Once daily MMX mesalazine for the treatment of mild-to-moderate ulcerative colitis: a phase II, dose-ranging study.

BACKGROUND: SPD476 (MMX mesalazine), is a novel, once daily, high-strength mesalazine formulation (1.2 g/tablet) that utilizes Multi Matrix System (MMX) technology to delay and extend delivery of the active drug throughout the colon. AIM: To assess the safety and efficacy of MMX mesalazine in patients with mild-to-moderately active ulcerative colitis, in a pilot, phase II, randomized, multicentre, double-blind, parallel-group, dose-ranging study (SPD476-202). METHODS: Thirty-eight patients with mild-to-moderately active ulcerative colitis were randomized to MMX mesalazine 1.2, 2.4 or 4.8 g/day given once daily for 8 weeks. Remission ulcerative colitis-disease activity index (UC-DAI) < or =1, a score of 0 for rectal bleeding and stool frequency, and > or =1 -point reduction in sigmoidoscopy score from baseline was the primary end point. RESULTS: Week 8 remission rates were 0%, 31% and 18% of patients receiving MMX mesalazine 1.2, 2.4 and 4.8 g/day respectively. No statistically significant difference in remission was observed between treatment groups. MMX mesalazine 2.4 and 4.8 g/day groups demonstrated greater improvement in overall UC-DAI and component scores from baseline, compared with the 1.2 g/day group. CONCLUSION: MMX mesalazine given as 2.4 or 4.8 g/day once daily is well tolerated and effective for the treatment of mild-to-moderately active ulcerative colitis.

[Acute disorders of intestinal perfusion; a nonrigid abdomen may still be acute]. / Acute doorbloedingsstoornissen van de darm: een soepele buik kan toch acuut zijn.

Three patients, a man aged 50 years and two women aged 46 and 45 years, with abdominal pains and an undistended abdomen, were found to have acute mesenteric ischaemia. The causes were: unknown, a thrombus in the descending aorta and severe atherosclerosis, respectively. In the male patient, only 30 cm of vital small intestine ultimately remained; in one woman embolectomy sufficed, in the other, resection of a limited portion of the jejunal tract. All three patients fully recovered. Acute mesenteric ischaemia is a potentially lethal disease. Diagnosis in the first reversible phase makes full recovery of the intestine possible. This may be difficult since the clinical signs and symptoms are not specific in this phase and invasive diagnostic procedures (angiography) are required for accurate diagnosis. By making an angiogram of the mesenteric vessels in each patient with severe abdominal pain, no signs of peritonitis and leukocytosis, without another diagnosis, reversible mesenteric ischaemia can be diagnosed and a vascular surgical reconstruction can be planned.

In vivo IgA coating of anaerobic bacteria in human faeces.

The bacterial flora in the human colon, although extremely diverse, has a relatively stable composition and non-infectious anaerobic bacteria are dominant. The flora forms a pool of numerous different antigens separated from mucosal immunocompetent cells by just a single layer of epithelial cells. Despite this thin barrier, however, the colonic mucosa is physiologically only mildly inflamed. This study looked at the mucosal humoral immune response against faecal anaerobes. By flow cytometric analysis the in vivo immunoglobulin coating of anaerobic bacteria in faecal samples of 22 healthy human volunteers was determined. In a previous study flow cytometric analysis of faecal bacteria has been found to be a very sensitive method to detect immunoglobulins on faecal bacteria. This technique showed that in vivo many bacteria are coated with IgA (24-74%) and less with IgG and IgM. The presence of many bacteria coated with IgA implies that IgA coating does not result in permanent removal of the species from the colon. The absence of immunoglobulin coating suggests that there is immunological unresponsiveness for anaerobic bacterial antigens. It is concluded that both immunological unresponsiveness and preferential coating with IgA are responsible for the relative absence of colonic mucosal inflammation.

Direct flow cytometry of anaerobic bacteria in human feces.

We describe a flow cytometry method for analysis of noncultured anaerobic bacteria present in human fecal suspensions. Nonbacterial fecal compounds, bacterial fragments, and large aggregates could be discriminated from bacteria by staining with propidium iodide (PI) and setting a discriminator on PI fluorescence and by exclusion of events with large forward scatter. Since anaerobic bacteria, which account for over 99.9% of all fecal bacteria, die during sample preparation, a fixation step was not necessary. A second aim of this study was to investigate the technical possibility of measurement of in vivo IgA coating of fecal anaerobic bacteria as well as their bacterial size. Fecal samples of 22 healthy human volunteers were analyzed. The fluorescence distribution of IgA-coated bacteria labeled with fluorescein isothiocyanate (FITC)-anti-Hu-IgA had overlap with noncoated bacteria. However, with match region subtraction, detection of low levels of specific FITC fluorescence on IgA-coated bacteria was achieved. The median bacterial two-dimensional surface area was 1.0 microns2. To validate flow cytometry data, all samples were analyzed with an image analysis system as well. With this new method, a rapid evaluation of fecal flora with high sensitivity for specific FITC fluorescence is possible without culturing.

A norfloxacin dose finding study for selective decontamination of the digestive tract in pigs.

Five pigs were treated orally with norfloxacin for 5 consecutive days in two well-separated periods. This was done to determine the lowest dose required to free the pigs of Enterobacteriaceae. In the first period of the study, the animals were treated with 400 mg per day while in the second treatment 800 mg norfloxacin was given. Daily faecal culturing indicated that the faeces became free of Enterobacteriaceae in 3-5 days when treated with 400 mg/day, while all animals were found negative on culturing after 3 days of treatment with 800 mg/day. Investigation of the concentration of norfloxacin in the faeces revealed that a substantial fraction of the dose was either absorbed or inactivated by faecal substances. An in vitro study in faeces confirmed that a substantial part, some 75% of the dose, may have been inactivated by intestinal contents. This finding helps to explain the much lower concentration of 120 mg norfloxacin per kg of faeces in the pig in comparison with the almost tenfold higher concentration reported to develop in man during treatment with an identical dose.