An in vitro study on 5-HT6 receptor antagonist induced hepatotoxicity based on biochemical assays and toxicogenomics.

We investigated the effects of two 5-HT(6) receptor antagonists on rat primary hepatocytes using a combined biochemical and toxicogenomics approach. Both compounds share the same pharmacological target, but displayed strikingly different toxicity profiles in pre-clinical animal studies: While R7199 caused hepatic steatosis in rats, no hepatotoxicity was observed with R0074. Here, we partially reproduced the steatosis findings seen in vivo using primary rat hepatocytes. Biochemical analyses and gene expression results generally supported the findings observed in the animal model and also allowed the differentiation of both compounds with regards to hepatotoxic potential. In particular, the induction of Cyp 2B and Cyp 3A1 directly correlates to the findings in the livers of treated animals. The effects on genes of the steroideogenic pathway relate to the deregulation of cholesterol homeostasis. We also observed the inhibition of beta-oxidation, indicating impaired lipid metabolism. Hence, gene expression analysis in combination with biochemical parameters can provide additional insight into the possible mechanisms underlying adverse events.

Minimizing DILI risk in drug discovery - A screening tool for drug candidates.

Drug-induced liver injury (DILI) is a leading cause of acute hepatic failure and a major reason for market withdrawal of drugs. Idiosyncratic DILI is multifactorial, with unclear dose-dependency and poor predictability since the underlying patient-related susceptibilities are not sufficiently understood. Because of these limitations, a pharmaceutical research option would be to reduce the compound-related risk factors in the drug-discovery process. Here we describe the development and validation of a methodology for the assessment of DILI risk of drug candidates. As a training set, 81 marketed or withdrawn compounds with differing DILI rates - according to the FDA categorization - were tested in a combination of assays covering different mechanisms and endpoints contributing to human DILI. These include the generation of reactive metabolites (CYP3A4 time-dependent inhibition and glutathione adduct formation), inhibition of the human bile salt export pump (BSEP), mitochondrial toxicity and cytotoxicity (fibroblasts and human hepatocytes). Different approaches for dose- and exposure-based calibrations were assessed and the same parameters applied to a test set of 39 different compounds. We achieved a similar performance to the training set with an overall accuracy of 79% correctly predicted, a sensitivity of 76% and a specificity of 82%. This test system may be applied in a prospective manner to reduce the risk of idiosyncratic DILI of drug candidates.

Long-term outcome of idiopathic hypereosinophilic syndrome--transition to eosinophilic gastroenteritis and clonal expansion of T-cells.

We describe a patient with idiopathic hypereosinophilic syndrome, without initial gastrointestinal symptoms, and their transition to eosinophilic gastroenteritis. This patient, a 65-year-old man, presented with fever, constitutional symptoms, peripheral and bone marrow eosinophilia 20 years ago. During the course of the disease, diarrhoea and malabsorption became prominent, whereas bone marrow eosinophilia regressed completely and blood eosinophilia regressed partially. Biopsies showed a severe eosinophilic gastroenteritis of the mucosal type involving the stomach, small bowel and colon. During the final years of the patient's disease, mucosal eosinophilia became less intense and a mucosal infiltration with T-cells dominated. At autopsy, immunopathological studies of small intestines and colon specimens showed a clonal expansion of morphologically normal T-cells in the intestinal mucosa, which expressed the abnormal phenotype CD2+CD3+CD4-CD5-CD8-. Flow cytometry examination of peripheral blood revealed a corresponding abnormal population of CD3+CD4-CD8- T-cells, indicating a systemic spread of the process. The patient eventually died of non-obstructive small bowel infarction with peritonitis 20 years after the onset of the first symptoms. We postulate that the destructive eosinophilic/lymphocytic inflammation is caused by a clonal proliferation of T-lymphocytes with probable secretion of Type 2 T(helper) cell cytokines and consecutive stimulation of eosinophils.

Investigation of ranitidine 150 mg bd or 300 mg bd in the treatment of reflux disease.

