BACKGROUND: Treatment of ulcerative colitis or Crohn's disease with sulphasalazine causes several adverse effects, including hepatitis. Sulphasalazine is cleaved by colonic bacteria into 5-aminosalicylic acid and sulphapyridine. Received wisdom was that 5-aminosalicylic acid was topically active, whereas sulphapyridine was absorbed and caused immunoallergic side effects. Mesalazine, a slow release formulation of 5-aminosalicylic acid, was expected to be a safe alternative. However, several cases of acute hepatitis have been reported. CASE REPORT: A 65 year old man had increased liver enzymes, anti-nuclear and anti-smooth muscle autoantibodies and IgG levels, and lesions of chronic hepatitis after 21 months of mesalazine treatment. Although liver dysfunction had been identified eight months earlier, simvastatin rather than mesalazine had been withdrawn, without any improvement. In contrast, liver enzyme and IgG levels became normal and autoantibodies disappeared after discontinuation of mesalazine administration. CONCLUSION: Contrary to initial expectations, mesalazine can cause most of the sulphasalazine induced adverse effects, and hepatic side effects may be almost as frequent. When liver dysfunction occurs, mesalazine administration should be discontinued to avoid the development of chronic hepatitis and liver fibrosis. (+info)
Impact on the composition of the faecal flora by a new probiotic preparation: preliminary data on maintenance treatment of patients with ulcerative colitis.
(10/393)
BACKGROUND: Although 5-aminosalicylic acid (5-ASA) oral compounds are the standard maintenance treatment for ulcerative colitis in remission, some patients cannot use them because of side-effects. Clinical and experimental observations have suggested the potential role of probiotics in inflammatory bowel disease therapy. AIM: To evaluate the effects on intestinal microflora and the clinical efficacy of a new probiotic preparation in patients with ulcerative colitis in remission. PATIENTS AND METHODS: Twenty patients with ulcerative colitis, intolerant or allergic to 5-ASA, have been treated with a new probiotic preparation (VSL#3, CSL, Milan, Italy) containing 5x10(11) cells/g of 3 strains of bifidobacteria, 4 strains of lactobacilli and 1 strain of Streptococcus salivarius ssp. thermophilus. Two doses of 3 g were administered o.d. for 12 months. Faecal samples for stool culture were obtained from the patients at the beginning of the trial and after 10, 20, 40, 60, 75, 90 days, 12 months and at 15 days after the end of the treatment. The following bacterial groups have been evaluated in the faeces: total aerobic and anaerobic bacteria, enterococci, Streptococcus thermophilus, lactobacilli, bifidobacteria, Bacteroides, clostridia, coliforms. Patients were assessed clinically every two months, and assessed endoscopically at 6 and 12 months or in relapse. RESULTS: Faecal concentrations of Streptococcus salivarius ssp. thermophilus, lactobacilli and bifidobacteria increased significantly in all patients, compared to their basal level, from the 20th day of treatment (P<0.05) and remained stable throughout the study. Concentrations of Bacteroides, clostridia, coliforms, total aerobic and anaerobic bacteria did not change significantly during treatment (P = N.S.). Fifteen of 20 treated patients remained in remission during the study, one patient was lost to follow up, while the remaining relapsed. No significant side-effects have been reported. CONCLUSIONS: These results show that this probiotic preparation is able to colonize the intestine, and suggest that it may be useful in maintaining the remission in ulcerative colitis patients intolerant or allergic to 5-ASA. Controlled trials are warranted to confirm these preliminary results. (+info)
Inhibition of interleukin-1-stimulated NF-kappaB RelA/p65 phosphorylation by mesalamine is accompanied by decreased transcriptional activity.
