Helmut Malchow

Oral budesonide for prevention of postsurgical recurrence in Crohn's disease

BACKGROUND & AIMS Prevention of postoperative recurrence after resection for Crohns disease (CD) would be of great clinical benefit. The efficacy of oral budesonide for prevention of endoscopic recurrence was evaluated in patients undergoing resection for ileal or ileocecal CD. METHODS Sixty-three patients received budesonide and 66 received placebo in a double-blind, randomized trial with parallel groups. Ileocolonoscopy, including biopsy, was performed after 3 and 12 months. Indications for surgery were fibrostenosis (78 patients), disease activity (41), and other reasons (10). RESULTS The frequency of endoscopic recurrence did not differ between the groups at 3 and 12 months. In patients with disease activity as indication for surgery, the endoscopic recurrence rate at the anastomosis was lower in the budesonide group at 3 months, although not significantly (21% vs. 47%; P = 0.11), and at 12 months (32% vs. 65%; P = 0.047). There was no such difference with respect to fibrostenosis as indication for surgery. No differences in adverse event patterns were found between the two groups. CONCLUSIONS Oral budesonide, 6 mg daily, offered no benefit in prevention of endoscopic recurrence after surgery for ileal/ileocecal fibrostenotic CD but decreased the recurrence rate in patients who had undergone surgery for disease activity.

Effects of Semisynthetic Diets on Xenobiotic Metabolizing Enzyme Activity and Morphology of Small Intestinal Mucosa in Humans

We studied the effects of semisynthetic (elemental) diets on the function and morphology of the human small intestine. The enzymatic capacity of the intestinal mucosa to metabolize lipophilic xenobiotics was investigated using jejunal biopsy specimens from 15 normal subjects who were on an isocaloric, nutritionally balanced semisynthetic diet for 7 days and thereafter on a normal home diet. Each subject underwent biopsy twice: on day 7 of semisynthetic diet and again on home diet 2-6 wk later. The jejunal mucosal tissue was examined by histologic morphometry and stereomicroscopy. Moreover, 25-50 mg of the biopsy material was homogenized and the following enzyme activities were determined in 20,000 g supernatant: for cytochrome P450-dependent monooxygenase activity with 7-ethoxycoumarin O-deethylase (EOD) and with nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome c reductase and for conjugation activity with 1-naphthol glucuronyltransferase (NGT). The NGT and reductase activities were unchanged by the dietary alterations. However, the EOD activity was significantly depressed on semisynthetic diet and rose to control range on home diet (from 5.3 +/- 2.5 to 12.4 +/- 8.6 pmol/min X 10 mg wet wt). Male subjects had significantly higher EOD activities than female subjects on semisynthetic diet (6.6 +/- 2.3 vs. 3.2 +/- 0.9) as well as on home diet (16.3 +/- 9.0 vs. 6.4 +/- 3.0). Semisynthetic diet also reduced the jejunal villous height significantly when compared with home diet (408 +/- 49 vs. 373 +/- 44 micron). Therefore, on semisynthetic diet the toxicity of dietary xenobiotics that are inactivated by the intestinal mucosa may be increased.

Immune status in Crohn's disease. I. Leukocyte and lymphocyte subpopulations in peripheral blood.

Proportions and absolute numbers of circulating leukocyte populations and lymphocyte subpopulations (T- and B-cells) were determined in 33 patients with Crohns disease (group CD), and were compared with those of age- and sex-matched healthy subjects. Group CD comprised 15 patients with newly diagnosed, short-standing, and untreated CD (group CD 1) and 18 patients with long-standing, previously drug treated CD (group CD 2). All CD groups showed a significant absoulte leukocytosis, based on a significant absolute and relative increase of the neutrophils, and, as far as group CD and CD 1 were concerned, also of the absolute number of monocytes. In group CD 1, absolute lymphocyte and relative as well as absolute T-cell numbers were close to normal. In contrast, in group CD 2 absolute as well as relative numbers of lymphocytes and absolute numbers of T-cells were highly significantly reduced, whereas the reduction of the relative T-cell concentration barely reached significance. The proportion of B-cells was significantly above normal in all patient groups, the absolute number in group CD only. Also group CD 1 showed considerably, though statistically insignificantly, higher than normal absolute B-cell numbers. In group CD 1 , there was an inverse correlation between absolute T-cell numbers and disease activity, and between absolute lymphocyte numbers and duration of disease. These data indicate that there is no gross numerical reduction of the carriers of the cell-mediated immunity as a primary predisposing factor for CD, but that a reduction of these cells occurs in the circulation after the disease has started.

Human gastric mucosal adenylate cyclase: activation by histamine-H2-receptor stimulation and inhibition by cimetidine in vitro and in peptic ulcer patients.

