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The CD8+CD28+/CD8+CD28− T lymphocyte balance is vital for human ulcerative colitis (UC) but has not been defined in experimental colitis. This investigation will try to identify the changes that occur in the CD8+CD28+/CD8+CD28− T lymphocyte balance during the progression of trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. The frequencies of blood CD8+CD28+ and CD8+CD28− T lymphocytes were detected in the rats belonging to the normal, model, and treated groups on five days using flow cytometry. The treated rats were administered with mesalazine and were euthanized after a 14-day treatment, as were the normal and model rats. The sensitivity and specificity of the CD8+CD28+/CD8+CD28− T lymphocyte balance in diagnosing early colitis were analyzed by receiver operating characteristics (ROC) curves. The frequencies of CD8+CD28+ and CD8+CD28− T lymphocytes in the colon tissue were tested via immunofluorescence. ELISA was used to measure the levels of the cytokines. Immunohistochemistry and Western blotting were used to detect the colonic expression of JAK3, STAT6, NFATc2, and GATA3. We found that the ratio of CD8+CD28+/CD8+CD28− T lymphocytes decreased, as did the level of interleukin-7, but not IL-12p40, IL-13, or IL-15, in the blood; however, the ratio increased along with JAK3, STAT6, NFATc2, and GATA3 in the colon of the rats with colitis. The changes were effectively reversed through the administration of mesalazine for 13 days. Surprisingly, the balance in the blood could sensitively distinguish rats with early colitis from normal rats. These data show that increase in CD8+CD28+ T cells in blood and decrease in CD8+CD28− T cells in colon are associated with experimental colitis.

Patients receiving 5-aminosalicylic acid (5-ASA) require long-term therapy to achieve good outcomes. Persistency (duration of time from initiation to discontinuation of therapy) is therefore an important consideration.To evaluate persistency in patients receiving various oral 5-ASA formulations.This retrospective, 12-month, cohort study examined new-starter patients (any age and diagnosis) from a large United States pharmacy database who filled a prescription for oral 5-ASA [Lialda(®), Asacol(®), Pentasa(®) 250 or 500 mg, balsalazide (generic and Colazal(®)), and olsalazine (Dipentum(®))] between March and September 2007. Persistency was evaluated monthly on the basis of prescription refill rates.Prescription and refill records were identified for 44,191 patients receiving oral 5-ASA. After 1 year, 20% of patients receiving Lialda were considered persistent and classified as continuing (refilling within a timeframe of up to twice the duration of the prescription), compared with 9% receiving Asacol, 7 (250 mg) and 10% (500 mg) receiving Pentasa, 10% receiving balsalazide, and 10% receiving Dipentum.Overall persistency with oral 5-ASA therapy was low. However, patients receiving once-daily Lialda had significantly higher persistency after 1 year of treatment than patients receiving other oral 5-ASA therapies.

Radiation proctitis is a common complication of pelvic radiation for which an optimal treatment remains undetermined. We assessed the efficacy of oral and topical mesalazine combination therapy for patients with naive radiation proctitis. A total of 23 patients with radiation proctitis were enrolled in the study over a period of 2 years. Three of these patients were excluded due to severe bleeding during the study. Twenty patients (mean age 60.3 years; two males, 18 females) were treated with oral mesalazine (3 × 1 g per day) plus a daily mesalazine suppository (1 g per day at bedtime) for 4 weeks. The efficacy of treatment was assessed according to the Subjective Objective Management Analytic (SOMA) scale for alleviation of clinical symptoms of rectal toxicity and sigmoidoscopic findings. The mean bleeding score improved significantly from 2.10 to 1.70 (p = 0.002) with mesalazine treatment. However, scores were not improved for pain (0.30–0.20, p = 0.163), tenesmus (0.50–0.45, p = 0.577), or stool frequency (0.35–0.30, p = 0.577). The improvements in the mean telangiectasia score (1.80–1.45, p = 0.005), bleeding point score (1.60–1.05, p

