An approach to the management of refractory ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology associated with dysregulation of the gastrointestinal mucosal immune system. It is characterized by a waxing and waning course and approximately 15% of UC patients will experience a severe episode. The first line treatment for severe colitis includes IV corticosteroids, however, 40% of patients are non-responsive to corticosteroid therapy and may require either colectomy, intravenous infliximab or intravenous cyclosporine within 3-5 days of presentation. This review focuses on the management and treatment approaches to refractory UC.

Randomised trial of once- or twice-daily MMX mesalazine for maintenance of remission in ulcerative colitis.

AIM: Maintenance treatment in ulcerative colitis should be as convenient as possible, to increase the chance of compliance. MMX mesalazine is a once-daily, high-strength (1.2 g/tablet) formulation of 5-aminosalicylic acid. This study evaluated the safety and efficacy of MMX mesalazine dosed once or twice daily as maintenance therapy in patients with ulcerative colitis. METHODS: This multicentre, randomised, open-label trial enrolled patients with strictly defined clinical and endoscopic remission, immediately following an episode of mild to moderate ulcerative colitis. Patients were randomised to MMX mesalazine 2.4 g/day as a single (2x1.2 g tablet) or divided dose (1x1.2 g tablet twice daily) for 12 months. RESULTS: 174 patients (37.9%; safety population n = 459) experienced 384 adverse events, the majority of which were mild or moderate in intensity. Eighteen patients (3.9%), nine in each group, experienced a total of 22 serious adverse events (10 in the once-daily and 12 in the twice-daily group). Most serious adverse events were gastrointestinal, experienced by 5 patients in the once-daily and 4 in the twice-daily group. At month 12, 64.4% (efficacy population, n = 451) of patients in the once-daily and 68.5% of patients in the twice-daily group were in clinical and endoscopic remission (p = 0.351). At month 12, 88.9% and 93.2% in each group, respectively, had maintained clinical remission (were relapse free). CONCLUSIONS: MMX mesalazine 2.4 g/day administered as a single or divided dose demonstrated a good safety profile, was well tolerated and was effective as maintenance treatment. High clinical and endoscopic remission rates can be achieved with once-daily dosing. TRIAL REGISTRATION NUMBER: NCT00151944.

Review article: 5-aminosalicylate formulations for the treatment of ulcerative colitis--methods of comparing release rates and delivery of 5-aminosalicylate to the colonic mucosa.

BACKGROUND: Many oral 5-aminosalicylic acid (5-ASA) formulations are designed to maximize 5-ASA release in the colon where it acts topically on the colonic mucosa. Delayed-release formulations and azo-prodrugs minimize 5-ASA absorption in the upper gastrointestinal (GI) tract. AIMS: To review methods for assessing 5-ASA release and colonic distribution from oral formulations, and the potential use of this information for guiding clinical decisions. METHODS: PubMed and recent conference abstracts were searched for articles describing techniques used to assess 5-ASA release from ulcerative colitis (UC) therapies. RESULTS: In-vitro GI models, although unable to simulate more complex aspects of GI physiology, can provide useful data on 5-ASA release kinetics and bioaccessibility. Gamma-scintigraphy is useful for investigating GI disintegration of different formulations, but may not accurately reflect 5-ASA distribution. Plasma pharmacokinetic studies provide data on systemic exposure, but not on colonic distribution or mucosal uptake. Mucosal biopsies provide direct evidence of colonic distribution and may predict clinical efficacy, but must be interpreted cautiously because of considerable inter-subject variability and other confounding factors. CONCLUSION: While assessment of 5-ASA release is important, limitations of individual measurement techniques mean that randomized clinical studies in UC patients remain the best guide for dosing and treatment regimen decisions.

Review article: Bowel preparation for colonoscopy--the importance of adequate hydration.

