Publications by authors named "Gerd A Kullak-Ublick"

168 Publications

Evaluating the Sensitivity and Specificity of Promising Circulating Biomarkers to Diagnose Liver Injury in Humans.

Toxicol Sci 2021 Jan 23. Epub 2021 Jan 23.

Drug Safety Research and Development.

Early diagnosis of drug-induced liver injury (DILI) continues to be a major hurdle during drug development and post marketing. The objective of this study was to evaluate the diagnostic performance of promising biomarkers of liver injury-glutamate dehydrogenase (GLDH), cytokeratin-18 (K18), caspase-cleaved K18 (ccK18), osteopontin (OPN), macrophage colony-stimulating factor (MCSF), MCSF receptor (MCSFR), and microRNA-122 (miR-122) in comparison to the traditional biomarker alanine aminotransferase (ALT). Biomarkers were evaluated individually and as a multivariate model in a cohort of acetaminophen overdose (n = 175) subjects and were further tested in cohorts of healthy adults (n = 135), patients with liver damage from various causes (n = 104), and patients with damage to the muscle (n = 74), kidney (n = 40), gastrointestinal tract (n = 37) and pancreas (n = 34). In the acetaminophen cohort, a multivariate model with GLDH, K18 and miR-122 was able to detect DILI more accurately than individual biomarkers alone. Furthermore, the three-biomarker model could accurately predict patients with liver injury compared to healthy volunteers or patients with damage to muscle, pancreas, gastrointestinal tract and kidney. Expression of K18, GLDH ad miR-122 was evaluated using a database of transcriptomic profiles across multiple tissues/organs in humans and rats. K18 mRNA (Krt18) and MiR-122 were highly expressed in liver whereas GLDH mRNA (Glud1) was widely expressed. We performed a comprehensive, comparative performance assessment of seven promising biomarkers and demonstrated that a three-biomarker multivariate model can accurately detect liver injury.
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http://dx.doi.org/10.1093/toxsci/kfab003DOI Listing
January 2021

Oxidative stress increases 1-deoxysphingolipid levels in chronic kidney disease.

Free Radic Biol Med 2021 Feb 12;164:139-148. Epub 2021 Jan 12.

Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, 250355, PR China; Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250355, PR China; Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. Electronic address:

Chronic kidney disease (CKD) leads to deep changes in lipid metabolism and obvious dyslipidemia. The dysregulation of lipid metabolism in turn results in CKD progression and the complications of cardiovascular diseases. To obtain a profound insight into the associated dyslipidemia in CKD, we performed lipidomic analysis to measure lipid metabolites in the serum from a rat 5/6 nephrectomy (5/6 Nx) model of CKD as well as in the serum from CKD patients. HK-2 cells were also used to examine oxidative stress-induced sphingolipid changes. Totally 182 lipid species were identified in 5/6 Nx rats. We found glycerolipids, total free fatty acids, and sphingolipids levels were significantly upregulated in 5/6 Nx rats. The atypical sphingolipids, 1-deoxysphingolipids, were significantly altered in both CKD animals and human CKD patients. The levels of 1-deoxysphingolipids directly relevant to the level of oxidative stress in vivo and in vitro. These results demonstrate that 1-deoxysphingolipid levels are increased in CKD and this increase directly correlates with increased kidney oxidative stress.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.01.011DOI Listing
February 2021

Cholesterol stimulates the cellular uptake of L-carnitine by the carnitine/organic cation transporter novel 2 (OCTN2).

J Biol Chem 2020 Dec 17. Epub 2020 Dec 17.

Clinical Pharmacology and Toxicology, University Hospital of Zurich, Switzerland.

The carnitine/organic cation transporter novel 2 (OCTN2) is responsible for the cellular uptake of carnitine in most tissues. Being a transmembrane protein OCTN2 must interact with the surrounding lipid microenvironment to function. Among the main lipid species that constitutes eukaryotic cells, cholesterol level is highly dynamic under a number of physio-pathological conditions. This work describes how plasma membrane cholesterol modulates OCTN2 transport of L-carnitine in human embryonic kidney 293 cells overexpressing OCTN2 (OCTN2-HEK293) and in proteoliposomes harboring human OCTN2. We manipulated the cholesterol content of intact cells, assessed by thin layer chromatography, through short exposures to empty and/or cholesterol-saturated methyl-β-cyclodextrin (mβcd), whereas free cholesterol was used to enrich reconstituted proteoliposomes. We measured OCTN2 transport using [3H]L-carnitine, and expression levels and localization by surface biotinylation and western blotting. A 20-minute preincubation with mβcd reduced the cellular cholesterol content and inhibited L-carnitine influx by 50% in comparison to controls. Analogously, the insertion of cholesterol in OCTN2-proteoliposomes stimulated L-carnitine uptake in a dose-dependent manner. Carnitine uptake in cells incubated with empty mβcd and cholesterol-saturated mβcd to preserve cholesterol content was comparable to controls, suggesting that the mβcd effect on OCTN2 was cholesterol dependent. Cholesterol stimulated L-carnitine influx in cells by markedly increasing the affinity for L-carnitine and in proteoliposomes by significantly enhancing the affinity for Na+ and, in turn, the L-carnitine maximal transport capacity. Because of the antilipogenic and antioxidant features of L-carnitine, the stimulatory effect of cholesterol on L-carnitine uptake might represent a novel protective effect against lipid-induced toxicity and oxidative stress.
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http://dx.doi.org/10.1074/jbc.RA120.015175DOI Listing
December 2020

Organic Cation Transporters in Human Physiology, Pharmacology, and Toxicology.

Int J Mol Sci 2020 Oct 24;21(21). Epub 2020 Oct 24.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, 8006 Zurich, Switzerland.

Individual cells and epithelia control the chemical exchange with the surrounding environment by the fine-tuned expression, localization, and function of an array of transmembrane proteins that dictate the selective permeability of the lipid bilayer to small molecules, as actual gatekeepers to the interface with the extracellular space. Among the variety of channels, transporters, and pumps that localize to cell membrane, organic cation transporters (OCTs) are considered to be extremely relevant in the transport across the plasma membrane of the majority of the endogenous substances and drugs that are positively charged near or at physiological pH. In humans, the following six organic cation transporters have been characterized in regards to their respective substrates, all belonging to the solute carrier 22 (SLC22) family: the organic cation transporters 1, 2, and 3 (OCT1-3); the organic cation/carnitine transporter novel 1 and 2 (OCTN1 and N2); and the organic cation transporter 6 (OCT6). OCTs are highly expressed on the plasma membrane of polarized epithelia, thus, playing a key role in intestinal absorption and renal reabsorption of nutrients (e.g., choline and carnitine), in the elimination of waste products (e.g., trimethylamine and trimethylamine N-oxide), and in the kinetic profile and therapeutic index of several drugs (e.g., metformin and platinum derivatives). As part of the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations, this article critically presents the physio-pathological, pharmacological, and toxicological roles of OCTs in the tissues in which they are primarily expressed.
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http://dx.doi.org/10.3390/ijms21217890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660683PMC
October 2020

The Role of Mitochondria in Drug-Induced Kidney Injury.

