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Background: Vedolizumab is a gut-selective humanized antibody that binds the α 4 β 7 integrin. We evaluated efficacy and safety of vedolizumab in Japanese patients with moderate-to-severe Crohn's disease (CD)., Methods: In this Phase 3, double-blind study (NCT02038920), 157 patients were randomized to receive intravenous vedolizumab 300 mg (n = 79) or placebo (n = 78) at Weeks 0, 2, and 6 (induction phase). Patients with CD activity index (CDAI)-70 response at Week 10 were randomized to receive vedolizumab 300 mg (n = 12) or placebo (n = 12) at Week 14, then every 8 weeks until Week 54 (maintenance phase). Primary endpoints were ≥ 100-point reduction in CDAI (CDAI-100 response) at Week 10 for induction, and clinical remission (CR: CDAI ≤ 150) at Week 60 for maintenance., Results: At Week 10, 26.6% of patients who received vedolizumab and 16.7% who received placebo achieved CDAI-100 response (odds ratio [OR] [95% confidence interval (CI)] 1.80 [0.82-3.96]; p = 0.145). At Week 60, 41.7% of vedolizumab-treated patients and 16.7% of placebo-treated patients achieved CR (OR [95% CI] 3.57 [0.53-23.95]; p = 0.178). The incidence of adverse events was similar in both treatment groups in both induction and maintenance phases. In patients without prior anti-TNFα exposure or with inadequate response to anti-TNFα, vedolizumab showed improved outcomes over placebo in the induction phase. Age might be a possible predictive factor of CR for future research., Conclusion: Vedolizumab showed a numerically greater efficacy versus placebo as induction therapy, but the difference was not statistically significant. Vedolizumab also showed a numerically greater efficacy in maintenance therapy, and was well tolerated.

Background: Although indigo naturalis (IN) is effective for patients with active ulcerative colitis (UC), IN was associated with adverse events (AEs), including pulmonary arterial hypertension (PAH). Our aim was to evaluate the occurrence of IN-associated AEs and to evaluate any IN dose-effect on AEs., Methods: A nationwide survey, using questionnaires, was conducted by conducted by the research group funded by the Ministry of Health, Labour and Welfare of Japan, between June 2017 and September 2018. A first questionnaire determined the occurrence of AEs associated with the therapeutic use of IN or herbal medicines containing IN in patients with UC. A second survey identified the clinical characteristics of patients who developed IN-associated critical AEs, namely, liver dysfunction, PAH, and intussusception., Results: Across 337 participating institutions, 49,320 patients with UC were identified, with IN used in 877 (1.8%). AEs were reported in 91 patients (107 events), including liver dysfunction (n = 40), gastrointestinal symptoms (n = 21), headache (n = 13), and PAH (n = 11). No dose-effect relationship between IN and AEs was identified. Liver dysfunction tended to be mild and reversible. Ten cases of intussusception were reported, with 40% of these patients requiring surgical resection. IN-induced PAH was recovered in patients who discontinued to use IN. No IN-associated deaths were reported., Conclusions: IN-associated AEs were identified among patients with UC, with liver dysfunction often being reversible, while surgical resection was required in a high proportion of patients who developed intussusception. Both healthcare workers and patients should adequately recognize the potential for AEs with the use of IN.

Objective Gastroesophageal reflux disease (GERD) is a highly prevalent disorder that negatively affects patients' quality of life and reduces their work productivity. The medical expenses associated with the treatment of GERD are the highest among all digestive diseases. Current guidelines recommend the administration of a standard dose of proton pump inhibitor (PPI) for eight weeks as an initial GERD treatment. However, there is growing concern regarding the safety of PPI treatment. Recently, a novel potassium-competitive acid blocker (P-CAB), vonoprazan (VPZ), was approved for the treatment of reflux esophagitis in Japan and may provide clinical benefits in GERD treatment. This study was conducted to evaluate the cost-effectiveness of a P-CAB, VPZ vs. a PPI, lansoprazole (LPZ), for the acute medical treatment of reflux esophagitis. Methods A clinical decision analysis was performed using a Markov chain approach to compare VPZ to LPZ in the acute treatment of reflux esophagitis in Japan. Results The P-CAB strategy was superior to the PPI strategy in terms of cost-effectiveness (direct cost per patient to achieve clinical success) and the number of days for which medication was required. Sensitivity analyses revealed that this superiority was robust within the plausible range of probabilities. This remained true even when the healing rates in cases of mild esophagitis were applied. Conclusion The P-CAB strategy was consistently superior to the conventional PPI strategy using the original LPZ in terms of cost-effectiveness and the number of days for which medication was required. Thus, VPZ appears to be the drug of choice for the acute medical treatment of reflux esophagitis.

