Discovery of DS34942424: An orally potent analgesic without mu opioid receptor agonist activity.

We identified (5'S)-10'-fluoro-6'-methyl-5',6'-dihydro-3'H-spiro[cyclopropane-1,4'-[2,6]diaza[2,5]methano[2,6]benzodiazonin]-7'(1'H)-one, 22b (DS34942424) with a unique and original bicyclic skeleton. 22b showed an orally potent analgesic in the acetic acid-induced writhing test and formalin test in ddY mice without sedation. Moreover, 22b did not exhibit mu opioid receptor agonist activity.

Discovery of conolidine derivative DS39201083 as a potent novel analgesic without mu opioid agonist activity.

We discovered a novel compound, 5-methyl-1,4,5,7-tetrahydro-2,5-ethanoazocino[4,3-b]indol-6(3H)-one sulfuric acid salt (DS39201083), which was formed by derivatization of a natural product, conolidine. DS39201083 had a unique bicyclic skeleton and was a more potent analgesic than conolidine, as revealed in the acetic acid-induced writhing test and formalin test in ddY mice. The compound showed no agonist activity at the mu opioid receptor.

Discovery of a novel bicyclic compound, DS54360155, as an orally potent analgesic without mu-opioid receptor agonist activity.

We synthesized derivatives of a natural alkaloid, conolidine, and evaluated these derivatives in the acetic acid-induced writhing test and formalin test in ddY mice after oral administration. As a result, we identified (5S)-6-methyl-1,3,4,5,6,8-hexahydro-7H-2,5-methano[1,5]diazonino[7,8-b]indol-7-one sulfate salt, 15a (DS54360155), with a unique and original bicyclic skeleton, as an analgesic more potent than conolidine. Moreover, 15a did not exhibit mu-opioid receptor agonist activity.

Endoscopic and Immunohistochemical Characteristics of Gastric Cancer with versus without Helicobacter Pylori Eradication.

BACKGROUND/AIMS: The rate of gastric cancer (GC) after Helicobacter pylori eradication has gradually increased; therefore, we investigate the clinicopathological features of GC following eradication in comparison with those of GC with H. pylori infection. METHODS: This study included 50 subjects with GC after eradication (GCE) and 151 patients with GC with H. pylori infection (GCI). Clinicopathological factors were assessed. The manifestation of GC was further evaluated using immunohistochemical analysis and in situ hybridization. RESULTS: Macroscopic analysis revealed a significantly higher ratio of depressed type /elevated type in the GCE compared with the GCI (30/19 vs. 61/77, p = 0.041). The gastric phenotype was more common in the GCE compared with the GCI, and the proportion of CDX2-positive cases was lower in the GCE (8 out of 18; 44.4%) compared with the GCI (18 out of 19; 94.7%; p = 0.00082). Ki-67 labeling index was significantly lower in the GCE (32.03 ± 22.15) compared with the GCI (79.20 ± 14.87, p < 0.0001). No patient in the GCE showed evidence of Epstein-Barr virus infection. CONCLUSION: The clinicopathological characteristics of GC following H. pylori eradication differ from those of GC in patients with H. pylori infection in terms of morphology, mucin phenotype, and proliferation rate.

Synthesis and biological evaluation of novel chiral diazepine derivatives as bombesin receptor subtype-3 (BRS-3) agonists incorporating an antedrug approach.

Novel compounds based on the lead BRS-3 agonists from our HTS compounds 2a and 2b have been synthesized with the focus on obtaining peripheral BRS-3 agonists. To identify potent anti-obesity compounds without adverse effects on the central nerve system, a labile carboxylic ester with an antedrug functionality was introduced onto the terminal position. Through the extensive synthetic exploration and the pharmacokinetic studies of oral administration in mice, the phenol ester 17c was selected due to the most suitable pharmacological profile. In the evaluation of food intake suppression in B6 mice, 17c showed significant in vivo efficacy and no clear adverse effect on heart rate and blood pressure change in dog iv infusion. Our study paved the way for development of anti-diabetes and obesity drugs with a safer profile.

