High-dose Ranitidine Research Articles

Idiopathic gastric acid hypersecretion: treatment implications for refractory acid/peptic disorders

Although in most patients with duodenal ulcer disease the ulcer heals after 8 weeks of treatment with standard doses of H2 blockers or other agents, in about 10% the ulcer does not heal. These patients are considered 'refractory' to treatment. Reasons often cited for non-healing include poor patient compliance, cigarette smoking, and non-steroidal anti-inflammatory drug (NSAID) use. Gastric acid hypersecretion also appears to be an important factor in non-healing with standard doses of antisecretory agents. We have defined idiopathic gastric acid hypersecretion as a basal acid output of greater than 10 mmol/h in the absence of an elevated fasting serum gastrin level (or a negative secretin test if gastrin level greater than 100 pg/ml) to exclude persons with Zollinger-Ellison syndrome. Among the acid/peptic-related disorders in which idiopathic gastric acid hypersecretion should be considered are refractory duodenal ulcer, refractory gastro-oesophageal reflux disease (especially patients with oesophagitis), postbleeding duodenal ulcer, and certain rare disorders such as hereditary angioedema. Some children with atypical abdominal pain may also be hypersecretors of gastric acid. Once identified, patients with refractory duodenal ulcer or gastro-oesophageal reflux disease are treated with incremental doses of ranitidine titrated against the level of gastric acid secretion that remains during therapy. Ranitidine was selected to avoid the dose-related antiandrogenic effects and potential hepatic cytochrome P450 system-related drug interactions that may occur with cimetidine. In most cases of refractory duodenal ulcer, doubling the standard dose of ranitidine (to 300 mg b.d.) is sufficient to achieve symptomatic relief and mucosal healing. Higher doses appear to be necessary for refractory oesophagitis. To date, no side effects have been associated with high doses of ranitidine (up to 1800 mg/day) for periods of longer than 6 months. Idiopathic gastric acid hypersecretion is an important factor in explaining why not all patients respond to a 'standard' ulcer-healing dose of H2 blocker, and it provides a rationale for use of higher-dose therapy as a safe and effective alternative to omeprazole or to combination drug therapy in refractory acid/peptic disease.

The Neuroendocrine System OF the Gut—AN Update

During the last few years the endocrine stomach has come into focus much due to the side-effects produced by powerful acid blockers. A sustained and marked inhibition of acid secretion in the rat results in hypergastrinemia, with gastrin cell hyperplasia, and a consequent hyperplasia of the ECL cells. This response of the ECL cells was predictable in view of previous observations that sustained hypergastrinemia causes ECL cell hyperplasia. While the gastrin cell hyperplasia levels off at about twice the normal cell density a few weeks after start of treatment, the ECL cells continue to proliferate for months to reach a five-fold higher density than normally. Evidence is accumulating that ECL cells proliferate through self replication. After life-long inhibition of acid production (high doses of ranitidine or omeprazole) or after extirpation of 75% of the acid-producing part of the stomach, ECL cell carcinoids develop. Endocrine cells in the gut often contain more than one putative messenger. Thus, gastrin cells in many species store GABA and peptide YY; in e.g. cat and man they store in addition a xenopsin-like peptide. Neuromedin U and pituitary adenylate cyclase activating peptide (PACAP) have recently been demonstrated in gut nerves. Their role in gut physiology remains to be identified.

Intravenous Therapy with High Doses of Ranitidine and Omeprazole in Critically Ill Patients with Bleeding Peptic Ulcerations of the Upper Intestinal Tract: An Open Randomized Controlled Trial

Thirty-nine critically ill patients with actively bleeding peptic ulcerations--Forrest Ib--in the stomach or duodenum were randomly allocated to intravenous therapy with 400 mg ranitidine per day or 80 mg omeprazole per day (120 mg on the 1st day) for 5 days. Successful therapy was proven by control endoscopy on day 6 if less than 2.5 liters of blood had to be transfused from the start of therapy to maintain a hemoglobin value of 10g/l or above. Treatment failure meant that more than 2.5 liters of blood were necessary to maintain a hemoglobin level above 10 g/l. Of 20 patients in the ranitidine group bleeding stopped in only 3 patients (15%). Of 17 patients who continued bleeding under ranitidine therapy the bleeding could be controlled in 13 patients after changing to omeprazole treatment. Of 19 patients in the omeprazole group bleeding stopped in 16 patients (84%). These results demonstrate that the significantly more effective reduction of acidity by omeprazole is promising for the therapy of bleeding peptic ulcerations and may reduce the need for invasive therapy or operation.

