-dependently and significantly (P<0.01) inhibited TNF activity. We conclude that misoprostol is a potent inhibitor of TNF systemic production and inhibits the gastric mucosal injury induced by endotoxemia. These studies suggest a potentially important therapeutic role for misoprostol in inflammatory diseases in which TNF exerts a contributory role.

Effects of Tolcapone, a Catechol-O-Methyltransferase Inhibitor, and Sinemet on Intestinal Electrolyte and Fluid Transport in Conscious Dogs

Tolcapone (T) is a novelcatechol-O-methyltransferase (COMT) inhibitor recentlyintroduced for the treatment of Parkinsons disease. Inclinical efficacy studies, T has been associated with alow incidence of diarrhea. The objectives of the study wereto examine whether T and its adjunctive drug Sinemet (S)could influence intestinal fluid and electrolytetransport as a possible cause for the diarrhea. The studies were conducted in conscious dogssurgically prepared with Thiry-Vella loops constructedfrom a 40-cm jejunal segment. A physiologically bufferedtest solution was perfused into the orad stoma and collected from the caudad stoma. Secretionswere collected at 15-min intervals and analyzed forvolume, electrolytes, lipid phosphorus, and protein. Theacute oral administration of T (10 and 30 mg/kg doses) was well tolerated. Concurrent acuteadministration of S (25 mg/kg) with T (30 mg/kg) wasalso well tolerated. The acute oral administration of Tinduced a dose-dependent efflux of intestinal fluid and electrolytes (sodium, potassium, chloride, andbicarbonate) secretion (P < 0.05). The oralcoadministration of S (25 mg/kg) with T (30 mg/kg)accelerated the onset of the stimulation of intestinalsecretion. Despite the significant stimulation ofintestinal secretion, none of the dogs developeddiarrhea, indicating the importance of intestinalcompensatory mechanisms. Neither T nor T&S affectedcalcium, lipid, or protein efflux rates, suggesting thatthe stimulated secretion was not a consequence ofintestinal mucosal injury. The chronic (seven-day)administration of T and T&S was associated withreduced intestinal secretory responses when comparedwith the acute administration of the same drugs; Senhanced the T-induced tolerance development. The basisfor such tolerance is unknown. In conclusion, the stimulatory systemic actions of tolcapone onintestinal secretion may, under certain conditions,contribute to the induction of diarrhea in susceptiblepatients.