`wjgpt@wjgnet.com
`doi:10.4292/wjgpt.v1.i2.43
`
`World J Gastrointest Pharmacol Ther 2010 April 6; 1(2): 43-50
`ISSN 2150-5349 (online)
`© 2010 Baishideng. All rights reserved.
`
`EDITORIAL
`
`Recent advances in the management of distal ulcerative
`colitis
`
`Ioannis E Koutroubakis
`
`Ioannis E Koutroubakis, Department of Gastroenterology,
`University Hospital Heraklion, PO BOX 1352, 71110 Heraklion,
`Crete, Greece
`Author contributions: Koutroubakis IE wrote the manuscript.
`Correspondence to: Ioannis E Koutroubakis, MD, PhD,
`Assistant Professor, Department of Gastroenterology, University
`Hospital Heraklion, PO BOX 1352, 71110 Heraklion, Crete,
`Greece. ikoutroub@med.uoc.gr
`Telephone: +30-28-10392253 Fax: +30-28-10542085
`Received: January 4, 2010 Revised: January 29, 2010
`Accepted: February 5, 2010
`Published online: April 6, 2010
`
`Abstract
`The most frequent localization of ulcerative colitis (UC)
`is the distal colon. In treating patients with active distal
`UC, efficacy and targeting of the drug to the distal colon
`are key priorities. Oral and rectal 5-aminosalicylic acid
`(5-ASA) preparations represent the first line therapy
`of mild-to-moderate distal UC for both induction and
`maintenance treatment. It has been reported that many
`UC patients are not adherent to therapy and that non-
`compliant patients had a 5-fold risk of experiencing a
`relapse. These findings led to the introduction of once-
`daily oral regimens of 5-ASA as better therapeutic op-
`tions in clinical practice due to improved adherence.
`New formulations of mesalazine, including the multi-
`matrix delivery system, and mesalazine granules, which
`allow once-daily administration, have been developed.
`They have been demonstrated to be efficacious in in-
`ducing and maintaining remission in mild-to-moderate
`distal UC in large clinical trials. However, existing data
`for distal UC are rather insufficient to make a compari-
`son between new and classical 5-ASA formulations. It
`seems that the new formulations are at least as effective
`as classical oral 5-ASA formulations. Other treatment
`options, in the case that 5-ASA therapy is not effective,
`include systemic corticosteroids, thiopurines (azathio-
`prine or 6-mercaptopurine), cyclosporine, infliximab and
`surgery. The combination of a prompt diagnostic work-
`
`up, a correct therapeutic approach and an appropriate
`follow-up schedule is important in the management of
`patients with distal UC. This approach can shorten the
`duration of symptoms, induce a prolonged remission,
`improve patient’s quality of life, and optimize the use of
`health resources.
`
`© 2010 Baishideng. All rights reserved.
`
`Key words: Aminosalicylates; Azathioprine; Infliximab
`mesalazine; Ulcerative colitis
`
`Peer reviewer: Brian Bressler, MD, MS, Assistant Professor,
`Division of Gastroenterology, University of British Columbia,
`770-1190 Hornby Street, Vancouver, BC V6Z 2K5, Canada
`
`Koutroubakis IE. Recent advances in the management of distal
`ulcerative colitis. World J Gastrointest Pharmacol Ther 2010;
`1(2): 43-50 Available from: URL: http://www.wjgnet.com/
`2150-5349/full/v1/i2/43.htm DOI: http://dx.doi.org/10.4292/
`wjgpt.v1.i2.43
`
`INTRODUCTION
`The majority of newly diagnosed adult patients with ul-
`cerative colitis (UC) present with disease limited to the
`distal or left side of the colon[1], which is also called distal
`UC. The term ‘‘distal UC’’, therefore, defines disease distal
`to the splenic flexure, which includes proctitis (involve-
`ment of rectum only), proctosigmoiditis (involvement of
`rectum and sigmoid colon) and left-sided colitis (involve-
`ment extending as far as the descending colon or splenic
`flexure). Cases with proctitis (E1) and left sided colitis
`(E2), according to the recent Montreal classification[2], are
`included. Approximately 80% of UC patients present as
`distal UC and about 20% present with extensive colitis or
`pancolitis[1]. The literature suggests that the course of distal
`UC varies. Its onset may be gradual or abrupt, and most
`patients experience remitting and relapsing symptoms.
