Omeprazole (20 mg daily) versus cimetidine (1200 mg daily) in duodenal ulcer healing and pain relief.

We conducted a double-blind, randomized, parallel group study in 169 patients with acute duodenal ulcers to compare omeprazole, 20 mg daily, with cimetidine, 600 mg twice daily. After 2 wk, 58% of the omeprazole-treated patients and 46% of the cimetidine-treated patients were completely healed (p = 0.056). After 4 and 6 wk 84% and 88% healed with omeprazole, and 80% and 89% healed with cimetidine (p = NS). After 2 wk, pain was completely gone in 62% of the omeprazole-treated patients versus 46% of the cimetidine-treated patients (p = 0.04). Clinical or laboratory adverse events were reported in 6 (7%) of the omeprazole-treated patients and 11 (13%) of the cimetidine-treated patients (p = NS). An adverse event caused withdrawal of 1 patient on omeprazole (anxiety and depression) and 2 patients on cimetidine (diarrhea and fall in hemoglobin). We conclude that omeprazole (20 mg daily) resulted in a trend toward more rapid ulcer healing compared with a relatively high dose of cimetidine (600 mg b.i.d.), and was preferred by patients for relief of ulcer pain.

Hindgut dysgenesis as a cause of constipation with delayed colonic transit.

In a patient complaining of constipation since birth, delayed transit time in the ascending colon was related to a congenital malformation of the hindgut, different from Hirschsprung's disease. This was associated with absence of the left lobe of the liver. There was no propagating electrical muscular activity in the distal bowel.

Treatment of gastric ulcer with enprostil.

This study evaluated the efficacy of two dosage levels of enprostil in 129 patients with gastric ulcer disease. Patients with endoscopically diagnosed gastric ulcer were randomly assigned to receive enprostil 70 micrograms, enprostil 35 micrograms, or a matching placebo capsule twice daily for six weeks. Ulcer healing rates were similar in all treatment groups after two weeks of therapy, but began to show some differences in favor of the enprostil treatment groups after four weeks. Greater differences were noted after six weeks of therapy, with healing rates of 70 percent in the 70-micrograms enprostil group, 82 percent in the 35-micrograms enprostil group, and 50 percent in the placebo group. The six-week healing rate in the 35-micrograms enprostil group was significantly greater than the placebo rate (p = 0.005). Comparison of healing rates in the active treatment groups and the placebo group after six weeks of therapy showed a correlation between therapeutic effect and ulcer size at baseline. This trend is illustrated by a 24 percent difference between the 35-micrograms enprostil group and the placebo group among patients with small (3 to 9 mm) ulcers, compared with a 46 percent difference between these two groups among patients with large (20 to 30 mm) ulcers. Thus, the effectiveness of enprostil is more readily demonstrable in patients with larger ulcers.

Cimetidine therapy for gastroesophageal reflux disease.

In a Canadian multicenter trial, a new dosing regimen of cimetidine (Tagamet)-600 mg given twice a day-was compared with the standard regimen of 300 mg four times a day in 118 evaluable patients with endoscopically proved esophagitis. More than 90% of the patients evaluated had clinically moderate to severe esophagitis. After four weeks of therapy, both regimens had significantly reduced the number of episodes and the severity and duration of the worst episodes of daytime and nighttime heartburn, as evaluated by visual analogue scales. After eight weeks of therapy, this improvement persisted. There was no difference between the regimens. Healing was observed endoscopically in 57% of patients receiving cimetidine 300 mg four times a day and in 55% of those receiving 600 mg twice a day. Side effects were infrequent and minor.

Quantitative determination of histamine metabolites by capillary gas chromatography.

A method using capillary gas chromatography is described for the determination of histamine and eight of its basic and acid metabolites in a single biological sample of serum, urine, or gastric juice. Ion-exchange chromatography and extraction with organic solvents are used for isolation and purification, and gas chromatography for identification and quantitation. The heptafluorobutyryl derivatives of histamine and some basic metabolites are compatible with nitrogen-phosphorus and electron capture detection modes and offer an excellent sensitivity (detection limit 0.1 pmol with electron capture). The acid metabolites are quantitated after esterification. The linearity range, the sensitivity, a partial study of reproducibility and typical chromatograms show that the method is adaptable to a variety of applications.

