The short- and long-term safety of 5-aminosalicylate products in the treatment of ulcerative colitis

5-aminosalicylic acid agents are effective in the treatment of ulcerative colitis. Balsalazide, mesalamine, and olsalazine are alternative formulations to sulfasalazine for the delivery of 5-aminosalicylic acid. The newer compounds might be better tolerated than sulfasalazine in some patients, as long as the intolerance is not due to hypersensitivity to 5-aminosalicylic acid. Adverse events requiring the withdrawal of therapy seem to occur less frequently with balsalazide, mesalamine, and olsalazine compared with sulfasalazine. If patients are unable to tolerate any one of these three 5-aminosalicylic acid-releasing preparations, they might be able to tolerate one of the others, as long as the intolerance is not due to hypersensitivity to 5-aminosalicylic acid.     

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.     

Colonic targeting of aminosalicylates for the treatment of ulcerative colitis.

Aminosalicylates (5-aminosalicylic acid) represent drugs of first choice in the treatment of ulcerative colitis. Two different therapeutic approaches have been employed to target the active 5-aminosalicylic acid to its site of action. Either inactive azo-prodrugs (e.g. sulfasalazine, olsalazine, balsalazide) or special galenic formulations have been developed for topical delivery of 5-aminosalicylic acid to the colon. However, as intestinal physiology, the extent of ulcerative colitis as well as drug disposition demonstrate large interindividual differences, acute healing rates (40-80%) and the maintenance of remission are quite variable. Apparently, therapeutic effects depend on local concentrations of 5-aminosalicylic acid in the colonic mucosa whereas systemic drug exposure might be one determinant of side effects. In general, 5-aminosalicylic acid is well tolerated and withdrawal from therapy is rare. Following administration of azo-prodrugs (e.g. olsalazine), lower plasma concentrations and higher delivery into the colon of 5-aminosalicylic acid can be observed in comparison to special galenic formulations of 5-aminosalicylic acid. Whether such changes in drug disposition will affect therapeutic efficacy remains to be proved by clinical data. Consequently, selection of a particular agent should be based primarily on clinical efficacy, profile of adverse effects, patients' acceptance and economic considerations.     

The effect of 5-aminosalicylic acid-containing drugs on sulfide production by sulfate-reducing and amino acid-fermenting bacteria

The toxic, bacterial metabolite sulfide is implicated in ulcerative colitis. Ulcerative colitis patients taking 5-aminosalicylic acid-containing drugs have lower fecal sulfide levels than those not taking these drugs. The effects of sulfasalazine, balsalazide, olsalazine, and 5-aminosalicylic acid on sulfide production were studied in a three-stage chemostat pulsed on days 1 to 3 with 5 g sulfasalazine (40 mM) and in pure cultures of amino acid-fermenting and sulfate-reducing bacteria. By the third day of sulfasalazine addition to the chemostat, sulfide concentrations in vessels 1 through 3 had dropped from 1.73, 1.78, and 1.43 mM to 0.01, 0.15, and 0.9 mM, respectively. In pure cultures, 50% inhibition of sulfide production from amino acids occurred at 2.5 +/- 0.05 mM for sulfasalazine, 5 +/- 0.2 mM for olsalazine, 6 +/- 1 mM for balsalazide, and more than 20 mM for 5-aminosalicylic acid. Fifty percent inhibition of sulfide production from sulfate occurred at 0.25 +/- 0.05 mM for sulfasalazine, 0.7 +/- 0.2 mM for balsalazide, and 9.0 +/- 1.0 mM for 5-aminosalicylic acid. The order of effectiveness of equimolar concentrations of drugs (most effective first) in this assay was sulfasalazine, then olsalazine (though given clinically at half the dose of other 5-aminosalicylic acid prodrugs) and balsalazide, and lastly 5-aminosalicylic acid. Inhibition of sulfide production by 5-aminosalicylic acid-containing drugs may contribute to their therapeutic effect in ulcerative colitis.     

