Karlernst Maier

Therapeutic Efficacy of Sulfasalazine and Its Metabolites in Patients with Ulcerative Colitis and Crohn's Disease

We studied the therapeutic efficacy of sulfasalazine and its metabolites sulfapyridine and 5-aminosalicylic acid in nine patients with Crohns disease and in 23 patients with ulcerative colitis. In a randomized, controlled trial, we treated 11 patients for six weeks with 1 g of sulfasalazine three times a day, seven patients with 0.5 g of sulfapyridine three times a day, and 14 patients with 0.5 g of 5-aminosalicylic acid suppositories three times a day. The clinical state of the disease was characterized by an activity index, quality of stool, and remission rate. In addition, we monitored plasma levels of sulfapyridine, 5-aminosalicylic acid, and their acetylated metabolites. The initial activity index (mean +/- S.D.) was significantly reduced by sulfasalazine (from 245 +/- 129 to 100 +/- 71; P < 0.001) and by 5-aminosalicylic acid (from 251 +/- 65 to 90 +/- 93; P < 0.0001), but sulfapyridine was without benefit. Stool quality was also improved by sulfasalazine (82 per cent of the cases) and by 5-aminosalicylic acid (79 per cent). The highest remission rate was achieved with 5-aminosalicylic acid (86 per cent), followed by sulfasalazine (64 per cent) and sulfapyridine (14 per cent). Our investigations show that 5-aminosalicylic acid is the active moiety of sulfasalazine and that this effective metabolite may be an alternative to sulfasalazine in inflammatory bowel disease.

Treatment of Crohn's Disease With Peroral 5-Aminosalicylic Acid

Eighteen patients with active Crohns disease entered an open trial with 5-aminosalicylic acid in a slow-release preparation. All had lesions of the small bowel. Ten of them also had Crohns disease of the colon. 5-Aminosalicylic acid, 500 mg three times daily, was administered for 6 wk. Even with meticulous monitoring, no side effects of any kind were observed, particularly no cases of renal affection, which could have been expected from animal studies. The clinical course was estimated as improved in 13 patients (72%), unchanged in 2 patients (11%), and aggravated in 3 patients (17%); 2 of these 3 were withdrawn from the study and switched to alternative treatment. The Crohns disease activity index decreased from a median of 226 points to 99 points. On the basis of these results, large-scale controlled therapeutic trails seem warranted in order to establish clinical evidence for the benefit of peroral treatment with 5-aminosalicylic acid in patients with Crohns disease.

Disposition of 5-aminosalicylic acid, the active metabolite of sulphasalazine, in man.

SummaryThe disposition of 5-aminosalicylic acid (5-AS), the therapeutically active metabolite of sulphasalazine (SZ), has been studied in patients with active inflammatory bowel disease, in patients with biliary tract disease and post-operative T-tube drainage, and in healthy volunteers. Subjects were treated 3 times a day either with 5-AS 0.5 g suppositories and a slow-release preparation or with SZ 1 g tid (equivalent to 5-AS 1.14 g/day). Plasma and urine concentrations of 5-AS and its acetylated major metabolite (AcAS) were monitored during one dosing interval. In a cross-over trial in 5 patients with ulcerative colitis no difference, was found in the dose-corrected mean (± SD) steady state plasma levels (Css) of 5-AS and AcAS between treatment with 5-AS suppositories (0.10±0.07 and 0.50±0.20 µg/ml, respectively) and SZ (0.12±0.14 and 0.67±0.14 µg/ml, respectively). Urinary excretion of total AS (5-AS+AcAS), too, was similar (192±70 and 179±79 mg/day) with both forms of treatment. The oral slow-release form of 5-AS produced slightly higher Css in 5 patients with Crohns disease (5-AS 0.21±0.22 µg/ml; AcAS 0.83±0.40 µg/ml) and in 5 healthy volunteers (5-AS 0.28±0.14 µg/ml; AcAS 1.10±0.43 µg/ml). Urinary recovery of total AS averaged 20±6% (patients) and 27±10% (volunteers). The cross-over trial in 7 patients with a biliary T-tube revealed that after single doses of 5-AS 1 g and SZ 2 g between 0.01% and 0.75% could be recovered in collected bile (85–500 ml/day) as total AS (traces of free 5-AS, and acetylated and glucuronidated 5-AS), indicating some enterohepatic circulation.

Disposition of ibuprofen in patients with liver cirrhosis : stereochemical considerations

SummaryFollowing a single oral dose of racemic ibuprofen 600mg the stereoselective disposition of its enantiomers was studied in 8 patients with moderate to severe cirrhosis. Compared with the elimination half-life (t1/2) of (−)-R- and (+)-S-ibuprofen in 8 healthy age-matched controls (1.7 ± 0.3h and 1.8 ± 0.5h, respectively), t1/2 was prolonged significantly (p < 0.045 and < 0.001, respectively) in patients with cirrhosis (t1/2 = 3.1 ± 1.7h and 3.4 ± l.Oh, respectively). Whereas the low amounts excreted unchanged into urine differed slightly in both groups studied, much less (p < 0.01) conjugated ibuprofen was recovered either as the R-enantiomer (0.9 ± 0.4% vs 4.1 ± 2.8% of the dose) or the S-enantiomer (6.4 ± 2.5% vs 26.5 ± 12.9% of the dose) in patients with cirrhosis. Metabolic inversion of the inactive (−)-R-ibuprofen to the active (+)-S-ibuprofen may be impaired in hepatic dysfunction since the normal ratio of areas under the curve (AUC) for R- and S-enantiomers (0.79 ± 0.18) was significantly (p < 0.02) higher in patients with cirrhosis (1.10 ± 0.28).In a second study, a single oral dose of 400mg (+)-S-ibuprofen was administered to 8 healthy volunteers and 8 patients with cirrhosis. Elimination of this enantiomer was slightly impaired as could be seen from the prolonged t1/2 (1.6 ± O.1h vs 2.6 ± 0.5h; p < 0.001) and the increase in AUC (101 ± 35 vs 144 ± 41 mg/L•h; p = 0.041).In conclusion, in patients with liver disease, hepatic elimination of ibuprofen is impaired. This should be taken into consideration especially if the racemic drug is used. Direct administration of the active (+)-S-enantiomer seems to offer less vulnerable treatment.