Background: Clinical evidence of lactulose for chronic constipation in Japan was lacking. We performed a randomized, double-blind, placebo-controlled, dose-finding study in Japanese patients with chronic constipation to estimate the optimal clinical dose of lactulose., Methods: Overall, 250 patients were randomized to receive SK-1202 (13, 26, or 39 g/day, as crystalline lactulose dosage) or placebo twice daily (morning and evening) orally for 2 weeks. The primary endpoint was the change from baseline frequency of spontaneous bowel movements (SBMs) at Week 1. The secondary endpoints included the change from baseline of SBMs at Week 2, percentage of patients experiencing SBM within 24 and/or 48 h of the initial dose, stool consistency, and constipation severity, and adverse events were also evaluated., Results: The 26 and 39 g/day of SK-1202 induced significantly and dose-dependently more increase in SBM at Week 1 than placebo (p = 0.003, p < 0.001). These groups also showed significant improvements in the secondary endpoints. There were no significant differences in the incidence of adverse drug reactions (ADRs) between the placebo and SK-1202 groups. Gastrointestinal disorder was the most common ADR, and diarrhea developed in 6 patients (9.7%) treated with 39 g/day; however, the symptoms were mild in severity and resolved after follow-up, dose reduction, or dose suspension. SK-1202 was generally well tolerated up to 39 g/day., Conclusion: Our results suggest that SK-1202 is useful in Japanese patients with chronic constipation, and optimal dose of SK-1202 is 26 g/day.