Front Physiol 2020 4;11:1079. Epub 2020 Sep 4.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

The kidneys utilize roughly 10% of the body's oxygen supply to produce the energy required for accomplishing their primary function: the regulation of body fluid composition through secreting, filtering, and reabsorbing metabolites and nutrients. To ensure an adequate ATP supply, the kidneys are particularly enriched in mitochondria, having the second highest mitochondrial content and thus oxygen consumption of our body. The bulk of the ATP generated in the kidneys is consumed to move solutes toward (reabsorption) or from (secretion) the peritubular capillaries through the concerted action of an array of ATP-binding cassette (ABC) pumps and transporters. ABC pumps function upon direct ATP hydrolysis. Transporters are driven by the ion electrochemical gradients and the membrane potential generated by the asymmetric transport of ions across the plasma membrane mediated by the ATPase pumps. Some of these transporters, namely the polyspecific organic anion transporters (OATs), the organic anion transporting polypeptides (OATPs), and the organic cation transporters (OCTs) are highly expressed on the proximal tubular cell membranes and happen to also transport drugs whose levels in the proximal tubular cells can rapidly rise, thereby damaging the mitochondria and resulting in cell death and kidney injury. Drug-induced kidney injury (DIKI) is a growing public health concern and a major cause of drug attrition in drug development and post-marketing approval. As part of the article collection "Mitochondria in Renal Health and Disease," here, we provide a critical overview of the main molecular mechanisms underlying the mitochondrial damage caused by drugs inducing nephrotoxicity.
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http://dx.doi.org/10.3389/fphys.2020.01079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500167PMC
September 2020

Untargeted Metabolomics Reveals Anaerobic Glycolysis as a Novel Target of the Hepatotoxic Antidepressant Nefazodone.

J Pharmacol Exp Ther 2020 11 26;375(2):239-246. Epub 2020 Aug 26.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (E.K., M.V., Z.G., B.S., S.L.S., S.H., G.A.K.-U.); Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETHZ), Zurich, Switzerland (E.K.);and Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland (G.A.K.-U.).

Mitochondrial damage is considered a hallmark of drug-induced liver injury (DILI). However, despite the common molecular etiology, the evolution of the injury is usually unpredictable, with some cases that are mild and reversible upon discontinuation of the treatment and others characterized by irreversible acute liver failure. This suggests that additional mechanisms of damage play a role in determining the progression of the initial insult. To uncover novel pathways potentially involved in DILI, we investigated in vitro the metabolic perturbations associated with nefazodone, an antidepressant associated with acute liver failure. Several pathways associated with ATP production, including gluconeogenesis, anaerobic glycolysis, and oxidative phosphorylation, were altered in human hepatocellular carcinoma-derived (Huh7) cells after 2-hour exposure to a 50 μM extracellular concentration of nefazodone. In the presence or absence of glucose, ATP production of Huh7 cells was glycolysis- and oxidative phosphorylation-dependent, respectively. In glucose-containing medium, nefazodone-induced ATP depletion from Huh7 cells was biphasic. Huh7 cells in glucose-free medium were more sensitive to nefazodone than those in glucose-containing medium, losing the biphasic inhibition. Nefazodone-induced ATP depletion in primary cultured mouse hepatocytes, mainly dependent on oxidative phosphorylation, was monophasic. At lower extracellular concentrations, nefazodone inhibited the oxygen consumption of Huh7 cells, whereas at higher extracellular concentrations, it also inhibited the extracellular acidification. ATP content was rescued by increasing the extracellular concentration of glucose. In conclusion, nefazodone has a dual inhibitory effect on mitochondrial-dependent and mitochondrial-independent ATP production. SIGNIFICANCE STATEMENT: Mitochondrial damage is a hallmark of drug-induced liver injury, yet other collateral alterations might contribute to the severity and evolution of the injury. Our in vitro study supports previous results arguing that a deficit in hepatic glucose metabolism, concomitant to the mitochondrial injury, might be cardinal in the prognosis of the initial insult to the liver. From a drug development standpoint, coupling anaerobic glycolysis and mitochondrial function assessment might increase the drug-induced liver injury preclinical screening performance.
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http://dx.doi.org/10.1124/jpet.120.000120DOI Listing
November 2020

Best practices for detection, assessment and management of suspected immune-mediated liver injury caused by immune checkpoint inhibitors during drug development.

J Autoimmun 2020 11 5;114:102514. Epub 2020 Aug 5.

Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address:

Immune checkpoint inhibitors (ICIs) have shown significant efficacy in patients with various malignancies, however, they are associated with a wide range of immune-related toxicities affecting many organs, including the liver. Immune-mediated liver injury caused by checkpoint inhibitors (ILICI) is a distinctive form of drug induced liver injury (DILI), that differs from most DILI types in presumed underlying mechanism, incidence, and response to therapeutic interventions. Despite increased awareness of ILICI and other immune-related adverse effects of ICIs reflected by recent guidelines for their management in post marketing clinical practice, there is lack of uniform best practices to address ILICI risk during drug development. As efforts to develop safer and more effective ICIs for additional indications grow, and as combination therapies including ICIs are increasingly investigated, there is a growing need for consistent practices for ILICI in drug development. This publication summarizes current best practices to optimize the monitoring, diagnosis, assessment, and management of suspected ILICI in clinical trials using ICI as a single agent and in combination with other ICIs or other oncological agents. It is one of several publications developed by the IQ DILI Initiative in collaboration with DILI experts from academia and regulatory agencies. Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, ILICI detection, approach to a suspected ILICI signal, causality assessment, hepatic discontinuation rules and additional medical treatment.
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http://dx.doi.org/10.1016/j.jaut.2020.102514DOI Listing
November 2020

Dual-Functional Plasmonic Photothermal Biosensors for Highly Accurate Severe Acute Respiratory Syndrome Coronavirus 2 Detection.

ACS Nano 2020 May 13;14(5):5268-5277. Epub 2020 Apr 13.

Institute of Environmental Engineering, ETH Zürich, Zürich 8093, Switzerland.

The ongoing outbreak of the novel coronavirus disease (COVID-19) has spread globally and poses a threat to public health in more than 200 countries. Reliable laboratory diagnosis of the disease has been one of the foremost priorities for promoting public health interventions. The routinely used reverse transcription polymerase chain reaction (RT-PCR) is currently the reference method for COVID-19 diagnosis. However, it also reported a number of false-positive or -negative cases, especially in the early stages of the novel virus outbreak. In this work, a dual-functional plasmonic biosensor combining the plasmonic photothermal (PPT) effect and localized surface plasmon resonance (LSPR) sensing transduction provides an alternative and promising solution for the clinical COVID-19 diagnosis. The two-dimensional gold nanoislands (AuNIs) functionalized with complementary DNA receptors can perform a sensitive detection of the selected sequences from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through nucleic acid hybridization. For better sensing performance, the thermoplasmonic heat is generated on the same AuNIs chip when illuminated at their plasmonic resonance frequency. The localized PPT heat is capable to elevate the hybridization temperature and facilitate the accurate discrimination of two similar gene sequences. Our dual-functional LSPR biosensor exhibits a high sensitivity toward the selected SARS-CoV-2 sequences with a lower detection limit down to the concentration of 0.22 pM and allows precise detection of the specific target in a multigene mixture. This study gains insight into the thermoplasmonic enhancement and its applicability in the nucleic acid tests and viral disease diagnosis.
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http://dx.doi.org/10.1021/acsnano.0c02439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158889PMC
May 2020

Medication as a risk factor for hospitalization due to heart failure and shock: a series of case-crossover studies in Swiss claims data.

