An open-label study of rabeprazole in patients with Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion.

BACKGROUND: Omeprazole and lansoprazole are both of proven efficacy in the treatment of Zollinger-Ellison syndrome and idiopathic gastric acid hypersecretion. Rabeprazole, which has a similar mechanism of action, has not previously been studied in these diseases. AIM: To determine the dose of rabeprazole that decreased basal acid output to safe levels in patients with Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion. METHODS: Patients with Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion were given rabeprazole 60 mg once daily for uncomplicated disease or 40 mg twice daily for complicated disease. Doses were titrated according to response and continued for 2 years. Efficacy was assessed primarily by measuring basal acid output. RESULTS: All patients had basal acid output before the next dose controlled to <10 mmol/h either at the starting dose or after minor dose titration. Control of acid output was maintained for 2 years. Consistent with this, most patients reported few gastrointestinal symptoms. Gastric biopsy showed no enterochromaffin-like cell dysplasia or neoplasia. CONCLUSIONS: Rabeprazole was an effective and well-tolerated treatment for Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion, which reliably reduced gastric acid output to safe levels. Although a dose of 60 mg once daily was appropriate for most patients in this study, doses may need adjustment according to individual response.

Rabeprazole versus omeprazole in preventing relapse of erosive or ulcerative gastroesophageal reflux disease: a double-blind, multicenter, European trial. The European Rabeprazole Study Group.

Gastroesophageal reflux disease (GERD) is a chronic condition, with 50-80% of patients experiencing recurrence within one year of completing initial treatment. In patients with erosive GERD, proton-pump inhibitors (PPI) provide faster healing and symptom relief than do H2-receptor antagonists and have become the treatment of choice. Rabeprazole is a new PPI with demonstrated efficacy in both the acute and maintenance treatment of erosive GERD. The primary objective was to compare efficacy and tolerability of rabeprazole and omeprazole in preventing relapse of healed erosive GERD. Secondary objectives included comparison of efficacy in preventing GERD relapse symptoms and in maintaining quality of life. In this multicenter, double-blind, parallel-group study, 243 patients with healed erosive GERD were randomised to receive rabeprazole 10 mg once daily in the morning (QAM) (N = 82); rabeprazole 20 mg QAM (N = 78); or omeprazole 20 mg QAM (N = 83). Endoscopies were performed at weeks 13, 26, 39 (if clinically indicated), and 52, or when symptoms suggested recurrence. Corpus biopsies were performed at each endoscopy, and antral biopsies were performed at study entry and exit. Rabeprazole 10 mg and 20 mg QAM were equivalent to omeprazole 20 mg QAM for all efficacy parameters. At week 52, relapse rates in the intent-to-treat populations were 5%, 4%, and 5% for rabeprazole 10 mg and 20 mg and omeprazole 20 mg, respectively. All treatments were well tolerated. In conclusion, both rabeprazole 10 mg and 20 mg QAM are equivalent to omeprazole 20 mg QAM in preventing recurrence of erosive GERD.

Nitric oxide is not involved in the initiation of insulin secretion from rat islets of Langerhans.

The involvement of nitric oxide as an intracellular messenger in the control of insulin secretion from pancreatic Beta cells was studied in rat islets of Langerhans by measuring: (i) nitric oxide generation in response to physiological insulin secretagogues; (ii) the effects of inhibitors of nitric oxide synthesis on insulin secretory responses to physiological secretagogues, and on insulin synthesis; (iii) changes in islet cyclic guanosine monophosphate in response to secretagogues; (iv) the effects of exogenous cyclic guanosine monophosphate and dibutyryl cyclic guanosine monophosphate on insulin secretion from electrically permeabilised islets and from intact, respectively. These studies produced no evidence that nitric oxide generation is required for the initiation of insulin secretion by common secretagogues. However, the results of our experiments suggest that the generation of nitric oxide may be involved in long-term, glucose-dependent increases in cyclic guanosine monophosphate content of islet cells, although the physiological relevance of these changes requires further investigation.

Spiking of intracellular calcium ion concentration in single cultured pig aortic endothelial cells stimulated with ATP or bradykinin.

