Maintenance of gastric pH above 6 with intravenous famotidine in patients with a bleeding duodenal ulcer.

BACKGROUND: The secondary prevention of bleeding from ulcers may be improved if antisecretory drugs are able to maintain a 24-h gastric pH close to neutral. AIM: To evaluate the effect of intravenous famotidine at a conventional dose of 40 mg/day on 24-h intragastric pH in patients with a bleeding duodenal ulcer, and to determine the dose required to maintain gastric pH > 6 by use of a Gastrojet (MIC, Switzerland) device (a pH meter-controlled programmable pump). METHODS: Twelve patients (nine men, three women), aged 24-78 years, admitted for a bleeding duodenal ulcer, were studied after active bleeding had stopped for at least 6 h. Gastric pH was recorded for two consecutive 24-h periods, each starting at 16.00 hours. The patients were fasted during these periods and received an infusion of 2.5 L of isotonic glucose. They were given famotidine, as a continuous i.v. infusion of 40 mg during one period, and at a rate determined by the Gastrojet during the other period (in a random sequence), with the aim of maintaining the gastric pH above 6. RESULTS: The 24-h median (interquartile range) pH and the mean (+/- S.E.M.) percentage of the 24-h period with a gastric pH > 6 were both significantly higher during the Gastrojet period than during the continuous infusion: 6.4 (6.3-6.5) vs. 5.7 (2.7-6.4) (P < 0.01) and 74 +/- 5% vs. 44 +/- 7% (P < 0.002), respectively. The mean dose of famotidine delivered by the Gastrojet was 172 mg (range: 101-200 mg). The entire available amount of famotidine (200 mg) was delivered in four of the 12 patients. The percentage of time at pH > 6 (mean +/- S.E.M.) was significantly higher at night (22.00 to 07.00 hours) than during the rest of the day (88 +/- 2 vs. 70 +/- 6%; P < 0.005) and the mean quantity of famotidine delivered per hour was significantly lower during the night (6.3 +/- 0.8 mg/h vs. 8.4 +/- 0.5 mg/h; P < 0.02). CONCLUSION: We conclude that 40 mg of famotidine delivered as a continuous i.v. infusion is not sufficient to maintain gastric pH > 6 for 24 h in duodenal ulcer patients. Our study with the Gastrojet device shows that it may be possible to achieve this goal by using a much larger dose, preferably delivered during the day.

Antibiotic versus maintenance therapy in the prevention of duodenal ulcer recurrence. Results of a multicentric double-blind randomized trial.

OBJECTIVES: Reduction of gastric acid secretion by maintenance therapy and eradication of Helicobacter pylori by antibiotic treatment have been shown to reduce duodenal ulcer relapse. This study compared the effect of two regimens, a 6-month maintenance on an H2 receptor antagonist versus a one-week antibiotic therapy, on the rate of duodenal ulcer relapse in duodenal ulcer patients with gastric H. pylori infection. METHODS: We conducted a 30-week, double-blind, double-dummy, multicentric clinical trial involving 119 patients (97 M, 22 F, mean age 39 +/- 14 years) randomly assigned to a daily dose of 40 mg famotidine for 6 weeks supplemented with, during the first week, either antibiotics (500 mg amoxicillin q.i.d. and 500 mg tinidazole t.i.d.-antibiotic group) or their placebo (maintenance group). Healed patients after 6 weeks entered the 6-month maintenance phase: the maintenance group received 20 mg famotidine at bedtime and the antibiotic group, a placebo. Endoscopy with antral biopsies was performed to allow a rapid urease test, culture and histological examination upon entry, after 6 weeks, 3 months, and 6 months and, whenever symptoms recurred. H. pylori status was regarded as positive if any one of these three tests was positive, and negative if all tests were negative. RESULTS: The 2 treatment groups were well balanced for all baseline characteristics. After 6 weeks, H. pylori was eradicated in 25 (45%) patients in the antibiotic group, and in 1 (2%) in the maintenance group (P < 0.01). In term of intention-to-treat, there was no significant difference in the healing rate after 6 weeks (93 and 83% in the antibiotic and maintenance groups, respectively; P = 0.15) or in the relapse rate after 6 months (13 and 28% in the antibiotic and maintenance groups, respectively; P = 0.17 Log-rank test). However, the overall failure rate (absence of healing, relapse) was lower (P = 0.04, Log-rank test) in the antibiotic group in which all relapses but one were observed in H. pylori positive patients. The rate of ulcer relapse (1/20) in patients of antibiotic group who remained free of H. pylori during the study, was significantly (P < 0.01) lower compared with that of H. pylori positive patients in the maintenance group (11/44). During the first 6-week period, more side effects were observed in the antibiotic group than in the maintenance group (4 vs 1 patient, respectively). CONCLUSIONS: Our results indicate no significant difference between ulcer relapse rates after 6 months following a one-week antibiotic therapy or long-term maintenance therapy. Short-term antibiotic therapy should be considered as a valuable alternative to the long-term maintenance therapy.