Olsalazine versus placebo in the treatment of mild to moderate ulcerative colitis: a randomised double blind trial.

The effect of olsalazine, an analogue of sulphasalazine, consisting of two molecules 5-aminosalicylic acid linked by an azobond has been investigated for the treatment of ulcerative colitis. In a randomised double blind trial we compared 2 g olsalazine with placebo for four weeks. Of the 105 patients, with mild to moderate ulcerative colitis, entered in the trial 52 received olsalazine, and 53 placebo. Treatment had to be terminated prematurely because of untoward effects of olsalazine (mainly diarrhoea) in three patients and treatment failure--that is, increased rectal bleeding in four patients (olsalazine group: one placebo group: three). After four weeks' treatment, a statistically significant improvement in the endoscopic findings in rectum and a positive trend in the reduction of rectal mucus and blood discharge was observed in the patients treated with olsalazine. No statistically significant difference was found for other factors, including stool frequency, consistency, urge to defecate, abdominal pain, and biopsy findings. A comparison between these clinical and endoscopic parameters at study entry and those at study completion (within drug evaluation) showed significant improvement in six of 10 parameters during treatment with olsalazine and in two of 10 during placebo treatment. This difference suggests the significant effect of olsalazine. We conclude that 2 g olsalazine was tolerated as well as placebo, apart from causing diarrhoea in some patients and was slightly superior to placebo during four weeks' treatment of mild to moderate ulcerative colitis. A study with 3 or 4 g olsalazine per day may show a more definite effect.     

Effects of sulphasalazine and disodium azodisalicylate on colonic PGE2 concentrations determined by equilibrium in vivo dialysis of faeces in patients with ulcerative colitis and healthy controls.

The role of arachidonic acid metabolites and the mode of action of 5-aminosalicylic acid, the active moiety of sulphasalazine and disodium azodisalicylate, in ulcerative colitis remain obscure. Therefore, experiments were performed in which the effects of medication on immunoreactive prostaglandin (PG) E2 concentrations in free faecal water were assessed using the equilibrium in vivo dialysis of faeces. Colonic PGE2 concentrations in patients with active ulcerative colitis (n = 11) ranged from 2035-18,000 pg/ml to be compared with a range of 103-188 pg/ml in healthy volunteers (n = 10; p less than 0.001). In all healthy volunteers PGE2 concentrations decreased slightly (p less than 0.05) after disodium azodisalicylate intake 2 g/day, whereas low dose disodium azodisalicylate (0.25 g/day) caused no change. In patients with ulcerative colitis in complete clinical, sigmoidoscopic, and histologic remission withdrawal of sulphasalazine (2 g/day; n = 6) increased PGE2 concentrations to values above normal levels (p less than 0.05) which returned to pretrial values (p less than 0.05) on disodium azodisalicylate (2 g/day; n = 7). In conclusion, increased PGE2 in free faecal water indicates an abnormality in the colonic mucosa, even in the absence of conventional signs of inflammation. We could not confirm the hypothesis that sulphasalazine and 5-aminosalicylic acid exert their therapeutic effect through promotion of endogenous cytoprotective prostaglandins. In contrast, the observation that raised PGE2 concentrations were normalised by disodium azodisalicylate in patients with inactive ulcerative colitis suggests that subclinical disease activity was decreased by 5-aminosalicylic acid.     

Colonic azodisalicylate metabolism determined by in vivo dialysis in healthy volunteers and patients with ulcerative colitis