Eur J Clin Pharmacol 2020 Jul 8;76(7):979-989. Epub 2020 Apr 8.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Purpose: Heart failure is among the leading causes for hospitalization in Europe. In this study, we evaluate potential precipitating factors for hospitalization for heart failure and shock.

Methods: Using Swiss claims data (2014-2015), we evaluated the association between hospitalization for heart failure and shock, and prescription of oral potassium supplements, non-steroidal anti-inflammatory drugs (NSAIDs), and amoxicillin/clavulanic acid. We conducted case-crossover analyses, where exposure was compared for the hazard period and the primary control period (e.g., 1-30 days before hospitalization vs. 31-60 days, respectively). Conditional logistic regression was applied and subsequently adjusted for addressing potential confounding by disease progression. Sensitivity analyses were conducted and stratification for co-medication was performed.

Results: We identified 2185 patients hospitalized with heart failure or shock. Prescription of potassium supplements, NSAIDs, and amoxicillin/clavulanic acid was significantly associated with an increased risk for hospitalization for heart failure and shock with crude odds ratios (OR) of 2.04 for potassium (95% CI 1.24-3.36, p = 0.005, 30 days), OR 1.8 for NSAIDs (95% CI 1.39-2.33, p < 0.0001, 30 days), and OR 3.25 for amoxicillin/clavulanic acid (95% CI 2.06-5.14, p < 0.0001, 15 days), respectively. Adjustment attenuated odds ratios, while the significant positive association remained (potassium OR 1.70 (95% CI 1.01-2.86, p = 0.046), NSAIDs OR 1.50 (95% CI 1.14-1.97, p = 0.003), and amoxicillin/clavulanic acid OR 2.26 (95% CI 1.41-3.62, p = 0.001).

Conclusion: Prescription of potassium supplements, NSAIDs, and amoxicillin/clavulanic acid is associated with increased risk for hospitalization. Underlying conditions such as pain, electrolyte imbalances, and infections are likely contributing risk factors. Physicians may use this knowledge to better identify patients at risk and adapt patient management.
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http://dx.doi.org/10.1007/s00228-020-02835-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306029PMC
July 2020

Obeticholic Acid Ameliorates Valproic Acid-Induced Hepatic Steatosis and Oxidative Stress.

Mol Pharmacol 2020 05 25;97(5):314-323. Epub 2020 Feb 25.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (Z.G., E.K., S.L.S., M.V., G.A.K.-U.); Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETHZ), Zurich, Switzerland (E.K.); and Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland (G.A.K.-U.)

Farnesoid X receptor (FXR), or NR1H4, protects the liver from insults of various etiologies. A role of FXR in drug-induced liver injury has also been hypothesized yet only marginally investigated. The aim of this study was to assess the effect of FXR activation on gene expression and phenotype of the liver of mice treated with valproic acid (VPA), or 2-propylpentanoic acid, a prototypical hepatotoxic drug. Obeticholic acid (OCA) was used to activate FXR both in mice and in human hepatocellular carcinoma (Huh-7) cells. Next-generation sequencing of mouse liver tissues was performed from control, VPA, and VPA + OCA-treated mice. Pathway analysis validation was performed using real-time reverse-transcription polymerase chain reaction, Western blotting, immunohistochemistry, and fluorometric assays. FXR activation induced antioxidative pathways, which was confirmed by a marked reduction in VPA-induced lipid peroxidation and endoplasmic reticulum stress. In vitro, VPA-induced oxidative stress was independent of lipid accumulation, stemmed from the cytoplasm, and was mitigated by OCA. In the liver of the mice treated with OCA, the levels of cytochrome P450 potentially involved in VPA metabolism were increased. The hepatic lipid-lowering effect observed in animals cotreated with VPA and OCA in comparison with that of animals treated with VPA was associated with regulation of the genes involved in the steatogenic nuclear receptor peroxisome proliferator-activated (PPAR) pathway. In conclusion, pronounced antioxidant activity, repression of the PPAR pathway, and higher expression of P450 enzymes involved in VPA metabolism may underlie the hepatoprotective of FXR activation during VPA treatment. SIGNIFICANCE STATEMENT: Valproic acid-induced oxidative stress occurs in absence of lipid accumulation and is not of mitochondrial origin. Valproic acid exposure induces the expression of the steatogenic nuclear receptor peroxisome proliferator-activated γ (PPARγ) and its downstream target genes. Constitutive activation of the farnesoid X receptor (FXR) reduces PPARγ hepatic expression and induces hepatic antioxidant activity. The variability in FXR expression level/activity, for instance in individuals carrying loss-of-function genetic variants of the FXR gene, could contribute to valproic acid pharmacokinetic and toxicokinetic profile.
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http://dx.doi.org/10.1124/mol.119.118646DOI Listing
May 2020

Farnesoid X receptor activation induces the degradation of hepatotoxic 1-deoxysphingolipids in non-alcoholic fatty liver disease.

Liver Int 2020 04 8;40(4):844-859. Epub 2020 Jan 8.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Background & Aims: Patients with non-alcoholic fatty liver disease (NAFLD) exhibit higher levels of plasma 1-deoxysphingolipids than healthy individuals. The aim of this study was to investigate the role of farnesoid X receptor (FXR) in 1-deoxysphingolipid de novo synthesis and degradation.

Methods: Mice were fed with a high-fat diet (HFD) to induce obesity and NAFLD, and then treated with the FXR ligand obeticholic acid (OCA). Histology and gene expression analysis were performed on liver tissue. Sphingolipid patterns from NAFLD patients and mouse models were assessed by liquid chromatography-mass spectrometry. The molecular mechanism underlying the effect of FXR activation on sphingolipid metabolism was studied in Huh7 cells and primary cultured hepatocytes, as well as in a 1-deoxysphinganine-treated mouse model.

Results: 1-deoxysphingolipids were increased in both NAFLD patients and mouse models. FXR activation by OCA protected the liver against oxidative stress, apoptosis, and reduced 1-deoxysphingolipid levels, both in a HFD-induced mouse model of obesity and in 1-deoxysphinganine-treated mice. In vitro, FXR activation lowered intracellular 1-deoxysphingolipid levels by inducing Cyp4f-mediated degradation, but not by inhibiting de novo synthesis, thereby protecting hepatocytes against doxSA-induced cytotoxicity, mitochondrial damage, and apoptosis. Overexpression of Cyp4f13 in cells was sufficient to ameliorate doxSA-induced cytotoxicity. Treatment with the Cyp4f pan-inhibitor HET0016 or FXR knock-down fully abolished the protective effect of OCA, indicating that OCA-mediated 1-deoxysphingolipid degradation is FXR and Cyp4f dependent.

