Risk of permanent stoma in extensive Crohn's colitis: the impact of biological drugs.

AIM: The overall risk of permanent stoma was determined in patients with extensive Crohn's colitis. An attempt was made to analyse whether biological drugs have modified the surgical approach in patients with anorectal involvement. METHOD: In all, 233 patients with Crohn's disease colitis operated on between 1995 and 2010 were reviewed retrospectively. Fifty-one were treated before 2002 (prebiological era) and 182 after 2002 (biological era). The relationship was determined between the use of immunosuppressors, biological drugs, the presence of perianal disease and anorectal stenosis and the rate of permanent stoma formation. RESULTS: In the prebiological era 23 (45.1%) patients without anorectal involvement underwent colectomy and ileorectal anastomosis, 17 (33.3%) with severe anorectal disease had proctocolectomy and 11 (21.6%) with anorectal involvement had abdominal colectomy with permanent ileostomy. In the biological era 73 (40.1%) patients without anorectal involvement underwent colectomy and ileorectal anastomosis, nine (5%) with severe anorectal involvement had proctocolectomy and 100 (54.9%) with anorectal involvement had colectomy with terminal ileostomy. Of these 100, 75 have subsequently been treated with biological drugs with full regression of anorectal lesions in 81.3%. Rates of permanent stoma in the prebiological and biological era were 60.8% and 19.2% (P < 0.001). Univariate and multivariate analysis showed that only the use of biological drugs was significantly associated with an increased rate of rectal preservation (P < 0.05). CONCLUSION: The risk of a permanent stoma in patients with Crohn's colitis and anorectal involvement is significantly reduced with combined surgical and biological treatment.

Selective cyclooxygenase-2 silencing mediated by engineered E. coli and RNA interference induces anti-tumour effects in human colon cancer cells.

BACKGROUND: Cyclooxygenase-2 (COX-2) overexpression is strongly associated with colorectal tumourigenesis. It has been demonstrated that the chronic use of non-steroidal anti-inflammatory drugs (COX inhibitors) partially protects patients from colorectal cancer (CRC) development and progression but induces severe cardiovascular side effects. New strategies for selective COX-2 blockade are required. METHODS: We developed an improved technique, based on RNA interference (RNAi), to gain a selective COX-2 silencing in CRC cells by a tumour-dependent expression of anti-COX-2 short-hairpin RNA (shCOX-2). Anti-COX-2 shRNA-expressing vectors were delivered in CRC cells (in vitro) and in colon tissues (ex vivo) using engineered Escherichia coli strains, capable of invading tumour cells (InvColi). RESULTS: A highly tumour-dependent shCOX-2 expression and a significant COX-2 silencing were observed in CRC cells following InvColi strain infection. Cyclooxygenase-2 silencing was associated with a strong reduction in both proliferative and invasive behaviour of tumour cells. We also demonstrated a pivotal role of COX-2 overexpression for the survival of CRC cells after bacterial infection. Moreover, COX-2 silencing was achieved ex vivo by infecting colon tissue samples with InvColi strains, leading to anti-inflammatory and anti-tumour effects. CONCLUSION: Our RNAi/InvColi-mediated approach offers a promising tool for a highly selective COX-2 blockade in vitro and in vivo.

Interaction of probiotic Lactobacillus and Bifidobacterium strains with human intestinal epithelial cells: adhesion properties, competition against enteropathogens and modulation of IL-8 production.

The human intestinal microbiota plays a pivotal role in human nutrition and health by promoting the supply of nutrients, preventing pathogen colonization and shaping and maintaining normal mucosal immunity. The depletion of the individual microbiota can result in a higher susceptibility to enteropathogenic bacteria infection. In order to reduce this risk, the use of food supplements containing probiotic bacteria has been recently addressed. In this paper, we investigate the protective role toward enteropathogen infection of probiotic strains belonging to Lactobacillus and Bifidobacterium. According to our experimental data, Lactobacillus acidophilus Bar13, L. plantarum Bar10, Bifidobacterium longum Bar33 and B. lactis Bar30 were effective in displacing the enteropathogens Salmonella typhimurium and Escherichia coli H10407 from a Caco-2 cell layer. Moreover, L. acidophilus Bar13 and B. longum Bar33 have been assessed for their immunomodulatory activity on IL-8 production by HT29 cells. Both strains showed the potential to protect enterocytes from an acute inflammatory response. These probiotic strains are potential candidates for the development of new functional foods helpful in counteracting enteropathogen infections.