Discovery of novel chiral diazepines as bombesin receptor subtype-3 (BRS-3) agonists with low brain penetration.

The discovery and optimization of a novel series of BRS-3 agonists are described. We explored a potent BRS-3 agonist with low brain penetration to avoid an adverse effect derived from central nervous system exposure. Through the derivatization process, chiral diazepines 9f and 9g were identified as possessing low brain penetration as well as potent in vitro activity against human and mouse BRS-3s.

Histological characteristics of gastric mucosa prior to Helicobacter pylori eradication may predict gastric cancer.

OBJECTIVE: Although Helicobacter pylori (H. pylori) eradication has been shown to inhibit gastric cancer, it does not completely suppress it. Therefore, risk factors of gastric cancer development following H. pylori eradication were examined. MATERIAL AND METHODS: A total of 2355 patients (1501 males and 824 females) underwent successful eradication of H. pylori. Endoscopic atrophy, histological gastritis, atrophy, intestinal metaplasia (IM), and operative link for gastritis assessment (OLGA) staging were subsequently evaluated. RESULTS: Following eradication, 33/2355 patients (25 males and 8 females) developed gastric cancer. Compared to a nongastric cancer group that was matched according to gender and age, the incidence of endoscopic atrophy (3.52 ± 1.45 vs. 4.85 ± 1.18, p < 0.001), histological atrophy at the greater curvature of the antrum (1.42 ± 0.80 vs. 1.95 ± 0.86, p = 0.0059), inflammation (2.05 ± 0.59 vs. 2.33 ± 0.66, p = 0.031), IM at the greater curvature of the corpus (0.06 ± 0.30 vs. 0.24 ± 0.54, p = 0.029), the ratio of OLGA-stage 0-II/III, IV (13/8 vs. 55/11, p = 0.038) were significantly higher for the gastric cancer group. Multivariate analysis also showed the highest odds ratio (6.26, 95% confidence interval or CI, 1.28-30.60, p = 0.023) for IM at the greater curvature of the corpus. CONCLUSIONS: Severe endoscopical atrophy, OLGA staging, histological atrophy at the antrum, inflammation, and particularly IM at the corpus, were identified as risk factors for gastric cancer development following H. pylori eradication. Therefore, eradication should be performed before these predictors develop.

Substituents at the naphthalene C3 position of (-)-Cercosporamide derivatives significantly affect the maximal efficacy as PPARγ partial agonists.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a potential drug target for treating type 2 diabetes. The selective PPARγ modulators (SPPARMs), which partially activate the PPARγ transcriptional activity, are considered to improve the plasma glucose level with attenuated PPARγ related adverse effects. However, the relationships between desired pharmacological profiles and ligand specific PPARγ transcriptional profiles have been unclear. And there is also little knowledge of how to control ligand specific PPARγ transcriptional profiles. Herein, we present synthesis of novel derivatives containing substituent at naphthalene C3 position of compound 1. The novel derivatives showed various maximal efficacies as PPARγ partial agonist.

Comparison of the efficacy of irsogladine maleate and famotidine for the healing of gastric ulcers after Helicobacter pylori eradication therapy: a randomized, controlled, prospective study.