BACKGROUND: Patient compliance with screening recommendations for colorectal cancer remains low, despite a 90% survival rate achieved with early detection. Bowel preparation is a major deterrent for patients undergoing screening colonoscopy. More than half of patients taking polyethylene glycol electrolyte lavage solution and sodium phosphate preparations experience adverse events, such as nausea and abdominal pain. Many adverse events may be associated with dehydration, including rare reports of renal toxicity in patients taking sodium phosphate products. Addressing dehydration-related safety issues through patient screening and education may improve acceptance of bowel preparations, promote compliance and increase the likelihood of a successful procedure. AIM: To evidence safety issues associated with bowel preparation are generally related to inadequate hydration. RESULTS: Dehydration-related complications may be avoided through proper patient screening, for example, renal function and comorbid conditions should be considered when choosing an appropriate bowel preparation. In addition, patient education regarding the importance of maintaining adequate hydration before, during and after bowel preparation may promote compliance with fluid volume recommendations and reduce the risk of dehydration-related adverse events. CONCLUSIONS: Proper patient screening and rigorous attention by patients and healthcare providers to hydration during bowel preparation may provide a safer, more effective screening colonoscopy.

Medical management of mild to moderate Crohn's disease: evidence-based treatment algorithms for induction and maintenance of remission.

BACKGROUND: Patients with Crohn's disease alternate between periods of active, symptomatic disease and periods of remission. The treatment goal for Crohn's disease is to induce and then maintain remission of symptoms. AIM: To review evidence from randomized, controlled, clinical trials on medical therapies for inducing and maintaining remission in patients with mild-to-moderate Crohn's disease, and to suggest the best evidence-based approaches for induction and maintenance therapies. METHODS: PubMed search using the following terms: sulfasalazine or salicylazosulfapyridine or aminosalicylate or aminosalicylic acid or mesalamine or mesalazine or corticosteroid or prednisone or prednisolone or methylprednisolone or budesonide or antibiotic or metronidazole or ciprofloxacin or immunosuppressive or azathioprine or mercaptopurine or thiopurine or methotrexate and Crohn's disease. RESULTS: Randomized, controlled trials demonstrated that sulfasalazine, budesonide, and conventional corticosteroids are effective for inducing remission of mild-to-moderate Crohn's disease when administered for a period of 8-16 weeks. An ideal maintenance therapy does not currently exist. CONCLUSIONS: Selection of maintenance therapy is based on a combination of evidence from controlled trials and patient features including disease severity and location, co-morbidities, previous response to treatment, and previous surgical resection. The options for maintenance therapy include therapy cessation and patient observation following successful induction, budesonide, or immunosuppressive therapy.

MMX Multi Matrix System mesalazine for the induction of remission in patients with mild-to-moderate ulcerative colitis: a combined analysis of two randomized, double-blind, placebo-controlled trials.

BACKGROUND: MMX mesalazine [LIALDA (US), MEZAVANT XL (UK and Ireland) MEZAVANT (elsewhere)] utilizes MMX Multi Matrix System (MMX) technology which delivers mesalazine throughout the colon. Two phase III studies have already evaluated MMX mesalazine in patients with active, mild-to-moderate ulcerative colitis. Aim To provide more precise estimates of the efficacy of MMX mesalazine over placebo by combining the patient populations from the two phase III studies. Methods Combined data from two 8-week, double-blind, placebo-controlled trials were analyzed. Patients randomized to MMX mesalazine 2.4 g/day (once daily or 1.2 g twice daily), 4.8 g/day (once daily) or placebo were reviewed. The primary end point was clinical and endoscopic remission (modified Ulcerative Colitis-Disease Activity Index of /=1-point reduction in sigmoidoscopy score from week 0). Results Data from 517 patients were analysed. 8-week remission rates were 37.2% and 35.1% in the MMX mesalazine 2.4 g/day and 4.8 g/day groups, vs. 17.5% on placebo (P < 0.001, both comparisons). 8-week complete mucosal healing rates were 32% in both MMX mesalazine groups compared with 16% on placebo. Adverse event frequency was similar in all groups. Conclusion MMX mesalazine is effective and generally well tolerated for inducing clinical and endoscopic remission of active, mild-to-moderate ulcerative colitis.

