Is mesalazine treatment effective in the prevention of diverticulitis? A review.

Diverticulitis is the most severe form of Diverticular disease (DD). An effective treatment strategy for its prevention has not yet been defined. This review aimed to provide a viewpoint on the role of mesalazine, also note as 5-aminosalicylic acid (5-ASA), in the prevention of diverticulitis. A systematic electronic search of relevant articles was performed using PubMed, Embase, Scopus, and Cochrane. Randomized controlled trials (RCTs), open trials, and retrospective studies, published between January 1999 and January 2020, were identified. Twelve eligible studies that analyzed primary or secondary outcomes of diverticulitis were included. The population included patients with symptomatic uncomplicated diverticular disease (SUDD), or patients with a history of diverticulitis. All studies compared 5-ASA to placebo, rifaximin, or other treatments. Two studies, including 359 patients, assessed the efficacy of 5-ASA in preventing the first appearance of diverticulitis in patients with SUDD. Of these, one showed that 5-ASA was effective, and one did not. Ten studies, including 2.995 patients, assessed the efficacy of 5-ASA treatment in preventing the recurrence of diverticulitis in patients with a history of diverticulitis. Four studies showed that 5-ASA had a certain degree of efficacy. All four RCTs demonstrated that 5-ASA did not significantly reduce the rate of diverticulitis recurrence. In a retrospective trial, 5-ASA was less effective than rifaximin in preventing diverticulitis recurrence. In an open trial, there was no difference between 5-ASA and probiotic treatment. Overall, there is currently conflicting evidence regarding the efficacy of 5-ASA treatment in the prevention of diverticulitis and further RCTs are needed.

Boswellia serrata and Salvia miltiorrhiza extracts reduce DMN-induced hepatic fibrosis in mice by TGF-beta1 downregulation.

BACKGROUND: Hepatic fibrosis is characterised by a progressive accumulation of fibrillar extracellular matrix (ECM) proteins, including collagen that occurs in chronic liver diseases. Transforming growth factor-beta1 (TGF-beta)/Smad3 signalling plays a major role in tissue fibrogenesis acting as a potent stimulus of ECM accumulation. AIM: To evaluate the effects of a combined therapy with anti-inflammatory Boswellia and anti-fibrotic Salvia extracts on the course of chronic hepatitis-associated fibrosis induced by dimethylnitrosamine (DMN) in mice, as well as on the hepatic expression of TGF-beta1 and Smad proteins. METHODS: Chronic hepatitis-associated fibrosis was induced in mice by intraperitoneal DMN administration. Mice were assigned to 5 groups: controls; DMN without any treatment; DMN treated orally with Boswellia extracts (50 mg/kg/day); DMN treated orally with Salvia extracts (150 mg/ kg/day); DMN treated orally with both Boswellia (50 mg/kg/day) and Salvia extracts (150 mg/kg/ day). The liver was excised for macroscopic examination and histological, morphometric and immunohistochemical (IHC) analyses. For IHC, alpha-smooth muscle actin (alpha-SMA), collagen types I-III, TGF-beta1, connective tissue growth factor (CTGF), Smad3, Smad7, CD3, PCNA and TUNEL antibodies were used. RESULTS: The combined oral administration of Boswellia and Salvia extracts improved the course and macroscopic findings of DMN-induced chronic hepatitis-associated fibrosis. The histological severity of the hepatic fibrosis showed a marked improvement following treatment and was associated with a reduction in the hepatic expression of alpha-SMA, collagen I-III, CTGF, TGF-beta1, Smad3, and Smad7. CONCLUSIONS: These data demonstrate that co-treatment of Boswellia plus Salvia extracts is effective in preventing hepatic fibrosis in DMN-induced chronic hepatitis. The anti-fibrotic properties are mainly related to Salvia extracts and appear to be mediated by the inhibition of the TGF-beta1/Smad3 pathway.

Early acid perception in NERD.

