Disposition of 5-aminosalicylic acid by 5-aminosalicylic acid-delivering compounds

The disposition of 5-aminosalicylic acid (5-ASA) from 5-ASA-delivering drugs was studied in eight healthy volunteers. Time-related urinary excretion and faecal excretion of 5-ASA and acetyl-5-ASA were measured after a single oral dose of the azo compounds sulphasalazine and olsalazine, of the slow-release compounds Pentasa, Asacol, and Salofalk, and of plain 5-ASA. Plain 5-ASA was rapidly excreted into urine and had a low faecal recovery, indicating fast absorption proximally in the intestine and little availability to the colon. After ingestion of both azo compounds and slow-release compounds, urinary excretion of 5-ASA was markedly delayed and reduced, and faecal excretion was enhanced. At all points of time there was a significant but not very marked difference in urinary excretion of 5-ASA after ingestion of the azo compounds and the slow-release compounds, in favour of the azo compounds. A significantly larger proportion of the ingested 5-ASA, moreover, was excreted in faeces after intake of azo compounds as compared with slow-release compounds.     

Disposition of 5-aminosalicylic acid by olsalazine and three mesalazine preparations in patients with ulcerative colitis: comparison of intraluminal colonic concentrations, serum values, and urinary excretion.

To compare the disposition of 5-aminosalicylic acid (5-ASA) and its acetylated metabolite during treatment with olsalazine and mesalazine, 14 patients with inactive ulcerative colitis were randomly assigned to olsalazine (1 g twice daily) and the mesalazines, Asacol (800 + 400 + 800 mg daily), Pentasa (750 + 500 + 750 mg daily), and Salofalk (750 + 500 + 750 mg daily) in a crossover design trial so that all received each drug for seven days. Intraluminal colonic concentrations of 5-ASA were estimated after five days by the method of equilibrium in vivo dialysis of faeces. A predose serum sample and a 24 hour urine collection were obtained on day seven. The 5-ASA and acetyl-5-aminosalicylic acid (Ac-5-ASA) values were determined by high performance liquid chromatography. Olsalazine almost doubled the colonic concentrations (mean 23.7 (SEM) (1.9) mmol/l) of its therapeutically active ingredient (5-ASA) compared with equimolar doses of Pentasa (12.6 (2.2) mmol/l; p less than 0.0003) and Salofalk (15.0 (2.0) mmol/l; p less than 0.003). At the same time, olsalazine treatment was associated with lower serum concentrations and urinary excretions (p less than 0.05) of 5-ASA and Ac-5-ASA compared with the mesalazine preparations. The low systemic load of 5-ASA provided by olsalazine reduces the potential risk of nephrotoxicity during long term treatment.     

Disposition of mesalazine from mesalazine-delivering drugs in patients with inflammatory bowel disease, with and without diarrhoea.

The disposition of mesalazine from the azo compounds sulphasalazine and olsalazine (Dipentum) and from the slow-release mesalazine drugs Pentasa, Asacol, and Salofalk was studied in 20 patients with inflammatory bowel disease. Ten of them had diarrhoea, and 10 had normal stools. On the last 2 days of a 7-day maintenance treatment with each of the study drugs urine and faeces were collected for determination of mesalazine, acetyl-mesalazine, and unsplit azo compound. In patients with and without diarrhoea the urinary and the faecal excretion of acetyl-mesalazine was lowest during treatment with olsalazine. The proportion of acetyl-mesalazine in faeces was highest during treatment with Pentasa in both groups. The presence of diarrhoea was associated with a decrease in the proportion of acetyl-mesalazine in faeces during treatment with all drugs, not significant only for Pentasa. The proportion of unsplit azo compound in faeces increased in the case of diarrhoea to almost 50%. It is concluded that in patients with inflammatory bowel disease diarrhoea substantially influences the disposition from all these drugs except Pentasa.     