Renal function was not impaired by treatment with 5-aminosalicylic acid in rats and man

SummaryIn rat experiments and a clinical trial we have examined the suspected nephrotoxic potential of 5-amino-salicylic acid (5-ASA), the biological active metabolite of sulfasalazine (SZ). Male Wistar rats were treated orally for 4 weeks daily with 30 and 200 mg 5-ASA/kg and 75 and 500 mg SZ/kg. The two renal marker enzymes N-acetyl-β-D-glucosaminidase (NAG; EC 3.2.1.30), alanineaminopeptidase (AAP; EC 3.4.11.2) and creatinine were monitored in urine. At the end of the experiment rats were sacrificed, the removed kidneys histologically examined and drugs, their metabolites and creatinine measured in plasma and urine. In 9 patients treated chronically for their Crohns disease with 3×0.5 g 5-ASA daily in form of suppositories and an oral preparation urinary excretions of NAG, AAP and serum creatinine were also monitored before and during therapy. Neither the animal experiments nor the observations in patients gave any evidence of nephrotoxic lesions induced by 5-ASA. Thus, our data show that in the doses applied, 5-ASA was devoid of altering renal excretion in rats and man.

Clinical Efficacy of Oral Mesalazine in Crohn’s Disease

A randomized controlled trial was performed to evaluate in Crohns disease the clinical efficacy and safety of a higher dose of a new slow-release preparation of mesalazine (500 mg tablets). Twenty-four patients created with 3 g mesalazine/day were compared with 26 patients treated with sulfasalazine (3 g/day) and methylprednisolone (initially 40 mg). All patients had active Crohns disease diagnosed by endoscopy, sonography and radiology. Patients were characterized before entry into the study and at two, four, eight and 12 weeks of treatment by activity indices according to Best and van Hees, as well as by erythrocyte sedimentation rate, thrombocyte count, Broca index and serum albumin. All clinical and laboratory parameters were well matched for the two groups of patients. During treatment with mesalazine and sulfasalazine/ methylprednisolone, clinical remission could be observed in 20 of 24 patients (83%) and 23 of 26 patients (88%), respectively. There was no difference between the two groups except for a slightly higher increase of the Broca index in the combined treatment group. Side effects were reported in three (12.5%) and six (23%) patients treated with mesalazine and sulfasalazine/methylprednisolone, respectively. In conclusion, oral mesalazine at a dose of 3 g/day was effective in active Crohns disease and was well tolerated by the patients.

Telomerase activity in chronic inflammatory bowel disease.

Patients with ulcerative colitis have an increased risk of developing colorectal cancer. Telomerase appears to be associated with cellular immortality and might serve as a diagnostic and prognostic marker in carcinogenesis. To test this hypothesis we measured telomerase by a score from 0 (no activity) to 4 (very high activity) in specimens obtained surgically from seven patients with adenocarcinoma of the colon. Intraindividual comparison was made among normal tissue (mean score ± SD: 0.7 ± 1.0), tissues adjacent to the tumor (2.7 ± 0.8), and the tumor center (3.0 ± 1.0). In addition, from 18 patients with ulcerative colitis, 10 patients with Crohns disease, and 14 patients without chronic inflammatory bowel disease, biopsies were collected from normal and inflamed areas of the colon. Independent of the duration (0–32 years), grade, and location of the diseases, the telomerase activities were comparable, ranging from 0.4 to 1.0 in ulcerative colitis and from 0.3 to 0.6 in Crohns disease and averaging 0.4 in controls. Apparently low telomerase activities are present in the mucosa of all patients and the enzyme is not yet upregulated in the potentially premalignant state of active ulcerative colitis, dismissing its prognostic value as an early tumor marker for this disorder.

Flumazemil Disposition and Elimination in Cirrhosis

Flumazenil, a new and specific benzodiazepine antagonist that appears to be free of intrinsic pharmacologic action, is extensively metabolized by oxidative processes and represents a high-clearance drug. Consequently, it could be anticipated that hepatic disease affects the elimination and oral bioavailability of flumazenil. Therefore, the pharmacokinetics of flumazenil was evaluated in eight patients who had moderate cirrhosis and in eight age-matched healthy volunteers after a single oral dose (30 mg) and after an intravenous dose (2 mg). The mean half-life (t1/2) was 0.8 versus 1.4 hours (p = 0.003) and total plasma clearance was 1201 versus 705 ml per minute (p = 0.009) for control subjects versus patients with cirrhosis. Bioavailability increased from the normal 28% to 65% (p = 0.001) in patients with hepatic dysfunction. Routine liver tests did not correlate with the elimination of flumazenil in individual patients. It can be concluded that elimination of flumazenil is impaired in patients who have stable alcoholic cirrhosis. Despite the relative wide margin of safety of flumazenil, somewhat lower doses could be effective in such patients if long-term oral use is anticipated.