Background: Vedolizumab safety and efficacy have been established in many populations all over the world, but have never been studied in Japan. We report results from a Phase 3, randomized, double-blind, placebo-controlled study of vedolizumab in Japanese patients with active ulcerative colitis (UC)., Methods: Patients with moderate-to-severe UC were enrolled into Cohort 1 (double-blinded) or Cohort 2 (open-label) in the induction phase. Cohort 1 was randomized 2:1 to receive 300 mg vedolizumab or placebo, while Cohort 2 received vedolizumab 300 mg only, at Weeks 0, 2, and 6. Patients from Cohorts 1 and 2 showing a clinical response to vedolizumab at Week 10 were randomized 1:1 to receive vedolizumab or placebo (double-blinded) at Week 14 and then every 8 weeks up to Week 54 as the maintenance phase. The primary endpoint was clinical response at Week 10, for the induction phase, and clinical remission at Week 60, for the maintenance phase., Results: A total of 292 patients were enrolled into the induction phase (246 in Cohort 1, 46 in Cohort 2); 83 patients achieved response to vedolizumab and were subsequently enrolled into the maintenance phase. Clinical response rates at Week 10 were 39.6% (65/164) and 32.9% (27/82) in the vedolizumab and placebo groups in Cohort 1, respectively (adjusted odds ratio [AOR] = 1.37, 95% CI 0.779-2.399; p = 0.2722). In the maintenance phase, clinical remission rate at Week 60 was significantly higher in the vedolizumab group, at 56.1% (23/41), versus 31.0% (13/42) for placebo (AOR = 2.88, 95% CI 1.168-7.108; p = 0.0210). Most adverse events were mild to moderate in intensity, and no deaths occurred during the study period., Conclusions: Vedolizumab showed numerically greater efficacy compared with placebo as induction therapy, but the difference was not statistically significant. Vedolizumab was significantly superior to placebo as maintenance therapy in Japanese patients with UC. Vedolizumab has favourable safety and tolerability in these patients., Trial Registration: ClinicalTrials.gov: NCT02039505., Competing Interests: Satoshi Motoya has received honoraria from Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co. Ltd., Janssen Pharmaceutical K.K., and Takeda Pharmaceutical Co. Ltd.; and has received research grants from Pfizer Japan Inc., Janssen Pharmaceutical K.K., and from Takeda Pharmaceutical Co. Ltd. Kenji Watanabe has received honoraria from AbbVie GK, Mitsubishi Tanabe Pharma Corporation, EA Pharma Co. Ltd., Takeda Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mochida Pharmaceutical Co. Ltd. and Janssen Pharmaceutical K.K.; has received research grants from EA Pharma Co. Ltd. and Takeda Pharmaceutical Co. Ltd.; has received scholarship grants from Astellas Pharma Inc., EA Pharma Co. Ltd., Takeda Pharmaceutical Co. Ltd., AbbVie GK, Kyorin Pharmaceutical Co. Ltd. and JIMRO Co. Ltd.; and was a recipient of endowed chairs funded by AbbVie GK, EA Pharma Co. Ltd., Zeria Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, JIMRO Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Asahi Kasei Medical Co. Ltd. and Mochida Pharmaceutical Co. Ltd. Haruhiko Ogata has received honoraria from Takeda Pharmaceutical Co. Ltd.; and has received scholarship grants from Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co. Ltd. and Pfizer Japan Inc. Takanori Kanai has received honoraria Mitsubishi Tanabe Pharma Corporation, Astellas Pharma Inc., Miyarisan Pharmaceutical Co. Ltd., AstraZeneca K.K. and Takeda Pharmaceutical Co. Ltd.; has received research grants from EN Otsuka Pharmaceutical Co. Ltd, Miyarisan Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Ezaki Glico Co. Ltd., Otsuka Pharmaceutical Co. Ltd. and Mitsubishi Tanabe Pharma Corporation; has received scholarship grants from AbbVie GK, Mochida Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Yakult Honsha Co. Ltd., Zeria Pharmaceutical Co. Ltd., Sumitomo Dainippon Pharma Co. Ltd., Ono Pharmaceutical Co. Ltd., EA Pharma Co. Ltd., Eisai Co. Ltd. and JIMRO Co. Ltd.; and was a recipient of endowed chairs funded by Chugai Pharmaceutical Co. Ltd., AbbVie GK, UCB Japan Co. Ltd., Mitsubishi Tanabe Pharma Corporation, EA Pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Zeria Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., JIMRO Co. Ltd. and Mochida Pharmaceutical Co. Ltd. Toshiyuki Matsui has received honoraria from EA Pharma Co. Ltd., Ajinomoto Seiyaku, Abbvie GK, Eisai Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Zeria Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co. Ltd. and Janssen Pharmaceutical K.K.; has received research grants from Takeda Pharmaceutical Co. Ltd., Miyarisan Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation and Otsuka Pharmaceutical Co. Ltd.; has received scholarship grants from Abbvie GK, Asahi Kasei Medical Co. Ltd., Astellas Pharma Inc., AstraZeneca K.K., EA Pharma Co. Ltd., Eisai Co. Ltd., MSD K.K., Otsuka Pharmaceutical Co. Ltd., JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Takeda Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku Co. Ltd. and Mochida Pharmaceutical Co. Ltd.; and was a recipient of endowed chairs funded by AbbVie GK, Asahi Kasei Medical Co. Ltd., Ajinomoto Seiyaku, Inflammatory Bowel Disease Advanced Clinical Treatment endowed chair, Regional/Emergency Medical Management endowed chair (Fukuoka), Eisai Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, UCB Japan Co. Ltd., EA Pharma Co. Ltd., Mochida Pharmaceutical Co. Ltd. and Chugai Pharmaceutical Co. Ltd. Yasuo Suzuki has received honoraria from Takeda Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA Pharma Co. Ltd., Zeria Pharmaceutical Co. Ltd., Mochida Pharmaceutical Co. Ltd. and Kyorin Pharmaceutical Co. Ltd.; and has received scholarship grants from Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA Pharma Co. Ltd., JIMRO Co. Ltd., Mochida Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd. and Kissei Pharmaceutical Co. Ltd. Mitsuhiro Shikamura, Kenkichi Sugiura, Kazunori Oda, Tetsuharu Hori, and Takahiro Araki are employees of Takeda Pharmaceutical Co. Ltd. Mamoru Watanabe has received honoraria from Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co. Ltd., EA Pharma Co. Ltd., Zeria Pharmaceutical Co. Ltd., Ajinomoto Seiyaku, and Eisai Co. Ltd.; has received research grants from Kaken Pharmaceutical Co. Ltd., Alfresa Pharma Corporation and Eisai Co. Ltd.; has received scholarship grants from EA Pharma Co. Ltd., Zeria Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Astellas Pharma Inc., MSD K.K., Daiichi Sankyo Co. Ltd., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Mochida Pharmaceutical Co. Ltd., Ayumi Pharmaceutical Corporation, Kissei Pharmaceutical Co. Ltd. and Miyarisan Pharmaceutical Co. Ltd.; and was a recipient of endowed chairs funded by Asahi Kasei Medical Co. Ltd., EA Pharma Co. Ltd., JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Kyorin Pharmaceutical Co. Ltd., AbbVie GK, Kyowa Hakko Kirin Co. Ltd., MSD K.K., Toray Industries, Inc., Chugai Pharmaceutical Co. Ltd., Gilead Sciences, Inc. and Fujirebio Inc. Toshifumi Hibi has received honoraria from Takeda Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, AbbVie GK, Zeria Pharmaceutical Co. Ltd., JIMRO Co. Ltd., EA Pharma Co. Ltd., Janssen Pharmaceutical K.K. and Pfizer Japan Inc.; has received scholarship grants from EA Pharma Co. Ltd., Nippon Kayaku Co. Ltd., Zeria Pharmaceutical Co. Ltd. and Mochida Pharmaceutical Co. Ltd.; and was a recipient of endowed chairs funded by Otsuka Holdings Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd. and EA Pharma Co. Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Based on the previous phase II/III studies of irritable bowel syndrome with constipation (IBS-C) in Japan that demonstrated the efficacy and safety of linaclotide 0.5 mg/d, we evaluated linaclotide at doses of 0.5 mg/d and lower in the treatment of Japanese patients with chronic constipation (CC)., Methods: This was a phase II randomized, double-blind, placebo-controlled, dose-finding study of linaclotide for Japanese patients with CC (n = 382, 64 men, 318 women, age 20-75). After a baseline period of two weeks, patients were randomized to receive placebo (n = 80), or 0.0625 mg (n = 82), 0.125 mg (n = 71), 0.25 mg (n = 73) or 0.5 mg (n = 76) of linaclotide during a two-week treatment period. The primary efficacy endpoint was change from baseline in weekly spontaneous bowel movement (SBM) frequency during the first week. Secondary endpoints included complete SBM (CSBM) responder rates and IBS-QOL. Safety and adverse events were also evaluated., Key Results: The change in SBM frequency during the first week (mean) was 3.89, 3.11, 3.87, and 3.85 for 0.0625 mg, 0.125 mg, 0.25 mg, and 0.5 mg for linaclotide, significantly higher than for placebo (1.91, P < 0.05). The CSBM responder, which is an important parameter, showed the greatest improvement at the 0.5 mg during the 2 week. The most frequent adverse event in the linaclotide groups was diarrhea., Conclusions & Inferences: Our results suggest that 0.0625, 0.125, 0.25, and 0.5 mg/d are effective doses of linaclotide for treating CC in Japanese patients. ClinicalTrials.gov: NCT02425722, supported by Astellas Pharma, Inc., (© 2018 The Authors. Neurogastroenterology & Motility Published by John Wiley & Sons, Ltd.)

