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Background and Aim: Tacrolimus is now considered to be one of the main therapeutic options for refractory ulcerative colitis. Both cytochrome P-450 3A5 (CYP3A5) and ATP-binding cassette subfamily B member 1 (ABCB1) associated with tacrolimus metabolism are known to have several genetic polymorphisms. However, it remains controversial whether these polymorphisms affect the therapeutic efficacy for ulcerative colitis. We aimed to investigate the influence of both CYP3A5 and ABCB1 polymorphisms on the efficacy of tacrolimus in ulcerative colitis treatment under the tight dose-adjusting strategy., Methods: Sixty-one Japanese patients with ulcerative colitis treated with tacrolimus were enrolled retrospectively. Tacrolimus treatment was performed using the tight dose-adjusting strategy. Genotyping for CYP3A5*3, ABCB1 1236C>T, 2677G>A,T, and 3435C>T were performed, and the clinical outcomes at 12 weeks after the initiation of tacrolimus were compared among the genotypes., Results: There was no association between the CYP3A5 genotypes and therapeutic efficacy. In contrast, a significant association was observed with the ABCB1 1236C > T polymorphism and therapeutic efficacy. The ABCB1 1236CC+CT groups (n = 41) had a significantly higher response rate (73% vs 35%; P = 0.004) and remission rate (61% vs 20%; P = 0.002) than the TT group (n = 20). The multivariate logistic regression analysis also revealed that ABCB1 1236C>T was identified as an independent factor associated with remission., Conclusions: ABCB1 1236C>T polymorphism significantly affects the therapeutic efficacy of tarcolimus at 12 weeks under the tight dose-adjusting treatment for ulcerative colitis., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: Colorectal endoscopic submucosal dissection (ESD) is recommended to be carried out only by endoscopists with sufficient experience in gastric ESD. However, early gastric carcinoma is less common in Western countries than in Japan, and endoscopic maneuverability differs between the stomach and colorectum. We assessed the feasibility of colorectal ESD carried out by endoscopists with no or little experience in gastric ESD., Methods: We analyzed en bloc resection, R0 resection and perforation rates in 180 consecutive colorectal ESD carried out by three endoscopists who had no or <5 cases of experience in gastric ESD. We also identified factors associated with R0 resection failure., Results: Overall en bloc and R0 resection rates were 93.3% (168/180) and 82.2% (148/180), respectively. All 11 cases with perforation were treated endoscopically. Dividing 180 cases into three learning phases (early, middle, or late phases), the en bloc and R0 resection rates increased from 88.3% and 75.0% in the early phase to 98.3% and 88.3% in the late phase, respectively. Perforation rate also improved from 10.0% to 3.3%. Factors associated with R0 resection failure were location at junctions (odds ratio: 6.8, 95% CI: 1.9-27.5), preoperative factors reflecting fibrosis (5.8, 1.9-19.0), and late phase (0.2, 0.1-0.7)., Conclusion: Endoscopists without experience in gastric ESD carried out colorectal ESD safely. In the early and middle phases (≤40 cases), they should treat mainly rectal lesions but may also resect lesions in the colon avoiding flexures. Lesions located at junctions and those with preoperative factors reflecting fibrosis should be resected after completing 40 procedures., (© 2017 The Authors. Digestive Endoscopy © 2017 Japan Gastroenterological Endoscopy Society.)

Aim: To investigate the microRNA (miRNA) expression during histological progression from colorectal normal mucosa through adenoma to carcinoma within a lesion., Methods: Using microarray, the sequential changes in miRNA expression profiles were compared in colonic lesions from matched samples; histologically, non-neoplastic mucosa, adenoma, and submucosal invasive carcinoma were microdissected from a tissue sample. Cell proliferation assay was performed to observe the effect of miRNA, and its target genes were predicted using bioinformatics approaches and the expression profile of SW480 transfected with the miRNA mimics. mRNA and protein levels of the target gene in colon cancer cell lines with a mimic control or miRNA mimics were measured using qRT-PCR and Western blotting. The expression levels of miRNA and target gene in colorectal tissue samples were also measured., Results: Microarray analysis identified that the miR-320 family, including miR-320a, miR-320b, miR-320c, miR-320d and miR-320e, were differentially expressed in adenoma and submucosal invasive carcinoma. The miR-320 family, which inhibits cell proliferation, is frequently downregulated in colorectal adenoma and submucosal invasive carcinoma tissues. Seven genes including CDK6 were identified to be common in the results of gene expression array and bioinformatics analyses performed to find the target gene of the miR-320 family. We confirmed that mRNA and protein levels of CDK6 were significantly suppressed in colon cancer cell lines with miR-320 family mimics. CDK6 expression was found to increase from non-neoplastic mucosa through adenoma to submucosal invasive carcinoma tissues and showed an inverse correlation with miR-320 family expression., Conclusion: MiR-320 family affects colorectal tumor proliferation by targeting CDK6, plays important role in its growth, and is considered to be a biomarker for its early detection.

