Feed-forward activation of STAT3 signaling limits the efficacy of c-Met inhibitors in esophageal squamous cell carcinoma (ESCC) treatment.

c-Hepatocyte growth factor receptor (Met) inhibitors have demonstrated clinical benefits in some types of solid tumors. However, the efficacy of c-Met inhibitors in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we discovered that c-Met inhibitors induced "Signal Transducer and Activator of Transcription (STAT3)-addiction" in ESCC cells, and the feedback activation of STAT3 in ESCC cells limits the tumor response to c-Met inhibition. Mechanistically, c-Met inhibition increased the autocrine of several cytokines, including CCL2, interleukin 8, or leukemia inhibitory factor, and facilitated the interactions between the receptors of these cytokines and Janus Kinase1/2 (JAK1/2) to resultantly activate JAKs/STAT3 signaling. Pharmacological inhibition of c-Met together with cytokines/JAKs/STAT3 axis enhanced cancer cells regression in vitro. Importantly, combined c-Met and STAT3 inhibitors synergistically suppressed tumor growth and promoted the apoptosis of tumor cells without producing systematic toxicity. These findings suggest that inhibition of the STAT3 feedback loop may augment the response to c-Met inhibitors via the STAT3-mediated oncogene addiction in ESCC cells.

BP-1-102 and silencing of Fascin-1 by RNA interference inhibits the proliferation of mouse pituitary adenoma AtT20 cells via the signal transducer and activator of transcription 3/fascin-1 pathway.

INTRODUCTION: The expression levels of signal transducer and activator of transcription 3 (STAT3) protein and Fascin-1 were inhibited using the STAT3 inhibitor BP-1-102 and RNA interference, respectively, to investigate the expression of AtT20 in mouse pituitary cells. The proliferative capacity and related molecular mechanisms of pituitary tumor cells were then analyzed. METHODS: Mouse AtT20 pituitary adenoma cells were divided into a control group (Pa group), a STAT3 inhibitor vehicle group (PA + DMSO group), a STAT3 inhibitor group (PA + BP-1-102 group), a Fascin-1 negative control group (PA + neg-siRNA group) and a Fascin-1 silenced group (PA + Fascin-siRNA group). The related protein expression and cell proliferation of the five groups were measured using immunofluorescence, Western blot and real-time RT-PCR, whereas their apoptosis and cell cycle were evaluated using CCK-8 and flow cytometry. RESULTS: Proliferation of AtT20 cells is inhibited with BP-1-102 enhanced apoptosis, at the same time reduced the expression of Fascin-1 and N-cadherin, and increased the expression of E-cadherin. After inhibiting Fascin-1, the expression of STAT3 decreased, the expression of N-cadherin decreased and the expression of E-cadherin increased. CONCLUSIONS: BP-1-102 is a novel drug with a great potential in pituitary tumors. Given their important roles in the growth of pituitary adenomas, STAT3 and Fascin-1 can be used as new treatment targets.

GABA, γ-Aminobutyric Acid, Protects Against Severe Liver Injury.

BACKGROUND: Acute liver failure (ALF) from severe acute liver injury is a critical condition associated with high mortality. The purpose of this study was to investigate the impact of preemptive administration of γ-aminobutyric acid (GABA) on hepatic injury and survival outcomes in mice with experimentally induced ALF. MATERIALS AND METHODS: To induce ALF, C57BL/6NHsd mice were administered GABA, saline, or nothing for 7 d, followed by intraperitoneal administration of 500 µg of tumor necrosis factor α and 20 mg of D-galactosamine. The study mice were humanely euthanized 4-5 h after ALF was induced or observed for survival. Proteins present in the blood samples and liver tissue from the euthanized mice were analyzed using Western blot and immunohistochemical and histopathologic analyses. For inhibition studies, we administered the STAT3-specific inhibitor, NSC74859, 90 min before ALF induction. RESULTS: We found that GABA-treated mice had substantial attenuation of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive hepatocytes and hepatocellular necrosis, decreased caspase-3, H2AX, and p38 MAPK protein levels and increased expressions of Jak2, STAT3, Bcl-2, and Mn-SOD, with improved mitochondrial integrity. The reduced apoptotic proteins led to a significantly prolonged survival after ALF induction in GABA-treated mice. The STAT3-specific inhibitor NSC74859 eliminated the survival advantage in GABA-treated mice with ALF, indicating the involvement of the STAT3 pathway in GABA-induced reduction in apoptosis. CONCLUSIONS: Our results showed that preemptive treatment with GABA protected against severe acute liver injury in mice via GABA-mediated STAT3 signaling. Preemptive administration of GABA may be a useful approach to optimize marginal donor livers before transplantation.

