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Olsalazine and sulphasalazine were compared in a double-blind, double-dummy trial in the prevention of relapse of ulcerative colitis over 6 months. The majority were taking sulphasalazine. They were randomized to receive either olsalazine, 500 mg b.d., or sulphasalazine, 1 g b.d. Of 82 patients, 16 relapsed on olsalazine compared with 10 of 82 on sulphasalazine. This difference was not statistically significant (p = 0.16). Twenty-one patients reported adverse events in the olsalazine group, of whom 16 were withdrawn, while 20 patients reported adverse events in the sulphasalazine group, with 9 of them being withdrawn. The differences were not statistically significant. No major haematological or biochemical abnormalities occurred. Thus, olsalazine is similar to sulphasalazine for the prevention of relapse of ulcerative colitis.

Olsalazine, 1 g/day, was administered orally for up to 9 months to 30 patients with ulcerative colitis in varying stages of activity. Olsalazine appeared to be effective in patients in remission and in those with mild to moderate disease activity, but did not appear to alter the clinical course in four patients with severely active disease. No significant side-effects were noted and no patient had to discontinue the drug. The low incidence of diarrhoea may be attributable to the dose which reduces local gut olsalazine/5-ASA concentrations. The imminent introduction of a tablet formulation may obviate this problem and encourage compliance with a twice-daily dosage. Olsalazine is well tolerated across the activity spectrum in ulcerative colitis, and this study suggests useful efficacy in maintaining remission and in controlling mild and moderate disease activity.

Fifty patients with ulcerative colitis, intolerant of sulphasalazine, were treated with 500 mg olsalazine twice daily for a 3-month trial period. Thirty-eight of the patients (76%) tolerated the drug well, and all continued to take it beyond the 3-month period. Twelve (24%) were withdrawn because of side effects, the commonest being diarrhoea. There were no haematologic or biochemical abnormalities. Thus, olsalazine is a useful drug for patients who are intolerant of sulphasalazine.

Strong evidence has been accumulating that mesalazine (5- aminosalicylic acid, 5-ASA) represents the therapeutic moiety of the standard drug sulphasalazine. Since the active metabolite avoids the toxic potential of sulphapyridine, this perception has initiated new therapeutic approaches, for example, two 5-ASA molecules have been coupled to form another prodrug (olsalazine) which again depends on a proper cleavage of the azobond by bacteria in the colon A more direct way has been applied successfully by administering 5-ASA itself in special galenic formulation (suppositories, enemas, controlled release preparations) to provide enough active material at the proposed sites of action in the terminal ileum and/or colon. One major advantage of all 5-ASA compounds, compared to sulphasalazine, is their 10-fold lower potential (incidence) for inducing allergic reactions or causing intolerance. Aside from rare hypersensitivity reactions, 5-ASA can cause nausea. vomiting, headache and gastrointestinal disturbances in 1 to 5% of patients. However, the new azocompound olsalazine induced diarrhea or loose stool in at least 10 to 15% of the treated patients which might limit its use in inflammatory bowel disease (IBD). In conclusion, the ‘old’ metabolite 5-ASA, in a ‘new’ design, offers an effective and very safe choice for the treatment of IBD.

Sulphasalazine is widely used in the maintenance treatment of ulcerative colitis but the optimum dose is not known. In the present study, 170 patients were allotted at random to three treatment groups, in which the daily dose was 1, 2 and 4 g respectively, and the trial period of treatment lasted for six months. A daily dose of 2 g was found to be much more efficacious than 1 g. A daily dose of 4 g was more efficacious than 2 g but at the price of fairly frequent symptomatic side-effects. Haematological abnormalities were observed at all dosage levels, but they occurred chiefly among the patients on 4 g daily. Both symptomatic and the haematological side-effects were usually associated with high concentrations of serum sulphapyridine and these high levels occurred chiefly among the slow acetylators. It is concluded that, for general use, a daily dose of 2 g sulphasalazine is satisfactory for the maintenance treatment of ulcerative colitis. If a patient does not do well on 2 g daily, it is worth trying a larger dose but in this case the patient's condition should be monitored by blood film, haemoglobin, MCV, and reticulocyte count.

