Anti-Citrullinated Protein Antibodies With Multiple Specificities Ameliorate Collagen Antibody-Induced Arthritis in a Time-Dependent Manner.

OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) are highly specific for rheumatoid arthritis (RA) and have long been regarded as pathogenic. Despite substantial in vitro evidence supporting this claim, reports investigating the proinflammatory effects of ACPAs in animal models of arthritis are rare and include mixed results. Here, we sequenced the plasmablast antibody repertoire of a patient with RA and functionally characterized the encoded ACPAs. METHODS: We expressed ACPAs from the antibody repertoire of a patient with RA and characterized their autoantigen specificities on antigen arrays and enzyme-linked immunosorbent assays. Binding affinities were estimated by bio-layer interferometry. Select ACPAs (n = 9) were tested in the collagen antibody-induced arthritis (CAIA) mouse model to evaluate their effects on joint inflammation. RESULTS: Recombinant ACPAs bound preferentially and with high affinity (nanomolar range) to citrullinated (cit) autoantigens (primarily histones and fibrinogen) and to auto-cit peptidylarginine deiminase 4 (PAD4). ACPAs were grouped for in vivo testing based on their predominant cit-antigen specificities. Unexpectedly, injections of recombinant ACPAs significantly reduced paw thickness and arthritis severity in CAIA mice as compared with isotype-matched control antibodies (P ≤ 0.001). Bone erosion, synovitis, and cartilage damage were also significantly reduced (P ≤ 0.01). This amelioration of CAIA was observed for all the ACPAs tested and was independent of cit-PAD4 and cit-fibrinogen specificities. Furthermore, disease amelioration was more prominent when ACPAs were injected at earlier stages of CAIA than at later phases of the model. CONCLUSION: Recombinant patient-derived ACPAs ameliorated CAIA. Their antiinflammatory effects were more preventive than therapeutic. This study highlights a potential protective role for ACPAs in arthritis.

Preclinical Pharmacokinetics and Acute Toxicity in Rats of 5-{[(2E)-3-Bromo-3-carboxyprop-2-enoyl]amino}-2-hydroxybenzoic Acid: A Novel 5-Aminosalicylic Acid Derivative with Potent Anti-Inflammatory Activity.

Compound 5-{[(2E)-3-bromo-3-carboxyprop-2-enoyl]amino}-2-hydroxybenzoic acid (C1), a new 5-aminosalicylic acid (5-ASA) derivative, has proven to be an antioxidant in vitro and an anti-inflammatory agent in mice. The in vivo inhibition of myeloperoxidase was comparable to that of indomethacin. The aim of this study was to take another step in the preclinical evaluation of C1 by examining acute toxicity with the up-and-down OECD method and pharmacokinetic profiles by administration of the compound to Wistar rats through intravenous (i.v.), oral (p.o.), and intraperitoneal (i.p.) routes. According to the Globally Harmonized System, C1 belongs to categories 4 and 5 for the i.p. and p.o. routes, respectively. An RP-HPLC method for C1 quantification in plasma was successfully validated. Regarding the pharmacokinetic profile, the elimination half-life was approximately 0.9 h with a clearance of 24 mL/min after i.v. administration of C1 (50 mg/kg). After p.o. administration (50 mg/kg), the maximum plasma concentration was reached at 33 min, the oral bioavailability was about 77%, and the compound was amply distributed to all tissues evaluated. Therefore, C1 administered p.o. in rats is suitable for reaching the colon where it can exert its effect, suggesting an important advantage over 5-ASA and indomethacin in treating ulcerative colitis and Crohn's disease.

In vitro release kinetics of graft matrices from Lannea coromandelica (Houtt) gum for treatment of colonic diseases by 5-ASA.

Polyacrylamide graft Jhingan gum (Jh-g-PAMs) was synthesized adopting microwave assisted graft co-polymerization technique. The synthesized graft copolymer was characterized by various analytical techniques such as Elemental analysis, FTIR, TGA, XRD and NMR. Following standard protocol, drug matrix tablets using 5-Aminosalicylic Acid (5-ASA) were prepared and swelling and erosion studies were carried out in different pH dissolution media. The result revealed that maximum swelling and erosion took place in pH 7.4 while the lowest was recorded in pH 1.2. The 'in vitro' drug release studies revealed that grades with higher grafting % exhibited more sustained release. The highest sustained release was observed in Jh-g-PAM 3 (%G 1231) in pH 1.2 while the least was observed in native gum in pH 7.4. Furthermore, the kinetic studies revealed that 'n' values in all dissolution media lies within 0.5-1.0 which suggested non-Fickian diffusion mode of release. From the above results, it can be said that controlled release of 5-ASA using graft material was successful and hence it can be explored for treatment of colon related diseases.