Individuals with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC) compared with the general population. Previous studies show this risk is strongly associated with dysplasia, extent of disease, duration of disease, and degree of inflammation, while chemoprevention of CRC has less support.Evaluate factors influencing risk of colorectal cancer development in inflammatory bowel disease patients.IBD patients with CRC were matched to controls by IBD type, age at diagnosis, sex, race, extent of disease, and disease duration. We compared body mass index, family history of IBD, family history of CRC, tobacco use, and cumulative and daily use of aminosalicylates, immunomodulators, folic acid, steroids, and nonsteroidal anti-inflammatory drugs. Statistical analysis was performed with logistic regression and receiver operating characteristic (ROC) curves.Of 1,594 IBD patients, 30 CRC patients were identified. Of these, 18 CRC patients were matched to 30 controls. More control patients used a cumulative aminosalicylate dose ofor=4,500 g (46.6% versus 5.6%; P = 0.047), folic acid (40.0% versus 16.7%; P = 0.002), cumulative folic acid dose ofor=1,400 mg (30.0% versus 11.1%; P = 0.014), and average daily folic acid dose ofor=1 mg (30.0% versus 16.7%; P = 0.002) compared with CRC patients. Multivariate analysis showed that a cumulative aminosalicylate dose ofor=4,500 g reduced the risk of CRC by 97.6% (P = 0.047). Folic acid reduced CRC risk by 89% (P = 0.002).Aminosalicylate and folic acid use may decrease the risk of CRC among IBD patients.

Background Historically, sulfasalazine (SSZ) and 5-aminosalicylates (5-ASAs) have been a mainstay of mild-to-moderate ulcerative colitis (UC) remission induction and maintenance therapy. Considering the pivotal role of intestinal microbial flora in pathophysiology of UC and antimicrobial activity of sulfapyridine, we hypothesized that SSZ might be more effective than 5-ASAs in the management of UC. Aim To compare the efficacy and tolerability of SSZ with each of the 5-ASAs (mesalamine, olsalazine, and balsalazide) by a meta-analysis technique. Methods Pubmed, Embase, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials were searched for studies compared efficacy and/or tolerability of SSZ with 5-ASAs in the management of UC. The search terms were: “sulfasalazine” or “sulfasalazine” and “5-aminosalicylic acid,” “mesalazine,” “mesalamine,” “olsalazine” or “balsalazide” and “ulcerative colitis.” Data were collected from 1966 to April 2008. There was no language restriction. “Overall improvement,” “relapse rate,” “total adverse events,” and “withdrawals because of adverse events” were the key outcomes of interest. Results Twenty randomized placebo controlled trials met our criteria and were included in the meta-analysis. Comparison of SSZ with mesalamine yielded a nonsignificant relative risk (RR) of 1.04 (95% confidence interval of 0.89–1.21, P = 0.63) for overall improvement, a nonsignificant RR of 0.98 (95% CI 0.78–1.23, P = 0.85) for relapse, a nonsignificant RR of 0.76 (95% CI 0.54–1.07, P = 0.11) for any adverse events, and a nonsignificant RR of 0.78 (95% CI 0.46–1.3, P = 0.33) for withdrawals due to adverse events. Comparison of SSZ with olsalazine yielded a nonsignificant RR of 1.14 (95% CI 0.91–1.43, P = 0.25) for overall improvement, a nonsignificant RR of 0.93 (95% CI 0.77–1.12, P = 0.42) for relapse, a nonsignificant RR of 1.21 (95% CI 0.9–1.61, P = 0.20) for any adverse events, and a nonsignificant RR of 1.53 (95% CI 0.93–2.52, P = 0.09) for withdrawals due to adverse events. Comparison of SSZ with balsalazide yielded a nonsignificant RR of 1.3 (95% CI 0.93–1.81, P = 0.12) for overall improvement, and a significant RR of 0.17 (95% CI 0.06–0.49, P = 0.001) for withdrawals because of adverse events. Conclusion SSZ does not differ from mesalamine or olsalazine in terms of efficacy and tolerability in UC. Withdrawal from study due to adverse events was significantly lower for balsalazide compared with SSZ. Convincing conclusions on the comparison of effectiveness and safety of balsalazide and SSZ in UC remains to be elucidated by further clinical trials. Considering the lower cost of treatment with SSZ and the equal rate of adverse events with other 5-ASAa, it is not surprising to suggest SSZ as a first-choice treatment for UC and reserve 5-ASAs for when SSZ intolerability occurs.