Clinical trial: sodium phosphate tablets are preferred and better tolerated by patients compared to polyethylene glycol solution plus bisacodyl tablets for bowel preparation.

BACKGROUND: Patient acceptance of bowel preparation can affect colon cancer screening compliance. Aim To compare patient acceptance, preference and tolerability of 32-sodium phosphate tablets vs. 2L polyethylene glycol solution plus 4 bisacodyl tablets for bowel preparation. METHODS: A prospective, randomized, investigator-blinded, multicentre trial was performed. Results were based on responses to a patient questionnaire. RESULTS: 411 patients (205 sodium phosphate; 206 polyethylene glycol plus bisacodyl) completed the study preparation and patient questionnaire prior to colonoscopy. More patients receiving sodium phosphate vs. polyethylene glycol plus bisacodyl found it easy to take (77% vs. 42%), reported it to be without taste (47% vs. 6%), found it easy to take with respect to volume of liquid prescribed (72% vs. 27%) and indicated they would take the same preparation again in the future (96% vs. 74%, P < 0.0001 for all). Fewer patients receiving sodium phosphate vs. polyethylene glycol plus bisacodyl had to take time off work or change ordinary activities to take the study preparation (18% vs. 52%, P < 0.0001). Nausea, vomiting, bloating and abdominal pain were reported less frequently with sodium phosphate (P < 0.0013). CONCLUSION: The 32-tablet sodium phosphate dosing regimen was easier to take and better tolerated, when compared to 2L polyethylene glycol plus bisacodyl tablets for bowel preparation.

Lack of correlation between natural killer activity and tumor growth control in nude mice with different immune defects.

To elucidate the in vivo role of natural killer (NK) cells, the growth of several murine and human tumors was studied in four variants of athymic, nude mice with different levels of NK activity. Beige-nude mice, homozygous for both the beige and the nude genes, had very low levels of NK activity, and their response to the B-cell mitogen, bacterial lipopolysaccharide, was lower than that of high-NK, adult NIH nude mice. Young and adult NIH nudes had different NK levels and showed different response in assays for K-cell, T-cell, and B-cell activity. The B-cell-defective NIH-II mice had slightly lower NK levels than adult NIH animals, but much lower response in the antibody-dependent cell-mediated cytotoxicity assay. No correlation was found between host NK activity and the s.c. growth of various human (LOX, CEM, K562) and murine (YAC-1) tumor cells. Low NK activity was not associated with increased lung colony formation in a metastasis model using i.v.-injected human (LOX) and murine (B16F10) melanoma cells. No relationship was found between host NK activity and the rate of elimination of i.v.-injected 5-iodo-2'-deoxyuridine-labeled LOX, B16F10, and YAC-1 cells from lungs, liver, or spleen. The results fail to support the view that NK cells exert significant direct effects on tumor cells in vivo.

Review article: monitoring of immunomodulators in inflammatory bowel disease.

The armamentarium of medications for the treatment of inflammatory bowel disease is growing and becoming more complicated to use. Immunomodulators are a class of medications that have found a niche for the treatment of Crohn's disease and ulcerative colitis. Because of the mounting supporting evidence for efficacy, the most commonly-used immunomodulators are azathioprine, mercaptopurine, methotrexate and ciclosporin. These medications are being used more often due to their steroid-sparing and potentially surgery-sparing effects. Immunomodulators are also known for a significant side-effect profile and require careful monitoring. This review provides the latest information for clinicians on efficacy, side-effects, dosing and monitoring of these medications for treatment of inflammatory bowel disease.

A randomized, double-blind, placebo-controlled trial of CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, in patients with corticosteroid-dependent Crohn's disease.