Maintenance of intragastric pH > 4 with famotidine in duodenal ulcer patients: factors influencing drug requirements.

The gastrojet, a closed loop pH feedback infusion pump capable of maintaining intragastric pH at a target value by infusing H2 blockers at variable rates, was used to assess factors influencing the quantity of famotidine required to maintain intragastric pH above 4 for 24 hours in 34 fed patients with duodenal ulcers. The following factors were considered: sex, age, duration of the disease, previous bleeding, previous poor response to H2 blockers (ulcer unhealed at six weeks, or recurrence within three months during maintenance treatment), activity of the ulcer disease, smoking habits, cirrhosis. The patients had taken no antisecretory drugs for the 15 days before the study. Two standardised meals were given during the study period (from 1000 to 1000). Fifty ml of famotidine (4 mg/ml) was loaded into infusion bags and the pump was programmed to deliver the drug intravenously at 11 rates varying from 0 to 40 microliters/min. The target pH was 4. Mean famotidine use was 111 mg (range 33 to 200), the 23 hour median pH was 5.3, and the mean time during which pH was above 4 was 75.4%. There was a negative correlation (p < 0.001) between famotidine delivery and the inhibition of gastric acidity. Statistical analysis showed that only cirrhosis significantly influenced drug delivery, median pH, and the time during which pH was above 4. Mean drug delivery in the cirrhotic and non-cirrhotic patients was 135 v 97 mg (p < 0.04), 23 hour median pH was 4.7 v 5.6 (p < 0.01), and the mean time at pH > 4 was 65.9 v 81.6% (p < 0.01). There were large interindividual variations in famotidine requirements, but not only cirrhosis was predictive of dose requirement. These results suggest that the appropriate amount of famotidine to treat duodenal ulcer in cirrhotic patients is probably higher than the usually recommended dose.

Comparison of omeprazole and famotidine on esophageal pH in patients with moderate to severe esophagitis: a cross-over study.

OBJECTIVES: This open cross-over study compared the effects on esophageal pH of omeprazole (O) (20 mg once a day) and famotidine (F) (40 mg b.i.d.) in 19 patients with proven acid gastroesophageal reflux (GER) complicated by erosive or ulcerated esophagitis. METHODS: Each drug was taken for 7 days. A wash-out interval of at least 3 days separated the two treatment periods in each subject. Twenty-four-hour pH measurements were performed in similar standardized conditions at 7 +/- 2 days, at the end of each period of treatment. RESULTS: Compared with the pretreatment results, both O and F reduced the following pH parameters: percent of time with esophageal pH < 4, total number of GER episodes, number of nocturnal GER episodes, and duration of the longest GER episodes. O was more effective than F except for the percent of time esophageal pH < 4 and the number of nocturnal GER episodes, not different between the two treatments. With O, GER was reduced to physiological value in 19 of the 19 patients and abolished in 13. With F, GER was normalized in 13 and abolished in four. The effects of both drugs and grading of esophagitis were not correlated. Both treatments were well-tolerated. CONCLUSIONS: In patients with acid GER complicated by ulcerative esophagitis, O, 20 mg daily, and F, 40 mg b.i.d. significantly reduced acid exposure. O was superior to F, but the latter drug improved significantly two important prognostic variables: the total percent of time pH < 4 and the nocturnal GER.