Background: Clinical testing to determine a suitable dose of linaclotide for Japanese patients with irritable bowel syndrome with constipation (IBS-C) was needed., Methods: This was a randomized, double-blind, placebo-controlled, dose-finding trial. Japanese patients with IBS-C diagnosed using Rome III criteria (n = 559, men/women: 49/510) were randomly assigned to 1 of 4 linaclotide doses (0.0625, 0.125, 0.25, or 0.5 mg) or placebo for the 12-week treatment period. The primary endpoint was responder rate of global assessment of relief of IBS symptoms during 12 weeks. The secondary endpoints included responder rates of complete spontaneous bowel movement (CSBM), SBM and abdominal pain/discomfort relief and others., Key Results: The primary endpoint was 23.2%, 36.2%, 38.7%, 34.8%, and 38.3% in placebo (n = 112), 0.0625 (n = 116), 0.125 (n = 111), 0.25 (n = 112), and 0.5 (n = 107) mg of linaclotide groups with the difference from the placebo group in each linaclotide group (13.0%, 15.5%, 11.6%, 15.1%, P > .05). Monthly responder rate of global assessment of relief of IBS symptoms at month 3 (48.6%), responder rate of CSBM during 12 weeks (45.8%), and responder rate of abdominal pain/discomfort relief during 12 weeks (32.7%) in the 0.5 mg were significantly higher than those in placebo group (29.5%, P < .01; 25.9%, P < .01; and 18.8%, P < .05 respectively). The most frequent adverse event in the linaclotide groups was diarrhea., Conclusions & Inferences: This study suggests that a linaclotide dose of 0.5 mg may be appropriate in Japanese patients with IBS-C., (© 2017 The Authors. Neurogastroenterology & Motility Published by John Wiley & Sons Ltd.)

