Long-term Antisecretory Therapy Research Articles

Use of Biodegradable Stent in Refractory Benign Oesophageal Stricture

Introduction: Oesophageal strictures are commonly seen in patients with accidental or intentional ingestion of corrosive substances. Long-term anti-secretory therapy and recurrent pneumatic balloon dilatations are the mainstay of management, if not surgery. There is anecdotal evidence in using biodegradable stents in this setting. Medical and endoscopic records (using Unisoft software) of a patient with benign refractory oesophageal stricture related to caustic ingestion were reviewed. We describe a 42-year-old woman with benign refractory oesophageal stricture related to intentional industrial bleach ingestion. This patient required 46 oesophageal pneumatic balloon dilatations over 5 years with frequent recurrence of clinical symptoms at short intervals. She manifested excellent response to biodegradable stent which gave her dysphagia-free survival for 18 months in addition to anti-secretory medications without any complication. Diagnosing and staging of corrosive upper gastrointestinal surgery is managed on individual basis. Use of biodegradable stent earlier in this setting prevents long-term morbidity and provides clinical remission effectively.

Surgical treatment of gastroesophageal reflux disease

Gastroesophageal reflux disease is by far the most prevalent disorder of the foregut. For a long time during the twentieth century, surgical therapy was the mainstay of treatment and the only chance for cure for patients with severe symptoms. Later, after introduction of proton pump inhibitor therapy in the early 1990 s, surgical therapy was considered widely a second choice option due to its potential morbidity and side effects. More recently, however, there is growing evidence that long-term antisecretory therapy might be associated to a number of adverse effects such as osteoporosis and increased risk of cardiovascular events. This is the rationale why interventional and surgical options are coming back into focus. The purpose of this review is to analyze and to discuss the current spectrum of surgical therapy of gastroesophageal reflux disease.

Long-Term Acid Suppressive Therapy May Prevent the Relapse of Lower Esophageal (Schatzki's) Rings: A Prospective, Randomized, Placebo-Controlled Study

Distal esophageal (Schatzki's) rings are a frequent cause of dysphagia. Bougienage is generally effective, but relapses are common. The aim of this study was to evaluate the effect of long-term antisecretory therapy on the relapse rate of lower esophageal rings after successful bougienage with Savary dilators. The study was performed on 44 consecutive patients with symptomatic Schatzki's rings, detected endoscopically, and/or radiologically. Graded esophageal dilation was performed as an outpatient procedure in a single session. After appropriate assessment with esophageal manometry and 24-h ambulatory esophageal pH monitoring, patients with documented GERD (n = 14) were treated with long-term omeprazole therapy. The remaining patients were blindly randomized to receive maintenance treatment with either omeprazole (group A-15 patients) or placebo (group B-15 patients). The necessity for redilation after documentation of the ring with endoscopy and/or radiology was considered as a relapse of the ring. The relapse rate was evaluated in all groups. All bougienages were performed without significant side effects. Eight patients (8 of 44, 18.2%) had one or more relapses after a mean (SD) of 19.0 (10.1) months. Patients with (n = 14) or without (n = 30) GERD were comparable with respect to sex, age, body mass index, cigarette and alcohol consumption, diameter of the esophageal lumen at the level of the ring, resting lower esophageal sphincter pressure, duration of dysphagia, need for taking antacids during the follow-up period, and duration of follow-up. There were no recurrences of Schatzki's ring in the group of patients with documented GERD (follow-up [mean +/- SD]: 43.8 +/- 9.3 months, range: 27-62). In group A (follow-up [mean +/- SD]: 37.1 +/- 17.1 months, range: 11-66), one patient relapsed after 13 months, while in group B (follow-up [mean +/- SD]: 34.3 +/- 14.6 months, range: 10-58), seven patients relapsed after a mean (SD) of 19.9 (10.6) months. The actuarial probability of relapse was higher in patients without therapy (group B) (p= 0.008). Our data support the hypothesis that, in patients with symptomatic Schatzki's rings, acid suppressive maintenance therapy after bougienage may prevent relapse of the ring.

Meta-analysis: Helicobacter pylori eradication therapy vs. antisecretory non-eradication therapy for the prevention of recurrent bleeding from peptic ulcer.

