[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Proton-pump inhibitors such as omeprazole are a standard treatment to prevent non-steroidal anti-inflammatory drug-induced upper gastrointestinal mucosal injuries. However, it is unclear which drugs may protect against all NSAID-induced digestive-tract injuries. Here, we compare the efficacy of the gastromucoprotective drug irsogladine with omeprazole in preventing NSAID-induced esophagitis, peptic ulcers, and small-intestinal mucosal injury in healthy subjects. METHODS: Thirty-two healthy volunteers were assigned to an irsogladine group (Group I; n = 16) receiving diclofenac sodium 75 mg and irsogladine 4 mg daily for 14 days, or an omeprazole group (Group O; n = 16) receiving diclofenac sodium 75 mg and omeprazole 10 mg daily for 14 days. Esophagitis and peptic ulcers were evaluated by esophagogastroduodenoscopy and small-intestinal injuries by capsule endoscopy, fecal calprotectin, and fecal occult blood before and after treatment. RESULTS: There was no significant difference between Group I and Group O with respect to the change in lesion score in the esophagus, stomach, and duodenum before and after treatment.NSAID treatment significantly increased the number of small intestinal mucosal breaks per subject by capsule endoscopic evaluation, from a basal level of 0.1 +/- 0.3 up to 1.9 +/- 2.0 lesions in Group O (p = 0.0002). In contrast, there were no significant changes in the mean number of mucosal breaks before and after co-treatment in Group I (0.3 +/- 0.8 to 0.5 +/- 0.7, p = 0.62), and the between-group difference was significant (p = 0.0040). Fecal calprotectin concentration, when the concentration before treatment was defined as 1, was significantly increased both in Group O (from 1.0 +/- 0.0 to 18.1 +/- 37.1, p = 0.0002) and Group I (from 1.0 +/- 0.0 to 6.0 +/- 11.1, p = 0.0280); the degree of increase in Group O was significantly higher compared with that in Group I (p<0.05). In addition, fecal occult blood levels increased significantly in Group O (p = 0.0018), but there was no change in Group I (p = 1.0), and the between-group difference was significant (p = 0.0031). CONCLUSION: Irsogladine protected against NSAID-induced mucosal injuries throughout the gastrointestinal tract, from esophagus to small intestine, significantly better than omeprazole.Trial registration: This study was registered in the UMIN Clinical Trials Registry (Registry ID number; UMIN000008114).
[Show abstract][Hide abstract] ABSTRACT: AIM: To assess adalimumab's efficacy with concomitant azathioprine (AZA) for induction and maintenance of clinical remission in Japanese Crohn's disease (CD) patients. METHODS: This retrospective, observational, single-center study enrolled 28 consecutive CD patients treated with adalimumab (ADA). Mean age and mean disease duration were 38.1 ± 11.8 years and 11.8 ± 10.1 years, respectively. The baseline mean Crohn's disease activity index (CDAI) and C-reactive protein were 177.8 ± 82.0 and 0.70 ± 0.83 mg/dL, respectively. Twelve of these patients also received a concomitant stable dose of AZA. ADA was subcutaneously administered: 160 mg at week 0, 80 mg at week 2, followed by 40 mg every other week. Clinical response and remission rates were assessed via CDAI and C-reactive protein for 24 wk. RESULTS: The mean CDAI at weeks 2, 4, 8, and 24 was 124.4, 120.2, 123.6, and 135.1, respectively. The CDAI was significantly decreased at weeks 2 and 4 with ADA and was significantly suppressed at 24 wk with ADA/AZA. Overall clinical remission rates at weeks 4 and 24 were 66.7% and 63.2%, respectively. Although no statistically significant difference in C-reactive protein was demonstrated, ADA with AZA resulted in a greater statistically significant improvement in CDAI at 24 wk, compared to ADA alone. CONCLUSION: Scheduled ADA with concomitant AZA may be more effective for clinical remission achievement at 24 wk in Japanese Crohn's disease patients.
