UNGAP best practice for improving solubility data quality of orally administered drugs.

An important goal of the European Cooperation in Science and Technology (COST) Action UNGAP (UNderstanding Gastrointestinal Absorption-related Processes, www.ungap.eu) is to improve standardization of methods relating to the study of oral drug absorption. Solubility is a general term that refers to the maximum achievable concentration of a compound dissolved in a liquid medium. For orally administered drugs, relevant information on drug properties is crucial during drug (product) development and at the regulatory level. Collection of reliable and reproducible solubility data requires careful application and understanding of the limitations of the selected experimental method. In addition, the purity of a compound and its solid state form, as well as experimental parameters such as temperature of experimentation, media related factors, and sample handling procedures can affect data quality. In this paper, an international consensus developed by the COST UNGAP network on recommendations for collecting high quality solubility data for the development of orally administered drugs is proposed.

Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report.

Important progress has been made in the management of Helicobacter pylori infection and in this fifth edition of the Maastricht Consensus Report, key aspects related to the clinical role of H. pylori were re-evaluated in 2015. In the Maastricht V/Florence Consensus Conference, 43 experts from 24 countries examined new data related to H. pylori in five subdivided workshops: (1) Indications/Associations, (2) Diagnosis, (3) Treatment, (4) Prevention/Public Health, (5) H. pylori and the Gastric Microbiota. The results of the individual workshops were presented to a final consensus voting that included all participants. Recommendations are provided on the basis of the best available evidence and relevance to the management of H. pylori infection in the various clinical scenarios.

The stomach in health and disease.

The stomach is traditionally regarded as a hollow muscular sac that initiates the second phase of digestion. Yet this simple view ignores the fact that it is the most sophisticated endocrine organ with unique physiology, biochemistry, immunology and microbiology. All ingested materials, including our nutrition, have to negotiate this organ first, and as such, the stomach is arguably the most important segment within the GI tract. The unique biological function of gastric acid secretion not only initiates the digestive process but also acts as a first line of defence against food-borne microbes. Normal gastric physiology and morphology may be disrupted by Helicobacter pylori infection, the most common chronic bacterial infection in the world and the aetiological agent for most peptic ulcers and gastric cancer. In this state-of-the-art review, the most relevant new aspects of the stomach in health and disease are addressed. Topics include gastric physiology and the role of gastric dysmotility in dyspepsia and gastroparesis; the stomach in appetite control and obesity; there is an update on the immunology of the stomach and the emerging field of the gastric microbiome. H. pylori-induced gastritis and its associated diseases including peptic ulcers and gastric cancer are addressed together with advances in diagnosis. The conclusions provide a future approach to gastric diseases underpinned by the concept that a healthy stomach is the gateway to a healthy and balanced host. This philosophy should reinforce any public health efforts designed to eradicate major gastric diseases, including stomach cancer.

Randomised clinical trial: esomeprazole for the prevention of nonsteroidal anti-inflammatory drug-related peptic ulcers in Japanese patients.

BACKGROUND: The use of proton pump inhibitors for prevention of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal adverse events is well documented. However, data regarding the efficacy and safety of this approach in Japan are scarce. AIM: To evaluate the efficacy and tolerability of esomeprazole in preventing NSAID-induced peptic ulcers in Japanese at-risk patients. METHODS: Male and female Japanese adult patients (aged ≥ 20 years) with endoscopically confirmed history of peptic ulcers who required long-term oral NSAID therapy for a chronic inflammatory condition were randomised to 24 weeks' treatment with esomeprazole 20 mg once daily or matching placebo. The primary end point was the Kaplan-Meier estimated proportion of ulcer-free patients. RESULTS: Overall, 343 patients were randomised to treatment (esomeprazole, n = 175; placebo, n = 168). The Kaplan-Meier estimated ulcer-free rate over the 24-week treatment period was significantly higher (log-rank P < 0.001) in esomeprazole-treated patients (96.0%; 95% CI 92.8, 99.1) than in placebo recipients (64.4%; 95% CI 56.8, 71.9). Esomeprazole was effective at preventing peptic ulcers in both Helicobacter pylori-positive and -negative patients (96.3% vs. 95.5% of patients ulcer-free, respectively); however, in the placebo group, the proportion of ulcer-free patients at 24 weeks was markedly lower among H. pylori-positive than -negative patients (59.7% vs. 69.9%). The NSAID type did not seem to affect the estimated ulcer-free rate with esomeprazole. Treatment with esomeprazole was well tolerated. CONCLUSION: Esomeprazole 20 mg once daily is effective and safe in preventing ulcer recurrence in Japanese patients with a definite history of peptic ulcers who were taking an NSAID (ClinicalTrials.gov identifier: NCT00542789).

Molecular epidemiological and mutational analysis of DNA mismatch repair (MMR) genes in endometrial cancer patients with HNPCC-associated familial predisposition to cancer.