Heartburn is the hallmark of gastroesophageal reflux disease. The hypothesis tested in this study is that the time of onset of this symptom may play a role in the development of mucosal lesions. During endoscopy of 61 patients complaining of heartburn and nine control subjects, gastric fluid was aspirated using a catheter introduced through the operative channel, and blindly instilled onto the esophageal mucosa before withdrawing the endoscope. Saline was used as control. Evocated symptoms and endoscopic lesions were recorded. Thirty-seven patients did not present esophageal lesions (nonerosive reflux disease [NERD]); 24 presented esophagitis (ERD). Instillation of gastric fluid on the esophageal mucosa elicited heartburn in 46% of patients with NERD, 8.3% with ERD, and 11.1% of controls. Symptoms lasted throughout the procedure but were no longer present when the gastroscope was withdrawn. The NERD value was significantly higher than that of ERD (P= 0.02) and controls (P= 0.02), while no difference was found between ERD and controls. Saline did not induce symptoms either in controls or patients. NERD patients show an early response to gastric fluid instillation much more frequently than ERD and controls. It is hypothesized that the early onset of symptoms in NERD patients may be a possibility to avoid the progress of mucosal lesions by claiming an earlier medical care.

Mesalazine vanishing time from rectal mucosa following its topical administration.

To investigate how long and how much Mesalazine (M) is available inside the rectal mucosa following its topical instillation, in patients (pts) with Ulcerative Colitis (UC). Two rectal biopsies for M concentration were obtained from 45 UC pts in clinical remission and on oral M treatment (OT), before a 4g enema randomly given to consentient pts every day (Group A, 15 pts), every 2 days (Group B, 15 pts) and every 3 days (Group C, 15 pts). Two additional biopsies were taken 1, 2 and 3 days after the last enema in group A, B and C respectively, at least 10 days later. All biopsies were immediately frozen at -80°C for later assay by means of high-performance light chromatography (HPLC). Data were analyzed using Student's t-test. Mean values±standard deviation of M mucosal concentration (ng/mg of tissue) were 1.32±1.41, 56.1±39.2, 9.65±6.60, and 6.39±5.03 in pts receiving OT alone, groups A, B and C, respectively. Values in Group A were statistically higher (p<0.001) than those in Groups B and C while no differences were found between Groups B and C. Values of OT were lower than groups A, B and C. M mucosal concentration rapidly decreases 2 days after a 4g enema, but after three days is still higher than OT alone. These results may provide data which would be useful to plan topical therapy and improve adherence to treatment.

The dyspeptic macrophage 30 years later: an update in the pathogenesis of Crohn's disease.

Alterations in autophagy leading to a defective intracellular response to low-level invasive bacteria are considered a major recent advance in the pathogenesis of Crohn's disease. A genome-wide association study has shown an association of Crohn's disease with the autophagy related 16-like 1 gene. A second autophagy gene, the immunity-related Guanosine triphosfatase, has also been found to be significantly associated with Crohn's disease. The enteric flora of Crohn's disease patients includes, more commonly than controls, strains of adherent/invasive E. coli. The high level of adherent/invasive E. coli colonizing the intestinal mucosa of patients with Crohn's disease strongly suggests that it may play an important role in the aetiopathogenesis of the disease. E. coli strains are able to cross the mucosal barrier, survive within macrophages and induce the secretion of TNFalpha and the formation of granuloma. Recently it has been clearly shown that Crohn's disease patients have a defective mucosal macrophage killing activity resulting in increased exposure to commensal bacteria and activation of T cells. However, the hypothesis of macrophages dysfunction in the pathogenesis of Crohn's disease was already suggested in 1977 by M. Ward, who introduced the concept of the "dyspeptic macrophage", consisting of an inability to degrade a variety of phagocytosed normal gut dietary and microbial luminal constituents. Defective autophagy and dyspeptic macrophages seems therefore indicate the same pathogenetic mechanism. What is really new is the demonstration that this impaired macrophage function is genetically determined.

Assessment of inflammatory activity in Crohn's disease by means of dynamic contrast-enhanced MRI.

PURPOSE: Our aim was to perform a dynamic study of contrast enhancement of the intestinal wall in patients with Crohn's disease to quantitatively assess local inflammatory activity. MATERIALS AND METHODS: We studied a population of 50 patients with histologically proven Crohn's disease. Magnetic resonance imaging (MRI) was performed using a 1.5-T magnet with a phased-array coil and acquisition of T2-weighted single-shot fast spin echo (SSFSE) half Fourier sequences before intravenous administration of gadolinium, and T1-weighted fast spoiled gradient (FSPGR) fat-saturated sequences before and after contrast administration. Before the examination, patents received oral polyethylene glycol (PEG) (1,000 ml for adults; 10 ml/Kg of body weight for children). Regions of interest (ROI) were placed on the normal and diseased intestinal wall to assess signal intensity and rate of increase in contrast enhancement over time. Data were compared with the Crohn's Disease Activity Index (CDAI). RESULTS: The diseased bowel wall showed early and intense uptake of contrast that increases over time until a plateau is reached. In patients in the remission phase after treatment, signal intensity was only slightly higher in diseased bowel loops than in healthy loops. There was a significant correlation between the peak of contrast uptake and CDAI. CONCLUSIONS: Dynamic MRI is a good technique for quantifying local inflammatory activity of bowel wall in patients with Crohn's disease.