Oral budesonide in the treatment of chronic refractory pouchitis.

BACKGROUND: Pouchitis is the major long-term complication after ileal-pouch nal anastomosis for ulcerative colitis. Ten to 15% of patients develop a chronic pouchitis, either treatment responsive or treatment refractory. AIM: To evaluate the efficacy of oral budesonide in inducing remission and improving quality of life in patients with chronic refractory pouchitis. METHODS: Twenty consecutive patients with active pouchitis, not responding after 1 month of antibiotic treatment were treated with budesonide controlled ileal release 9 mg/day for 8 weeks. Symptomatic, endoscopic and histological evaluations were undertaken before and after treatment according to Pouchitis Disease Activity Index. Remission was defined as a combination of Pouchitis Disease Activity Index clinical score of < or = 2, endoscopic score of < or = 1 and total Pouchitis Disease Activity Index score of < or = 4. The quality of life was assessed with the Inflammatory Bowel Disease Questionnaire. RESULTS: Fifteen of 20 patients (75%) achieved remission. The median total Pouchitis Disease Activity Index scores before and after therapy were, respectively, 14 (range 9-16) and 3 (range 2-10) (P < 0.001). The median Inflammatory Bowel Disease Questionnaire score also significantly improved from 105 (range 77-175) to 180 (range 85-220) (P < 0.001). CONCLUSION: Eight-week treatment with oral budesonide appears effective in inducing remission in patients with active pouchitis refractory to antibiotic treatment in this open-label study.

Controlled study using wireless capsule endoscopy for the evaluation of the small intestine in chronic refractory pouchitis.

BACKGROUND: Pouchitis is a common long-term complication after ileal pouch anal anastomosis for ulcerative colitis. Chronic refractory pouchitis is a treatment-resistant condition that affects 5-15% of patients. AIM: To test the hypothesis of a small bowel involvement using wireless capsule endoscopy. MATERIAL AND METHODS: This is a single-blind, prospective, cohort study. Twenty-four patients: 16 were patients with chronic refractory pouchitis and eight, with a macroscopically and histologically normal ileal pouch, were considered as control subjects. Diagnosis of pouchitis was confirmed using the pouchitis disease activity index. All subjects were submitted to wireless capsule endoscopy procedure. Within 2 weeks before wireless capsule endoscopy, patients underwent a pouch endoscopy and a small bowel follow-through. Re-examination of the colonic surgical and histological specimens was also performed. RESULTS: One patient with chronic pouchitis was excluded because of incomplete bowel cleaning. At small bowel follow-through of 16 patients, two subjects (13%) showed only a focal ectasia of the middle ileum and a substenosis of the pouch. At wireless capsule endoscopy all the 15 evaluable patients with chronic pouchitis (100%) showed diffuse lesions from duodenum to ileum consisting of aphthae, erosions, erythema, atrophy, cobblestone, deep/fissural ulcers. CONCLUSIONS: This enteropathy needs further research, and wireless capsule endoscopy could be useful to show involvement of small bowel in patients with chronic pouchitis.

Beclomethasone dipropionate versus mesalazine in distal ulcerative colitis: a multicenter, randomized, double-blind study.