SummaryBiopsy specimens of human fundic mucosa from 96 subjects were assayed for adenylate cyclase activity to characterize specificity of the histamine receptor with selective agonists and antagonists in vitro, and to study the effect of cimetidine therapy. Histamine and the selective histamine H2-receptor agonist dimaprit were almost equally potent throughout the concentration-response curve (10−7–10−3 mol/l); maximal stimulation was obtained with concentrations of 10−4–10−3 mol/l, and half maximal stimulation with about 10−5 mol/l. The selective H1-receptor agonist PEA 10−5 and 10−3 mol/l failed to stimulate adenylate cyclase. Mepyramine 10−6 mol/l, a selective H1-receptor antagonist, and cimetidine 10−6 mol/l, a selective H2-receptor antagonist, did not affect basal adenylate cyclase activity. Histamine-stimulated adenylate cyclase was inhibited in a concentration dependent manner by cimetidine 10−7 and 10−5 mol/l, but not by the same concentrations of mepyramine. Almost identical basal adenylate cyclase activities of about 150 pmol cAMP/mg protein/20 min were found in gastric mucosal biopsies from controls and from peptic ulcer patients, whether or not treated with cimetidine. Histamine 10−5 mol/l doubled adenylate cyclase activity in the controls and the untreated ulcer group, but was completely ineffective in specimens from the cimetidine-treated peptic ulcer patients. The data underline the concept that the effects of histamine on acid secretion and on adenylate cyclase activity are linked together and that the therapeutic effect of cimetidine in ulcer treatment is related to histamine H2-receptor blockade followed by inhibition of adenylate cyclase.

Adenylate cyclase in human gastric mucosa: its activation by histamine in morphologically different biopsy specimens.

ZusammenfassungIn morphologisch unterschiedlichen Biopsieproben aus der Fundus-, Antrum- und Duodenalschleimhaut von insgesamt 134 Personen wurde die basale und histaminstimulierte Adenylat-Cyclaseaktivität untersucht. Basale und stimulierte Adenylat-Cyclaseaktivität der Schleimhaut des oberen Gastrointestinaltrakts war log-normal verteilt. Nur die Adenylat-Cyclase der Fundusschleimhaut, nicht dagegen die der Antrum- und Duodenalschleimhaut war durch Histamin stimulierbar. In der Fundusschleimhaut betrug die basale Aktivität im Mittel 148, in Gegenwart von 10−5 mol/l Histamin 292 pmol cAMP/mg Protein/20 min. Die Stimulierbarkeit der Adenylat-Cyclase nahm in histologisch gesichert normaler Fundusschleimhaut mit dem Alter und im Biopsiematerial von Patienten mit histologisch diagnostizierter verschiedengradig chronischer Gastritis mit zunehmender Schleimhautatrophie ab. Die Stimulierbarkeit der Adenylat-Cyclase der Fundusschleimhaut durch Histamin war bei Patienten mit einem Magen- oder Duodenalulcus nicht signifikant von der des Normalkollektivs verschieden, obwohl in der Gruppe Duodenalulcus die höchsten Werte gefunden wurden. Demgegenüber war bei Patienten mit 2/3-Resektion nach Billroth I und II die Wirkung von Histamin auf die Enzymaktivität eindeutig vermindert. Da eine histamin-empfindliche Adenylat-Cyclase nur im sekretorischen Anteil des Magens nachweisbar ist und dieser Effekt einer morphologisch intakten Schleimhaut bedarf, lassen die hier vorliegenden Befunde darauf schließen, daß die Wirkungen von Histamin auf Adenylat-Cyclase und Säuresekretion zusammengehörige Vorgänge sind.SummaryIn morphologically different biopsy specimens from fundic, antral and duodenal mucosa of 134 persons, basal and histamine stimulated adenylate cyclase activity was studied: Basal and stimulated adenylate cyclase activities were log-normally distributed. Only in the fundic but not in the antral and duodenal mucosa adenylate cyclase was sensitive to histamine. The mean basal activity in the fundic gastric mucosa was 148, in response to 10−5 mol/l histamine 292 pmol cAMP/mg protein/20 min. In human fundic biopsy specimens histologically identified as normal gastric mucosa, the stimulatory effect of histamine on adenylate cyclase decreased with the individuals age. In bioptic material from patients suffering from histologically proven chronic gastritis the histamine effect decreased with the degree of atrophy. A similar loss of histamine sensitivity was found in gastric mucosal biopsies of antrectomized individuals operated at least 5 years before by the Billroth I or II method, whereas in the mucosa of patients with gastric or duodenal ulcer no loss occurred. In contrast, the most pronounced stimulatory action of histamine was found in this latter group. Since a histamine sensitive adenylate cyclase is localized only in the glandular area of the fundic mucosa and the histamine sensitivity depends on a morphological intact structure of the mucosa, it can be concluded, that the effects of histamine on adenylate cyclase and on hydrochloric acid secretion have to be considered as a mechanism linked together.

Adrenaline Sensitive Adenylate Cyclase in Human Gastric Mucosa

Basal and adrenaline-stimulated adenylate cyclase (AC) was studied in biopsy specimens of the gastric and duodenal mucosa from 112 individuals. AC activities were log normally distributed. AC of fundic and antral gastric mucosa responded to adrenaline in a concentration-dependent manner, that of the duodenal mucosa did not respond to adrenaline. The degree of activation in biopsies of normal gastric mucosa was similar to that of patients with chronic atrophic gastritis or patients antrectomized according to the Billroth method. AC in biopsies from cimetidine-treated peptic ulcer patients was less sensitive to adrenaline than AC in biopsies from untreated patients. The threshold concentration of cimetidine to inhibit adrenaline-stimulated AC in vitro was 10(-6) mol/l. The data provide evidence of an adrenaline-sensitive AC in cells other than parietal cells and show an inhibitory action of cimetidine on the catecholamine-sensitive AC in the human gastric mucosa.