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PubMed1991

The production of an amine-modified derivative of 5-aminosalicylic acid by activated neutrophils. Roles for myeloperoxidase and chloride ions.

Following incubation with activated neutrophils, two metabolites of 5-aminosalicyclic acid (5-ASA) were identified by HPLC. These two metabolites accounted for approximately 60% and 20% of the original 5-ASA. The formation of the major metabolite was prevented by pre-incubation with the peroxidase inhibitor, azide, and reduced by the omission of chloride ions from the incubation medium, or the presence of catalase. A similar product was generated by sodium hypochlorite or myeloperoxidase/H2O2, mass spectroscopical analysis being consistent with it being 5-nitroso-salicylate. Our finding suggests that the efficacy of 5-ASA results from its ability to react with and so scavenge hypochlorite ions. The amount of amine-modified 5-ASA in the faecal stream may thus provide an indicator for hypochlorite production in the bowel.

Aminosalicylic Acids↗
PubMed1991

Scavenger effect of sulfasalazine, 5-aminosalicylic acid, and olsalazine on superoxide radical generation.

The in vitro antioxidant capacity of sulfasalazine (SASP), its metabolites (SP, 5-ASA), and olsalazine (OAZ), was studied by evaluating their effects on superoxide (O2-.) production. Assay systems were the xanthine-xanthine oxidase (X/XOD) reaction and phorbol myristate acetate (PMA)-activated polymorphonuclear leukocytes (PMNs), using the cytochrome c (cyt-c) reduction assay and a luminol-dependent chemiluminescence method. 5-ASA, SASP, and OAZ showed a dose-dependent scavenger effect in both O2-. generating systems, 5-ASA being the most powerful (greater than 50% of inhibition in the PMNs system and greater than 70% in the X/XOD system at 10 microM concentration). SP had an inhibitory effect only in the PMNs system but did not modify the activity of xanthine oxidase, thus excluding a scavenger action. These data suggest that the scavenger effect of 5-ASA, SASP, and OAZ may be an important mechanism of action.

Aminosalicylic Acids↗
PubMed1997

[Hypersensitivity to 5-aminosalicylic acid. Value of desensitization by oral route].

BACKGROUND: Treatment with sulphasalazine of patients with mild and moderate forms of Crohn's disease may result in side effects in some of them. CASE REPORT: An 11-year-old girl with Crohn's disease was given 40 mg/kd/day of sulphasalazine after achieving remission with prednisone. She developed urticaria and eosionophilia 8 days later, then extended skin edema during a second course of sulphasalazine requiring methyl prednisolone therapy. Mesalazine administration (25 mg/kg/day), one month later, resulted to watery stools, vomiting, and fever, a side effect observed again after two further mesalazine challenges of one-month interval. Eosionophilia was present and the lymphocyte stimulation test with mesalazine was positive. Successful desensitization to sulphasalazine could be obtained 9 months later permitting further safe administration of this drug up to 18 months. CONCLUSION: Hypersensitivity to sulphasalazine may be successfully overcame by oral desensitization, especially in those patients with low-grade activity of Crohn's disease.

Administration, Oral↗
PubMed1990

Mesalazine (5-aminosalicylic acid) suppositories in the treatment of ulcerative proctitis or distal proctosigmoiditis. A randomized controlled trial.

A multicentre double-blind study was conducted to evaluate the efficacy and tolerability of 1 g or 1.5 g mesalazine daily compared with placebo in 94 patients with mild to moderate distal proctosigmoiditis (less than 20 cm). The study end point was the determination of clinical, endoscopic, and histologic remission rates at 4 weeks. Eleven patients, nine receiving placebo and two receiving 1.5 g mesalazine, withdrew during trial, mostly because of worsening of symptoms. At 4 weeks clinical remission was achieved in 7 of 31 (39%) patients with placebo, in 22 of 32 (69%) patients in the 1 g mesalazine group, and 23 of 31 (74%) patients in the 1.5 g mesalazine group. No serious clinical or biochemical side effect of treatment was reported. Mesalazine suppositories are safe, well tolerated, and very effective in patients with active distal proctosigmoiditis: 500 mg twice daily appears a suitable dose regimen.