Recently, a high rate of endometrial cancer has been reported in women with hereditary non-polyposis colorectal cancer (HNPCC), suggesting a relationship between familial endometrial cancers and HNPCC. Familial endometrial cancers constitute only about 0.5% of all endometrial carcinomas and it is essential to examine family histories in detail. A mutational analysis of three DNA mismatch repair (MMR) genes (hMLH1, hMSH2 and hMSH6) in patients with endometrial cancer who meet our criteria for familial predisposition to HNPCC-associated endometrial cancers was performed. Mutations were detected in 18 of the 120 patients (15.0%). Most HNPCC-related endometrial cancers do not meet the New Amsterdam Criteria for HNPCC. These clinical criteria may identify only some HNPCC-associated endometrial cancers. Establishing the correct family history for endometrial cancer patients is important for diagnosing familial endometrial carcinomas. An analysis of MMR genes may be useful for patients with endometrial cancer showing familial aggregation. In addition, gynecologists must be accurately informed, and it is important to perform large-scale, multicenter studies both nationwide and internationally.

Muir-Torre syndrome caused by partial duplication of MSH2 gene by Alu-mediated nonhomologous recombination.

We describe a 54-year-old man with a pedicled tumour on the neck. The surgical specimen revealed a sebaceous carcinoma. He belonged to a cancer-prone family susceptible to gastrointestinal cancer. Systemic evaluation for latent malignancies revealed early-stage colonic adenocarcinoma. These findings were compatible with Muir-Torre syndrome (MTS). Microsatellite instability was detected in the sebaceous carcinoma, suggesting a DNA mismatch repair gene mutation. Moreover, duplication of exon 7 generated a nonsense codon at codon 427 of the MSH2 gene causing truncation of MSH2 protein. Immunohistochemical analysis showed diminished MSH2 protein levels in the sebaceous carcinoma and colonic adenocarcinoma. To date, there have been no reports showing duplication of exon 7 of the MSH2 gene in MTS or hereditary nonpolyposis colorectal cancer kindreds. Furthermore, the present case indicates that the dermatologist plays an important role in the diagnosis of MTS and evaluation for latent malignancies.

Double balloon endoscopy in two hundred fifty cases for the diagnosis and treatment of small intestinal disorders.

Double balloon endoscopy is based on a new insertion mode in which two balloons at the distal ends of both an endoscope and an overtube are operated in combination. We have performed 419 enteroscopic examinations in 250 patients using the Fujinon double balloon endoscopy system between September 2000 and October 2005. Total enteroscopy was successfully achieved by the combination of both oral and anal approaches in 55 out of 71 cases in whom total enteroscopy was intended. Of 250 patients, ulcerative and/or erosive lesions were found in 49 cases and tumors/polyps were found in 49 cases. We also found 26 cases of vascular lesion, including angiodysplasia. Endoscopic treatments, including hemostasis using either clipping devices or electro coagulation, polypectomy, endoscopic mucosal resection, balloon dilation, and stent placement was successfully carried out. Double balloon enteroscopy is both feasible and useful technique for the diagnosis as well as treatment of small intestinal disorders.

Endoscopic submucosal dissection using sodium hyaluronate, a new technique for en bloc resection of a large superficial tumor in the colon.

En bloc resection of superficial tumors in the colon is challenging but beneficial for the precise diagnosis and treatment. We have been using a novel technique of endoscopic submucosal dissection with a viscous substance, sodium hyaluronate, and a needle knife in combination with a small-caliber-tip transparent hood and succeeded in the endoscopic en bloc resection of large superficial tumors in the colon. We endoscopically treated superficial tumors larger than 20mm in diameter of the colon in 166 patients between June 1998 and March 2005. All the lesions were successfully resected endoscopically and en bloc resection was achieved in 77% of them. Even large superficial tumors in the colon can be resected in one piece by using this technique.

Helicobacter pylori eradication induces marked increase in H+/K+-adenosine triphosphatase expression without altering parietal cell number in human gastric mucosa.