OBJECTIVE: Helicobacter pylori eradication therapy alone cannot heal gastric ulcers in Japanese patients. Irsogladine has previously been shown to accelerate the healing of gastric ulcers after H. pylori eradication therapy. And we previously reported that histamine H(2) receptor antagonists inhibit gastric ulcer relapse after H. pylori eradication therapy. We therefore compared the efficacy of irsogladine with famotidine as appropriate treatments for ulcers after eradication therapy. METHODS: Gastric ulcer patients with H. pylori infection (n = 119) were randomized to treatment with irsogladine 4 mg/day (n = 60) or famotidine 40 mg/day (n = 59) following 1-week H. pylori eradication therapy. After treatment, assessments of gastric ulcer healing were performed. RESULTS: The ulcer healing rates in patients receiving irsogladine and famotidine were 85.2% (46/54) and 79.6% (43/54), respectively, and were not significantly different (p = 0.4484). In the famotidine group, the healing rate was significantly lower in patients who drink alcohol than in those who do not (60.0% vs. 91.2%; p = 0.0119). However, in the irsogladine group the healing rate did not differ between patients who drink alcohol and those who do not. Furthermore, the healing rate in smokers was significantly higher in the irsogladine group (88.0%) than in the famotidine group (59.1%) (p = 0.0233). CONCLUSIONS: Irsogladine and famotidine are both acceptable in treatment after H. pylori eradication therapy in gastric ulcer patients. Findings also suggest that irsogladine is more beneficial than famotidine in patients who drink alcohol and smoke.

Discovery of a novel selective PPARgamma modulator from (-)-Cercosporamide derivatives.

In an investigation of (-)-Cercosporamide derivatives with a plasma glucose-lowering effect, we found that N-benzylcarboxamide derivative 4 was a partial agonist of PPARgamma. A SAR study of the substituents on carboxamide nitrogen afforded the N-(1-naphthyl)methylcarboxamide derivative 23 as the most potent selective PPARgamma modulator. An X-ray crystallography study revealed that compound 23 bounded to the PPARgamma ligand binding domain in a unique way without any interaction with helix12. Compound 23 displayed a potent plasma glucose-lowering effect in db/db mice without the undesirable increase in body fluid and heart weight that is typically observed when PPARgamma full agonists are administrated.

(-)-Cercosporamide derivatives as novel antihyperglycemic agents.

In our exploratory campaign for an antihyperglycemic agent with a novel mechanism of action, (-)-Cercosporamide 1, which is known as an antifungal agent, showed a potent plasma glucose lowering effect in hyperglycemic KK/Ta mice. The trouble was that it was accompanied by a decrease in food intake and a loss of body weight. We synthesized some (-)-Cercosporamide derivatives and succeeded to separate these actions. N,O-ketal type derivatives, especially compound 10, had the most potent plasma glucose lowering effect without affecting the food consumption or body weight.

Gastrointestinal stromal tumor of the lesser omentum: a case report and review of the literature.

A 72-year-old woman visited our hospital for a routine health examination and underwent abdominal ultrasonography, which revealed an intra-abdominal tumor. Abdominal computed tomography and magnetic resonance imaging showed a well-defined solid mass of ~3 cm in diameter lying adjacent to the stomach. The mass was preoperatively diagnosed as gastrointestinal stromal tumor of the stomach. At laparotomy, a well-encapsulated tumor was found in the lesser omentum. It was slightly adherent to the stomach wall but was removed without difficulty. Therefore, only enucleation of the tumor was performed. The excised tumor, which was 35 × 30 × 25 mm3 in size, had a white cut surface without necrosis or hemorrhage. According to the pathological findings, the tumor was classified as a very low-risk gastrointestinal stromal tumor originating in the lesser omentum. Gastrointestinal stromal tumor of the lesser omentum is very rare, and surgical resection is the only effective treatment modality.

Computed tomography of the gastrointestinal manifestation of hereditary angioedema.

We report a case of gastrointestinal manifestation of hereditary angioedema. Computed tomography (CT) revealed wall thickening of the gastric antrum, duodenum, and jejunum. Dilatation of the third part of the duodenum, thickening of the small bowel mesentery and omentum, and retroperitoneal edema were present. The importance of considering this condition in patients presenting such CT findings correlated with the appropriate history is discussed.

Long-term outcome of laparoscopic wedge resection for gastric submucosal tumor compared with open wedge resection.