Twenty patients with symptoms and endoscopic changes of gastro-oesophageal reflux were randomly allocated to treatment with either ranitidine 150 mg bd, or 300 mg bd for 8 weeks. Symptoms, endoscopic appearances, histopathology of oesophageal biopsies and 22-h intra-oesophageal pH profile in ambulant patients on standard diets were recorded before and at the end of the treatment period. Symptoms improved rapidly and markedly on either dose of ranitidine. Both doses produced significant improvement of the endoscopic appearances, but there were no differences in symptomatic and endoscopic improvement related to the dose. Biopsy appearances and the 22-h oesophageal pH profile remained unchanged on either dose of ranitidine.

[Esophageal intramural pseudodiverticulosis]. / Pseudodivertikulose des Osophagus.

We report two cases of esophageal intramural pseudodiverticulosis (EIPD). EIPD is a rare condition characterized by multiple flask-shaped outpouchings in the esophageal wall representing dilated excretory ducts of submucosal glands. Dysphagia is the leading symptom. On endoscopy, minute openings in the esophageal wall, and sometimes a segmental candida esophagitis or a benign stenosis not originating from an erosive reflux esophagitis are found.

[Pathogenesis of gastroesophageal reflux]. / Die Pathogenese der gastro-ösophagealen Refluxkrankheit.

Gastro-oesophageal reflux (GOR) is common. Nearly all healthy individuals experience occasional or frequent reflux episodes, with or without symptoms, which occur during spontaneous relaxations of the lower oesophageal sphincter, predominantly after meals. It is not known how neural, hormonal and muscular factors contribute to this. A proportion of the patients with reflux disease have normal lower oesophageal sphincter pressures, and their reflux episodes occur during spontaneous sphincter relaxations following the pattern of normals. Nevertheless, most patients with reflux disease have decreased lower oesophageal sphincter pressure, and manoeuvres which increase the intraabdominal pressure provoke "stress" reflux. If the sphincter pressure is very low, "free" reflux occurs; the cause of decreased sphincter pressure is not known. Pharmacological and gastric factors also facilitate GOR. The noxious potency of reflux material on the oesophageal epithelium depends on its components [( H+], pepsin, bile salts, trypsin) and the contact time, which is prolonged during supine and nocturnal reflux episodes, i.e. when clearance function is impaired. In complicated reflux disease it is necessary to consider this multifactorial model of the pathogenesis of reflux disease, and to go on to more sophisticated diagnostic procedures (manometry, scintiscanning, prolonged pH-monitoring) in order to identify an individual patients' predominant pathogenetic factor.

[Skin changes in liver diseases]. / Hautveränderungen bei Lebererkrankungen.

The liver is the second largest organ in the human body. An association between the skin and the liver has been recognized for centuries. Indeed, there is not always a correlation between the severity of the liver disease and the skin changes and they often are not specific. Several types of interaction between the skin and the liver are encountered: 1. Liver disease may cause skin changes. 2. The skin and the liver may be involved by the same pathologic process. 3. Skin disease may cause-liver abnormalities. 4. The liver may be damaged by drugs used to treat skin disease. In the following, the first two conditions are discussed.

[Chronic gastritis. Pathogenesis, clinical aspects and therapy]. / Chronische Gastritis. Pathogenese, Klinik und Therapie.

