• Archives of Pharmacal Research
• /
• 제26권4호
• /
• pp.264-269
• /
• 2003

5-Aminosalicylic acid (5-ASA) is an active ingredient of therapeutic agents used for Crohn s disease and ulcerative colitis. Because it is absorbed rapidly and extensively in the upper intestine, delivery of the agent specifically to the colon is necessary. We selected taurine as a colon-specific promoiety and designed 5-aminosalicyltaurine (5-ASA-Tau) as a new colon-specific prodrug of 5-aminosalicylic acid (5-ASA). It was expected that introduction of taurine would restrict the absorption of the prodrug and show additive effect to the anti-inflammatory action of 5-ASA after hydrolysis. 5-ASA-Tau was prepared in good yield by a simple synthetic route. The apparent partition coefficient of 5-ASA-Tau in 1-octanol/pH 6.8 phosphate buffer or $CHCl_3$/pH 6.8 phosphate buffer was 0.10 or 0.18, respectively, at $37^{\circ}C$. To determine the chemical and biochemical stability in the upper intestinal environment, 5-ASA-Tau was incubated in pH 1.2 and 6.8 buffer solutions, and with the homogenates of tissue and contents of stomach or small intestine of rats at $37^{\circ}C$. 5-ASA was not detected from any of the incubation medium with no change in the concentration of 5-ASA-Tau. On incubation of 5-ASA-Tau with the cecal and colonic contents of rats, the fraction of the dose released as 5-ASA was 45% and 20%, respectively, in 8 h. Considering low partition coefficient and stability in the upper intestine, 5-ASA-Tau might be nonabsorbable and stable in the upper intestine. After oral administration, it would be delivered to the colon in intact form and release 5-ASA and taurine. These results suggested 5-ASA-Tau as a promising colon-specific prodrug of 5-ASA.

• Asian Pacific Journal of Cancer Prevention
• /
• 제15권8호
• /
• pp.3477-3482
• /
• 2014

Objective: Patients with inflammatory bowel disease (IBD) have an increased risk of extra-intestinal cancer, whereas its impact on cholangiocarcinoma (CC) remains unknown. The aim of this study was to obtain a reliable estimate of the risk of CC in IBD patients through a meta-analysis of clinical observational studies. Methods: Relevant studies were retrieved by searching PUBMED, EMBASE and Web of Science Databases up to Dec 2013. Four population-based case-control and two cohort studies with IBD were identified. Summary relative risk (RR) and its corresponding 95% confidence interval (CI) were calculated using a random-effects model. Potential sources of heterogeneity were detected using subgroup analyses. Results: The pooled risk estimate indicated IBD patients were at increased risk of CC (RR = 2.63, 95%CI = 1.47-4.72). Moreover, the increased risk of CC was also associated with Crohn's disease (RR = 2.69, 95%CI = 1.59-4.55) and ulcerative colitis (RR = 3.40, 95%CI = 2.50-4.62). In addition, site-specific analyses revealed that IBD patients had an increased risk of intrahepatic CC (ICC) (RR = 2.61, 95%CI = 1.72-3.95) and extrahepatic CC (ECC) (RR = 1.47, 95%CI = 1.10-1.97). Conclusions: This study suggests the risk of CC is significantly increased among IBD patients, especially in ICC cases. Further studies are warranted to enable definite conclusions to be drawn.

• Asian Pacific Journal of Cancer Prevention
• /
• 제14권5호
• /
• pp.2689-2698
• /
• 2013

Epithelial-to-mesenchymal transition (EMT) is a collection of events that allows the conversion of adherent epithelial cells, tightly bound to each other within an organized tissue, into independent fibroblastic cells possessing migratory properties and the ability to invade the extracellular matrix. EMT contributes to the complex architecture of the embryo by permitting the progression of embryogenesis from a simple single-cell layer epithelium to a complex three-dimensional organism composed of both epithelial and mesenchymal cells. However, in most tissues EMT is a developmentally restricted process and fully differentiated epithelia typically maintain their epithelial phenotype. Recently, elements of EMT, specially the loss of epithelial markers and the gain of mesenchymal markers, have been observed in pathological states, including epithelial cancers. Increasing evidence has confirmed its presence in human colon during colorectal carcinogenesis. In general, chronic inflammation is considered to be one of the causes of many human cancers including colorectal cancer(CRC). Accordingly, epidemiologic and clinical studies indicate that patients affected by ulcerative colitis and Crohn's disease, the two major forms of inflammatory bowel disease, have an increased risk of developing CRC. A large body of evidence supports roles for the SMAD/STAT3 signaling pathway, the NF-kB pathway, the Ras-mitogenactivated protein kinase/Snail/Slug and microRNAs in the development of colorectal cancers via epithelial-tomesenchymal transition. Thus, EMT appears to be closely involved in the pathogenesis of colorectal cancer, and analysis refered to it can yield novel targets for therapy.