Azodisalicylate, a second generation drug of sulfasalazine, delivers twice the amount of 5-aminosalicylic acid to the colonic lumen on a molar basis when split by bacterial azoreductases. In 6 patients with inactive ulcerative colitis, the colonic metabolism of sulfasalazine and azodisalicylate was studied by equilibrium in vivo dialysis of feces to measure the therapeutically relevant concentrations of their metabolites (5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid) in free fecal water. After oral intake of sulfasalazine (2 g/day) the total luminal concentrations of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid determined by high-performance liquid chromatography were higher (median 14 mmol/L) than previously reported and almost doubled (median 25 mmol/L, p less than 0.05) when sulfasalazine was replaced by the same dose of azodisalicylate. In contrast, the corresponding serum concentrations were negligible. After administration of azodisalicylate to 12 healthy volunteers, a similar distribution of the metabolites was found. In nearly all cases, the concentrations of azodisalicylate in fecal dialysates were below the detection limit (6 mumol/L). We conclude, therefore, that oral azodisalicylate is a highly effective means of delivery of 5-aminosalicylic acid to the colonic mucosa. In addition, determination of the active metabolites in free fecal water seems important for the interpretation of results obtained in vitro concerning the mode of drug action.     

Sulphasalazine induced seminal abnormalities in ulcerative colitis: results of mesalazine substitution.

Seminal abnormalities are commonly found during sulphasalazine treatment. Although these changes appear reversible after drug withdrawal this may result in colitis relapse. Animal studies suggest that 5-aminosalicylic acid, the active component of sulphasalazine, does not impair fertility. Sixteen patients with quiescent ulcerative colitis were studied. Each patient produced three samples of semen at weekly intervals. Of the 48 samples analysed 39.6% showed oligospermia, 41.7% showed an increased number of abnormal forms and 91.7% showed impaired motility. Nine patients substituted enteric coated mesalazine (5-aminosalicylic acid) for sulphasalazine for a minimum period of three months. During this time one patient developed a salmonella associated colitis relapse; the others remained well. Improvement in sperm count (p less than 0.02), motility (p less than 0.001) and morphology (p less than 0.02) occurred in all cases. To date, four successful pregnancies have resulted, three in couples complaining of long term infertility. Treatment with enteric-coated mesalazine allows the recovery of seminal abnormalities induced by sulphasalazine in patients with colitis.     

Sulphasalazine and 5-aminosalicylic acid in long-term treatment of ulcerative colitis: report on tolerance and side-effects

BACKGROUND: Use of sulphasalazine in ulcerative colitis patients is hampered by a variety of side-effects, including male infertility. 5-aminosalicylic acid is better tolerated and has been increasingly used to treat patients intolerant/allergic to sulphasalazine but it may also be associated with side-effects. AIM: To evaluate tolerance of long-term treatment with sulphasalazine and 5-aminosalicylic acid in ulcerative colitis. METHODS: Side-effects to sulphasalazine (2-3 g/day) and 5-aminosalicylic acid (1.2-2.4 g/day) were recorded in 685 patients: 410 patients received only sulphasalazine, 130 only 5-aminosalicylic acid, and 145 both drugs. In patients with side-effects to sulphasalazine, a desensitisation protocol (rechallenge) was attempted to improve tolerance, and patients still presenting side-effects after desensitisation were switched to 5-aminosalicylic acid. Male fertility was also assessed in 42 males on sulphasalazine and on 5-aminosalicylic acid. RESULTS: Side-effects were observed in 110/555 patients (20%) on sulphasalazine and in 18/275 patients (6.5%) on 5-aminosalicylic acid during a median period of follow-up of 7 and 5 years, respectively. Desensitisation was achieved in 40% of patients intolerant to sulphasalazine. 5-aminosalicylic acid intake induced side-effects in 2/130 patients (1.5%) who had not taken sulphasalazine before versus 4/91 patients (4%) tolerating sulphasalazine and 12/54 patients (22%) intolerant/allergic to sulphasalazine, the difference in incidence of side-effects in the two latter groups being statistically significant (4.4% vs 20.8%, p=0. 001). Fertility was found to be affected in all patients on sulphasalazine but improved when put onto 5-aminosalicylic acid. CONCLUSIONS: 5-aminosalicylic acid should be considered the drug of choice in the treatment of ulcerative colitis bearing in mind that intolerance or allergy may occur in a few patients also on this drug.     