To perform a meta-analysis comparing the efficacy of Helicobacter pylori eradication therapy vs. antisecretory non-eradication therapy for the prevention of recurrent bleeding from peptic ulcer. A search was made of the Cochrane Controlled Trials Register, MEDLINE, EMBASE, CINAHL and several congresses for controlled clinical trials comparing the efficacy of H. pylori eradication therapy vs. antisecretory non-eradication therapy for the prevention of peptic ulcer re-bleeding. Studies with all patients taking non-steroidal anti-inflammatory drugs were excluded. Extraction and quality assessment of the studies were performed by two reviewers. In the first meta-analysis, the mean percentage of re-bleeding in the H. pylori eradication therapy group was 4.5%, compared with 23.7% in the non-eradication therapy group without long-term antisecretory therapy [odds ratio, 0.18; 95% confidence interval (CI), 0.09-0.37; 'number needed to treat' (NNT), 5; 95% CI, 4-8]. In the second meta-analysis, the re-bleeding rate in the H. pylori eradication therapy group was 1.6%, compared with 5.6% in the non-eradication therapy group with maintenance antisecretory therapy (odds ratio, 0.25; 95% CI, 0.08-0.76; NNT, 20; 95% CI, 12-100). When only patients with successful H. pylori eradication were included, the re-bleeding rate was 1%. The treatment of H. pylori infection is more effective than antisecretory non-eradication therapy (with or without long-term maintenance antisecretory treatment) in the prevention of recurrent bleeding from peptic ulcer. Consequently, all patients with peptic ulcer bleeding should be tested for H. pylori, and eradication therapy should be prescribed to infected patients.

Early events in proton pump inhibitor-associated exacerbation of corpus gastritis.

Antisecretory therapy may exacerbate Helicobacter pylori corpus gastritis. The rate and mechanism(s) remain unknown. To investigate the early events in proton pump inhibitor therapy on antral and corpus H. pylori gastritis. Nine H. pylori-infected volunteers underwent gastric biopsy with jumbo forceps for culture and histology. Histology was scored in the range 0-5 using a visual analogue scale. The depth of inflammation in gastric pits was scored in the range 1-3 (superficial or less than one-third, one-third to two-thirds and greater than two-thirds of the gastric pit, respectively). Tissue interleukin-1 beta and interleukin-8 levels were measured by enzyme-linked immunoabsorbent assay. Omeprazole, 20 mg b.d., was given for 6.5 days and biopsies were repeated on day 7. Proton pump inhibitor therapy resulted in a fall in H. pylori density in the antrum and corpus. Inflammation and tissue levels of interleukin-8 and interleukin-1 beta decreased in the antrum and increased in the corpus mucosa. There was a significant increase in the depth of inflammation to include the proliferative zone in the corpus. Within 1 week of starting proton pump inhibitor therapy, there was a marked extension of corpus inflammation into the gastric pit and an increase in corpus mucosal interleukin-1 beta and interleukin-8 levels. H. pylori eradication should be considered for all patients receiving long-term antisecretory therapy.

Gastric secretion

This article summarizes data published during the past year that improve our understanding of the mechanisms by which various neurotransmitters, paracrine agents, and hormones regulate gastric acid secretion and are themselves regulated. The main stimulants of acid secretion are histamine, gastrin, and acetylcholine. The main inhibitor is somatostatin, which exerts a tonic restraint on parietal, enterochromaffin-like (ECL), and gastrin cells. Histamine, released from ECL cells, stimulates the parietal cell directly via H(2) receptors and indirectly via H(3) receptors coupled to inhibition of somatostatin secretion. Gastrin, acting via gastrin/cholecystokinin-B (CCK-B), now termed CCK(2), receptors on ECL cells activates histidine decarboxylase, releases histamine, and induces ECL hypertrophy and hyperplasia. The latter might be responsible for the rebound hyperacidity observed after withdrawal of long-term antisecretory therapy. The neurotransmitter pituitary adenylate cyclase-activating polypeptide stimulates histamine secretion from isolated ECL cells, but its physiologic role, if any, is not known. Acetylcholine, released from gastric postganglionic intramural neurons, stimulates the parietal cell directly via muscarinic M(3) receptors and indirectly by inhibiting somatostatin secretion. Although infection with H. pylori is associated with increased basal and stimulated acid outputs in patients with duodenal ulcer, most people infected with the organism are asymptomatic and have pangastritis with decreased acid output. In the latter, eradication of the bacterium leads to an increase in gastric acidity and is associated with a two-to threefold increase in gastroesophageal reflux.