Systematic review with meta-analysis: high prevalence and cost of continued aminosalicylate use in patients with ulcerative colitis escalated to immunosuppressive and biological therapies.

BACKGROUND: Aminosalicylates are the most frequently prescribed treatment for ulcerative colitis (UC). In the absence of empirical evidence, clinicians are uncertain whether to continue aminosalicylates in patients with UC after escalating therapy. AIMS: To quantify concomitant aminosalicylate use in UC randomised clinical trials (RCTs), identify factors associated with their use, and estimate treatment costs of concomitant aminosalicylate therapy. METHODS: MEDLINE, Embase, and CENTRAL were searched from inception to 1 March 2017 for placebo-controlled RCTs of immunosuppressants, biologics, or oral small molecules in adults with UC. The proportion of patients prescribed concomitant aminosalicylates at trial entry was pooled using a random-effects model. Meta-regression was performed to assess trial-level factors associated with aminosalicylate use. Treatment costs were estimated using 2018 formulary data from five Canadian provinces. RESULTS: Thirty-two trials were included (23 induction only, nine induction, and maintenance trials). The pooled proportion of patients co-prescribed aminosalicylates was 80.7% (95% CI 75.5%-85.1%), with considerable observed heterogeneity (I2  = 95%). In univariable meta-regression, aminosalicylate use was not associated with trial design, setting, year of publication, disease severity, disease duration, or drug class. The estimated direct annual treatment cost of concomitant aminosalicylates is ~$20 million for the Canadian UC population, assuming conservative estimates of UC prevalence, aminosalicylate use and dose, and the lowest cost formulation. CONCLUSIONS: Approximately 80% of UC patients entering clinical trials of immunosuppressants, biologics, or oral small molecules continue to use aminosalicylates. An RCT is needed to inform the benefits and harms of continuing vs stopping aminosalicylates in patients escalating therapy.

The STAT3 inhibitor S3I-201 suppresses fibrogenesis and angiogenesis in liver fibrosis.

Liver fibrosis is a common pathological response to chronic hepatic injury. STAT3 is actively involved in the fibrogenesis and angiogenesis seen in liver fibrosis. S3I-201 (NSC 74859) is a chemical inhibitor of STAT3 activity, which blocks the dimerization of STAT3, STAT3-DNA binding and transcription activity. This study evaluated the effects of S3I-201 against liver fibrosis. S3I-201 inhibited the proliferation, migration, and actin filament formation in primary human hepatic stellate cells (HSCs), as well as the expression of α-SMA, collagen I and TIMP1 in both primary HSC and in a CCl4-induced fibrosis mouse model. S3I-201 induced both apoptosis and cell cycle arrest in the HSC cell line (LX-2). S3I-201 inhibited the expression of fibrogenesis factors TGFß1 and TGFßRII, as well as the downstream phosphorylation of Smad2, Smad3, Akt and ERK induced by TGFß1. In addition to fibrogenesis, both in vitro and in vivo assays showed that S3I-201 inhibited angiogenesis through expression suppression of VEGF and VEGFR2. Moreover, S3I-201 also had a synergistic effect with sorafenib, an FDA approved liver cancer drug, in the proliferation, apoptosis, angiogenesis and fibrogenesis of HSC. S3I-201 suppressed liver fibrosis through multiple mechanisms, and combined with sorafenib, S3I-201 could be a potentially effective antifibrotic agent.

Disrupting interaction of PSD-95 with nNOS attenuates hemorrhage-induced thalamic pain.

