J. H. M. Van Tongeren

An index of inflammatory activity in patients with Crohn's disease.

An objective and quantitative standard of inflammatory activity for patients with Crohns disease was developed. This Activity Index (AI) was derived from data of 63 patients with Crohns disease who had been submitted to a total of 85 clinical examinations. On the basis of 18 predictor variables three physicians gave an overall evaluation of the severity of inflammatory activity in each patient. Stepwise multiple regression analysis was used to investigate which combination of variables contributed most to the overall evaluation. The combination of the following nine variables gave a very good correlation (r = 0.95) with the overall evaluation: serum albumin, ESR, body weight related to length, abdominal mass, sex, temperature, stool consistency, bowel resection, and extraintestinal symptoms related to Crohns disease. This combination of variables expressed in a score that was used as an activity index proved to be very useful in the assessment of disease activity and of the effect of therapy. Index values below 100 are associated with inactive disease, values between 100 and 150 can be regarded as indicating slight inflammatory activity, values between 150 and 210 as indicating moderate, and values above 210 as indicating severe-to-very-severe inflammatory activity.

Effect of sulphapyridine, 5-aminosalicylic acid, and placebo in patients with idiopathic proctitis: a study to determine the active therapeutic moiety of sulphasalazine.

Suppositories of sulphapyridine, 5-aminosalicylic acid, and placebo were used in 45 patients with idiopathic proctitis to determine the active part of sulphasalazine. Each patient used one of the suppositories twice daily for four weeks in a double-blind controlled trial. Complete clinical remission with normal rectal mucosa on sigmoidoscopy occurred in 60% of patients given 5-aminosalicylic acid, but in only 13% and 27% of those given sulphapyridine and placebo respectively. Twelve patients were included twice. In eight of these patients 5-aminosalicylic acid was given one time and sulphapyridine (two patients) or placebo (six patients) another time. Clinical remission occurred in each patient with 5-aminosalicylic acid, but in only one patient during other therapy. The results suggest that 5-aminosalicylic acid is the active therapeutic moiety of sulphasalazine.

Effect of sulphasalazine in patients with active Crohn's disease: a controlled double-blind study.

The response of active Crohns disease to sulphasalazine (4-6 g per day) has been studied in a placebo-controlled trial. The study was carried out at two hospitals. From August 1977 to August 1979 all patients with established Crohns disease were examined for their eligibility for the trial. A nine-item index of inflammatory activity was used as the primary measure of response. The variables in this index were serum albumin, ESR, body weight released to height, abdominal mass, temperature, stool consistency, bowel resection, and extraintestinal symptoms related to Crohns disease. A favourable response to therapy was defined as a decrease of the activity index with 25% or more at the end of the trial period, compared with the initial value. Twenty-six patients (13 in each treatment group) have been followed up for six months. The response of active Crohns disease to sulphasalazine was significantly better than to placebo.

Methods and Procedures

Albumin concentration in serum was determined electrophoretically with cellulose acetate as vehicle (483). Since this method involves the use of amido-black which binds more strongly to albumin than to the globulin fractions, the values given are relatively high. Controls (n = 32): 45.8–55.1 g/1.

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 disodium azodisalicylate in healthy subjects. A possible new drug for inflammatory bowel disease.

The disposition of disodium azodisalicylate and salicylazosulfapyridine was studied in 6 healthy volunteers. After a single oral dose (1.0 g disodium azodisalicylate; 2.3 g salicylazosulfapyridine) maximum serum concentrations of the intact compound ranged between 1.4 and 6.8 mumol/L and 32 and 114 mumol/L, respectively. Mean residence time and serum half-life of disodium azodisalicylate were considerably longer than those of salicylazosulfapyridine, probably because of a higher apparent volume of distribution. Both compounds were largely split by colonic bacteria and comparable amounts of the active moiety, (acetyl-)5-aminosalicylic acid, were recovered in feces. During long-term ingestion of disodium azodisalicylate (1.0 g/day) it took 6-19 days to reach a steady state. Serum concentrations of disodium azodisalicylate at steady state were low: 2.2-8.4 mumol/L. The serum half-life was 6-10 days. It is concluded that the disposition of disodium azodisalicylate is similar, in important respects, to that of salicylazosulfapyridine. Disodium azodisalicylate, therefore, deserves therapeutic trial.