STAT3 is involved in IL-6-Mediated Downregulation of Hepatic Transporters in Mice.

Interleukin (IL)-6 decreases hepatic expression of numerous transporters. Although IL-6 signaling occurs through STAT3, the extent of the involvement of the STAT3 signaling pathway has not been elucidated. PURPOSE: Our objective was to investigate whether IL-6-mediated effects occur through STAT3, and whether PXR plays a role in this regulation. METHOD: PXR null (-/-) or wild-type (+/+) male mice were pre-dosed with a selective STAT3 inhibitor S3I-201 (7.5 mg/kg ip) or vehicle (n=5-8/group) 30 minutes before receiving a single dose of IL-6 (1 µg ip) or saline. Animals were sacrificed after 6 hours and liver samples were analyzed using qRT-PCR and western blotting. RESULTS: As compared to saline controls, IL-6 decreased the expression of Cyp3a, Abcb1a, Abcc3, and Slco1a4 20-70% similarly in PXR (+/+) and (-/-) mice at 6 hr, while downregulation of Abcb11, Abcc2, Slc10a1and Slco2b1 was only seen in PXR (+/+). Pre-administration of S3I-201 attenuated IL-6-mediated changes of most transporters in PXR (+/+) and PXR (-/-) mice. At early times after IL-6 administration (10-120 minutes), transcript levels of Socs3, PXR, Abcb1a, Abcc3, Abcb11, Slco1a4 and Slco2b1were increased in PXR (+/+) mice. CONCLUSIONS: Our findings demonstrate that IL-6 imposes a significant downregulation of numerous ABC and SLC transporters in liver primarily through activation of the STAT3 signaling pathway. Based on time-dependent changes in transporter expression, downregulation likely occurs downstream of STAT3 activation.  As IL-6 is elevated in many diseases, understanding the underlying mechanism(s) involved in transporter dysregulation will allow us to predict potential drug-disease interactions.

Targeting phosphorylation of STAT3 delays tumor growth in HPV-negative anal squamous cell carcinoma mouse model.

Although conventional chemoradiotherapy is effective for most anal squamous cell carcinoma (ASCC) patients, HPV-negative ASCC patients respond poorly to this treatment and new therapeutic approach is required. Our group has previously established an HPV-negative ASCC mouse model and demonstrated that signal transducer and activation of transcription 3 (STAT3) is hyper-activated in the model. Here, we show that in vivo inhibition of STAT3 by S3I-201 effectively delays tumor growth in ASCC mouse model indicated by significantly smaller tumor size and burden in the treatment group compared with control group at the same point. Further analysis shows that survivin and Ki67, important biomarkers for tumor cell survival and proliferation, are significantly reduced after S3I-201 treatment. Additionally, flow cytometry and immunohistofluorescent assays reveal decreased Myeloid-derived suppressor cell (MDSC) and tumor-associated macrophage (TAM) populations in the S3I-201 treatment group, which indicates a reversion of the immunosuppressive environment, unraveling the potential role for S3I-201 in immunosuppression in ASCC. Together these results for the first time demonstrated the anti-tumor effects of STAT3 inhibitor S3I-201 in HPV-negative ASCC mouse model and its multiple effects on cancer cells and immune system. Thus we conclude that S3I-201 may be a novel therapeutic approach for HPV-negative ASCC patients.