High Doses of Ranitidine in Maintenance Therapy of Duodenal Ulcer Patients

Chronic duodenal ulceration is a recurrent disease. Acute exacerbations may be treated effectively with H2-receptor blockers and a variety of other agents. Intermittent treatment may pose risks of recurrence and complication, and these may be greatly reduced by maintenance treatment. Operative management also reduces recurrence rates, which, however, are commoner in patients coming to surgery nowadays. Full-dose maintenance therapy is an effective option for selected patients.

High Doses of Ranitidine in Patients with Reflux Oesophagitis

As in duodenal and gastric ulcer patients, a highly significant correlation between suppression of 24-h intragastric acidity and healing rates in reflux oesophagitis patients was demonstrated by meta-analysis of data obtained from the literature (r = 0.90; p less than 0.001). Furthermore, we have demonstrated in eight patients with reflux oesophagitis that 2-week treatment courses with 300 mg ranitidine twice daily and 300 mg four times daily progressively decreased 24-h intraoesophageal acidity but only moderately elevated basal and meal-stimulated serum gastrin concentrations, significantly below gastrin values obtained after a 2-week treatment course with 20mg omeprazole once daily. Further studies are awaited to demonstrate long-term effects on both healing rates and serum gastrin responses with high doses of histamine H2-receptor antagonists.

Efficacy and Safety of Omeprazole in the Long-Term Treatment of Peptic Ulcer and Reflux Oesophagitis Resistant to Ranitidine

A total of 143 patients with peptic ulceration of the duodenum, stomach and oesophagus who did not respond to 3 or more months of high-dose treatment with ranitidine, 450 mg or more daily, were treated with oral omeprazole, 40 mg daily. In 94% of the patients, ulcers healed within 2-8 weeks. After healing, 133 patients underwent long-term maintenance treatment with omeprazole, 40 mg daily, for 1-5 years (continuing). During maintenance therapy with omeprazole, no endoscopically verified relapses occurred, and no drug-related adverse effects were seen. There were no significant changes in routine laboratory tests in any patient, including 27 with concomitant liver cirrhosis. Basal serum gastrin levels, which were already elevated by the previous high-dose ranitidine treatment, rose to 4 times normal levels after 4 months of treatment with omeprazole. Thereafter, no further increases in basal serum gastrin levels were observed, even after 5 years of administration. The volume density of argyrophilic cells in the oxyntic mucosa increased during omeprazole treatment, but no dysplasia of the gastric enterochromaffin-like cells was seen. In conclusion, omeprazole was highly effective in healing ranitidine-resistant peptic ulcers, and subsequent maintenance therapy with omeprazole, 40 mg daily, was found to be effective and safe over the period observed.

Management of gastro-oesophageal reflux disease. Are there alternatives to omeprazole?

Several studies have clearly demonstrated that omeprazole is highly efficacious in the management of patients with gastro-oesophageal reflux disease. In particular, wherever H2-receptor antagonists fail to produce results--in patients with severe disease--omeprazole has been shown to be of major value. However, new alternatives are forthcoming; a new generation of more potent H2-receptor antagonists will be available, while 24 pH studies with high-dose ranitidine have shown that acid reflux is suppressed more efficiently than with standard doses. The prokinetic drug cisapride appears to be of importance, not only in the management of patients with mild reflux disease, but also of cases with severe disease when cisapride is combined with a H2-receptor antagonist. Such a combination could also be of value as an alternative to omeprazole in long-term therapy, since it has not yet been shown that indefinite treatment with omeprazole of patients with reflux disease will be safe. In addition, the value of long-term sucralfate, effective in short-term therapy, needs to be evaluated in patients with chronic reflux disease who will not be operated. In forthcoming studies, it will be advisable to incorporate 24-hour pH measurements to detect periods of nonacid suppression more accurately. The future of medical management of gastro-oesophageal reflux disease appears to be promising.

