Effects of spiroglumide, a gastrin receptor antagonist, on acid secretion in humans

Beltinger, Johannes; Hildebrand, Pius; Drewe, Jürgen; Christ, Andreas; Hlobil, K.; Ritz, Mary C.; D’Amato, Massimo; Rovati, Lucio C.; Beglinger, C.

doi:10.1046/j.1365-2362.1999.00424.x

Cited by 23 publications

(17 citation statements)

References 21 publications

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“…A number of CCK-2 receptor antagonists have been reported, these include L-365,260, L-740,093, YM022, YF476, spiroglumide, and gastrozole [10,74,83]. These are useful for experimental studies, and have for example provided evidence supporting a role for gastrin in post-prandial increases in gastric acid secretion [8]. There is on going work to determine whether these and related compounds might be useful in the clinic.…”

Section: Cck-2 Receptors and Signal Transductionmentioning

confidence: 99%

Gastrin: old hormone, new functions

Dockray

Dimaline

Varró

2004

Pflugers Arch - Eur J Physiol

111

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It is exactly a century since the gastric hormone gastrin was first described as a blood-borne regulator of gastric acid secretion. The identities of the main active forms of the hormone (the "classical gastrins") and their cellular and molecular sites of action in regulating acid secretion have all attracted sustained attention. However, recent work on peptides derived from the gastrin precursor that do not stimulate acid secretion ("non-classical gastrins"), together with studies on mice over-expressing the gene, or in which the gastrin gene has been deleted, suggest hitherto unsuspected roles in regulating cell proliferation, migration, and differentiation. Moreover, microarray and proteomic studies have identified previously unsuspected target genes of the classical gastrins. Some of the newer actions have implications for our understanding of the progression to cancer in oesophagus, stomach, pancreas and colon, all of which have recently been linked in one way or another to dysfunctional signalling involving products of the gastrin gene. The present review focuses on recent progress in understanding the biology of both classical and non-classical gastrins.

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Section: Cck-2 Receptors and Signal Transductionmentioning

confidence: 99%

Gastrin: old hormone, new functions

Dockray

Dimaline

Varró

2004

Pflugers Arch - Eur J Physiol

111

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“…Studies performed on healthy volunteers [262] confi rmed the inhibitory activity against gastrin-induced acid secretion and also showed its ability to inhibit postprandial gastric secretion. Despite these promising results, the development of spiroglumide was ended because more potent and selective derivatives became available.…”

Section: Gastrin (Cck 2 ) Antagonistsmentioning

confidence: 93%

Acid Suppression Therapy: Where Do We Go from Here?

Scarpignato

Pelosini²,

Mario³

2006

Dig Dis

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The dramatic success of pharmacological acid suppression in healing peptic ulcers and managing patients with gastroesophageal reflux disease (GERD) has been reflected in the virtual abolition of elective surgery for ulcer disease, a reduction in nonsteroidal anti-inflammatory drug (NSAID)-associated gastropathy and the decision by most patients with reflux symptoms to continue medical therapy rather than undergo surgical intervention. However, a number of challenges remain in the management of acid-related disorders. These include management of patients with gastroesophageal symptoms who do not respond adequately to proton pump inhibitor (PPI) therapy, treatment of patients with nonvariceal upper gastrointestinal bleeding, prevention of stress-related mucosal bleeding, optimal treatment and prevention of NSAID-related gastrointestinal injury, and optimal combination of antisecretory and antibiotic therapy for the eradication of Helicobacter pylori infection. A number of new drugs are currently being investigated to provide a significant advance on current treatments. Some of them (namely potassium-competitive acid blockers (P-CABs) and CCK₂-receptor antagonists) have already reached clinical testing while some others (like the antigastrin vaccine, H₃-receptor ligands or gastrin-releasing peptide receptor antagonists) are still in preclinical development and need the proof of concept in human beings. Of the current approaches to reduce acid secretion, P-CABs and CCK₂-receptor antagonists hold the greatest promise, with several compounds already in clinical trials. Although the quick onset of action of P-CABs (i.e. a full effect from the first dose) is appealing, the results of phase II studies with one such agent (namely AZD0865) did not show any advantages over esomeprazole. Thanks to their limited efficacy and the development of tolerance it is unlikely that CCK₂ antagonists will be used alone as antisecretory compounds but, rather, their combination with PPIs will be attempted with the aim of reducing the long-term consequences of hypergastrinemia. While H₂-receptor antagonists (especially soluble or over-the-counter formulations) will become the ‘antacids of the third millennium’ and will be particularly useful for on-demand symptom relief, clinicians will continue to rely on PPIs to control acid secretion in GERD and other acid-related diseases. In this connection, several new PPI formulations have been developed and two novel drugs (namely ilaprazole and tenatoprazole) are being studied in humans. The recently introduced immediate-release (IR) omeprazole formulation (currently available only in the USA) quickly increases intragastric pH and, given at bedtime, seems to achieve a better control of nocturnal acidity. IR formulations of other PPIs (including the investigational ones) will probably be available in the future and will enlarge our therapeutic armamentarium. Amongst the novel PPIs, tenatoprazole appears to be a true advance in the acid suppress...