Adult↗
PubMed1992

Prandial and diurnal effects on the absorption of orally administered enteric coated 5-aminosalicylic acid (5-ASA).

Plasma and urine concentrations of 5-ASA and its N-acetyl metabolite 5-AcASA were measured over 48 h in 12 young healthy male subjects, who received three doses of three times enteric coated 500 mg 5-ASA tablets at 7 h interval, on two occasions 14 days apart. On one occasion the doses were given after standard meals; on the other occasion, they were given 1 h before meals. Administration of the tablets after meals delayed systemic drug absorption but did not affect the extent of absorption. There was a sharp rise in the plasma concentrations of 5-ASA and 5-AcASA in the early morning (i.e. circa 24 h after administration of the 1st dose) independent of when the tablets were taken with respect to the meals. This suggests that tablets or tablet fragments remained in the stomach until the later part of the night. Thus, diurnal effects may be more important than prandial effects in the evaluation of the kinetics of 5-ASA and its metabolites after peroral administration of enteric coated tablets.

Administration, Oral↗
PubMed1994

Intermittent versus continuous 5-aminosalicylic acid treatment for maintaining remission in ulcerative colitis.

We performed a 12-month clinical trial to compare the relative effectiveness of an intermittent 5-ASA regimen and a continuous 5-ASA regimen for the maintenance treatment of patients with ulcerative colitis in remission. Fifty patients with ulcerative colitis in remission for a minimum period of 1 month participated in the study. Twenty five patients received an intermittent treatment with 5-ASA tablets (2.4 g for the first week of each month) and 25 received a continuous treatment with tablets (1.6 g each day). Patients were assessed clinically every two months and endoscopically every 6 months. Our results show that the two treatments were equally effective. The relapse-free rates at 12 months were 71% in patients receiving the intermittent treatment and 66% in patients given the continuous treatment. This difference is not statically significant. Further studies are needed to assess whether the intermittent regimen can be an alternative to life-long treatment in patients who have maintained remission for a long period of time.

Administration, Oral↗
PubMed1992

Prooxidant properties of 5-aminosalicylic acid. Possible mechanism for its adverse side effects.

There is a growing body of experimental and clinical evidence to suggest that oral or rectal administration of 5-ASA or 5-ASA conjugates is associated with significant adverse side effects including pancreatitis, hepatitis, and renal toxicity. The objective of this study was to assess the ability of 5-ASA to interact with low-molecular-weight iron to yield oxygen-derived free radicals and to determine whether these oxidants could damage model biological compounds. We found that 5-ASA was very effective at chelating ferric iron (Fe3+), and it rapidly reduced Fe3+ to the ferrous form (Fe2+). Addition of the 5-ASA/Fe2+ chelate to solutions containing polyunsaturated fatty acids or deoxyribose resulted in lipid peroxidation and oxidative carbohydrate degradation, respectively. These results are consistent with the formation of the highly reactive (and cytotoxic) hydroxyl radical. Formation of this free radical species was confirmed by the ability of hydroxyl radical scavengers (dimethyl sulfoxide, dimethyl thiourea) to inhibit the 5-ASA/Fe-mediated oxidative reactions. Maximum hydroxyl radical formation was achieved at a 5-ASA-to-Fe3+ ratio of 1.0 (20 microM 5-ASA and 20 microM Fe3+). Increasing this ratio significantly inhibited OH. formation with a concomitant reduction in lipid peroxidation and deoxyribose degradation. Finally, we demonstrated that 5-ASA promotes the reductive release of Fe3+ from ferritin. Data obtained in this study suggest that 5-ASA may, under certain conditions, promote the formation of potentially injurious free radical species. These oxidative reactions may contribute to some of the adverse side effects known to be associated with the newer preparations of 5-ASA.