Therapeutic Options in Severe Reflux Oesophagitis

Standard doses of H2-receptor antagonists are usually effective in milder forms of reflux oesophagitis, but these lower doses induce relatively low healing rates in more severe forms of the disease. In the patients with severe reflux oesophagitis, prokinetic or mucosa-protecting agents do not offer better results, whereas a combination of standard doses of H2-receptor antagonists with prokinetic or mucosa-protecting agents results in no or only marginally better results than obtained with H2-receptor antagonist mono-therapy. Several studies have shown that insufficient inhibition of gastric acid secretion is the major reason for the low healing rates obtained with standard doses of H2-receptor antagonists. It has recently been shown that higher doses of ranitidine increase the time the oesophageal pH is above 4 and induce higher healing rates in patients with severe reflux oesophagitis. Therefore, we now have three therapeutic options for patients with severe reflux oesophagitis: first, higher doses of hi...

Quantitative Studies of Gastric Endocrine Cells in Patients Receiving Long-term Treatment with Omeprazole

A total of 36 patients with chronic gastric or oesophageal peptic ulceration (including 6 with antrectomy), resistant to high-dose ranitidine treatment for at least 3 months, were successfully treated with omeprazole 20-60 mg/day, for periods up to 3 years. Fasting serum gastrin levels were monitored at regular intervals during therapy and multiple gastric mucosal biopsies were taken during gastroscopy every 3-6 months. Gastrin levels increased significantly during the first 6 months of therapy from a mean of 81.5 to 206 pg/ml; a slight decrease was observed thereafter. There was no significant increase in the volume density of argyrophilic cells in the oxyntic mucosa. No clusters of endocrine cells were found in the oxyntic mucosa and no change of G-cell volume density occurred in the antral mucosa under therapy. Omeprazole therapy did not result in any changes in gastrin levels or oxyntic argyrophilic cells in the antrectomized patients. It is concluded that the moderate hypergastrinaemia observed during long-term omeprazole treatment in man does not induce hyperplasia of argyrophilic cells in the oxyntic mucosa.

H2-Receptor Antagonists in the Treatment of Reflux Oesophagitis

H2-receptor antagonists are useful for relief of symptoms and in the healing of reflux oesophagitis. The therapeutic response is related to the initial degree of severity of oesophagitis, and standard doses of H2-receptor antagonists are only reliably effective in the treatment of mild disease. Pharmacodynamic studies indicate that in patients with more severe grades of oesophagitis standard doses of H2-receptor antagonists may be less effective at inhibiting gastric secretion and reducing total reflux time. This is associated with a suboptimal response to therapy. In non-responders to standard dose therapy, 24-h intra-oesophageal pH profiles can be normalized by increasing the dose of H2-receptor antagonist. A high-dose ranitidine regimen (300 mg four times daily) markedly improves healing of oesophagitis and symptom relief compared with standard therapy. Reflux oesophagitis relapses rapidly after cessation of medical therapy. It appears that continuous treatment with doses similar to those required to a...

Omeprazole in the Long-term Management of Patients with Acid-related Diseases Resistant to Ranitidine

