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At least 631 records · Page 35Linked to original sources
PubMed2000

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.

Adult↗
PubMed2004

Mesalazine (5-aminosalicylic acid) micropellets show similar efficacy and tolerability to mesalazine tablets in patients with ulcerative colitis--results from a randomized-controlled trial.

BACKGROUND: Formulations containing 5-aminosalicylic acid, such as mesalazine, are the gold standard of treatment for mild-to-moderate ulcerative colitis. Current oral regimens require the use of large tablets and frequent dosing to reach the recommended treatment dose. Mesalazine micropellets were designed to allow less frequent dosing in an easier to swallow formulation. AIM: To compare the efficacy of mesalazine micropellets with the tablet formulation in patients with mild-to-moderate ulcerative colitis. METHODS: This phase 2, double-blind, active-controlled, parallel-group, multiple dose clinical trial randomized 362 patients to either mesalazine micropellets or tablets, at a dosage of 3 g/day. The primary efficacy end-point was the incidence of clinical remission within 8 weeks, defined as the sum of clinical activity index components 1-4 (CAI(C1-4)) < or = 2. RESULTS: CAI(C1-4) decreased significantly in both treatment groups within 8 weeks. The micropellet formulation showed confirmatory non-inferiority with statistical significance compared with the tablet formulation, with regard to the incidence of clinical remission (odds ratio in according-to-protocol population 1.008; 95% CI: 0.623-1.632). There was no significant difference in the incidence of adverse events. CONCLUSIONS: The mesalazine micropellet formulation is as effective as tablets in patients with mild-to-moderate ulcerative colitis, enabling a larger dose to be taken comfortably and conveniently, thereby potentially improving patient compliance, treatment response and quality of life.

Administration, Oral↗
PubMed1999

Validation of a pharmacokinetic model of colon-specific drug delivery and the therapeutic effects of chitosan capsules containing 5-aminosalicylic acid on 2,4,6-trinitrobenzenesulphonic acid-induced colitis in rats.

A pharmacokinetic model of colon-specific drug delivery developed in a previous study has been validated by use of 5-aminosalicylic acid (5-ASA) as a model anti-inflammatory drug. The simulation curves obtained from the pharmacokinetic model were in good agreement with experimental data obtained after oral administration of 5-ASA-containing chitosan capsules. The concentrations of 5-ASA in the large intestinal mucosa after drug administration were higher than after administration of the drug in carmellose suspension. We then attempted colon-specific delivery of an anti-ulcerative colitis drug, in chitosan capsules, to accelerate healing of 2,4,6-trinitrobenzenesulphonic acid sodium salt (TNBS)-induced colitis in rats. To confirm this therapeutic model, salazosulphapyridine (SASP), a commercially available 5-ASA prodrug, was used as positive control. Colonic injury and inflammation were assessed by measuring myeloperoxidase activity and visual assessment (damage score), respectively. Because SASP is effective against TNBS-induced colitis in rats, use of the SASP-sensitive TNBS-induced colitis model validated the therapeutic effects of 5-ASA-containing chitosan capsules, which were significantly better than those of a suspension of the drug in carmellose. These findings suggest that our pharmacokinetic model of colon-specific drug delivery can accurately evaluate this colon-specific delivery system and that 5-ASA-containing chitosan capsules are more effective than other 5-ASA formulations for treatment of TNBS-induced colitis in rats.

Administration, Oral↗
PubMed2004

Determination of impurities in the drug 5-aminosalicylic acid by micellar electrokinetic capillary chromatography using an electrolyte pH that approaches the isoelectric point of the parent compound.

Process impurities found in the drug substance 5-aminosalicylic acid were determined by micellar electrokinetic capillary chromatography (MECC). In order to enhance the detection of trace impurities, the parent drug was dissolved to an unusually high concentration of 5 mg/mL. To reduce the dispersive processes of electromigration dispersion and anti-stacking, both of which occur at high solute concentration, the electrolyte pH was adjusted to be close to the apparent isoelectric point (pI) of the zwitterionic drug. In this fashion, the net charge on the solute should approach zero thereby minimizing the aforementioned sources of band-broadening. Two additional developments are reported. Short sodium hydroxide washes were used to optimize the MECC reproducibility. The elimination of anti-stacking permitted the use of peak heights to quantitate low level impurities with improved precision. The method was compared to the high-performance liquid chromatographic (HPLC) method found in the United States Pharmacopoeia (USP). Both the MECC and HPLC methods were found to be similar with regard to migration-retention time reproducibility, peak area-height reproducibility, linearity and limit of quantitation. The MECC separation is 2x faster than HPLC. Both methods meet the system suitability requirements described in the USP.

Chromatography, High Pressure Liquid↗
PubMed2006

A molecular mechanism for the anti-inflammatory effect of taurine-conjugated 5-aminosalicylic acid in inflamed colon.