Long-term oral plus topical mesalazine in frequently relapsing ulcerative colitis.

BACKGROUND: In cross-sectional studies, it was demonstrated that the therapeutic effect of mesalazine is closely related to its mucosal concentration. AIM: This study was carried out to verify in a longitudinal study if it was possible to improve the clinical course of ulcerative colitis at high risk of recurrence by increasing mucosal mesalazine concentration. METHODS: Eighteen consecutive ulcerative colitis patients on continuous oral 5-ASA treatment (2.4-3.2 g/day) in clinical remission who had had at least four moderate to severe relapses in the preceding 2 years (referred period) were assigned to assume oral (3.2-4.8 g/day) and topical (4 g/day) mesalazine in order to increase mucosal drug concentration and were followed up for 2 years (study period). The localisation of disease was 12 pancolitis, six left colitis. The number and severity of recurrences, number of visits and endoscopies, courses of steroids and days of hospitalisation were compared with those of the previous 2 years. Rank signed test for paired data was used for statistical analysis. RESULTS: The total number of recurrences was significantly lower during the study period in comparison with that of referred period (8 versus 80, respectively, p < 0.0001). No courses of steroids or hospitalisation were necessary during study period in comparison with those of referred period (0 versus 33, p < 0.0001; 0 versus 93, p = 0.03, respectively). A total number of 249 visits were done during the referred period and 116 during the study period (p < 0.0001) with a total of 87 endoscopies during referred period and 44 during study period (p < 0.0001). CONCLUSIONS: The continuous use of topical mesalazine associated with a high oral dosage significantly improves the clinical course of ulcerative colitis patients at high risk of relapse.

Infliximab in spondyloarthropathy associated with Crohn's disease: an open study on the efficacy of inducing and maintaining remission of musculoskeletal and gut manifestations.

OBJECTIVE: To evaluate the efficacy and tolerability of anti-tumour necrosis factor alpha (TNFalpha) monoclonal antibody (infliximab) in the treatment of spondyloarthropathy (SpA) associated with active and inactive Crohn's disease (CD). METHODS: Twenty four patients with SpA associated with active or inactive CD (16 active, 8 quiescent) were treated with anti-TNFalpha monoclonal antibody (infliximab) with repeated infusions for a period of 12-18 months. The treatment aimed at ameliorating the general musculoskeletal and spinal pain, controlling peripheral arthritis and enthesitis, decreasing the BASDAI score, modifying acute phase reactants, and reducing CD activity. RESULTS: Infliximab improved both gastrointestinal (p<0.01) and overall articular symptoms (BASDAI, p<0.01; general musculoskeletal and spinal pain, p<0.01; peripheral arthritis, p<0.01) in patients with active CD. Additionally, infliximab effectively controlled not only axial involvement and peripheral arthritis but also enthesitis (p<0.01) and prevented inflammatory bowel disease reactivation in patients with inactive CD and low inflammatory markers. Amelioration of gut and musculoskeletal involvement persisted for up to 12 months. CONCLUSION: Infliximab may act on the inflammation of entheses and of periarticular structures, which usually does not cause a change in the haematological markers that are the main indicators of pain and joint ankylosis in SpA. Infliximab induces and maintains remission of CD while at the same time treating active and severe SpA, suggesting that it should be the preferred drug for the treatment of active and severe SpA associated with active or quiescent CD.

N-Butyrate rectal transport in cirrhotic patients.