A 47-year-old woman was admitted to our hospital urgently with sudden-onset hematochezia. She was temporarily in a state of hemorrhagic shock. As we strongly suspected bleeding from the small intestine, peroral double-balloon enteroscopy was performed, and indicated a 2.0-cm diameter hemispheric elevated lesion in the jejunum. Moreover, a blood clot was observed at the top of the protrusion. The site was marked by injecting India ink, without taking a biopsy specimen, to avoid further hemorrhaging. Subsequently, laparoscopic partial small bowel resection was performed. On histopathological examination, the lesion was found to be a sac-like submucosal arterial aneurysm, with a diameter of 3.5 mm, comprising several small abnormal arteries. The final diagnosis was a ruptured submucosal aneurysm of the small intestine. Ruptured submucosal aneurysms are very rarely observed in the small intestine. Only a few reports have described their endoscopic findings. Our experience indicates that small bowel enteroscopy may be useful for managing ruptured submucosal aneurysms of the small intestine.

Background/Aims. Antitumor necrosis factor antibodies and calcineurin inhibitors have shown good therapeutic efficacy for steroid-refractory ulcerative colitis (UC). Although some studies have compared the efficacy of infliximab (IFX) and cyclosporin A, there are no published studies comparing IFX and tacrolimus (Tac). This study aimed to compare therapeutic efficacies between IFX- and Tac-based strategies for steroid-refractory UC. Methods. Between July 2009 and August 2013, 95 patients with steroid-refractory UC received either IFX (n = 48) or Tac (n = 47) in our hospital. In the IFX group, the patients continued to receive maintenance treatment with IFX. In the Tac group, patients discontinued Tac treatment up to 3 months and subsequently received thiopurine. We retrospectively compared the therapeutic outcomes between the groups. Results. There was no significant difference in the colectomy-free rate, clinical remission rate, and clinical response rate at 2 months between the groups. However, relapse-free survival was significantly higher in the IFX group than in the Tac group (p < 0.001; log-rank test). The proportions of serious adverse events did not differ between the groups. Conclusion. The findings of our study showed that IFX and Tac have similar short-term therapeutic efficacy for steroid-refractory UC. Maintenance treatment with IFX, however, yields better long-term outcomes than Tac-thiopurine bridging treatment.

Purpose: Since colorectal endoscopic submucosal dissection (ESD) requires higher-level skills than endoscopic mucosal resection (EMR), it is recommended to acquire sufficient experience in gastric ESD prior to attempting colorectal ESD. We evaluated the ability of experienced endoscopists with limited experience in gastric ESD to perform colorectal ESD., Methods: We retrospectively reviewed 120 colorectal ESDs performed by two endoscopists who had expertise in colonoscopy and colorectal EMR but experience of fewer than five gastric ESDs. Main outcomes were the en bloc resection rate with tumor-free margins (R0 resection rate) and adverse events rate. Using only clinical characteristics prior to ESD, we also identified factors affecting outcomes., Results: A total of 113 patients (94.2 %) received en bloc resection, and the R0 resection rate was 80.0 % (96/120). Perforation and postoperative hemorrhage occurred in eight (6.7 %) and two (1.7 %) patients, respectively. Dividing the 120 cases into three learning phases, R0 resection and perforation rates improved from 77.5 % (31/40) and 12.5 % (5/40) in phase 1 to 85.0 % (34/40) and 2.5 % (1/40) in phase 3, respectively. Multivariate analysis revealed that lesions at junctions (dentate line, sigmoid-descending junction, splenic flexure, hepatic flexure, ileocecal valve) and lesions with factors reflecting fibrosis in the submucosal layer (based on endoscopic findings before ESD) were significantly correlated with R0 resection failure, with adjusted odds ratios of 10.5 (95 % CI 2.1-67.6) and 10.4 (2.7-48.6), respectively., Conclusions: Colorectal ESD is feasible for experienced endoscopists with limited experience in gastric ESD. Novices should avoid lesions at junctions or those with factors reflecting fibrosis.