AIM: To evaluate CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, for the treatment of corticosteroid-dependent Crohn's disease. METHODS: Patients with corticosteroid-dependent Crohn's disease (use of prednisolone 15-40 mg/day or budesonide 9 mg/day for at least 8 weeks, a previous failed attempt to discontinue corticosteroids within 8 weeks, and Crohn's Disease Activity Index score 150 points or less) were enrolled in a 16-week, randomized, double-blind, placebo-controlled trial. The patients received intravenous CDP571 (20 mg/kg at week 0 and 10 mg/kg at week 8) or placebo. Corticosteroid therapy was decreased following a predefined schedule. The primary efficacy end-point was the percentage of patients with corticosteroid-sparing [i.e. no disease flare (Crohn's Disease Activity Index score > or =220 points) and no longer requiring corticosteroid therapy] at week 10. The major secondary efficacy end-point was corticosteroid-sparing at week 16. RESULTS: Seventy-one patients received treatment. Corticosteroid-sparing was achieved by 19 of 39 (48.7%) CDP571 patients and 13 of 42 (40.6%) placebo patients (P = 0.452) at week 10, and by 18 of 39 (46.2%) CDP571 patients and seven of 32 (21.9%) placebo patients (P = 0.032) at week 16. CDP571 therapy was well-tolerated and the incidence of serious adverse events was similar to placebo. CONCLUSIONS: The CDP571 was effective for corticosteroid-sparing at week 16 but not week 10, and was well-tolerated in patients with corticosteroid-dependent Crohn's disease.

Clinical implications of Barrett's esophagus.

Barrett's esophagus is a medical condition in which the squamous mucosa that normally lines the distal esophagus is replaced by a columnar type of epithelium. Most definitions that have been used for inclusion of patients in studies have indicated that columnar mucosa must extend 3 cm or more above the gastroesophageal junction. The precise length refers to the distance above the manometrically defined lower esophageal sphincter. This measurement is somewhat cumbersome to make on a routine basis for all patients at the time of endoscopy and thus is generally not done. It is important to realize that the gastroesophageal junction can be visually identified at the area where the esophagus tapers, in the region of the lower esophageal sphincter. The tapering of the esophagus in the region of the lower esophageal sphincter may be difficult to determine when lower esophageal sphincter pressures are low; thus, we commonly say that Barrett's esophagus is defined as columnar mucosa 3 cm above the region where the gastric folds end.

Successful use of alternate waste nitrogen agents and hemodialysis in a patient with hyperammonemic coma after heart-lung transplantation.

BACKGROUND: Lethal hyperammonemic coma has been reported in 2 adults after lung transplantation. It was associated with a massive elevation of brain glutamine levels, while plasma glutamine levels were normal or only slightly elevated. In liver tissue, glutamine synthetase activity was markedly reduced, and the histologic findings resembled those of Reye syndrome. The adequacy of therapy commonly used for inherited disorders of the urea cycle has not been adequately evaluated in patients with this form of secondary hyperammonemia. OBJECTIVE: To determine whether hemodialysis, in conjunction with intravenous sodium phenylacetate, sodium benzoate, and arginine hydrochloride therapy, would be efficacious in a patient with hyperammonemic coma after solid-organ transplantation. DESIGN: Case report. SETTING: A children's hospital. PATIENT: A 41-year-old woman with congenital heart disease developed a hyperammonemic coma with brain edema 19 days after undergoing a combined heart and lung transplantation. METHODS: Ammonium was measured in plasma. Amino acids were quantitated in plasma and cerebrospinal fluid by column chromatography. The effectiveness of therapy was assessed by measuring plasma ammonium levels and intracranial pressure and performing sequential neurological examinations. RESULTS: The patient had the anomalous combination of increased cerebrospinal fluid and decreased plasma glutamine levels. To our knowledge, she is the first patient with this complication after solid-organ transplantation to survive after combined therapy with sodium phenylacetate, sodium benzoate, arginine hydrochloride, and hemodialysis. Complications of the acute coma included focal motor seizures, which were controlled with carbamazepine, and difficulty with short-term memory. CONCLUSIONS: The aggressive use of hemodialysis in conjunction with intravenous sodium phenylacetate, sodium benzoate, and arginine hydrochloride therapy may allow survival in patients after solid-organ transplantation. An acute acquired derangement in extra-central nervous system glutamine metabolism may play a role in the production of hyperammonemia in this illness that resembles Reye syndrome, and, as in other hyperammonemic disorders, the duration and degree of elevation of brain glutamine levels may be the important determining factors in responsiveness to therapy.