Data about colonic mucosa transport of short-chain fatty acids in cirrhotic patients are still lacking. The aim of the present study was to compare the rectal mucosa transport of n-butyrate and its effect on transport of other electrolytes and endoluminal pH in normal subjects and in cirrhotic patients by using a rectal dialysis technique. Thirteen subjects with normal hepatic function tests and 17 cirrhotic patients were enrolled. Dialysis bags containing 80 mmol/liter of butyrate in a neutral pH (6.8) electrolyte solution were placed in the rectum of enrolled subjects for 60 min. Net transport rate was calculated for butyrate, sodium, chloride, potassium, and bicarbonate. The differences in pH between initial and final dialysis solutions was also evaluated in the two groups in the study. Net butyrate absorption was significantly lower in cirrhotic patients than in controls (65.2 +/- 38.6 vs 101.2 +/- 45.3 nmol/min/cm2, respectively; P = 0.02). Furthermore, cirrhotic patients showed a lower HCO3 secretion than controls (-26.9 +/- 19.9 vs -45.1 +/- 20.0, respectively; P = 0.01). No differences were found in transport of the other electrolytes. The pH in the final dialysis solution in cirrhotic patients was not significantly lower than in the controls (7.15 vs 7.35; P = 0.1). In conclusion, the impairment of butyrate absorption and the concurrent reduction of bicarbonate secretion observed in cirrhotic patients may suggest a selective hypoactivity of apical HCO3-/SCFA- antiport located at the colonocyte apical membrane.

Survival and causes of death in Italian patients with ulcerative colitis. A GISC nationwide study.

BACKGROUND: Death rate for patients with ulcerative colitis has changed over last few decades. Recent studies indicate that cumulative long-term mortality is comparable to that in general population, and that deaths may depend on causes not strictly related to colonic disease. AIM: To evaluate overall and cause-specific mortality rate in a large group of Italian patients with ulcerative colitis. METHODS: A total of 2,066 ulcerative colitis patients aged >18 years consecutively diagnosed in twenty Italian Gastroenterology Units between 1964 and 1995 were followed-up from diagnosis until 1997. Standardised Mortality Ratios and Relative Survival Ratios were calculated. RESULTS: Overall mortality of patients with ulcerative colitis was comparable to that in general population with 93 deaths observed versus 92.1 expected (standardises mortality ratio, 1.0; 95% confidence interval, 0.8-1.2). Significantly higher mortality was observed in patients under 30 years of age at diagnosis (standardised mortality ratio, 2.7; 95% confidence interval, 1.3-4.9), and in those diagnosed before 1974 (standardised mortality ratio, 2.7; 95% confidence interval, 1.1-5.7). Proctocolitis and complications from surgery were mentioned in 11 and 5 certificates, respectively. A significant excess of deaths was observed for colorectal cancer (colon: standardised mortality ratio, 3.0; 95% confidence interval, 1.0-6.9; rectum: standardised mortality ratio, 4.4; 95% confidence interval, 1.2-11.3), and haemolymphopoietic neoplasms (standardised mortality ratio, 2.8; 95% confidence interval, 1.0-6.1), in particular multiple myeloma and non-Hodgkin lymphoma. A significant deficit of deaths was observed for cancer of the respiratory system (standardised mortality ratio, 0.3; 95% confidence interval, 0.1-1.0). CONCLUSIONS: This study confirms that, also in Italy, mortality of patients with ulcerative colitis is comparable to that in general population. Only 12% of deaths were due to ulcerative colitis itself, whereas 10% of deaths were attributed to colorectal cancer. Deaths from colorectal cancer occurred, on average, 9 years after diagnosis of ulcerative colitis, suggesting that the risk of cancer is not limited to patients with long-standing colitis. As to mortality for causes unrelated to colitis, there was an excess of deaths due to malignancies of the haemolymphopoietic system.

Mucosal 5-aminosalicylic acid concentration inversely correlates with severity of colonic inflammation in patients with ulcerative colitis.

BACKGROUND AND AIM: The treatment of ulcerative colitis (UC) with 5-aminosalicylic acid (5-ASA) does not have the same therapeutic effect in all patients. We tested the hypothesis that the effectiveness of the drug is related to its mucosal concentration. PATIENTS: Twenty one UC patients receiving oral 5-ASA (2.4-3.2 g/day) were enrolled in the study. Four were also receiving topical treatment (2 g/day). METHODS: Six endoscopic biopsies were taken from the rectum for measurement of 5-ASA concentrations (ng/mg) by HPLC; soluble interleukin 2 receptor (sIL-2R) concentrations (U/ml) were measured by ELISA and histology. Endoscopic and histological appearance was graded on a four point scale (0-3). The Wilcoxon's rank test and Pearson's correlation coefficient were used for statistical analysis. RESULTS: Mucosal concentrations of 5-ASA were significantly higher (p=0.03) in patients with endoscopic scores of 0-1 compared with those with scores of 2-3 (16.1 (range 10.2-45) v 5. 5 (3.5-17.4), respectively) and in patients with lower histological inflammation compared with those with more severe scores (17.4 (10. 5-45) v 8.9 (3.5-17.2), respectively) (p<0.01). In contrast, mucosal sIL2-R concentrations were significantly lower in patients with slight endoscopic and histological lesions than in those with more severe disease. A significative inverse correlation (r=-0.85) was found between 5-ASA and sIL-2R mucosal concentrations (p=0.00008). CONCLUSIONS: In patients with UC, in the same area of the intestinal tract, we found that the higher the 5-ASA mucosal concentrations, the lower the IL-2R levels and endoscopic and histological scores. We hypothesise that maintenance of high mucosal 5-ASA concentrations in all colonic segments could contribute to improve clinical outcome in UC patients.

