Suppression of nocturnal acid secretion with famotidine accelerates gastric ulcer healing.

Although nocturnal acid secretion has been emphasized in the pathophysiology and treatment of duodenal ulcer, its importance in gastric ulcer disease has been questioned. To explore this area, this multicenter U.S. trial compared the effect of a once-daily nighttime dose of H2-receptor antagonist with placebo on the healing of gastric ulcer and relief of associated symptoms. One hundred fifty-seven patients with endoscopically verified benign gastric ulcers were randomized in a double-blind fashion to either famotidine (40 mg at bedtime) or placebo. Antacid tablets were allowed as needed. The healing rates for famotidine were 45%, 66%, and 78% at weeks 4, 6, and 8, respectively. In comparison, placebo healing rates were 39%, 44%, and 64%. These differences were statistically significant in favor of famotidine at weeks 6 (p less than or equal to 0.01) and 8 (p less than or equal to 0.05), as well as in a life-table analysis (p less than or equal to 0.05). Nocturnal famotidine was also significantly better than placebo with respect to time to complete relief of pain and to the percentage of patients with complete relief of pain. No concomitant factor (including ulcer size, ulcer location, smoking history, or regular alcohol use) affected healing rates in this study. Famotidine was well-tolerated and no serious clinical or laboratory adverse effects were judged to be related to this dosing regimen of famotidine. In conclusion, suppression of nocturnal acid secretion with famotidine (40 mg at bedtime) was more effective than placebo in promoting the healing of acute benign gastric ulcer and its associated symptoms. The results of this study suggest that suppression of nocturnal acid secretion alone is as effective as "around the clock" acid suppression in the healing of benign gastric ulcer.

Absence of luminal intrinsic factor after gastric bypass surgery for morbid obesity.

Abnormally low serum cobalamin levels (less than 180 pg/ml) have been observed in 154 of 429 patients (36%) at an average of 22 months (range 3-64 months) after gastric bypass surgery for morbid obesity. Twenty-four patients underwent a Schilling test and retrograde endoscopy of the bypassed gastric segment to determine the presence of intrinsic factor (IF) in gastric aspirates and in mucosal biopsies at 22 +/- 4 months after surgery. Five patients had a normal cobalamin level (405 +/- 44 pg/ml), and gastric juice intrinsic factor was present in three of them (11 +/- 7 ng/ml). Nineteen patients had a low cobalamin level (113 +/- 8 pg/ml), and gastric juice IF was found in only two subjects of this group (10 ng/ml each). Basal gastric juice IF concentration of healthy control subjects was 24 +/- 5 ng/ml. Schilling test results were normal in all five patients of the first group and in only nine patients of the group with cobalamin deficiency after surgery. To assess whether IF was present within the parietal cells of subjects with absent luminal IF, we studied gastric biopsy material of 14 patients using a well-characterized indirect immunoperoxidase method. IF was identified in fundic mucosal biopsy specimens of all 14 patients with absent gastric juice IF. We conclude that cobalamin deficiency occurs in a significant number of patients after gastric bypass and is associated with absence of gastric juice IF. We propose that this abnormality might be caused by inadequate secretion of IF from the bypassed stomach.

Gastric ulcer healing after laser treatment in dogs.

Endoscopic laser photocoagulation of ulcers is increasingly used to produce hemostasis in patients who are actively bleeding or in patients with stigmata of recent hemorrhage. Little information is available describing ulcer healing rates after laser treatments. The aim of this study was to compare the healing rates of gastric ulcers treated with laser energy (Nd:YAG) with untreated ulcers in dogs. Two standard gastric ulcers (12-14 mm diameter) were created in each dog stomach using an ulcer maker (Quinton) under endoscopic guidance and one was randomly selected for laser treatment (L), while the other served as control (C). Ten laser spots were applied circumferentially around the ulcer crater with a mean energy of 595 J per ulcer. Ten dogs were studied; four of which were sacrificed after one week and six after two weeks. Healing of treated ulcers was compared with that of control ulcers and expressed as a percentage of the initial ulcer surface. Histologic injury and reepithelialization were scored by two pathologists unaware of the treatment. Laser-treated ulcers healed significantly slower than untreated ulcers at one week (53% L vs 94% C, P less than 0.05) and histologic injury was greater in ulcers treated with laser photocoagulation. At two weeks, only 82% of the laser-treated ulcer surface was healed in comparison with 94% (P less than 0.05) healing in untreated ulcers, although the mean histologic injury score was not different at two weeks. Reepithelialization was decreased both at one week (11% L vs 71% C, P less than 0.01) and at two weeks (75% L vs 100% C, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Intraoperative video panendoscopy for diagnosing sites of chronic intestinal bleeding.