The development of de novo Crohn's disease (CD) after orthotopic liver transplantation (OLT) is rare, possibly due to the continuous use of immunosuppressive treatment. Although several cases of CD following OLT have been reported worldwide, there are currently so such cases in Japan. We herein report the case of a patient who newly developed CD after undergoing OLT for congenital biliary atresia. The patient subsequently underwent ileocecal resection and has since maintained clinical remission. This is the first report of this condition in Japan. We also review the literature concerning cases of de novo inflammatory bowel disease (IBD) developing after OLT, and discuss the causes of and role of immunosuppressive agents in treating IBD.

Background: The efficacy of colorectal endoscopic submucosal dissection (ESD) has been reported mainly from Japanese referral centers. However, ESD is technically difficult and associated with a higher risk of adverse events than endoscopic mucosal resection, especially for novices performing colorectal ESD with little experience in gastric ESD. The current study evaluated the results of colorectal ESD during the clinical learning curve by retrospectively examining the results of colorectal ESD performed by four endoscopists who had experience with fewer than five cases of gastric ESD., Methods: The study retrospectively investigated the first 20 cases managed by each endoscopist, for a total of 80 cases. The main outcome measurements were procedural time, en bloc resection rate with tumor-free margins (R0 resection rate), and adverse events rate. From among clinicopathologic characteristics, factors that affected main outcome measurements were identified., Results: Of the 80 cases (56 colonic and 24 rectal lesions; 44 granular laterally spreading tumors (LSTs) and 23 nongranular LSTs, 5 depressed, and 8 protruding), 54 cases (67.5%) had resection using a standard tip-type knife, and 26 cases (32.5%) had resection using a small scissors-type knife. The mean tumor diameter was 34.9 ± 14.1 mm, and the mean procedural time was 108.8 ± 53.4 min. The resection in 75 cases (93.8%) was performed en bloc, and the R0 resection rate was 75% (60/80). Perforation occurred in six cases (7.5%) and postoperative hemorrhage in three cases (3.8%). Multivariate analyses showed that colonic lesions and larger lesions (≥40 mm) were significantly associated with prolonged procedural time (≥90 min). Use of the scissors-type knife was significantly associated with a higher R0 resection rate. Perforation occurred only in colonic lesions., Conclusions: For novices in colorectal ESD, beginning with rectal and smaller lesions may be advisable. Also, using scissors-type knives may increase the R0 resection rate.

To explore the relationship between UPR and autophagy in intestinal epithelial cells, we investigated whether autophagy was induced by endoplasmic reticulum (ER) stress in colon cancer cell lines. We demonstrated that autophagy was induced by ER stress in HT29, SW480, and Caco-2 cells. In these cells, inositol-requiring enzyme1α (IRE1α) and C/EBP homologous protein (CHOP) were involved in the ER stress-autophagy pathway, and CHOP was a regulator of IRE1α protein expression. Our findings suggest that CHOP promotes IRE1α and autophagy especially in ER stress conditions. This study will provide important insights into the disclosure of the ER stress-autophagy pathway., (Copyright © 2014 Elsevier Inc. All rights reserved.)

An association between FCGR3A-158 V/F polymorphism and biological responses to infliximab has been reported in Crohn's disease (CD) in Western countries. However, little is known about the mechanism by which gene polymorphism affects the responses to infliximab. The aims of this study were to confirm the association in Japanese CD patients and to reveal the effect of gene polymorphism on biological responses to infliximab. Japanese CD patients were examined retrospectively at weeks 8 and 30. Clinical and biological responses were assessed by the Crohn's disease activity index and C-reactive protein levels, respectively. The infliximab-binding affinity of natural killer (NK) cells from FCGR3A-158 V/V, V/F and F/F donors was examined. Infliximab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) activities were also determined using transmembrane TNF-α-expressing Jurkat T cells as target cells and peripheral blood mononuclear cells (PBMCs) from V/V, V/F and F/F donors as effector cells. Biological responses at week 8 were statistically higher in V/V patients, whereas no significant differences were observed in either clinical responses at weeks 8 and 30 or biological responses at week 30 among the three genotypes. NK cells and PBMCs from V/V patients also showed higher infliximab-binding affinity and infliximab-mediated ADCC activity, respectively. Our results suggest that FCGR3A-158 polymorphism is a predicting factor of biological responses to infliximab in the early phases. FCGR3A-158 polymorphism was also found to affect the infliximab-binding affinity of NK cells and infliximab-mediated ADCC activity in vitro, suggesting that an effect on ADCC activity influences biological responses to infliximab in CD patients.