Background: Tenapanor (RDX5791, AZD1722), a small molecule with minimal systemic availability, is an inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3). Tenapanor acts locally in the gut to reduce absorption of sodium and phosphate. It is being developed for the treatment of patients with hyperphosphatemia in CKD requiring dialysis and patients with constipation-predominant irritable bowel syndrome. We report the safety, pharmacodynamics, and pharmacokinetics of tenapanor in Japanese volunteers., Methods: In this phase 1, double-blind study (NCT02176252), healthy Japanese adults (aged 20-45 years) received single-dose tenapanor 180 mg (n = 6), repeated-dose tenapanor 15, 30, 60, or 90 mg twice daily (n = 12 each) for 7 days, or placebo (n = 14). All participants received a standardized diet., Results: Single and repeated doses of tenapanor resulted in higher mean stool sodium content vs. placebo (single dose, 41.9 mmol/day; repeated dose, range of means 21.3-32.2 mmol/day; placebo, 4.1 mmol/day) accompanied by lower urinary sodium content (single dose, 110 mmol/day; repeated dose, 101-112 mmol/day; placebo, 143 mmol/day). Additionally, stool phosphorus content was increased (single dose, 31.0 mmol/day; repeated dose, 17.6-24.8 mmol/day; placebo, 16.8 mmol/day) and urinary phosphorus content decreased (single dose, 18.7 mmol/day; repeated dose, 15.3-19.4 mmol/day; placebo, 25.5 mmol/day). Tenapanor had minimal systemic exposure, provided a softer stool consistency, and was well tolerated., Conclusions: Tenapanor treatment reduced absorption of intestinal sodium and phosphate from the gut in Japanese adults. Tenapanor had minimal systemic exposure and was well tolerated. Further research into the clinical benefits of tenapanor is warranted.

The efficacy of thiopurines, including azathioprine (AZA) and 6-mercaptopurine (6MP), has been demonstrated for the treatment of inflammatory bowel disease (IBD). The most common and serious adverse event of treatment with thiopurines altered by doctors is leukopenia. Hair loss is also a serious event that could be a critical reason for patients to decline thiopurine treatment. Thiopurine-induced severe hair loss causes cosmetic problems, and it takes a long time to recover. In a recent study, NUDT15 R139C was strongly associated with thiopurine-induced leukopenia in Korean and Caucasian populations. In this study, we performed an association study to investigate and replicate the association of R139C with adverse events of thiopurines in Japanese patients. A total of 142 Japanese patients with IBD, with histories of thiopurine treatment, were examined. NUDT15 R139C was genotyped using a custom TaqMan genotyping assay. Adverse events including leukopenia were reviewed from medical records. The 6MP dose was adjusted to AZA equivalents by multiplying with 2 as a thiopurine dose. Five patients developed severe hair loss and all of them were risk homozygous (T/T) for R139C. No early severe hair loss was observed in patients with the C/T or C/C genotype (P=3.82 × 10(-16), odds ratio=212). The association of R139C with early (<8 weeks) leukopenia (white blood cells<3000 mm(-3)), which was previously reported in Korean patients, was replicated in our Japanese IBD cohort (P=1.92 × 10(-16), odds ratio=28.4). However, we could not confirm the association with late leukopenia in the Japanese subjects. Patients with the C/T genotype discontinued treatment or required thiopurine dose reduction significantly earlier than patients with the C/C genotype (P=1.45 × 10(-4)); however, on manipulating the doses, there was no significant difference in the thiopurine continuation rates between the groups. In the maintenance period, the frequencies of 6MP usage were higher, and the doses of thiopurines were significantly lower in patients with the C/T genotype than in those with the C/C genotype (0.574±0.316 mg kg(-1) per day vs 1.03±0.425 mg kg(-1) per day, P=6.21 × 10(-4)). NUDT R139C was significantly associated with early severe hair loss in Japanese patients with IBD. We also verified the previously reported association of R139C with early leukopenia in a different East Asian population. It is recommended that treatment with thiopurines should be avoided for patients with the T/T genotype. Low-dose 6MP (0.2-0.3 mg kg(-1) per day) could be used rather than AZA for the patients with C/T genotype to continue thiopurine treatments. However, late leukopenia and other several adverse events could not be completely predicted by R139C genotypes.

Objectives: To evaluate the incidence of hepatic steatosis after pancreatectomy and whether pancrelipase improves steatosis more effectively than other conventional digestive enzymes., Methods: Patients who underwent distal pancreatectomy, pancreaticoduodenectomy (PD), or total pancreatectomy (TP) from August 2008 to July 2013 were included. Incidence of newly developed hepatic steatosis recognized by computed tomography and outcomes by treatment with pancrealipase or other enzymes were evaluated., Results: A total of 473 patients were evaluated. Among 366 patients who did not take any digestive enzymes until the recognition of steatosis or the last follow-up date, hepatic steatosis was recognized in 3% (4/130), 17% (38/229), and 45% (3/7) of patients after distal pancreatectomy, PD, and TP, respectively, during the median follow-up of 641 days. Seventy patients including 25 patients taking digestive enzymes showed hepatic steatosis and were treated with pancrelipase (20 patients), other enzymes (19 patients), or no enzyme (31 patients). Cumulative improvement rate after 1 year of treatment in the 3 groups was 92%, 51%, and 56%, respectively, and that of the pancrelipase group was significantly better than the other 2 groups., Conclusion: The risk of hepatic steatosis should be a concern after PD and TP. Treatment with pancrelipase was more effective compared to other enzymes.