Anastomotic configuration and mucosal 5-aminosalicyclic acid (5-ASA) concentrations in patients with Crohn's disease: a GISC study. Gruppo Italiano per lo Studio del Colon e del Retto.

OBJECTIVE: Recurrence of Crohn's disease quite inevitably occurs after resection of distal small bowel and proximal colon, involving the neoterminal ileum close to the anastomosis. Oral 5-aminosalicylic acid (5-ASA) administered soon after surgery delays recurrence and reduces its severity. We recently observed that in operated patients submitted to prophylactic treatment with oral 5-ASA the rate of recurrence was significantly higher in those with end-to-end anastomosis than in those with other types of anastomosis (end-to-side, side-to-side). The hypothesis investigated in the present study was that patients with end-to-side or side-to-side anastomosis would benefit from a higher mucosal concentration of 5-ASA with respect to patients with end-to-end anastomosis. Therefore, the mucosal 5-ASA concentration was measured in the perianastomotic area of both groups. METHODS: The study was carried out in 19 patients submitted to radical surgery for Crohn's ileitis or ileocolitis, under oral prophylactic treatment with 5-ASA (Asacol). All patients were on regular endoscopic follow-up and were free of recurrence. Two biopsies were collected 3 cm from the anastomosis, in the neoterminal ileum, and two biopsies were collected at the colonic site 3 cm below the anastomosis. 5-ASA concentrations (ng/mg) were measured in tissue homogenates by high-performance liquid chromatography (HPLC) with electrochemical detection. RESULTS: The mucosal concentration of 5-ASA in the neoterminal ileum was significantly lower in patients with end-to-end anastomosis than in those with other types of anastomosis (median values: 29.4 ng/mg vs 92.9 ng/mg respectively; p < 0.001). Six of 10 patients (60%) with end-to-end anastomosis, but none of the nine patients with other types of anastomosis, showed 5-ASA mucosal concentrations <40 ng/mg at the neoterminal ileum. On the contrary, no patients with end-to-end anastomosis showed mucosal concentrations of 5-ASA >90 ng/mg, compared with the 57% of patients in the group with other types of anastomosis. No differences were observed for colonic biopsies. CONCLUSIONS: The different mucosal concentrations in these two groups may be explained by the difference in segmental transit time induced by the different anastomotic configurations. A slower preanastomotic transit time, demonstrated in patients with end-to-side or side-to-side anastomosis, could offer a prolonged contact time between the intestinal content and the mucosa, resulting in an increase in drug absorption.

Multiple organ dysfunction in ulcerative colitis.

OBJECTIVE: The mortality rate in severe ulcerative colitis (UC) is commonly attributed to major colonic complications or surgical procedures. Early recognition of the severity of the colitis, intensive medical treatment, and prompt surgery have all contributed to improving its outcome over the past 40 yr. Recently, we have observed some fatal cases of severe UC in which death was related to multiple organ dysfunction syndrome (MODS). This complication, associated with a very high mortality rate, may occur in several acute critical diseases, both infectious and noninfectious, but has so far not been reported in UC. The aim of this study was to evaluate the prevalence and outcome of MODS in severe UC. METHODS: The records of 180 consecutive patients admitted to the Gastrointestinal Unit, University of Rome for an acute severe attack of UC during the period 1976-1998 were retrospectively analyzed. Severity of UC was defined according to the criteria of Truelove and Witts. MODS was defined according to the original criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference 1992. All patients were on a standard intensive regimen consisting of total parenteral nutrition and hydrocortisone 100 mg q.i.d. Colectomy was performed according to the timing of the Oxford intensive regimen. RESULTS: Of these 180 severe UC patients, 11 (6.1%) experienced clinical and laboratory features of MODS. The lung was involved in five patients, the kidney in three, the liver in seven, the central nervous system in three, the hematological system in three, and the pancreas in one. MODS was preceded by toxic megacolon in five patients and by so-called "impending megacolon" in four, whereas in two patients no previous complications of UC were observed. MODS developed during the first attack of colitis in seven patients and during relapse in four. The overall mortality rate was 12/180 (6.6%). Of the 12 patients who died, eight (72.7%) had MODS. CONCLUSIONS: These data indicate that UC must be included among the causes of MODS. In our referral center for inflammatory bowel diseases, MODS was responsible for the majority of UC cases with a fatal outcome. The timely identification of signs of MODS should prompt admission to an intensive care unit and emergency surgery.

