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Effect of short-term topical corticosteroid treatment on mucosal enzyme systems in patients with distal inflammatory bowel disease.

BACKGROUND/AIMS: Glucocorticoids, even when administered topically, have a known early benefit on diarrheal symptoms in inflammatory bowel diseases which may not be explained exclusively by their anti-inflammatory effect. Therefore, we evaluated a possible early effect of topically administered glucocorticosteroids on the mucosal function of patients with distal inflammatory bowel disease in a prospective, controlled study, which was blinded for histological evaluation. METHODOLOGY: Eleven patients with distal ulcerative colitis or Crohn's disease, and 8 patients without intestinal inflammation were studied. A sigmoidoscopy with biopsy sampling (8-10) was performed before and 3 days after rectal administration of a hydrocortisone acetate foam preparation (100 mg b.i.d.). Prior to and after topical steroid treatment, basolateral (Na++K+)-ATPase activity (coupled optical assay), specific 3H ouabain binding (rapid filtration method), 5'-nucleotidase (microdetection method of phosphorus), and mucosal DNA levels (diphenylamine reaction) were determined from biopsy homogenates. Morphological and clinical characteristics were assessed according to established scores. RESULTS: Short-term topical GCS treatment significantly (p<0.05) stimulated (Na++K+)-ATPase activity (103%) as well as the number of active (Na++K+)-ATPase molecules (190%). In the healthy mucosa, only (Na++K+)-ATPase activity was stimulated (124%, p<0.05; specific 3H ouabain binding: 33%; p=0.09). As an unspecific GCS effect, apical 5'-nucleotidase was also stimulated (p<0.05; IBD: 50%; controls: 200%). As assessed by endoscopic and histological scores, as well as by mucosal DNA levels, morphological signs of intestinal inflammation remained unchanged during the study, whereas the daily stool frequency decreased significantly (p<0.05). CONCLUSIONS: In patients with distal inflammatory bowel disease, short-term treatment with topical GCS leads to a quick recovery from diarrheal symptoms, due to the early improvement of mucosal function prior to the occurrence of the well-known anti-inflammatory GCS effect.

5'-Nucleotidase↗

PubMedDate not supplied

Phase II clinical trial of combined natural interferon-beta plus recombinant interferon-gamma treatment of chronic hepatitis B.

BACKGROUND/AIMS: Alpha-interferon (IFN-alpha) is an effective treatment for chronic hepatitis B but only 25-40% of patients will profit from a long-term beneficial response to the currently recommended schedule of 3-6 MU given 3 times a week for 6 months. Clinical trials are therefore needed to investigate alternative modifications of interferon therapy, including combinations of different antivirals or immune modulators in order to improve the therapeutic approach to chronic hepatitis B infection. In a phase II trial we evaluated whether a combination of natural interferon-beta (nIFN-beta) with strong antiviral activity plus recombinant interferon-gamma (rIFN-gamma) with a predominantly immunomodulatory activity is able to increase the response rate compared to historical controls treated with IFN-alpha in a conventional regimen. METHODOLOGY: Forty patients with chronic hepatitis B were included in this trial of combined interferon therapy at a dosage of 6 MU nIFN-beta during week 1 followed by 3 MU for weeks 2-4 plus rIFN-gamma at a daily subcutaneous (s.c.) injection of 150 microg during the entire 4 weeks of the treatment period. Patients entered the trial on the basis of the following criteria: hepatitis B surface antigen (HBsAG), HBeAG and HBV-DNA positive for at least 6 months, HDV, EBV, CMV, anti-HIV negative, and chronic hepatitis proven on biopsy taken within 4 weeks of entry as well as 6 and/or 12 months after interferon therapy. The final diagnosis and classification of chronic hepatitis has been based on guidelines according to a revised classification of chronic hepatitis (Desmet 1994). The post-treatment follow-up was 12 months. RESULTS: The combined interferon therapy achieved complete responses with seroconversion from HBeAG to anti-HBe and a negative HBV-DNA (dot blot) test, as well as normalization of ALT activity in 15 patients, and partial response with negativation of HBV-DNA concomitant to a decrease in aminotransferase activity to near normal levels in 6 patients. Nineteen patients showed no response to viral markers but showed relief of clinical symptoms as well as pronounced decrease of serumtransaminase activity. Grading of liver biopsies demonstrated an improvement of histologic parameters after the interferon regimen in half of the evaluable patients (n=22). Histological response has been quantified by a reduction in the score of histological activity (HAI-index) from 12.6 before to 7.6 after interferon therapy, and in the inflammation and cellular degeneration score (ICD) from 9.9 to 5.2. Histological response, however, failed to show a consistent correlation with serologic response. This medium-dose combination of interferon-beta and interferon-gamma was tolerated very well by the patients, this good tolerability being explained by tachyphylaxis in response to daily interferon doses. No serious side effects or decompensation of liver function were observed during the 4-week period of therapy or the follow-up, despite the special clinical situation where 60% of the patients included in the study presented with histologically proven cirrhosis (35% of them with clinical manifestation of mildly decompensated cirrhosis). CONCLUSIONS: This short-term regimen of combined nIFN-beta + rIFN-gamma therapy in patients with chronic hepatitis B proved to be equieffective to long-term treatment with interferon-alpha and combines high clinical tolerability with good practicability, as it can be administered on an in-patient basis, ensuring close patient monitoring.

Adolescent↗