Micellar nano-carriers for the delivery of STAT3 dimerization inhibitors to melanoma.

The objective of this research was to develop polymeric micellar formulations of inhibitors of signal transducer and activator of transcription 3 (STAT3) dimerization, i.e., S3I-1757 and S3I-201, and evaluate the activity of successful formulations in B16-F10 melanoma, a STAT3 hyperactive cancer model, in vitro and in vivo. STAT3 inhibitory agents were encapsulated in methoxy poly(ethylene oxide)-b-poly(ε-caprolactone) (PEO114-b-PCL22) and methoxy poly(ethylene oxide)-b-poly(α-benzyl carboxylate-ε-caprolactone) (PEO114-b-PBCL20) micelles using co-solvent evaporation. Polymeric micelles of S3I-1757 showed high encapsulation efficiency (>88%), slow release profile (<32% release in 24 h) under physiological conditions, and a desirable average diameter for tumor targeting (33-54 nm). The same formulations showed low encapsulation efficiencies and rapid drug release for S3I-201. Further studies evidenced the delivery of functional S3I-1757 by polymeric micelles to B16-F10 melanoma cells, leading to a dose-dependent inhibition of cell growth and vascular endothelial growth factor (VEGF) production comparable with that of free drug. Encapsulation of S3I-1757 in polymeric micelles significantly reduced its cytotoxicity in normal bone marrow-derived dendritic cells (DCs). Micelles of S3I-1757 were able to significantly improve the function of B16-F10 tumor-exposed immunosuppressed DCs in the production of IL-12, an indication for functionality in the induction of cell-mediated immune response. In a B16-F10 melanoma mouse model, S3I-1757 micelles inhibited tumor growth and enhanced the survival of tumor-bearing mice more than free S3I-1757. Our findings show that both PCL- and PBCL-based polymeric micelles have potential for the solubilization and delivery of S3I-1757, a potent STAT3 inhibitory agent.

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder.

PURPOSE: Cisplatin (CDDP) is frequently used in combination chemotherapy with paclitaxel for treating urothelial carcinoma of the urinary bladder (UCUB). CDDP cross-resistance has been suggested to develop with paclitaxel, thus hindering successful UCUB treatment. Therefore, elucidating the mechanisms underlying CDDP-induced anticancer drug resistance is imperative and may provide an insight in developing novel therapeutic strategy. EXPERIMENTAL DESIGN: Loss-of-function assays were performed to elucidate the role of the EGFR and STAT3 in CDDP-induced CCAAT/enhancer-binding protein delta (CEBPD) expression in UCUB cells. Reporter and in vivo DNA-binding assays were employed to determine whether CEBPD directly regulates ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily C member 2 (ABCC2) activation. Finally, a xenograft animal assay was used to examine the abilities of gefitinib and S3I-201 (a STAT3 inhibitor) to reverse CDDP and paclitaxel sensitivity. RESULTS: CEBPD expression was maintained in postoperative chemotherapy patients, and this expression was induced by CDDP even in CDDP-resistant UCUB cells. Upon CDDP treatment, CEBPD activated ABCB1 and ABCC2. Furthermore, the EGFR/STAT3 pathway contributed to CDDP-induced CEBPD expression in UCUB cells. Gefitinib and S3I-201 treatment significantly reduced the expression of CEBPD and enhanced the sensitivity of CDDP-resistant UCUB cells to CDDP and paclitaxel. CONCLUSIONS: Our results revealed the risk of CEBPD activation in CDDP-resistant UCUB cells and suggested a therapeutic strategy for patients with UCUB or UCUB resisted to CDDP and paclitaxel by combination with either gefitinib or S3I-201. Clin Cancer Res; 23(2); 503-13. ©2016 AACR.

Overcoming resistance of targeted EGFR monotherapy by inhibition of STAT3 escape pathway in soft tissue sarcoma.