Colonic diverticulosis imposes a significant burden on industrialized societies. The current accepted causes of diverticula formation include low fiber content in the western diet with decreased intestinal content and size of the lumen, leading to the transmission of muscular contraction pressure to the wall of the colon, inducing the formation of diverticula usually at the weakest point of the wall where penetration of the blood vessels occurs. Approximately 20 % of the patients with colonic diverticulosis develop abdominal symptoms (i.e., abdominal pain and discomfort, bloating, constipation, and diarrhea), a condition which is defined as symptomatic uncomplicated diverticular disease (SUDD). The pathogenesis of SUDD symptoms remains uncertain and even less is known about how to adequately manage bowel symptoms. Recently, low-grade inflammation, altered intestinal microbiota, visceral hypersensitivity, and abnormal colonic motility have been identified as factors leading to symptom development, thus changing and improving the therapeutic approach. In this review, a comprehensive search of the literature regarding on SUDD pathogenetic hypotheses and pharmacological strategies was carried out. The pathogenesis of SUDD, although not completely clarified, seems to be related to an interaction between colonic microbiota alterations, and immune, enteric nerve, and muscular system dysfunction (Cuomo et al. in United Eur Gastroenterol J 2:413-442, 2014). Greater understanding of the inflammatory pathways and gut microbiota composition in subjects affected by SUDD has increased therapeutic options, including the use of gut-directed antibiotics, mesalazine, and probiotics (Bianchi et al. in Aliment Pharmacol Ther 33:902-910, 2011; Comparato et al. in Dig Dis Sci 52:2934-2941, 2007; Tursi et al. in Aliment Pharmacol Ther 38:741-751, 2013); however, more research is necessary to validate the safety, effectiveness, and cost-effectiveness of these interventions.

Recent studies have shown a low adherence rate to maintenance treatment in patients with inflammatory bowel disease (IBD). We sought to assess the medication-taking behavior in a cohort of patients with IBD. We prospectively included IBD patients from the outpatient clinic who agreed to answer a questionnaire about prescribed treatment and adherence. Physicians registered clinical data including prescribed medications. Two hundred fourteen patients (115 Crohn's disease/99 ulcerative colitis) were included. The most prescribed medications were oral mesalazine (56.5%) and immunomodulators (41.1%). Forty-three percent of patients admitted to occasionally forgetting to take their medication but only 7.5% of them did it voluntary. Oral mesalazine and azathioprine were the drugs with the poorest compliance, with nonadherence rates of 45% and 25% of the total prescribed doses, respectively. The only factor associated with a better adherence was a more complicated course of the disease-steroid dependency, steroid refractoriness, need for infliximab treatment, hospitalization, or surgery (P=.02). Twenty percent of patients admitted to self-medicating. An important proportion of patients with IBD admit to forget some doses of the prescribed medication in the setting of a specialized unit of a referral centre.

The aim of this study was to assess the efficienchyperbaric oxygen alone and in combination with 5-aminosalicylic acid in THE acetic acid–induced colitis model, a well-known experimental model of inflammatory bowel disease in rats. Rats were randomly divided into FIVE groups. In the noncolitis control group, rats were given isotonic saline, while in the other groups rats were treated by intracolonic administration of 4% acetic acid. In group 2, the untreated control group, no additional therapy was applied. In groups 3, 4, and 5 hyperbaric oxygen, 5-aminosalicylic acid. and 5-aminosalicylic acid + hyperbaric oxygen therapies were applied, respectively. Administration of acetic acid caused an inflammatory response in all animals. Histopathologic score was significantly higher in group 2 than in any other group. 5-Aminosalicylic acid and hyperbaric oxygen significantly decreased the histopathologic score (P < 0.05). Myeloperoxidase activity was also reduced significantly by 5-aminosalicylic acid (P < 0.05) but not by hyperbaric oxygen. The most prominent ameliorative effect, however, was seen in group 5 and the histopathologic score and myeloperoxidase activity were significantly lower than in groups 3 (P < 0.05) and 4 (P < 0.001). Hydroxyproline level also increased significantly in group 5, but not in groups 3 and 4 (P < 0.001). These findings indicate that hyperbaric oxygen therapy is effective in reducing the extent of colitis induced by acetic acid, although it is not as potent as 5-aminosalicylic acid. The combination of hyperbaric oxygen and 5-aminosalicylic acid, however, led to a much more prominent reduction in the severitcolitis. Hyperbaric oxygen may have a promising place in the treatment of inflammatory bowel disease.