Aminosalicylic Acids↗
PubMed1991

Availability of mesalazine (5-aminosalicylic acid) from enemas and suppositories during steady-state conditions.

The local and systemic bioavailability of a mesalazine enema (Pentasa, Ferring A/S, Denmark) and a mesalazine suppository (Pentasa, Ferring) was assessed during steady-state conditions. Eleven healthy subjects took 1 g of the enema or the suppository twice daily for 1 week, with a drug-free period of at least 1 week in between. At the end of each treatment period the urine and faeces were collected for 48 h, and the concentrations of mesalazine and the metabolite acetyl-mesalazine were measured. Plasma concentrations of drug and metabolite were measured hourly during a 12-h dose interval. The faecal water concentration of mesalazine was significantly higher after suppository treatment (55.7 mmol/l) compared with enema treatment (31.7 mmol/l) (p less than 0.01). The systemic absorption was low; 15% of daily mesalazine dose was recovered in urine after enema treatment and 10% after suppositores (p less than 0.01). Plasma concentrations were low, and no accumulation of either mesalazine or acetyl-mesalazine occurred. In conclusion, the enema and the suppository can be continuously administered as 1 g of mesalazine twice daily, respectively, giving high faecal water concentrations of mesalazine and a low systemic absorption.

Administration, Rectal↗
PubMed1976

Combined para-aminosalicylic acid and dietary therapy in long-term control of hypercholesterolemia and hypertriglyceridemia (Types IIa and IIb hyperlipoproteinemia).

The hypolipidemic effect of PAS-C-diet treatment was studied in 63 patients with Types IIa and IIb hyperlipoproteinemia for 6-36 months. Serum lipids and body weights of all patients were stabilized by a low cholesterol-saturated fat-refined carbohydrate diet before the initiation of an eight-week placebo-drug single-blind crossover study. During the placebo period the plasma lipids levels, mean +/- SD: cholesterol 355 +/- 63.5 mg%, triglyceride 141 +/- 68.7 mg%, and LDL-cholesterol 279 +/- 56.8 mg% were lowered to 274 +/- 53.1 mg+, 98 +/- 40.6 mg%, and 209 +/- 52.9 mg%, respectively (P less than 0.001 in each instance), with 7.5-11.0 grams of PAS-C/day given in one to three divided doses. In ten patients who have completed three years of treatment similar results were obtained. They showed no tendency to develop drug tolerance. Eight had watery diarrhea during the initial period which promptly subsided with interruption of drug therapy. Reintroduction of PAS-C in smaller dose (4.5 g/day) with gradual increment to effective dosage level was tolerated by all. No hematologic, hepatic, and ophthalmologic abnormalities were demonstrated by periodic monitoring. The hypoplipidemic effect of the drug was found to be diminished by alcohol and caloric excess.

Adolescent↗
PubMed1989

5-Aminosalicylic acid concentration in mucosal interstitium of cat small and large intestine.

Uncertainty regarding the concentration of 5-ASA within the mucosal interstitium has been a major limitation of defining the protective mechanisms of 5-ASA in intestinal inflammation. Therefore, we measured the concentration of 5-ASA in intestinal lymph and venous plasma during luminal perfusion of the cat small and large intestine with 10 mM 5-ASA. Blood and lymph flows were measured in each segment. 5-ASA and N-acetyl-5-ASA were extracted from plasma and lymph and quantified using fluorescence spectroscopy. Luminal perfusion of the terminal ileum with 5-ASA resulted in the following concentration profile: intestinal venous plasma (143 +/- 30 micrograms/ml) much greater than lymph (43 +/- 17 micrograms/ml) = systemic arterial plasma (40 +/- 11 micrograms/ml). In the colon the local venous plasma concentration of 5-ASA was 20 +/- 6 micrograms/ml compared to 2.0 +/- 1.0 micrograms/ml in systemic arterial plasma. N-Acetyl-5-ASA was found to comprise less than 5% of the total metabolite concentration in both ileum and colon. We also found that 58% of luminal 5-ASA was absorbed per minute in the terminal ileum, whereas only 3%/min was absorbed from the colon. The results of this study suggest that: (1) the mucosal interstitial concentration of 5-ASA in the terminal ileum and colon are approximately 100 micrograms/ml (654 microM) and 20 micrograms/ml (164 microM), respectively; and (2) the rate of 5-ASA absorption in the terminal ileum is approximately seven times greater than that in the colon.