Although epidermal growth factor receptor (EGFR) is often over-expressed in soft tissue sarcoma (STS), a phase II trial using an EGFR inhibitor gefitinib showed a low response rate. This study identified a new secondary resistance mechanism of gefitinib in STS, and developed new strategies to improve the effectiveness of EGFR inhibition particularly by blocking the STAT3 pathway.We demonstrated that seven STS cell lines of diverse histological origin showed resistance to gefitinib despite blockade of phosphorylated EGFR (pEGFR) and downstream signal transducers (pAKT and pERK) in PI3K/AKT and RAS/ERK pathways. Gefitinib exposure was not associated with decrease in the ratio of pSTAT3/pSTAT1. The relative STAT3 abundance and activation may be responsible for the drug resistance. We therefore hypothesized that the addition of a STAT3 inhibitor could overcome the STAT3 escape pathway.We found that the addition of STAT3 inhibitor S3I-201 to gefitinib achieved synergistic anti-proliferative and pro-apoptotic effects in all three STS cell lines examined. This was confirmed in a fibrosarcoma xenografted mouse model, where the tumours from the combination group (418mm3) were significantly smaller than those from untreated (1032mm3) or single drug (912 and 798mm3) groups.Our findings may have clinical implications for optimising EGFR-targeted therapy in STS.

Enhanced anti-ischemic stroke of ZL006 by T7-conjugated PEGylated liposomes drug delivery system.

The treatment for ischemic stroke is one of the most challenging problems and the therapeutic effect remains unsatisfied due to the poor permeation of drugs across the blood brain barrier (BBB). In this study, HAIYPRH (T7), a peptide that targeted to transferrin receptor (TfR) can mediate the transport of nanocarriers across the BBB, was conjugated to liposomes for ischemic stroke targeting treatment of a novel neuroprotectant (ZL006). T7-conjugated PEGylated liposomes (T7-P-LPs) loaded with ZL006 (T7-P-LPs/ZL006) were showed satisfactory vesicle size and size distribution. Furthermore, the cellular uptake results showed that T7 modification increased liposomes uptake by the brain capillary endothelial cells (BCECs) and little cytotoxicity of liposomes with or without ZL006 was observed. The in vivo biodistribution and near-infrared fluorescence imaging evidenced that T7 modification rendered liposomes significantly enhanced the transport of liposomes across the BBB. The pharmacodynamic study suggested that, T7-P-LPs/ZL006 exhibited reduced infarct volume and ameliorated neurological deficit compared with unmodified liposomes or free ZL006. T7-P-LPs/ZL006 could be targeted to brain and displayed remarkable neuroprotective effects. They could be used as a potential targeted drug delivery system of ischemic stroke treatment.

Saccharomyces boulardii does not prevent relapse of Crohn's disease.

BACKGROUND & AIMS: Saccharomyces boulardii is a probiotic yeast that has been shown to have beneficial effects on the intestinal epithelial barrier and digestive immune system. There is preliminary evidence that S boulardii could be used to treat patients with Crohn's disease (CD). We performed a randomized, placebo-controlled trial to evaluate the effects of S boulardii in patients with CD who underwent remission during therapy with steroids or aminosalicylates. METHODS: We performed a prospective study of 165 patients who achieved remission after treatment with steroids or salicylates; they were randomly assigned to groups given S boulardii (1 g/day) or placebo for 52 weeks. The primary end point was the percentage of patients in remission at week 52. Time to relapse, Crohn's disease activity index scores, and changes in parameters of inflammation were secondary end points. RESULTS: CD relapsed in 80 patients, 38 in the S boulardii group (47.5%) and 42 in the placebo group (53.2%, a nonsignificant difference). The median time to relapse did not differ significantly between patients given S boulardii (40.7 weeks) vs placebo (39.0 weeks). There were no significant differences between groups in mean Crohn's disease activity index scores or erythrocyte sedimentation rates or in median levels of C-reactive protein. In a post hoc analysis, nonsmokers given S boulardii were less likely to experience a relapse of CD than nonsmokers given placebo, but this finding requires confirmation. CONCLUSIONS: Although the probiotic yeast S boulardii is safe and well tolerated, it does not appear to have any beneficial effects for patients with CD in remission after steroid or salicylate therapies.