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`Koutroubakis IE. Treatment of distal ulcerative colitis
`
`As for all cases of inflammatory bowel disease, the aim
`of medical management of patients with distal UC is to
`induce remission in active disease and to minimize the risk
`of relapse. In treating active distal UC, efficacy and targeting
`of the drug to the distal colon are key priorities. Moreover,
`for maintenance therapy, long-term toxicity and factors
`that affect compliance are important. Treatment options
`include 5-aminosalicylic acid (5-ASA and derivatives),
`corticosteroids and immunosuppressive therapy. Emerging
`data suggest that early, aggressive treatment of distal UC
`may prevent or delay proximal extension, an occurrence
`that otherwise is common[3].
`The main recent advances in conventional therapy
`for distal UC are once-daily mesalazine therapy, the new
`delivery system utilizing Multi Matrix System (MMX)
`technology, the newly developed micropellet formulations
`of 5-ASA and the reappraisal of high-dose mesalazine and
`immunomodulators. Especially the recent introduction of
`novel 5-ASAs provides a wider choice to clinicians of oral
`therapy for UC patients.
`5-ASA is the standard first-line treatment for mild-
`to-moderate distal UC. Since 5-ASA is believed to act
`topically, the development of 5-ASA formulations aim to
`minimize the systemic absorption of 5-ASA from the small
`intestine and to maximize the delivery of the active drug to
`the site of inflammation in the colon. Various rectal gels,
`liquids, and foam enemas have been developed and fulfil
`these criteria by delivering 5-ASA directly to the site of
`inflammation, while ensuring minimal systemic absorption.
`However, these formulations are often associated with
`adverse events, such as leakage and abdominal bloating.
`Moreover, many patients find rectal formulations imprac-
`tical and, as a result, compliance with prescribed dosing
`regimens is poor. Consequently, rectal formulations are
`mainly used as add-on therapy[4].
`Only 40%-60% of the patients who are newly diagnosed
`or have longstanding disease are adherent to therapy[5]. It
`was shown that non-compliant patients had a 5-fold risk of
`experiencing a relapse as compared to patients taking more
`than 80% of their prescribed mesalazine medication[6].
`Treatment alternatives to 5-ASAs include other topical
`preparations for rectal administration and oral and intrave-
`nous therapies.
`This review discusses recent clinical trials pertaining to
`the management of distal UC. It summarizes the evidence
`for recent developments in the use of established therapies,
`as well as emerging novel therapies.
`
`TREATMENT OF THE ACUTE PHASE
`Several medications are available for the treatment of the
`acute phase of distal UC. Oral formulations and topical
`therapies with aminosalicylates or corticosteroids have
`shown to be highly effective in this situation. Meta-analysis
`of the published data and important relative reviews have
`been published[4,7-10].
`In patients with mild-to-moderately active ulcerative
`proctitis, rectal administration of suppositories of 5-ASA
`
`or corticosteroids has been established as first-line thera-
`pies. In this setting, suppositories of 5-ASA are more
`effective than rectal steroids and has been shown to be
`more effective than oral 5-ASA[11].
`Patients with active distal UC can be treated with rectal
`5-ASA (enemas, foams, or suppositories), oral 5-ASA,
`or a combination of both. Several controlled trials have
`shown that rectal therapies have a more rapid effect than
`oral treatment[12,13]. Meta-analysis of the published data
`showed that rectal 5-ASA is superior to placebo and to
`conventional rectal corticosteroids for inducing remission
`of symptoms, endoscopy, and histology of distal UC[7].
`Moreover, it has been found that the combination of
`oral and rectal 5-ASA further improves the efficacy and
`speed of improvement in patients with distal UC without
`differences in safety[13].
`Although a dose response of oral mesalazine for active
`UC has been suggested, the benefit of mesalamine 4.8 g/d
`over 2.4 g/d is limited to symptom improvement rather
`than remission of the disease[10]. The ASCEND Ⅱ trial
`suggested that 4.8 g is superior to 2.4 g in patients with
`moderately active UC[14]. However, other recent studies do
`not suggest a difference[10].
`There is evidence that distal active UC of mild-moder-
`ate severity should initially be treated with a combination
`of topical aminosalicylates and oral mesalazine ((cid:305)(cid:3)(cid:21) g/d).