Gastroesophageal Reflux Disease

To review the management of gastroesophageal reflux disease (GERD) in adults with esophageal complications (esophagitis, stricture, adenocarcinoma, or Barrett metaplasia) or extraesophageal complications (otolaryngological manifestations and asthma). Peer-reviewed publications located via MEDLINE or cross-citation. Emphasis was placed on new developments in diagnosis and therapeutics. Thus, fewer than 10% of identified citations are discussed. Controlled therapeutic trials were emphasized. The validity of pathophysiological observations and uncontrolled trials were critiqued by the author. Esophagitis is typically a chronic, recurring disorder treated with long-term antisecretory therapy, titrated to disease severity. Laparoscopic [correction of Laparascopic] antireflux surgery is an alternative strategy, but neither long-term efficacy data nor an appropriate controlled trial comparing it with proton pump inhibitor therapy exists. The main risk of esophagitis is adenocarcinoma arising from Barrett metaplasia, the incidence of which is increasing. Strong evidence suggests that both reflux-induced asthma and otolaryngological complications (subglottic stenosis, laryngitis, pharyngitis, or cancer) can occur without esophagitis. While the otolaryngological manifestations usually respond to antisecretory medications, reflux-induced asthma responds convincingly only to antireflux surgery. Although esophagitis and GERD symptoms predictably respond to antisecretory medicines, the risk of adenocarcinoma from Barrett metaplasia dictates that if heartburn is refractory to treatment, chronic (>5 years), or accompanied by dysphagia, odynophagia, or bleeding, it should be evaluated by endoscopy. Thereafter, patients with Barrett metaplasia require surveillance endoscopy to control the cancer risk. Reflux-induced asthma remains a vexing problem in the absence of either medical therapy or proven efficacy of a reliable mechanism of prospectively identifying affected patients.

The effects of omeprazole and famotidine on mucin and PGE2 release in the rat stomach.

Gastric antisecretory agents may inhibit the synthesis or secretion of gastric mucin during acid suppression, which would interfere with mucosal protection and limit the efficacy of the agents. Rats were dosed with famotidine, omeprazole, or buffer control for 4 weeks. Mucin synthesis, mucin histochemistry, mucin carbohydrate composition and prostaglandin E2 (PGE2) release were measured during and after drug treatment. PGE2 release was maximally inhibited after 2 weeks of omeprazole or 4 weeks of famotidine. Total glycoprotein synthesis was inhibited at all times by omeprazole, but only after the cessation of dosing with famotidine. Sulphated glycoprotein synthesis was inhibited by both drugs at 2 weeks. PGE2 release and sulphated glycoprotein synthesis were restored to control values or more by the 5th day after the end of dosing, at which time total glycoprotein synthesis was significantly suppressed in both groups. Histologically, a reduction of PAS-positive surface mucus was observed after 2 weeks of dosing in both groups. Both famotidine and omeprazole reduced the sialic acid content during and after treatment. These results suggest that long-term anti-secretory therapy also affects the production of factors involved in primary gastric mucosal defence, which should be considered in the assessment of response to treatment in clinical trials.

Acid suppression and gastric mucosal cell biology

This review examines recent concepts of gastric mucosal cell biology in relation to acid inhibition. Powerful acid-inhibitory drugs have been associated with the production of enterochromaffin-like (ECL) cell proliferation and the induction of ECL-cell carcinoids in rats. The ECL-cell lineage and its renewal is discussed, and the factors that regulate ECL-cell proliferation are reviewed. Current methods in use for assessing genotoxicity in gastric mucosa are scrutinized; the much discussed claim that antisecretory drugs induce unscheduled DNA synthesis is examined, and the methodology that is the basis for these claims is found defective and wanting. The nature of ECL-cell proliferation in rats receiving lifelong treatment with H2-receptor antagonists or acid pump inhibitors is explored, and their relationship to ECL-cell proliferation and ECL-cell carcinoids discussed. It is concluded that aged rats are very prone to developing endocrine proliferations, and this may be related to the multiple endocrine neoplasia syndrome found in humans. There is no evidence at present that long-term antisecretory therapy causes significant ECL-cell proliferation in humans.