Oral 5-aminosalicylic acid preparations in treatment of inflammatory bowel disease an update

Therapeutic efficacy of 5-aminosalicylic acid (5-ASA) preparations is reviewed. In the acute treatment of Crohn's disease, Pentasa and Salofalk seem to be more effective than placebo. When it is given in an equimolar 5-ASA regimen, Salofalk appears to be at least as effective as sulfasalazine (SAS) in the treatment of both Crohn's disease and ulcerative colitis. Asacol and SAS are equally effective in maintenance therapy of ulcerative colitis. Dipentum was more efficient than placebo. There was only a low incidence of side effects from oral 5-ASA preparations, but larger-scale trials may be needed for a more accurate profile of adverse reactions.     

Bioavailability of 5-aminosalicylic acid from slow release 5-aminosalicylic acid drug and sulfasalazine in normal children

The bioavailability of a controlled release 5-aminosalicylic acid preparation (Pentasa) was investigated in nine healthy children after a medication period of six days (1000 mg/day) and compared with sulfasalazine (Salazopyrin) (2000 mg/day). The local bioavailability in the distal gut lumen, reflected by the 5-aminosalicylic acid concentration in the fecal water, showed comparable values after Pentasa (4.44 mmol/liter) and Salazopyrin (6.25 mmol/liter). The concentration ofN-acetyl-5-ASA was significantly higher after Pentasa, reflecting the more proximal release of 5-aminosalicylic acid compared with Salazopyrin. No relation was found between the 5-aminosalicylic acid fecal water concentration and the 5-aminosalicylic acid dose per kilogram of body weight. The urinary excretion of 5-aminosalicylic acid andN-acetyl-5-aminosalicylic acid was higher after Pentasa than after Salazopyrin (32% vs 25%). Dose interval plasma concentration curves showed low values after both preparations. Based on the concept that the fecal water concentration is decisive for the efficacy of 5-aminosalicylic acid in distal inflammatory bowel disease, Pentasa treatment offers a relevant alternative in cases of Salazopyrin intolerance or allergy in children. The higher systemic bioavailability from Pentasa warrants monitoring of the renal function.     

Concentrations of 5-ASA and Ac-5-ASA in human ileocolonic biopsy homogenates after oral 5-ASA preparations.

Intramucosal 5-aminosalicylic acid (5-ASA) and acetylated 5-ASA (Ac-5-ASA) concentrations were determined in ileocolonic biopsy specimens from 61 patients with irritable bowel syndrome treated for one week with near equimolar doses of different slow release preparations of 5-ASA (Claversal, Asacol, or Pentasa) or azo-bound drugs (Salazopyrin, Dipentum). The transit time in these patients was accelerated by a laxative, metoclopramide, and colonic lavage. The presence of 5-ASA in the mucosa was confirmed by autofluorescence. The highest concentrations of 5-ASA were obtained after Asacol (mean (SEM), 298.5 (37.3) ng/mg wet wt), followed by Claversal 500 mg (108.8 (11.7) ng/mg wet wt) and Pentasa (25.7 (2.2) ng/mg wet wt). Very low concentrations only were observed after Claversal 250 mg (0.3 (0.03) ng/mg wet wt), Salazopyrine (1.2 (0.1) ng/mg wet wt), and Dipentum (11.0 (3.2) ng/mg wet wt). The results for Ac-5-ASA were similar but the concentrations were generally lower. Serum concentration-time curves over eight hours were obtained from 34 healthy volunteers after a single oral dose of 400 to 500 mg of the different drugs. For the slow release forms, an apparently inverse relationship was found between the area under the curve of the serum concentrations and the intramucosal concentrations, supporting the importance of the local availability of the drug. This inverse relationship was absent for the azo-bound drugs. Colonic washout induced mechanical removal of intraluminal 5-ASA with a secondary disturbance in absorption resulting in a rapid decline in the serum concentrations. However, only for Dipentum did this result in significantly lower 5-ASA mucosal concentrations. This is the first reported attempt to evaluate the mucosal availability of 5-ASA after different oral preparations. It shows that where transit time is accelerated higher mucosal concentrations occur after slow release preparations (except for Claversal 250 mg) than after azo-bound drugs. Additional studies are necessary to correlate these concentrations with clinical effects.     