BACKGROUND: Topical beclomethasone diproprionate has shown efficacy in ulcerative colitis. AIM: To assess, in a multicenter, randomized, double-blind study, the tolerability and safety of topical beclomethasone diproprionate (3mg) enema and foam versus mesalazine (2g) enema and foam in mild-moderate distal ulcerative colitis. PATIENTS: In 15 referral gastrointestinal units, 99 patients with distal ulcerative colitis were enrolled. This number was lower than planned according to the statistical analysis, due to a low recruitment rate. METHODS: Patients were randomly assigned to random preparations (beclomethasone diproprionate enema, beclomethasone diproprionate foam, mesalazine enema, mesalazine foam) once nightly for 8 weeks, with clinical and endoscopical assessment (Disease Activity Index score) at baseline (T0), 4 (T4) and 8 weeks (T8). Results were expressed as median and range (95% confidence interval). The efficacy was assessed by comparing the Disease Activity Index value at T4 and T8 by using the Student's t-test or the Wilcoxon-Mann-Whitney test. RESULTS: Efficacy was comparable in the beclomethasone diproprionate or mesalazine groups at both T4 and T8 (response at T4: beclomethasone diproprionate 78% [95% confidence interval 0.6-0.8] versus mesalazine 79% [95% confidence interval 0.6-0.8]; T8: beclomethasone diproprionate 84% [95% confidence interval 0.7-0.9] versus mesalazine 90% [95% confidence interval 0.7-1.0]; p=n.s.; remission at T4: beclomethasone diproprionate 24% [95% confidence interval 0.1-0.3] versus mesalazine 28% [95% confidence interval 0.1-0.3]; remission at T8: beclomethasone diproprionate 36% [95% confidence interval 0.2-0.5] versus mesalazine 52% [95% confidence interval 0.3-0.6]; p=n.s.). The Disease Activity Index lowered at T4 and T8 versus T0 in the four groups (T4 versus T0: beclomethasone diproprionate foam Disease Activity Index 2 versus 6 p<0.0001; beclomethasone diproprionate enema 4 versus 6, mesalazine enema 3 versus 6, mesalazine foam 3.5 versus 7, p<0.001 for all three groups; T8 versus T0: p<0.01). The Disease Activity Index lowered at T8 versus T4 in the beclomethasone diproprionate enema and foam (Disease Activity Index: 2 versus 4 and 1 versus 4, respectively; p<0.05) and in the mesalazine enema (Disease Activity Index: 1.5, range 0-4 versus 3, range 0-12; p<0.01), but not in the mesalazine foam group (Disease Activity Index: 1, range 0-9 versus 3.5, range 0-8; p=n.s.). The safety profile was favourable for all groups. CONCLUSIONS: Beclomethasone diproprionate and mesalazine enema and foam show a comparable tolerability and efficacy in mild active distal ulcerative colitis.

Stress and brain functional changes in patients with Crohn's disease: A functional magnetic resonance imaging study.

BACKGROUND: In Crohn's disease (CD) patients, stress is believed to influence symptoms generation. Stress may act via central nervous system pathways to affect visceral sensitivity and motility thus exacerbating gastrointestinal symptoms. The neural substrate underpinning these mechanisms needs to be investigated in CD. We conducted an explorative functional magnetic resonance imaging (fMRI) study in order to investigate potential differences in the brain stress response in CD patients compared to controls. METHODS: 17 CD patients and 17 healthy controls underwent a fMRI scan while performing a stressful task consisting in a Stroop color-word interference task designed to induce mental stress in the fMRI environment. KEY RESULTS: Compared to controls, in CD patients the stress task elicited greater blood oxygen level dependent (BOLD) signals in the midcingulate cortex (MCC). CONCLUSIONS & INFERENCES: The MCC integrate "high" emotional processes with afferent sensory information ascending from the gut. In light of these integrative functions, the stress-evoked MCC hyperactivity in CD patients might represent a plausible neural substrate for the association between stress and symptomatic disease. The MCC dysfunction might be involved in mechanisms of central disinhibition of nociceptive inputs leading to amplify the visceral sensitivity. Finally, the stress-evoked MCC hyperactivity might affect the regulation of intestinal motility resulting in exacerbation of disease symptoms and the autonomic and neuroendocrine regulation of inflammation resulting in enhanced inflammatory activity.

Review article: aminosalicylates for distal colitis.