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Nuclear factor kappaB (NF-kappaB) is an inducible transcription factor that regulates genes important in immunity and inflammation. The activity of NF-kappaB is highly regulated: transcriptionally active NF-kappaB proteins are sequestered in the cytoplasm by inhibitory proteins, IkappaB. A variety of extracellular signals, including interleukin-1 (IL-1), activate NF-kappaB by inducing phosphorylation and degradation of IkappaB, allowing nuclear translocation and DNA binding of NF-kappaB. Many of the stimuli that activate NF-kappaB by inducing IkappaB degradation also cause phosphorylation of the NF-kappaB RelA (p65) polypeptide. The transactivating capacity of RelA is positively regulated by phosphorylation, suggesting that in addition to cytosolic sequestration by IkappaB, phosphorylation represents another mechanism for control of NF-kappaB activity. In this report, we demonstrate that mesalamine, an anti-inflammatory aminosalicylate, dose-dependently inhibits IL-1-stimulated NF-kappaB-dependent transcription without preventing IkappaB degradation or nuclear translocation and DNA binding of the transcriptionally active NF-kappaB proteins, RelA, c-Rel, or RelB. Mesalamine was found to inhibit IL-1-stimulated RelA phosphorylation. These data suggest that pharmacologic modulation of the phosphorylation status of RelA regulates the transcriptional activity of NF-kappaB, independent of nuclear translocation and DNA binding. These findings highlight the importance of inducible phosphorylation of RelA in the control of NF-kappaB activity. (+info)
Treatment with sulfasalazine or sulfapyridine, but not 5-aminosalicyclic acid, inhibits basic fibroblast growth factor-induced endothelial cell chemotaxis.
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OBJECTIVE: Rheumatoid arthritis (RA) is characterized by leukocyte recruitment and angiogenesis. We investigated the effects of sulfasalazine (SSZ) and its metabolites, sulfapyridine (SP) and 5-aminosalicylic acid (5-ASA), on components of angiogenesis, namely, endothelial cell (EC) chemotaxis and proliferation, as well as on EC chemokine and soluble adhesion molecule expression. METHODS: SSZ, SP, and 5-ASA were assayed for their effects on basic fibroblast growth factor (bFGF)-induced human dermal microvascular endothelial cell (HMVEC) chemotaxis and proliferation. EC were plated on Matrigel to assess the effect of SSZ on EC tube formation. Enzyme-linked immunosorbent assays were performed to determine changes in HMVEC production of interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), growth-related oncogene alpha (GROalpha), epithelial neutrophil-activating peptide 78 (ENA-78), soluble E-selectin (sE-selectin), and soluble intercellular adhesion molecule 1 (sICAM-1) upon treatment with SSZ or its metabolites. RESULTS: HMVEC incubated with SSZ or SP exhibited reduced bFGF-induced chemotaxis (59%, [n = 7] and 22%, [n = 3], respectively) (P<0.05). SSZ and SP decreased basal HMVEC proliferation, while 5-ASA increased proliferation (P<0.05; [n = 5]). SSZ decreased bFGF-induced HMVEC proliferation (P<0.05 [n = 5]). SSZ inhibited phorbol 12-myristate 13-acetate-induced HMVEC tube formation (P<0.05; [minimum n = 5]). Tumor necrosis factor alpha-stimulated HMVEC shedding of sICAM-1 was reduced by incubation with either SSZ (19%) or 5-ASA (23%) (P<0.05; [n = 6]). SP inhibited cytokine-stimulated HMVEC expression of IL-8 and MCP-1 (P<0.05; [n = 4]). Neither SSZ nor its metabolites had any effect on HMVEC production of sE-selectin, GROalpha, or ENA-78. CONCLUSION: These results demonstrate that SSZ and its metabolite SP may affect the pathogenesis of RA by inhibiting EC chemotaxis, proliferation, tube formation, and expression of sICAM-1, IL-8, and MCP-1. (+info)
Scintigraphic imaging and absorption of a 5-aminosalicylic acid enema in patients with ileorectal anastomosis.