Chronic diarrhea and colitis are common in patients positive for human immunodeficiency virus (HIV) under highly active antiretroviral treatment (HAART). This prospective double-blind study explores the effect of mesalamine vs. placebo in HIV-positive patients. Thirteen HIV-infected patients with noninfectious chronic diarrhea and > 250 CD4+ cells/mm(3) were randomized to mesalamine (2.4 g/day; n = 9) or placebo (n = 4) for 6 weeks. Colonoscopy was performed at baseline and week 6, and biopsies were obtained to calculate the Biopsy Activity Index (BAI). Diarrhea was assessed at baseline and end of treatment using the Disease Activity Index (DAI). Patients and clinicians completed Patient Global Improvement index (PGI) and Clinical Global Improvement index (CGI) at weeks 2 and 6. Comparisons at week 6 were statistically significant between mesalamine and placebo groups for BAI (P = 0.03), DAI (P = 0.007), PGI (P = 0.008), and CGI (P = 0.008). Furthermore, major improvements were documented in the mesalamine group at week 6 compared to baseline for all variables, whereas the placebo group did not have any. Mesalamine was effective for treatment of chronic diarrhea and moderate nonspecific colitis in HIV patients.

Butyrate represents the main source of energy for colonic epithelial cells; however, its availabilty/utilization is impaired in ulcerative colitis (UC). In the present randomized, double-blind, placebo-controlled pilot study, the safety and efficacy of colonic targeted oral sodium butyrate tablets, coated with a pH-dependent soluble polymer, have been evaluated in ulcerative colitis. Thirty patients with mild to moderate colitis underwent a six-week course of oral sodium butyrate (4 g/day) plus oral mesalazine (2.4 g/day), (Group A) or of oral mesalazine plus placebo (Group B). Clinical, endoscopic, and histologic data were collected at the beginning and the end of the study. Twenty-five patients completed the study (12 in group A, 13 in group B). No untoward side effects were reported. In group A, seven patients underwent remission and four improved; in Group B the numbers were 5 and 5, respectively. After treatment, all clinical parameters had significantly improved in both treatment arms compared to pretreatment findings. The UC disease activity index (UCDAI) score decreased from 7.27 ± 2.02 to 2.58 ± 2.19 (P < 0.05) in the combined treatment group and from 6.07 ± 1.60 to 3.46 ± 1.98 (P < 0.05) in group B. The endoscopic and histologic scores also significantly improved after treatment in both groups (P < 0.05). The difference between the two treatment arms was not significant, but a significantly better improvement vs baseline values (P < 0.05) was observed in the combined treatment group vs the mesalazine group, when considering both the clinical index (Δ9.58 ± 4.19 vs 5.92 ± 3.48) and the UCDAI score (Δ4.67 ± 2.19 vs 2.54 ± 2.18). A more favorable trend, although not significant, was observed for all individual parameters in group A. In conclusion, results of the present pilot study indicate that oral butyrate is safe and well tolerated. These data also suggest that oral butyrate may improve the efficacy of oral mesalazine in active ulcerative colitis and prompt the need of a large scale investigation to confirm the present findings.

The ability of 5-aminosalicylic acid and olsalazine to inhibit colonic aberrant crypts and tumors was investigated in 1,2-dimethylhydrazine-treated rats. The effect of these drugs on the rates of tumor apoptosis and proliferation was studied as potential mechanisms for their action. 5-Aminosalicylic acid reduced the number of aberrant crypt foci by over one third, while olsalazine had no effect on this parameter. However, both agents effectively reduced tumor number and load, increased the rate of tumor apoptosis, and reduced the rate of tumor cell proliferation. In conclusion, 5-aminosalicylic acid and olsalazine are both ultimately effective chemopreventive agents in this model; however, only 5-aminosalicylic acid inhibited the formation of aberrant crypt foci. The inhibitory effect of these agents in tumors is related to the inhibition of proliferation and the induction of apoptosis.

This 12-month, double-blind, placebo-controlled study randomized 205 ulcerative colitis patients in remission to placebo or controlled-release mesalamine at 4 g/day for 12 months. Patients were stratified to either pancolitis or left-sided disease, based on previous diagnosis. Maintenance of remission was defined as a sigmoidoscopic index of

The bioavailability of a controlled release 5-aminosalicyclic acid preparation (Pentasa) was investigated in nine healthy children after a medication period of six days (1000 mg/day) and compared with sulfasalazine (Salazopyrin) (2000 mg/day). The local bioavailability in the distal gut lumen, reflected by the 5-aminosalicylic acid concentration in the fecal water, showed comparable values after Pentasa (4.44 mmol/liter) and Salazopyrin (6.25 mmol/liter). The concentration of N-acetyl-5-ASA was significantly higher after Pentasa, reflecting the more proximal release of 5-aminosalicyclic acid compared with Salazopyrin. No relation was found between the 5-aminosalicylic acid fecal water concentration water concentration and the 5-aminosalicylic acid dose per kilogram of body weight. The urinary excretion of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid was higher after Pentasa than after Salazopyrin (32% vs 25%). Dose interval plasma concentration curves showed low values after both preparations. Based on the concept that the fecal water concentration is decisive for the efficacy of 5-aminosalicylic acid in distal inflammatory bowel disease, Pentasa treatment offers a relevant alternative in cases of Salazopyrin intolerance or allergy in children. The higher systemic bioavailability from Pentasa warrants monitoring of the renal function.