About two-thirds of patients with ulcerative colitis have an inflammatory involvement distal to the splenic flexure and therefore may be effectively treated with topical treatment. This allows the delivery of the active drug directly to the site of inflammation, limiting the systemic absorption and the potential side effects. Topical aminosalicylate therapy is the most effective approach, provided that the formulation reaches the upper extent of the disease. Suppositories should be considered the treatment of choice for proctitis and distal sigmoiditis. A 1 g Pentasa-suppository once daily induces a quicker clinical and endoscopic remission and was better tolerated than a 500-mg suppository twice daily. Enemas, foams and gel, thanks to their proximal spread, should be the treatment of choice for proctosigmoiditis and left-sided colitis. Oral aminosalicylates are less effective than topical therapies for patients with active disease; however, a combination of oral and topical aminosalicylates can be successfully tried in refractory patients. Topical aminosalicylates also play an important role in the maintenance of remission, and the combination of oral plus rectal 5-aminosalicylate is superior to the single agent. Patients who prefer not to continue on long-term rectal therapy can be treated with oral aminosalicylates.

Antibiotic treatment of Crohn's disease: results of a multicentre, double blind, randomized, placebo-controlled trial with rifaximin.

BACKGROUND: Clinicians often employ antibiotics in Crohn's disease. Rifaximin is active against bacteria frequently found in the intestinal mucosa of Crohn's disease patients. AIM: To evaluate the difference in efficacy between once and twice/daily oral administration of rifaximin and placebo in the treatment of active Crohn's disease. METHODS: We enrolled 83 patients with mild-to-moderate Crohn's disease and randomized to three treatments for 12 weeks: Group A (rifaximin 800 mg o.d. + placebo), Group B (rifaximin 800 mg b.d.) and Group C (placebo b.d.). RESULTS: Clinical remission was achieved by 52% of Group B, 32% (A) and 33% (C). Clinical response was seen in 67% (B), 48% (A) and 41% (C), without reaching a statistically significant difference. Treatment failures were: 4% (B), 12% (A) and 33% (C), (P = 0.010). Remission and response rates of rifaximin 800 mg b.d. were significantly higher than those of placebo and rifaximin 800 mg o.d. in patients with elevated C reactive protein values (P < 0.05). CONCLUSIONS: Rifaximin 800 mg b.d. was superior to placebo in inducing clinical remission of active Crohn's disease. Although this difference was not statistically significant, the number of the failures in the placebo group was significantly higher than those who received rifaximin 800 mg b.d.

Rectal cell proliferation and colon cancer risk in ulcerative colitis.

Cell proliferation kinetics of 30 patients affected by extensive ulcerative colitis in remission have been studied with autoradiography of rectal biopsies incubated with tritiated thymidine. The results have been compared with those of 20 control subjects without evidence of colonic diseases, and of 16 patients with multiple nonfamilial colonic adenomas. The labeling index was similar in the three groups (P = NS). On the contrary, the labeling frequency (SEM) in the upper 40% of the crypt (phi h value) was 0.04 +/- 0.01 in controls, 0.16 +/- 0.02 in ulcerative colitis, and 0.10 +/- 0.01 in adenoma patients (P less than 0.001 ulcerative colitis versus controls, P less than 0.01 adenomas versus controls, P = NS ulcerative colitis versus adenomas). The distribution of phi h values in ulcerative colitis showed a bimodal trend with 22 patients having mean phi h values similar to adenoma patients (0.10 +/- 0.01) and 8 with higher values (0.30 +/- 0.02). No relationship was found between phi h values and duration of colitis, age of patients, or age at onset of symptoms. These data show that cell kinetics studies can detect patients at particularly high risk of colon cancer, and that additional factors should determine colon cancer risk level in ulcerative colitis.

Combined carriership of TLR9-1237C and CD14-260T alleles enhances the risk of developing chronic relapsing pouchitis.