Aminosalicylic Acids↗
PubMed1991

Steady-state pharmacokinetics of a new 4-gram 5-aminosalicylic acid retention enema in patients with ulcerative colitis in remission.

The pharmacokinetic profile of a new 4-g 5-aminosalicyclic acid (5-ASA) retention enema, Mesasal, was investigated. Nine patients with ulcerative colitis in remission and one patient with mild disease activity received one enema for seven consecutive nights. They were admitted to hospital for administration of the eighth enema. Plasma concentration and urinary excretion of 5-ASA and acetyl-5-aminosalicyclic acid (Ac-5-ASA) were studied for 45 h and faecal excretion for 24 h after administration of the last enema. The median peak plasma concentration of 5-ASA was 0.92 (range, 0.59-1.87) micrograms/ml at a median of 11 h after administration, and of Ac-5-ASA 1.62 (range, 1.03-4.36) micrograms/ml at a median of 12 h after administration. On average, the plasma concentration of Ac-5-ASA was almost twice that of 5-ASA at each sampling period. At 24 h after administration the median plasma concentration for 5-ASA was 0.12 (range, 0-0.77) micrograms/ml and for Ac-5-ASA 0.36 (range, 0.01-1.6) micrograms/ml. At 45 h after administration low levels of both 5-ASA (less than 0.2 micrograms/ml) and Ac-5-ASA (less than 0.3 microgram/ml) were noted in two patients, low levels of only Ac-5-ASA (less than 0.1 microgram/ml) in two patients, and neither 5-ASA nor Ac-5-ASA in the other six patients. All patients had detectable urinary levels of both 5-ASA and Ac-5-ASA during the first 4 h after administration. Median urinary recovery during 45 h was 12.6% (range, 5.6-22.2%), indicating a low absorption at steady-state conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Comparison of budesonide and 5-aminosalicylic acid enemas in active distal ulcerative colitis.

BACKGROUND: Budesonide is a new corticosteroid with high topical anti-inflammatory activity but little systemic effect. The aim of the present study was to compare the efficacy and safety of budesonide enema (2 mg/100 mL) and 5-ASA enema (mesalazine 1 g/100 mL) given for 4 weeks in the treatment of active distal ulcerative colitis and proctitis. METHODS: Ninety-seven patients were studied in a multicentre single-blind randomized group-comparative trial. The primary efficacy variables were endoscopy and histopathology scores obtained at 0, 2 and 4 weeks. Clinical symptoms were the secondary efficacy variables. Haematology, chemistry and adverse events were the safety variables. RESULTS: Budesonide and 5-ASA enemas both resulted in a significant improvement in endoscopy and histopathology scores but no difference could be demonstrated between the two treatment groups. There was also a significant improvement of symptoms (number of bowel movements per day, quality of stools, presence of blood and mucus, and state of well-being) within both groups but no difference between the two treatment groups. The clinical remission rate at 4 weeks was, however, 38% for patients treated with budesonide enema but 60% for those treated with 5-ASA enema (P = 0.03). No adverse events attributed to the study drugs were recorded in either of the groups. CONCLUSIONS: Budesonide enema 2 mg/100 mL appears to be as efficient and well-tolerated as 5-ASA enema in the treatment of active distal ulcerative colitis and proctitis.

Adult↗
PubMed2000

Allopurinol in addition to 5-aminosalicylic acid based drugs for the maintenance treatment of ulcerative colitis.