A total of 143 patients with peptic ulceration of the duodenum, stomach or oesophagus, who did not respond to 3 or more months high-dose treatment with ranitidine (450 mg or more daily), were admitted to oral treatment with omeprazole, 40 mg/day. In 94.4% of the patients, ulcers healed within 2-6 weeks. After healing of their ulcers, 122 patients were admitted to long-term maintenance treatment with omeprazole, 40 mg/day; 91 patients have been on the drug for 1-5.5 years. During maintenance therapy with omeprazole, 40 mg/day, no relapses (verified by endoscopy) have yet occurred and no drug related adverse effects have been observed. There were no significant changes in routine laboratory tests in any patients, including 27 with concomitant liver cirrhosis. Serum gastrin levels were already elevated approximately 2-fold during the initial high-dose ranitidine treatment and rose a further 2-fold at 2-3 months of omeprazole treatment. Thereafter, no further increase of serum gastrin was observed even after 5.5 years of continuous observation. Volume density of G and D cells in the antral mucosa did not change significantly. The volume density of argyrophilic cells in the oxyntic mucosa was 0.73 +/- 0.1% before the start of omeprazole treatment and 0.85 +/- 0.09% after 17-24 months of continuous treatment with omeprazole (ns). In antrectomized patients the volume density was lower (0.23 +/- 0.04%). No clusters of argyrophilic cells were observed in any of the groups. In a control group of patients with gastrinoma the volume density of these cells was higher (1.3 +/- 0.23%, n = 8).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Increasing Doses of Ranitidine on Exposure of the Oesophagus to Gastric Acid in Patients with Reflux Oesophagitis

To investigate the effect of doses of ranitidine higher than those presently recommended for the treatment of patients with reflux oesophagitis on features of gastro-oesophageal reflux, we compared the effect of two times 300 mg and four times 300 mg ranitidine daily on gastro-oesophageal reflux features measured by continuous 24-h ambulatory pH-metry, 5 cm above the manometrically determined lower oesophageal sphincter in eight patients with erosive or ulcerative reflux oesophagitis resistant to ranitidine treatment with twice daily 150 mg for 12 weeks. During both higher doses of ranitidine there were significant decreases in the total number of reflux episodes with a pH below 4.0 (p < 0.05 and p <0.01, respectively), the number of episodes with pH below 4.0 lasting longer than 5 min (p < 0.01), and the fraction of time that the oesophagus was exposed to reflux with pH < 4.0 (p <0.01) when compared with no treatment. The median pH in the oesophagus was significantly increased by the two doses of ranitid...

Esophageal candidosis in progressive systemic sclerosis: occurrence, significance, and treatment with fluconazole.

Esophageal mucosal brushings from 51 consecutive patients with progressive systemic sclerosis (PSS) (group I), 18 PSS patients continuously treated with high-dose ranitidine or omeprazole (group II), 34 controls referred to the outpatient clinic for endoscopy (group III), and 10 patients receiving long-term potent antireflux therapy for idiopathic gastroesophageal reflux (group IV) were cultured for Candida albicans. There were 44%, 89%, 9%, and 0% Candida albicans culture-positive patients in groups I through IV, respectively. Fifteen patients with candida esophagitis from group II were treated with fluconazole systemically. Eleven and 14 patients became culture-negative after 2 and 4 weeks' treatment, respectively. Three months after fluconazole withdrawal the recurrence rate was 100%. It is concluded that esophageal dysmotility predisposes for candidosis. Adding gastric acid inhibitory treatment to dysmotility enhances the risk significantly (p less than 0.01). The efficiency of fluconazole treatment was close to 100%, but so was the recurrence rate within a short period.

Long-term omeprazole treatment in man: effects on gastric endocrine cell populations.