Intraoperative video panendoscopy was performed in 14 patients with chronic, recurrent gastrointestinal bleeding. All of the study patients had undergone extensive and expensive diagnostic testing including multiple radiographic contrast studies of the gastrointestinal tract, upper and lower endoscopy, nuclear bleeding scans, and selective mesenteric angiography without definition of the bleeding source. Intraoperative video panendoscopy, employing a segmental advance and look technique, allowed visualization and transillumination of the entire gut and identified mucosal disease in 13 patients (93 percent). Angiodysplasia of the colon and small intestine was the most common pathologic finding. Intraoperative video panendoscopy significantly influenced the operation performed in 13 patients (93 percent). Postoperative complications were minimal, with none being directly attributable to intraoperative video panendoscopy. Bleeding was totally controlled in 10 patients (71 percent) during a mean follow-up period of 25 months. Intraoperative video panendoscopy is a valuable technique for assisting in the management of the patient with recurrent gastrointestinal bleeding.

Multicenter trial of sucralfate suspension for the treatment of reflux esophagitis.

The efficacy of sucralfate suspension in the treatment of reflux esophagitis was assessed in a multicenter, randomized, double-blind, placebo-controlled trial. Sixty-eight patients with symptomatic and endoscopic esophagitis received either sucralfate suspension (n = 31) or liquid placebo (n = 37) for eight weeks. The two groups were comparable at entry with the exception that despite randomization, a disproportionately high number of patients with esophageal ulcers were assigned to receive sucralfate. After four and eight weeks of treatment, both groups had reduced heartburn frequency and severity, but there was no difference in improvement between sucralfate and placebo (p greater than 0.05). Endoscopic results after eight weeks of sucralfate treatment revealed complete healing in 36 percent (placebo, 35 percent) and improvement in an additional 45 percent (placebo, 24 percent). Although neither of these differences was significant, the percent of patients in whom healing or improvement occurred with sucralfate (81 percent) was greater than with placebo (59 percent) (p = 0.07). These data fail to establish that eight weeks of treatment with sucralfate suspension improves symptoms or heals lesions in reflux esophagitis at a rate significantly greater than placebo. However, the unequal distribution of patients with ulcers and the trend toward endoscopic improvement indicate that a potential beneficial effect of sucralfate suspension for the treatment of reflux esophagitis cannot be excluded.

Gastric bypass.

The success of gastric bypass probably depends on factors other than merely the restrictive size of the gastric pouch and outlet. Postoperative dumping and a mild degree of malabsorption derived from the redirection of intestinal contents contribute to long-term success. Thus, gastric bypass combines some elements of both malabsorptive and gastric restrictive procedures.

Histologic and endoscopic studies before and after gastric bypass surgery.

The purposes of this study were to establish a standardized multiparameter analysis system for histologic grading of gastritis and to compare histologic changes with endoscopic findings in the proximal and distal bypassed stomach in obese patients undergoing gastric bypass surgery. Three groups, comprising a total of 91 patients, were studied: a preoperative group (34 patients), a postoperative group at one year (33 patients), and a postoperative group at two years (24 patients). the biopsy specimens from the proximal and distal bypassed stomach were compared in all groups. Seventeen histologic variables were evaluated by three observers to classify the severity of gastritis. Forty percent of the patients in the postoperative group demonstrated histologic evidence of nonerosive, superficial gastritis, slightly more in the proximal stomach. Endoscopy showed significantly more bile reflux and inflammation in the distal stomach than the proximal stomach in nearly all patients. Our study demonstrates a significant discrepancy between bile reflux observed endoscopically and the histologic findings after gastric bypass surgery. No metaplastic or dysplastic changes were found up to two years postoperatively, but further studies are needed to determine the long-term endoscopic and histologic endoscopic and histologic sequelae of gastric bypass surgery.