Long-term outcome of patients with distal ulcerative colitis and inflammation of the appendiceal orifice.

BACKGROUND AND AIMS: Skip inflammation of the appendiceal orifice has been described in distal UC (UC-IAO) but long-term clinical outcomes are poorly established. Our aim was to evaluate the long-term clinical outcomes of UC-IAO as compared to classic distal UC. METHODS: Patients with UC-IAO were identified from the local IBD database. Disease outcome and therapeutic requirements during follow-up were accurately collected, and compared with a control group of patients with distal UC without peri-appendiceal involvement matched by disease extent (proctitis/distal), smoking habit, and date and age at diagnosis. RESULTS: Fourteen UC patients were found to have UC-IAO, most of them with initial extent of UC limited to the rectum. All patients were initially managed with mesalazine administered orally (28.5%), topically (28.5%), or in combination (43%). After a median follow-up of 78 months (interquartile range--IQR 45-123) most UC-IAO patients were successfully managed with oral and/or topical aminosalicylates. Only one of them developed proximal disease progression. As compared to controls, no differences in clinical outcomes or therapeutic requirements were found. CONCLUSIONS: Patients with UC-IAO tend to present a mild course, with a low probability to develop proximal progression of disease extent or to require immunosuppressive therapy or colectomy.

[Analysis of total cost of treatment of patients with inflammatory bowel diseases].

The article stresses that among the chronic diseases of the digestive tract occupy a special place inflammatory bowel disease (IBD)--UC and BC with multiple complications and the onset of early disability of patients. IBD is a serious issue of gastroenterology, since their etiology remains unknown, and specific treatment hasn't yet been developed. Finally, the prevalence and social significance of IBD also occupy a leading place among the diseases of the digestive organs, since they are characterized by recurrent course and have adverse medical and social prognosis. According to sources in various countries annually spend huge money for treatment of IBD. The costs of IBD depends on the severity and nature of complications, duration of illness, the choice of treatment, frequency of hospitalization and the patient's country of residence. Various studies demonstrate the feasibility of using more modern efficient methods of treatment (MSSC + therapy) to reduce the incidence of complications associated with IBD, resulting in huge costs.

2-methoxy-5-amino-N-hydroxybenzamide sensitizes colon cancer cells to TRAIL-induced apoptosis by regulating death receptor 5 and survivin expression.

TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis is a crucial event in the control of tumor growth. However, many cancer cells, including colon cancer cells, are resistant to TRAIL-driven cell death. We have recently shown that 2-methoxy-5-amino-N-hydroxybenzamide (herein termed 2-14), a novel derivative of mesalamine, induces endoplasmic reticulum stress in colon cancer cells. Because endoplasmic reticulum stress-induced signals regulate the expression of molecules involved in TRAIL-driven apoptosis, we examined whether 2-14 makes colon cancer cells sensitive to TRAIL. Colon cancer cells were cultured with 2-14 and/or TRAIL. Death receptor (DR) 4/DR5 were analyzed by real-time PCR and flow cytometry. TRAIL pathway-associated proteins and extracellular signal-regulated kinase (ERK) were assessed by Western blotting. The in vivo capability of 2-14 to sensitize colon cancer cells to TRAIL-induced apoptosis was evaluated in a syngenic colon cancer model in which CT26-derived grafts were induced in mice. 2-14 promoted ERK-dependent induction of DR5, thereby enhancing TRAIL-mediated caspase-8 activation and apoptosis. Analysis of TRAIL-related pro- and antiapoptotic factors and functional studies revealed that survivin is involved in the protection of colon cancer cells against TRAIL-driven apoptosis. Notably, 2-14 enhanced ubiquitination and proteasome-mediated degradation of survivin. These data were confirmed in a murine model of TRAIL-resistant colon cancer in which 2-14 upregulated DR5, reduced survivin expression, and synergized with TRAIL in inhibiting tumor growth. Similarly, intraperitoneal administration of 2-14 to mice upregulated DR5 and downregulated survivin in a model of colitis-associated colon cancer. These findings indicate that 2-14 acts as a sensitizer for TRAIL-induced apoptosis and suggest that 2-14 can be useful in the therapy for TRAIL-resistant colon cancer.