Background/aims: No study has reported whether perioperative administration of Daikenchuto (TJ-100) reduced paralytic ileus after pancreaticoduodenectomy (PD)., Methodology: Forty-five consecutive patients that were scheduled to undergo PD at Wakayama Medical University Hospital between August 2010 and August 2011 were enrolled in this study including the first cohort (n = 15) as the control group and the subsequent cohort (n = 30) as the TJ-100 group. This trial was registered at UMIN-CTR ID# 000005056., Results: Postoperative paralytic ileus occurred more frequently in the control group (73.3% of the control group and 20.0% of the TJ-100 group; p = 0.001). The first passages of flatus significantly improved earlier in the TJ-100 group than in the control group (p = 0.014). A multiple cytokine assay of the drainage and serum showed that IL-9 and IL-10 in the drainage was significantly higher on postoperative day 1 in the TJ-100 group. There were no complications associated with the preoperative administration of TJ-100 before surgery, and no significant differences were observed between the two groups in the incidence of postoperative Gradel-2 diarrhea (CTCAE4.0)., Conclusions: Perioperative administration of TJ-100 was feasible and reduced the incidence of paralytic ileus in PD, and further randomized controlled trials should be conducted.

Background & Aims: Lubiprostone is an activator of the type 2 chloride channel that facilitates spontaneous bowel movement (SBM). We performed phase 3 studies to determine whether lubiprostone increases the frequency of SBM in patients with chronic idiopathic constipation (CIC) in Japan, and whether long-term administration of lubiprostone increases the quality of life of patients with CIC., Methods: We performed a randomized, double-blind, placebo-controlled, phase 3 trial of lubiprostone. Patients with CIC (n = 124) were assigned randomly to groups given placebo (n = 62) or lubiprostone (48 μg/day; n = 62) for 4 weeks. The primary efficacy end point was the change from baseline in the weekly average number of SBMs after 1 week of administration. In a long-term study of efficacy and safety, 209 patients with CIC were given lubiprostone (24 μg twice daily) for 48 weeks., Results: Daily administration of lubiprostone induced a significantly greater change, from baseline, in the weekly average number of SBMs at week 1 (increase of 3.7 ± 2.8), compared with placebo (increase of 1.3 ± 1.8; P < .001). The frequency of SBMs during each week of the study period was significantly higher after subjects began receiving lubiprostone than at baseline (P < .0001 at all weeks). Long-term administration of lubiprostone significantly increased scores from the Short-Form health survey and irritable bowel syndrome quality-of-life questionnaire, compared with baseline. We did not observe any severe adverse reactions to lubiprostone., Conclusions: In phase 3 studies in Japan, lubiprostone increased the weekly average number of SBMs and increased the quality of life of patients with CIC. Clinical Trial Notification of the Japanese Regulatory Authorities: 20-3296 and 20-3300., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background/aims: Adalimumab (ADA) is a self-injectable anti-tumor necrosis factor-α antibody used for treating Crohn’s disease (CD). Although self-injecting ADA may be convenient for patients, few reports have assessed patients receiving ADA self-injection therapy., Methodology: We conducted a questionnaire survey involving outpatients on ADA self-injection therapy at four university hospitals. We analyzed the degree of satisfaction with and adherence to the self-injection therapy and performed sub-analyses., Results: Responses were obtained from 124 patients. Before treatment initiation, 38% patients replied that they were unwilling to accept the self-injection therapy. However, after treatment initiation, 75% patients were satisfied with the treatment. 66 patients previously treated with infliximab (IFX), the degree of treatment satisfaction was significantly higher in patients who felt burdened to the time required for IFX infusion than in those who had not felt burdened (P < 0.05). Patient adherence to ADA was high (85%). Multivariate analysis regarding adherence revealed that duration of disease (OR, 0.99), degree of treatment efficacy satisfaction (OR, 13.42), and schedule registration (OR, 7.95) were significant. Safety assessment results were within the range of those already reported., Conclusions: ADA self-injection was thought to have good adherence and a safe administration method according to patients’ assessments.