Based on clinical and histopathological features, three different types of chronic gastritis can be distinguished: gastritis A is confined to the proximal stomach and is the result of an autoimmunological process with antibodies against parietal cells and intrinsic factor. It is a rare disorder and may lead to pernicious anaemia. Distal, antral gastritis B is caused by an infection of the gastric mucosa with Helicobacter pylori (HP). Its incidence increases with age (greater than 50% above age 50). Gastritis C may be caused by drugs and alcohol but is mainly found in gastric remnants after partial resection as a consequence of biliary reflux. Gastritis A rarely causes symptoms. A relationship between gastritis B and C and non-ulcer dyspepsia (NUD) is highly controversial. Gastritis B is very closely associated with peptic ulcer disease. HP-positive antral gastritis seems to be the prerequisite for ulcer formation. All 3 types of gastritis carry an increased risk of malignancy, which seems to be positively correlated with hypoacidity, the chronicity of the inflammation and the histopathological feature of intestinal metaplasia. Noninvasive diagnostic tests (serology, breath tests, scintigraphy) are available, but the diagnosis of gastritis is still mainly based on endoscopy and biopsy. Treatment of gastritis A is not possible. Gastritis B can be healed by eradication of HP using bismuth salts and antibiotics but only combinations of 2-3 compounds seem to afford long-term positive results. Further clinical trials are needed to determine whether such treatment is justified in patients with gastritis and NUD. In patients with chronic recurrent peptic ulcers eradication of HP prevents relapses and heals ulcer disease. Gastritis C complicated by severe symptoms or ulcer can only be successfully treated by a biliary diversion, i.e. Roux-Y-gastrojejunostomy. The discovery that gastritis B is caused by HP improves our understanding of peptic ulcer disease and will change therapeutic concepts.

Severe hypersensitivity syndrome to lamotrigine confirmed by lymphocyte stimulation in vitro.

BACKGROUND: The anticonvulsant lamotrigine has been associated with severe adverse events such as the hypersensitivity syndrome and severe bullous reactions. So far, specific immunologic tests have rarely been performed to demonstrate specific sensitization. METHODS: A 36-year-old man suffering from epilepsy was concomitantly treated with high doses of sodium valproate and lamotrigine. About 1 month later, a severe hypersensitivity syndrome occurred affecting skin, lymph nodes, and liver. Three months later, skin tests and lymphocyte stimulation tests with anticonvulsants were performed. RESULTS: Skin tests were negative with all drugs; lymphocyte stimulation tests were twice positive with lamotrigine. Later re-exposure to sodium valproate was tolerated. CONCLUSIONS: Lamotrigine may elicit a severe hypersensitivity syndrome. Particularly high initial doses and concomitant treatment with sodium valproate increase the risk of cutaneous reactions. The lymphocyte stimulation test was used to identify the culprit drug. Lymphocyte sensitization to the drug or a metabolite may be involved in the pathogenesis.

Immune-mediated type A gastritis and glomerulonephritis.

The first two cases reported in the literature of patients with immune-mediated type A gastritis with microcarcinoids (as part of a polyglandular syndrome type II in one) in combination with chronic glomerulonephritis are presented. Immune-mediated type A gastritis appears to be another immunologic disorder that can be associated with chronic glomerulonephritis.

[Atrioventricular block after carotid pressure in hypothyroidism: normalisation after substitution treatment (author's transl)]. / Atrioventrikulärer Block nach Carotisdruck bei Hypothyreose. Normalisierung nach Substitution.

Severe auto-immune hypothyroidism, probably after hyperthyroidism, was diagnosed in a 79-year-old woman with hypothyroidism (T3 and T4 immeasurably low) without the classical signs of myxoedema heart. On carotid sinus pressure transitory first degree AV block occurred and, on one occasion, complete AV block. This response disappeared after substitution treatment for four weeks with 50 microgram L-thyroxine. Further examination half a year later, on a maintenance of 75 microgram thyroxine, also gave a negative response to carotid sinus pressure.

[Prolonged course of an idiopathic hypereosinophilic syndrome with transition to eosinophilic gastroenteritis]. / Langzeitverlauf eines idiopathischen hypereosinophilen Syndroms mit Ubergang in eine eosinophile Gastroenteritis.