Conclusions: Our study identifies FXR-Cyp4f as a novel regulatory pathway for 1-deoxysphingolipid metabolism. FXR activation represents a promising therapeutic strategy for patients with metabolic syndrome and NAFLD.
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http://dx.doi.org/10.1111/liv.14340DOI Listing
April 2020

Effects of Farnesiferol B on Ischemia-Reperfusion-Induced Renal Damage, Inflammation, and NF-κB Signaling.

Int J Mol Sci 2019 Dec 12;20(24). Epub 2019 Dec 12.

College of Traditional Chinese Medicine; Shandong Co-innovation Center of TCM Formula; Institute for Literature and Culture of Chinese Medicine; Key Laboratory of Traditional Chinese Medicine for Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.

Background: G-protein-coupled bile acid receptor (TGR5), a membrane bile acid receptor, regulates macrophage reactivity, and attenuates inflammation in different disease models. However, the regulatory effects of TGR5 in ischemia/reperfusion (I/R)-induced kidney injury and inflammation have not yet been extensively studied. Therefore, we hypothesize that Farnesiferol B, a natural TGR5 agonist, could alleviate renal I/R injury by reducing inflammation and macrophage migration through activating TGR5.

Methods: Mice were treated with Farnesiferol B before I/R or sham procedures. Renal function, pathological analysis, and inflammatory mediators were examined. In vitro, the regulatory effects of Farnesiferol B on the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway in macrophages were investigated.

Results: After I/R, Farnesiferol B-treated mice displayed better renal function and less tubular damage. Farnesiferol B reduced renal oxidative stress and inflammation significantly. In vitro, Farnesiferol B treatment alleviated lipopolysaccharide (LPS)-induced macrophage migration and activation, as well as LPS-induced NF-κB activation through TGR5.

Conclusions: Farnesiferol B could protect kidney function from I/R-induced damage by attenuating inflammation though activating TGR5 in macrophages. Farnesiferol B might be a potent TGR5 ligand for the treatment of I/R-induced renal inflammation.
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http://dx.doi.org/10.3390/ijms20246280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940812PMC
December 2019

Prediction of health care expenditure increase: how does pharmacotherapy contribute?

BMC Health Serv Res 2019 Dec 11;19(1):953. Epub 2019 Dec 11.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Background: Rising health care costs are a major public health issue. Thus, accurately predicting future costs and understanding which factors contribute to increases in health care expenditures are important. The objective of this project was to predict patients healthcare costs development in the subsequent year and to identify factors contributing to this prediction, with a particular focus on the role of pharmacotherapy.

Methods: We used 2014-2015 Swiss health insurance claims data on 373'264 adult patients to classify individuals' changes in health care costs. We performed extensive feature generation and developed predictive models using logistic regression, boosted decision trees and neural networks. Based on the decision tree model, we performed a detailed feature importance analysis and subgroup analysis, with an emphasis on drug classes.

Results: The boosted decision tree model achieved an overall accuracy of 67.6% and an area under the curve-score of 0.74; the neural network and logistic regression models performed 0.4 and 1.9% worse, respectively. Feature engineering played a key role in capturing temporal patterns in the data. The number of features was reduced from 747 to 36 with only a 0.5% loss in the accuracy. In addition to hospitalisation and outpatient physician visits, 6 drug classes and the mode of drug administration were among the most important features. Patient subgroups with a high probability of increase (up to 88%) and decrease (up to 92%) were identified.

Conclusions: Pharmacotherapy provides important information for predicting cost increases in the total population. Moreover, its relative importance increases in combination with other features, including health care utilisation.
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http://dx.doi.org/10.1186/s12913-019-4616-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907182PMC
December 2019

Plasma Membrane Cholesterol Regulates the Allosteric Binding of 1-Methyl-4-Phenylpyridinium to Organic Cation Transporter 2 (SLC22A2).

J Pharmacol Exp Ther 2020 01 17;372(1):46-53. Epub 2019 Oct 17.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland (S.H., Z.G., G.A.K.-U., M.V.); Key Laboratory of Traditional Chinese Medicine for Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China (Z.G.); and Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland (G.A.K.-U.)

The human organic cation transporter 2 (OCT2) mediates the first step of tubular secretion of most positively charged substances. We describe the role of plasma membrane cholesterol in OCT2 activity. Human embryonic kidney 293 cells overexpressing OCT2 (OCT2-HEK293) and wild-type HEK293 cells (WT-HEK293) were employed. Cellular cholesterol content, assessed by thin layer chromatography, was manipulated using empty methyl--cyclodextrin (mcd) and cholesterol-presaturated mcd (RAMEB). The effect of mcd on OCT2 protein stability and oligomerization state was evaluated by immunofluorescence and Western blotting. Transport activity of OCT2 was measured using [H]1-methyl-4-phenylpyridinium (MPP). A 20-minute incubation with mcd reduced the total cellular cholesterol content by 40% to 60% as compared with that in untreated cells, without altering the content of the other main lipid species. In this condition, OCT2-mediated uptake of MPP was reduced by ∼50%. When cells were coincubated with empty mcd and RAMEB, the cholesterol content and OCT2-mediated uptake of MPP were comparable to those in untreated cells, suggesting that the mcd effect on OCT2 activity was cholesterol dependent. In untreated cells, the MPP influx kinetics was allosteric, whereas in cells treated with mcd, one binding site was observed. Our findings suggest that changes in cellular cholesterol content can dramatically alter OCT2-mediated transport, potentially resulting in abnormal tubular secretion and unexpected drug toxicity and drug-drug interactions. SIGNIFICANCE STATEMENT: Plasma membrane cholesterol is important for the allosteric properties of OCT2. From a pharmacologic standpoint, the variability in cholesterol content stemming from certain pathophysiologic conditions such as aging and acute kidney injury should be taken into account as additional source of interpatient pharmacokinetic/pharmacodynamic variability and unexpected toxicity profile of OCT2 substrates, which can escape preclinical and clinical development.
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http://dx.doi.org/10.1124/jpet.119.260877DOI Listing
January 2020

Endothelial SIRT6 blunts stroke size and neurological deficit by preserving blood-brain barrier integrity: a translational study.

Eur Heart J 2020 04;41(16):1575-1587

Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, Schlieren 8952, Switzerland.

Aims: Aging is an established risk factor for stroke; genes regulating longevity are implicated in the pathogenesis of ischaemic stroke where to date, therapeutic options remain limited. The blood-brain barrier (BBB) is crucially involved in ischaemia/reperfusion (I/R) brain injury thus representing an attractive target for developing novel therapeutic agents. Given the role of endothelial cells in the BBB, we hypothesized that the endothelial-specific expression of the recently described longevity gene SIRT6 may exhibit protective properties in stroke.