Oroileal transit of slow release 5-aminosalicylic acid.

The predominant active anti-inflammatory moiety in chronic inflammatory bowel disease is 5-aminosalicylic acid (5-ASA). As unprotected 5-ASA is rapidly absorbed in the upper gastrointestinal tract several slow release preparations have been developed to permit passage of 5-ASA to the lower small bowel and to the colon. To investigate luminal kinetics and extent of the release of 5-ASA intraluminal concentrations and loads of this compound together with that of its main metabolite acetyl-5-aminosalicylic acid (ac-5-ASA) were studied, over 15 hours after giving the slow release preparation Salofalk at a dose of 500 mg orally together with a test meal. Plasma concentrations and urinary excretion were also measured. Six healthy volunteers swallowed an 11 lumen oroileal tube, which allowed marker perfusion, aspiration of luminal content from the duodenum, mid-jejunum, and ileum, and recording of intestinal motility. Emptying of 5-ASA into the duodenum started after emptying of the meal, together with the first phase III of interdigestive motility. Mean luminal concentrations of 5-ASA and ac-5-ASA increased continuously from duodenum (both: 15 to 30 micrograms/ml) to ileum (60 to 110 micrograms/ml and 80 to 150 micrograms/ml respectively) over three hours and decreased over the next three hours. During 10 hours after eating, 30% of the total dose passed the ileum in solution and another 10% were excreted in urine. Thus about 60% reached the colon unreleased from tablets and another 30% were in solution. The ratio of 5-ASA and ac-5-ASA in solution was about 1:1 in the duodenum and 1:1.5 to 1:2 in the more distal small intestine. The data suggest that the large quantities of intraluminal ac-5-ASA are generated in the intestinal mucosa and reach the lumen by back diffusion. The results show that most of the 5-ASA from this slow release preparation is delivered into the colon, which explains its effectiveness in ulcerative colitis. The considerable luminal concentrations already present in the distal ileum might justify therapeutic trials in Crohn's disease.     

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)     

Effect of a slow-release 5'-aminosalicylic acid preparation on disease activity in Crohn's disease

A short-term double-blind controlled trial has been performed comparing a slow-release 5'-aminosalicylic acid (5-ASA) tablet (Pentasa) with placebo in the outpatient treatment of mild and moderate active Crohn's colitis. The disease activity was measured objectively by quantitation of the faecal excretion of 111In-labelled autologous granulocytes, which directly reflects gut inflammation. Twelve patients were randomized to receive either Pentasa or placebo. After 10 days of treatment faecal granulocyte excretion fell in all patients receiving 5-ASA, while no consistent change was found in the placebo group. These results suggest that this slow-release preparation of 5-ASA should be tested in larger controlled therapeutic trials over a longer period of time.     

Intestinal luminal pH in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugs

Measurements of luminal pH in the normal gastrointestinal tract have shown a progressive increase in pH from the duodenum to the terminal ileum, a decrease in the caecum, and then a slow rise along the colon to the rectum. Some data in patients with ulcerative colitis suggest a substantial reduction below normal values in the right colon, while limited results in Crohn's disease have been contradictory. Determinants of luminal pH in the colon include mucosal bicarbonate and lactate production, bacterial fermentation of carbohydrates and mucosal absorption of short chain fatty acids, and possibly intestinal transit. Alterations in these factors, as a result of mucosal disease and changes in diet, are likely to explain abnormal pH measurements in inflammatory bowel disease (IBD). It is conceivable that reduced intracolonic pH in active ulcerative colitis impairs bioavailability of 5-aminosalicylic acid from pH dependent release formulations (Asacol, Salofalk) and those requiring cleavage by bacterial azo reductase (sulphasalazine, olsalazine, balsalazide), but further pharmacokinetic studies are needed to confirm this possibility. Reports that balsalazide and olsalazine may be more efficacious in active and quiescent ulcerative colitis, respectively, than Asacol suggest that low pH may be a more critical factor in patients taking directly pH dependent release than azo bonded preparations. Reduced intracolonic pH also needs to be considered in the development of pH dependent colonic release formulations of budesonide and azathioprine for use in ulcerative and Crohn's colitis. This paper reviews methods for measuring gut pH, its changes in IBD, and how these may influence current and future therapies.     