Objective: Stress is thought to be one of the triggers of relapses in patients with inflammatory bowel disease (IBD). We examined the rate of relapse in IBD patients before and after the Great East Japan Earthquake., Design: A retrospective cohort study., Settings: 13 hospitals in Japan., Participants: 546 ulcerative colitis (UC) and 357 Crohn's disease (CD) patients who received outpatient and inpatient care at 13 hospitals located in the area that were seriously damaged by the earthquake. Data on patient's clinical characteristics, disease activity and deleterious effects of the earthquake were obtained from questionnaires and hospital records., Primary Outcome: We evaluated the relapse rate (from inactive to active) across two consecutive months before and two consecutive months after the earthquake. In this study, we defined 'active' as conditions with a partial Mayo score=2 or more (UC) or a Harvey-Bradshaw index=6 or more (CD)., Results: Among the UC patients, disease was active in 167 patients and inactive in 379 patients before the earthquake. After the earthquake, the activity scores increased significantly (p<0.0001). A total of 86 patients relapsed (relapse rate=15.8%). The relapse rate was about twice that of the corresponding period in the previous year. Among the CD patients, 86 patients had active disease and 271 had inactive disease before the earthquake. After the earthquake, the activity indices changed little. A total of 25 patients experienced a relapse (relapse rate=7%). The relapse rate did not differ from that of the corresponding period in the previous year. Multivariate analyses revealed that UC, changes in dietary oral intake and anxiety about family finances were associated with the relapse., Conclusions: Life-event stress induced by the Great East Japan Earthquake was associated with relapse in UC but not CD.

Selective peroxisome proliferator-activated receptor gamma (PPARγ) modulators are expected to be a novel class of drugs improving plasma glucose levels without PPARγ-related adverse effects. As a continuation of our studies for (-)-Cercosporamide derivatives as selective PPARγ modulators, we synthesized substituted naphthalene type compounds and identified the most potent compound 15 (EC(50) = 0.94 nM, E(max) = 38%). Compound 15 selectively activated PPARγ transcription and did not activate PPARα and PPARδ. The potassium salt of compound 15 showed a high solubility and a good oral bioavailability (58%). Oral administration of the potassium salt remarkably improved the plasma glucose levels of female Zucker diabetic fatty rats at 1 mg/kg. Moreover, it did not cause a plasma volume increase or a cardiac enlargement in Wistar-Imamichi rats, even at 100 mg/kg., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

The upper gastrointestinal tract is not generally considered a target organ in ulcerative colitis (UC). However, several cases showing upper gastrointestinal involvement in UC have been reported. In this report, we present 2 rare cases of diffuse duodenitis accompanying pancolonic UC. Case patient 1 was a 44-year-old man who developed diffuse duodenitis shortly after colectomy and was successfully treated with mesalazine. Case patient 2 was a 25-year-old woman who developed diffuse duodenitis under a steroid-free condition and was successfully treated with prednisolone. The 2 patients had Helicobacter pylori-negative duodenitis that resembled colonic lesions of UC in both the endoscopic and histological findings. No evidence of Crohn's disease was found in these cases. We diagnosed both cases as typical UC-associated diffuse duodenitis. The occurrence of gastrointestinal involvement in UC has been attracting attention because such lesions could potentially open a new window for studying the etiology and pathogenesis of UC. Further studies involving a large number of patients are needed to clarify whether the upper gastrointestinal tract is a target organ in UC.

In this study, we analyzed the clinical courses and the pregnancy outcomes in Japanese women with inflammatory bowel disease (IBD) in our hospital in the recent 10 years. We analyzed 49 pregnancies in 38 patients with ulcerative colitis (UC) and 24 pregnancies in 16 patients with Crohn's disease (CD) retrospectively. The results indicated that pregnancy has less influence on the clinical courses of IBD and that IBD also has less influence on the pregnancy outcomes. However, we should pay attention to the results that the patients with CD tend to deteriorate if conception occurs when CD is active and that patients with active UC tend to have more adverse pregnancy outcomes than patients in remission. In conclusion, patients with IBD are recommended to become pregnant when the diseases are in remission and treatment using selected safe medications should be continued during the pregnancy.

