Current Drug Targets - Volume 12, Issue 10, 2011

Ulcerative colitis (UC) and Crohn's disease (CD) are the two major forms of inflammatory bowel disease (IBD). We have made tremendous advances in our knowledge of the genetics, pathogenesis, and therapy of CD; however, by contrast, UC has been always relegated to a “Cinderella status”. Scientists have given the study of the pathogenesis of UC only minor attention, while the medical community have made UC even less the focus of their efforts to develop new drugs and improved therapeutic strategies [1, 2]. Why has this happened? Such disregard appears paradoxical, not least because UC was described at least 70 years before CD, and is at least twice as prevalent [3]. Several possible reasons could be postulated. First, CD is perceived as a more severe disease, while UC has a more benign course. Second, the traditional drugs for UC are generally considered to be effective for the treatment of mild or moderate disease. Third, the more severe cases of UC have traditionally been referred for colectomy, which is considered a curative strategy. Indeed, following surgery with restorative proctocolectomy and ileal pouch-anal anastomosis, most patients have an excellent long-term functional outcome. Taken together, these aspects have led to the minor investment by the scientific and medical communities, and as a consequences, new treatment options are only pursued as a logical next step in the development of therapeutics for CD. However approximately 50% of patients with UC have a chronically active disease, with a tremendous impact on quality of life, while defects in continence and sexual dysfunction are common problems [4]. In addition, pouch failure can occur following surgery, with the most common causes being pouchitis, pelvic sepsis and poor function. Finally, although it is rare for patients with UC to go on to develop colon cancer, nevertheless the risk is sufficiently great that long-term follow-up is required. Over the past decade it has become clear that considering CD and UC jointly under the title IBD is overly simplistic, and that given the differences in the pathogenesis and underlying genetics, they should be considered as two distinct entities if therapeutic strategies are to be effective. This special issue of Current Drug Targets therefore highlights the advances in our understanding of UC, reviewing the current state of the art in a disease that should not be disregarded.

The pathogenesis of ulcerative is still poorly understood. With the introduction of new culture-independent techniques the research on the intestinal microbiota has revealed an important reduction of Bacteroidetes and Firmicutes leading to a reduced biodiversity and dysbiosis in these patients. Going in depth, the intestinal barrier is covered under physiologic conditions by a mostly sterile mucus layer. Besides a reduction of mucus thickness or an alteration in mucus composition hypothesized for human ulcerative colitis, new evidence coming from mouse models has introduced a novel concept based on cellular stress due to misfolded mucus-associated proteins opening a new research area for the epithelial cell lining. A dysregulated immune response involving the innate (e.g. toll-like receptors, dendritic cells, etc) and the adaptive immune system (e.g. effector T-cells, regulatory T-cells, eosinophils, neutrophils, etc) may follow or precede the macroscopic lesions. The immune response in ulcerative colitis is represented principally by secretion of interleukin-5 and -13 being the latter responsible for the direct cytotoxicity against the epithelial cells. In latter stages the role of interleukin- 17 producing cells, apparently differently regulated compared with Crohn's disease, remains to be elucidated. Finally, human ulcerative colitis is characterized by the presence of various types of autoantibodies including pANCA, antibodies against goblet cells and the isoforms 1 and 5 of human tropomyosin. The pathogenic potential of these antibodies is still debated. The present review focus on new achievements in the various scenarios converging to the clinical and histopathological feature of ulcerative colitis.

Substantial progress has been made in the last years in characterizing the susceptibility genes involved in IBD pathogenesis, especially for Crohn's disease. Although some genetic factors associated with Crohn's disease also predispose individuals to ulcerative colitis, markers specific only for ulcerative colitis have been found. Recent genomewide association studies in ulcerative colitis have identified several new loci, and suggested many new potential pathways. The identified susceptibility genes and their variants could be useful to predict disease course and to improve stratification of patients, when correlated with other subphenotypes. Moreover, understanding the biological pathways involved in the disease could lead to the development of new treatments and molecules that specifically target such pathways, discover different therapeutic approaches and eventually progress to personalized treatment.