Effects of oral potassium supplements on upper gastrointestinal mucosa: multicenter clinical comparison of three formulations and placebo.

In a carefully controlled multicenter investigation of the effects of oral potassium chloride (KCl) supplements on the gastrointestinal mucosa, 120 healthy men with no endoscopically apparent gastrointestinal lesions were confined to a research ward for 18 days. By random assignment, they were given 60 mEq/day (20 mEq TID) of KCl as either a microencapsulated gelatin capsule, a wax/polymer matrix tablet, or a powder-in-liquid formulation or a placebo capsule for two weeks. All subjects were given glycopyrrolate concomitantly to delay gastric emptying. After treatment was completed, endoscopic examinations of the esophagus, stomach, and duodenum were performed and evaluated by specialists blinded to the particular treatment given. Mild to moderate gastrointestinal irritation, characterized by erythema and edema, was found with similar frequency in all four treatment groups. Two of 30 subjects given the microencapsulated KCl had a single erosion each. Single or multiple erosions were also observed in 14/30 men given the wax/polymer matrix tablet, in 7/30 given the powder, and in 1/30 given placebo. One subject given the wax/polymer matrix tablet had a gastric ulcer. The incidence of gastrointestinal injury with the microencapsulated form was significantly less (P less than 0.01) than that with the wax/polymer matrix tablet and was not significantly different from that seen with either the powder or placebo.

Lidocaine inhibition of esophageal peristalsis and lower esophageal sphincter pressure in baboons.

Intravenous lidocaine was infused at 0.82 ml/min in a concentration of 1.2 mg/ml (2.3 mg/kg) for 120 min in awake chair-restrained baboons (Papio anubis), and measurements of esophageal peristalsis and LES pressure were compared before and after lidocaine or control infusions. Lidocaine produced a progressive and significant (P less than 0.05) decrease in amplitude in the peristaltic wave in the smooth muscle portion of the distal esophagus during the 120-min infusion. Lower esophageal sphincter pressure was similarly significantly lower than control after the infusion of lidocaine (P less than 0.05). Velocity and duration of the peristaltic wave were unchanged during the infusion. The decreased amplitude occurred during therapeutic and stable serum concentrations of lidocaine. It did not appear that the inhibitory effect of lidocaine was due to an induction of prostaglandin synthesis, because pretreatment of animals with indomethacin did not change the inhibitory effect of lidocaine, and serum metabolites of prostacyclin decreased during the infusion. Furthermore, the inhibitory effect of lidocaine was not topical. The response to the muscarinic agonist, bethanechol was similar in lidocaine-treated animals and control animals. The preservation of a bethanechol response after lidocaine inhibition of LES pressure and distal esophageal amplitude suggests that lidocaine acts proximal to the muscarinic receptor in the esophageal body and smooth muscle portion of the lower esophageal sphincter. This study suggests that lidocaine produces an inhibitory effect on the peristaltic wave and lower esophageal sphincter pressure that is similar to inhibitory effects described after anticholinergic agents and calcium channel blocking drugs, but intravenous lidocaine infusion requires a longer period of time to produce inhibition of muscle function.

Retrograde endoscopy of the bypassed stomach segment after gastric bypass surgery: unexpected lesions.

Surgical measures for the treatment of morbid obesity include gastric bypass of the stomach and duodenum. We endoscopically evaluated the bypassed segments in 51 patients three to 24 months after a standard gastric bypass procedure. Retrograde endoscopy was successful in 33 of the patients (65%). There was significantly more gastritis by endoscopic grading in the distal bypassed segment than in the proximal part of the stomach. The gastritis in the bypassed segment was associated with pooled bile in 97% of the patients. The severity of gastritis did not appear to be related to the time after surgery and was as severe three months after surgery as it was at 24 months. Histologically, the gastritis was nonconfluent, and often the histologic and endoscopic findings were at variance. There was intestinal metaplasia in biopsy specimens from the distal pouch in four of the 33 patients. The mechanism for the high incidence of gastritis is unknown, but may be related to decreased antral motility due to distention of the proximal pouch with food. These patients require close observation for changes in the bypassed segment of stomach that may occur as a consequence of chronic inflammation.