Scintigraphic evaluation of liver masses: cavernous hepatic hemangioma.

Hepatic cavernous hemangioma must be included in the differential diagnosis of any hepatic solid mass. It is the second most common neoplasm of the liver, following intrahepatic metastases. With the exception of giant or symptomatic HCH, it does not require specific intervention. The ability to diagnose HCH radiologically (Table 2) has significant clinical importance. When confronted with clinical data and a preliminary radiologic study suggestive of HCH, serial planar blood-pool scintigraphy (with SPECT if the lesion is < 3-4 cm) should probably be the initial diagnostic examination. In comparison to MRI, it is safer, less expensive and easier for some patients to tolerate. For small, deep seated lesions or those adjacent to the heart or large vessels, MRI is the preferred test. Dynamic CT is probably most useful in patients with normal renal function in whom optimal imaging of the extrahepatic abdomen is desired. If the etiology of an incidental hepatic mass suspected to be an HCH is still not evident after these studies, angiography or biopsy are the remaining options. As described, angiography is sensitive and relatively specific for HCH. Although percutaneous biopsy may be associated with increased risk of bleeding, fine-needle biopsy has been shown to be safe for hemangiomas. However, fine-needle biopsy is more useful for confirming a suspected malignancy than for actually diagnosing hemangioma.

Approach to corticosteroid-dependent and corticosteroid-refractory Crohn's disease.

Corticosteroids are considered a drug of choice for the treatment of patients with moderately to severely active Crohn's disease (CD), an inflammatory bowel disease characterized by chronic recurrent flares of disease activity. However, among patients receiving corticosteroid therapy for induction of remission, 20% have corticosteroid-refractory disease and 36% of those with an initial response develop corticosteroid dependency within 1 year. Chronic corticosteroid exposure in patients who are corticosteroid dependent increases the risk for serious drug-related adverse effects. Withdrawal or reduction of corticosteroid therapy without exacerbation of symptoms is therefore recognized as an important goal of treatment. Therapies that have been shown to facilitate "steroid sparing' include the immunomodulators azathioprine/6-mercaptopurine and methotrexate and the antitumor necrosis factor-alpha monoclonal antibody infliximab. In corticosteroid-dependent patients, budesonide may be substituted for conventional corticosteroid therapy without loss of response and with less risk for toxicity, but its long-term efficacy requires further evaluation. A preliminary controlled study suggests that the investigational anti-TNF monoclonal antibody CDP-571 may also be clinically beneficial as a corticosteroid-sparing agent. This review summarizes the clinical evidence that supports consideration of these agents as alternatives in patients with CD who are dependent on, refractory to, or intolerant of conventional corticosteroid therapy.

Increased expression of interleukin-8 mRNA in ulcerative colitis and Crohn's disease mucosa and epithelial cells.

: Interleukin-8 (IL-8) is a chemotactic cytokine (chemokine), which both attracts and activates granulocytes. IL-8 could have a central function in the initiation and perpetuation of the inflammatory bowel diseases (IBD), due to its relative resistance to inactivation and long half-life in vivo. Using a quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay, we have observed elevated levels of IL-8 mRNA in colonic mucosal sections obtained from surgically resected specimens from ulcerative colitis (UC) and Crohn's disease (CD) patients with actively inflamed mucosa. The level of IL-8 mRNA expression in the intestinal mucosal biopsies from UC and CD patients was much greater in involved as opposed to noninvolved mucosal sections. The highest expression of IL-8 mRNA detected by RT-PCR was in UC mucosa and in isolated intestinal epithelial cells from UC patients. Increased IL-8 production by cells in IBD intestinal mucosa as well as IBD epithelial cells may be involved in the continuous attraction and activation of granulocytes in the inflamed intestine in both UC and CD patients. Chemokines, such as IL-8, are potent chemoattractant molecules and may have a central role in the augmentation and perpetuation of inflammation in IBD.