Role of mesalazine in acute and long-term treatment of ulcerative colitis and its complications

BACKGROUND: Sulfasalazine, consisting of 5-aminosalicylic acid bound to sulfapyridine by a diazo bond, was first used for treatment of ulcerative colitis in the early 1940s and later found effective in placebo-controlled trials for acute disease and for long-term maintenance of remission. Later studies found that the active moiety is 5-ASA (mesalazine, mesalamine) and the sulfapyridine moiety acts as a carrier molecule but causes many of the symptomatic adverse reactions. METHODS: Review of the literature. RESULTS: The finding that 5-ASA in the active motility led to the development of mesalazine prodrugs, olsalazine (Dipentum) and balsalazide (Colazide, Colazal), and targeted release mesalazine preparations, such as Asacol, Pentasa, and Salofalk, as well as enemas and suppository preparations for distal disease. Most patients with adverse effects from sulfasalazine will tolerate mesalazine. Mesalazine has been shown equivalent or superior to sulfasalazine, and superior to placebo, with a dose-response benefit, in inducing remission of acute disease. and comparable to sulfasalazine and superior to placebo for long-term maintenance of remission. Better tolerance of mesalazine and the ability to use higher doses favor its use in patients intolerant of sulfasalazine and in patients failing to respond to usual doses of sulfasalazine. Adverse effects from mesalazine are uncommon, but include idiosyncratic worsening of the colitis symptoms and renal toxicity. Mesalazine is safe to use during pregnancy and for nursing mothers. As maintenance therapy, mesalazine may reduce the risk of developing colorectal carcinoma. CONCLUSION: Mesalazine represents effective and well-tolerated first-line therapy for mildly to moderately acute disease as well as for the long-term maintenance treatment in the patient with ulcerative colitis.     

A dynamic model of once-daily 5-aminosalicylic acid predicts clinical efficacy

New once daily mesalamine formulations may improve adherence to medication usage.Response to Asacol and other forms of 5-aminosalicyclic acid(5-ASA)is better correlated with tissue concentrations and best predicted by concentrations of the drug within the lumen of the colon.Our group used computer simulation to predict colonic 5-ASA levels after Asacol administration.In our study,the model simulated Asacol distribution in the healthy colon,and during quiescent and active ulcerative colitis.An Asacol dosage ...     

Drug therapy for ulcerative colitis

Ulcerative colitis (UC) is an inflammatory destructive disease of the large intestine occurred usually in the rectum and lower part of the colon as well as the entire colon. Drug therapy is not the only choice for UC treatment and medical management should be as a comprehensive whole.Azulfidine, Asacol, Pentasa, Dipentum, and Rowasa all contain 5-aminosalicylic acid (5-ASA), which is the topical anti-inflammatory ingredient. Pentasa is more commonly used in treating Crohn‘s ileitis because Pentasa capsules release more 5-ASA into the small intestine than Asacol tablets. Pentasa can also be used for treating mild to moderate UC. Rowasa enemas are safe and effective in treating ulcerative proctitis and proctosigmoiditis. The sulfafree 5-ASA agents (Asacol, Pentasa, Dipentum and Rowasa) have fewer side effects than sulfa-containing Azulfidine. In UC patients with moderate to severe disease and in patients who failed to respond to 5-ASA compounds,systemic (oral) corticosteroids should be used. Systemic corticosteroids (prednisone, prednisolone, cortisone, etc.)are potent and fast-acting drugs for treating UC, Crohn‘s ileitis and ileocolitis. Systemic corticosteroids are not effective in maintaining remission in patients with UC.Serious side effects can result from prolonged corticosteroid treatment. To minimize side effects, corticosteroids should be gradually reduced as soon as the disease remission is achieved. In patients with corticosteroid-dependent or unresponsive to corticosteroid treatment, surgery or immunomodulator is considered. Immunomodulators used for treating severe UC include azathioprine/6-MP,methotrexate, and cyclosporine. Integrated traditional Chinese and Western medicine is safe and effective in maintaining remission in patients with UC.     