We evaluated the efficacy, tolerance, and acceptance of a new 5-ASA colonic foam versus 5-ASA liquid enema in the short-term treatment of active ulcerative colitis in a three-week prospective, randomized, investigator-blind study, enrolling 233 patients from 12 outpatient clinics in Italy. In arm 1 of the study, 117 patients with mild attacks received 2 g of 5-ASA as foam or enema at bedtime. In arm 2, 116 patients with moderate attacks were given 4 g of 5-ASA as foam or enema at bedtime. End points were defined as complete relief of symptoms, and endoscopic and histological evidence of remission or improvement. In patients with mild relapse, 34 of 63 (54%) treated with foam were in clinical remission after only 10 days compared with 17 of 51 (31%) treated with enemas (P

No studies have evaluated the effectiveness of 5-ASA against oxidative DNA damage in experimental models of diversion colitis.To evaluate the effects of 5-ASA against oxidative DNA damage in an experimental model of diversion colitis.Twenty-six Wistar rats were divided into two groups corresponding to sacrifice at 2 or 4 weeks after fecal diversion of the left colon by means of proximal colostomy and distal mucosa fistula. Each group was divided into two subgroups according to intervention in excluded colon performed with 0.9% saline solution or 5-ASA. Level of oxidative DNA damage was determined by comet assay in cells obtained from segments with and without fecal stream before and after H2O2 challenge. For statistical analysis, was used one-way analysis of variance (ANOVA), adopting a 5% significance level (P0.05).Levels of DNA damage were always higher in colon segments without fecal stream, regardless of the intervention solution employed. DNA damage in colon segments with and without fecal stream in animals irrigated with 5-ASA was lower when compared with those treated with saline solution, regardless of time of irrigation. These levels remained lower after intervention with 5-ASA, even after H2O2 challenge.Enema with 5-ASA reduces oxidative DNA damage in epithelial cells of colon segments without fecal stream, even after H2O2 challenge, confirming the effects of 5-ASA against DNA damage by oxygen free radicals.

Background 5-Aminosalicylates are the standard treatment for induction and maintenance of remission in mild-to-moderate ulcerative colitis. In recent years, the 5-aminosalicylic acid-containing pro-drug balsalazide has been the focus of attention. Aim To compare the efficacy and tolerance of balsalazide and mesalazine by meta-analysis. Methods Pubmed, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for studies comparing the efficacy and/or tolerance of balsalazide with mesalazine in the management of UC. The search terms were: “mesalazine” or “5-aminosalicylic acid” and “balsalazide” and “ulcerative colitis.” Data were collected from 1966 to 2007 (up to February). There was no language restriction. “Symptomatic remission,” “complete remission,” “relapse rate,” “total adverse events,” and “withdrawals because of adverse events” were the key outcomes of interest. Results Six randomized placebo-controlled clinical trials met our criteria and were included in the meta-analysis. In these “symptomatic remission,” “complete remission,” “relapse rate,” “total adverse events,” and “withdrawals because of adverse events” were evaluated in three, three, two, five, and six of the trials, respectively. They included 653 patients consisting of 55.4% men and 44.6% women randomized to receive either balsalazide or mesalazine. Pooling of three trials for symptomatic remission yielded a significant relative risk (RR) of 1.23 (95% confidence interval of 1.03–1.47, P = 0.02). The summary RR for complete remission in three trials was 1.3 (95% CI of 1.002–1.68, P = 0.048). Pooling of two trials for the outcome of relapse yielded a non-significant RR of 0.77 (95% CI of 0.56–1.07, P = 0.12). Pooling five studies from which data for any adverse events were extracted, yielded a non-significant RR of 0.87 (95% CI of 0.75–1.001, P = 0.53). The summary RR for withdrawals because of adverse events in six trials was 0.69, a non-significant RR (95% CI of 0.37–1.29, P = 0.24). Conclusion Balsalazide is more effective than mesalazine in induction of remission, but balsalazide has no benefit compared with mesalazine in preventing relapse in the population selected. The number of patients with any adverse events and withdrawals because of severe adverse events is similar for mesalazine and balsalazide.