Single pig aortic endothelial cells in culture loaded with the Ca(2+)-sensitive fluorescent dye Indo-1 were stimulated with ATP (0.1-100 microM) or bradykinin (0.1-5.0 nM). Spiking or oscillations of [Ca2+]i were seen in approx. 50% of cells stimulated with either agonist. Non-spiking or transient responses in which [Ca2+]i returned to pre-stimulation levels rapidly 9120-250 s), or sustained responses in which [Ca2+]i remained elevated for many minutes, were seen in a further 20% of cells in each case, stimulated with either agonist. There was a marked variation between individual cells in the latency, magnitude, frequency and overall pattern of oscillations induced by ATP and bradykinin, although the patterns of response to bradykinin were less variable. In cells where repetitive spikes were seen, a relation between concentration of ATP and the latency of the response and the frequency of spiking was evident. Effects of removal of extracellular Ca2+, elevation of extracellular K+ concentration (35 or 70 mM) or exposure to phorbol 12,13-dibutyrate or 1,2-dioctanoyl-sn-glycerol were tested on the spiking Ca2+ responses. Each of these procedures reversibly slowed or prevented Ca2+ spiking evoked by ATP or bradykinin. In contrast, the inactive phorbol ester 4 alpha-phorbol didecanoate had no effect on Ca2+ spiking evoked by these hormones. Our results thus indicate that the responses of single cells to ATP or bradykinin exhibit marked heterogeneity, and suggest that secretory events driven by extracellular Ca2+ may be regulated by repetitive spikes or oscillations of Ca2+.

Role of intracellular mediators in glucagon secretion: studies using intact and electrically permeabilized rat islets of Langerhans.

The roles of calcium, cyclic AMP (cAMP), activation of protein kinase C (PKC) and the effect of ATP on glucagon secretion were investigated in intact and permeabilized rat islets of Langerhans, Ca2+ (10 nM-10 microM) stimulated glucagon secretion from electrically permeabilized islets in a dose-dependent manner. Forskolin and cAMP stimulated secretion from intact and permeabilized islets respectively, the latter at both sub-stimulatory (50 nM) and stimulatory (10 microM) Ca2+ concentrations. The tumour-promoting phorbol ester phorbol 12-myristate 13-acetate (PMA) increased secretion from both intact and permeabilized islets. In the latter, PMA increased glucagon release at both Ca2+ concentrations, the effect being enhanced at the stimulatory Ca2+ concentration, over and above that caused by Ca2+ alone. Reduction of ATP content by incubation with the metabolic inhibitor 2,4-dinitrophenol resulted in an increased basal release of glucagon from intact islets, whilst arginine-induced glucagon secretion was abolished in both intact and permeabilized islets. Ca2+-induced glucagon secretion required MgATP in the permeabilized islets of Langerhans. These results suggest that Ca2+ acts as an initiator of glucagon secretion, whilst cAMP and activation of PKC may exert their effect as modulators of secretion. ATP is required for glucagon secretion in electrically permeabilized islets and is necessary for arginine-induced glucagon secretion in both intact and permeabilized islets.

Role of protein kinase C in arginine-induced glucagon secretion from isolated rat islets of Langerhans.

This study investigated the effect of pretreatment with the phorbol ester phorbol 12-myristate 13-acetate (PMA) on arginine-induced glucagon secretion. Isolated islets of Langerhans were pretreated by culturing for 18-24 h in the presence of 200 nM of the tumour-promoting phorbol ester PMA or 200 nM of the non-tumour-promoting phorbol ester 4-phorbol didecanoate (PDD). Islets pretreated with PMA did not secrete glucagon in response to 0.1 or 1 microM PMA on subsequent incubation, in contrast to PDD-pretreated islets which responded significantly on subsequent incubation with PMA. Pretreatment with PMA led to impairment of arginine-induced glucagon secretion. PMA-pretreated islets permeabilized by high-voltage discharge retained their normal secretory responses to calcium and cyclic AMP, but had an impaired secretory response to PMA. These results suggest (1) that protein kinase C (PKC) is likely to be present in the A cell, (2) that short-term culture in tumour-promoting phorbol ester leads to down-regulation of PKC, (3) that the PKC pathway is involved in arginine-induced glucagon secretion and (4) that pretreatment does not effect the A cell response to other intracellular mediators.