Olsalazine sodium (5,5'-azodisalicylic acid (OLZ] was given to eight healthy volunteers as a 10 mg i.v. bolus dose and as a 1 g oral dose with and without food. To five fasting participants single oral doses of 2 g and 4 g were given. Blood and urine were collected during three weeks after each dose and were assayed for OLZ, a conjugate identified as a sulphate of OLZ (OLZs), 5-aminosalicylic acid (5-ASA), and N-acetyl-5-aminosalicylic acid (ac-5-ASA). The study showed that: 1. OLZ had a very short elimination half-life, mean 56 min. 2. OLZ was absorbed from the intestinal tract to a very small extent, as seen from the low systemic availability and low urinary excretion, 2.3% and 0.31% respectively, for a 1 g dose taken fasting. 3. OLZ was present in the serum partly as a conjugate, which was identified as an O-sulphate. Following the i.v. dose the serum half-life of the O-sulphate was estimated to be 7 days. 4. Food intake did not influence the systemic availability of OLZ and ac-5-ASA. 5. There was no dose-dependent increase of OLZ absorption with single doses up to 2 g, but a 4-g dose showed a more than two-fold increase in the individual peak serum concentration and in the systemic availability of OLZ. However, there was no significant increase in the mean residence time (MRT) for OLZ or in the serum concentration of either 5-ASA or ac-5-ASA at a dose of 4 g.

The discovery of an acid labile metabolite of olsalazine, tentatively identified as olsalazine-O-sulphate, is described. Due to its acid labile properties, this conjugate was previously co-determined with olsalazine. Based on this finding, a new assay has been developed making it possible to determine both olsalazine and olsalazine-O-sulphate simultaneously. The initial aim of this study was to simplify an original analytical method in order to improve sample throughput without loss of sensitivity. However, during this work, a previously unidentified acid labile metabolite was discovered. The characterization of this metabolite is described here.

Olsalazine (azodisalicylate) is a new drug in which two molecules of 5-aminosalicylic acid are linked by an azo bond. Its role in the treatment of mildly active, distal ulcerative colitis was investigated. Sixty patients were randomly allocated to receive olsalazine 1 g or a placebo as a retention enema nightly for two weeks. Clinical improvement was seen in 19 (66%) and sigmoidoscopic improvement in 17 (59%) of the 29 patients receiving olsalazine compared with 12 (43%) and 11 (39%), respectively, of the 28 in the control group. These differences were not significant. In a second trial 40 patients were randomised to receive oral olsalazine 2 g daily or a placebo capsule for two weeks. Significant clinical and sigmoidoscopic improvement was seen in the patients receiving oral olsalazine compared with the patients receiving placebo capsules. Oral olsalazine may be valuable in the treatment of mildly active ulcerative colitis. Its role in maintaining remission is yet to be determined.

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.

The effect of olsalazine on stool output and the transit of a solid radiolabelled meal through the stomach, small intestine and colon was studied in six patients with ulcerative colitis intolerant of sulphasalazine. Olsalazine 250 mg four times daily significantly accelerated gastric emptying (mean +/- SD; 45.3 +/- 24.2 min v 67.3 +/- 33.1 min, p less than 0.05), mouth to caecum transit time (242 +/- 41 min v 325 +/- 33 min, p less than 0.02) and whole gut transit time (60.5 +/- 26 h v 37.8 +/- 17.8 h, p less than 0.05). No significant changes were seen in mean daily stool weight (215 +/- 41 g v 162 +/- 62 g) and mean daily stool frequency (2.2 +/- 0.6 v 2.4 +/- 1.8). None of these patients developed diarrhoea, but acceleration of gastric and intestinal transit may be responsible for the diarrhoea reported in some patients taking this drug.