Methods And Results: SIRT6 endothelial expression was reduced following stroke. Endothelial-specific Sirt6 knockout (eSirt6-/-) mice, as well as animals in which Sirt6 overexpression was post-ischaemically induced, underwent transient middle cerebral artery occlusion (tMCAO). eSirt6-/- animals displayed increased infarct volumes, mortality, and neurological deficit after tMCAO, as compared to control littermates. Conversely, post-ischaemic Sirt6 overexpression decreased infarct size and neurological deficit. Analysis of ischaemic brain sections revealed increased BBB damage and endothelial expression of cleaved caspase-3 in eSIRT6-/- mice as compared to controls. In primary human brain microvascular endothelial cells (HBMVECs), hypoxia/reoxygenation (H/R) reduced SIRT6 expression and SIRT6 silencing impaired the barrier function (transendothelial resistance) similar to what was observed in mice exposed to I/R. Further, SIRT6-silenced HBMVECs exposed to H/R showed reduced viability, increased cleaved caspase-3 expression and reduced activation of the survival pathway Akt. In ischaemic stroke patients, SIRT6 expression was higher in those with short-term neurological improvement as assessed by NIHSS scale and correlated with stroke outcome.

Conclusion: Endothelial SIRT6 exerts a protective role in ischaemic stroke by blunting I/R-mediated BBB damage and thus, it may represent an interesting novel therapeutic target to be explored in future clinical investigation.
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http://dx.doi.org/10.1093/eurheartj/ehz712DOI Listing
April 2020

Renal glycosuria as a novel early sign of colistin-induced kidney damage in mice.

Antimicrob Agents Chemother 2019 Oct 7. Epub 2019 Oct 7.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, 8006 Zurich, Switzerland.

The polymixin colistin represents a last resort antibiotic for multidrug resistant infections, but its use is limited by the frequent onset of acute drug-induced kidney injury (DIKI). It is essential to closely monitor kidney function prior to and during colistin treatment in order to pinpoint early signs of injury and minimise long-term renal dysfunction. To facilitate this, a mouse model of colistin-induced nephrotoxicity was used to uncover novel early markers of colistin-induced DIKI. Increased urinary levels of kidney injury molecule 1 (Kim-1) as well as glycosuria were observed in colistin-treated mice, where alterations of established clinical markers of acute kidney injury (serum creatinine and albuminuria) and emerging markers such as cystatin C were inaccurate in flagging renal damage as confirmed by histology. A direct interaction of colistin with renal glucose reabsorption was ruled out by a -inhibition assay in mouse brush border membrane vesicles (BBMV). Immunohistochemical examination and protein quantification by western blotting showed a marked reduction in the protein amount of sodium-glucose transporter 2 (Sglt2), the main kidney glucose transporter, in renal tissue from colistin-treated mice in comparison to control animals. Consistently, BBMV isolated from treated mouse kidneys also showed a reduction in glucose uptake when compared to BBMV isolated from control kidneys. These findings support pathology observations of colistin-induced proximal tubule damage at the site of the brush border membrane, where Sglt2 is expressed, and open avenues for the study of glycosuria as a sensitive, specific, and accessible marker of DIKI during colistin therapy.
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http://dx.doi.org/10.1128/AAC.01650-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879251PMC
October 2019

Renal Reabsorption of Folates: Pharmacological and Toxicological Snapshots.

Nutrients 2019 Oct 2;11(10). Epub 2019 Oct 2.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, 8006 Zurich, Switzerland.

Folates are water-soluble B9 vitamins that serve as one-carbon donors in the de novo synthesis of thymidylate and purines, and in the conversion of homocysteine to methionine. Due to their key roles in nucleic acid synthesis and in DNA methylation, inhibiting the folate pathway is still one of the most efficient approaches for the treatment of several tumors. Methotrexate and pemetrexed are the most prescribed antifolates and are mainly used in the treatment of acute myeloid leukemia, osteosarcoma, and lung cancers. Normal levels of folates in the blood are maintained not only by proper dietary intake and intestinal absorption, but also by an efficient renal reabsorption that seems to be primarily mediated by the glycosylphosphatidylinositol- (GPI) anchored protein folate receptor α (FRα), which is highly expressed at the brush-border membrane of proximal tubule cells. Folate deficiency due to malnutrition, impaired intestinal absorption or increased urinary elimination is associated with severe hematological and neurological deficits. This review describes the role of the kidneys in folate homeostasis, the molecular basis of folate handling by the kidneys, and the use of high dose folic acid as a model of acute kidney injury. Finally, we provide an overview on the development of folate-based compounds and their possible therapeutic potential and toxicological ramifications.
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http://dx.doi.org/10.3390/nu11102353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836044PMC
October 2019

Hypermethylation-associated downregulation of microRNA-4456 in hypersexual disorder with putative influence on oxytocin signalling: A DNA methylation analysis of miRNA genes.

Epigenetics 2020 Jan - Feb;15(1-2):145-160. Epub 2019 Sep 22.

Department of Clinical Sciences/Psychiatry, Umeå University, Umeå, Sweden.

Hypersexual disorder (HD) was proposed as a diagnosis in the DSM-5 and the classification 'Compulsive Sexual Behavior Disorder' is now presented as an impulse-control disorder in ICD-11. HD incorporates several pathophysiological mechanisms; including impulsivity, compulsivity, sexual desire dysregulation and sexual addiction. No previous study investigated HD in a methylation analysis limited to microRNA (miRNA) associated CpG-sites. The genome wide methylation pattern was measured in whole blood from 60 subjects with HD and 33 healthy volunteers using the Illumina EPIC BeadChip. 8,852 miRNA associated CpG-sites were investigated in multiple linear regression analyses of methylation M-values to a binary independent variable of disease state (HD or healthy volunteer), adjusting for optimally determined covariates. Expression levels of candidate miRNAs were investigated in the same individuals for differential expression analysis. Candidate methylation loci were further studied for an association with alcohol dependence in an independent cohort of 107 subjects. Two CpG-sites were borderline significant in HD - cg18222192 (MIR708)( < 10E-05, = 5.81E-02) and cg01299774 (MIR4456)(p < 10E-06, = 5.81E-02). MIR4456 was significantly lower expressed in HD in both univariate (p < 0.0001) and multivariate (p < 0.05) analyses. Cg01299774 methylation levels were inversely correlated with expression levels of MIR4456 (p < 0.01) and were also differentially methylated in alcohol dependence (p = 0.026). Gene target prediction and pathway analysis revealed that MIR4456 putatively targets genes preferentially expressed in brain and that are involved in major neuronal molecular mechanisms thought to be relevant for HD, e.g., the oxytocin signalling pathway. In summary, our study implicates a potential contribution of MIR4456 in the pathophysiology of HD by putatively influencing oxytocin signalling.
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http://dx.doi.org/10.1080/15592294.2019.1656157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961682PMC
September 2019

Drug-induced liver injury.

Nat Rev Dis Primers 2019 08 22;5(1):58. Epub 2019 Aug 22.

National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Centre, Nottingham University Hospital NHS Trust and University of Nottingham, Nottingham, UK.

Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs either as a predictable event when an individual is exposed to toxic doses of some compounds or as an unpredictable event with many drugs in common use. Drugs can be harmful to the liver in susceptible individuals owing to genetic and environmental risk factors. These risk factors modify hepatic metabolism and excretion of the DILI-causative agent leading to cellular stress, cell death, activation of an adaptive immune response and a failure to adapt, with progression to overt liver injury. Idiosyncratic DILI is a relative rare hepatic disorder but can be severe and, in some cases, fatal, presenting with a variety of phenotypes, which mimic other hepatic diseases. The diagnosis of DILI relies on the exclusion of other aetiologies of liver disease as specific biomarkers are still lacking. Clinical scales such as CIOMS/RUCAM can support the diagnostic process but need refinement. A number of clinical variables, validated in prospective cohorts, can be used to predict a more severe DILI outcome. Although no pharmacological therapy has been adequately tested in randomized clinical trials, corticosteroids can be useful, particularly in the emergent form of DILI related to immune-checkpoint inhibitors in patients with cancer.
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http://dx.doi.org/10.1038/s41572-019-0105-0DOI Listing
August 2019

microRNA-206 modulates the hepatic expression of the organic anion-transporting polypeptide 1B1.

Liver Int 2019 12 3;39(12):2350-2359. Epub 2019 Sep 3.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zürich, Switzerland.

Background & Aims: The organic anion-transporting polypeptide 1B1 (OATP1B1) is an anion exchanger expressed at the hepatocyte sinusoidal membrane, which mediates the uptake of several endogenous metabolites and drugs. OATP1B1 expression level and activity are major sources of inter-patient variability of pharmacokinetics and pharmacodynamics of several drugs. Besides the genotype, factors that contribute to the inter-individual variability in OATP1B1 expression level are practically unknown. The aim of this work was to uncover novel epigenetic mechanisms of OATP1B1 regulation.

Methods: A functional screening strategy to assess the effect of microRNAs on the uptake of estrone-3-sulphate, an OATP1B1 substrate, into human hepatocellular carcinoma (Huh-7) cells was used. microRNA-206 (miR-206) expression in human liver tissues was measured by real-time RT-PCR. OATP1B1 expression in Huh-7 and in human liver tissues was assessed by real-time RT-PCR, Western blotting and immunostaining. The mRNA-miRNA interaction was assessed by reporter assay.

Results: miR-206 mimic repressed mRNA and protein expression of OATP1B1 in Huh-7 cells. The intracellular accumulation of estrone-3-sulphate was reduced by 30% in cells overexpressing miR-206. The repressive effect of miR-206 on the activity of the firefly luciferase gene 2 under the control of the OATP1B1 3' untranslated region was lost upon deletion of the predicted miR-206 binding site. Hepatic miR-206 level negatively correlated with OATP1B1 mRNA and protein levels extracted from normal human liver tissues.

Conclusions: miR-206 exerts a suppressive effect on OATP1B1 expression by an epigenetic mechanism. Individuals with high hepatic levels of miR-206 appear to display lower level of OATP1B1.
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http://dx.doi.org/10.1111/liv.14212DOI Listing
December 2019

Pharmacovigilance in ophthalmology in Switzerland: an analysis of the most frequently reported ocular adverse drug reactions within the last 25 years.

Swiss Med Wkly 2019 06 30;149:w20085. Epub 2019 Jun 30.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland / National Poisons Information Centre, Tox Info Suisse, Associated Institute of the University of Zurich, Switzerland / Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH, Zurich, Switzerland.

Aims Of The Study: Although systemic drugs can exert local effects on the eye, ophthalmology is a medical specialty with perhaps the fewest assessed adverse drug reactions (ADRs), representing a particular challenge in pharmacovigilance. Our aim was to quantify ADRs in ophthalmology in Switzerland, with a focus on angiogenesis inhibitors.

Methods: Individual case safety reports (ICSRs) on suspected ADRs reported in Switzerland from January 1991 to June 2016 were extracted from the WHO Global ICSR database, VigiBase™. ICSRs were analysed in relation to treatment duration, patient age, route of administration, patient sex and reported symptoms.

Results: A total of 80,515 ICSRs were reported in Switzerland during the reference period. Reactions linked to eye disorders accounted for 2793 (3.5%) cases. The main Anatomic Therapeutic Chemical / Defined Daily Dose drug classes associated with eye disorders were drugs acting on the nervous system (27.7%) followed by drugs “acting on sensory organs” (20.2%) and antineoplastic agents (18.0%). Most cases involved adult patients (70.6%). Patients over 60 years accounted for 815 (29.2%) ICSRs, and reactions in children were significantly less frequent (8.2%). Older patients were exposed to a higher number of drugs, and the majority of serious reactions involved children and older patients. A significant positive correlation between polypharmacy and seriousness of reported reactions was observed. The reported drugs were categorised as “suspected” in 51.1%, “concomitant” in 43.3% and “interacting” in 2.6% of cases. “Visual impairment” was the most commonly reported adverse reaction, experienced by 635 (22.7%) of patients (7.2% of all reported eye-related symptoms). The majority of reactions were transient, as 4173 (47.1%) completely resolved. Severe reactions included fatal outcome in 18 patients (0.6%) and blindness in 78 patients (2.6%). Since 2000, the intravitreous vascular endothelial growth factor (VEGF) inhibitors bevacizumab, aflibercept and ranibizumab accounted for 99 ICSRs. Retinal haemorrhage (reporting odds ratio [ROR] 10.36, 95% confidence interval [95% CI] 2.65–40.50; p <0.001), blindness (ROR 3.73, 95% CI 1.08–12.96; p = 0.04) and uveitis (ROR 6.91, 95% CI 1.64–29.13; p = 0.01) were significantly more frequently reported for aflibercept than for bevacizumab and ranibizumab.

Conclusions: ADRs that affect the eye represented 3.5% of all pharmacovigilance reports during the reporting period. Whereas retinal haemorrhage and uveitis are known adverse reactions to angiogenesis inhibitors, the reported cases of blindness and death should heighten awareness of potential safety issues associated with VEGF inhibitors for the treatment of proliferative eye disorders.
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http://dx.doi.org/10.4414/smw.2019.20085DOI Listing
June 2019

Drugs and hepatic transporters: A review.

Pharmacol Res 2020 04 17;154:104234. Epub 2019 Apr 17.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Rämistrasse 100, CH-8091 Zürich, Switzerland.

The liver is the primary organ for the metabolic degradation of xenobiotics. Transmembrane transport proteins from the ABC and the SLC families mediate the uptake of endogenous compounds and xenobiotics into the hepatocyte as well as their elimination from the cells. Multiple processes are involved. The uptake of xenobiotics in hepatocytes is mediated by organic anion transporting polypeptides (OATPs) and by organic anion and cation transporters (OATs and OCTs). The elimination of drugs and metabolites from the liver cell back to the bloodstream is accomplished mainly by multidrug resistance-associated protein 3 (MRP3) and MRP4, while the elimination towards the biliary canaliculi is mediated by several different transporters (MRP2, BCRP, MDR1 and MATE1). Since bile acids and their salts are toxic detergents for hepatocytes, they have to be eliminated efficiently. This task is accomplished by the bile salt export pump BSEP. Two further transporters, MDR3 and ATP8B1 are involved in the proper constitution of bile. All these transporters can be influenced, mainly inhibited by a number of drugs, but also by metabolites from endogenous compounds such as estrogens. Additionally, rare monogenetic diseases exist which can be explained by absence of function or dysfunction of specific hepatic transporters, such as progressive familial intrahepatic cholestasis type 2 by genetic modifications in BSEP that lead to a loss of transporter function. Functional impairment of other transporters by genetics or by drugs also leads to liver injury, a potentially life-threatening disease that is still not fully understood. Hence, the interplay between drugs and hepatic transporters is multiple, and the knowledge of this interplay helps in understanding the etiology and molecular mechanisms behind some forms of (drug-induced) liver injury.
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http://dx.doi.org/10.1016/j.phrs.2019.04.018DOI Listing
April 2020

Lipid Accumulation and Chronic Kidney Disease.