The bypassed stomach.

Retrograde duodenogastroscopy solves the problem of postoperative evaluation of the gastric bypass patient. The stomach may be bypassed to treat morbid obesity, but it no longer need be inaccessible. Endoscopic gastritis is rare in the proximal gastric pouch but common in the distal gastric segment and may be related to the presence of bile. Although the gastric mucosa is histologically normal in half of the gastric bypass patients, acute and chronic gastritis, regenerative changes, and intestinal metaplasia may develop in either or both segments. The causes and implications of these endoscopic and histologic findings are unknown.

The Greenville gastric bypass. Progress report at 3 years.

Two hundred and ten morbidly obese patients underwent a standardized gastric bypass procedure between February 1980 and November 1983. We conclude, based on 100% follow-up, that the operation is safe (operative mortality--1%, significant complications--10%) and effective (reoperation rate--4%). Only one patient failed to lose more than 25% of preoperative weight. The operation produced a mean weight loss in the group from 289 pounds (202-505) before surgery to 176 pounds (118-308) at 18 months after surgery. Stated as "per cent of ideal weight," patients lost from a preoperative mean of 214% (153-350) to 130% (88-189) at 18 months. Maximum weight loss was reached by 18 months after the procedure and was maintained during 36 months of observation in over 95% of patients. When patients were divided into four groups according to preoperative weight, weight loss occurred at a roughly similar rate, but heavier patients, although they lost more weight, plateaued at a higher weight than patients originally less obese. Striking and objective benefits were seen in patients with diabetes, hypertension, heart disease, and pulmonary insufficiency.

Glucose is the major component controlling irregular spike activity after feeding in primates.

The aim of this study was to examine the caloric components responsible for the postprandial increase in small intestinal electrical spike activity. Monopolar electrodes were surgically placed on the jejunum and on the ileum of 8 cynomolgus monkeys 2 wk before study. Myoelectric activity was measured after a 14-h fast, and was compared with activity seen either after feeding or after intragastric injection of test solutions [MCT oil (100 kcal), Crisco oil (100 kcal), glucose (40 kcal), glucose polymer (100 kcal), or an equivalent volume of saline control]. Data were analyzed by a spike train analysis program to provide activity front cycle length, quantitative measurements of the activity, front spike activity, and frequency of irregular spike activity before and after feeding. Oral feeding of a predominantly carbohydrate banana meal or an intragastric solution resulted in a significant delay in periodic activity fronts and a significant increase in jejunal postprandial spike activity over fasted irregular spike activity. Increases in postprandial spike activity appeared to parallel increases in the serum glucose concentration. These studies demonstrate that phasic fasting spike activity occurs in the primate small intestine and that this activity is disrupted by oral feeding. Carbohydrates were responsible for the increased postprandial spike activity and for the disruption of regular spike activity after meals. A local effect of the carbohydrate is the most likely explanation. With carbohydrate or fat solutions, changes can occur in postprandial spike activity independent of the delay in periodic activity front activity. The increase in postprandial spike activity and the postprandial delay in periodic activity front activity appear to be controlled through separate mechanisms.

Decreased esophageal peristaltic amplitude in response to prostaglandin E1 and prostacyclin in the baboon.