The efficacy, safety and disposition of olsalazine was assessed in patients with left-sided ulcerative colitis or proctitis in a double-blind placebo controlled trial. Thirty patients with a mild-to-moderate attack of ulcerative colitis were randomly allocated to olsalazine capsules, 1 g b.d., or placebo for 6 weeks. Good clinical response was found in six patients receiving olsalazine and in two receiving placebo. Improvement in sigmoidoscopic findings and histological appearance of rectal biopsies was also seen more often in olsalazine-treated patients. Plasma concentrations of olsalazine were significantly higher in patients who improved. Olsalazine showed an advantage over placebo which needs to be confirmed by further studies; it was safe in sulphasalazine-sensitive patients but appeared to cause watery diarrhoea in two patients.

The optimal dose of olsalazine was evaluated in 37 patients with active ulcerative colitis. (16 had mild and 21 had moderate disease.) They were randomized to two groups - olsalazine, 2 g (Group A, 17 patients) and 3 g (Group B, 20 patients). The drug was administered orally at 0.5 g/day initially, then increased to 2 or 3 g/day after 1 week and continued for a further 4 weeks. Corticosteroids or immunosuppressants were not used. Group A consisted of 4 patients with total colitis, 10 with left-sided disease and 3 with proctitis, and group B of 7, 11 and 2, respectively. Efficacy was evaluated by number and consistency of stools, presence of blood and mucus, laboratory data and endoscopic examination. In group A, ten cases (59%) improved clinically, 6 were unchanged and 1 was exacerbated, and in B, the number of cases were 11 (55%), 5 and 4, respectively. The clinical improvement was confirmed by endoscopic examination in the 5th week. Diarrhoea was a common side-effect: 4 cases (24%) in group A and 9 (45%...

Olsalazine is a new drug for the treatment of ulcerative and Crohn's colitis. The toxicological, pharmacological and pharmacokinetic profiles of olsalazine are excellent; the only side-effect noted from clinical trials with olsalazine is an increased incidence of loose stools and occasional diarrhoea. At high olsalazine concentrations, a direct effect on the net water absorption of the intestine is apparent. This effect is not due to a decrease in absorption, but to an induction of a rapidly reversible, Cl- dependent water secretion. In rats experimentally subjected to olsalazine induced diarrhoea (150 mg/kg), a total adaptation occurs within 3-4 days. This adaptation is not due to tachyphylaxis, but to an increased absorption capacity in the colon and caecum. Similar adaptation has been noted in other species including man.

Fifty-six patients with ulcerative colitis of mild to moderate severity were entered into a randomized, double-dummy comparison of sulphasalazine, 3 g/day, with olsalazine, 3 g/day. Patients were assessed clinically, and by sigmoidoscopy and biopsy, on entry and at 5 weeks. Both agents produced a similar reduction in stool frequency and in the passage of blood and mucus. Improvements in sigmoidoscopic and histological appearances of the rectal mucosa were observed to a similar extent in both groups of patients. Two patients treated with olsalazine were withdrawn because of increased diarrhoea attributable to the medication. Two patients given sulphasalazine for the first time developed a skin rash. Other side-effects seen during the trial were mild. In this small short-term study, oral olsalazine appeared to be as effective as sulphasalazine in the treatment of mild to moderate ulcerative colitis.

After a single dose of olsalazine, the maximum serum concentration of the intact compound is much lower than after an equivalent dose of sulphasalazine. In both compounds the diazo bond is largely split by colonic bacteria and comparable amounts of the metabolites 5-ASA and acetyl-5-ASA are recovered in the faeces. During long-term ingestion of olsalazine, 1-4 weeks are required to reach a steady state, and serum concentrations of the parent drug are low. It is demonstrated that olsalazine is rapidly sulphated into the metabolite, olsalazine-O-sulphate, which has a long half-life. Acetyl-5-ASA is more stable and more soluble than 5-ASA; however, the therapeutic efficacy of acetyl-5-ASA in inflammatory bowel disease is not proven.