The clinical presentation at the time of diagnosis and the disease course of ulcerative colitis (UC) are heterogeneous and variable over time. In population-based epidemiological follow-up studies from the last decades, the extent of UC has shown only slight variation. At diagnosis, the initial extent is evenly distributed among proctitis, leftsided, and extensive colitis with some exceptions. The disease course may vary from a single attack to chronic symptoms that reduce the quality of life as well as lead to disease extension, colectomy or even to the development of colitisassociated colorectal cancer in some cases. Important predictive clinical factors and biomarkers of disease course have been under increasing scrutiny. Those identified may eventually lead to a more personalized, tailored therapy. In this review article, the authors summarize the available evidence on the natural history and predictive markers for evaluating the course of UC.

5-Amino-salicylic (5-ASA) is up to now the treatment of choice in the induction and maintenance of remission of mild-to-moderate ulcerative colitis (UC). Sulfasalazine, despite similar efficacy, is hampered by more side effects, but in presence of peripheral arthopaties it remains the treatment of choice. The new delayed release MMX formulation seems to be promising in reducing compliance problems, but further studies are warranted to show the superiority of new MMX formulation compared with the older formulations of 5-ASA. Some trials evaluated also the efficacy and safety of oncedaily dosing of older 5-ASA formulations in maintenance of remission, finding a greater adherence to therapy in the group given the once daily regimen, compared with the classic twice daily groups. Regarding the efficacy of alternative treatment such us probiotics and antibiotics, the current data are not sufficient to promote their use in clinical practice. Clinical evidence supports the use of topical 5-ASA in active mild to moderate distal UC showing superior efficacy to placebo, topical corticosteroids, and oral 5-ASA. A combination of oral and rectal 5-ASA produces additional efficacy in both limited and extensive UC. Topical 5-ASA formulations are effective also for the maintenance of remission, however long term treatment may not be acceptable to many patients. Other topical drugs (E. Coli Nissle, propionyl-L-carnitine, butyrate, tacrolimus, rosiglitazone) have been investigated with conflicting results. The possible chemopreventive role of long term treatment with 5-ASA strengthens the indication to the long term use of 5-ASA.

The goals of treatment for ulcerative colitis (UC) are to induce and maintain corticosteroid-free remission, thereby reducing hospitalizations and surgeries and preventing longer-term disease complications including colorectal cancer. Despite an incomplete evidence base, thiopurine immunomodulators remain a principle therapeutic option for patients failing aminosalicylate monotherapy and requiring multiple courses of corticosteroids. In this review, we outline the current evidence supporting the role of thiopurines in achieving these treatment goals in UC, including discussions of the important safety issues regarding their use. We also explore some of the recent evidence emerging in regards to the risks of lymphoproliferative disease, dosage optimization strategies and the role of thiopurines in achieving mucosal healing in UC and ultimately changing natural history outcomes for our patients.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is thought to affect 1780000 patients in USA and Europe. Its incidence is increasing rapidly in Asia. Drugs with proven clinical activity that are currently used in UC patients include salicylates, steroids, azathioprine and infliximab. None of them is active in every patient and all carry significant side effects. There is a need for other active drugs in UC. Low dose methotrexate has been used for decades in psoriasis, rheumatoid arthritis and Crohn's disease. In these diseases, it is an active, well tolerated and cheap drug. In UC there have been several open series, most of which are retrospective. Overall, these studies have shown promising results, with response rates of 50 to 72 %. There have been two randomized clinical trials of methotrexate vs. placebo in UC. Both were negative but methotrexate was prescribed orally at suboptimal doses. So far, there is no evidence for the efficacy of methotrexate in UC. Therefore, there is a need for clinical trials with methotrexate using adequate dosage and the parenteral route. Two multicenter randomized trials of methotrexate 25 mg/week parenterally vs. placebo are either ongoing (METEOR, the European trial) or being built up (MERIT, the US trial). These trials should determine if methotrexate is a valuable therapeutic option in UC.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by chronic inflammation affecting the colonic mucosa, that can extend to the whole large bowel. The severity of mucosal lesions directly reflects the disease activity and severity and may be prognostic for an aggressive behavior of the pathology. Remission, is usually defined as resolution of symptoms. Recently, mucosal healing (MH) has emerged as an important end point of any shortterm medical therapy for IBD. It may predict long-term remission and may impact on the natural history of the disease in Crohn's disease (CD), while data in UC patients are still limited. This review of the literature is focused on the recent evidence on the impact of medications on MH in UC and on the impact of MH on the natural course of UC.