Treating TNBS-induced colitis in rats with probiotics.

BACKGROUND/AIMS: We aimed to investigate the therapeutic effects of Peifeikang, a probiotics compound, on colitis in rats induced by trinitrobenzene sulfonic acid and to elucidate its potential mechanism. MATERIAL AND METHODS: We evaluated the therapeutic effects of Peifeikang by analysis of the disease activity index, colonic mucosa damage index, and histopathological score of the inflamed colons, by measurement of colonic myeloperoxidase activity through spectrophotometric assay, by determination of colonic positivities of tumor necrosis factor-alpha and interleukin-10 via immunochemical staining, and by detection of serum levels of tumor necrosis factor-alpha and interleukin-10 with enzyme-linked immunosorbent assay. RESULTS: Intrarectal administration of trinitrobenzene sulfonic acid caused colonic inflammation similar to human ulcerative colitis with significantly increased disease activity index, colonic mucosa damage index, histopathological score, and colonic myeloperoxidase activities (p<0.05). After treatment with Peifeikang or olsalazine alone, or both, disease activity index, colonic mucosa damage index, histopathological score, and colonic myeloperoxidase activities decreased significantly (p<0.05). The relief of trinitrobenzene sulfonic acid-induced colitis was accompanied by significantly decreased production of tumor necrosis factor-alpha in both serum and intra-colon (p<0.05) and by significantly increased production of interleukin-10 in both serum and intra-colon (p<0.05). CONCLUSIONS: Peifeikang can effectively ameliorate trinitrobenzene sulfonic acid-induced colitis in rats, the underlying mechanism of which may be attributed to the modulatory effects of Peifeikang on the production of tumor necrosis factor-alpha and interleukin-10.

The effect of chitosan as internal or external coating on the 5-ASA release from calcium alginate microparticles.

The effect of chitosan as internal or external coating on the mesalamine (5-ASA) release from calcium alginate microparticles (CaAl) was studied, and a delayed release of 5-ASA system intended for colonic drug delivery was developed. The external chitosan coating was developed by immersion of wetted CaAl in chitosan solution and the internal coating by mixing 5-ASA with chitosan solution and drying before the preparation of CaAl. Both systems were coated with Acryl-EZE® using combined fluid bed coating and immersion procedure. The results showed that in phosphate medium (pH 7.5), chitosan as 5-ASA coating promotes a quick erosion process accelerating drug release, but chitosan as external coating (CaAlCS) does not increase the T (50) value compared with the microparticles without chitosan (CaAl). Chitosan as internal or external coating was not effective to avoid the quick 5-ASA release in acidic medium (pH 1.2). The presence of ß-glucosidase enzymes increases significantly the 5-ASA release for CaAl, while no effect was observed with chitosan as internal or external coating. Fourier transform infrared spectroscopy, thermogravimetric analysis, and X-ray data revealed that 5-ASA did not form a solid solution but was dispersed in the microparticles. The Acryl-EZE® coating of microparticles was effective because all the formulations showed a low release, less than 15%, of 5-ASA in acid medium at pH 1.2. Significant differences in the percentage of 5-ASA released between formulations were observed in phosphate buffer at pH 6.0. In phosphate buffer at pH 7.2, all the formulations released 100% of 5-ASA.

Efficacy of a novel sphingosine kinase inhibitor in experimental Crohn's disease.

AIM: Activation of sphingosine kinase (SK) is a key response to many inflammatory processes. The present studies test the hypothesis that an orally available SK inhibitor, ABC294640, would be effective in rodent models of Crohn's disease. METHODS: Trinitrobenzene sulfonic acid (TNBS) was administered rectally to mice and rats. Rats were treated with ABC294640 orally alone or in combination with olsalazine and disease progression was monitored. RESULTS: For both rodent species, treatment with ABC294640 attenuated disease progression. Colon samples from the ABC294640-treated animals had improved histology and cytokine parameters when compared with vehicle-treated animals. The expression of SK was similarly increased in TNBS-treated animals and in human colon tissue specimens from inflammatory bowel disease patients relative to normal, control patients. CONCLUSIONS: Sphingosine kinase may be a critical mediator of colonic damage during intestinal inflammation, and pharmacologic inhibitors of this enzyme may prove useful in the treatment of Crohn's disease.