Hemorrhages occurring within the thalamus lead to a pain syndrome. Clinical treatment of thalamic pain is ineffective, at least in part, due to the elusive mechanisms that underlie the induction and maintenance of thalamic pain. The present study investigated the possible contribution of a protein-protein interaction between postsynaptic density protein 95 (PSD-95) and neuronal nitric oxide synthase (nNOS) to thalamic pain in mice. Thalamic hemorrhage was induced by microinjection of type IV collagenase into unilateral ventral posterior medial/lateral nuclei of the thalamus. Pain hypersensitivities, including mechanical allodynia, heat hyperalgesia, and cold allodynia, appeared at day 1 post-microinjection, reached a peak 5-7 days post-microinjection, and persisted for at least 28 days post-microinjection on the contralateral side. Systemic pre-treatment (but not post-treatment) of ZL006, a small molecule that disrupts PSD-95-nNOS interaction, alleviated these pain hypersensitivities. This effect is dose-dependent. Mechanistically, ZL006 blocked the hemorrhage-induced increase of binding of PSD-95 with nNOS and membrane translocation of nNOS in thalamic neurons. Our findings suggest that the protein-protein interaction between PSD-95 and nNOS in the thalamus plays a significant role in the induction of thalamic pain. This interaction may be a promising therapeutic target in the clinical management of hemorrhage-induced thalamic pain.

Dissociation of nNOS from PSD-95 promotes functional recovery after cerebral ischaemia in mice through reducing excessive tonic GABA release from reactive astrocytes.

Mechanisms underlying functional recovery after stroke are little known, and effective drug intervention during the delayed stage is desirable. One potential drug target, the protein-protein interaction between neuronal nitric oxide synthase (nNOS) and postsynaptic density protein 95 (PSD-95), is critical to acute ischaemic damage and neurogenesis. We show that nNOS-PSD-95 dissociation induced by microinjection of a recombinant fusion protein, Tat-nNOS-N1-133 , or systemic administration of a small-molecule, ZL006, from day 4 to day 10 after photothrombotic ischaemia in mice reduced excessive tonic inhibition in the peri-infarct cortex and ameliorated motor functional outcome. We also demonstrated improved neuroplasticity including increased dendrite spine density and synaptogenesis after reducing excessive tonic inhibition by nNOS-PSD-95 dissociation. Levels of gamma-aminobutyric acid (GABA) and GABA transporter-3/4 (GAT-3/4) are increased in the reactive astrocytes in the peri-infarct cortex. The GAT-3/4-selective antagonist SNAP-5114 reduced tonic inhibition and promoted function recovery, suggesting that increased tonic inhibition in the peri-infarct cortex was due to GABA release from reversed GAT-3/4 in reactive astrocytes. Treatments with Tat-nNOS-N1-133 or ZL006 after ischaemia inhibited astrocyte activation and GABA production, prevented the reversal of GAT-3/4, and consequently decreased excessive tonic inhibition and ameliorated functional outcome. The underlying molecular mechanisms were associated with epigenetic inhibition of glutamic acid decarboxylase 67 and monoamine oxidase B expression through reduced NO production. The nNOS-PSD-95 interaction is thus a potential target for functional restoration after stroke and ZL006, a small molecule inhibitor of this interaction, is a promising pharmacological lead compound. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Old drug, new indication: Olsalazine sodium reduced serum uric acid levels in mice via inhibiting xanthine oxidoreductase activity.

Hyperuricemia, a long-term purine metabolic disorder, is a well-known risk factor for gout, hypertension and diabetes. In maintaining normal whole-body purine levels, xanthine oxidase (XOD) is a key enzyme in the purine metabolic pathway, as it catalyzes the oxidation of hypoxanthine to xanthine and finally to uric acid. Here we used the protein-ligand docking software idock to virtually screen potential XOD inhibitors from 3167 approved small compounds/drugs. The inhibitory activities of the ten compounds with the highest scores were tested on XOD in vitro. Interestingly, all the ten compounds inhibited the activity of XOD at certain degrees. Particularly, the anti-ulcerative-colitis drug olsalazine sodium demonstrated a great inhibitory activity for XOD (IC50 = 3.4 mg/L). Enzymatic kinetic studies revealed that the drug was a hybrid-type inhibitor of xanthine oxidase. Furthermore, the drug strikingly decreased serum urate levels, serum/hepatic activities of XOD at a dose-dependent manner in vivo. Thus, we demonstrated a successful hunting process of compounds/drugs for hyperuricemia through virtual screening, supporting a potential usage of olsalazine sodium in the treatment of hyperuricemia.

Discovery and preclinical development of a novel prodrug conjugate of mesalamine with eicosapentaenoic acid and caprylic acid for the treatment of inflammatory bowel diseases.