The contribution of sulphate reducing bacteria and 5-aminosalicylic acid to faecal sulphide in patients with ulcerative colitis

BACKGROUND: Butyrate oxidation within the colonocyte is selectively inhibited by hydrogen sulphide, reproducing the metabolic lesion observed in active ulcerative colitis. AIMS: To study generation of hydrogen sulphide by sulphate reducing bacteria (SRB) and the effects of 5-aminosalicylic acid (5-ASA) in patients with ulcerative colitis in order to identify a role of this noxious agent in pathogenesis. PATIENTS: Fresh faeces were obtained from 37 patients with ulcerative colitis (23 with active disease) and 16 healthy controls. METHODS: SRB were enumerated from fresh faecal slurries and measurements made of sulphate reducing activity, and sulphate and hydrogen sulphide concentrations. The effect of 5-ASA on hydrogen sulphide production was studied in vitro. RESULTS: All controls and patients with active ulcerative colitis carried SRB and total viable counts were significantly related to the clinical severity grade. SRB were of two distinct types: rapidly growing strains (desulfovibrios) which showed high sulphate reduction rates, present in 30% of patients with ulcerative colitis and 44% of controls; and slow growing strains which had little activity. In vitro, 5-ASA inhibited sulphide production in a dose dependent manner; in patients with ulcerative colitis not on these drugs faecal sulphide was significantly higher than in controls (0.55 versus 0.25 mM, p=0.027). CONCLUSIONS: Counts and carriage rates of SRB in faeces of patients with ulcerative colitis are not significantly different from those in controls. SRB metabolism is not uniform between strains and alternative sources of hydrogen sulphide production exist in the colonic lumen which may be similarly inhibited by 5-ASA. The evidence for hydrogen sulphide as a metabolic toxin in ulcerative colitis remains circumstantial.     

In vivo profiles of eicosanoids in ulcerative colitis, Crohn's colitis, and Clostridium difficile colitis

To compare the local release of arachidonic acid metabolites in inflammatory diarrheal disease, in vivo equilibrium dialysis of the rectum was done in consecutive untreated patients with ulcerative colitis (n = 20), Crohn's colitis (n = 10), and Clostridium difficile colitis (n = 7). All patients had endoscopically proven rectal inflammation. Eicosanoid profiles were determined in rectal dialysates by radioimmunoassay after preliminary purification. Concentrations of prostaglandin E2, prostaglandin F2 alpha, and thromboxane B2, but not 6-keto-prostaglandin F1 alpha, were raised in all groups and compared with healthy controls. The highest levels within each group were obtained in patients with widespread epithelial damage, as judged by endoscopy. In patients with ulcerative colitis, an extreme rise in prostaglandin E2 and thromboxane B2 were observed. Similarly, concentrations of leukotriene B4 were substantially increased in ulcerative colitis, but in Crohn's colitis and Clostridium difficile colitis only those patients with rectal ulcerations showed elevations. These findings probably reflect more severe tissue damages in ulcerative colitis, but differences between disease groups in cell-to-cell interaction may also contribute. The data suggest, therefore, that therapeutic inhibition of lipoxygenase pathways may prove more effective in ulcerative colitis than in Crohn's disease.     

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.     

Effects of topical 5-aminosalicylic acid and prednisolone on prostaglandin E2 and leukotriene B4 levels determined by equilibrium in vivo dialysis of rectum in relapsing ulcerative colitis

To determine the influence of inflammation and topical treatment with 5-aminosalicylic acid or prednisolone on arachidonic acid metabolism in vivo, we carried out a double-blind controlled study on the release of prostaglandin E2 and leukotriene B4 to the rectal lumen in 24 consecutive patients with proven distally located ulcerative colitis. Before and at days 15 and 29 a dialysis bag was placed in the emptied rectum for 4 h prior to assessing clinical, endoscopic, and histologic disease activity. A single enema was given daily at bedtime (1 g 5-aminosalicylic acid or 25 mg prednisolone) until complete remission or for a maximum of 4 wk. Clinical and endoscopic remission was obtained in 16 (7 on 5-aminosalicylic acid) and 11 (3 on 5-aminosalicylic acid) patients, respectively. Luminal concentrations of prostaglandin E2 and leukotriene B4 were positively correlated to disease activity and significantly decreased among the prednisolone-treated patients. In both treatment groups a decrease toward normal levels occurred in patients responding to therapy. In retrospect, the pretreatment prostaglandin E2 and leukotriene B4 levels were significantly higher in patients not responding to therapy than in those improving during treatment. In conclusion, luminal prostaglandin E2 and leukotriene B4 levels may prove more useful predictors of the outcome of treatment in relapsing ulcerative colitis than clinical indices of disease activity.     

Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis

BACKGROUND AND AIMS: There are limited evidence based data concerning the use of azathioprine in ulcerative colitis. We aimed to compare the efficacy of azathioprine and oral 5-aminosalicylic acid in inducing remission of steroid dependent ulcerative colitis. METHODS: Seventy two patients with steroid dependent ulcerative colitis were admitted to this investigator-blind study. Steroid dependence was defined as a requirement for steroid therapy > or =10 mg/day during the preceding six months, with at least two attempts to discontinue the medication. The disease had to be clinically and endoscopically active at study entry, and all patients were taking systemic prednisolone (40 mg/day). Patients were randomised to receive azathioprine 2 mg/kg/day or oral 5-aminosalicylic acid 3.2 g/day, for a six month follow up period. The outcome of the treatment was defined as (1) success, indicating induction of clinical and endoscopic remission and steroid discontinuation, or (2) failure, indicating the absence of clinical and endoscopic remission and therefore the need for at least one further cycle of systemic steroids to control symptoms, apart from the initial one, or colectomy. RESULTS: Significantly more patients in the azathioprine than in the 5-aminosalicylic acid group had clinical and endoscopic remission, and discontinued steroid therapy, both in the intention to treat (azathioprine v 5-aminosalicylic acid: 19/36 patients (53%) v 7/36 (21%); odds ratio (OR) 4.78 (95% confidence interval (CI) 1.57-14.5)) and per protocol (azathioprine v 5-aminosalicylic acid: 19/33 patients (58%) v 7/34 (21%); OR 5.26 (95% CI 1.59-18.1)) analysis. CONCLUSIONS: Azathioprine is significantly more effective than 5-aminosalicylic acid in inducing clinical and endoscopic remission and avoiding steroid requirement in the treatment of steroid dependent ulcerative colitis.     

5-Aminosalicylic acid enemas: effective agent in maintaining remission in left-sided ulcerative colitis

The efficacy of 5-aminosalicylic acid enemas in maintaining remission in left-sided ulcerative colitis was studied. Twenty-five patients in remission for at least 2 mo were randomized to receive either 1-g 5-aminosalicylic acid or placebo enemas daily and were followed up for 1 yr. Eleven of 13 patients randomized to placebo relapsed after a mean of 16 wk. Nine of 12 patients randomized to 5-aminosalicylic acid remained in remission for 1 yr, 2 others in remission withdrew by request, and 1 relapsed at 10 wk. The difference between relapse rate on 1-g 5-aminosalicylic acid versus placebo was significant (p less than 0.005). Seven patients entered the blinded trial a second time. Three of 4 patients randomized to 5-aminosalicylic acid remained in remission and 1 relapsed. Three randomized to placebo relapsed at a mean of 14 wk. One-gram 5-aminosalicylic acid enemas are safe and effective in maintaining remission in patients with left-sided ulcerative colitis.     

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.     

Clinical experience of the tolerance of mesalazine and olsalazine in patients intolerant of sulphasalazine

We assessed the tolerance and safety of two new preparations designed to release 5-aminosalicylic acid in the colon in patients with ulcerative colitis who were intolerant of sulphasalazine. Twenty-eight of 37 patients (76%) given mesalazine and 18 of 21 patients (86%) given olsalazine tolerated the new preparations with no adverse effects. No haematologic or biochemical abnormalities were detected. Adverse reactions to the new preparations were usually but not always similar to those they had previously encountered with sulphasalazine, but a few patients experienced rash and diarrhoea. In some patients intolerant of one of the new preparations, their tolerance of the other was assessed. Three patients intolerant of mesalazine tolerated olsalazine. Similarly, three other patients intolerant of olsalazine tolerated mesalazine. We conclude that not all adverse effects of sulphasalazine are due to the sulphapyridine part of the molecule. Some are due to the released 5-aminosalicylic acid and some to the parent compound. Both drugs are likely to prove useful in the management of patients intolerant of sulphasalazine.     