Little is known about the outcomes of laparoscopic wedge resection (LWR) in comparison with conventional open wedge resection (OWR) for gastric submucosal tumor. Outcomes of 21 patients who underwent LWR (n = 14) or OWR (n = 7) for gastric submucosal tumor between 1993 and 2004 were investigated. We compared the short-term and long-term operative results between the 2 groups. LWR showed several advantages over OWR for gastric submucosal tumor: less blood loss, lower fever on day 1, lower analgesic usage rate, earlier first postoperative flatus and oral intake, lower leukocyte count on days 1 and 7, and lower C-reactive protein level on days 1 and 3. All patients, except 2 with histologically diagnosed high-risk gastrointestinal stromal tumor, survived during the mean follow-up period of 60 months. LWR is feasible for the management of patients with gastric submucosal tumor.

Influence of bile reflux and Helicobacter pylori infection on gastritis in the remnant gastric mucosa after distal gastrectomy.

BACKGROUND: Two main pathogenic factors, bile reflux and Helicobacter pylori infection, have been identified in the remnant stomach, but it is still unclear which factor is important in the pathogenesis of gastritis in the remnant stomach after distal gastrectomy. METHODS: In 184 patients who had had distal gastrectomy performed using the Billroth-I procedure (B-I; n-106), Billroth-II procedure (B-II; n-36), and jejunal interposition (J-I; n-42) we examined the severity of remnant gastritis endoscopically and carried out examinations for H. pylori infection and histological examination. RESULTS: The endoscopic severity of remnant gastritis was grade 1 or more in 101 of the 106 B-I patients (95.3%) and in all 36 B-II patients (100%). But, of the 42 J-I patients, the grade was 0 in 33 (78.6%). The endoscopic severity of remnant gastritis was significantly milder for J-I than for B-I (P < 0.001) and B-II (P < 0.001). H. pylori infection was confirmed in 59 of the 106 B-I patients (55.6%), 21 of the 36 B-II patients (58.3%), and 32 of the 42 J-I patients (76.1%). The rate of H. pylori infection was higher for J-I patients than for B-I (P < 0.05), but not for B-II patients (P = 0.1495). The severity of chronic and active inflammatory cellular infiltration tended to be inverse proportional relation with the endoscopic severity of the remnant gastritis. Furthermore, the histological inflammation and activity scores of H. pylori-positive patients were higher than those of H. pylori-negative patients, without regard to the endoscopic grade of gastritis. CONCLUSIONS: Reconstruction techniques play an important role in the prevention of bile reflux, and we found that endoscopically more severe remnant gastritis was associated with a lower rate of H. pylori infection and with a lower degree of inflammatory cellular infiltration.

Regression of liver fibrosis in cases of chronic liver disease type C: quantitative evaluation by using computed image analysis.

OBJECT: It was reported that the liver fibrosis is reduced in patients with chronic liver disease type C after eradication of HCV. Degree of fibrosis was expressed by the classical fibrosis scoring system (F0-F4) at present. However a change of subtle reduction of fibrosis cannot be expressed in its fibrosis score and thus we measured an area of fibrosis and compared detailed change of the fibrosis area in paired liver biopsy. METHODS: For quantitative assessment of liver fibrosis, we measured an area of fibrosis using computed digital image analysis and pursued the rate of a fibrosis area for whole biopsied liver tissue of 25 patients with HCV infection (20 complete response patients to IFN therapy who showed viral eradication: CR and 5 non-treated ones with IFN but had conservative therapy: CT). RESULTS: In CR group, fibrosis rate was 7.2 +/- 1.5% before therapy, 2.7 +/- 0.5% after the therapy and they were significantly regressed. In CT group, fibrosis rate was 8.4 +/- 4.3% at the first biopsy, 15.9 +/- 7.7% at the second biopsy. CONCLUSIONS: Regression of liver fibrosis could be confirmed in patients with virologic response to IFN even in patients with liver cirrhosis. Our quantitative evaluation provided information superior to that obtained by the classical fibrosis staging score system.

Indications for pylorus-preserving gastrectomy for gastric cancer based on lymph node metastasis.

