Low dose balsalazide (1.5 g twice daily) and mesalazine (0.5 g three times daily) maintained remission of ulcerative colitis but high dose balsalazide (3.0 g twice daily) was superior in preventing relapses.

BACKGROUND: Balsalazide is a new 5-aminosalicylic acid (5-ASA) containing prodrug. Its efficacy in comparison with standard mesalazine therapy and the optimum dose for maintaining remission of ulcerative colitis are still unclear. AIMS: To compare the relapse preventing effect and safety profile of two doses of balsalazide and a standard dose of Eudragit coated mesalazine. METHODS: A total of 133 patients with ulcerative colitis in remission were recruited to participate in a double blind, multicentre, randomised trial: 49 patients received balsalazide 1.5 g twice daily, 40 received balsalazide 3.0 g twice daily, and 44 received mesalazine 0.5 g three times daily. Efficacy assessments were clinical activity index (CAI) and endoscopic score according to Rachmilewitz, and a histological score. In addition, laboratory tests were performed and urinary excretion of 5-ASA and its metabolite N-Ac-5-ASA was analysed. The study lasted for 26 weeks. RESULTS: Balsalazide 3.0 g twice daily resulted in a significantly higher clinical remission rate (77.5%) than balsalazide 1.5 g twice daily (43.8%) and mesalazine 0.5 g three times daily (56.8%) (p=0.006). The respective times to relapse were 161 days, 131 days (p=0.003), and 144 days (NS). Accordingly, pairwise contrasts of the final endoscopic score demonstrated a significant difference (p=0.005) between the two balsalazide treatment groups while differences between either of these two groups and mesalazine were not statistically significant. Patients treated with balsalazide excreted less 5-ASA and N-Ac-5-ASA than patients receiving mesalazine but these differences were not statistically significant. Discontinuation of the trial because of adverse effects occurred in nine patients: three in the balsalazide 1.5 g twice daily group, two in the balsalazide 3.0 g twice daily group, and four in the mesalazine 0.5 g three times daily group. No clinically important new drug safety related findings were identified in this study. CONCLUSIONS: High dose balsalazide (3.0 g twice daily) was superior in maintaining remission in patients with ulcerative colitis compared with a low dose (1.5 g twice daily) or a standard dose of mesalazine (0.5 g three times daily). All three treatments were safe and well tolerated.

Olsalazine versus mesalazine in the treatment of mild to moderate ulcerative colitis.

AIM: To compare the efficacy and tolerability of olsalazine sodium with enteric-coated mesalazine in inducing endoscopic remission in patients with mild to moderate active ulcerative colitis. PATIENTS AND METHODS: Patients with mild to moderate active ulcerative colitis were randomized to receive either olsalazine sodium, 3 g/day (n = 88), or mesalazine, 3 g/day (n = 80), for up to 12 weeks. RESULTS: Of the patients treated with olsalazine sodium, 52.2% achieved endoscopic remission, compared with 48.8% of patients treated with mesalazine. This difference was not significant (P = 0.67). There was a nonsignificant trend for patients with left-sided colitis or a more severe endoscopic grade to achieve remission if they were treated with olsalazine sodium than if they were treated with mesalazine. Both treatments were comparable with respect to clinical activity index and an investigator's global assessment. Seventy patients reported one or more adverse events; adverse events were seen in 45% of olsalazine sodium-treated patients and in 36% of mesalazine-treated patients. Eleven patients treated with olsalazine sodium and nine patients treated with mesalazine withdrew from the study because of adverse events. One patient treated with olsalazine sodium compared with two treated with mesalazine stopped treatment because of diarrhoea. Serious adverse events occurred in three patients treated with olsalazine sodium and in four treated with mesalazine. CONCLUSION: Therapeutic effectiveness and tolerance to the treatment did not differ between olsalazine sodium, 3 g/day, and mesalazine, 3 g/day, in inducing endoscopic remission in patients with mild to moderate active ulcerative colitis within 12 weeks of treatment.

[Patient oriented, prospective comparative study of three different pump systems for artificial enteral nutrition]. / Patientenorientierte, prospektive Vergleichsstudie drei verschiedener Pumpensysteme für die künstliche enterale Ernährung.