Combined oral sodium butyrate and mesalazine treatment compared to oral mesalazine alone in ulcerative colitis: randomized, double-blind, placebo-controlled pilot study.

Butyrate represents the main source of energy for colonic epithelial cells; however, its availability/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 (delta9.58 +/- 4.19 vs 5.92 +/- 3.48) and the UCDAI score (delta4.67 +/- 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.

Rectal and colonic mesalazine concentration in ulcerative colitis: oral vs. oral plus topical treatment.

AIM: To measure mucosal concentrations of mesalazine in ulcerative colitis patients treated with oral mesalazine alone, compared to patients treated with both topical and oral mesalazine. METHODS: Twenty-two patients with mild to moderate ulcerative colitis were randomized to receive 2.4 g/day of oral mesalazine (11 patients) or 2.4 g/day oral plus 4 g/day of topical mesalazine (11 patients). After 2 weeks of treatment, endoscopic biopsies specimens were taken from the rectum and in descending colon just distal of the splenic flexure and stored to -80 degrees C for later assay (HPLC). Wilcoxon's rank sum test for unpaired data was used for the statistical analysis. RESULTS: Mucosal levels of mesalazine in the rectum were significantly higher in patients who received oral plus topical treatment than in those who had oral treatment alone (52.1 ng/mg, range: 13.6-122.1 vs. 0.2 ng/mg, range: 0.2-9.7, respectively; P < 0.0001). Similarly, in the descending colon, the mucosal concentrations of mesalazine were significantly higher in patients who had oral plus topical treatment than in those receiving oral treatment alone (46.6 ng/mg, range: 6-112.6 vs. 15.9 ng/mg, range: 2.3-42.4, respectively; P=0.01). CONCLUSIONS: Topical treatment of mesalazine significantly increases mucosal concentrations of mesalazine up to the splenic flexure, supporting the rationale to treat left-sided ulcerative colitis with topical formulations of mesalazine.

Dextran sulfate sodium (DSS) colitis in rats: clinical, structural, and ultrastructural aspects.

Aim of this study was to assess the structural, ultrastructural, immunohistochemical, and clinical aspects in Sprague-Dawley rats with dextrane sulfate sodium (DSS)-induced colitis. Colitis was induced in Sprague-Dawley rats by seven days of DSS oral administration followed by seven days of tap water only (for one, two and three cycles). Controls were fed with water only. Segments of proximal, mid-, and distal colon of each animal were adequately prepared for light and scanning electron microscope observations. The severity of the lesions was scored histologically. For immunohistochemical study, a cocktail of S-100, NSE, and antineurofilament antibodies was used. Symptoms such as weight, feces consistency, diarrhea, hematochezia were recorded daily. From a clinical point of view symptoms appeared significantly later after the first cycle than after the second and third cycles and lasted significantly longer in the second and third cycles. Treated rats showed a slower weight gain rate by 20% compared to controls, and the whole colon length appeared to be significantly shorter after colitis induction compared to controls. Structural observations by light microscopy showed prominent involvement of the distal colon. Immunohistochemical study of both submucosal and myoenteric nerve plexuses was similar to controls. Scanning electron microscope observations of the colonic mucosal surface in colitis rats showed a complete subversion of its architecture, characterized by dilatations of gland crypt openings, dropout of goblet cells, and inhomogeneous distribution or lack of microvilli. These were most evident after the third cycle. In conclusion, experimental DSS colitis in SD rats appeared to be highly reproducible and shared most features with human UC, not only from a structural and clinical but also from an ultrastructural point of view.