NKX2.3 is a promising candidate for susceptibility genes to inflammatory bowel disease (IBD). The aim of this study was to perform a candidate gene analysis of NKX2.3 in Japanese IBD and to examine how the risk allele (haplotype) affects susceptibility to IBD using allelic expression ratios of NKX2.3 mRNA in the involved colonic mucosa. A total of 344 patients with Crohn's disease (CD), 253 patients with ulcerative colitis (UC), and 243 healthy controls (HCs) were genotyped for 3 tag-single nucleotide polymorphisms (SNPs; rs10883365, rs888208, and rs11596008) around NKX2.3. The allelic expression ratio of NKX2.3-mRNA was examined by TaqMan assay using rs888208 as an allelic (haplotypic) marker. Two SNPs (rs10883365 and rs888208) were significantly associated with UC (p = 7.79 × 10(-4), odds ratio [OR] = 1.54 [95% confidence interval (95% CI) 1.20-1.99], p = 7.70 × 10(-3), OR = 1.41 [95% CI 1.10-1.81], respectively) and 1 SNP (rs10883365) was associated with CD (p = 0.0366, OR = 1.29 [95% CI 1.02-1.63]). Haplotype B formed by the 3 SNPs demonstrated a significant association with UC (p = 6.11 × 10(-4), OR = 1.56 [95% CI 1.21-2.00]). Subgroup analyses indicated that rs10883365 was significantly associated mainly with colonic CD (p = 1.99 × 10(-3), OR = 1.91 [95% CI 1.27-2.88], vs HCs). The allelic expression ratios of NKX2.3 mRNA transcribed from haplotype B (risk haplotype) to haplotype A (the nonrisk haplotype) in the involved mucosa from 10 IBD patients were significantly higher than the allelic ratio of respective genomic DNA (p = 0.00195). We confirmed the association of SNP rs10883365 located in the 5' flanking region of NKX2-3 with Japanese UC and colonic CD and determined the risk haplotype (haplotype B) for UC. The demonstrated allelic expression imbalance supports the idea that the risk haplotype of NKX2.3 confers susceptibility to UC through increasing expression of NKX2.3 mRNA in the colonic mucosa., (Copyright © 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Peroxisome proliferator-activated receptor γ (PPARγ; NR1C3) is known as a key regulator of adipocytogenesis and the molecular target of thiazolidinediones (TZDs), also known as antidiabetic agents. Despite the clinical benefits of TZDs, their use is often associated with adverse effects including peripheral edema, congestive heart failure, and weight gain. Here we report the identification and characterization of a non-thiazolidinedione PPARγ partial agonist, Cerco-A, which is a derivative of the natural product, (-)-cercosporamide. Cerco-A was found to be a binder of the PPARγ ligand-binding domain in a ligand competitive binding assay and showed a unique cofactor recruitment profile compared to rosiglitazone. A crystal structure analysis revealed that Cerco-A binds to PPARγ without direct hydrogen bonding to helix12. In PPARγ transcriptional activation assay and an adipocyte differentiation assay, Cerco-A was a potent partial agonist of PPARγ. After a 14-day oral administration, once per day of Cerco-A in Zucker diabetic fatty (ZDF) rats, an apparent decrease of plasma glucose and triglyceride was observed, as with pioglitazone. To evaluate drug safety, Cerco-A was administered for 13 days orally in non-diabetic Zucker fatty (ZF) rats. Each of the hemodilution parameters (hematocrit, red blood cells number, and hemoglobin), which are considered as undesirable effects of TZDs, was improved significantly compared to pioglitazone. While Cerco-A showed body weight gain, as with pioglitazone, Cerco-A had significantly lower effects on heart and white adipose tissues weight gain. The results suggest that Cerco-A offers beneficial effects on glycemic control with attenuated undesirable side effects.

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., (2010 Elsevier Ltd. All rights reserved.)