In a prospective cross-over study involving 30 patients, three different pump systems for artificial enteral nutrition were compared: the Nutromat, Flexiflo, and Frenta systems. Depending upon the degree of acceptance, a controlled sequence of priority of the pump systems was established. In addition, 12 functions and features of the different systems were scored using a scoring key (scores: +2, +1, +/- 0, -1, -2). The Nutromat was adjudged the best system by 53% of the patients, the Flexiflo system was preferred by 30%, and the Frenta system by 17%, of the patients. In the average overall rating of functions and features, the Nutromat scored 1.3 ("good"), the Flexiflo 0.8 ("satisfactory"), and the Frenta system 0.4 ("adequate"). All in all, more than half the patients assessed the Nutromat as the most pleasant and also best pump system.

Feasibility and effectiveness of a defined-formula diet regimen in treating active Crohn's disease. European Cooperative Crohn's Disease Study III.

In a randomized multicenter trial the efficacy of treatment of active Crohn's disease by means of a liquid defined formula diet (DFD) was tested and compared with a combination of 6-methyl-prednisolone and sulfasalazine. A total of 95 patients participated in the study. By the end of 6 weeks, among 44 patients randomized to drug treatment, 32 showed improvement of the Crohn's disease activity index (CDAI) as compared with 21 of 51 patients receiving oral DFD (p less than 0.05). The proportion of withdrawals in the DFD group (29 of 51) was sevenfold higher than in the drug group (4 of 44). However, most patients (20 of 29) receiving DFD withdrew because of the unpalatability of the liquid diet. Analysis of patients in each group who finished the study showed equal effectiveness of DFD and the drug regimen. In these subsets of patients the CDAI decreased from 280.8 +/- 90.6 to 151.7 +/- 86.5 (DFD) and from 263.7 +/- 86.3 to 129.3 +/- 63.7 (drug), respectively. Improvement of inflammation factors was similar in both groups at the end of the study, although improvement was delayed in the DFD group. In conclusion, our data show a superiority of the drug combination over DFD in the treatment of Crohn's disease under the conditions of this trial. The results do suggest, however, that DFD offers a therapeutic alternative to prednisolone and sulfasalazine in a subgroup of patients, which has to be closer characterized in further studies.

Relationships between blood chemistry and histology of the rectal mucosa in Crohn's disease.

In the scope of the ECCDS, established to test the efficacy of prednisolone and/or sulfasalazine in Crohn's disease, the relationships of blood chemistry and CDAI to histology of rectal mucosa were studied in 115 patients by means of univariate and multivariate statistical analyses. Laboratory and histologic markers of inflammation tend to be correlated. But these correlations are definitively weak. Thus, the predictive value of histology for blood chemistry or CDAI is very low. Laboratory indices and CDAI are relatively inaccurate means of assessing disease severity at tissue level and vice versa.

Relationships between drug regime and histology of rectal mucosa in Crohn's disease.

In the scope of the ECCDS, testing the efficacy of prednisolone and/or sulfasalazine in Crohn's disease, the relationships between drug regime and histology of rectal mucosa were studied. Rectal biopsies, gained at start and after termination of treatment were available in 57 patients. Additionally, biopsies of 20 normal controls were studied. The biopsies, cut completely in serial sections, were investigated by quantitative histological methods. The data were evaluated by multivariate discriminant analyses. The nearest approach of histologic pattern to normal was found after combined treatment with prednisolone and sulfasalazine, followed by prednisolone monotherapy. The effect of sulfasalazine as monotherapy was poor. The degree of normalisation in histologic pattern agrees very well with the CDAI in our subsets. Overall, effective therapy was reflected in histology of rectal mucosa by a decrease of acute inflammatory alterations and an increase of mononuclear infiltration. Only minor individual effects of the various drug regimes were found.

Comparative radiological and morphological study of human pancreas. Pancreatitis like changes in postmortem ductograms and their morphological pattern. Possible implication for ERCP.

A postmortem study by ductography and histology was performed on 69 human pancreata with no clinical or histological signs of chronic pancreatitis. The ductograms, supplemented by five postmortem ductograms of chronic pancreatitis, were independently evaluated by six clinicians, skilled in ERCP; the degree of alteration was estimated by simple rating, forced choice rating, and by determination of the grade of chronic pancreatitis, Histologically, the amount of intraductal epithelial proliferation, periductal, intralobular and perilobular fibrosis, intraductal protein plugs, and fat necrosis was determined by semiquantitative methods. The six ductographical evaluations significantly differed in the level of their data, but corresponded in the range of distribution. All evaluations were correct regarding judgement of ductograms from patients with chronic pancreatitis. Ductograms of patients without chronic pancreatitis, however, were also frequently classified as chronic pancreatitis; overall 81% (minimal 37%, moderate 33%, severe 11%). This high level of false positive diagnosis indicates the frequency of pancreatitis like lesions in the main duct and its side branches in patients without chronic pancreatitis. Ductal lesions were significantly correlated with perilobular fibrosis. This finding favours the assumption, that in the non-inflamed pancreas, perilobular fibrosis plays a key-role in the development of ductal alterations, as in chronic pancreatitis. Perilobular fibrosis may result from intralobular inflammation caused by age-dependent intraductal epithelial hyperplasia.