World Journal of Gastroenterology 05/2013; 19(17):2676-2682. · 2.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective The calcineurin inhibitor tacrolimus has been shown to be safe and effective as salvage therapy for steroid-refractory ulcerative colitis (UC). Since differences in the onset of action between various agents are thought to influence the achievement and maintenance of disease remission, top-down or accelerated step-up therapy with tacrolimus may be useful. However, the efficacy of tacrolimus in moderate to severe UC patients not receiving concomitant steroids remains unknown. Methods Ten patients (11 attacks) with active, moderate to severe UC were treated with oral tacrolimus at a dose of 0.1 mg/kg body weight daily. The dosages were adapted to maintain trough whole-blood levels of 10 to 15 ng/mL to induce remission and 5 to 10 ng/mL to maintain remission. Lichtiger scores, the incidence of adverse effects (serum creatinine and glucose) and long-term outcomes were assessed. Results At four weeks after the initiation of tacrolimus therapy, clinical remissions were observed for eight attacks (72.7%) and clinical responses were demonstrated for three attacks. At 12 weeks after the initiation of tacrolimus treatment, clinical remissions were achieved for nine attacks (90%). After a mean follow-up of 10.4 months, clinical remissions were maintained for eight of 11 attacks. During the tacrolimus treatment, the serum creatinine and glucose levels were not significantly elevated. Conclusion Oral tacrolimus is a safe and effective therapy for the treatment of moderate to severe UC in patients not receiving concomitant treatment with systemic steroids. Although further studies are required to establish the efficacy and safety of oral tacrolimus therapy in patients with UC, oral tacrolimus may represent a top-down or accelerated step-up treatment option for patients with moderate to severe UC.
Internal Medicine 01/2013; 52(1):15-20. · 0.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endoscopic submucosal dissection (ESD) is reported to be a safe and reliable procedure for the elderly, but these reports could have already had a bias at the time ESD was performed. However, the reports have not clearly stated the criteria of indications. In the present study, we retrospectively elucidated the usefulness and problems of ESD for early gastric cancer in elderly patients (≥ 65 years) in comparison with non-elderly patients.
The subjects were selected from 412 consecutive patients with early gastric cancer (515 lesions) for which ESD was performed between June 2002 and February 2010. The following were used for analysis between groups: pre- and postoperative performance status (PS) of subjects, prevalence rates of pre-existing comorbidities, characteristics of lesions, treatment outcomes, durations of hospitalization, operating times, incidence rates of complications and durations of hospitalization, and postoperative hemorrhage rates, and duration of hospitalization in patients with anticoagulant therapy.
Of the lesions in the elderly, four patients (1.0%) were elderly with a PS of 3. The PS increased to six patients (1.6%) after the procedure. None of the non-elderly had a PS of 3 before or after the procedure. The ratio of patients with a pre-existing comorbidity was higher in the elderly than in the non-elderly. There were no differences between the two groups in the characteristics of the lesions, their duration of hospitalization, their operating times, or the incidence rates of complications. However, the elderly with perforations had a significantly longer hospitalization than the comparable non-elderly. The percentage of the patients taking anticoagulant drugs was significantly higher among the elderly. Of the patients on anticoagulant therapy, the duration of hospitalization tended to be longer in the elderly but no significant difference was found. None of the non-elderly with postoperative hemorrhage had received anticoagulant therapy. In the elderly with postoperative hemorrhage, 15.8% of the lesions were in those who had received anticoagulant therapy, indicating a significantly higher percentage of such lesions in the elderly group.
We conclude that ESD is useful in elderly patients because there is a similar risk as for the non-elderly if the approach is individualized, and the following are taken into consideration when making the final decision of performing ESD in an elderly patient: patients should have a PS of 0, 1, or 2; determine whether or not anticoagulant therapy can be discontinued and whether or not treatment can be performed reliably without complications.
Journal of Gastroenterology and Hepatology 04/2012; 27 Suppl 3:63-9. · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Collagenous colitis (CC) is a well-known cause of chronic non-bloody diarrhea, especially in elderly women. CC is characterized histopathologically by an increase in the thickness of the subepithelial collagen layer to at least 10 μm, epithelial damage, and chronic inflammation of the lamina propria. Generally, the colonic mucosa in CC is macroscopically normal, although minor, non-specific abnormalities may be found. Due to the recent advancement of endoscopic and diagnostic technologies, however, microscopic mucosal abnormalities and specific longitudinal linear lacerations of the mucosa characteristic of CC have been identified. The association of CC with non-steroidal anti-inflammatory drugs and proton pump inhibitors has also been reported. Since definitive diagnosis of CC has to rely on pathologically documented collagen bands and mononuclear infiltration, the efficiency and precision of colonic biopsy need to be improved. Of the 29 CC patients that we have encountered at our institution, it was in 15 of 29 cases that the endoscopic finding that we performed a biopsy on was apparent. Our comparison of the endoscopic and histopathological findings of CC in the 15 patients showed that the mucosa frequently appeared coarse and nodular on the surface of the mucosa, which was also significantly thicker in collagen bands, demonstrating a strong correlation between collagen band formation and CC. Also, the coarse and nodular surface of the mucosa was most frequently seen affecting the proximal colon. The results suggest that endoscopic observation and biopsy of the proximal colon, where a coarse and nodular surface of the mucosa is often found, may be useful for confirmation of the diagnosis in patients with suspected CC.