Nutrients 2019 Mar 28;11(4). Epub 2019 Mar 28.

Institute for Literature and Culture of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.

Obesity and hyperlipidemia are the most prevalent independent risk factors of chronic kidney disease (CKD), suggesting that lipid accumulation in the renal parenchyma is detrimental to renal function. Non-esterified fatty acids (also known as free fatty acids, FFA) are especially harmful to the kidneys. A concerted, increased FFA uptake due to high fat diets, overexpression of fatty acid uptake systems such as the CD36 scavenger receptor and the fatty acid transport proteins, and a reduced β-oxidation rate underlie the intracellular lipid accumulation in non-adipose tissues. FFAs in excess can damage podocytes, proximal tubular epithelial cells and the tubulointerstitial tissue through various mechanisms, in particular by boosting the production of reactive oxygen species (ROS) and lipid peroxidation, promoting mitochondrial damage and tissue inflammation, which result in glomerular and tubular lesions. Not all lipids are bad for the kidneys: polyunsaturated fatty acids (PUFA) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) seem to help lag the progression of chronic kidney disease (CKD). Lifestyle interventions, especially dietary adjustments, and lipid-lowering drugs can contribute to improve the clinical outcome of patients with CKD.
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http://dx.doi.org/10.3390/nu11040722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520701PMC
March 2019

Kounis syndrome: A retrospective analysis of individual case safety reports from the international WHO database in pharmacovigilance
.

Int J Clin Pharmacol Ther 2019 May;57(5):240-248

Objective: Kounis syndrome (KS) is an acute coronary syndrome with coronary spasm, acute myocardial infarction and stent thrombosis that can be associated with a variety of drugs as an adverse drug reaction (ADR). To characterize this rare phenomenon, we analyzed all cases of KS in the WHO database for pharmacovigilance.

Materials And Methods: All cases of KS worldwide until December 31, 2017, were included and analyzed in terms of age, sex, country, year of ADR, seriousness, clinical outcome, suspected drugs, administration, reported reaction, and -MedDRA terms. Time to onset of the ADR was calculated, and a subgroup analysis of KS associated with analgesics was performed. IC025 values were calculated for the most frequently reported pain medication to indicate the strength of relation between ADR and the suspected analgesics.

Results: A total of 403 cases of KS reported from 17 countries were included, of which 121 cases were associated with analgesics (subgroup). Males were more frequently affected overall (267 (66%) males vs. 123 (31%) females), whereas in the subgroup, males and females were equally affected (58 (48%) males vs. 56 (46%) females). Median reported patient age was 57 years (range 2 - 99) overall vs. 48 years (range 20 - 85) in the subgroup. Nearly all cases were classified as serious (370 (92%) overall vs. 119 (98%) subgroup). The most frequently suspected substance was amoxicillin/clavulanic acid (n = 50, 9.3%) overall and ibuprofen (n = 33, 6.2%) in the subgroup, respectively. Most drugs were administered orally (21% overall vs. 21% subgroup) and intravenously (18.7% overall vs. 8% subgroup) in either group. A high proportion of patients with "life threatening" reactions received intravenous administration (37%) of the suspected drug.

Conclusion: Antibiotics and analgesics are the drug classes most often associated with KS. The way of administration might have an influence on the seriousness of the reaction.
.
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http://dx.doi.org/10.5414/CP203344DOI Listing
May 2019

Molecular Mechanisms of Colistin-Induced Nephrotoxicity.

Molecules 2019 Feb 12;24(3). Epub 2019 Feb 12.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, 8006 Zurich, Switzerland.

The emergence of multidrug resistant (MDR) infections and the shortage of new therapeutic options have made colistin, a polymyxin antibiotic, the main option for the treatment of MDR Gram-negative bacterial infections in the last decade. However, the rapid onset of renal damage often prevents the achievement of optimal therapeutic doses and/or forces the physicians to interrupt the therapy, increasing the risk of drug resistance. The proper management of colistin-induced nephrotoxicity remains challenging, mostly because the investigation of the cellular and molecular pharmacology of this drug, off the market for decades, has been largely neglected. For years, the renal damage induced by colistin was considered a mere consequence of the detergent activity of this drug on the cell membrane of proximal tubule cells. Lately, it has been proposed that the intracellular accumulation is a precondition for colistin-mediated renal damage, and that mitochondria might be a primary site of damage. Antioxidant approaches (e.g., ascorbic acid) have shown promising results in protecting the kidney of rodents exposed to colistin, yet none of these strategies have yet reached the bedside. Here we provide a critical overview of the possible mechanisms that may contribute to colistin-induced renal damage and the potential protective strategies under investigation.
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http://dx.doi.org/10.3390/molecules24030653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384669PMC
February 2019

The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation.

BMC Gastroenterol 2019 Jan 7;19(1). Epub 2019 Jan 7.

Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Background: Tissue inflammation in inflammatory bowel diseases (IBD) is associated with a decrease in local pH. The gene encoding G-protein-coupled receptor 65 (GPR65) has recently been reported to be a genetic risk factor for IBD. In response to extracellular acidification, proton activation of GPR65 stimulates cAMP and Rho signalling pathways. We aimed to analyse the clinical and functional relevance of the GPR65 associated single nucleotide polymorphism (SNP) rs8005161.

Methods: 1138 individuals from a mixed cohort of IBD patients and healthy volunteers were genotyped for SNPs associated with GPR65 (rs8005161, rs3742704) and galactosylceramidase (rs1805078) by Taqman SNP assays. 2300 patients from the Swiss IBD Cohort Study (SIBDC) were genotyped for rs8005161 by mass spectrometry based SNP genotyping. IBD patients from the SIBDC carrying rs8005161 TT, CT, CC and non-IBD controls (CC) were recruited for functional studies. Human CD14+ cells were isolated from blood samples and subjected to an extracellular acidic pH shift, cAMP accumulation and RhoA activation were measured.

Results: In our mixed cohort, but not in SIBDC patients, the minor variant rs8005161 was significantly associated with UC. In SIBDC patients, we observed a consistent trend in increased disease severity in patients carrying the rs8005161-TT and rs8005161-CT alleles. No significant differences were observed in the pH associated activation of cAMP production between IBD (TT, CT, WT/CC) and non-IBD (WT/CC) genotype carriers upon an acidic extracellular pH shift. However, we observed significantly impaired RhoA activation after an extracellular acidic pH shift in IBD patients, irrespective of the rs8005161 allele.