36 patients with chronic gastric or oesophageal peptic ulceration (including 6 with antrectomy), resistant to high-dose ranitidine treatment for at least 3 months, were successfully treated with 40-60 mg of omeprazole daily for periods between 1 and 2 years. Fasting serum gastrin levels were monitored at regular intervals during therapy and multiple gastric mucosal biopsies were taken during gastroscopy every 3-6 months. Gastrin levels increased significantly during the first 6 months of therapy from a medium level of 81.5 to 206 pg/ml, a slight decrease was seen thereafter. In 10 patients investigated before the start of the treatment and after 1 and 2 years, the volume density of argyrophilic cells in the oxyntic mucosa increased from 0.43 +/- 0.08 to 0.91 +/- 0.14% during the first year; this change was statistically significant. No further increase was observed thereafter. No such difference could be demonstrated between a larger group of 18 patients investigated before and after 1 year of treatment with omeprazole (0.806 +/- 0.1 vs. 0.93 +/- 0.08%) and between a larger group of 22 untreated patients and 17 patients treated for 17-24 months with omeprazole (0.73 +/- 0.1 vs. 0.86 +/- 0.09%). The volume density of argyrophilic cells found in 8 patients with gastrinoma amounted to 1.37 +/- 0.22%. No clusters of endocrine cells were found in omeprazole-treated patients. The D cell volume density in the antral mucosa decreased significantly during the first months of treatment, but steadily increased thereafter to reach pretreatment values after 17 months. There was no change in G cell volume density under therapy. No changes in gastrin levels or oxyntic argyrophilic cells were observed in the antrectomized patients. It is concluded that the hyperplasia of argyrophilic cells observed in some patients during long-term omeprazole treatment is mediated by hypergastrinaemia.

Therapy with omeprazole in patients with peptic ulcerations resistant to extended high-dose ranitidine treatment.

94 patients with peptic ulcerations of duodenum, stomach, and esophagus, who did not respond to 3 or more months high-dose (450 or 600 mg) treatment with ranitidine, were treated orally with 40 mg omeprazole daily. After healing all patients were offered long-term maintenance therapy with the same dose for 5 years. In 75 patients the peptic ulcerations healed within 4 weeks, in 13 patients within 8 weeks, and in 3 patients only after an increase to 60 mg omeprazole daily. In 3 patients the ulcers did not heal. So far 83 patients have entered long-term maintenance therapy. 59 of these patients are on the drug between 1 and 4 years. During maintenance therapy with 40 mg omeprazole no relapses have occurred up to now as demonstrated by endoscopy and no drug-related adverse effects were observed. Routine laboratory tests remained without significant changes in all patients including 18 patients with concomitant liver cirrhosis. Serum gastrin levels were already elevated during the initial high-dose ranitidine treatment (106 +/- 15.4 pg/ml). 4 weeks after the start of omeprazole treatment serum gastrin levels rose to 4 times normal levels (195 +/- 28 pg/ml). Thereafter, no further increase in serum gastrin was observed even up to 4 years of continuous observation. It is therefore concluded that omeprazole is highly effective in healing ranitidine-resistant peptic ulcerations and that omeprazole maintenance therapy with 40 mg omeprazole is safe during the time observed and highly effective in the prevention of ulcer recurrence.

What is an intractable duodenal ulcer and how should it be managed?

An intractable duodenal ulcer is an ulcer that has not healed after 8 weeks of full-dose treatment with a modern anti-ulcer drug. Such ulcers are relatively rare--perhaps five in 100 patients will have intractable duodenal ulceration. The differential diagnosis includes non-compliance as a cause of continuing ulceration, hypersecretion of gastric acid or other rare causes of ulcers in the duodenum. Investigations should include biopsy of the continuing ulceration at endoscopy, measurement of fasting plasma gastrin and routine haematology and biochemistry profiles. An intractable duodenal ulcer can be treated either by using a powerful antisecretory regimen (high doses of ranitidine or famotidine or a conventional dose of omeprazole), by changing to tripotassium dicitrato bismuthate or, in exceptional circumstances, by extremely careful surgical intervention.

Effect of inhibition of acid secretion on the regulatory peptides in the rat stomach

The effect of inhibiting acid secretion by pharmacologic agents on the gastric content of regulatory peptides has been determined by radioimmunoassay and immunocytochemistry. Plasma, antral, and fundic concentrations of gastrin were elevated in rats rendered virtually achlorhydric by treatment with high-dose omeprazole (400 μmol/kg daily for 10 wk). This was associated with an increase in the number and staining intensity of gastrin immunoreactive cells. A clear reciprocal relationship was observed between antral gastrin and somatostatin as assessed by both quantitative and qualitative methods. These changes had disappeared 10 wk after treatment was stopped. No alteration was found in the concentrations of other regulatory peptides proposed as important in control of acid secretion. Plasma and antral gastrin concentrations were elevated in rats treated with high-dose ranitidine (700 μmol/kg daily), but to a lesser extent than during omeprazole therapy, and somatostatin concentrations were unchanged.