Double‐blind comparison of 5‐aminosalicylic acid and acetyl‐5‐aminosalicylic acid suppositories in patients with idiopathic proctitis

Suppositories containing 300 mg 5‐aminosalicylic acid (1.96 mmol) or 425 mg acety1‐5‐aminosalicylic acid (1.96 mmol) were used in 40 patients with idiopathic proctitis to determine the efficacy of acetyl‐5‐aminosalicylic acid in treating this bowel inflammation. Each patient was treated with 5‐aminosalicylic acid or acetyl‐5‐aminosalicylic acid suppositories twice daily for 4 weeks in a double‐blind trial. Four patients were included twice in the trial. The second time they were treated with the alternative regimen. Six patients in the acetyl‐5‐aminoscylic acid group did not complete the trial, four of them because of diarrhoea. Complete clinical remission with normal rectal mucosa on sigmoidoscopy was achieved in 10 out of 18 patients on 5‐aminosalicylic acid and in only two out of 15 in the acetyl‐5‐aminosalicylic acid group (P= 0.03). A favourable histological improvement was demonstrated with 5‐aminosalicylic acid suppositories, but the difference with acetyl‐5‐aminosalicylic acid was not significant (P= 0.059). Three of the four patients who received both drugs recovered with 5‐aminosalicylic acid; in none of them was acetyl‐5‐aminosalicylic acid effective. The results from this study and from previous investigations show that acetyl‐5‐aminosalicylic acid is not superior to placebo.

Influence of intestinal transit time on azo-reduction of salicylazosulphapyridine (Salazopyrin).

During a normal and an accelerated intestinal transit, in seven healthy volunteers, the recoveries of salicylazosulphapyridine (SASP) and its split products sulphapyridine (SP) and 5-aminosalicylic acid (5-ASA) were determined in urine and faeces. The azo-reduction of SASP and consequently the recovery of 5-ASA in the faeces was found to be substantially decreased during an accelerated intestinal transit. In addition, in 18 patients with inflammatory disease of the colon during maintenance therapy of SASP it could be demonstrated that the serum SP levels were related to the diarrhoeal state and did not correlate with disease activity. As recent studies have reported that 5-ASA is possibly the active therapeutic moiety of SASP, the ineffectiveness of SASP therapy in patients with active colitis may be ascribed to the reduced azo reduction of SASP as the result of profuse diarrhoea.

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.

Disposition of 5-Aminosalicylic Acid from 5-Aminosalicylic Acid-Delivering Drugs during Accelerated Intestinal Transit in Healthy Volunteers

In eight healthy volunteers accelerated intestinal transit time was induced with bisacodyl, and urinary and faecal excretion of sulphasalazine, olsalazine, 5-aminosalicylic acid (5-ASA), and acetyl-5-ASA was studied after a single oral dose of 3.3 mmol sulphasalazine, olsalazine, Pentasa, and Salofalk and 2.6 mmol of Asacol. The faecal and urinary excretion of acetyl-5-ASA was lowest after intake of sulphasalazine and olsalazine and highest after intake of Pentasa and Salofalk. The figures for Asacol were intermediate. This indicates insufficient release of 5-ASA from sulphasalazine and olsalazine. When the results of this study are compared with those of a previous study without accelerated transit time, the disposition of 5-ASA from all the 5-ASA-delivering drugs is influenced unfavourably by an accelerated gut transit but most pronounced in the case of sulphasalazine, olsalazine, and Asacol. The impaired release from the azo compounds sulphasalazine and olsalazine is a result of far less complete splitting of the diazo bond.