Use of colonic eicosanoid concentrations as predictors of relapse in ulcerative colitis: double blind placebo controlled study on sulphasalazine maintenance treatment.

To establish whether concentrations of eicosanoids determined by equilibrium in vivo dialysis of faeces and equilibrium in vivo dialysis of rectum might predict a relapse in ulcerative colitis, 23 patients with completely inactive disease, maintained on sulphasalazine, stopped treatment and entered a prospective study. Concentrations of prostaglandin E2 were determined by radioimmunoassay on purified faecal and rectal dialysates at entry, at two weeks, and at two, six, and 12 months. If the above concentrations exceeded control concentrations (0.5 ng/ml and 1.0 ng/ml in faecal and rectal fluid, respectively) at any study day, the patient was allocated at random to double blind treatment with sulphasalazine 2 g/day, or placebo for six months. A relapse, defined as recurrence of symptoms accompanied by endoscopic inflammation occurred in none of six and in four of five patients allocated to sulphasalazine and placebo, respectively (p less than 0.05). In no case a normal rectal prostaglandin E2 concentration was associated with a relapse in the short term, but only two of 12 patients observed passively remained in remission. In retrospect, leukotriene B4 was a less sensitive predictor of relapse than prostaglandin E2. We conclude that raised concentrations of prostaglandin E2 in rectal dialysis fluid identify patients with a substantial risk of relapse.     

Experience with topical administration of 4-aminosalicylic acid in ulcerative colitis

4-Aminosalicyclic acid was applied topically in a daily dose of 1.4 gm for two weeks in ten patients with ulcerative colitis. After favorable results, the therapeutic effects of 4-aminosalicylic acid and salazopyrin enemas were compared in a two-week cross-over open trial, in 20 patients suffering from recurrent ulcerative colitis involving the rectum and rectosigmoid. No significant difference was found in the changes of the endoscopic picture of the mucosa. The results did not show a significant difference between 4-aminosalicylic acid and salazopyrin enemas, either in the clinical activity or in the histologic picture. 4-Aminosalicylic acid seems to be a suitable drug for improving the clinical symptoms of ulcerative proctitis.     

Olsalazine or sulphasalazine in first attacks of ulcerative colitis? A double blind study.

Olsalazine (2 g/day) and sulphasalazine (3 g/day) were compared in a double blind three centre trial in 37 patients presenting with first attack of distal colitis. Sigmoidoscopic appearances, rectal biopsies, and symptom and stool diary records were used to assess benefit and adverse effects. Both groups showed a similar decrease in stool frequency (p less than 0.001). The proportion of unformed stools was also decreased, but to a lesser extent (p less than 0.05) in those taking olsalazine (78% v 55%; p less than 0.001) compared with those taking sulphasalazine (72% v 28%; p less than 0.001). There was a diminution in the proportion of stools containing blood in both groups (olsalazine: 61% v 22%; p less than 0.001/sulphasalazine: 67% v 37%; p less than 0.001). Sigmoidoscopic and histological appearances and clinical activity improved significantly and to a similar extent in both groups. Intolerance was encountered in two patients on olsalazine and four on sulphasalazine; intolerance to sulphasalazine being even higher (five of seven patients) in a preliminary study using a dose of sulphasalazine releasing the same amount of 5-aminosalicylic acid as 2 g olsalazine. Olsalazine was at least as effective as sulphasalazine in the treatment of new patients with distal colitis, and in a dose releasing an equivalent amount of 5-aminosalicylic acid was better tolerated.