AIM: To investigate the single nucleotide polymorphisms (SNPs) in genes involved in bacterial recognition and the susceptibility to pouchitis or pouchitis severity. METHODS: Analyses of CD14 -260C>T, CARD15/NOD2 3020insC, Toll-like receptor (TLR)4 +896A>G, TLR9 -1237T>C, TLR9+2848G>A, and IRAKM + 22148G>A SNPs were performed in 157 ileal-pouch anal anastomosis (IPAA) patients (79 patients who did not develop pouchitis, 43 infrequent pouchitis patients, 35 chronic relapsing pouchitis patients) and 224 Italian Caucasian healthy controls. RESULTS: No significant differences were found in SNP frequencies between controls and IPAA patients. However, a significant difference in carriership frequency of the TLR9-1237C allele was found between the infrequent pouchitis and chronic relapsing pouchitis groups [P = 0.028, oddos ratio (OR) = 3.2, 95%CI = 1.2-8.6]. This allele uniquely represented a 4-locus TLR9 haplotype comprising both studied TLR9 SNPs in Caucasians. Carrier trait analysis revealed an enhanced combined carriership of the alleles TLR9 -1237C and CD14 -260T in the chronic relapsing pouchitis and infrequent pouchitis group (P = 0.018, OR = 4.1, 95%CI = 1.4 -12.3). CONCLUSION: There is no evidence that the SNPs predispose to the need for IPAA surgery. The significant increase of the combined carriership of the CD14 -260T and TLR9 -1237C alleles in the chronic relapsing pouchitis group suggests that these markers identify a subgroup of IPAA patients with a risk of developing chronic or refractory pouchitis.

Mesalazine 4 g daily given as prolonged-release granules twice daily and four times daily is at least as effective as prolonged-release tablets four times daily in patients with ulcerative colitis.

BACKGROUND: High doses of mesalazine usually result in an inconvenient dosage schedule and reduced compliance. The goal of this trial was to compare the effects of mesalazine 4 g daily given as prolonged-release granules in packets of 1 g with that of prolonged-release tablets of 0.5 g. METHODS: Two hundred twenty-seven patients with mild-to-moderate ulcerative colitis were randomized to treatment with two packets twice daily (Gr-b.i.d.), 1 packet four times daily (Gr-q.i.d.) or 2 tablets four times daily (Ta-q.i.d.) for 8 weeks. A disease activity index (ulcerative colitis disease activity index: UC-DAI) was calculated, and the granules were defined as noninferior to the tablets if the lower limit of the 95% CI for the differences was more than -1 UC-DAI score unit. RESULTS: Noninferiority of the granules compared with the tablets was demonstrated. The mean improvement in the UC-DAI in the treatment groups Gr-b.i.d., Gr-q.i.d., and Ta-q.i.d. were 3.2, 2.9, and 2.4, respectively; the proportion of complete responders in the three groups 39%, 37%, and 31%, respectively. There were no differences in side effects. CONCLUSION: Mesalazine 4 g daily given as prolonged-release granules twice and four times daily is at least as effective as prolonged-release tablets four times daily in patients with mild to moderate ulcerative colitis. The patients preferred the twice daily dosing.

Review article: medical treatment of severe ulcerative colitis.

Severe colitis is a life-threatening complication of ulcerative colitis. Early recognition of the severity of the colitis and intensive treatment and monitoring have all contributed to improved outcome. Since their introduction in 1950s, corticosteroids are the first line therapy for severe active ulcerative colitis (UC). Several prognostic parameters (such as stools movement per day, C-reactive protein, increased amount of intestinal gas or small bowel dilation, hypoalbuminemia, fever etc) help the physician to quickly introduce cyclosporin or to refer the patient to the surgeon. This decision requires a careful evaluation of the patient and a medical /surgical team. Infliximab seems to be a promising drug but more controlled trial are needed.

Review article: problematic proctitis and distal colitis.

About two-thirds of patients with ulcerative colitis have an inflammatory involvement distal to the splenic flexure, and therefore may be effectively treated with topical treatment, allowing the delivery of the active drug directly to the site of inflammation and limiting systemic absorption and potential side-effects. Topical aminosalicylate therapy is the most effective approach, and most patients will benefit hugely, provided that the formulation reaches the upper extent of the disease. Therefore, the choice of topical preparation should be based on the proximal extent of the disease and on patient preference. Oral aminosalicylates are less effective than topical therapies; however, a combination of oral and topical aminosalicylates can be successful in refractory patients. Alternatives to aminosalicylates are the new glucocorticoids, budesonide and beclometasone dipropionate, either as enemas or oral formulations (only beclometasone dipropionate). A combination of oral or rectal new glucocorticoids with rectal aminosalicylates should be considered in patients refractory to either approach. When these measures fail, treatment with oral glucocorticoids is necessary. An intensive intravenous steroid regimen is also helpful for patients refractory to oral steroids. Alternative treatments include short-chain fatty acid enemas, nicotine enemas and patches, acetarsol suppositories, ciclosporin enemas and epidermal growth factor enemas. Several factors potentially having a negative impact on therapeutic response include concurrent enteric pathogens, coexistent irritable bowel syndrome, patient nonadherence to therapy, inadequate dosing and duration of therapy, and proximal progression of the disease. Surgical colectomy may be required in those rare patients refractory or intolerant to pharmacotherapy.