Prevention of post-operative recurrence of Crohn's disease requires adequate mucosal concentration of mesalazine. Gruppo Italiano per lo Studio del Colon e del Retto.

BACKGROUND: Surgical resection of Crohn's disease is followed by early recurrence in a high percentage of patients. Mesalazine has been shown to be effective in the prevention of post-operative recurrence, but some 50% of patients under treatment recur at 3 years of follow-up. AIM: To establish whether the mucosal concentration of mesalazine might affect the development of post-operative recurrence. METHODS: Colon-ileoscopy was performed in 25 consecutive patients resected for Crohn's disease. The mean time from surgery was 14 months. After the operation, all patients were taking oral mesalazine (Asacol, 2.4 g/day). Ten patients showed signs of endoscopic recurrence (apthae, ulcers, narrowing of the lumen) in the neoterminal ileum, five of whom also showed juxta-anastomotic colonic involvement. Fifteen patients were free of recurrence. At endoscopy, four biopsies were taken from the perianastomotic area (two specimens at the ileal site and two specimens at the colonic site of the anastomosis). The specimens were weighed and immediately frozen at -80 degrees C. Mesalazine concentration (ng/mg) was measured in tissue homogenates by high- performance liquid chromatography with electrochemical detection. Fisher's exact test was used for the statistical analysis. RESULTS: The mean value of mucosal mesalazine concentration, expressed as ng/mg of tissue, was significantly lower in patients with recurrence than in those without recurrence both in the ileum (mean +/- s.d.: 21.6+/-28.3 vs. 70.9+/-47.4; P = 0.007) and in the colon (25.8+/-26.4 vs. 60.3+/-32.5; P = 0.010). CONCLUSIONS: The mucosal concentration of mesalazine in the juxta-anastomatic area is significantly lower in patients with recurrence than in those free of recurrence. These data could suggest an association between mucosal mesalazine concentrations and the clinical effectiveness of the drug.

Circulating soluble factor-inhibiting natural killer (NK) activity of fresh peripheral blood mononuclear cells (PBMC) from inflammatory bowel disease (IBD) patients.

This study was performed in order to assess the cytotoxic activity, both natural (NK) and antibody-dependent (ADCC), of PBMC from 38 IBD patients and correlate it with their clinical features. Cytotoxicity assays were performed using sensitive target cells for NK and ADCC activities. In some experiments, highly purified NK cells, obtained both by Percoll density gradient and by co-culturing non-adherent PBMC with RPMI 8866 feeder cells, were used as effector cells. Furthermore, we evaluated NK cell parameters such as number, surface expression of adhesion molecules (CD11a/CD18, CD49d and CD54) and response to different stimuli. We observed a decreased NK cytotoxicity of PBMC from IBD patients, both in ulcerative colitis (UC) and Crohn's disease (CD), independently of the clinical activity of disease. In contrast, the ADCC lytic activity was within normal range. The lower NK cytotoxic activity observed in our IBD patients cannot be related to a decreased number of NK cells, surface expression of adhesion molecules, defective response to IL-2 and maturative defect. Decreased NK activity was induced in PBMC of controls when serum of patients was added and this was unrelated to monocyte-derived modulating factor(s). Our data show a decreased natural killing by fresh PBMC from IBD patients. This lower activity seems to be unrelated to a primary NK cell defect, since purified NK cells exhibited normal levels of killing. It might be hypothesized that serum factors, possibly derived from lymphocytes, with inhibitory properties on NK activity, might be functionally active in the blood of IBD patients, thus modulating NK activity.

Carbonic anhydrase I reduction in colonic mucosa of patients with active ulcerative colitis.

Ulcerative colitis (UC) is associated with low intracolonic pH and unbalanced transmucosal ionic exchanges. Along the gastrointestinal tract carbonic anhydrase isoenzyme I (CA-I) is specifically expressed in colon epithelium and is involved in mucosal control of ion, fluid, and acid-base balance. Since altered CA-I expression may play some role in UC, CA-I was measured at the mRNA and protein level and carbonic anhydrase (CA) enzyme activity was determined in colon biopsies of 14 UC patients (6 remission, 4 mild, 4 moderate UC) and of 12 healthy subjects. Patients with mild or moderate UC showed a significant reduction of CA-I mRNA and protein and of total CA activity in the inflamed mucosa compared to controls. Patients with UC in remission showed a pattern of CA-I expression and CA activity similar to controls. This is the first report showing a reduction in the expression of CA-I in active UC.