BACKGROUND: To investigate the value of combined treatment with allopurinol and 5-aminosalicylic (5-ASA) based drugs as maintenance treatment for ulcerative colitis (UC). METHODS: 199 patients with UC in remission but with active disease during the preceding 3 years were included. Allopurinol 100 mg twice daily or placebo was added to the 5-ASA based maintenance treatment. Clinical and endoscopic follow up was performed after 1, 6 and 12 months. RESULTS: Intention-to-treat analysis after 6 and 12 months showed similar results in both groups. A log-rank test showed that 77% in the allopurinol compared to 59% in the placebo group were still in remission after 6 months (P=0.0083) and 62% and 53% after 12 months, respectively (P=0.0936). This was mainly due to a higher than expected number of relapses during the first 3 months in the placebo group. After the first 3 months, the rate of relapse in each group was similar. CONCLUSIONS: It appears possible that allopurinol in combination with 5-ASA is better than 5-ASA alone for a 6-month, but not a 12-month period. This has to be verified in further dose-ranging studies.

Adult↗
PubMed2004

5-aminosalicylic acids and the risk of renal disease: a large British epidemiologic study.

BACKGROUND & AIMS: This study was performed to quantify the risk of renal disease in patients using aminosalicylates (5-ASA). METHODS: Data from the United Kingdom General Practice Research Database were used to estimate the incidence of renal disease in adult patients with inflammatory bowel disease (IBD) or prescription for 5-ASA and in patients without IBD. In a nested case-control analysis, each case of renal disease was matched to 5 controls. RESULTS: Among the 19,025 5-ASA users with IBD, 130 patients developed renal disease (incidence rate of 0.17 cases per 100 patients per year). The incidence among patients with IBD but without 5-ASA use was 0.25 and among patients without IBD was 0.08. In the case-control analysis, the crude odds ratio (OR) for renal disease in current 5-ASA users was 1.60 (95% confidence interval [95% CI]: 1.14-2.26); the adjusted OR was 0.86 (95% CI: 0.53-1.41). For recent users, the crude OR was 4.18 (95% CI: 2.59-6.76) and adjusted OR 2.48 (95% CI: 1.33-4.61); for past users (last prescription more than 12 months before), 1.71 (95% CI: 1.09-2.70) and 0.99 (95% CI: 0.55-1.76), respectively. Although the numbers were small, mesalazine and sulfasalazine users had comparable risks (crude OR for current and recent users of OR 2.08 [95% CI: 1.44-3.01] and 1.84 [95% CI: 1.20-2.82], respectively). In only a few records was renal disease attributed to interstitial nephritis or 5-ASA use. CONCLUSIONS: Users of 5-ASA have an increased risk of renal disease that may be partly attributable to the underlying disease. Although renal disease is a recognized adverse effect of 5-ASA, the incidence appears to be low and does not appear to be related to either the dose or type of 5-ASA used.

Adolescent↗
PubMed1999

[Consequences of galenic differences and outcome of clinical trials with budesonide and 5-aminosalicylic acids for therapy of Crohn disease].

Budesonide in both galenic forms is suitable for the treatment of a flare of Crohn's disease of up to moderate activity. The same holds true for 5-amino-salicylates, although they are less effective. Topical steroids delay but do not prevent relapses. Aminosalicylates may be used in the postoperative situation for prevention of relapse but are not significantly effective after drug-induced remission.

Anti-Inflammatory Agents↗
PubMed2002

Cancer prevention in inflammatory bowel disease and the chemoprophylactic potential of 5-aminosalicylic acid.

The risk of colorectal cancer is increased in ulcerative colitis and Crohn's colitis. Regular dysplasia surveillance colonoscopy in chronic colitis generally has been adopted as a strategy to prevent colorectal cancer or at least to diagnose it in an earlier stage. This has not been proven to reduce mortality, but it does provide the clinician and the patient with some confidence that they are participating in an active strategy to deal with the problem of colorectal cancer in chronic colitis. Disease extent and duration have long been held to be risk factors for colorectal cancer in chronic colitis, and recently some special risk groups have been identified which may require either more intensive surveillance or alternative approaches to cancer prevention. These include patients with primary sclerosing cholangitis, patients with first-degree relatives with sporadic colon cancer, and possibly, patients with backwash ileitis. There is an emerging interest in potential chemopreventative strategies in both sporadic and colitis-associated colorectal cancer. There also have been suggestive data that chronic maintenance 5-aminosalicylate use might reduce the risk of developing colorectal cancer. Recent data have suggested some potential preventative benefit of using ursodeoxycholic acid in patients with ulcerative colitis and primary sclerosing cholangitis. The scientific rationale for using these agents is sound but clinical data are lacking to fully support these approaches as chemoprevention in chronic colitis at present.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn's Disease.