Sulphasalazine, devised by Dr Nana Svartz for the treatment of 'infective polyarthritis', has been used in the treatment of inflammatory bowel disease for more than 40 years. Many controlled trials have shown that sulphasalazine 4g daily will induce remissions in between one-half and three-quarters of patients with acute attacks of ulcerative colitis. When given in a dosage of 2g daily it will prevent relapses in quiescent colitis. Relapses are 5 times more likely in untreated patients. It is less effective in Crohn's disease, where it exerts only a transient benefit in patients with active colonic disease and fails to prevent relapse or recurrence. Sulphasalazine is absorbed from the small intestine, re-excreted in bile and carried to the colon, where its azo bond is split by bacteria to release sulphapyridine, which is absorbed and is responsible for most of the drug's side effects, and 5-aminosalicylic acid, which is the active therapeutic moiety of the drug and exerts a beneficial topical action on the colonic mucosa. Side effects are common but are mainly reversible and not serious. Those related to high concentrations of sulphapyridine and to poor acetylation of the drug include gastrointestinal intolerance, malaise, headache, arthralgia, drug fever, effects on red blood cells and reversible male infertility. More serious, idiosyncratic side effects are skin rashes, leucopenia and agranulocytosis. Rarely, neurotoxicity, hepatotoxicity, polyarteritis, pulmonary fibrosis, a lupus-like syndrome and haemorrhagic colitis are produced. It is possible to desensitise most patients with drug-induced skin rashes. A number of less toxic alternatives to sulphasalazine have been devised and are undergoing trial. They either convey 5-aminosalicylic acid in a coated tablet to the colon or, when conjugated to a non-toxic carrier, release 5-aminosalicylic acid by bacterial cleavage there. Sulphasalazine remains a most useful drug in the treatment of inflammatory bowel disease after 40 years of use.

This study is a double-blind controlled trial in 86 patients of the efficacy of retention enemas containing 4 g 5-aminosalicylic acid (5-ASA), believed to be the active metabolite of sulphasalazine, compared with retention enemas of 100 mg of hydrocortisone for the topical treatment of mild or moderate ulcerative colitis. 5-ASA enemas given to 44 patients were significantly more effective than hydrocortisone enemas given to 42 patients, and produced 93, 93, and 77% remission in clinical, sigmoidoscopic, and histological terms, respectively, compared with corresponding remission rates of 57, 54, and 33% in the hydrocortisone treated patients.

The stability of disodium azodisalicylate, 5-aminosalicylic acid and acetyl-5-aminosalicylic acid dissolved in distilled water and in urine or mixed with faeces to which HgCl2 was added, was studied at -20 degrees C, 4 degrees C and room temperature.In water, no marked differences were found between the three storage regimens. In urine, disodium azodisalicylate and acetyl-5-aminosalicylic acid were stable, while the 5-ASA concentration decreased when stored at 4 degrees C and room temperature. In faeces stored during seven days, a marked decrease in 5-aminosalicylic acid concentration to about zero was found when it was kept at 4 degrees C and room temperature. No marked change in the concentration of disodium azodisalicylate and 5-aminosalicylic acid added to the faeces-HgCl2-mixtures appeared.

To examine the tolerance and pharmacokinetics of long-term olsalazine administration, increasing doses of the drug were given to 31 patients with ulcerative colitis. All patients were refractory to or intolerant of sulphasalazine. Complete azo-reduction occurred in most cases. Concentrations of 5-ASA, but not acetyl-5-ASA, in faecal dialysates increased dose-dependently. Estimates of efficacy were more favourable among those intolerant of sulphasalazine. Patients with high prostaglandin E2 levels determined by equilibrium in vivo dialysis of rectum were less likely to benefit from treatment. In conclusion, olsalazine is a highly effective means of delivering 5-ASA to the colonic mucosa. Long-term use of olsalazine in controlled trials may be considered safe, even in high doses.