`Concerning topical treatment alone, steroids or mesalazine
`are also effective, but mesalazine is more effective than
`steroids. Each one, as well as oral aminosalicylates alone,
`is less effective than combination therapy[15]. The response
`to oral and rectal therapy should be apparent in about 2
`wk and, if rectal bleeding persists, then the response is
`slow and steroid therapy should continue.
`In the case that rectal 5-ASA or corticosteroids and
`oral 5-ASA therapy are not effective, then oral corticos-
`teroids should be administered. Usually, the suggested
`dose of oral prednisone (or equivalent) is 40 mg daily,
`which leads to rapid clinical response in the majority of
`patients[9]. After a clinical response, prednisone is tapered
`(5 mg to 10 mg/1-2 wk) with the rate of tapering depend-
`ing on the disease severity and rapidity of improvement.
`At the same time, oral and rectally administered 5-ASA
`therapy should be continued with the goal of maintaining
`remission of UC once prednisone is discontinued.
`Patients with severe distal UC should be hospitalized
`and treated with IV corticosteroids. Another option in
`these cases is the use of infliximab. Systemic corticos-
`teroids are appropriate if symptoms of active distal UC
`do not respond rapidly to mesalazine. Severe distal UC
`is usually an indication for hospitalization for intensive
`treatment with systemic administration of the therapy[15].
`Treatment with corticosteroids intravenously is evaluated
`after about 5 d.
`In cases with moderate-to-severe active disease who
`have failed therapy with aminosalicylates, corticosteroids,
`or immunomodulators, the administration of infliximab
`is indicated. The evidence for this is provided from two
`large randomized, double-blind, controlled trials: ACT-1
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`and ACT-2 where 56% of the patients had left-sided or
`distal UC suggesting that infliximab is effective in this
`group of patients[16]. However, it should be realized that
`the steroid-free remission rate after 7 mo (30 wk) on
`infliximab is only 21%[16]. Furthermore, infliximab seems
`to be effective as a rescue therapy to avoid colectomy in
`severe UC unresponsive to intravenous steroids in short-
`term and long-term follow-up[17,18]. The role of infliximab
`in cases with severe distal UC that are resistant to therapy,
`and whether it is an alternative to surgery, remains to be
`established.
`
`MAINTENANCE TREATMENT
`All patients with distal UC are at risk for relapse and
`should receive maintenance treatment. The vast majority
`of untreated patients will relapse by 1 year, whereas
`maintenance therapy significantly decreases the risk of
`relapse[9]. Therefore, long-term treatment is indicated for
`reduction of the risk of relapse, but also for decrease of
`proximal extension of the disease and for reduction in the
`development of carcinoma. Only a few cases with mild
`ulcerative proctitis do not require maintenance treatment.
`The choice of the appropriate maintenance therapy
`for a patient with distal UC should be based on the
`efficacy of the medication in combination with its long-
`term safety, tolerability, convenience and acceptability to
`the patient.
`The mainstay of maintenance therapy for distal UC
`has been 5-ASA for the past few decades. Rectally admin-
`istered 5-ASA preparations are effective for maintenance
`of remission in most patients with distal UC. The combi-
`nation of rectal and oral 5-ASA may be the most effective
`strategy. However, rectal formulations are often associ-
`ated with undesirable side effects (leakage and abdominal
`bloating), and many patients find them impractical and
`compliance with this treatment is poor. Therefore, long-
`term 5-ASA for oral maintenance treatment of distal UC
`is usually preferred by patients and doctors. It is of note
`that using 5-ASA therapy for maintaining remission after
`patients required prednisone is a common practice, but it
`is not based on the literature.
`The dose-response of 5-ASA formulations in main-
`tenance therapy of distal UC has not been definitively
`evaluated.
`Where 5-ASA has insufficient efficacy, immune modu-
`lation is indicated. Thiopurines (azathioprine and 6-mer-
`captopurine) have been found to be superior to placebo in
`maintaining remission in distal UC[19,20]. Overall, oral ther-
`apy with azathioprine or 6-mercaptopurine is reserved for
`patients with steroid-dependent distal UC and those with
`chronic disease that is refractory to other drugs. Patients
`with early stage disease have higher steroid-free remission
`rates on azathioprine compared to patients with late stage
`disease[21]. Moreover, it has been suggested that increasing
`the dose of azathioprine up to 2.5 mg/kg appeared ben-
`eficial in patients who had not responded to 2 mg/kg per
`day[20].