Relationships between clinical data and histology of the large bowel in Crohn's disease and ulcerative colitis.

Histologic changes of rectal biopsies were compared with clinical data in 83 patients suffering from Crohn's disease, 78 patients with ulcerative colitis, and 87 normal controls. Additionally, colonic biopsies were studied in 82 Crohn's disease patients. The biopsies were cut in serial sections and examined by quantitative and semiquantitative methods, determining changes of superficial epithelium, crypts, stroma, and submucosa. The statistical evaluation was performed by univariate and multivariate analyses. In normal controls, 2.6 percent of the correlations existing between histologic and clinical data were significant; in rectal biopsies of Crohn's disease 8.9 percent, in colonic biopsies of Crohn's disease 6.7 percent, and in ulcerative colitis 10.4 percent. Multiple stepwise regression analyses revealed a distinct predictive value of histology of rectal biopsies for the clinical activity index according to Best et al. in Crohn's disease. Most effective histologic changes were content of goblet cells and acute inflammatory lesions. In colonic biopsies, significant predictive values were found for diarrhea, anal fissures, and meteorism. Most effective variables in prediction of diarrhea were granuloma and eosinophilic and histiocytic infiltration; in prediction of anal fissures increased basophilia of epithelium and leukocytic infiltration of crypts; in prediction of meteorism increased basophilia of epithelium and hyperemia. In ulcerative colitis, significant predictive values were present for activity of disease on colonoscopy and the blood content of thrombocytes. Most effective variables in the prediction of colonoscopically determined activity were histiocytic and neutrophilic infiltration, height of the cryptal epithelium, and cryptal distance; in the prediction of thrombocytic values cryptal length, cryptal distance, and plasmacellular infiltration. In normal controls, no consistent predictive value of histology was found. Though each multivariate statistical method depends on the underlying sample, at least the first variables entering the multiple regression analyses are of high value in the estimation of clinical parameters by morphologic methods. Thus, the study elucidates the high value of rectal biopsies in estimating the activity of illness, both in Crohn's disease and in ulcerative colitis.

European Cooperative Crohn's Disease Study (ECCDS): colonoscopy.

130 patients with Crohn's disease were colonoscopied in a multicenter trial. The obtained data were analyzed with respect to gathering information on the inflammation pattern, as well as on the importance and prognostic value of special lesions in Crohn's colitis. In 52 patients a second endoscopy was performed at the end of the 2-year study period. Ulcerations and aphthous lesions were the most common lesions, followed by pseudopolyps, cobblestone lesions and stenosis. In general, there was an increasing, distal gradient in the frequency of severe lesions. patients with Crohn's colitis alone had more signs of inflammation than patients with additional involvement of the small intestine. A segmental pattern was the most common form of inflammation. The group of patients (14%) with a continuous pattern did not deviate from the whole collective in clinical activity. In patients with previous resections, inflammation near the anastomosis was accompanied more often than not by stenosis. Patients with ulcerations had a rather short time since confirmation of the diagnosis. Cobblestone lesions and pseudopolyps correlated with short symptomatology. During the follow-up of the study, patients taking steroids or a combination with prednisolone and sulfasalazine seem to have better results than those under placebo or sulfasalazine alone, as regards the more severe symptoms.

The granuloma in Crohn's disease. A bioptical study.

Serial sections of 1434 colonic and rectal biopsies of 347 patients with Crohn's disease were performed. The relationship between the incidence of granulomas and the inflammatory alterations of the mucosa and some clinical parameters was studied. The presence of granulomas depends on the severity of inflammatory alterations and not on the site of the biopsy. The number of granulomas per mm3 increases from caecum to rectum. The incidence of granulomas decreases with age, duration of illness and under a conservative therapy. If several biopsies, taken at the same or at different times, are studied, granulomas can be found in 40-50% of these patients.

European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment.