Mesalamine (5-ASA) is one of the drugs indicated as first line therapy in ulcerative colitis for induction and maintenance of remission. Sulfasalazine and formulations of 5-ASA (pH-dependent and controlled release formulations) were developed to minimize the systemic absorption and maximize the delivery of the mesalamine to colon. Although, its efficacy and safety is well documented there are approximately 30% nonresponders to 5-ASA therapy. This necessitates the need for novel therapeutic options to improve the efficacy and safety of the currently available 5-ASA therapy. CLX-103 is a novel, patented prodrug molecular conjugate of mesalamine, eicosapentaenoic acid and caprylic acid designed to offer incremental benefits over the currently approved 5-ASA formulations. Results of in vitro and in vivo studies showed that CLX-103, was stable in simulated gastric fluid, but undergoes enzymatic hydrolysis in the small/large intestines to release the active moiety. Our data also showed that the active moiety is retained in the targeted intestinal tissues (ileum and colon) over a longer period of time in relation to sulfasalazine. The in vitro data supports the observed in vivo plasma kinetics of 5-ASA characterized by longer Tmax, low Cmax after the oral administration of CLX-103. Efficacy study of CLX-103 in acute dextran sodium sulfate (DSS) mouse colitis model showed improved potency measured as Disease Activity Index (DAI) and histological scores in the colon as compared to sulfasalazine. These findings indicate that CLX-103 could offer a differentiated drug product which is more efficacious and safer than the currently approved 5-ASA formulations in the treatment of inflammatory bowel diseases.

[Determination of in vitro synergy by a checkerboard method when 3 core antimicrobial agents of the retreatment new scheme combined against MDR-MTB and XDR-MTB].

OBJECTIVE: In order to detect the in vitro synergistic effect of 4 drugs-pasiniazid (PA), moxifloxacin, rifabutin and rifapentini on multidrug-resistant mycobacterium tuberculosis (MDR-MTB) and extensively drug-resistant mycobacterium tuberculosis(XDR-MTB), which were core drugs of"The program of retreatment research of tuberculosis". METHOD: The checkerboard method was used to detect the minimum inhibitory concentration (MIC) of antituberculosis drug combination schemes (moxifloxacin-PA, moxifloxacin-PA-rifabutin and moxifloxacin-PA-rifapentini) to 40 strains of clinical drug resistant MTB(20 strains of MDR-MTB and 20 XDR-MTB) and the standard strain H37Rv, by calculating the fractional inhibitory concentration index of joint action in vitro to judge the combined effect, with fractional inhibitory concentration index(FICI)≤0.5 and FICI≤0.75 as the basis of 2 drugs and 3 drugs showing synergy. RESULTS: The FICI of moxifloxacin-PA scheme for DR-MTB was 0.125 to 1.000, only 5 strains with a FICI ≤0.5, showing synergistic effect. The FICI of moxifloxacin-Pa-rifabutin scheme with 20 strains of MDR-MTB ranged from 0.310 to 1.260, 10 strains with a FICI≤0.75, showing synergistic effect. The FICI of moxifloxacin-PA-rifabutin scheme with 20 strains of XDR-MTB ranged from 0.215 to 1.250, 11 strains with a FICI≤0.75, showing synergistic effect. The FICI of moxifloxacin-PA-rifapentini scheme with 20 strains of MDR-MTB ranged from 0.150 to 0.780, 19 strains with a FICI≤0.75, showing synergistic effect. The FICI of moxifloxacin-PA-rifapentini scheme with 20 strains of XDR-MTB ranged from 0.200 to 1.280, 16 strains with a FICI≤0.75, showing synergistic effect. CONCLUSIONS: The synergistic effect of moxifloxacin-PA scheme was poor, but showing better synergy when further combined with rifabutin or rifapentini. Rifabutin showed better effect than rifapentini, but the synergistic effect of moxifloxacin-PA-rifabutin combination scheme was poor than that of moxifloxacin-PA-rifapentini combination scheme.

Modification of platelet proteins by malondialdehyde: prevention by dicarbonyl scavengers.