`
`Koutroubakis IE. Treatment of distal ulcerative colitis
`
`The use of azathioprine in distal UC is less indicated
`than in extensive UC. Moreover, the relapse rate after drug
`withdrawal is significantly lower in distal UC compared
`to extensive UC[22]. A recent meta-analysis showed that
`thiopurine drugs are more effective than placebo for the
`prevention of relapse in UC, with a number needed to
`treat of 5 and an absolute risk reduction of 23%[23].
`Methotrexate has also been used to maintain remission
`in patients with steroid-dependent UC who fail to respond
`to or who are intolerant of thiopurines, but the evidence
`is mainly based on uncontrolled studies with small sample
`sizes and heterogeneous doses[24,25]. In a recent study,
`clinical response to methotrexate was seen in 7 of 9 (78%)
`of UC patients who were refractory to thiopurines and
`15 of 23 (65%) who were intolerant to thiopurines[26].
`However, the data are limited and evidence is lacking to
`recommend methotrexate to maintain remission in UC.
`
`REFRACTORY DISTAL UC
`Refractory distal UC is a term with different definitions,
`but the most accepted is that of the case who failed or
`has partial therapeutic response to conventional therapy.
`A patient with refractory distal UC requires a complete
`evaluation of possible exogenous and endogenous
`factors contributing to this refractory condition. Enteric
`infections, such as clostridium difficile, campylobacter
`jejuni, salmonella, shigella, cytomegalovirus, herpes simplex
`virus and various parasitic infections, should be excluded.
`It is of note that the prevalence and case fatality of UC
`patients complicated by clostridium difficile infection rose
`significantly during last few years[27].
`Moreover, other reasons for refractoriness include
`poor adherence with therapy, inadequate concentrations
`of the active drug, unrecognised complications (such as
`proximal constipation) or inappropriate diagnosis (such
`as co-existent irritable bowel syndrome, Crohn’s disease,
`mucosal prolapse, or very rarely, cancer)[15]. Medication
`history should be obtained in detail since some agents,
`specifically nonsteroidal anti-inflammatory drugs and
`antibiotics, may play a role in the activity of the disease.
`Another parameter that should be taken into account
`is approximately half of the patients with proctitis or
`distal UC present with progression of the disease and
`this possibility should be examined in cases that present
`with refractoriness. Moreover, possible worsening of the
`symptoms by 5-ASA preparations, although rare, should
`be kept in mind and, in this case, aminosalicylates should
`be discontinued.
`Patients with distal UC not responding to rectal and/
`or oral 5-ASA or corticosteroids present a treatment di-
`lemma. Options for therapy for these refractory patients
`include infliximab and cyclosporine. Infliximab 5 mg/kg
`induction (0, 2 and 6 wk) followed by maintenance ther-
`apy (every 8 wk) offers an effective treatment option for
`patients with refractory distal UC. The use of infliximab
`has also been found to be effective in preventing colecto-
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`Koutroubakis IE. Treatment of distal ulcerative colitis
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`my in some cases with refractory UC[17,18], but in cases that
`are finally operated on, it seems that there are increases in
`the risk of short-term postoperative complications. This
`is supported by the findings of a recent meta-analysis[28].
`Intravenous cyclosporine (2-4 mg/kg per Id) is effective
`in refractory patients with distal UC but is associated with
`rare and potentially life-threatening side effects, such as
`nephrotoxicity, opportunistic infections, and seizures.
`Patients who respond to cyclosporine require azathioprine
`or 6-mercaptopurine for maintenance of remission[9].
`In severe refractory distal UC not responding to inten-
`sive treatment, or if the symptoms of the disease have
`major adverse effects on a patient’s quality of life, surgery
`should be considered. Overall, patients with distal UC are
`less likely to require surgery than patients with extensive
`UC. Among patients who have a colectomy for refractory
`UC, 10%-35% are reported to have distal disease[29,30].
`
`NEW ORAL MESALAZINE
`FORMULATIONS
`The most important aim of treatment for UC with 5-ASA
`is to deliver high concentrations of the drug topically to
`areas with active inflammation. Various formulations have
`been developed to enable release of orally administered
`5-ASA in the colon.