A multicenter double-blind study of the effectiveness of sulfasalazine and 6-methylprednisolone, alone and in combination, was conducted on 452 patients with Crohn's disease. One hundred sixty patients were previously untreated; 292 patients were previously treated. The Crohn's disease activity index (CDAI) was used to determine whether a patient had active (CDAI greater than or equal to 150, n = 215) or quiescent disease (CDAI less than 150, n = 237). Treatment of active disease consisted of high-dose 6-methylprednisolone, 6-methylprednisolone combined with 3 g of sulfasalazine, 3 g of sulfasalazine alone, or placebo, and lasted 6 wk. Patients in remission received maintenance doses of one of these drug regimens for periods of up to 2 yr. One hundred ninety-two patients completed the 2-yr study period. Results were evaluated using life-table analysis and outcome ranking. These methods showed 6-methylprednisolone to be the most effective drug in overall comparison of all patients (p less than 0.001); in previously treated patients (p less than 0.001); and in subgroups: active disease (p less than 0.001), only small bowel disease (p less than 0.05), and both small bowel and colon disease (p less than 0.05). Combination of 6-methylprednisolone and sulfasalazine was the most effective regimen in previously untreated patients (p less than 0.05) and when disease was localized in the colon (p less than 0.001). Sulfasalazine alone was least effective in overall comparison of all patients (p less than 0.05) and in all strata. Drug treatment was of no significant benefit to patients with quiescent disease. Continuous administration of low doses of 6-methylprednisolone, or the combination regimen, was beneficial in patients who responded initially to treatment of active disease. The addition of sulfasalazine, however, offered no advantage.

[Sugar-free diet as long-term or interval treatment in the remission phase of Crohn disease--a prospective study]. / Zuckerfreie Diät als Langzeit- bzw. Intervallbehandlung in der Remissionsphase des Morbus Crohn eine prospektive Studie.

20 patients with Crohn's disease were entered into a prospective study, after they had been submitted to standard treatment of the acute phase. In this study long term treatment or treatment between the acute relapses of the disease consisted in daily doses of 8 mg methylprednisolone and 3 mg salazosulfapyridine; in addition the diet was sugar-free and rich in fibers. When remission continued (activity index below 150 point) the drugs were stopped and only dietary treatment was continued. The course of the disease was followed by frequent endoscopic examinations and by determinations of the activity index according to Best. 16 patients were in remission after an average treatment period of 19.6+/-6.6 months without drugs only using the dietary regimen described. 4 cases relapsed after 7.5+/-4.3 months (activity index greater tha 150 points, intestinal ulcerations); they had to be treated again according to the acute phase standard treatment schedule. These results encourage further trials, where after 6 months of drug treatment the drugs are stopped, and only dietary treatment is continued during the remission phase.

[Beware: propafenon potentiates the effect of oral anticoagulants]. / Cave: Propafenon potenziert Wirkung von oralen Antikoagulantien.

In a 68 years old female patient with premature ventricular contractions who was treated with phenprocoumon (Marcumar) because of pulmonary infarction, propafenon (Rytmonorm)--a new anti-arrhythmic drug--lead to an increased effect of coumarin. Inspite of pausing with coumarin for eight days the low Quick rates (less than 15%) did not increase until propafenon was stopped. Afterwards the coumarin treatment was continued with 1,5 to 3 mg a day. In case of a combined treatment with propafenon and coumarin Quick rates should be controlled frequently.

[Atenolol in the treatment of premature ventricular contractions. A double blind study in 68 patients (author's transl)]. / Die Behandlung ventrikulärer Extrasystolen mit Atenolol Eine Doppelblindstudie mit 68 Fällen.

The effects of atenolol, a cardioselective beta-blocker, on premature ventricular contractions (PVC) were tested in 68 patients in a double blind trial. 35 patients received 100 mg atenolol p.o/day for 5 days, 33 patients received placebo. A computer-based monitoring system permitted an accurate count of all PVC over a 10-hours pre-drug period and after a 5-days treatment. In both groups there was a significant reduction in PVC frequency, but there was no significant difference between the atenolol group and the placebo group. 45 of 68 patients had a coronary heart disease as cause of PVC, 22 patients in the atenolol group and 23 patients in the placebo group. The statistical examination of those patients only showed results different from the total group. In the atenolol group there was a significant reduction in PVC frequency, average reduction 85% (p less than 0.001). The reduction of PVC frequency inthe atenolol was significantly greater than in the placebo group (p = 0.009). There was a significant reduction in systolic blood pressure and heart rate in the atenolol group, too. Atenolol is an alternative drug in the treatment of PVC in patients with coronary heart disease. The reduction of blood pressure and anginal attacks is an advantage over other conventional antiarrhythmic drugs.