There is a strong association between chronic inflammation and cancer formation. This correlation has been well observed in patients with long standing inflammatory bowel disease (IBD) who are at high risk of colorectal cancer (CRC). At present, there is a lack of good markers for predicting the progression from normal to neoplastic mucosa in patients with IBD. IBD patients who are ‘at-risk’ of CRC should be identified, evaluated and should also be enrolled in surveillance program, regardless of their disease activity. Early identification of dysplasia and its appropriate management using endoscopic techniques or surgery are essential in patients with long-standing IBD, to minimize CRC morbidity and mortality. Gastroenterologists should work along with experienced, specialised gastrointestinal pathologists, surgeons and with fully informed and compliant IBD patients' to ensure the success of surveillance programme in early detection of CRC.

Ulcerative Colitis (UC) is an idiopathic chronic inflammation. Its etiology is still largely unknown. Environmental and genetic factors in combination with the microbial flora or specific microorganisms are thought to trigger the gut inflammation, leading to the activation of the intestinal immune response. Immune and non-immune cells create a cross talk via the secretion of soluble mediators and expression of cell adhesion molecules, resulting in further cell activation. Mediators such as cytokines and chemokines play a key role in cell recruitment and polarization, intercellular signal amplification or activation and differentiation. Lack of balance between pro-inflammatory and antiinflammatory cytokines is crucial in the pathogenesis of IBD. Conventional therapy of UC quite commonly fails to avoid complications or colectomy and the therapeutic armamentarium remains still limited. New therapeutic options, such as, biological therapy, gene therapy, hematopoietic stem cell transplantation, and leucoapheresis, have been investigated recently. Biological therapy is focused on different targets involved in the inflammatory process. Several new biological drugs have been introduced in the last decade or are under investigation for the treatment of IBD. They include anti TNF-α agents, anti adhesion molecules, anti IL-12/23, anti IL-6R and more. We review the recent advances in biological therapy for UC treatment beyond the anti-TNFs.

Infliximab has demonstrated its efficacy in moderate to severe ulcerative colitis. The Active Ulcerative Colitis Trial (ACT) -1 and 2 have demonstrated the beneficial impact of infliximab on the short-term colectomy rate. However, data evaluating this outcome beyond one year remains scarce. To provide evidence on the potential impact of infliximab on the long-term colectomy rate in patients suffering from ulcerative colitis, data was reviewed from randomized and controlled studies, referral center studies and population-based studies, in adult and pediatric populations. In the prebiologic era, 9-33%, 50% and 29% of adult patients with ulcerative colitis underwent colectomy in clinical trials, referral center studies and population-based cohorts, respectively. In the pediatric population, 9-61% and 8-20% underwent colectomy in referral centers and population-based cohorts, respectively. Between 10 and 36% of adult patients treated with infliximab for ulcerative colitis underwent colectomy in clinical trials, referral center studies and population-based cohorts. In the pediatric population treated with infliximab, long-term data is lacking, with colectomy rates ranging from 16 to 28%. Whether infliximab proves to be a disease modifying treatment in ulcerative colitis in the long term remains to be elucidated and will require further long-term prospective studies.

Acute severe ulcerative colitis is a serious condition that requires early hospitalization, with intensive monitoring and treatment. Despite the recent progress in the medical approach of Inflammatory Bowel Diseases acute severe ulcerative colitis remains a clinical challenge, with a mortality rate of nearly 1%. As of today, I.V. corticosteroids remain the 1st-line therapy for this complication. For non-responders (up to one-third of patients) possible options are surgery - whose timing is a critical point in the overall management of the disease - or rescue therapy with 2nd- line agents such as Cyclosporine and Infliximab. Here we will review the published studies dealing with the use of these medications in acute severe ulcerative colitis.

It is estimated that 50% of patients who have undergone ileal pouch-anal anastomosis (IPAA) surgery for UC will develop at least one episode of pouchitis. The risk of developing pouchitis is much higher in patients with preoperative extraintestinal manifestations and primary sclerosing cholangitis. In acute pouchtis metronidazole or ciprofloxacin have shown efficacy, however there is some evidence that ciprofloxacin may have better and has less toxic. In patients with chronic pouchitis antibiotics are less effective, and maintenance therapy may be required. In cases of refractoriness to conventional therapy a combination of two antibiotics for a prolonged period or infliximab may be effective. Starting maintenance treatment with highly concentrated probiotics is recommended as primary and secondary prophylaxis.