Aim: For patients with bowel obstruction, intestinal decompression by a long tube is recommended. We assessed the usefulness of a new technique for insertion of a long tube with a guidewire placed by transnasal ultrathin endoscopy., Methods: Nineteen patients who had been diagnosed as suffering from bowel obstruction underwent long-tube insertion with the ropeway technique using a guidewire placed by transnasal endoscopy. Thirty-three patients who had undergone conventional insertion of a long tube were included as controls. The success rate of intubation of the small bowel and the time required for the procedure were compared between the subjects and controls., Results: The success rate of intubation was 94.7% (18/19) in subjects and 84.8% (28/33) in controls (P = 0.53). The time required for insertion in the subjects and controls was 24.1 +/- 8.1 min and 48.7 +/- 25.3 min, respectively, with a statistically significant difference (P < 0.001). No complications relevant to the procedure were encountered in either of the groups., Conclusion: Long-tube insertion facilitated by transnasal endoscopy reduces the time required for insertion in comparison with the conventional technique without endoscopy. Endoscopy-assisted long-tube insertion with the ropeway method is a safe and useful procedure for decompression in patients with bowel obstruction.

Background: It is often difficult to insert a long intestinal tube in the small bowel of patients with bowel obstruction, and it often results in long procedure time and severe patient distress., Objective: To assess the usefulness of the ropeway method by using a guidewire placed with the assistance of transnasal ultrathin endoscopy in long-tube insertion for patients with bowel obstruction., Design: Prospective, randomized, controlled, single-center study., Patients and Interventions: Thirty-four consecutive patients with bowel obstruction requiring decompression participated in the study and were randomized to the insertion of a long tube with the ropeway method (ILTR) group (ie, insertion along an endoscopically placed guidewire that was passed through only the distal 4 cm of the tube) or insertion by a conventional method group (C group)., Main Outcome Measurements: The time required for the procedure (main), success rate, x-ray exposure time, and intensity of patient distress measured with a visual analog scale of 1 to 5 (better to worse)., Results: The mean (+/- standard deviation) duration of the procedure in the successful cases in the ILTR group and the C group was 16.1 +/- 5.6 minutes and 26.4 +/- 13.8 minutes, respectively (P = .010). The success rate was 100% in the ILTR group and 88% in the C group (P = .48). The mean (+/- standard deviation) x-ray exposure time and intensity of patient distress were, respectively, 16.4 +/- 8.7 minutes and 33.2 +/- 12.3 minutes (P < .001) and 2.6 +/- 0.7 and 3.7 +/- 1.2 (P = .016)., Limitations: Single-center study and small sample size to evaluate overall safety., Conclusions: Long-tube insertion for bowel obstruction with the ropeway method facilitated by transnasal ultrathin endoscopy was superior to conventional fluoroscopic placement with regard to overall procedure success, time required, and patient comfort.

Background: Clinical demand for total colonoscopy (TCS) is increasing. Improvement of the cecal intubation rate and shortening of the examination time would expand the capacity for TCS., Objective: To assess the efficacy of a transparent hood attached to the tip of a colonoscope for cecal intubation in TCS., Design: Prospective, randomized, controlled study., Setting: Single tertiary-referral center., Interventions: TCS., Main Outcome Measurements: Cecal intubation time and rate, complications, patient discomfort, and detection rate of colonic polyps., Methods: Patients who were to undergo screening and/or surveillance TCS for colorectal cancer were invited to participate in the study. Cecal intubation time and rate, complications, patient discomfort, and detection rate of colonic polyps were evaluated., Results: A total of 592 patients enrolled in this study were randomly allocated to the hood group and no-hood group. The mean (SD) cecal intubation time in the hood group and the no-hood group was 10.2 +/- 12.5 minutes and 13.4 +/- 15.8 minutes, respectively (P = .0241). The effect of its use was more prominent in the expert endoscopists group compared with those with moderate experience. The cecal intubation rate and the detection rate of small polyps in the 2 groups were similar. The grade of patient discomfort was significantly lower in the hood group. No complications were encountered with the use of the hood., Conclusions: Use of a transparent hood on the tip of a colonoscope shortened the time required for cecal intubation and decreased patient discomfort; such use was more effective among experts in shortening the examination time.

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.

