Fumihiro Hirayama

Induction of gastric ulcer and intestinal metaplasia in Mongolian gerbils infected with Helicobacter pylori

Although the clinical data strongly suggest that Helicobacter pylori is associated with gastroduodenal diseases in humans, 1-3 there is no direct proof that these diseases are actually caused by H. pylori itself. Many animal models infected with H. pylori have already been studied to determine its pathogenesis, 4-1~ but none of these models mimics human H. pylori infection and subsequent pathology. We describe the first precise evidence of H. pylori infection in laboratory animals that mimics human H. pylori infection.

Development of poorly differentiated adenocarcinoma and carcinoid due to long-term Helicobacter pylori colonization in Mongolian gerbils

Abstract: A Mongolian gerbil model was used to clarify whether long-term colonization by Helicobacter pylori is an important risk factor for the development of gastric cancer. Fifty-nine gerbils (3 controls and 56 gerbils inoculated with H. pylori) were killed at various times (average, 23 months) more than 12 months after H. pylori inoculation. In the H. pylori-inoculated group, poorly differentiated adenocarcinoma was observed in the pylorus of 1 gerbil, and carcinoid was observed in the fundus of the stomach in 18 gerbils. No lesions were found in the stomachs of the 3 control gerbils. The results imply that long-term colonization by H. pylori is an important risk factor for the development of gastric adenocarcinoma and carcinoid.

EVALUATION OF COMBINED ANTIBIOTIC-OMEPRAZOLE THERAPIES IN HELICOBACTER PYLORI-INFECTED MONGOLIAN GERBILS

Abstract: Mongolian gerbils are a laboratory host for gastric colonization with Helicobacter pylori, showing gastritis followed by typical gastric ulcer after infection with H. pylori. In such gerbils, we evaluated combined therapies of amoxicillin (AMPC) and clarithromycin (CAM) as antibiotics, and omeprazole (OPZ) as a H+/K+ adenosine triphosphatase (ATPase) inhibitor. The gerbils were orally inoculated with 2 × 108 bacilli of H. pylori ATCC 43504. Four weeks after inoculation, the infected gerbils were orally treated singly with OPZ, AMPC, and CAM, and their insufficient efficacy on bacterial clearance was confirmed by a polymerase chain reaction technique, and by a culture method. In contrast, combined therapy of OPZ plus either AMPC or CAM showed significant bacterial clearance, demonstrating the efficacy of this combined therapy in the gerbil model. Mongolian gerbils are suggested to be useful for the pharmacological evaluation of anti-H. pylori compounds.

Synthesis and structure-activity relationships of 7-(2-aminoalkyl)morpholinoquinolones as anti-Helicobacter pylori agents.

A series of the titled compounds was synthesized and tested for anti-Helicobacter pylori activities. We discovered Y-34867 having the most potent activity against Helicobacter pylori among the quinolones tested along with high photostability. Furthermore, Y-34867 showed an excellent therapeutic effect in the experimental Helicobacter pylori infected Mongolian gerbil model.

Synthesis and structural optimization of 7-(3,3-disubstituted-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acids as antibacterial agents

Abstract A series of the titled compounds were synthesized and tested for antibacterial activities in comparison with typical fluoroquinolones. ( S )-3-Aminomethyl-3-fluoromethyl derivative (Y-688) was confirmed to be optimal because of being most active especially against Gram-positive bacteria including fluoroquinolone-resistant strains and showing high photostability.

Long-term effects of Helicobacter pylori eradication in Mongolian gerbils

Background: In this study, to clarify whether Helicobacter pylori eradication alters the course of the development of gastric mucosal changes in the stomach, we examined the long-term effects of H. pylori eradication on H. pylori-inoculated gerbils. Methods: A total of 40 H. pylori-inoculated gerbils were randomized and subjected, at 22 months after inoculation, to eradication treatment with dual therapy of omeprazole plus clarithromycin, or with therapy with a novel quinolone compound, Y-34867, alone. The animals were killed at the start of administration (control group) or at 8 months after the completion of therapy (vehicle or eradication-treatment groups). Results: Severe histopathological changes in the gastric mucosa were observed in all H. pylori-inoculated gerbils at the start of administration. At 8 months after completion of therapy, the frequency of gastritis, erosion, intestinal metaplasia, and gastric carcinoid in the eradication therapy groups was markedly reduced compared with that in the control and vehicle groups. Values for anti-H. pylori IgG titer, bacterial counts, and gastrin also decreased significantly. Conclusions: These results suggest that H. pylori eradication may have had a therapeutic effect not only on gastritis, erosion, and gastric ulcer but also on glandular atrophy, intestinal metaplasia, and gastric carcinoid.