Background: Thirty to forty-five percent of ulcerative colitis (UC) patients show non-adherence to aminosalicylates, and non-adherence has been reported to increase the risk of clinical relapse. Because Japan differs from Western countries in terms of health care and drugs administered, adherence to aminosalicylates in Japan may differ from that elsewhere. Therefore, we examined aminosalicylate adherence and its relationship to the risk of clinical relapse of UC in Japan., Methods: A 1-year, prospective cohort study was conducted in 104 outpatients with UC in remission who had taken aminosalicylates >6 months. Aminosalicylate adherence was evaluated using data from a self-administered questionnaire and medical records. Non-adherence was defined as taking <80 % of the prescribed dose of aminosalicylates. The primary outcome was the record of clinical relapse in medical charts., Results: Twenty-nine patients (27.9 %) were evaluated as showing non-adherence. Among all subjects, 24 patients (23.1 %) relapsed. The non-adherence group had a higher rate of 1-year relapse than did the adherence group (41.3 vs. 16.0 %). Multiple Cox regression analysis showed that non-adherence increased the risk of clinical relapse 2.3-fold (hazard ratio 2.3, 95 % confidence interval 1.004-5.24, p = 0.04)., Conclusions: Although the adherence rate in this study was slightly higher than that in previous studies, Japanese patients with UC who were not adherent to their medications had a twofold greater risk of relapse than those who were. These results indicate the importance of early identification of patients with non-adherence. A program to support medication taking behavior is needed to prevent UC relapse.

What Is Known and Objective: Calcium channel blockers (CCBs), which have been widely used for the treatment of hypertension and angina pectoris, decrease lower oesophageal sphincter pressure and, as a result, can exacerbate gastrointestinal disease. In a previous study, increased risk of exacerbation of gastrointestinal disease among elderly patients following treatment with CCBs was identified. The prevalence of gastrointestinal diseases has increased in elderly patients, and it is possible that treatment with CCBs may have undesirably influenced this increase. The change in risk of gastrointestinal disease can be estimated by analysing changes in the prescription of antisecretory drugs as an outcome of exacerbation of gastrointestinal disease caused by CCBs., Methods: It was hypothesized that patients who were prescribed CCBs would also change their use of antisecretory drugs. From September 2005 to August 2009, a dynamic retrospective cohort study was performed at five community pharmacies in Nagasaki, Japan, to assess alteration of antisecretory drug therapy following treatment with CCBs. Correlations with alterations of antisecretory drug therapy were determined by the Cox proportional hazards model., Results and Discussion: The proposed study included 260 patients who were prescribed CCBs and 155 controls. During the study period, 53 patients were prescribed CCBs and 13 controls altered their antisecretory drug therapy; the hazard ratio was 2·22 (95% CI 1·25-4·26)., What Is New and Conclusion: Calcium channel blocker treatment of patients with gastrointestinal disease was associated with alteration in frequency of prescription and an increase in dosage of antisecretory drugs. For clinical management of hypertension, alternative antihypertensive drugs may be considered for patients with gastrointestinal diseases. Further studies are required to determine the influence of CCB therapy on gastroesophageal diseases, suggested by the increase in use of antisecretory drugs., (© 2011 Blackwell Publishing Ltd.)

Background and Aim: Little is known about the efficacy and safety of infliximab for ulcerative colitis refractory to tacrolimus. The aim of this study was to evaluate the efficacy and safety of infliximab in the induction of remission in ulcerative colitis patients with persistent symptoms despite tacrolimus therapy., Methods: We report a retrospective, observational, single-center case series of 12 consecutively enrolled patients with ulcerative colitis refractory to tacrolimus that received infliximab therapy for the induction of remission. Eight patients received a single infusion of infliximab, and four received two or more infusions. Median follow-up duration was 16.0 months (range, 1.6-41.4 months). The clinical response was evaluated based on a modified Truelove-Witts severity index., Results: Six patients (50.0%) achieved clinical remission within 30 days. Overall cumulative colectomy-free survival was estimated to be 58.3% at 41.4 months. Adverse events included an elevation of liver enzymes (1/12; 8.3%) and a mild infusion reaction (1/12; 8.3%). No mortality occurred., Conclusions: Infliximab can induce remission in patients with ulcerative colitis who do not tolerate or respond to tacrolimus therapy.