BACKGROUND/AIMS: It is necessary to study the relation between lymph node metastasis in the suprapyloric or lesser curvature regions and clinicopathologic findings in order to determine the indications for pylorus-preserving gastrectomy. METHODOLOGY: We reviewed all pertinent data from the cases of 109 patients with gastric cancer located mainly in the middle third of the stomach focusing particularly on status of lymph node metastasis and clinicopathologic findings. All patients had been treated by conventional gastrectomy with regional lymph node dissection (D2 or D3). RESULTS: Lymph node metastases were found in the lesser curvature or suprapyloric regions in 18 patients. Primary tumors were located in the lesser curvature side in 15 of these 18 patients and in the greater curvature side in only 3. Primary tumors in the greater curvature side with involvement in the lesser curvature or suprapyloric lymph nodes were greater than 4.0 cm in diameter, whereas primary tumors in the lesser curvature side with such metastasis were greater than 1.3 cm. CONCLUSIONS: Indications for pylorus-preserving gastrectomy with preserving of the pyloric branch of the vagal nerve perhaps can be expanded to middle stomach cancer located in the greater curvature side that is less than 4.0 cm in diameter.

Interferon therapy for hepatitis C virus (HCV)-related advanced chronic hepatitis after treatment of recurrent hepatocellular carcinoma: a successful case.

A complete response was obtained by interferon (IFN) therapy for hepatitis C virus (HCV)-related advanced chronic hepatitis after curative treatment of initial and recurrent hepatocellular carcinoma (HCC). The patient is alive 73 months after diagnosis of initial HCC and is in a tumor-free state 53 months after diagnosis of the last HCC. This case suggest that it is possible to suppress recurrence and to prolong the life of patients with HCV-related advanced chronic hepatitis, if a complete response is obtained by means of IFN therapy after the curative treatment of the recurrent HCC.

Feasibility and functional efficacy of distal gastrectomy with jejunal interposition for gastric cancer: a case series.

INTRODUCTION: Distal gastrectomy with jejunal interposition (DGJI) has been used in our institution for selected patients with gastric cancer as a function-preserving gastrectomy. The aim of this retrospective study was to clarify the feasibility and functional efficacy of DGJI. METHODS: A retrospective analysis was performed in 61 patients who underwent DGJI between 2002 and 2011. RESULTS: Mean operation time was 393.8 min and blood loss was 463.3 ml. Postoperative early major complications developed in 2 (3.3%) patients. The most common complication was gastric stasis, occurring in 7 (11.5%) patients. All patients with complications recovered with conservative treatment, and no operative mortality occurred. Endoscopy 1 year after operation revealed reflux gastritis in 1 patient. Reflux esophagitis was not found in any patient. However, anastomotic ulcer was found in 12 (22.2%) patients over the 1-year period after operation. No patient reported symptoms of early and late dumping syndrome, and 1 (1.9%) patient self-reported diarrhea. CONCLUSIONS: DGJI was a feasible and safe procedure with several advantages in terms of less incidence of reflux gastritis and esophagitis, dumping syndrome and diarrhea. However, this procedure is complicated and time-consuming, and it is necessary to be aware of the potential occurrence of an anastomotic ulcer at the site of the gastrojejunostomy after DGJI.

Five-year survival after surgery for invasive micropapillary carcinoma of the stomach.

Invasive micropapillary carcinoma (IMPC) of the breast, urinary bladder, ovary, and colon has been reported. However, few reports have described IMPC of the stomach. In addition, IMPC has been described as a histological indicator for lymphatic invasion and nodal metastasis, resulting in poor prognosis. We report a case of 5-year survival after surgery for IPMC of the stomach. A 69-year-old woman was admitted to our hospital with symptoms of upper abdominal pain. Upper gastrointestinal endoscopy revealed a tumor at the antrum of the stomach. Histological examination of the biopsy specimen indicated poorly differentiated adenocarcinoma. The patient underwent distal gastrectomy with lymph node dissection. Microscopic examination of the specimen revealed that the tumor consisted of an invasive micropapillary component. Carcinoma cell clusters were floating in the clear spaces. The patient recovered uneventfully and remains alive without recurrence 5 years after surgery.