[Show abstract][Hide abstract] ABSTRACT: Intestinal deformity and stenosis are induced by fibrosis during the process healing of intestinal chronic inflammation in inflammatory bowel disease (IBD). Potent anti-inflammatory treatment of patients with Crohn's disease (CD) may induce fibrous stenosis, and this is often difficult to treat in clinical practice. Therefore, it is necessary to develop a treatment strategy that concomitantly exhibits repair/regenerative and anti-fibrotic effects, in addition to the current anti-inflammatory effect, for the treatment of inflammatory bowel diseases. However, the relationship between the course of inflammatory activity and the healing process and fibrogenesis has not been elucidated; although the complex involvement of various factors in the mechanism of biological fibrosis has been investigated. Simvastatin (SIMV), an HMG-CoA reductase inhibitor, exhibits anti-inflammatory and anti-fibrotic effects. The current study established a model of the regeneration/healing process from TNBS-induced colitis and investigated the anti-inflammatory and anti-fibrotic effects of SIMV.
Four groups of TNBS-induced colitis model were prepared using male SJL/J mice: A: Normal control group, B: control group, and C and D: treatment groups. The mucosal healing process was classified into three phases (an early phase: inflammation period, a mid-phase: regeneration promoting period, and a late phase: regeneration-converging period), and inflammation, the expression of fibrosis-related growth factors, and induction of apoptosis of fibrosis-related cells were compared in each period.
(1) The clinical findings showed that SIMV showed anti-inflammatory effects with body weight gain and improvement of epithelial injury in the late phase. Histological (macroscopic/microscopic) improvement was noted in the mid- and late phases. The inflammatory cytokine (TNF-α) level significantly decreased in the mid- and late phases in the high-dose treatment group. (2) SIMV also had anti-fibrotic effects characterized by a dose-dependent decrease in the level of a fibrosis-related growth factor (CTGF) in the early and mid-phases, irrespective of inflammation or changes in the TGF-β(1) level. Dose-dependent induction of apoptosis was noted in both fibroblasts and myofibroblasts from a relatively early stage.
The results suggested that SIMV induces anti-fibrotic activity that is not directly involved in the anti-inflammatory effect from a relatively early stage the healing process of TNBS-induced colitis.
Digestive Diseases and Sciences 09/2011; 57(2):335-44. · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Colorectal cancer is one of the most serious complications of ulcerative colitis (UC), and the risk of UC-associated neoplasia increases as the region and duration of the disease increase. Selective cyclooxygenase (COX)-2 inhibitors effectively diminish carcinogenesis in a murine UC model. However, this may exacerbate colitis. The selective COX-2 inhibitor etodolac is marketed as a racemic mixture of the R- and S-enantiomers. The biochemical and pharmacological effects of etodolac are caused by the S-enantiomer, while the R-enantiomer lacks COX-inhibitory activity. In this study, we evaluated the effect of R-etodolac on colitis-related mouse colon tumorigenesis. The mice received 1,2-dimethlhydrazine (DMH), and then chronic colitis was induced by administration of two cycles of DSS (each cycle: 3% DSS for 7 days followed by distilled water for 14 days). The mice were sacrificed 28 days after the completion of both cycles. Mice were divided into the following groups: group A served as a disease control; group B received a low (2-mg/kg) dose of R-etodolac every 3 days during the entire period; group C received a high (10-mg/kg) dose of R-etodolac on the same schedule as group B; and group D served as a normal control. Administration of R-etodolac decreased the disease activity index during the DSS administration cycle. The mean number of tumors was 17.8, 15.2, 6.0, and 0 in groups A-D, respectively. In group C, R-etodolac significantly suppressed the occurrence of neoplasia (p<0.05). Although R-etodolac treatment did not affect COX-2 expression, it significantly enhanced expression of E-cadherin in both neoplastic lesions and background mucosa (i.e., lesion-free colon). Thus, administration of R-etodolac exerts a suppressive effect on the development of neoplasia in a murine model of DSS-induced colitis without exacerbation of the colitis. These results suggest that R-etodolac could be useful in the prevention of UC-associated neoplasia.