The thromboxane synthase converts prostaglandin H(2) to thromboxane A(2) and malondialdehyde (MDA) in approximately equimolar amounts. A reactive dicarbonyl, MDA forms covalent adducts of amino groups, including the ε-amine of lysine, but the importance of this reaction in platelets was unknown. Utilizing a novel LC/MS/MS method for analysis of one of the MDA adducts, the dilysyl-MDA cross-link, we demonstrated that dilysyl-MDA cross-links in human platelets are formed following platelet activation via the cyclooxygenase (COX)-1/thromboxane synthase pathway. Salicylamine and analogs of salicylamine were shown to react with MDA preferentially, thereby preventing formation of lysine adducts. Dilysyl-MDA cross-links were measured in two diseases known to be associated with increased platelet activation. Levels of platelet dilysyl-MDA cross-links were increased by 2-fold in metabolic syndrome relative to healthy subjects, and by 1.9-fold in sickle cell disease (SCD). In patients with SCD, the reduction of platelet dilysyl-MDA cross-links following administration of nonsteroidal anti-inflammatory drug provided evidence that MDA modifications of platelet proteins in this disease are derived from the COX pathway. In summary, MDA adducts of platelet proteins that cross-link lysines are formed on platelet activation and are increased in diseases associated with platelet activation. These protein modifications can be prevented by salicylamine-related scavengers.

Colon-specific prodrugs of 4-aminosalicylic acid for inflammatory bowel disease.

Despite the advent of biological products, such as anti-tumor necrosis factor-α monoclonal antibodies (infliximab and adalimumab), for treatment of moderate to severe cases of inflammatory bowel disease (IBD), most patients depend upon aminosalicylates as the conventional treatment option. In recent years, the increased knowledge of complex pathophysiological processes underlying IBD has resulted in development of a number of newer pharmaceutical agents like low-molecular-weight heparin, omega-3 fatty acids, probiotics and innovative formulations such as high-dose, once-daily multi-matrix mesalamine, which are designed to minimize the inflammatory process through inhibition of different targets. Optimization of delivery of existing drugs to the colon using the prodrug approach is another attractive alternative that has been utilized and commercialized for 5-aminosalicylic acid (ASA) in the form of sulfasalazine, balsalazide, olsalazine and ipsalazine, but rarely for its positional isomer 4-ASA - a well-established antitubercular drug that is twice as potent as 5-ASA against IBD, and more specifically, ulcerative colitis. The present review focuses on the complete profile of 4-ASA and its advantages over 5-ASA and colon-targeting prodrugs reported so far for the management of IBD. The review also emphasizes the need for reappraisal of this promising but unexplored entity as a potential treatment option for IBD.

The use of biologic therapy in pregnancy: a gastroenterologist's perspective.

PURPOSE OF REVIEW: Inflammatory bowel disease (IBD) often affects women in their peak reproductive years, and therapy is often continued during pregnancy to maintain stable disease activity. Therapeutic options have expanded over the last 2 decades with the advent of new biologic options. It is, therefore, important for the gastroenterologists and other clinicians caring for patients with IBD to understand safety data regarding the treatment options, both biologic and nonbiologic, in pregnant IBD patients. RECENT FINDINGS: In general, quality of evidence in this area remains low. However, larger prospective studies are beginning to provide evidence regarding the potential safety of biologics both alone and in conjunction with nonbiologic therapy. SUMMARY: The majority of treatment options for IBD appears to be of low risk and may often be continued through pregnancy and lactation. Not treating IBD, for example, by discontinuing therapy prior to or with pregnancy, may pose a greater risk to mother and fetus in many cases.

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.

Effect of Etiasa on the expression of matrix metalloproteinase-2 and tumor necrosis factor-α in a rat model of ulcerative colitis.

The aim of this study was to determine the disease activity index (DAI) and the colonic mucosa damage index (CMDI), and to detect the colonic mucosal expression levels of matrix metalloproteinase-2 (MMP-2) and tumor necrosis factor-α (TNF-α) in rats with ulcerative colitis (UC). We also aimed to investigate the protective role of Etiasa in UC. Sprague Dawley (SD) rats were randomly divided into three groups: the control, an Etiasa-treated group and a UC model group. Rats were sacrificed on days 14, 21, 35 or 56 following the administration of treatment by enema and the DAI, CMDI and colonic expression levels of MMP-2 and TNF-α were assessed. In the UC model group, the DAI and CDMI scores and the colonic expression levels of MMP-2 and TNF-α increased significantly compared with the control at all timepoints, and were also significantly higher than those in the Etiasa-treated group. In conclusion, the expression levels of MMP-2 and TNF-α increased significantly in rats with UC. Etiasa reduces colonic mucosal damage by downregulating the expression of MMP-2 and TNF-α.

Ankylosing spondylitis or Crohn's disease? Case report and review of the literature.

A 27-year-old male with a 2 year history of ankylosing spondylitis (AS) was investigated for intermittent episodes of diarrhea and found to have granulomatous ileitis. Differential diagnosis, discussions regarding similarities in immune alterations in both AS and Crohn's disease and therapeutic options are presented in this paper.