`Commercially available 5-ASA includes azo-bond
`prodrugs, such as sulfasalazine, olsalazine and balsalazide,
`and delayed and controlled-release forms of mesalazine.
`Although emphasis has been placed on the manner in
`which different delivery systems may influence responses
`to 5-ASAs, the evidence in clinical practice for variability
`in efficacy among these products is rather weak.
`Two major problems have appeared during the last
`decades with the use of oral 5-ASA in UC patients. The
`first is that azo-bonded and delayed-release formulations
`may not deliver therapeutically effective doses of 5-ASA
`to the left colon. There is evidence from clinical studies
`showing mucosal 5-ASA concentrations using azo-
`bonded or bolus-release formulations to be highest in the
`right colon, whereas in the rectum, the concentration of
`5-ASA is significantly lower[31,32]. The second is that these
`formulations were given multiple times daily since this has
`been considered essential to ensure that therapeutically
`effective 5-ASA doses are maintained in the colon.
`This approach has been shown to be efficacious for the
`treatment of UC in clinical studies, but patient compliance
`has been demonstrated to be poor in clinical practice, with
`the result of reduced drug efficacy and poorer disease
`control[6]. Therefore, the once-daily oral formulations of
`5-ASA have been suggested as a better therapeutic option
`in clinical practice due to improved adherence.
`Concerning safety, the majority of oral 5-ASA agents
`have safety profiles similar to that of a placebo in large
`clinical trials. Only sulfasalazine is not well tolerated since
`it is associated with dose-related side effects including
`nausea, vomiting, dyspepsia, anorexia, and headache.
`
`There are no definitive data suggesting that one 5-ASA
`preparation is superior to another. The choice of 5-ASA
`agent for treatment of a patient with distal UC should be
`based upon tolerability, ability to titrate dose to effect and
`cost.
`New mesalazine formulations have been developed with
`the aim of both increasing the adherence to oral mesalazine
`treatment and avoiding topical administration of the drug.
`
`MMX mesalazine
`The recently developed MMX technology (in Italy by
`Cosmo S.p.A. Corp) involves incorporating mesalazine
`into a lipophilic matrix that is itself dispersed within a
`hydrophilic matrix to delay and prolong dissolution. There
`is a gastroresistant polymer film that prevents initial drug
`release until exposed to a pH of 7 or higher, so the film
`coat normally starts to dissolve only in the terminal ileum.
`In this case the hydrophilic matrix is exposed to intestinal
`fluids and swells, leading to the formation of a viscous
`gel mass with a slow and gradual release of mesalazine
`throughout the length of the colon[33].
`Initially, the efficacy of MMX mesalazine was compared
`with mesalazine enema in patients with left-sided active
`UC. Clinical remission occurred in 60% of patients in
`the MMX group and in 50% of the enema group. Similar
`improvement was seen in the endoscopic and histological
`pattern. In addition, the adherence rate in remission was
`92% in the MMX group and 65% in the enema group[34].
`In a large randomized, double-blind, placebo-cont-
`rolled trial, Lichtenstein et al[35] investigated the efficacy of
`MMX mesalazine 1.2 g twice daily and 4.8 g once-daily
`compared with a placebo for 8 wk, for the induction of
`remission in patients with mild-to moderate UC. Both
`MMX mesalazine groups achieved statistically significant
`clinical and endoscopic remission compared with the
`placebo (34.1% and 29.2% vs 12.9%, 2.4 g/d and 4.8 g/d
`vs placebo, P < 0.001 and P = 0.009, respectively). Another
`large double-blind, placebo-controlled, multicenter clinical
`trial, by Kamm et al[36] randomized patients with active,
`mild-to-moderate UC to receive MMX mesalazine 2.4
`g once daily, MMX mesalazine 4.8 g once daily, placebo,
`or a delayed-release (EUDRAGIT S-coated) mesalazine
`800 mg 3 times daily. Significantly more patients achieved
`clinical and endoscopic remission at week eight in the
`MMX mesalazine groups compared with the placebo
`group (40.5% and 41.2% vs 22.1% with 2.4 g/d, 4.8 g/d vs
`placebo; P = 0.01 and P = 0.007). In contrast, the group
`of delayed-release mesalazine demonstrated only a trend
`for improvement (32.6% vs 22.1%, P = 0.124). It is of note
`that, in the subgroup analysis, no significant difference in
`the remission rates between extensive and left-sided colitis
`was found in the four groups of this study.
