Molecular mechanisms of drug-induced hepatic steatosis

Steatosis of the liver is defined by an excess accumulation of intracellular triglycerides within the hepatocytes. Nonalcoholic fatty liver disease ranges from simple steatosis to nonalcoholic steatohepatitis. It is a serious health problem worldwide, reported to affect 15 – 30 % of the population in developed countries. Inordinate accumulation of fat is damaging to the liver, because high levels of triglycerides, free fatty acids, or intermediates of lipid metabolism are extremely problematic for a cell. A further problem is that nonalcoholic fatty liver disease can be a risk factor for developing adverse reactions to drugs, interfering with hepatic lipid metabolism, leading to idiosyncratic drug-induced liver injury. Drug-induced liver injury has been the major cause of drugs failing market-approval or for later withdrawal from the market. An improved preclinical detectability of such adverse reactions would therefore be highly appreciated by the industry, as well as by patients. The present work consists of three projects investigating molecular mechanisms of drug-induced hepatic steatosis in vitro, and is emphasizing on the application of an optimized method to measure the acylcarnitine pattern of cells, treated with toxicants. We focused on the measurement of acylcarnitines, because they are known to reflect the cellular acyl-CoA pattern, allowing us to make interpretations on the specific location of inhibition by a substance. Furthermore, the liquid chromatography-tandem mass spectrometry method, used for this determination, allows for a fast and economic workup and analysis of a high number of samples, applicable for high-throughput screenings. Additionally, the small sample volume needed for the analysis allows this assay to be linked together with many other 96-well format assays. An important finding in our study was that the acylcarnitine method repeatedly turned out to be a more sensitive approach to identify drugs inhibiting fatty acid oxidation, as the older, well-established methods, such as radio-enzymatic determination of β-oxidation inhibition, or lipid accumulation experiments. In the first paper, we aimed to establish and optimize the semi-quantitative acylcarnitine measurement with three specific and well-characterized inhibitors of fatty acid oxidation. We compared, as well as supplemented, the results of the new method with older, well-established methods. In a second step of the study, we applied the same methods on three compounds, of which adverse reactions are not well understood, to obtain new insights about their steatogenic mechanisms. In the two following papers, investigating the catechol-O-methyl-transferase inhibitors tolcapone and entacapone, we aimed to expand the knowledge of tolcapone-associated steatosis and liver toxicity observed in clinics. Entacapone was included as well, because of its structural similarity. We studied in detail effects on lipid metabolism, as well as on their actions on mitochondrial respiration and cell death, for a comprehensive toxicological study about the two drugs

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Whole-body hybrid positron emission tomography imaging yields clinically relevant information in the staging and restaging of sinonasal tumors

BACKGROUND Whole-body hybrid positron emission tomography (PET) imaging is increasingly used for sinonasal tumors. However, only empirical data exist on the additional, clinically relevant information derived from these techniques. METHODS This study included 96 regionalized magnetic resonance imaging (MRI) of the sinonasal tract/neck and separate hybrid FDG-PET/CT or FDG-PET/MRI in 74 patients. Additional radiological information (ARI) obtained from each hybrid examination was analyzed and its clinically relevance was determined. Clinically relevant information (CRI) was categorized with regard to primary tumor site, regional lymph node metastases, distant metastases, second primary tumors, and non-neoplastic findings. RESULTS A total of 45/96 (46.9%) hybrid PET examinations revealed ARI. CRI was found in 32/96 (33.3%) examinations and concerned the primary tumor site (6.1%), regional lymph node metastases (4.1%), distant metastases (14.3%), second primary tumors (7.3%), and non-neoplastic findings (5.1%). CONCLUSIONS Hybrid PET imaging yields additional radiological information translating into clinically relevant information in a substantial proportion of patients with sinonasal tumors

Eisenmenger Syndrome: JACC State-of-the-Art Review

Although major breakthroughs in the field of pediatric cardiology, cardiac surgery, intervention, and overall care improved the outlook of congenital heart disease, Eisenmenger syndrome (ES) is still encountered and remains a complex clinical entity with multisystem involvement, including secondary erythrocytosis, increased thrombotic and bleeding diathesis, high arrhythmogenic risk, progressive heart failure, and premature death. Clearly, care for ES is best delivered in multidisciplinary expert centers. In this review, we discuss the considerable recent progress in understanding the complex pathophysiology of ES, means of prognostication, and improvement in clinical outcomes achieved with pulmonary arterial hypertension–targeted therapies. Additionally, we delineate areas of uncertainty in various aspects of care, discuss gaps in current evidence, and review current status in less privileged countries and propose initiatives to reduce disease burden. Finally, we propose the application of emerging technologies to enhance the delivery and quality of health care related to ES and beyond