Localization and inhibitory actions of galanin at the feline lower esophageal sphincter.

Intrinsic reflexes of the lower esophageal sphincter (LES) are mediated by specific arrangements of excitatory and inhibitory nerves. We have previously described an excitatory reflex at the feline LES mediated by a bombesin-like peptide (BN) which causes release of substance P (SP) to directly contract the LES. Galanin is a neurotransmitter in the enteric nervous system which colocalizes in neurons containing vasoactive intestinal peptide (VIP). The aims of this study were to determine: (1) the distribution of galanin at the feline LES; (2) the effect of galanin on basal LES tone; (3) the effect of galanin on agonist-induced LES contractions by BN, SP and bethanechol; and (4) the effect of galanin on LES relaxation induced by esophageal distension and exogenous VIP. Galanin-like immunoreactivity (galanin-LI) was localized in neurons that were widely distributed throughout the LES and adjacent organs. Galanin-LI was most abundant in the circular muscle, muscularis mucosa and myenteric plexus of the LES. In anesthetized cats, intra-arterial galanin had no effect on basal LES pressure in a dose range of 10(-11) to 10(-6) g/kg. Galanin (5.10(-7) g/kg) reduced the LES contractile response to SP by 65 +/- 8% (P = 0.0001). This galanin-mediated inhibition of SP was not blocked by tetrodotoxin. Galanin similarly decreased the LES contractile response to BN (63 +/- 7%, P = 0.005) and bethanechol (55 +/- 17%, P = 0.012). Galanin had no effect on the LES relaxation induced by esophageal distension or exogenous VIP. We conclude: (1) galanin-LI is present in neurons at the feline LES; (2) galanin has no effect on basal sphincter tone, but inhibits contractions of the LES by both direct and indirect agonists; and (3) galanin does not effect the LES relaxation induced by esophageal distension or VIP.

Risk factors for the development of colorectal carcinoma and their modification.

In this article the authors review factors determining risk for the development of colorectal cancer (CC) and their modification. Emphasis is placed on understanding the difference between average risk and high risk individuals. Risk factors including genetics, diet, environment, and coexistent diseases are discussed. The data regarding modification of risk via dietary, pharmaceutical, and prophylactic endoscopic and surgical interventions are reviewed.

Advances in inflammatory bowel disease.

Optimal management of patients with IBD requires a multidisciplinary approach involving primary care physicians, gastroenterologists, surgeons, radiologists, and nutritionists. The rapidly evolving medical armamentarium promises better quality of life for patients afflicted with these complex, chronic diseases. It is expected that future development of biologic agents will add to the therapeutic options, although it may complicate treatment algorithms. Surgical advancements, particularly in ileoanal anastomosis and bowel preservation by strictureplasty, have improved outcome dramatically. The focus on development of new therapies and refinement of older ones demands a constant attention to the latest peer-reviewed literature and that the clinician keep abreast of the various advancements that have been summarized here.

Cancer in inflammatory bowel disease.

Patients with inflammatory bowel disease, including both ulcerative colitis (UC) and Crohn's disease, are at increased risk for the development of gastrointestinal carcinoma, particularly colorectal adenocarcinoma. The current options to reduce this cancer risk include prophylactic colectomy, periodic endoscopic screening with colectomy performed in those patients found to have dysplastic colonic mucosa, or expectant management with no routine surveillance regimen. Despite the lack of data demonstrating effectiveness of surveillance colonoscopy, this approach has become the standard of care in most communities in the United States. Although it has fallen out of fashion in recent years, prophylactic colectomy remains a good option for reducing cancer risk for select patients with UC.