(13/393)
Ileorectal anastomosis (IRA) is a possible surgical treatment for hyperacute and drug-unresponsive forms of ulcerative colitis (UC). UC relapses in the rectal remnant usually are prevented by chronic administration of 5-aminosalicylic acid (5-ASA) in topical formulations. The relationships between intestinal absorption and pattern of luminal spread of 5-ASA enemas are still unknown in patients with IRA. We correlated the absorption of a 5-ASA enema with its spread in the distal bowel of patients with IRA as assessed by 99mTc radioenema imaging. METHODS: Eight patients with UC in remission and previous IRA received a therapeutic 50-mL 5-ASA enema labeled with 99mTc-sulfer colloid. Absorbed 5-ASA and its major metabolite, acetyl 5-ASA, were measured in plasma, and dynamic images of radiolabeled enema were obtained for 6 h. The retrograde ileal spread (RIS) was determined and expressed as percentage of total enema radioactivity. Plasma levels of 5-ASA and acetyl 5-ASA were measured in six healthy volunteers after administration of the same enema volume with no radiolabeling. RESULTS: The mean 5-ASA plasma level was 0.70 microg/mL (range 0.37-0.95 microg/mL) in patients and 0.96 microg/mL (range 0.78-1.16 microg/mL) in healthy volunteers (P = not significant), and the mean acetyl 5-ASA plasma levels were 0.89 microg/mL (range 0.44-1.19 microg/mL) and 0.84 microg/mL (range 0.51-1.02 microg/mL), respectively (P = not significant). Radioenema imaging allows RIS assessment of patients with IRA. The mean value was 8.5% (range 2%-19.3%) of administered radioactivity, which correlated significantly with the total absorption of 5-ASA in the IRA group (P = 0.033, linear correlation test). Rectal wall contractions recognized by dynamic radioenema imaging were defined as a common cause of RIS episodes. CONCLUSION: In IRA patients, 5-ASA plasma levels were similar to those in healthy volunteers after administration in enema. Only part of a 50-mL 5-ASA enema reaches the ileum, and radiolabeled imaging shows the degree and number of these RIS episodes. The absorption of 5-ASA can increase in patients compared with healthy volunteers, in the presence of either occasional but significant ileal spread associated with postural factors and abdominal wall contraction or multiple moderate episodes of radioenema backdiffusion related to rectal wall motility. (+info)
Beneficial effects of ropivacaine in rat experimental colitis.
(14/393)
Ropivacaine, a new, long-acting local anesthetic agent, has been shown to have beneficial effects in the treatment of ulcerative colitis. Treatment with this drug results in prompt symptomatic relief. The aim of this study was to examine the effects of ropivacaine on mucosal healing and to investigate whether ropivacaine can restore the decreased colonic contractility seen in the diseased state. Colitis was induced in rats by a single intrarectal administration of trinitrobenzene sulfonic acid. Mucosal healing was assessed after 1 week of therapy. The effects on colonic contractility were examined either after 1 week of treatment or by application of the drugs to untreated, inflamed rat colon segments placed in organ baths. After the induction of colitis, daily intracolonic treatment with ropivacaine for 1 week reduced morphological damage and myeloperoxidase activity. One week of treatment also restored the contractile response to acetylcholine. By adding ropivacaine directly to untreated inflamed colonic segments in organ baths, the contractile response to acetylcholine was increased compared with controls. For comparison, the effects of budesonide and 5-aminosalicylic acid were also examined. Ropivacaine improved mucosal healing and restored colonic motor activity in experimental colitis, similar to budesonide but superior to 5-aminosalicylic acid. (+info)
Mesalazine-induced apoptosis of colorectal cancer: on the verge of a new chemopreventive era?
(15/393)
BACKGROUND: It is an accepted fact that non-steroidal anti-inflammatory drugs (NSAIDs) are potent inhibitors of colorectal carcinogenesis. However, the major disadvantages of NSAIDs are gastrointestinal and renal toxicity. We conducted a prospective pilot study on the effects of the safe salicylic acid derivative, mesalazine, on apoptosis and proliferation of tumour cells and on normal tissue in colorectal cancer patients. METHODS: Patients with colorectal cancer were asked to take mesalazine enemas for 14 days. Biopsies from malignant and normal tissue were taken prior to and after this treatment. Apoptosis was scored on haematoxylin/eosin-stained tissue sections, and cell proliferation was assessed by the proliferation marker Ki-67. RESULTS: Ten out of 14 patients completed the study. The apoptotic score increased significantly in the tumour samples (pre-treatment 14.6 +/- 1.3 vs. post-treatment 19.4 +/- 0.8; P < 0.03). The apoptotic index in the normal mucosa was unchanged (pre-treatment 3.1 +/- 0.4 vs. post-treatment 2.9 +/- 0.3; N.S.). The cell proliferation in malignant tissue, according to the Ki-67 score, was hardly affected by mesalazine (pre-treatment 522 +/- 38 vs. post-treatment 493 +/- 39; N.S.). There was no effect on the Ki-67 index of normal mucosa (pre-treatment 24.2 +/- 2.0 vs. post-treatment 28.3 +/- 2.0; N.S.). CONCLUSIONS: This pilot study conducted in patients with colorectal cancer clearly shows that mesalazine selectively induces apoptosis of tumour cells. On the basis of these findings, which need to be confirmed in larger studies, it may be speculated that 5-ASA could be useful in the chemoprevention of colorectal cancer. (+info)
Rectal and colonic mesalazine concentration in ulcerative colitis: oral vs. oral plus topical treatment.
(16/393)
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. (+info)