Effect of famotidine on renal transplant patients treated with ciclosporine A.

The influence of a 7-day course of 40 mg famotidine administered orally on the pharmacokinetics of ciclosporine A at steady-state has been investigated in 10 renal transplant patients. Famotidine did not appear to significantly alter the pharmacokinetics of ciclosporine A. This might be ascribed to the limited potential of famotidine for inhibiting microsomal enzyme function. Moreover, plasma creatinine concentrations and creatinine clearance remained stable. Our results suggest that famotidine has no noticeable interaction with ciclosporine A.

Pharmacokinetics of famotidine in patients with cirrhosis and ascites.

The pharmacokinetics of famotidine has been investigated in ascitic cirrhotic patients. 10 decompensated cirrhotic patients were studied (9m, 1f), who had normal renal function, and six healthy control subjects (4m, 2f), matched for age, sex and weight. Each subject received on two occasions, at least four days apart, a single oral (40 mg) or intravenous dose (20 mg) of famotidine, at 21.00 h in a randomised manner. Serial blood samples were collected and famotidine in plasma was determined by a HPLC/UV method. Plasma data were subjected to non compartmental pharmacokinetic analysis. There were no statistically significant differences in pharmacokinetic parameters between the two groups after either the intravenous or oral administration of famotidine. The findings suggest that the dose of famotidine may not require any adjustment in ascitic patients without renal failure.

Immunohistochemical characterization of gastrinomas with antibodies specific to different fragments of progastrin.

The characterization of the tumors and their metastasis in patients with the Zollinger-Ellison syndrome is currently based on the immunohistochemical identification of gastrin cells. However, sometimes tumoral cells fail to react with common C-terminal gastrin antibodies. In order to clarify this failure, we carried out morphologic, morphometric and immunocytochemical analyses performed on light and electron microscope levels of 6 pancreatic and 1 metastatic gastrinomas, using antibodies raised against various sequences of human progastrin. On the basis, in light microscopy, of qualitative analysis of immunostaining within cells and of immunostained cell numbers, gastrin 34 residue seemed to be the prominent form in 2 of the tumor tissues, G-17 in 1 tumor which was not responsive with C terminus progastrin and N terminus G-34 antisera, and progastrin in the metastatic tissue that did not contain typical gastrin (G-like) cells. Two tumors failed to react with all antisera used. At the electron microscope level, immunogold staining revealed that progastrin was present only in the progranules and gastrin 34 in both progranules and intermediate granules. Quantitative studies performed on 3 tumors showed that, within a given tumoral cell, about 25 percent of progranules contained progastrin while 75 percent contained gastrin 34. We concluded that different forms of gastrin can be immunodetected in a gastrinoma tissue, depending on the regions, and that the distribution of progastrin fragments is variable from tumor to tumor. So, specific antibodies to different fragments of progastrin may help to the characterization of gastrinomas.

[Long-term efficacy and tolerability of omeprazole in 20 patients with severe Zollinger-Ellison syndrome]. / Efficacité et tolérance à long terme de l'oméprazole chez 20 malades présentant un syndrome de Zollinger-Ellison sévère.