In previous reports, a novel colon-specific prodrug, 5-aminosalicyltaurine (5-ASA-Tau) administered orally, is successfully delivered to and liberates 5-aminosalicylic acid (5-ASA) and taurine in the inflamed large intestine of rats. Furthermore, the prodrug ameliorates the 2,4,6-trinitrobenzene-sulfonic acid-induced colitis, and taurine acts not only as a carrier but also as an active therapeutic agent. In this study, we investigated the anti-inflammatory properties of the prodrug at a molecular level. After rectal administration of taurine, formation of taurine chloramine (TauCl) in the inflamed colonic tissue was examined using high-performance liquid chromatography. In human colon epithelial cell lines, nuclear factor-kappaB (NF-kappaB) activity was accessed using an NF-kappaB-dependent luciferase reporter gene. Protein levels were monitored by Western blotting. DNA binding activity of the NF-kappaB subunit p65 was determined using a DNA binding assay kit. A millimolar level of TauCl was formed in the inflamed tissue. TauCl inhibited tumor necrosis factor (TNF)-dependent NF-kappaB activation by modifying thiol(s) on p65 and blocking DNA binding. In addition, 5-ASA inhibited phosphorylation of p65 at serine 536, which is critical for transcriptional activity of NF-kappaB. Furthermore, combined TauCl/5-ASA treatment additively inhibited TNF-dependent NF-kappaB activation. Together, our data suggest that the colon-specific carrier taurine contributes to the clinical effect of the prodrug by potentiating the inhibitory effect of the active ingredient 5-ASA on a major proinflammatory signal, TNF-dependent NF-kappaB activation in the inflamed large intestine.

Animals↗
PubMed2001

A new 5-aminosalicylic acid multi-unit dosage form for the therapy of ulcerative colitis.

The aim of the present study was to develop a multi-unit dosage form containing 5-aminosalicylic acid (5-ASA) for the treatment of ulcerative colitis (UC), optimised on the basis of recent studies indicating that UC patients have higher intestinal pH than was previously thought to be the case. Pellets with a drug content of 77.4% were prepared by a granulation and spheronization process and then coated with a new pH sensitive poly(meth)acrylate copolymer (Eudragit((R)) FS 30D) to achieve site specific drug release close to the ileocecal valve. Dissolution tests were carried out in a paddle dissolution apparatus in media simulating pH conditions at various locations in the gastrointestinal tract. The pellets released rapidly at pH values above 7.5. Between 6.8 and 7.2 drug release was found to be zero order, while at pH 6.5 and below no release occurred. In a biorelevant medium which simulates the fasting proximal small intestine fluid it was shown that neither surfactants (sodium taurocholate and lecithin) nor changes in ionic strength trigger drug release. Compared to 5-ASA pellets coated with the well established Eudragit((R)) S, and to currently marketed products licensed for the treatment of UC, the multi-unit dosage form coated with the new polymer exhibited an in vitro dissolution profile more appropriate to the pH profile of the ileum and the colon observed in UC patients.

Acrylates↗
PubMed1998

Antioxidant activity of 5-aminosalicylic acid against peroxidation of phosphatidylcholine liposomes in the presence of alpha-tocopherol: a synergistic interaction?

Oxidative damage has been implicated in the pathogenesis of inflammatory bowel diseases. 5-Aminosalicylic acid (5-ASA), the anti-inflammatory drug commonly used in the treatment of this condition, has been shown to possess antioxidant properties considered to be of particular importance in the pathologic context of these diseases. However, its action mechanisms are far from being completely elucidated, especially regarding its antioxidant properties in the presence of endogenous antioxidants such as alpha-tocopherol (alpha-T), the major defence system of biomembranes against lipid peroxidation. In this study we investigated the scavenging activity of 5-ASA toward peroxyl radicals generated at different sites of soybean PC liposomes, used as model membranes, either alone or in combination with alpha-T. 5-ASA, separately, shows strong scavenging activity toward peroxyl radicals generated in the aqueous phase by thermal decomposition of 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH), inducing a clear concentration-dependent inhibition period, either of oxygen consumption or of conjugated diene hydroperoxides production. HPLC analysis indicates that 5-ASA is consumed, at a constant rate, throughout the reaction, and when the inhibition period is over, the oxidation rate is resumed. On the other hand, apart from a slight decrease in the rate of oxidation, 5-ASA is unable to suppress efficiently lipid peroxidation, when the reaction starts inside the lipid membranes, by thermal decomposition of 2,2'-azobis(2,4-dimethylvaleronitrile) (AMVN). When 5-ASA is combined with alpha-T, and the oxidation starts in the aqueous phase, an additive inhibitory effect occurs between both compounds. 5-ASA protects efficiently alpha-T against initial attack from AAPH-peroxyl radicals, delaying its consumption. On the other hand, if the reaction starts inside the lipid bilayer, 5-ASA prolongs significantly the inhibitory period produced by alpha-T on the initial rate of oxidation, as measured by oxygen consumption and conjugated diene hydroperoxides. This inhibitory effect points to a synergistic interaction between 5-ASA and alpha-T, since 5-ASA, by itself, is unable to suppress the oxidation reaction. Therefore, 5-ASA reveals an important cooperative effect with alpha-T, either affording an efficient protection to this antioxidant compound, when free radicals are generated in the aqueous site, or potentiating its activity when oxidation is initiated inside the lipid bilayer. Taking into account that the ascorbic acid content decreases significantly in the inflamed mucosa of patients with inflammatory bowel diseases, our data are, certainly, a very important contribution to the knowledge of the anti-inflammatory action of 5-ASA.

Amidines↗