`The efficacy of MMX mesalazine as maintenance
`therapy was examined in a more recent multicenter
`study[37]. Patients with UC were randomized to receive
`MMX mesalazine 2.4 g/d once daily, or delayed-release
`(EUDRAGIT S-coated) mesalazine 2.4 g/d twice daily,
`administered in a double-dummy fashion for 12 mo. All
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`patients were in remission with at least one documented
`relapse in the previous year. The data from this study
`indicate that MMX mesalazine 2.4 g/d once daily and
`delayed-release mesalazine 2.4 g/d twice daily are similarly
`tolerated and effective in the maintenance of remission
`of distal UC. However, when only the Italian population
`was examined, statistically significant treatment differences
`favouring MMX mesalazine were revealed.
`In theory, once-daily dosing with MMX mesalazine may
`improve patient compliance and have higher remission rates
`than delayed-release mesalazine in the treatment of patients
`with distal UC. In order to confirm this theory, future
`studies evaluating compliance rates in clinical practice and
`larger studies focused on distal UC are required.
`
`Mesalazine granules
`Another new formulation of 5-ASA, which is becoming
`more widespread, is the micropellet release system, which
`allows once daily dosing in an easy-to-swallow formula-
`tion. It is provided as individual sachets containing a sin-
`gle dose, using granules to effect a delayed and sustained
`release of 5-ASA with similar delivery properties and sys-
`temic exposure to tablets.
`Mesalazine granules are a multiparticulate formulation
`with an enteric acid-resistant film coating. Their dissolution
`starts approximately at pH > 6.0, leading to a delayed and,
`due to the inner polymer matrix, prolonged release of the
`active ingredient throughout the entire colon[38].
`The mesalazine micropellet formulation was found
`to be as effective as tablets (EUDRAGIT L-coated mesa-
`lazine) in patients with mild-to-moderate UC, enabling a
`larger dose to be taken comfortably and conveniently with
`possible impact on patient compliance[39].
`In a recent study, the administration of a 3 g once-daily
`dose of mesalazine granules was found at least as effective
`as a divided dose of 1 g given three times daily, leading a
`substantial proportion of patients with mild-to-moderate
`active UC into clinical and endoscopic remission. Espe-
`cially for patients with distal UC, the clinical remission rate
`was significantly higher in the group using a once-daily
`dose compared to a three times daily dose (86% vs 73%, P
`= 0.03)[40].
`In another recent study, after 1 year of treatment,
`70.9% of the group given 2 g mesalazine granules once
`daily remained in remission vs 58.9% of the group given
`1 g mesalazine granules twice daily; this difference was
`statistically significant (P = 0.024), indicating the increased
`efficacy of once daily, compared with twice daily, dosing[41].
`These findings suggest that once daily treatment with
`mesalazine granules could be offered as a first choice of
`induction or maintenance treatment for UC patients.
`
`OTHER NEW MEDICATIONS
`Probiotics
`VSL#3, a probiotic preparation containing 8 different
`bacterial strains, has been found to be effective in inducing
`remission of mild-to-moderate active UC, as well as in main-
`
`Koutroubakis IE. Treatment of distal ulcerative colitis
`
`taining remission[42,43]. Concerning maintenance treatment
`of UC, E. coli Nissle 1917 has been found to be equivalent
`to mesalazine in maintaining remission in UC, including
`patients who were treated after an acute episode of UC[44].
`The conclusion of a Cochrane review of randomized,
`controlled trials of probiotics in UC was probiotics added
`to standard therapy may provide modest benefits in the
`reduction of disease activity in patients with mild-to-
`moderately active UC[45].
`
`Beclomethasone diproprionate
`Recently, steroids with a colonic release mechanism and
`low systemic bioavailability, such as beclomethasone dipro-
`prionate are becoming available. Oral beclomethasone
`diproprionate in combination with oral 5-ASA has been
`found to be significantly more effective than 5-ASA alone
`in the treatment of patients with extensive or left-sided
`active UC[46]. In another large study of patients with active
`left-sided or extensive colitis, beclomethasone diproprion-
`ate 5 mg/d had an effect similar to that of mesalazine, but
`without systemic steroid side-effects[47]. Beclomethasone
`diproprionate has also been used in an enema with compa-
`rable tolerability and efficacy to mesalazine enema in mild
`active distal UC[48].