Omeprazole efficacy and tolerance were evaluated in 20 patients with longstanding Zollinger-Ellison syndrome (ZES) committed to long-term antisecretory therapy. The study included 13 men and 7 women, aged 53 (30-74) years (median and range). Nineteen patients presented with epigastric pain, 14 with vomiting, and 9 with diarrhea. All patients had gastroduodenal ulcerations, associated with esophagitis in 9 cases. Median and extreme values for basal acid output (BAO) and serum gastrin (SG) levels before omeprazole treatment were 41 (3.7-80) mmol H+/h and 413 (111-11,490) pg/ml, respectively. In 18 patients, omeprazole treatment was initiated because of resistance to H2-antagonists, and in 2 patients because of carbothioamide RP 40749 discontinuation. Initial doses of omeprazole were 60 mg per day in 10 patients and ranged from 80 to 160 mg per day in the others. Esophagogastrectomy was performed in one patient at day 15 because of esophageal stenosis. In the remaining 19 patients, median duration of treatment was 16 (7-54) months and median doses of omeprazole were 70 (20-160) mg per day during the survey. Omeprazole therapy was highly effective in inducing rapid disappearance of clinical abnormalities in 18 of 19 patients. Twenty-two days after initiation of treatment, median BAO was 4 (0-14) mmol/h and ulcerations had healed in 17 of 19 patients. Median BAO was less than 5 mmol/h during follow-up. However, asymptomatic ulcer recurrence was noted in 4 patients, but disappeared quickly after omeprazole doses were increased. Median basal gastrin level was 700 (116-36.625) pg/ml at the least determination and was statistically higher than pretreatment values (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Gastric endocrine cell behavior in Zollinger-Ellison patients upon long-term potent antisecretory treatment.

Serum gastrin and gastric endocrine cell numerical densities were examined in 22 patients with long-standing Zollinger-Ellison syndrome who were receiving either ranitidine, omeprazole, or other antisecretory drugs (SMS 201-995 or pirenzepine with or without ranitidine) for long periods of time. Fifteen patients had iterative biopsies. Twenty-one subjects with normal endoscopy, serum gastrin, and acid secretion served as controls. Individual fundic argyrophil cell density was above the highest control value in 77% of the patients, whatever the treatment. Argyrophil cell densities tended to be higher in women than in men. During the survey, fundic carcinoids developed in one ranitidine- and in one omeprazole-treated patient. Fundic argyrophil cell densities were correlated with serum gastrin levels (r' = 0.730, p less than 0.001). Antral somatostatin cell density was not modified in any patients as compared with controls, nor was antral gastrin cell density except in omeprazole-treated patients. In these patients, gastrin cell density and gastrin to somatostatin cell ratio were significantly higher than in all other patients or controls. Such increases may indicate true gastrin cell hyperplasia in relation to drug-induced profound acid inhibition.

Gastrin processing in primary culture of gastrinoma cells.

There is a general agreement on the cell specificity of gastrin processing. In order to investigate this processing in Zollinger-Ellison (ZE) patients, we have studied in two primary gastrinoma cultures (one from a pancreatic tumor, the other from a liver metastasis) the proportion of progastrin fragments using immunochemical and immunohistological methods. In tumor extracts as well as in sera, the predominant gastrin form differed between the two patients (i.e. being G17 and G34, respectively). In the two gastrinoma cultures, RIA determinations and electron microscopic observations indicated that the proportion of progastrin increased with time while that of G17 and G34 decreased. On the other hand, as the culture time extended, an increasing proportion of nonimmunostained secretory granules was observed suggesting the presence of other gastrin precursors (e.g. Gly-extended progastrin). From these findings, we suggest that gastrinoma culture cells could be a valuable tool in the biochemical approach to gastrin processing in ZE tumors.

Gastrin secretion by gastrinoma cells in long-term culture.

Gastrinoma cells from surgical specimens of a primary pancreatic tumor and an hepatic metastasis in two patients with a Zollinger-Ellison syndrome were grown and subcultured for 7 mo. Cultured cells displayed a strong reactivity to heptadecapeptide gastrin antibody and maintained an ultrastructural appearance resembling that of the original tumor cells with the presence of secretory granules of variable size and electron density. Cultured cells also showed the ability to secrete immunoreactive gastrin, and this secretion was further concentration-dependently stimulated by secretin (10(-10)-10(-6) M), carbachol (10(-6) M), and bombesin (10(-10)-10(-6) M). The latter peptide was the more potent stimulant with a maximal effect at 10(-9) M (460 +/- 20% of basal release; P less than 0.05). This stimulation occurred in the absence of extracellular Ca2+ and was potentiated by the addition of dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP; 10(-3) M) into the culture medium. The somatostatin analogue, somatostatin-(201-995), did not alter basal gastrin release but inhibited secretin, carbachol, and bombesin stimulation. Moreover, DBcAMP (10(-3) M) and Ca2+ (1-3 mM) stimulated gastrin release; Ca2+ ionophore A23187 (6 micrograms/ml) enhanced gastrin response to Ca2+ in the early time intervals of incubation. Furthermore the phorbol ester derivative, 12-O-tetradecanoyl phorbol-13-acetate, dramatically stimulated gastrin release (10 times the basal value). We conclude that gastrinoma cells can be cultured over an extended period with maintenance of their capacity to secrete gastrin in response to various hormones and mediators.(ABSTRACT TRUNCATED AT 250 WORDS)