A dynamic model of once-daily 5-aminosalicylic acid predicts clinical efficacy

New once daily mesalamine formulations may improve adherence to medication usage.Response to Asacol and other forms of 5-aminosalicyclic acid(5-ASA)is better correlated with tissue concentrations and best predicted by concentrations of the drug within the lumen of the colon.Our group used computer simulation to predict colonic 5-ASA levels after Asacol administration.In our study,the model simulated Asacol distribution in the healthy colon,and during quiescent and active ulcerative colitis.An Asacol dosage ...     

Steady-state kinetics of 5-aminosalicylic acid and sulfapyridine during sulfasalazine prophylaxis in ulcerative colitis

Fifteen adult and 19 pediatric outpatients with ulcerative colitis were studied to determine the steady-state kinetics of 5-aminosalicylic acid (5-ASA) released from salazosulfapyridine (SASP). Results of excretion in adults (mean 24-h recovery of 5-ASA, 21% in urine and 57% in feces) were compatible with those of healthy volunteers. Since mean SASP dose/kg body weight (about 50 mg/kg) and compliance (reflected in sulfapyridine recovery) were equal in adults and pediatric patients, the results of the patient groups could be compared. Near-complete azo reduction of SASP occurs in children. Absorption and excretion of 5-ASA and metabolism to acetyl-5-ASA did not differ statistically between pediatric and adult patients. However, the fecal excretion of the drug and its metabolites was significantly lower in young patients, although fecal concentrations were the same. The present results demonstrate that SASP is an excellent sustained-release drug for the delivery of 5-ASA to the lower part of the bowel system and provide a reference for comparison of 5-ASA kinetics after treatment with newer 5-ASA preparations.     

Disposition of Mesalazine from Mesalazine-Delivering Drugs in Patients with Inflammatory Bowel Disease,with and without Diarrhoea

Rijk MCM, van Schaik A, van Tongeren JHM. Disposition of mesalazine from mesalazine-delivering drugs in patients with inflammatory bowel disease, with and without diarrhoea. Scand J Gastroenterol 1992;27:863-868.

The disposition of mesalazine from the azo compounds sulphasalazine and olsalazine (Dipentum^®) and from the slow-release mesalazine drugs Pentasa^®, Asacol^®, and Salofalk^® was studied in 20 patients with inflammatory bowel disease. Ten of them had diarrhoea, and 10 had normal stools. On the last 2 days of a 7-day maintenance treatment with each of the study drugs urine and faeces were collected for determination of mesalazine, acetyl-mesalazine, and unsplit azo compound. In patients with and without diarrhoea the urinary and the faecal excretion of acetyl-mesalazine was lowest during treatment with olsalazine. The proportion of acetyl-mesalazine in faeces was highest during treatment with Pentasa in both groups. The presence of diarrhoea was associated with a decrease in the proportion of acetyl-mesalazine in faeces during treatment with all drugs, not significant only for Pentasa. The proportion of unsplit azo compound in faeces increased in the case of diarrhoea to almost 50%. It is concluded that in patients with inflammatory bowel disease diarrhoea substantially influences the disposition from ail these drugs except Pentasa.     

Effect of polymer coating on faecal recovery of ingested 5-amino salicylic acid in patients with ulcerative colitis.