N,N'-Bis(5-aminosalicyl)-L-cystine is a potential colon-specific 5-aminosalicylic acid prodrug with dual therapeutic effects in experimental colitis.

To evaluate N,N'-bis(5-aminosalicyl)-L-cystine (5-ASA-Cys) as a potential colon-specific 5-aminosalicylic acid prodrug with dual therapeutic effects in experimental colitis, the pharmacokinetics and therapeutic activity were investigated after oral administration of 5-ASA-Cys and amelioration of experimental colitis was compared after rectal administration of 5-aminosalicylic acid (5-ASA) and/or cysteine. In addition, the gluthathione (GSH) level in the inflamed colonic tissue was examined after administration of cysteine or 5-ASA-Cys. Oral administration of 5-ASA-Cys delivered much greater amount of 5-ASA to the large intestine and excreted lower amount of 5-ASA via urine than that of free 5-ASA. Oral administration of 5-ASA-Cys ameliorated experimental colitis of rats induced by TNBS, which was more effective than that of sulfasalazine. Although cysteine administered rectally was not significantly effective, intracolonic treatment with both 5-ASA and cysteine showed a synergic effect in alleviating the rat colitis. Furthermore, not only 5-ASA-Cys administered orally but also cysteine administered rectally increased the glutathione level in the inflamed colonic tissue. Taken together, these results suggest that 5-ASA-Cys is a potential colon specific 5-ASA prodrug with dual therapeutic effects on experimental colitis and cysteine modulation of the glutathione level may be relevant to the dual effects of the prodrug.

Strategies to improve adherence and outcomes in patients with ulcerative colitis.

This review examines studies of patient adherence to 5-aminosalicylic acid therapy conducted outside the context of a controlled therapy trial, considers the reasons why patients do not adhere to their medication and its consequences, and interventions to improve adherence and disease outcomes. Non-adherence in the inflammatory bowel disease population tends to mirror other chronic illnesses, in the range of 40-60%. Factors that appear to affect adherence include younger age, single status, heavy pill burden, perception of lack of benefit and feeling uninformed about the effect of medication. Three important outcomes of non-adherence include increased risk for disease activity, increased healthcare costs and the possible increased risk of dysplasia/colorectal cancer. Strategies to improve adherence include patient education and 'health literacy', along with discussing patient misperceptions and fears on an individual basis, decreasing the daily regimen and switching to high-dose formulations, and incorporating patient self-management techniques into practice.

Novel 5-aminosalicylic acid formulations in ulcerative colitis: old dog, new tricks.

Ulcerative colitis is a chronic inflammatory bowel disease, often associated with abdominal pain, rectal bleeding, fatigue, and poor quality of life. Although 5-aminosalicylic acid (5-ASA) preparations are the mainstay of treatment of this condition, the observed efficacy of many current formulations is limited by delivery systems that require multiple-daily dosing schedules and are associated with poor patient adherence. It is of critical importance that patients adhere to medication regimens, because failure to do so has been shown to result in a greater number of disease flares and an increased risk of complications, including colorectal cancer. Patient-friendly formulations of 5-ASA have recently been approved or are in development to overcome the limitations of many older formulations and improve remission rates. As a major point of contact for many patients with ulcerative colitis, it is essential that gastrointestinal nurses keep abreast of such relevant developments in treatment options. Indeed, nurses are a crucial educational conduit for patients and are in a unique position to serve as trusted educators on important issues. This review provides an update on recent advances in 5-ASA therapy to ensure that gastrointestinal nurses are aware of potential strategies for improving clinical outcomes of patients with ulcerative colitis.