• ALGAE
• /
• 제35권2호
• /
• pp.201-212
• /
• 2020

The inflammatory bowel diseases (IBD) including ulcerative colitis and Crohn disease are characterized by chronic inflammation throughout the gastrointestinal tract. The prevalence of IBD has been increasing worldwide, and has sometimes led to irreversible impairment of gastrointestinal structure and functions. In the present study, we identified a new sulfoquinovosylmonoacylglycerols (SQMG) (1) together with two known SQMGs (2 and 3) regulating intestinal inflammation from the brown alga Turbinaria ornata. The anti-inflammatory properties of two bioactive SQMGs, 1 and 2 were evaluated using an in vitro co-culture system consisting of human epithelial Caco-2 cells and PMA (phorbol 12-myristate 12-acetate)-differentiated THP-1 macrophages. Treatment with 1 or 2 inhibited the production nitric oxide and prostaglandin E₂ induced by lipopolysaccharide and interferon γ challenge. The expressions of inducible nitric oxide synthase and cyclooxygenase 2 were markedly down-regulated in response to inhibition of nuclear factor κB translocation to nucleus. These findings suggest the potential use of the brown alga T. ornata and its biologically active metabolites SQMGs as pharmaceutical adjuvants in the treatment of inflammation-related diseases, including IBD.

• Pediatric Gastroenterology, Hepatology & Nutrition
• /
• 제17권3호
• /
• pp.147-154
• /
• 2014

Purpose: Gender differences in paediatric patients with inflammatory bowel disease (IBD) are frequently reported as a secondary outcome and the results are divergent. To assess gender differences by analysing data collected within the Swiss IBD cohort study database since 2008, related to children with IBD, using the Montreal classification for a systematic approach. Methods: Data on gender, age, anthropometrics, disease location at diagnosis, disease behaviour, and therapy of 196 patients, 105 with Crohn's disease (CD) and 91 with ulcerative or indeterminate colitis (UC/IC) were retrieved and analysed. Results: The crude gender ratio (male : female) of patients with CD diagnosed at <10 years of age was 2.57, the adjusted ratio was 2.42, and in patients with UC/IC it was 0.68 and 0.64 respectively. The non-adjusted gender ratio of patients diagnosed at ${\geq}10$ years was 1.58 for CD and 0.88 for UC/IC. Boys with UC/IC diagnosed <10 years of age had a longer diagnostic delay, and in girls diagnosed with UC/IC >10 years a more important use of azathioprine was observed. No other gender difference was found after analysis of age, disease location and behaviour at diagnosis, duration of disease, familial occurrence of IBD, prevalence of extra-intestinal manifestations, complications, and requirement for surgery. Conclusion: CD in children <10 years affects predominantly boys with a sex ratio of 2.57; the impact of sex-hormones on the development of CD in pre-pubertal male patients should be investigated.

• Pediatric Gastroenterology, Hepatology & Nutrition
• /
• 제16권3호
• /
• pp.171-177
• /
• 2013

Purpose: This study was aimed to evaluate the frequency and course of adverse events associated with azathioprine treatment in Korean pediatric patients with inflammatory bowel disease. Methods: Total of 174 pediatric patients (age range, 1 to 19 years) with inflammatory bowel disease who received azathioprine in order to maintain remission at Samsung Medical Center (Seoul, Korea) from January 2002 through December 2012 were included in this study. Medical records of these subjects were retrospectively reviewed regarding the development of adverse events associated with azathioprine treatment. Results: Ninety-eight patients (56.3%) of 174 patients experienced 136 episodes of adverse events, requiring dose reduction in 31 patients (17.8%), and discontinuation in 18 patients (10.3%). The mean dose of azathioprine that had been initially administered was $1.32{\pm}0.42$ mg/kg/day. Among the adverse reactions, bone marrow suppression developed in 47 patients (27.0%), requiring dose reduction in 22 patients (12.6%) and discontinuation in 8 patients (4.6%). Other adverse events that occurred were gastrointestinal disturbance (15.5%), hair loss (12.1%), pancreatitis (7.5%), arthralgia (6.9%), hepatotoxicity (2.9%), skin rash/allergic reactions (2.9%), headache/dizziness (2.3%), sepsis (0.6%), and oral mucositis (0.6%). Conclusion: Bone marrow suppression, especially leukopenia was most commonly associated with azathioprine treatment in Korean pediatric inflammatory bowel disease patients. Close observation for possible adverse events is required in this population with inflammatory bowel diseases who are under treatment with azathioprine.