We report a case of a patient with ulcerative colitis receiving maintenance therapy consisting of a combination of azathioprine and mesalamine, whose disease relapsed when the treatment with the salicylate was interrupted. An analysis of azathioprine metabolites present in the blood of the patient revealed that the concentration of the active metabolites of thiopurine had dropped below the therapeutic range following interruption of the mesalamine therapy and that this could have caused the relapse. Therapeutic monitoring of azathioprine metabolites would therefore seem to be advisable in patients starting on or interrupting a salicylate treatment regimen.

In uncomplicated diverticular disease, treatment is aimed at relieving symptoms. The aim of the present study was to evaluate the efficacy of mesalazine for symptomatic relief of uncomplicated diverticular disease of the colon. Two hundred sixty-eight consecutive eligible outpatients (122 male, 146 female; age, 66.1 years; range, 31–81 years) were enrolled in four treatment schedules in a randomized fashion: Group R1 (66 patients), rifaximin, 200 mg bid; Group R2 (69 patients), rifaximin, 400 mg bid; Group M1 (67 patients), mesalazine, 400 mg bid; and Group M2 (66 patients), mesalazine, 800 mg bid. Treatments were administered for 10 days every month for 12 months. Clinical evaluations were performed at admission and at 3-month intervals for 12 months considering 12 clinical variables (upper and lower abdominal pain/discomfort, tenesmus, diarrhea, abdominal tenderness, fever, bloating, general illness, nausea, emesis, dysuria, bleeding) graded as 0 = no symptoms, 1 = mild, 2 = moderate, and 3 = severe. The Global Symptomatic Score (GSS) was calculated using the sum of each symptom score. Two hundred forty-four patients completed the 12- month study; 24 were discontinued (14 treated with rifaximin and 10 treated with mesalazine) either as voluntary dropouts or because they developed side effects and/or complications. Group M2 demonstrated a lower frequency of many symptoms after 6 and 12 months of treatment; the mean GSS was significantly lower in Group M2 after 6 and 12 months of therapy by both intention-to-treat and per-protocol analyses. Patients treated with mesalazine (Groups M1+M2) had a lower GSS than subjects treated with rifaximin (Groups R1+R2) during the 12-month follow-up period. We conclude that cyclic administration of mesalazine is effective for symptomatic relief of uncomplicated diverticular disease of the colon. Some symptoms showed greater improvement with mesalazine, 800 mg bid, than with the other treatment schedules.

Forty consecutive patients affected by recurrent attacks of symptomatic uncomplicated diverticular disease of the colon were evaluated to investigate the effectiveness of 2 different mesalazine therapeutic schedules in preventing recurrence of the disease. The patients were randomly enrolled and treated with mesalazine 1.6 g/d (group A) or mesalazine 1.6 g/d 10 days per month (group B). Thirty-four patients completed the study (85%): 3 (7.5%, 1 in group A and 2 in group B) were lost to follow-up, 2 (5%, both group B) were withdrawn from the study for protocol violation, and 1 (2.5%) for hospital admission for stroke (group A). Twenty-three patients (67.65%) were symptom free after 24 months of treatment (overall symptomatic score, 0): 14 of 18 in group A (per-protocol, 77.78%; intention to treat, 70% [95% confidence interval [CI], 61.5–91.8]), 9 of 16 in group B (per protocol, 56.25%; intention to treat, 45% [95% CI, 61.5–91.8]; P < 0.05). Four patients (10%) improved, but were not completely symptom free. Six patients (15%) showed recurrence of symptoms: 1 in group A (5.56%) and 5 in group B (31.25%; P < 0.005; overall symptomatic score, 68). Daily mesalazine supplying seems to be more effective than cyclic supplying in maintaining remission in recurrent symptomatic uncomplicated diverticular disease.

Mesalazine is a first-line drug in pediatric inflammatory bowel disease, and is effective as primary treatment and maintenance therapy. It's usually well tolerated, but various side effects have been described. A 15-year-old female with ulcerative colitis developed polyuria, polydipsia, vomiting, and fatigue. She was receiving mesalazine (500 mg, thrice daily, p.o.) and prednisolone for 4 months. She was detected as acute tubular injury as she had dehydration, acidosis, hypostenuria, hematuria, proteinuria, low levels of potassium, uric acid and bicarbonate. These findings were attributed to interstitial nephritis as a side effect of mesalazine, however as renal biopsy was disapproved by the parents, it was not confirmed. After discontinuation of mesalazine her renal tubular functions improved. Potassium and phosphorus supplements were stopped after 7 months, although she had to continue bicarbonate supplementation. We conclude that regular renal screening is important in patients receiving 5-ASA therapy to prevent rare but serious complications, such as interstitial nephritis sometimes leading to chronic renal failure.