We investigated the effect of dexamethasone (DEX) at clinical doses on the pharmacokinetics of quinidine (QN) in dogs. Dogs (5 healthy 1-year-old male beagles) were orally administered DEX once daily for 5 days at 2.5 or 7.5 mg/day. QN (2 mg/kg) was intravenously injected 3 weeks before and one day after the DEX treatment. The plasma concentration of QN was determined by high-performance liquid chromatography with fluorometric detection. Plasma concentrations of albumin and alpha(1)-acid glycoprotein (AGP) were determined by a bromocresol green method and a single immunodiffusion method, respectively. In order to calculate unbound concentrations of QN in plasma, the binding kinetics of QN in plasma was examined by an ultrafiltration method using pooled plasma from the 5 dogs when they were drug-free. Total body clearance of QN was decreased dose-dependently By the DEX treatment, although the decrease was not statistically significant. Elimination half-lives significantly increased (more than twice at 7.5 mg), and intrinsic clearance significantly decreased (about 50%). The volume of distribution increased significantly (about two-fold). Plasma levels of AGP significantly decreased, and the unbound fraction of QN in plasma significantly increased. Our results demonstrate that clinical doses of DEX significantly affect the pharmacokinetics of QN, a CYP3A substrate in dogs, by decreasing CYP3A activity and plasma AGP levels. There is a possibility that adverse drug-drug interaction occurs during DEX therapy through its effects on CYP3A activity and plasma AGP levels.

Objective: To evaluate the effect of oral administration of dexamethasone (DEX) at clinically relevant doses on metabolic activities of cytochrome P450 (CYP) isoenzymes in dogs and rats., Animals: 15 healthy 1-year-old male Beagles and 20 healthy 10-week-old male Wistar rats., Procedure: Hepatic microsomes were harvested from dogs treated orally with DEX at 2.5 and 7.5 mg for 5 days and from rats treated orally with DEX at 0.75, 6, and 48 mg/kg for 5 days. 7-ethoxyresorufin, tolbutamide, bufuralol, and midazolam were used as CYP1A, CYP2C, CYP2D, and CYP3A substrates, respectively. Concentrations of metabolites formed by CYPs were measured by use of high-performance liquid chromatography, except for the resorufin concentrations measured by use of a fluorometric method. Reaction velocity-substrate concentration data were analyzed to obtain maximum reaction velocity (Vmax) and Michaelis-Menten constant (Km)., Results: Values of Vmax for midazolam 4-hydroxylation were significantly decreased by treatment with DEX at 2.5 and 7.5 mg in dogs, although values of Km were not affected. Values of Vmax for bufuralol 1'-hydroxylation were also decreased by treatment with DEX. In rats, values of Vmax for midazolam 4- hydroxylation were significantly decreased by treatment with DEX at 0.75 and 6 mg/kg but significantly increased at 48 mg/kg. Other reactions were not affected by treatment with DEX., Conclusions and Clinical Relevance: Our results indicate that DEX downregulates the CYP3A subfamily when administered at clinically relevant doses to dogs. The effect of downregulation of CYP3A in dogs treated with DEX should be considered to avoid adverse effects from coadministration of drugs.

Objective: To evaluate the inhibitory potency of ketoconazole (KTZ) on the metabolic activities of isozymes of cytochrome P-450 (CYP) in dogs., Animals: 4 healthy 1-year-old male Beagles., Procedure: Hepatic microsomes were harvested from 4 dogs after euthanasia. To investigate the effects of KTZ on CYP metabolic activities, 7-ethoxyresorufin, tolbutamide, bufuralol, and midazolam hydrochloride were used as specific substrates for CYP1A1/2, CYP2C21, CYP2D15, and CYP3A12, respectively. The concentrations of metabolites formed by CYP were measured by high-performance liquid chromatography, except for the resorufin concentrations that were measured by a fluorometric method. The reaction velocity-substrate concentration data were analyzed to obtain kinetic variables, including maximum reaction velocity, Michaelis-Menten constant, and inhibitory constant (Ki)., Results: KTZ competitively inhibited 7-ethoxyresorufin O-deethylation and midazolam 4-hydroxylation; it noncompetitively inhibited tolbutamide methylhydroxylation. Bufuralol 1'-hydroxylation was inhibited slightly by KTZ. The mean Ki values of KTZ were 10.6+/-6.0, 170+/-2.5, and 0.180+/-0.131 microM for 7-ethoxyresorufin O-deethylation, tolbutamide methylhydroxylation, and midazolam 4-hydroxylation, respectively., Conclusions and Clinical Relevance: In dogs, KTZ at a therapeutic dose may change the pharmacokinetics of CYP3A12 substrates as a result of inhibition of their biotransformation. Furthermore, no influence of KTZ on the pharmacokinetics of CYP1A1/2, CYP2C21, and CYP2D15 substrates are likely. In clinical practice, adverse drug effects may develop when KTZ is administered concomitantly with a drug that is primarily metabolized by CYP3A12.