• 한국약용작물학회지
• /
• 제26권3호
• /
• pp.233-239
• /
• 2018

Background: Inflammation plays an important role in various diseases, including ulcerative colitis, Behcet's disease, and rheumatoid arthritis. In this study, we investigated the anti-inflammatory effects of Morus alba L. extracts obtained using different extraction methods (water extraction or high temperature extraction) on RAW264.7 cells. Methods and Results: Extracts from the central part (including the heartwood, sapwood, cambiun, and phloem) and bark (including the periderm and cortex) of Morus alba L. were obtained using either water or high temperature extraction. The following extract were obtained: MA1, water extract from the central part of Morus alba L., MA2, high temperature extract from the central part of Morus alba L., MA3, water extract from the bark of Morus alba L., and MA4, high temperature extract from the bark of Morus alba L. None of these extracts was observed to be cytotoxic to RAW264.7 cells. The MA2 extract reduced the production of LPS-induced NO (nitric oxide), $PGE_2$ (prostaglandin $E_2$), $TNF-{\alpha}$, IL-6, and $IL-1{\beta}$ production in LPS-stimulated RAW264.7 cells. Conclusions: These results indicated that the inflammatory response was moderated by MA2. Treatment with MA2 could be used as a natural medicine for treating diseases involving inflammation. However, further experiments are required to determine how the high temperature extraction method alters the active ingredients in the extract and influences the anti-inflammatory effects of Morus alba L..

• 약학회지
• /
• 제42권1호
• /
• pp.5-11
• /
• 1998

5-Aminosalicyl-L-aspartic acid (5-ASA-Asp) and 5-aminosalicyl-L-glutamic acid (5-ASA-Glu) were synthesized as new colon-specific prodrugs of 5-aminosalicylic acid (5-ASA), their apparent partition coefficients, and the extent of conversion in the homogenates of tissue and contents of various G.I. Tract segments of rats were evaluated. These prodrugs were stable in the homogenate of tissue and contents of stomach, proximal small intestine (PSI) or distal small intestine (DSI). Release of 5-ASA from 5-ASA-Asp after incubation with the cecal and colonic contents for 8hrs at $37^{\circ}C$ was 18%, and 8%, respectively. No significant conversion of prodrug was observed in the cecal and colonic contents of rats pretreated with kanamycin sulfate, which indicated that microbial enzymes were responsible for the cleavage of these prodrugs.

• Pediatric Gastroenterology, Hepatology & Nutrition
• /
• 제25권3호
• /
• pp.180-193
• /
• 2022

Pediatric inflammatory bowel disease (PIBD) is a multisystem disorder characterized by intestinal and extraintestinal manifestations and complications. Cerebrovascular events (CVE) are rare extraintestinal complications in patients with PIBD. Statistics show that 3.3% patients with PIBD and 1.3-6.4% adult patients with inflammatory bowel disease (IBD) experience CVE during the course of the disease. Therefore, this study aimed to review the records of children with IBD who developed CVE during the course of the disease. We retrospectively reviewed 62 cases of PIBD complicated by CVE. The mean patient age at the time of thrombotic events was 12.48±4.13 years. The incidence of ulcerative colitis was significantly higher than that of Crohn's disease (43 [70.5%] vs. 13 [21.3%] patients). Most patients (87.93%) were in the active phase of IBD at the time of CVE. The mean time interval between the onset of IBD and CVE was 20.84 weeks. Overall, 11 (26.83%) patients showed neurological symptoms of CVE at disease onset. The most frequent symptom on admission was persistent and severe headaches (67.85%). The most common site of cerebral venous thrombosis was the transverse sinuses (n=23, 53.48%). The right middle cerebral artery (n=3, 33.34%) was the predominant site of cerebral arterial infarction. Overall, 41 (69.49%) patients who were mostly administered unfractionated heparin or low-molecular-weight heparin (56.09%) recovered completely. Patients with IBD are at a risk of thromboembolism. CVE may be the most common type of thromboembolism. Based on these findings, the most common risk factor for CVE is IBD flares. In patients with CVE, anticoagulant therapy with heparin, followed by warfarin, is necessary.

• Pediatric Gastroenterology, Hepatology & Nutrition
• /
• 제26권4호
• /
• pp.181-192
• /
• 2023

Purpose: The development of assistive devices has allowed for the performance of capsule endoscopy in children. Anticipating the capsule's transit time could affect the efficacy of the investigation and potentially minimize the fasting period. This study determined the predictors of small bowel transit time for small-bowel capsule endoscopy in children and adolescents with inflammatory bowel disease. Methods: We retrospectively examined children and adolescents with inflammatory bowel disease who underwent capsule endoscopy by the age 18 at a Japanese tertiary care children's hospital. Small bowel transit time predictors were analyzed using multiple regression with explanatory variables. Results: Overall, 92 patients, aged 1-17 years, with inflammatory bowel disease (63 Crohn's disease and 29 ulcerative colitis cases) were examined for factors affecting small bowel transit time. In the simple regression analysis, diagnosis, age, height, weight, serum albumin, general anesthesia, and small intestine lesions were significantly associated with small bowel transit time. In the multiple regression analyses, serum albumin (partial regression coefficient: -58.9, p=0.008), general anesthesia (partial regression coefficient: 127, p<0.001), and small intestine lesions (partial regression coefficient: 30.1, p=0.037) showed significant associations with small bowel transit time. Conclusion: Hypoalbuminemia, the use of general anesthesia for endoscopic delivery of the capsule, and small intestine lesions appeared to be predictors of prolonged small bowel transit time in children and adolescents with inflammatory bowel disease. Expecting the finishing time may improve examination with a fasting period reduction, which benefits both patients and caregivers.