Gastric regulatory peptides in rats with reduced acid secretion.

Gastric acid secretion is known to be controlled by a complex system of interacting factors. Amongst these, regulatory peptides make a significant contribution. In the present study, immunocytochemistry and radioimmunoassay were used to investigate gastric regulatory peptides in animals with pharmacologically reduced gastric acid secretion. Increased numbers of densely immunostained antral gastrin-immunoreactive (G) cells were seen in rats which had been rendered virtually achlorhydric by administration of high-dose (400 mumol/kg daily) omeprazole over a 10-week period. These morphological changes were accompanied by increases in the plasma, antral and fundic concentrations of gastrin, as measured by radioimmunoassay. In contrast, antral somatostatin-containing cells were reduced, and there was a corresponding fall in the tissue content of the peptide. Ten weeks after treatment had ceased, the peptide profiles had returned to normal. No other regulatory peptide, whether endocrine or neural, appeared to alter during treatment with high-dose omeprazole. Treatment with high-dose (700 mumol/kg daily) ranitidine also caused an elevation in the G cell population and the antral and plasma content of gastrin, but to a lesser extent than that observed during omeprazole treatment. Somatostatin cells and tissue levels did not alter in these animals, and no other morphological changes could be detected. Radioimmunoassay, however, measured reduced quantities of vasoactive intestinal peptide, peptide histidine isoleucine and calcitonin gene-related peptide. Achlorhydria, induced by omeprazole at a dosage of 250-500 times that required for effective acid inhibition in man and animals, therefore resulted in reciprocal changes in gastrin and somatostatin cells. These changes are support for the postulated roles of these peptides in the control of gastric acid secretion.

Ranitidine--pharmacology and clinical use.

SUMMARY Ranitidine is a new histamine H2-receptor antagonist which differs in chemical structure from both histamine and cimetidine. Animal studies have shown that it is a potent, specific competitive antagonist with a highly effective inhibitory action upon the release of acid and pepsin in gastric secretion invoked by a wide range of secretory stimulants. Similar pharmacological properties have been shown in man. It has no other measurable pharmacological effect resulting from blockade of histamine H2-receptors, nor does it appear to exert any other biological effects in man. The gastric secretory inhibitory effects of ranitidine are qualitatively similar to those of cimetidine but are 4–9 times more potent on a weight-for-weight basis. The pharmacodynamics and pharmacokinetics are such that by administering ranitidine 150 mg morning and night, effective inhibition of intragastric acidity is achieved. Ranitidine has a greater selectivity of action than cimetidine so avoiding certain unwanted effects such as interference with enzymic degradation of a wide range of drugs metabolised by the liver mixed function oxygenase system, antiandrogenic effects and the propensity to cause confusion in the elderly. In short term treatment of duodenal ulceration, ranitidine 150 mg twice daily relieves symptoms and heals ulcers with an expected rate of approximately 80% over four weeks rising to over 90% during eight weeks of treatment, compared with placebo healing rates of around 30%. Similarly, the gastric ulcer healing rate of 60–70% at four weeks and 85% at three months was superior to placebo rates of 40–50%. In both duodenal and gastric ulcer, responses were similar to those previously reported with cimetidine. Nightly maintenance treatment with ranitidine 150 mg significantly reduces the rate of recurrence in patients with duodenal or gastric ulceration. In reflux oesophagitis, ranitidine 150 mg twice daily for six weeks reduces symptoms, and improves endoscopic appearances. Higher doses of ranitidine have been shown to control patients with the Zollinger-Ellison syndrome resistant to cimetidine. There are some reports of beneficial effects of ranitidine on acute upper gastrointestinal haemorrhage. Administered before anaesthesia, ranitidine decreases the volume and elevates the pH of gastric juice and may reduce morbidity and mortality arising from aspiration pneumonitis.