The long-term oral ketoconazole (KTZ) treatment extensively inhibits hepatic CYP3A activity. We investigated the effect of the KTZ treatment on hepatic and intestinal extraction of nifedipine (NIF) using beagle dogs. Four dogs were given orally KTZ for 20 days (200 mg, bid). NIF was administered either intravenously (0.5 mg/kg) or orally (20 mg) 10 and 20 days before the KTZ treatment and 10 and 20 days after start of KTZ treatment. CLtot of NIF after intravenous administration decreased to about 50% during the KTZ treatment. C(max) and AUC after oral administration increased to 2.5-fold and fourfold, respectively, by the KTZ treatment. The hepatic extraction ratio of NIF decreased to about a half by KTZ. A significant decrease in intestinal extraction ratio was not observed. In conclusion, the KTZ treatment inhibits hepatic extraction more profoundly than intestinal extraction of NIF. Therefore, inhibition of hepatic extraction of NIF by the KTZ treatment mainly results in substantial increase in systemic bioavailability in dogs. Because KTZ inhibits human CYP3A activities similar to canine CYP3A activities, the long-term oral KTZ treatment may dramatically increase bioavailability of NIF or other CYP3A substrates in humans., (Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association.)

To evaluate effects of multiple dosing of ketoconazole (KTZ) on hepatic CYP3A, the pharmacokinetics of intravenous midazolam (MDZ, 0.5 mg/kg) before and during multiple dosing of KTZ were investigated in beagle dogs. KTZ tablets were given orally to dogs (n = 4) for 30 days (200 mg b.i.d.). With coadministration of KTZ, t(1/2beta) of MDZ were significantly increased both on day 1 (2-fold) and on day 30 (3-fold). Total body clearance (CL(tot)) of MDZ declined gradually during the first 5 days after the start of KTZ treatment, and thereafter CL(tot) appeared to reach a plateau phase (one-fourth), depending on plasma KTZ concentrations. The effects of KTZ on the biotransformation of MDZ were also investigated using dog liver microsomes (n = 5). The K(i) values of KTZ for MDZ 1'-hydroxylation and 4-hydroxylation were 0.0237 and 0.111 microM, respectively, indicating that KTZ extensively inhibits hepatic CYP3A activity in dogs. CL(tot) values estimated from in vitro K(i) values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma were consistent with in vivo CL(tot) of MDZ. The results in this study suggest that KTZ treatment is necessary until plasma concentrations of the drug reach a steady state to evaluate the effect of multiple dosing of the drug on hepatic CYP3A in vivo. In addition, it is suggested that K(i) values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma enable precise in vitro-in vivo scaling.

We examined the effect of age on capacity for myocardial hypertrophy, pressure-generating ability and coronary circulation after imposition of pressure-overload. Marked right ventricular and cellular hypertrophy was observed 1 week after pulmonary artery constriction in the developmental phase of rats (2 months of age) and after 3 weeks in the young-adult rats (7 months). In old rats (18 months) similar increases in peak right ventricular pressure did not produce significant hypertrophy even after 3 weeks. The right ventricular hypertrophy at the organ and cell levels in response to pressure-overload decreased with age. In vivo pressure-generating ability, which was determined by maximum isovolumic pressure during pulmonary artery occlusion, correlated with the degree of myocardial hypertrophy in each age group. During the ascending aortic constriction experiment the age-associated diminution in hypertrophic response was also observed in the left ventricle. Coronary dilator capacity, which was determined after brief ischemia in an isolated, blood-perfused, beating but nonworking heart model, was decreased in the presence of myocardial hypertrophy in young-adult rats (7 months) and in the absence of significant myocardial hypertrophy in old rats (18 months). The age-associated diminution in capacity for myocardial hypertrophy, pressure-generating ability and maladaptation in the coronary circulation may explain the higher incidence of heart failure or increased vulnerability of the myocardium to ischemic episodes during hemodynamic stress in aged patients.