In the treatment of inflammatory bowel disease the main anti-inflammatory component of sulphasalazine is 5-ASA. Based on the same azo-splitting principle in the colon as sulphasalazine, the new drug olsalazine was developed. Olsalazine consists of two 5-ASA molecules joined by an azo bridge. Pharmacokinetic studies have shown that on oral administration there is little systemic absorption of olsalazine. Almost the whole dose passes into the colon, where the olsalazine is completely split into 5-ASA and subsequently excreted in faeces and urine. It can be concluded that from all toxicological and pharmacological aspects, olsalazine is a safe drug. Olsalazine will present the colonic mucosa with twice the amount of 5-ASA/unit compared with sulphasalazine (the present drug of choice) without concomitant delivery of sulphapyridine, which is believed to carry most of the drug's side-effects. Thus, olsalazine seems to be a suitable drug for long-term treatment of ulcerative colitis in man.

Experience of 804 patients treated with olsalazine has shown that this new 5-ASA based drug has a safe clinical profile and good tolerance. The only common side-effect was loose stools or overt diarrhoea, which necessitated withdrawal of the drug in 6.3% of the patients.

Olsalazine is a novel compound presently under development for the treatment of ulcerative colitis. Olsalazine sometimes causes diarrhoea; one of the possible explanations could be an increased load of bile acids in the colon. Bile acid ileostomy output was therefore measured enzymatically and after oral administration of tauro-23-[75Se]selena-25-homocholic acid (SeHCAT) in eight subjects during intake of placebo or olsalazine. The bile acid output showed great individual variations during both treatment periods, but there was no indication that olsalazine interfered with bile acid handling in the terminal ileum.

The knowledge that 5-aminosalicylic acid (5-ASA) is the active compound of sulphasalazine and that it acts topically has stimulated the use of 5-ASA containing enemas and ocher similar compounds such as olsalazine and 4-aminosalicylic acid (4-ASA). 5-ASA enemas have been shown to be effective in controlling active disease in clinical trials and have also been shown to be of benefit in prevention of relapses. Olsalazine enemas have not demonstrated significantly better results than placebo 4-ASA enemas are effective but the results obtained have differed as to effective dose

Purified intestinal macrophages obtained at resections for colonic neoplasms were investigated for chemotaxis to leukotriene B4 (LTB4) by the Millipore filter assay and leading front technique. Possible inhibition by drugs effective in the treatment of chronic inflammatory bowel disease (sulphasalazine, olsalazine, its active moiety 5-aminosalicylic acid (5-ASA), and the 5-ASA metabolite N-acetylated-5-ASA (ac-5-ASA)) was tested at therapeutic colonic concentrations of 0.01-10 mM. Leukotriene B4 at a dose of 10 nM was equipotent with casein (5 g litre-1) as regards chemoattraction of macrophages. Sulphasalazine, olsalazine and 5-ASA were potent inhibitors of macrophages chemotaxis to LTB4 with IC50 values of 0.43, 0.39 and 0.24 mM, respectively. These concentrations are below the lowest concentration of 5-ASA (2 mM) in the colonic lumen during conventional sulphasalazine treatment of patients with chronic inflammatory bowel disease. The inhibition of macrophage chemotaxis by these drugs may be important for this limitation of the local inflammatory process in chronic inflammatory bowel disease, and may in part explain the beneficial effect of systemic and local treatment with sulphasalazine. Leukotriene B4 appears to be an important inflammatory mediator for the activation of macrophages in colonic inflammation.

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Twenty-three patients with serious side-effects due to sulphasalazine were treated with olsalazine, a novel 5-ASA compound. Side-effects were attributed to an allergic reaction in 16 patients. Five male patients had impaired sperm quality with infertility. One patient had leucopenia, and one had eosinophilic pneumonitis. None of these side-effects was seen during treatment with olsalazine. The sperm quality of the men improved, and four of their wives became pregnant. In two patients, olsalazine was discontinued because of severe diarrhoea. Olsalazine seems to be a safe drug in the treatment of chronic inflammatory bowel disease.