Review article: treatment of mild to moderate ulcerative colitis and pouchitis.

The meta-analyses of published trials have shown topical therapy with 5-aminosalicylic acid (5-ASA) to be the treatment of choice in active distal ulcerative colitis. Oral aminosalicylates are effective for both distal and extensive ulcerative colitis, but in distal colitis the rates of improvement and remission are usually lower than those reported for rectal 5-ASA therapy. An alternative to 5-ASA therapy is represented by the new steroids; budesonide and beclometasone dipropionate (BDP) enemas, the most extensively studied, have been shown to be as effective as conventional steroids but with a significantly lower inhibition of plasma cortisol. Patients who do not respond to 5-ASA or new steroids should be treated with oral steroids. Azathioprine or 6-mercaptopurine may be effective in patients who do not respond or cannot be weaned off steroids. Treatment of pouchitis is largely empirical and few controlled studies have been carried-out. Antibiotics are the treatment of choice and most patients make a good response to metronidazole or ciprofloxacin. Chronic refractory pouchitis may benefit from a prolonged course of a combination of antibiotics. Highly concentrated probiotics (VSL#3) are effective both for the prevention of pouchitis onset and the prevention of relapses.

Review article: the management of refractory Crohn's disease.

Refractoriness to conventional therapy is a common and intriguing problem in Crohn's disease patients. At the present time there is no agreement on its definition and several mechanisms are involved in its determination. Immunosuppressors, such as azathioprine (AZA), 6-mercaptopurine (6MP) and methotrexate (MTX) are effective drugs for controlling the inflammatory process and avoid chronic glucocorticosteroid treatment and its related side-effects. Recently, the introduction of tumour necrosis factor antibodies (infliximab) has dramatically changed the natural history of Crohn's disease and its therapeutic approach. Several studies have determined the efficacy, mechanisms and safety of infliximab. However, this molecular approach has also left several questions unanswered about the mechanisms of refractoriness, possible concomitant treatments and long-term safety and efficacy.

Oral budesonide as maintenance therapy in Crohn's disease--results of a 12-month study. Global Budesonide Study Group.

BACKGROUND: Budesonide is a corticosteroid with high topical anti-inflammatory activity and low systemic activity due to rapid inactivation. We have assessed the efficacy and safety of an oral controlled ileal release (CIR) preparation of budesonide for maintenance of remission in patients with ileal or ileocaecal Crohn's disease. METHODS: In a double-blind, multicentre trial, 75 patients in clinical remission (Crohn's Disease Activity Index, CDAI, < or = 150) were randomly assigned to receive placebo, budesonide 3 mg or budesonide 6 mg daily for 12 months. Trial drugs were given at a fixed dose and without concomitant medication. The primary outcome measure was relapse, defined as a CDAI > 150 together with an increase of at least 60 units from entry. A patient was also considered to have a relapse if withdrawn from the study due to clinical deterioration, whether or not a CDAI value could be calculated at that time. RESULTS: There were no statistically significant differences in the relapse rate at any time-point throughout the study. By 12 months the proportion of patients having relapsed were 48, 46 and 60% in those patients treated with budesonide 6 mg, 3 mg and placebo, respectively (N.S.). Treatments were well tolerated, and the proportion of patients with suppressed adrenal function (according to predetermined criteria) were 50% (6 mg), 26% (3 mg) and 17% (placebo) (P = 0.096). CONCLUSIONS: In the present study, relapse rate and time to relapse were similar in the patients treated with budesonide CIR, 6 mg daily or 3 mg daily or with placebo, throughout 12 months. This is in contrast to the two previous trials with identical design, where a significant effect of budesonide CIR in prolonging the median time to relapse was found. Possible reasons for the negative results of the present study include small sample size, and the fact that there was a high placebo response.

