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 As a training set, 81 marketed or withdrawn compounds with differing DILI rates - according to the FDA categorization - were tested in a combination of assays covering different mechanisms and endpoints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.

[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.

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.

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.

[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.

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.

Is there a relation between risk groups or initial CD4 T cell counts and prevalence of seborrheic dermatitis in HIV-infected patients?

OBJECTIVES: (i) To investigate whether there is a difference in the prevalence of seborrheic dermatitis (SD) between homo- or bisexual HIV-infected patients and HIV-infected intravenous drug users, (ii) to study whether the initial CD4 T cell count at the first positive HIV test is of any significance for the prevalence of SD and furthermore to analyze whether (iii) antiretroviral treatment influences the prevalence and time course of SD. PATIENTS AND METHODS: Since 1992 we have been following, within the scope of the Swiss HIV Cohort Study, a group of individuals with proven HIV infection. In this study all HIV-infected patients belonging either to the risk group of homo- or bisexuals or that of intravenous drug users were included for further analysis. RESULTS: We included 226 men and 51 women. The ages ranged from 17 to 68 years (mean 30.1). One hundred and forty-four were homo- or bisexual men and 133 (82 men and 51 women) were intravenous drug users. Out of these 277 HIV-infected patients, 66 (23.8%) had SD at baseline and 7 (2.5%) developed SD during the observation period (male:female = 68:5). CONCLUSION: In our study we found that (i) the risk group influences the prevalence and time course of SD, yet that (ii) neither the initial CD4 T cell count nor (iii) antiretroviral treatment is of any significance.

[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.

[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.

[Liver cell carcinoma as a late complication of Alagille syndrome (arterio-hepatic dysplasia)]. / Leberzellkarzinom als Spätkomplikation des Alagille-Syndroms (arterio-hepatische Dysplasie).

The Alagille syndrome which is also known as arterio-hepatic dysplasia is an autosomal dominant inherited disorder. In several cases cytogenetic studies revealed an interstitial deletion of the short arm of chromosome 20. The hypoplasia or paucity of the interlobular bile ducts causes a chronic intrahepatic cholestasis. The association with facial dysmorphia, embryotoxon posterior, pulmonary stenosis and vertebral deformities are required for the diagnosis of the complete Alagille syndrome. The occurrence of hepatocellular carcinoma as a late complication of the Alagille syndrome was recognized only 11 years after the first publication by Alagille et al. So far 15 cases complicated by hepatocellular carcinoma have been reported. There is one family where all four siblings suffered from hepatocellular carcinoma. Our own case concerns a 31 year old man who died of hepatocellular carcinoma. The postmortem study of his medical history reaching back to childhood allowed the diagnosis of an unrecognized Alagille syndrome.

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.

[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.

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.

[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.

[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.

[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.

Reduction in early recurrence of variceal bleeding by propranolol.

Survival after variceal bleeding depends greatly on the outcome of the immediate posthaemorrhagic period. This may in turn depend on the recurrence of bleeding. We therefore prospectively evaluated the influence of propranolol on the recurrence of variceal haemorrhage during the early period after the acute bleeding episode. Twenty consecutive patients with acute variceal haemorrhage and liver disease were randomly assigned to treatment either with propranolol or placebo orally for 14 days. Propranolol significantly decreased the rate of recurrence of variceal haemorrhage during this early period (p = 0.0028; 95% confidence interval in the placebo group, 90 +/- 20%; in the beta blocker group, 20 +/- 26%). Whereas a recurrence of variceal bleeding occurred in 9 of 10 patients in the placebo group, only 2 of 10 rebled during treatment with propranolol. These results suggest that propranolol may prevent rebleeding in the crucial early period after acute haemorrhage from oesophageal varices.