Prostaglandins have been shown to produce significant decreases in lower esophageal sphincter pressure (LESP), although their effect on esophageal peristalsis is unknown. We studied the effect of infusion of prostaglandin E1 (PGE1) or prostacyclin (PI) on esophageal peristalsis in the proximal and distal esophagus in the awake baboon. Peristalsis was recorded using a polyvinyl catheter and a pneumohydraulic perfusion system and was induced by wet swallows. PGE1 infusion significantly (P less than 0.01) diminished peristaltic amplitude in proximal and distal esophagus by 51% and 77%, respectively. The wave duration was significantly (P less than 0.001) shortened by PGE1 in the distal esophagus, but not in the proximal esophagus. Similarly, prostacyclin significantly (P less than 0.05) decreased peristaltic amplitude in proximal and distal esophagus by 31% and 67%, respectively. As seen with PGE1, PI decreased distal esophageal amplitude significantly (P less than 0.02) more than proximal esophageal amplitude. Equivalent decreases in mean arterial blood pressure seen during prostaglandin infusion were reproduced by bleeding with no changes in measurements of peristaltic activity. Decreased peristaltic wave amplitude and duration suggest that prostaglandins exert a modulating local effect on esophageal muscle. In addition, this effect appears to be more pronounced on distal smooth muscle than on proximal striated muscle in the baboon esophagus.

Verapamil--a potent inhibitor of esophageal contractions in the baboon.

Verapamil, a calcium channel blocking agent, has been shown to be a potent inhibitor of smooth muscle contraction. We studied the effects of verapamil on lower esophageal sphincter pressure and esophageal peristalsis in 5 awake baboons. An infusion of verapamil (80 micrograms/kg . min) decreased amplitude of peristalsis by 63% in the smooth muscle segments of the esophagus but had no effect on striated muscle. Duration of peristaltic waves in the smooth muscle portion of the esophagus was also shortened, but there was no effect on velocity of the contraction wave. Lower esophageal sphincter pressure decreased by 74% during verapamil infusion. These studies suggest that verapamil or other calcium channel blocking agents may be of potential use in the treatment of esophageal motility disorders associated with increased pressure.

Migrating action-potential complex activity in absence of fluid production is produced by B subunit of cholera enterotoxin.

The myoelectric response and fluid output from in vivo rabbit ileal loops injected with B subunits of purified cholera enterotoxin are compared with the response to the purified cholera holotoxin. Migrating action-potential complex (MAPC) frequency is similar after injection of purified cholera toxin or B subunits. In contrast, fluid output after B-subunit injection is significantly (P less than 0.05) less than fluid output after purified cholera toxin injection. Specific antiserum to the holotoxin incubated with holotoxin at equivalence significantly decreased both MAPC activity (P less than 0.05) and fluid output (P less than 0.001) from the purified toxin. Purified cholera toxin and B subunits, modified by reaction with 2-nitrophenylsulfonyl chloride to produce monomeric B fractions with decreased GM1 ganglioside-binding properties, produced significantly (P less than 0.05) less fluid output and MAPC activity. Binding of the toxin or B subunits in the aggregated form is essential for the expression of MAPC activity or fluid output. These results suggest that the B subunit of cholera toxin produces MAPC activity in the rabbit ileum in the absence of fluid production. Furthermore, previous assumptions that MAPC activity is linked to fluid secretion should be reconsidered. It appears that the gut responses to cholera toxin, fluid production, or MAPC activity are produced by separate mechanisms.

Prostaglandin E1 effects on resting and cholinergically stimulated lower esophageal sphincter pressure in cats.

Intraluminal esophageal manometry with a sleeve catheter was used to compare the magnitude of decrease in lower esophageal sphincter (LES) pressure produced by an arterial or venous infusion of prostaglandin E1 in cats. Arterial PGE1 produced significantly lower LES pressures than venous PGE1 (p less than 0.05). Maximal decrease of 75% in basal LES pressure occurred with an associated 15% decrease in systolic blood pressure. The site of action of PGE1 in producing LES hypotension was studied by injection of either edrophonium, or bethanechol during the maximal PGE1 effect. Bethanechol, which acts directly on sphincteric smooth muscle, produced an increase in LES pressure during both saline and PGE1 infusion, while the increases in LES pressure seen with edrophonium during saline infusion were blocked during the PGE1 infusion. From these studies, we conclude that PGE1 produces LES hypotension in the cat by an inhibitory effect on the cholinergic pathway responsible for maintaining LES tone. These studies pharmacologically reproduce the LES pressure abnormality previously reported in the cat during acid-induced esophagitis and support the hypothesis that PGE1 may be involved in the pathogenesis of acute acid-induced lower esophageal sphincter abnormalities.