Quantitation of histamine and some of its basic methylated metabolites in biological materials by gas-liquid chromatography.

A method which measures histamine, its basic metabolites, and some analogs in biological materials is described. The procedure consists of ion-exchange chromatography and chromatography on silicic acid for isolation and purification, and gas chromatography for identification and quantitation. The isolated compounds are prepared for gas chromatography by double derivatization with heptafluorobutyric anhydride and acetic anhydride. One of the synthetic histamine analogs, 2-methylhistamine, is used as an internal standard. The metabolites can be quantitated at a level as low as 1.5 nmol/100 microliters final concentration. The method is adaptable to a variety of applications, with good reproducibility and sensitivity. A number of different biological samples have been analyzed.

Acute necrosis of the intestinal mucosa with high serum levels of diamine oxidase.

A patient with acute necrosis of the intestinal mucosa and high serum diamine oxidase activity is described. The 71-year-old woman, with a history of hypertension and cardiovascular and peripheral arteriosclerotic disease, presented with acute epigastric pain, vomiting, and a deteriorating hemodynamic condition. Serum level of the intestinal enzyme diamine oxidase (DAO) obtained on admission, approximately 24 hr after the onset of symptoms, was 7.4 times above the normal value. An exploratory laparotomy performed 6 hr later revealed cyanosis and areas of transmural necrosis involving the entire small bowel. The bowel was not resected because of the extent of lesion. Thirty hours after the first sample was taken and 2 hr before death, the serum DAO level was only slightly above normal. It is suggested that this biochemical marker could provide a valuable tool for the early diagnosis of intestinal ischemia.

Comparative effects of two cimetidine regimens on 24-hour intragastric acidity in patients with asymptomatic duodenal ulcer.

The effect of 600 mg of cimetidine given twice daily on 24-hour intragastric hydrogen ion (H+) concentration was compared with that of the standard regimen of 300 mg of cimetidine given four times daily in six patients with asymptomatic duodenal ulcer. According to the double-blind, Latin-square, repeated-measures design, all subjects followed each cimetidine regimen and a placebo regimen for one week. Acid secretion studies and determinations of drug and gastrin levels in the blood were carried out on the last day of each treatment week. Although 600 mg of cimetidine BID suppressed H+ after breakfast and during the night, compared with placebo treatment (P less than 0.01), the 300-mg QID regimen suppressed H+ only after breakfast and supper (P less than 0.05). A higher percentage of pH readings greater than or equal to 3.0 were obtained with 600 mg of cimetidine BID than with 300 mg of cimetidine QID during the night (P less than 0.05); compared with percentages when placebo was taken, the percentages of pH readings greater than or equal to 3.0 were greater both overnight and during a 24-hour period only when 600 mg of cimetidine was given BID (P less than 0.01). The observed difference in intragastric H+ suppression after each regimen could not be explained by variations in serum concentrations of cimetidine or serum concentrations of gastrin. Despite similar peaks of serum cimetidine after evening doses of 300 or 600 mg of cimetidine, nocturnal intragastric acidity was lower in subjects given 600 mg BID. Further, H+ levels after lunch were similar in both cimetidine-treated groups, despite markedly higher serum cimetidine concentrations in patients receiving 600 mg BID. Pharmacokinetic studies showed equivalent elimination half-times and 24-hour areas under the curve of serum cimetidine concentration in patients on the two cimetidine regimens. Postprandial integrated gastrin responses were of similar magnitude in patients on either cimetidine regimen. There was no significant difference in mean serum gastrin concentrations during the night in placebo-treated and cimetidine-treated patients. Only a weak correlation was observed between H+ and serum gastrin concentration. Although a fluctuation of the H+:gastrin ratio occurred after each meal in all groups, the ratio was suppressed by both dosages of cimetidine. The findings suggest that a regimen of 600 mg of cimetidine BID is superior to the standard regimen of 300 mg QID in suppressing intragastric acidity in patients with asymptomatic duodenal ulcer.

Release of intestinal diamine oxidase by histamine in rats.