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“…122 In humans, this CCK 2 antagonist dose-dependently antagonized gastrin-stimulated gastric acid and fluid responses with a competitive-like profile. 123 In a subsequent Phase I randomized, double-blind, placebo-controlled trial in healthy male volunteers, spiroglumide significantly decreased basal acid output in response to food ingestion as well as postprandial intragastric acidity. 124 However, despite its excellent oral bioavailability, the low affinity and selectivity at CCK 2 receptors (micromolar range) precluded further development of spiroglumide as a potential therapeutic tool for peptic ulcer diseases.…”

Section: Cck 2 Receptor Antagonistsmentioning

confidence: 98%

“…123 In a subsequent Phase I randomized, double-blind, placebo-controlled trial in healthy male volunteers, spiroglumide significantly decreased basal acid output in response to food ingestion as well as postprandial intragastric acidity. 124 However, despite its excellent oral bioavailability, the low affinity and selectivity at CCK 2 receptors (micromolar range) precluded further development of spiroglumide as a potential therapeutic tool for peptic ulcer diseases. 78 The chemical manipulation of the structure of spiroglumide has led to more potent and selective CCK 2 antagonists.…”

Section: Cck 2 Receptor Antagonistsmentioning

confidence: 98%

Cholecystokinin antagonists: Pharmacological and therapeutic potential

Herranz

2003

Medicinal Research Reviews

168

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Cholecystokinin (CCK) is a regulatory peptide hormone, predominantly found in the gastrointestinal tract, and a neurotransmitter present throughout the nervous system. In the gastrointestinal system CCK regulates motility, pancreatic enzyme secretion, gastric emptying, and gastric acid secretion. In the nervous system CCK is involved in anxiogenesis, satiety, nociception, and memory and learning processes. Moreover, CCK interacts with other neurotransmitters in some areas of the CNS. The biological effects of CCK are mediated by two specific G protein coupled receptor subtypes, termed CCK(1) and CCK(2). Over the past fifteen years the search of CCK receptor ligands has evolved from the initial CCK structure derived peptides towards peptidomimetic or non-peptide agonists and antagonists with improved pharmacokinetic profile. This research has provided a broad assortment of potent and selective CCK(1) and CCK(2) antagonists of diverse chemical structure. These antagonists have been discovered through optimization programs of lead compounds which were designed based on the structures of the C-terminal tetrapeptide, CCK-4, or the non-peptide natural compound, asperlicin, or derived from random screening programs. This review covers the main pharmacological and therapeutic aspects of these CCK(1) and CCK(2) antagonist. CCK(1) antagonists might have therapeutic potential for the treatment of pancreatic disorders and as prokinetics for the treatment of gastroesophageal reflux disease, bowel disorders, and gastroparesis. On the other hand, CCK(2) antagonists might have application for the treatment of gastric acid secretion and anxiety disorders.

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Effects of spiroglumide, a gastrin receptor antagonist, on acid secretion in humans

Abstract: Gastrin receptor blockade with CR2194 alters gastric acid secretion in response to food ingestion or to sham feeding. The results support a physiological role for gastrin in regulating acid secretion in humans.

Cited by 23 publications

References 21 publications

Gastrin: old hormone, new functions

Gastrin: old hormone, new functions

Acid Suppression Therapy: Where Do We Go from Here?

Cholecystokinin antagonists: Pharmacological and therapeutic potential

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