BACKGROUND AND AIMS: Gastric acid secretion is downregulated by Helicobacter pylori infection and upregulated after its eradication, but the mechanisms are still unclear. We examined the effects of H pylori eradication on the number of parietal cells and on expression of molecules functioning in acid secretion in the human gastric mucosa. METHODS: We enrolled 111 consecutive men with chronic gastritis induced by H pylori. Biopsy specimens were endoscopically obtained before and 12 weeks after successful eradication of H pylori and parietal cell numbers were counted. mRNA expression levels of H+/K+-adenosine triphosphatase (H+/K+-ATPase), anion exchanger 2, M3 muscarinic receptor, intrinsic factor, and interleukin 1beta were determined with a real time reverse transcriptase-polymerase chain reaction method. The severity of gastric atrophy was evaluated using the serum pepsinogen I/II ratio. RESULTS: No significant difference was observed in parietal cell numbers before and after H pylori eradication. Median mRNA expression levels of H+/K+-ATPase in the gastric mucosa increased 250-fold after H pylori eradication accompanied by attenuation of interleukin 1beta. A large increase in H+/K+-ATPase expression was observed even in patients with severe atrophic gastritis. In contrast, fold increases in mRNA expression levels, including intrinsic factor, anion exchanger 2, and M3 muscarinic receptor, after eradication therapy, were limited to 1.4, 2.3, and 2.5 times, respectively. CONCLUSIONS: In the absence of alteration of parietal cell number, gastric H+/K+-ATPase mRNA expression was markedly restored after successful H pylori eradication, suggesting a central role for the restoration of H+/K+-ATPase expression in gastric acid secretion recovery after H pylori eradication.

Contamination with hepatitis B virus DNA in gastrointestinal endoscope channels: risk of infection on reuse after on-site cleaning.

BACKGROUND AND STUDY AIMS: The incidence of viral contamination in the air, water and suction/accessory channels of gastrointestinal endoscopes was examined in order to evaluate the risk of infection. MATERIALS AND METHODS: After endoscopic examinations, including biopsy procedures, in 17 patients who were positive for hepatitis B virus surface antigen and eight patients who were positive for hepatitis C virus antibody, the endoscopes were cleaned on site by suctioning and flushing the air and water channels with an enzyme detergent. First samples were then collected by flushing 5 ml of sterile water through each channel. After mechanical reprocessing, second samples were collected in the same way. Virological studies were carried out with real-time polymerase chain reactions for hepatitis B virus DNA and hepatitis C virus RNA. RESULTS: Hepatitis B virus DNA was detected in five of the first samples recovered from the suction/accessory channels of the endoscopes (titers of 1.3 x 10 (4) to 2.5 x 10 (5) copies/ml), while no contamination was detected after reprocessing ( P = 0.0445). The first samples from one water channel and three air channels were also positive for hepatitis B virus DNA, but were negative after reprocessing ( P > 0.5, P = 0.227, respectively). No hepatitis C virus RNA was detected in any of the samples. CONCLUSIONS: These results indicate that all of the channels were potential sources of viral infection.

Histamine-2 receptor expression in gastric mucosa before and after Helicobacter pylori cure.

BACKGROUND: Helicobacter pylori infection prevents the occurrence of the tolerance phenomenon of Histamine-2 (H2) receptor antagonists. Gastro-esophageal reflux disease develops in some cases with the restoration of acid secretion after H. pylori eradication therapy. AIM: To clarify the mechanisms of H2 receptor restoration after the eradication of H. pylori on parietal cells. METHODS: We enrolled 80 consecutive asymptomatic male patients with H. pylori infection, having chronic gastritis with or without the presence of peptic ulcers. Biopsy specimens from the greater curvatures at the mid-corpus of the stomach were obtained endoscopically from all subjects before and 12 weeks after the eradication of H. pylori. Degrees of gastric atrophy were evaluated by serum pepsinogen levels. The amounts of mRNA expression of H2 receptor were evaluated in each subject's gastric mucosa by real time reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: H2 receptor mRNA expression levels significantly correlated with serum pepsinogens I and II ratios. The expression level of H2 receptor mRNA was lower in subjects with hypergastrinemia. The median expression level of H2 receptor after H. pylori eradication was threefold greater than prior to treatment. In addition, its restoration became more pronounced in subjects with severe gastric atrophy. However, a comparatively low restoration of H2 receptor mRNA was found in subjects with hypergastrinemia. CONCLUSIONS: H2 receptor mRNA levels decrease with the progression of gastric atrophy induced by H. pylori infection, and are restored after H. pylori eradication. Such expression levels of H2 receptor may explain a part of the tolerance phenomenon to H2 receptor antagonists.

Comparison of hemostatic effects by route of H2 receptor antagonist administration following endoscopic mucosal resection in patients with neoplastic gastric lesions.

BACKGROUND: To date, there has not been an in-depth investigation to identify differences in the effects of bleeding prevention among different routes of administration of H2 receptor antagonists to treat gastric ulcers following endoscopic mucosal resection (EMR). AIM: To prospectively compare the frequency of bleeding following EMR between patients treated with intravenous (IV) famotidine and those with oral famotidine. METHODS: Fifty-three patients with neoplastic gastric lesions (33 carcinoma and 20 adenoma) treated by EMR were included. Subjects underwent EMR with circumferential mucosal incision assisted by submucosal injection of sodium hyaluronate (EMRSH), followed by IV or oral (PO) administration of famotidine at a dosage of 40 mg/day for 2 days. Patients with odd ID numbers were assigned to IV therapy (30 cases) while even numbers were given PO therapy (23 cases). Frequencies and endoscopic findings of bleeding during the first 2 days after EMR were examined. RESULTS: Frequency of bleeding within 2 days after EMR was 3 and 4% in IV and PO patients, respectively, showing no significant difference. No significant difference was seen in the endoscopic findings of bleeding and therapy, either, with respective IV and PO findings at 23 and 26%. CONCLUSIONS: No significant difference was observed in frequency of bleeding within 2 days after gastric EMR between IV and oral administrations of famotidine.