Sulfasalazin e has been the traditional mode of therapy for the management of in ammatory bowel disease (IBD). It consists of sulfapyridin e and aminosalicylate (5-ASA) moieties linked by an azo bond. While effective in the treatment of IBD, 10 ± 45% of patients are unable to tolerate the medication due to adverse reactions (1± 8). Most of the side effects have been attributed to the inactive sulfapyridin e component of sulfasalazin e (1, 3, 9). Recently, a number of aminosalicy late products have been developed that are not dependent upon the sulfapyridin e moiety (10, 11). Oral and topical forms of 5-aminosal icylic acid (5-ASA) (12± 23) and 4-aminosalicylic acid (4-ASA) (24 ± 30) have been demonstrated to have therapeutic ef® cacy. Trials of mesalamine and osalazine demonstrated that these agents have signi® cantly less adverse reactions when compared to sulfasalazin e. Although 70 ± 90% of patients unable to tolerate sulfasalazine can tolerate oral mesalamine and osalazine, some patients have been reported to have fever and rash (31± 33). In addition, other patients have exhibited side effects similar to those observed with sulfasalazin e, including pancreatit is (34 ± 36), myocarditis (37), hepatotoxicity (38), renal toxicity (39, 40) and neuropathy (41) with mesalazine and/or osalazine. Topical products are reported to have less frequent adverse reactions because of their limited systemic absorption (16, 42). This is the ® rst reported case of an individual who experienced severe, systemic adverse reactions that can be attributed to 5-ASA supposito ries. CASE REPORT

A new compound, APAZA, consisting of a molecule of 5-aminosalicylic acid linked to one molecule of 4-aminophenylacetic acid by an azo bond, was testedfor its ability to inhibit acute colitis in rats caused by Clostridium difficile toxin A. When administered chronically for 5 days in drinking water, APAZA significantly inhibited toxin A-induced myeloperoxidase activity, luminal fluid accumulation, and structural damage to the colon at doses of from 1 to 100 mg/kg x day. For comparison, sulfasalazine was administered in identical doses and was found to significantly inhibit toxin A-induced colitis only at the dose of 100 mg/kg x day. When 4-aminophenylacetic acid alone was administered chronically in drinking water, it also inhibited toxin A-induced colonic inflammation at a dose of 100 mg/kg x day. In order to determine if 4-aminophenylacetic acid has a direct anti-inflammatory effect on the colon rather than a systemic effect, 4-aminophenylacetic acid was administered acutely to surgically prepared isolated colonic segments by intraluminal injection in anesthetized rats 30 min before toxin A was injected. 4-Aminophenylacetic acid strongly and significantly inhibited toxin A-induced colitis in this experiment at doses as low as 10 microg/segment. It is concluded that APAZA is a potent inhibitor of toxin A-induced colonic inflammation in rats and that its constituent, 4-aminophenylacetic acid, is responsible for this increased protection against colitis compared to the 5-aminosalicylic acid component of sulfasalazine.

We aimed to improve symptoms by means of mesalazine in symptomatic colonic diverticular disease patients. One hundred seventy outpatients (98 M, 72 F; age, 67.1 years; range, 39–84 years) were assigned to four different schedules: rifaximin, 200 mg bid (Group R1: 39 pts), rifaximin, 400 mg bid (Group R2: 43 pts), mesalazine, 400 mg bid (Group M1: 40 pts), and mesalazine, 800 mg bid (Group M2: 48 pts), for 10 days per month. At baseline and after 3 months we recorded 11 clinical variables (upper/lower abdominal pain/discomfort, bloating, tenesmus, diarrhea, abdominal tenderness, fever, general illness, nausea, emesis, dysuria), scored from 0 = no symptoms to 3 = severe. The global symptomatic score was the sum of all symptom scores. After 3 months in all schedules but Group R1, 3 of the 11 symptoms improved (P < 0.03); the global score decreased in all groups but Group R1 (P < 0.0001). Mesalazine-treated patients had the lowest global score at 3 months (P < 0.001). Mesalazine is as effective as rifaximin (higher dosage schedule) for diminishing some symptoms, but it appears to be better than rifaximin for improving the global score in those patients.