Comparison of mesalazine suppositories in proctitis and distal proctosigmoiditis.

BACKGROUND: Mesalazine suppositories at 500 mg b.d. are a safe and effective treatment for patients with ulcerative proctitis or distal proctosigmoiditis. Recently a mesalazine 1 g suppository (Pentasa) has been developed. METHODS: Fifty patients with active ulcerative colitis extending not beyond 20 cm from the anus on sigmoidoscopy, participated in a randomized single-blind study comparing the efficacy, tolerance and acceptance of the new Pentasa mesalazine 1 g suppository, given once daily versus Claversal mesalazine 500 mg suppository b.d. RESULTS: After 2 weeks, clinical remission was observed in 16 of 25 (64%) in the Pentasa group and in 7 of 25 (28%) in the Claversal 500 mg b.d. treated group; sigmoidoscopic remission occurred in 13 of 25 (52%) in the Pentasa group and in six of 25 (24%) in the Claversal group (P < 0.01). After 4 weeks, clinical and sigmoidoscopic remission were observed, respectively, in 84 and 76% of patients treated with Pentasa suppositories, and in 80 and 72% of patients treated with Claversal suppositories 500 mg b.d. (P = N.S.). The patients' evaluation for tolerability and practicality showed that the Pentasa suppository was significantly superior to the Claversal suppository. CONCLUSIONS: Pentasa 1 g suppository once daily induces a quicker clinical and sigmoidoscopic remission, and was better tolerated, than the Claversal 500 mg suppository b.d., and it may represent an advance for the topical treatment of distal proctosigmoiditis.

Review article: monitoring activity in ulcerative colitis.

The monitoring of patients with ulcerative colitis is easier than in patients with Crohn's disease for several reasons: the severity of symptoms and activity of inflammation tend to run parallel in ulcerative colitis when involvement of the large bowel is more extensive. The easy accessibility of the colonic mucosa by endoscopic and histologic examination provides further information concerning the degree of inflammation. In severe attacks, the patient must be admitted to hospital and monitored carefully. Clinical and laboratory parameters (such as daily stools, CRP, fever, haemoglobin, albumin, etc.) and plain abdominal X-ray are useful in monitoring the activity of the disease and to predict the outcome. In mild to moderate attacks, endoscopic and histologic evaluation are the best methods for choosing the appropriate treatment and for assessing response.

Bioavailability of single and multiple doses of a new oral formulation of 5-ASA in patients with inflammatory bowel disease and healthy volunteers.

AIMS: An oral multiparticulate coated formulation of 5-aminosalicylic acid (5-ASA: mesalazine) has been developed to provide a controlled release of the drug, in a pH-dependent fashion, in the distal ileum and colon. The purpose of the present study was to assess the systemic availability of the drug and its metabolite, acetyl-5-ASA, following single (800 mg) and multiple (2400 mg for 56 days) oral dose administration. METHODS: Three groups were investigated: six healthy volunteers, six patients with ulcerative colitis, and nine patients with Crohn's disease in remission. In the single oral dose study (800 mg) all three groups participated, whereas in the multiple oral dose study (2400 mg/day for 56 days) only the patients with inflammatory bowel disease took part. Plasma and urine 5-ASA and Ac-5-ASA were measured for 48 h. RESULTS: In the single oral dose regimen, systemic absorption of 5-ASA and Ac-5-ASA were low and did not differ between the three groups. Only about 20% of the 5-ASA given was absorbed, with more than 80% of the drug being available in the terminal ileum and colon for therapeutic activity. The multiple oral dose regimen in patients with inflammatory bowel disease produced a significantly higher plasma concentration and urine excretion of both 5-ASA and Ac-5-ASA by the end of the treatment, in comparison to the first dose. There was a statistically higher systemic absorption of 5-ASA in patients with ulcerative colitis than in patients with Crohn's disease. After 56 days of dosing, no adverse event was reported and laboratory screening tests remained within normal ranges. CONCLUSIONS: The new oral 5-ASA formulation is gradually released throughout the small and large intestine, reflected by a low plasma concentration of the drug and its metabolite, with about 80% of the drug being available for ileum-colon therapeutic activity.