Diamine oxidase activity was measured in the intestinal mucosa, lymph, and in the serum of rats, to determine whether histamine, a substrate of diamine oxidase, liberates this enzyme from its mucosal storage site(s). Histamine induced a sharp rise in intestinal lymph flow, lymph protein, and lymph diamine oxidase, lasting less than 1 h after the histamine injection. The rise in lymph diamine oxidase activity was dose dependent over a narrow concentration range (0.05-0.2 mmol/kg, i.v. and 0.15-0.6 mmol/kg i.d.). It did not correlate with the dose dependent increase in lymph flow or lymph protein. A single maximal intraduodenal dose of histamine caused a 41.6-fold increase in the lymph diamine oxidase activity and a 2.4-fold increase in the serum enzyme level temporarily. A second injection of histamine, 2 h after the first, resulted in a comparatively smaller increase in the lymph enzyme. The extent of the reduction was dependent on the magnitude of the first injection. The results suggest that histamine causes a limited liberation of diamine oxidase from the intestinal mucosa. The function of this enzyme release may be a protective response by the mucosa to reduce toxic levels of free histamine, either liberated by the mucosal tissue or absorbed from the intestinal lumen.

Effect of intestinal ischemia on diamine oxidase activity in rat intestinal tissue and blood.

This study examines the effect of increasing duration of intestinal ischemia on the mucosal integrity and the release of the enzyme diamine oxidase from the small intestine. Acute ischemia was produced by the occlusion of the superior mesenteric artery, and the subsequent changes in DNA and 125I-albumin content in the lumen were taken as indices of intestinal lesions. Diamine oxidase activity was measured in the intestinal lumen, mucosa, lymph, and serum. Occlusions of the superior mesenteric artery for periods of more than 60 min resulted in significant leakage of 125I-albumin (i.v.) into the lumen. In contrast, luminal DNA content rose significantly after 15 min of ischemia and continued to increase proportionally with the increased duration of the occlusion up to 120 min. Similarly, diamine oxidase activity was augmented in the lumen after 15 min of occlusion and rose sharply as the ischemic period was lengthened up to 60 min, leveling off thereafter. Increases in the diamine oxidase activity were also observed in the intestinal lymph and serum, reaching levels that were 2.6 and 3.6 times that of the control respectively after 60 min of ischemia. These findings suggest that intestinal ischemia reduces the diamine oxidase content in the intestinal mucosa by desquamation of the surface epithelial cells and by releasing the enzyme into the intestinal interstitial fluid, from which at least a portion is transported to the blood via the lymphatics. The early release of diamine oxidase seems to occur before the mucosal barrier is broken.

Methyl histamines and gastric secretion.

1. The previous findings that N-methylhistamine and N-dimethylhistamine are more potent stimulators of gastric secretion than histamine have been confirmed in dogs with Heidenhain pouches or gastric fistulas.2. In cats with gastric fistulas, doses of N-methylhistamine of 0.25 or 0.5 mumole/hr produced 1.4-1.6 times as much HCl as equimolar doses of histamine.3. The maximal HCl outputs of dogs with Heidenhain pouches to histamine, N-methylhistamine, and N-dimethylhistamine were not significantly different, though lesser doses of the N-methyl derivatives were required to produce the maxima. At the one-half maximal level, N-dimethylhistamine showed a twofold greater potency than histamine.4. When given slowly or quickly via arteries supplying blood to the stomach of dogs or cats with gastric fistulas or via the artery to a Heidenhain pouch in a dog, 0.1-1.0 mumole N-methylhistamine or N-dimethylhistamine produced 4.1-13.9 times as much HCl as equimolar doses of histamine.5. Injection of histamine or N-methylhistamine via the portal vein in two dogs with gastric pouches stimulated less secretion of HCl than injection of the same doses via a systemic vein.6. The results allow the conclusion that N-methylhistamine and N-dimethylhistamine are more potent stimulators of acid gastric secretion than histamine in dogs and cats, particularly when delivered directly via the arterial route to the gastric mucosa, and support the prospect that N-methylhistamine or N-dimethylhistamine or both are natural chemostimulators of the parietal cells.