It has been suggested that polymer coating might retard jejunal absorption of 5-amino salicylic acid (5-ASA) and thus promote delivery to its colonic site of action. Twenty three patients with active (nine), or quiescent (14) ulcerative colitis were given either uncoated or coated 5-ASA (Asacol) 400 mg qds for one to three weeks, after which they ingested five 1.5 ml dialysis membrane sachets which were recovered from the stool in the next 72 hours. After one week of treatment the concentration of 5-ASA in the faecal dialysate, urine, and fasting plasma in those receiving the coated and uncoated preparations were respectively: 25.4 +/- 5.1 compared with 1.2 +/- 0.4 mmol/l (p less than 0.001); 0.34 +/- 0.21 compared with 0.70 +/- 0.29 mmol/24h (NS) and 11.1 +/- 4.2 compared with 0.07 +/- 0.03 mumol/l (p less than 0.02). Faecal excretion of the drug appeared to be greater in patients with active colitis than in those with quiescent disease. Thus coating with pH dependent methacrylic acid copolymer B is a very effective method of promoting delivery of 5-ASA to the colon, stool dialysate concentrations being 20 fold more than those in controls. Increased trough plasma concentrations in the polymer coating group probably reflect delayed intestinal absorption but no evidence of plasma accumulation after 21 days of therapy was found.     

Pharmacology and pharmacokinetics of 5-aminosalicylic acid

There is accumulating clinical evidence that 5-aminosalicylic acid (5-ASA), a primary metabolite of sulfasalazine (SAS), represents the therapeutic active moiety of the azo-compound SAS in the treatment of chronic inflammatory bowel disease (IBD). Since it is presumed that 5-ASA acts from the lumen of the intestine, it is important to know how much 5-ASA is released from its special galenic formulations. After liberation of 5-ASA in the terminal ileum (only slow release oral preparations of 5-ASA) and colon (5-ASA suppositories and enemas), 5-ASA is only partly absorbed. A major part of this 5-ASA is presystemically eliminated, eg, N-acetylated during its first passage through the intestinal mucosa and liver. Mean steady state plasma levels of unchanged 5-ASA are rather low (range 0.02 to 1.2 μg/ml) whereas those of Ac-5-ASA are always higher (range 0.1 to 2.9 μg/ml). This is due to the rapid elimination of 5-ASA (t1/2=0.4 to 2.4h) and the slightly slower renal excretion of the Ac-5-ASA (t1/2=6 to 9h, renal clearance=200 to 300 ml/min). The knowledge of the pharmacokinetic properties of 5-ASA from different drug formulations might contribute to a better understanding of its mode of action in IBD.     

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.     

Glomerular and tubular renal functions after long-term medication of sulphasalazine, olsalazine, and mesalazine in patients with ulcerative colitis

To date there are only few reports evaluating the potential nephrotoxic reactions of the new 5-aminosalicylic acid (5-ASA) preparations in patients with ulcerative colitis (UC). The aim of this study was to screen the tubular and glomerular functions in patients with UC in maintenance treatment with either 5-ASA azo-compounds (sulphasalazine and olsalazine) or mesalazine. Patients with UC in clinical remission treated with either sulphasalazine, olsalazine, or mesalazine for more than 1 year were included in an open, single-blind retrospective Norwegian multicenter study. Serum and urine creatinine, serum and urine beta2-microglobulin, urine N-acetyl-beta-glucoseamidase (NAG), urine alkaline phosphatase, urine microalbumin, urine alanine amino peptidase, and urine beta2-microglobulin were measured. Fifty-two females and 75 males (n = 127), ages 20-69, were evaluated. Thirty-six patients were treated with sulphasalazine (mean treatment time 10.1+/-6.6 years [mean +/- SD]), 32 patients were treated with olsalazine (2.3+/-1.4 years), and 59 patients with mesalazine (3.2+/-2.0 years). At inclusion, there were no significant differences in the serum or urine values between the groups. In 17 patients (1 patient [3%] in the sulphasalazine group, 4 patients [13%] in the olsalazine group, and 12 patients [20%] in the mesalazine group), at least one abnormal serum and/or urine value was detected. After 10 years of treatment, only one abnormal value was found among the 19 patients in the sulphasalazine group. The abnormal values observed in the other groups indicated minor glomerular or tubular renal damage. In conclusion, long term sulphasalazine treatment appears to be safe and free of nephrotoxic side effects, whereas minor glomerular and tubular impairment are observed in a few patients treated with olsalazine and mesalazine.