BACKGROUND: Prevention of relapses is a major issue in the management of Crohn's disease. Corticosteroids, the mainstay of treatment of acute exacerbations are not effective in the maintenance of remission and its chronic use is limited by numerous adverse events. A number of randomised controlled trials comparing various 5-ASA agents with either placebo or other drugs have had conflicting results. OBJECTIVES: To conduct a systematic review to evaluate the efficacy of oral 5-ASA agents for the maintenance of medically-induced remission in Crohn's disease. SEARCH STRATEGY: We searched MEDLINE (1966 to January 2004), EMBASE (1984-January 2004), the Cochrane Central Register of Controlled Trials from the Cochrane Library (Issue 1, 2004) and the IBD Review Group Specialized Trials Register. We hand-searched the articles cited in each publication. SELECTION CRITERIA: We included randomised controlled trials which compared oral 5-ASA agents with either placebo or sulphasalazine, with treatment durations of at least 6 months. DATA COLLECTION AND ANALYSIS: Data extraction and assessment of methodological quality of each study were independently performed by two reviewers. Any disagreement among reviewers was resolved by consensus. The main outcome measure was the occurrence of relapse as defined by the primary studies. Odds ratios of relapse rates and their 95% confidence intervals were calculated. MAIN RESULTS: 5-ASA VERSUS PLACEBO. In the main analysis, we used as the denominator the total number of patients randomised. We assumed that participants who dropped out of the study, and on whom there was no post withdrawal information, had relapsed during the study period. Using the fixed effects model, the odds ratio for 6 studies where participants were followed up for 12 months was 1.00 (95%CI, 0.80 to 1.24). Using the random effects model in a sensitivity analysis had little effect on the results with an OR of 0.93 (95% CI, 0.65 to 1.33). For the seventh study where follow up was for 24 months, the odds ratio was 0.98; 95% CI, 0.51 to 1.90. In further sensitivity analyses, we analysed only participants who completed the study and ignored the dropouts. The odds ratio (fixed effects model) for the 6 studies where follow up was for 12 months was 0.74 (95% CI, 0.57 to 0.96), but using the random effects model, the OR was 0.68 (95% CI 0.45 to 1.02). The OR for the seventh study where follow up was for 24 months (Gendre 1993a), was 0.86; 95% CI, 0.42 to 1.78. 5-ASA VERSUS SULPHASALAZINE. We did not find any study that satisfied the inclusion criteria. AUTHORS' CONCLUSIONS: We found no evidence in this review to suggest that 5-ASA preparations are superior to placebo for the maintenance of medically-induced remission in patients with Crohn's disease. Therefore it appears that additional randomised trials of this regime are not justified.

Administration, Oral↗
PubMed2005

Synthesis and anti-inflammatory testing of some new compounds incorporating 5-aminosalicylic acid (5-ASA) as potential prodrugs.

This work includes the synthesis of 15 final compounds (6a-h and 7b-h) as prodrugs of 5-ASA in the form of the acid itself, esters and amides linked by an amide linkage through a spacer to the endocyclic ring N of nicotinamide. Also, 15 new intermediate compounds were prepared. The target compounds (6b, 6f, 7b, and 7e-h) revealed potent analgesic and anti-inflammatory activities in comparison to sulfasalazine and 5-ASA. In addition, ulcerogenicity, LD50, in vivo and in vitro metabolism of compound 7f were determined.

Analgesics↗