Author: Mika Yuki ; Kyoichi Adachi ; Shunji Ishihara ; Mohammad Azharul Karim Rumi ; Hiroshi Sato ; Masahiro Ono ; Yasunobu Ishihara ; Cesar Francisco Ortega-Cava ; Hideaki Kazumori ; Yoshikazu Kinoshita

Hypergastrinemia is known to cause hyperplasia of the gastric mucosa, especially in gastric enterochromaffinlike (ECL) cells. In some clinical conditions causing hypergastrinemia, such as long-term gastric-acid inhibition and gastric-mucosa atrophy, hyperplastic ECL cells may develop into gastric carcinoid tumors. A newly developed gastrin-receptor antagonist, S-0509, has been reported to block gastrin-induced stimulation of gastric-acid secretion. We therefore investigated whether S-0509 inhibits the omeprazole- and gastrin-stimulated hyperproliferation of gastric mucosa, especially of ECL cells. Daily administration of omeprazole and gastrin in male Sprague-Dawley rats induced marked hypergastrinemia and increased proliferation of gastric-mucosa cells. The numbers of ECL cells and of ECL cells producing messenger RNA for regenerating gene, a potent growth factor for gastric-mucosa cells, were also augmented by long-term administration of omeprazole and gastrin. Coadministration of S-0509 with omeprazole or gastrin almost completely inhibited the omeprazole- and gastrin-induced changes in gastric mucosa, including mucosal thickening and ECL hyperplasia. S-0509 did not induce gastric-mucosa atrophy, even when administered for as long as 4 weeks. In summary, we have found that a newly developed gastrin receptor antagonist, S-0509, inhibits omeprazole- and gastrin-induced mucosal hyperplasia, especially ECL-cell hyperplasia, in rats.

01 Jan 2003·Journal of Pharmacological SciencesQ3 · MEDICINE

On the Mechanisms Underlying Histamine Induction of Gastric Mucosal Lesions in Rats With Partial Gastric Vascular Occlusion

Q3 · MEDICINE

ArticleOA

Author: Susumu Okabe ; Kikuko Amagase

Although it is well known that histamine induces gastric mucosal lesions in laboratory animals, the fundamental mechanisms remain unclear. In order to further analyze the vascular mechanisms underlying histamine-induced lesions, a new model was developed in the glandular stomach via administration of histamine (40 mg/kg, s.c.) twice to rats with partial gastric vascular occlusion (ligated left gastric artery and vein) also subjected to pylorus ligation. Both antagonists of histamine H(2)-receptors (roxatidine and famotidine) and H(1)-receptors (epinastine and tripelennamine) significantly inhibited lesion formation at doses that did not inhibit acid secretion. Combined treatment of tripelennamine and famotidine synergistically inhibited lesion formation. Nitro L-arginine methyl ester inhibited lesion development; inhibition was reversed by concomitantly administered L-arginine. Indomethacin, diclofenac, and SC-560 (a selective COX-1 inhibitor), but not rofecoxib (a selective COX-2 inhibitor), significantly inhibited lesion formation. In addition, sodium bicarbonate, pirenzepine, S-0509 (a gastrin/CCK(2) inhibitor), omeprazole, sucralfate, and a prostaglandin analog also significantly inhibited lesion formation. It was concluded that the mechanism by which histamine induces gastric lesions in rats with partial gastric vascular occlusion appears to involve extensive vasodilation resulting from histamine acting on microvasculature histamine H(1)- and H(2)-receptors, generation of endogenous nitric oxide and prostaglandins, with the presence of gastric acid.

01 Jan 2003·DrugsQ1 · MEDICINE

New Molecular Targets for Treatment of Peptic Ulcer Disease

Q1 · MEDICINE

Review

Author: Frank S. Lehmann ; Pius Hildebrand ; Christoph Beglinger

Most patients with peptic ulcer disease are currently treated with proton pump inhibitors or histamine H(2) receptor antagonists. The long-term use of these compounds has been associated with two potential problems. Firstly, proton pump inhibitors may induce enterochromaffin-like (ECL) cell hyperplasia. Secondly, ulcers may relapse despite maintenance therapy with histamine H(2) antagonists. This has been the rationale for the development of new antisecretory agents, including antagonists against gastrin and gastrin releasing peptide (GRP), as well as ligands to histamine H(3) receptors. Several potent, high affinity cholecystokinin (CCK)-2 receptor antagonists have recently been identified such as L-365260, YM-022, RP-73870, S-0509, spiroglumide and itriglumide (CR-2945). Current data suggest that they all have antisecretory and anti-ulcer effects. In addition to reducing acid production, CCK-2 receptor antagonists may possibly also accelerate gastric emptying, a combination of functions which could potentially be beneficial in patients with functional dyspepsia. Receptors for bombesin and its mammalian counterpart GRP have been localised in the brain, spinal cord and enteric nerve fibres of the gut as well as on secretory cells and smooth muscle cells of the intestinal tract. Current data clearly indicate that endogenous GRP is involved in the regulation of basal and postprandial acid secretion. However, at this stage it is not clear whether GRP agonists or GRP antagonists can be developed into useful drugs. The peptide has a wide range of biological effects and it is likely that analogues of GRP or antagonists of the peptide affect not only gastric acid secretion but also induce considerable side effects. Histamine plays a central role in the stimulation of acid secretion. After their detection in the brain, H(3) receptors have been identified in a variety of tissues including perivascular nerve terminals, enteric ganglia of the ileum and lung, and ECL cells. Despite many studies, the role of H(3) receptors in the regulation of gastric acid secretion is still unclear. Controversial data have been presented, and study results largely depend on the species and experimental models. It seems unlikely that proton pump inhibitors or H(2) receptor antagonists will be replaced in the near future by new antisecretory agents. The current shortcomings of the new compounds include mainly their reduced clinical effectiveness and pharmacological limitations. However, the development of these new antisecretory compounds provides interesting tools to assess the physiological and pharmacological role of different receptors within the gastrointestinal tract. The use of CCK-2 receptor antagonists in patients with functional dyspepsia and Zollinger-Ellison syndrome should be examined in randomised, controlled trials.

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Indication	Highest Phase	Country/Location	Organization	Date
Peptic Ulcer	Phase 1	JP	Shionogi & Co., Ltd.	-

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