Ulcerative colitis (UC) is a chronic inflammatory condition of the mucosa affecting the rectum and extending up the colon in a continuous manner. Its etiology is unknown, but is most probably the result of the interaction of genetic and environmental factors. Approximately 30% of UC patients will need to undergo surgery at some point during their lifetime, despite progresses made in medical therapies. Indications for surgery include acute severe colitis with its complications, steroid-or antiTNF-refractory colitis (or growth impairment in children), and the onset of colorectal dysplasia/cancer. Recently, the introduction of biologic agents has provided a rationale for prolonging medical therapy before considering surgery in the treatment of active, moderate to severe colitis. When surgery becomes indicated, especially in the urgent setting, it usually involves dealing with immunosuppressive medications, possibly impacting the onset of post-operative septic complications. In both acute and chronic settings, patients should be informed about the medical and surgical options and their respective prognoses; the crucial decision regarding the timing for surgery should be shared by both gastroenterologists and colorectal surgeons. The aim of the present review is to highlight surgical indications and options for UC patients as well as the evidence about surgical complications following medical therapies, in order to aid clinicians in determining the best timing for surgery.

The perception that Crohn's disease is a more severe process than ulcerative colitis, led to the initial development of a majority drugs, and testing of treatment strategies, in the former. In the absence of similar studies in ulcerative colitis, information of Crohn's disease studies may help the clinician in decision making in UC. Studies on aminosalicylates show that drugs with a topical effect which are not effective in Crohn's disease may still have efficacy in ulcerative colitis, and this should be considered in future drug development. The best efficacy of corticorteroids is achieved with high doses of 1 mg/kg/day, and reaching remission may be delayed by several weeks, although nonresponse in the initial days should lead to treatment escalation, in particular in severe patients. Thiopurines have a steroidsparing effect, and the duration of treatment should be at least 4 years; caution should be exerted in using these drugs in EBV negative young patients and in the older population for the risk of lymphoma. Anti-TNF monoclonal antibody therapy is optimized by use of induction followed by scheduled maintenance as opposed to episodic treatment, resulting in higher sustained response rates and lower immunogenicity. Associations of non-biological immunosuppressants with anti- TNF antibodies can further increase therapeutic efficacy maintaining a safe profile. Patients under combined therapy with sustained clinical and biological remission and mucosal healing may be candidates to stop anti-TNF treatment. The majority of these recommendations need to be specifically studied in patients with ulcerative colitis before generalization in clinical practice.

Dendrimers, by virtue of their therapeutic value, have recently generated enormous interest among biomedical scientists. Advancement of dendrimeric nano-architecture with well defined size, shape and controlled exterior functionality embraces promise in biomedical and pharmaceutical applications such as drug delivery, solubilization, DNA transfection and diagnosis. Highly branched, monodisperse, stable molecular level and low polydispersity with micellelike behavior possessing nano-scale container property distinguish these structures as inimitable and optimum carrier for those applications. Dendrimers has been evaluated for delivery of different types of bioactives inside the cells. Different types of techniques are being used for exploring dendrimer safety and efficacy via cell cytotoxicity assays, cell uptake studies by fluorescent microscopy, cell line studies, flow cytometry, gamma scintigraphy and confocal microscopy; are being used over a decade. Among these, cell line studies are widely used for ex vivo characterization of dendrimers and other nanocarriers. Cell lines are homogeneous population of cells, stable after mitosis, and have an unlimited capacity for division. This review focuses on the use of different cell line studies including anticancer drugs, anti-HIV drugs, antiinflammatory drugs, anti-tubercular-drugs, photodynamic therapy, hormonal therapy employing dendritic nanocarrier.

The prevalence of type 2 diabetes is evolving globally at an alarming rate. This fact is mainly the result of our global lifestyle “modernization” that has resulted in overweight and obesity. Dysfunction of peroxisome proliferator activated receptor-gamma (PPAR-γ) has been implicated in the development of insulin resistance, while a reduce expression of many PPAR-γ regulated genes has been observed in an obese diabetic state. Thiazolidinediones (TZDs) are potent exogenous agonists of PPAR-γ, which augment the effects of insulin to its cellular targets and mainly at the level of adipose tissue. Preclinical and clinical studies have demonstrated that apart from their glucose-lowering activity, these drugs also regulate the production of inflammatory mediators by cells that play a pivotal role in the pathogenesis of atherosclerosis. This paper summarizes the evolving changes observed in an enlarged adipose tissue and examines the activity of TZDs in their main cellular targets. It also discusses whether these cellular pleiotropic effects can result in a clinically meaningful outcome, in terms of cardiovascular benefit, in this population.