Olsalazine, 2 g/day, was compared with placebo in 126 patients with mild or moderate ulcerative colitis. Evaluation after 4 weeks revealed a significant improvement in endoscopic findings in the rectum and sigmoid colon and in the clinical parameters rectal mucus and blood discharge, whereas no significant difference was found between olsalazine and placebo groups in clinical parameters, such as stool frequency and consistency, urge to defecate, abdominal pain and biopsy findings. It is concluded that olsalazine, 2 g/day, is tolerated as well as placebo except that it caused diarrhoea in some patients.

Circulating lymphocytes and their subpopulations were counted using monoclonal antibodies in an immunofluorescence assay. No differences were found, during or after the course of olsalazine, in white cell count, the number and proportion of circulating lymphocytes, T lymphocytes, B lymphocytes, helper-type T cells or suppressor-cytotoxic-type T cells. The helper-type T cell to suppressor-cytotoxic-type T cell ratio did not alter significantly when subjects were taking olsalazine. These results are similar to those found in patients taking sulphasalazine, and suggest that olsalazine does not exert its effect by quantitative alteration of circulating immune cells.

This is an interim report of an ongoing non-comparative, open study of olsalazine in patients with proven ulcerative colitis. A total of 78 patients have so far been entered into this study between December 1985 and December 1986. Follow-up data are currently available in the first 59 patients (34 males; age range 17-75 years; mean age 46 years). The patients were given a mean initial daily dose of olsalazine, 1.4 g, as gelatine capsules for a mean duration of 4 months. Some patients were either in remission or had active colitis not requiring hospitalization. Other patients were either not in full remission (30 patients), experienced unacceptable side-effects on current medication (18 patients) or, in the opinion of the investigator, had the capacity to benefit from olsalazine treatment (19 patients). Of 59 patients, 21 were taking concomitant steroids (usually by enema) at the start, and subsequently as required. Of the 59 patients, 49 (83%) remain on olsalazine (dose range 0.75-3 g/day). Currently, 17 ...

Among the general population of patients with ulcerative colitis, there exists a group who are intolerant or allergic to sulphasalazine. The two major metabolites of sulphasalazine are 5-aminosalicylic acid (5-ASA) and sulphapyridine. Sulphapyridine is thought to be responsible for the majority of adverse reactions. It is generally accepted that 5-ASA is primarily responsible for the therapeutic effects in active ulcerative colitis. Olsalazine consists of two salicylate molecules linked together at the 5-position by a diazo bond and is split by colonic bacteria to liberate 5-ASA. Eleven patients (six males, aged 19-67 years, median age 30 years) with active ulcerative colitis, intolerant to sulphasalazine, were entered in an open, uncontrolled trial of olsalazine. With regard to the extent of disease, 3 had proctitis, 6 had distal colitis and 2 had extensive or total ulcerative colitis. Olsalazine, 1 g/day, was given for 4 weeks. Results were as follows:No serious side-effects were seen, but 3 patients ex...

Olsalazine has been observed to induce diarrhoea in 4.9% of patients. In vivo trials in rat ileum and colon suggest stimulation of secretion by olsalazine. The in vitro effect of olsalazine was examined on active anion secretion by rabbit distal ileum compared to sulphasalazine and 5-aminosalicylic acid (5-ASA). Rabbit terminal ileal strips were mounted in Ussing chambers, and the mucosal and serosal surfaces were selectively exposed to 3.0, 5.0, 1.0, 0.1 and 0.001 mM of olsalazine, sulphasalazine and 5-ASA. The maximal short circuit current (Isc, a measure of active anion secretion) was determined for each concentration. Olsalazine significantly stimulated anion secretion at concentrations above 0.001 mM with a more pronounced effect (approximate ED50 of 0.5 mM) when added to the mucosal surface. In contrast, sulphasalazine and 5-ASA demonstrated no secretory effect. Additional studies of transmucosal fluxes and chemical mediation of these effects are in progress and will be reported. Olsalazine stimulat...