Prospective study of the need for long-term antisecretory therapy in patients with Zollinger-Ellison syndrome following successful curative gastrinoma resection.

A long-term cure is now possible in more than 30% of selected patients with Zollinger-Ellison syndrome who undergo gastrinoma resection. The need, however, for continued gastric acid antisecretory therapy in these patients remains controversial. The current study was designed to determine whether post-operative antisecretory therapy is needed in patients who have undergone successful gastrinoma resection and, if so, to attempt to define criteria with which to identify patients who require therapy. Twenty-eight consecutive patients who had previously undergone curative gastrinoma resection were prospectively studied. When antisecretory therapy was discontinued, 43% (12/28) of these patients developed gastro-oesophageal reflux, diarrhoea, acid-peptic symptoms or endoscopic evidence of acid-peptic disease within 2 weeks and were deemed to have failed a trial of antisecretory drug withdrawal. The remaining 57% (16/28) of patients who successfully discontinued antisecretory therapy were followed for a mean time of 31 months after withdrawal of therapy. Analysis of acid output studies pre-operatively, as well as at the time of drug withdrawal, demonstrated that patients who were unable to discontinue antisecretory therapy exhibited higher pre-operative maximal acid output values and higher basal acid output values at the time of attempted drug withdrawal than patients who were able to discontinue therapy. Despite these findings, there was significant overlap in acid output values between groups so that it was not possible to define specific acid output criteria for successful drug withdrawal. Pre-operative clinical characteristics, such as the presence or absence of gastro-esophageal reflux or acid-peptic disease, or post-operative laboratory values, such as the fasting serum gastrin level, did not correlate with the ability to discontinue antisecretory therapy. We conclude that following successful curative gastrinoma resection, 40% of patients still require antisecretory therapy and that both symptom evaluation as well as upper endoscopy should be used to guide attempted drug withdrawal. Although patients who are not able to discontinue therapy have significantly higher acid output measurements than those who are able to discontinue therapy, neither acid output criteria nor any other laboratory or clinical characteristics are able to predict the need for continued antisecretory therapy in these patients.

Current diagnosis and management of Zollinger-Ellison syndrome.

The treatment of patients with Zollinger-Ellison syndrome (ZES) has undergone dramatic evolution during the past decade. Although initially regarded as an incurable tumor, resection of gastrinoma for potential cure has been reported in 30% to 40% of selected patients in recent series. Conversely, although definitive control of acid hypersecretion is achieved by total gastrectomy, histamine (H2)-receptor antagonists and the newly introduced agents omeprazole and somatostatin analogues allow effective medical therapy of gastric acid overproduction. Confirmation of the diagnosis is best achieved with the I.V. secretin stimulation test, and tumor localization techniques are mandatory to identify candidates for operative tumor resection. Intraoperative sonography and careful exploration are required for tumor removal; successful tumor resection is associated with prolonged survival. The majority of patients (60%) are still found to have malignant disease at the time of diagnosis, but 10-year overall survival commonly exceeds 40%. The presence of multiple endocrine neoplasia type I (MEN-I) is seen in 10% to 25% of patients; correction of hypercalcemia alone may have therapeutic benefit in some ZES patients, and while gastrinoma resection is rarely possible, MEN-I patients demonstrate prolonged survival. The choice of medical rather than surgical therapy for acid hypersecretion depends on the suitability of each patient for careful and repeated endoscopic and chemical studies, versus the likelihood of a successful postoperative outcome. Socioeconomic, geographic, and related medical factors in each case may dictate the form of long-term antisecretory therapy. Exploration for possible tumor resection is indicated for virtually all patients who have no documented metastatic disease.