5-Aminosalicylic acid inhibits colitis-associated but not sporadic colorectal neoplasia in a novel conditional Apc mouse model.

Genetic predisposition, life-style habits and inflammatory bowel diseases (IBD)-related colitis are a main risk factor for colorectal cancer (CRC). 5-Aminosalicylic acid (5-ASA, mesalazine) is a mainstay therapy in IBD and believed to reduce the risk for developing CRC. We aimed to determine the ability of 5-ASA enemas to inhibit the development of sporadic and colitis-related neoplasia in mice. FabplCre;Apc(15lox/+) mice, which spontaneously develop sporadic colorectal tumours, were treated at 5 weeks of age with 5-ASA or placebo enemas for 3 weeks and examined for colorectal tumourigenesis at 8 weeks of age. Colitis-related tumour development was investigated in these mice by administration of dextran sodium sulphate, inducing intestinal inflammation and accelerating colorectal tumourigenesis, combined with treatment of 5-ASA or placebo enemas during and/or after colitis induction. 5-ASA significantly reduced colitis-accelerated neoplasia development by 50%, from 19.4 +/- 2.7 to 9.4 +/- 2.4 (mean tumour numbers +/- SEM, P = 0.02), in the distal part of the large intestine covered by the enema. 5-ASA was only effective when given during and/or after the intestinal inflammatory period. 5-ASA did not reduce, however, sporadic neoplasia development in the FabplCre;Apc(15lox/+) mice. 5-ASA tended to reduce proliferation of epithelial cells in the colitis-associated colorectal tumours but not in the sporadic colorectal tumours. In conclusion, 5-ASA medication inhibits the development of colitis-associated tumours in FabplCre;Apc(15lox/+) mice when administered during and/or after the induction of inflammation. 5-ASA does not reduce, however, sporadic tumour development in this mouse model.

Review article: new drug formulations, chemical entities and therapeutic approaches for the management of ulcerative colitis.

BACKGROUND: Treatment options for ulcerative colitis (UC) are expanding with the development of novel drug formulations and dosing regimens and new chemical entities. Although the goals of medical therapy for UC remain unchanged, that is to induce and to maintain remission, focus has also centred on improving patient compliance, modifying the natural course of disease and healing the mucosa. AIM: To examine novel formulations, new chemical entities and novel therapeutic approaches to the management of UC. METHODS: Searches for all studies related to UC treatment in Medline and abstracts from major national and international meetings published in the last 10 years. RESULTS: 5-Aminosalicylic acids (5-ASA) remain the standard first-line treatment for patients with mild to moderately active UC. New formulations with altered delivery, and new dosing regimens have demonstrated possible improvements in efficacy compared with historically available preparations and dosing patterns. Once-daily dosing, micropellet formulations,and high-dose tablets offer enhanced efficacy and improved compliance. 5-ASA is now recognized as a ligand for peroxisome proliferator activated receptor-gamma (PPAR-gamma) and it has a role as a chemo-preventive agent in long-standing UC. New colonic release corticosteroid formulations help to limit systemic toxicity; turmeric, tacrolimus and infliximab have shown promising results. New anti-inflammatory targeted therapies include an anti-CD3 antibody, selective integrin blockers, anti-IL-2 antibody and PPAR-gamma agonists. CONCLUSION: The evolution of novel oral 5-ASA formulations and dosage regimens,and recent development of new molecules have expanded the therapeutic armamentarium of UC.

Treatment of inflammatory bowel disease: a review of medical therapy.

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal tract. While a cure remains elusive, both can be treated with medications that induce and maintain remission. With the recent advent of therapies that inhibit tumor necrosis factor (TNF) alpha the overlap in medical therapies for UC and CD has become greater. Although 5-ASA agents have been a mainstay in the treatment of both CD and UC, the data for their efficacy in patients with CD, particularly as maintenance therapy, are equivocal. Antibiotics may have a limited role in the treatment of colonic CD. Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy; non-systemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal UC respectively are also effective in mild-moderate disease. 6-mercaptopurine (6-MP) and its prodrug azathioprine are steroid-sparing immunomodulators effective in the maintenance of remission of both CD and UC, while methotrexate may be used in both induction and maintenance of CD. Infliximab and adalimumab are anti-TNF agents approved in the US and Europe for the treatment of Crohn's disease, and infliximab is also approved for the treatment of UC.