`
`Budesonide MMX
`The available oral formulations of budesonide have
`mainly been developed to treat ileocolonic Crohn’s disease
`and not distal colonic lesions, due to their characteristic
`pattern of drug release in the gut. Budesonide enema is
`both effective and safe for the treatment of active distal
`UC[49]. Recently, a budesonide-MMX 9 mg formulation
`was developed and investigated in patients with UC.
`In a pilot study, budesonide-MMX induced a fast and
`significant clinical improvement in active left-sided UC
`without suppression of adrenocortical functions and
`without toxicity[50].
`
`Adalimumab
`Adalimumab is an anti-TNF agent similar to infliximab,
`but administered subcutaneously with less immunogenicity.
`Trials on adalimumab in UC are ongoing. A small series
`with preliminary data in patients with mild-to-moderate
`UC who had secondary failure to infliximab showed that
`adalimumab was well-tolerated and effective in maintaining
`clinical remission in a subgroup of patients with UC with
`lost response or intolerance to infliximab[51,52].
`
`Parnaparin MMX
`Parenteral administration of low-molecular weight heparins
`(LMWHs) has been taken into consideration in the treatment
`of UC with conflicting results. Recent experimental data
`proved that parnaparin sodium, a LMWH with a mean
`molecular mass around 5000, delivered by catheter into
`the colon of rat was highly effective in ameliorating
`dinitrobenzene (DNB)-induced colitis[53]. This lead to the
`suggestion that the administration of parnaparin sodium,
`contained in tablets delivering the product directly into the
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`Cosmo Ex 2005-p. 5
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`3
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`7
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`9
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`Koutroubakis IE. Treatment of distal ulcerative colitis
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`lumen of the colon, could represent a promising approach
`to treat UC. In a recent study, parnaparin sodium, in the
`form of colon-released tablets using MMX technology, has
`been found to be a safe and effective treatment of distal
`UC[54].
`
`Curcumin (Turmeric)
`Curcumin is a biologically active natural phytochemical
`substance present in turmeric, and since it has anti-inflam-
`matory and antioxidant properties, it has been suggested
`to be beneficial in UC. In a recent study, UC patients who
`received curcumin as maintenance treatment had signifi-
`cantly less relapses compared to patients in the placebo
`group. Moreover, curcumin significantly improved both
`clinical activity and endoscopic indices, suggesting that it is
`effective and safe for maintaining remission in patients with
`quiescent UC[55].
`
`CONCLUSION
`Distal UC is the most frequent form of this disease at
`diagnosis. In treating active distal UC, efficacy and targeting
`of the drug to the distal colon are key priorities.
`Oral and rectal 5-ASA preparations represent the best
`therapeutic option for most patients with mild-to-moderate
`distal UC for both induction and maintenance treatment.
`There is evidence that early and aggressive treatment of
`distal UC may prevent or delay proximal extension.
`The data showing that many UC patients are not adhe-
`rent to therapy and that non-compliant patients had a 5-fold
`risk of experiencing a relapse has led to the introduction of
`once-daily oral regimens of 5-ASA as a better therapeutic
`option in clinical practice due to improved adherence.
`New formulations of mesalazine, including MMX
`mesalazine and mesalazine granules, have been shown to
`be efficacious in inducing and maintaining remission in
`mild-to-moderate distal UC in large clinical trials. However,
`existing data, especially for distal UC, are rather insufficient
`to make a comparison between new and classical 5-ASA
`formulations. It seems that the new formulations are at
`least as effective as classical oral 5-ASA formulations.
`Other treatment options, in the case that 5-ASA therapy
`is not effective, include systemic corticosteroids, thiopurines
`(azathioprine or 6-mercaptopurine), cyclosporine, infliximab
`and surgery.
`The combination of a prompt diagnostic work-up, a
`correct therapeutic approach and an appropriate follow-
`up schedule is important in the management of patients
`with distal UC. This approach can shorten the duration of
`symptoms, induce a prolonged remission, improve patient
`quality of life, and optimize the use of health resources.
`
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