[How to express results of 24-hour gastric pH measurement? Choice of a mode of expression in 27 healthy subjects]. / Comment exprimer les résultats de la pH-métrie gastrique sur 24 heures? Choix d'un mode d'expression chez 27 sujets sains.

Twenty-four hour intragastric acidity was studied in 27 healthy subjects (mean age = 29 yrs) by continuous recording in standardized conditions. Data obtained were expressed according to several analytical methods as used extensively elsewhere. In our study, there was a wide discrepancy in results from one subject to another. The use of median values of pH was more appropriate than mean values to express half-hour acidity levels for 24 hours. The median value of H+ concentration is recommended as well. The median value of pH varied from 1 to 4.8 with a slight rise during the second half of the night. During the postprandial period, increase of pH values was prolonged over 2 h 30 in 50 p. 100 of subjects. Profile of pH allowed to demonstrate the distribution of pH value without excluding the extreme values. Both periodicity of pH measurement (30 or 60 min) and parameters used to quantify acidity (percentage of time or pH value at or below threshold values) did not modify results. As measured over a 24 hours period, the percentage of time (mean +/- SEM) at or below pH 1.5 and 3.5 was 54 +/- 3 p. 100 and 85 +/- 2 p. 100, respectively. Daytime and night-time profiles were similar. Mean 24 h H+ concentration (mean +/- SEM) was 47 +/- 35 mmol/l, with, once again, similarity between day and night-time values. The mean 24 h pH values underestimated true acidity with respect to median values.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-acting somatostatin (SMS 201-995) in the management of Zollinger-Ellison syndrome: evidence for sustained efficacy.

Five patients with Zollinger-Ellison syndrome (ZES) have been treated during 9-12 months with long-acting somatostatin (SMS 201-995). Basal acid output presented a sustained decrease in 4 of 5 cases, below 10 mmol/h in three patients, allowing ranitidine discontinuation. No escape phenomenon was observed. Maximal acid secretion progressively decreased, suggesting an SMS antitrophic effect. Serum gastrin level was affected in a greater extent, showing a mean 87% decrease throughout the treatment period. Thus three patients kept normal serum gastrin levels in the long-term; one escaped to SMS after 9 months. Associated endocrine neoplasia were poorly influenced by SMS. No convincing evidence of tumor size variation was noted. Tolerance of SMS was excellent in the five patients. SMS' antitrophic and antigastrin properties could be of great interest in long-term management of ZES.

Hepatic plasmocytoma: sonographic and CT findings.

The sonographic and CT features of a case of solitary plasmocytoma of the liver are described. Dynamic CT findings of the tumor differ only slightly from those encountered in cavernous hemangiomas. Liver biopsy under ultrasound or CT guidance followed by immunohistochemical procedure can provide prompt diagnosis of this rare solitary liver tumor.

Hepatic vein obstruction in idiopathic hypereosinophilic syndrome.

We report an association between idiopathic hypereosinophilic syndrome and obstruction of the hepatic veins (Budd-Chiari syndrome). Budd-Chiari syndrome was assessed by liver biopsy and hepatic phlebography and documented by computed tomography. Postmortem examination revealed fibrous occlusion of the hepatic venous tree, as well as fibrosis of the endocardium and of myocardial and pulmonary vessels. To our knowledge, the association between idiopathic hypereosinophilic syndrome and Budd-Chiari syndrome has never previously been reported. Since it has been suggested that hypereosinophilia might cause endothelium damage, a link between these two entities is postulated.