Pericryptal fibroblast sheath in intestinal metaplasia and gastric carcinoma.

BACKGROUND AND AIMS: In the progression of chronic gastritis, gastric mucosal cells deviate from the normal pathway of gastric differentiation to an intestinal phenotype which is closely related to gastric carcinoma. However, to date, it has not been elucidated whether the intestinal metaplasia is merely a change in the epithelium or whether the underlying mesenchyme also changes from gastric type to intestinal type. We have investigated the relationship between intestinal metaplasia and the pericryptal fibroblast sheath (PCFS) in the mesenchyme. In addition, we also examined PCFS in gastric carcinoma. METHODS: We determined the existence of PCFS in the intestinal metaplastic mucosa and carcinoma of both human and Cdx2 transgenic mouse stomach. PCFS was determined using the antibody against alpha-smooth muscle actin and electron microscopic observations. RESULTS: PCFS formed an almost complete layer around the small and large intestinal crypts while it did not exist around the normal gastric glands in both mice and humans. PCFS was seen around the glands of intestinal metaplastic mucosa in both Cdx2 transgenic mouse and human stomachs. However, PCFS was virtually absent in the intestinal-type gastric adenocarcinoma area. CONCLUSION: We successfully demonstrated that the epithelium as well as the mesenchyme changed from the gastric type to the intestinal type in intestinal metaplasia and that PCFS disappeared in intestinal-type gastric carcinoma.

Cdx1 induced intestinal metaplasia in the transgenic mouse stomach: comparative study with Cdx2 transgenic mice.

BACKGROUND AND AIMS: Gastric intestinal metaplasia, which is mainly induced by Helicobacter pylori infection, is thought to be a precancerous lesion of gastric adenocarcinoma. Intestinal metaplastic mucosa expresses intestine specific homeobox genes, Cdx1 and Cdx2, in the human gastric mucosa. We and others have reported that ectopic expression of Cdx2 in the gastric epithelium generates intestinal metaplasia in the transgenic mouse model. METHODS: To clarify the differences in the roles of Cdx1 and Cdx2 in intestinal metaplasia, we generated transgenic mice expressing Cdx1 in the gastric mucosa and compared Cdx1 induced gastric mucosal morphological changes with Cdx2 induced intestinal metaplasia. RESULTS: The gastric mucosa in Cdx1 transgenic mice was completely replaced by intestinal metaplastic mucosa, consisting of all four intestinal epithelial cell types: absorptive enterocytes, goblet, enteroendocrine, and Paneth cells. Paneth cells, which were not recognised in Cdx2 transgenic mice, were in the upper portion of the intestinal metaplastic mucosa. Pseudopyloric gland metaplasia, which was induced in Cdx2 transgenic mice, was not recognised in Cdx1 transgenic mice. Proliferating cell nuclear antigen (PCNA) positive cells were diffusely scattered in Cdx1 induced intestinal metaplastic mucosa while PCNA positive cells in Cdx2 induced intestinal metaplastic mucosa were in the base of the metaplastic mucosa. Intestinal metaplastic mucosa of Cdx1 transgenic mouse stomach was significantly thicker than that of wild-type or Cdx2 transgenic mouse stomach. CONCLUSIONS: We have confirmed that Cdx1 induced gastric intestinal metaplasia but that it differed from Cdx2 induced intestinal metaplasia in differentiation, structure, and proliferation.

A case of inflammatory fibroid polyp causing small-bowel intussusception in which retrograde double-balloon enteroscopy was useful for the preoperative diagnosis.

We showed a newly developed method, retrograde double-balloon enteroscopy, to be useful for preoperative diagnosis in a case of inflammatory fibroid polyp accompanied by small-bowel intussusception. A 64-year-old woman was admitted to our hospital with small-bowel intussusception. Results of radiographic and ultrasonographic examination were suggestive of a small-bowel mass. Retrograde double-balloon enteroscopy was performed in an attempt to make a preoperative diagnosis. Endoscopic observation, in combination with histological findings derived from endoscopic biopsy, was suggestive of an inflammatory fibroid polyp. The patient then underwent laparotomy with minimal incision, which revealed a polypoid mass leading to a jejunojejunal intussusception, without bowel necrosis, and a partial small-bowel resection was performed. The pathological diagnosis was an inflammatory fibroid polyp.