Objective: In patients with advanced cancer, malignant bowel obstruction (MBO) causes gastrointestinal symptoms such as nausea and vomiting leading to severely impaired oral food intake. Thus, MBO markedly diminishes the quality of life (QOL) of these patients because placement of a nasogastric tube becomes necessary. Many studies have shown that octreotide (SMS201-995; SMS), a synthetic analog of somatostatin, is effective for controlling the symptoms of MBO. This study was conducted to assess the efficacy and safety of 300-microg/day initial dose of SMS in Japanese patients with MBO and to investigate the clinical benefit of patients achieved by the improvement of nausea/vomiting based on subjective assessment., Methods: The subjects were patients with MBO that was refractory to other medical treatment and who had suffered at least two vomiting episodes per day for two consecutive days or had required a nasogastric tube. After enrollment, patients received SMS (300 microg/day) subcutaneously as a continuous injection for 6 days. Patients who responded to this 6-day course of treatment continued to receive the drug., Results: Among 25 patients who were enrolled, 11 (44.0%) responded to treatment with resolution or improvement of nausea/vomiting. Their symptomatic improvement was assessed by quantitatively measuring the level of control of nausea/vomiting and by using a self-administered QOL questionnaire that evaluated the frequency and severity of nausea/vomiting, the proportion of patients enjoying recreational activities and the overall patient satisfaction with the therapy. SMS was well tolerated, and nausea and agitation were the only adverse events potentially related to this drug., Conclusion: The results of the study confirmed that the 300-microg/day dose of SMS is safe and effective for patients with MBO uncontrolled by other therapies and suggested that the relief of symptoms with nausea/vomiting by SMS could contribute to improvement of the QOL of patients.

Background: Gastroesophageal reflux disease (GERD) impairs the patient's quality of life (QOL), but the effect of long-term maintenance therapy in elderly patients is unknown., Methods: We conducted a long-term prospective study. Forty-four GERD patients (11 males; mean age 74 years; QUEST score of at least 6 points) were enrolled in this study. Step-down therapy was selected (proton-pump inhibitor [PPI], histamine-2 receptor antagonist and prokinetic agents for 1 month, respectively). Optimal medication for each patient was continued for 5 years. The efficacy, safety of treatment and reflux symptoms were analyzed. The profiles of the patients who had to continue PPI maintenance therapy were also analyzed., Results: Reflux symptoms were reduced by the PPI based step-down therapy (baseline 13.8 times/month, after 3.2 times/month, P < 0.001). Reflux symptoms improved in 34 patients (77%). None of the 44 patients had to cease treatment because of side-effects and none experienced any complications during the 5-year period. The prevalence of Helicobacter pylori (Hp) infection in the PPI group (29%, 4/14) was significantly lower (P < 0.01) than in the other treatment group (72%, 21/29). The serum pepsinogen I/II ratio in the PPI treatment group (5.7 +/- 0.5) was significantly higher (P < 0.01) than in the others (4.0 +/- 0.3). The predictive factors for PPI maintenance therapy were Hp-negative status and serum pepsinogen I/II ratio >6.0 (odds ratio 12.0, 95% confidence interval 2.7-54.2)., Conclusions: Long-term medication for GERD selected on the basis of the patient's profile (i.e. Hp status and gastric atrophy) improved reflux symptoms.

Objective: The aim of this investigation was to elucidate retrospectively the therapeutic effect of infliximab in patients with active Crohn's disease (CD) under nutritional therapy., Material and Methods: Using a review of the clinical records in 24 nationwide institutions specializing in inflammatory bowel disease, the short-term effect of infliximab in 97 patients with active CD was retrospectively investigated. The Crohn's disease activity index (CDAI) at baseline and after 2 weeks of a single infliximab administration (5 mg/kg) was compared among patients under total parenteral nutrition (TPN group, n=36), those following an elemental or polymeric diet (EN group, n=49) and those without TPN and EN (NN group, n=12). A decrease in CDAI >or= 70 or a CDAI value <150 at 2 weeks was regarded as effective., Results: There was no difference in CDAI at baseline among the three groups. In each group, CDAI decreased significantly (from 250 (195-290) [median (interquartiles)] to 152 (123-233) in the TPN group, p<0.0001; from 259 (200-325) to 180 (130-238) in the EN group, p<0.0001; from 278 (222-291) to 164 (132-196) in the NN group, p=0.003). Infliximab was effective in 63.9% of patients in the TPN group, in 55.1% of those in the EN group and in 75% of the NN group. There was no statistical difference in efficacy among the three groups (p=0.4). Multivariate logistic regression analysis revealed younger age to be a significant factor related to the efficacy of infliximab., Conclusions: Infliximab is effective in patients with CD under TPN or EN. Age at infliximab administration may be predictive of response to infliximab.