Idiopathic hypereosinophilic syndrome (IHES) is a multi-system disorder of unknown origin with eosinophilic infiltration of bone marrow and various organs, including the gastrointestinal tract. Involvement of the heart has a poor prognosis. The etiology of eosinophilic gastroenteritis (EGE) also is unclear. In this disease there is exclusive involvement of the gastrointestinal tract (including liver/bile ducts) and prognosis usually is good. Transition from one disease to the other has not yet been described. We report the 20 years' history of a male patient with an initial IHES without gastrointestinal symptoms and transition to a clinically pure EGE with resolution of any other involvement. At the age of 45 years the patient developed IHES with fever and constitutional symptoms. Fluctuating eosinophilia and symptoms necessitated continuous steroid therapy. After a 10 years' disease course watery diarrhea and malabsorption syndrome became more and more prominent. On the other hand, bone marrow eosinophilia regressed completely and blood eosinophilia partially. Biopsies showed a severe EGE of the mucosal type with involvement of the whole gastrointestinal tract. Besides the prominent eosinophilia there was a dense infiltration of the intestinal mucosa with T-lymphocytes invading the epithelium. We postulate that the destructive eosinophilic/lymphocytic inflammation is caused by a pathologic proliferation of T-lymphocytes with liberation of type 2 helper cell cytokines and consecutive stimulation of eosinophils.

[Ischemic colitis as a cause of intestinal bleeding after marathon running]. / Ischämische Kolitis als Ursache einer Darmblutung bei Marathonlauf?

A 33-year-old long-distance runner had three episodes of bloody diarrhoea, all occurring after competitive marathon runs. Colonoscopy revealed a small lesion in the caecum histologically compatible with ischaemia of the mucosa. The discussion centres on the pathophysiology of impaired intestinal blood supply during excessive effort and the frequency of gastrointestinal symptoms and occult blood loss due to jogging.

[Long-term suppression of acid secretion with omeprazole use in metastatic gastrinoma]. / Langzeitsuppression der Säuresekretion durch Omeprazol bei einem metastasierenden Gastrinom.

We report on the clinical signs, diagnosis and 8-year course in a 54-year-old female patient with myeloma and gastrinoma with liver metastasis and associated Cushing syndrome treated for the last 3 years with the new H+/K+-ATPase inhibitor omeprazole which has successfully suppressed the massive gastric acid hypersecretion.

[Incidence of postoperative deep vein thrombosis in general surgical and urological patients an investigation by means of the 125I-Fibrinogen test in 95 patients withoug prophylaxis (author's transl)]. / Häufigkeit postoperativer tiefer Venenthrombosen bei Patienten der Allgemeinen Chirurgie und Urologie Eine Untersuchung mit dem 125J-Fibrinogentest bei 95 Patienten ohne medikamentöse Prophylaxe

We present the results of a control group of 95 patients who were thoroughly investigated in a prospective, randomized study, where the efficacy of small doses of s.c. heparin and dextran 40 is checked. The 125I-fibrogen test was used in all patients. 1. 35.8% of the patients develop deep vein thrombosis (DVT) during the first post-operative week. More than half of them show bilateral thrombosis. 2. There is no statistically significant difference in the thrombosis incidence between males and females. 3. 47% of the patients over 60 years develop postoperative DVT. Among those younger than 60 years, only 23% have DVT (P less than 0.025). 4. The DVT incidence in surgery of the colon is 58.3%. 5. Surgery for a malignant disease means probably increased risk for DVT (P less than 0.025). 6. More than half of the patients having a previous history of varicose veins develop postoperative DVT (P less than 0.025). 7. Obese patients are statistically seen not more prone to develop DVT than those of normal body build. 8. Immediately after operation 32.4% of DVT are diagnosed, 24 hrs. later 61.8%. 94% of all DVT are diagnosed up to the third postoperative day. 9. With the exeption of one patient, all DVT develop in the calf veins, 3/4 of all abnormal values were measured in the midcalf region.

Drug hypersensitivity syndrome to carbamazepine and human herpes virus 6 infection: case report and literature review.

We describe a patient with a drug-induced hypersensitivity syndrome to carbamazepine and a concomitant active infection with human herpes virus 6 (HHV-6). The potential role of HHV-6 regarding the drug-induced hypersensitivity syndrome is discussed and the main clinical features of this potentially fatal adverse drug reaction are highlighted.