Conclusions: The T allele of rs8005161 might confer a more severe disease course in IBD patients. Human monocytes from IBD patients showed impaired pH associated RhoA activation upon an acidic pH shift.
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http://dx.doi.org/10.1186/s12876-018-0922-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323805PMC
January 2019

Do clinical and laboratory parameters predict thiopurine metabolism and clinical outcome in patients with inflammatory bowel diseases?

Eur J Clin Pharmacol 2019 Mar 4;75(3):335-342. Epub 2019 Jan 4.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Rämistrasse 100, CH-8091, Zürich, Switzerland.

Purpose: The thiopurines azathioprine and 6-mercaptopurine are frequently used for remission maintenance in patients with inflammatory bowel diseases. However, there are therapy failures, and it is unclear whether clinical and laboratory parameters can be used to predict thiopurine metabolite concentrations (as a surrogate for adequate remission maintenance therapy) and clinical outcome in these patients.

Methods: In this retrospective analysis of clinical routine patient data, multivariate statistical models based on Linear Mixed Models regression and Generalized Estimating Equations logistic regression were developed. The adequacy of the models was assessed using Pearson's correlation and a receiver operating characteristic curve.

Results: This study included 273 patients and 1158 thiopurine metabolite measurements as well as routine laboratory and clinical data. In the statistical models, thiopurine metabolite concentrations and the odds of non-remission based on different clinical and laboratory parameters were computed. Correlation (r) between predicted and measured thiopurine metabolites were 0.40 (p < 0.001) for 6-thioguanine nucleotides and 0.53 (p < 0.001) for 6-methyl-mercaptopurine nucleotides, respectively. The model for remission classified data sets in remission and non-remission with a sensitivity of 63% and a specificity of 73%. The area under the receiver operating characteristic curve of the model was 0.72.

Conclusions: Although the models are not yet accurate enough to be used in clinical routine, model-based prediction of thiopurine metabolite concentrations and of outcome is feasible. Until more accurate models are developed and validated, traditional therapeutic drug monitoring of thiopurine metabolites in patients with inflammatory bowel diseases under thiopurine therapy stays the best tool to individualize therapy.
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http://dx.doi.org/10.1007/s00228-018-02616-7DOI Listing
March 2019

Statin-associated immune-mediated necrotizing myopathy: a retrospective analysis of individual case safety reports from VigiBase.

Eur J Clin Pharmacol 2019 Mar 15;75(3):409-416. Epub 2018 Nov 15.

Department of Clinical Pharmacology and Toxicology and Regional Pharmacovigilance Centre, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Purpose: Statins represent an effective treatment for hyperlipidaemia. Immune-mediated necrotising myopathy (IMNM), a form of statin myopathy, has recently been described, and is characterized by elevated creatine kinase, presence of antibodies against HMG-CoA and no improvement after drug discontinuation, even with immunosuppressive treatment. Information on IMNM is mainly from case reports and small case series. Therefore, all reported cases of IMNM in VigiBase, the WHO global database of individual case safety reports (ICSRs) including the underlying reporting patterns, were analysed to characterize more detailed this adverse drug reaction.

Methods: ICSRs of IMNM up to October 1, 2016 were extracted from VigiBase. Corresponding case narratives were requested from responsible national authorities to maximize the available data. The reports were analysed in terms of reporting criteria, co-reported terms, patient demographics, clinical data, administered medication, latency time, seriousness of the reaction and outcome.

Results: One hundred one deduplicated ICSRs of IMNM were reported from 17 countries until October 2016. Approximately two thirds of the cases were from the year 2016. Slightly more males than females were affected (52 [57%] males vs 39 [42%] females). Median reported patient age was 68 years (range 16 - 87 years). Ninety-one cases (99%) were classified as serious. Median latency time was 26 months (range 1 - 288 months). Median creatine kinase value was 6860 U/L (range 576 - 35,000 U/L). In total, eight patients (9%) had recovered from IMNM. Atorvastatin was the most frequently reported statin in 80% of cases.

Conclusions: The number of IMNM reports has increased in recent years. IMNM associated with statin treatment seems to occur worldwide. Most IMNM cases were reported with atorvastatin. No dose dependency of statin-associated IMNM pathogenesis was identified.
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http://dx.doi.org/10.1007/s00228-018-2589-zDOI Listing
March 2019

Safety differentiation: emerging competitive edge in drug development.

Drug Discov Today 2019 01 19;24(1):285-292. Epub 2018 Sep 19.

Novartis Institutes for Biomedical Research, Translational Medicine, Pre-Clinical Safety, Basel, Switzerland.

With increasing expectations to provide evidence of drug efficacy, safety, and cost-effectiveness, best-in-class drugs are a major value driver for the pharmaceutical industry. Superior safety is a key differentiation criterion that could be achieved through better risk:benefit profiles, safety margins, fewer contraindications, and improved patient compliance. To accomplish this, comparative safety assessments using innovative and adaptive nonclinical and clinical outcome-based approaches should be undertaken, and continuous strategic adjustments must be made as the risk:benefit profiles evolve. Key success criteria include scientific expertise and integration between all disciplines during the full extent of the drug development process.
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http://dx.doi.org/10.1016/j.drudis.2018.09.009DOI Listing
January 2019

Deleterious role of endothelial lectin-like oxidized low-density lipoprotein receptor-1 in ischaemia/reperfusion cerebral injury.

J Cereb Blood Flow Metab 2019 11 3;39(11):2233-2245. Epub 2018 Aug 3.

Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Schlieren, Switzerland.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is implicated in cardiovascular disease by modulating apoptosis and oxidative stress. We hypothesized that LOX-1 may be involved in pathophysiology of stroke by mediating ischaemia/reperfusion (I/R)-dependent cell death. Transient middle cerebral artery occlusion (tMCAO) was performed in wild-type (WT) mice, endothelial-specific LOX-1 transgenic mice (eLOX-1TG) and WT animals treated with LOX-1 silencing RNA (siRNA). In WT mice exposed to tMCAO, LOX-1 expression and function were increased in the MCA. Compared to WT animals, eLOX-1TG mice displayed increased stroke volumes and worsened outcome after I/R. Conversely, LOX-1-silencing decreased both stroke volume and neurological impairment. Similarly, in HBMVECs, hypoxia/reoxygenation increased LOX-1 expression, while LOX-1 overexpressing cells showed increased death following hypoxia reoxygenation. Increased caspase-3 activation was observed following LOX-1 overexpression both in vivo and in vitro, thus representing a likely mediator. Finally, monocytes from ischaemic stroke patients exhibited increased LOX-1 expression which also correlated with disease severity. Our data unequivocally demonstrate a key role for LOX-1 in determining outcome following I/R brain damage. Our findings could be corroborated in human brain endothelial cells and monocytes from patients, underscoring their translational relevance and suggesting siRNA-mediated LOX-1 knockdown as a novel therapeutic strategy for stroke patients.
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http://dx.doi.org/10.1177/0271678X18793266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827115PMC
November 2019