Therapy with oral 5-aminosalicylic acid for inflammatory bowel disease has been reported as effective and safe. We report two cases of biochemically proven mild acute pancreatitis occurring 2 and 14 days, respectively, after oral 5-aminosalicylic acid therapy was instituted for inflammatory bowel disease. A hypersensitivity mechanism might be involved, owing to possible erratic systemic absorption of the drug. We suggest clinical and biochemical monitoring for patients undergoing oral 5-aminosalicylic acid therapy in order to confirm its possible association with acute pancreatitis and to assess the actual incidence of such an adverse reaction.

Rectal treatment with enemas, foams, and suppositories is the most efficient method of delivering an adequate quantity of locally active drugs to the distal colon. In a pilot study carried out by colonoscopy in four patients, it was observed that 4 g 5-ASA in 20 ml foam spread up or beyond the splenic flexure and more extensively than 2 g 5-ASA in 10 ml foam. Therefore we have undertaken a study in order to compare by scintigraphy the colonic distribution of 4 g 5-ASA foam versus 4 g 5-ASA in 100 ml liquid enemas in 10 patients with ulcerative colitis using a crossover randomized design. Both preparations were labeled with 100 MBq [99mTc] sulfur colloid before administration. Anterior scans were taken at intervals for 4 hr. Activity, expressed as a percentage of total radioactivity, was measured in the rectum, sigmoid, descending, transverse, and ascending colon. Six patients had the same extent of spread with the two formulations; in three patients with foam and in one patient with enema a greater spread was observed. the foam reached the upper limit of disease in all cases, while enema failed in two cases. The maximum spread with foam was observed within 30 min in nine of 10 patients compared with seven of 10 after enema. Compared to enema, foam distributes more uniformly and seems to persist longer in the descending and sigmoid colon. The 5-ASA colonic foam shows some more favorable characteristics than enema for the local treatment of left-sided ulcerative colitis. © 1992 Plenum Publishing Corporation.

A 44-year-old man was diagnosed with distal ulcerative colitis (UC) when he had hematochezia at the age of 34. He had had a few relapses on maintenance oral mesalazine. He desired a total colonoscopy in the clinical remission. Physical examination showed no abnormalities and routine laboratory tests were normal. Colonoscopy disclosed the appendiceal orifice inflammation (AOI) with reddish and friable mucosa and mucopus (Fig. 1). The remaining colorectum showed no inflammation. He remains well during the follow-up. Since Cohen et al. first coined ‘‘ulcerative appendicitis’’ [1], AOI is uncommon but has increasingly been recognized in patients of distal UC. UC classically extends proximally from the rectum without skip lesions. Isolated AOI has been more frequently observed in patients with less extensive UC and is unlikely the result of patchy improvement due to treatments. The human appendix has long been recognized as a vestigial remnant. Although the pathogenesis of UC has not been fully clarified, clinical evidence has revealed the protective role of appendicectomy on onset and severity of UC [2, 3], indicating the appendix as a priming site for UC [4]. Experimental studies of murine models have also shown that the appendix may serve a central role in antigen sampling and immunological signaling [5]. Therefore, further studies of AOI may unveil not only its clinical implication but also the immunopathogenesis of UC. References

The fate of 5-aminosalicylic acid (5-ASA), which is used in the treatment of chronic inflammatory bowel diseases, was studied in six healthy volunteers receiving doses of 100 mg and 250 mg intravenous bolus as well as 250 mg per os (slow release). Following intravenous administration, the drug was rapidly eliminated with a plasma half-life of about 40 min, mainly due to rapid metabolism. No parent drug was recovered in feces, and the total recovery following oral administration (30%) was significantly lower than following the intravenous doses (77% and 72%). Nonlinear pharmacokinetics were suggested as the 2.5-fold increase in intravenous dose was followed by a significant relative increase (greater than 2.5) in the renal elimination of 5-ASA, as well as a significant decrease (less than 2.5) in the elimination of the metabolite N-acetyl-5-ASA. There was also a trend towards a decreasing total body clearance and metabolic ratio. The present study confirms earlier findings on the pharmacokinetics of 5-ASA and suggests a possible saturation of the N-acetylating system in the dose range studied. This may be of interest in the design of controlled-release formulations and dosage regimes for the treatment of diseases of the small-bowel, where 5-ASA is easily absorbed. Further, for the first time, a marked difference in the intestinal fate compared to the systemic fate of the drug is demonstrated, suggesting alternative presystemic metabolism of 5-ASA, which may bear relevance to its mode of action. Further studies on the pharmacokinetics of 5-ASA, preferably in patients, are warranted.