[Epidemiology of skin diseases in HIV-infected patients: a prospective cohort study]. / Epidemiologie von Hauterkrankungen bei HIV-infizierten Patienten: eine prospektive Kohortenstudie.

Along with the rising AIDS epidemic, the recognition of mucocutaneous lesions indicating HIV infection is important not only for dermatologists but also for general practitioners. During 36 months we prospectively followed 357 HIV-1-infected patients on a regular base, and all the dermatologic findings were evaluated statistically. Several skin problems such as seborrheic dermatitis, may occur early in HIV infection. Mollusca contagiosa, oral hairy leukoplakia and Kaposi's sarcoma are often clinical signs of marked disease progression with very low CD4-cell counts.

[Gastritis associated with Gastrospirillum hominis--a zoonosis?]. / Gastrospirillum-hominis-assoziierte Gastritis--eine Zoonose?

We found spiral bacteria (non-Helicobacter pylori, SB) in gastric biopsies of 5 patients corresponding to an incidence of 0.3%. The bacteria were found on the surface of the gastric mucosa and in part tightly packed within the crypts. Contrary to Helicobacter pylori, most of them had no direct contact to the surface and crypt epithelium. They are distinctly coiled, 3.6-5.5 microns in length and on average 0.5 microns thick. Ultrastructural studies revealed sheathed flagella at each pole. In one case the bacteria displayed periplasmic fibrils in pairs as also described in cultures of SB from cats' stomachs. In all 5 cases there was histological evidence of inflammation of the gastric mucosa, i.e. one acute diffuse gastritis, one case of granulomatous and three of slight to medium grade chronic gastritis. Biopsies of 2 patients showed a positive urease reaction in the CLO test. Morphologically very similar SB occur as commensals in the stomachs of various animals, in particular dogs and cats. We investigated the stomachs of four dogs and four cats and found all to be infested with SB. The bacteria were found not only on the surface of the mucosa and in crypts, but within the glands of the corpus and antrum and often also within parietal (oxyntic) cells. Yet despite bacterial colonization there was no evidence of gastritis in dogs. However, all of the cats' stomachs showed slight to medium grade chronic gastritis. Cultivation of SB has not been successful so far, with the exception of cats' stomachs. Since the germs have been defined only morphologically, the question as to how close the relationship is among SB of various origins must for the time being remain unanswered. Furthermore, species-specific pathogenicity and the possibility of contagion from animal to man has not yet been clarified.

[Duplication cyst of the stomach antrum as the cause of an acute gastric emptying disorder in an adult]. / Duplikationszyste des Magenantrums als Ursache einer akuten Magenentleerungsstörung beim Erwachsenen.

HISTORY AND CLINICAL FINDINGS: A 35-year old woman without previous history of gastrointestinal complaints developed increasing upper abdominal pain with nausea and postprandial vomiting over 2 days during which she had been unable to take any food. She had no fever; her general physical condition was slightly reduced. While her abdomen felt soft on palpation, she had epigastric pain on pressure but no resistance to palpation. INVESTIGATIONS: Blood picture and routine laboratory tests were unremarkable. Plain film of the abdomen demonstrated marked gastric retention. Abdominal ultrasound showed an invagination in the gastric antrum suggesting a layering phenomenon. Gastroscopy revealed a submucosal tumour-like lesion with central ulceration which obstructed gastric exit. TREATMENT AND COURSE: After conclusion of the diagnostic tests on the first hospital day partial gastric resection (Billroth I) was performed as, in the absence of any surrounding reaction, a leiomyoma had been suspected. The further course was without complication and she was discharged on the 13th hospital day. The surgical specimen revealed a duplication cyst of the gastric antrum. CONCLUSION: (Endo)sonography, computed tomography and endoscopy make it possible to diagnose duplication cyst, as long as it is included in the differential diagnosis of acute abdomen in an adult. Emergency resection of the cyst is indicated because of the acute nature of the symptoms. But even in less urgent cases or as an incidental finding it is the treatment of choice.