Publications by authors named "Katharina M Rentsch"

65 Publications

Direct Comparison of Clinical Characteristics, Outcomes, and Risk Prediction in Patients with COVID-19 and Controls-A Prospective Cohort Study.

J Clin Med 2021 Jun 17;10(12). Epub 2021 Jun 17.

Department of Cardiology and Cardiovascular Research Institute Basel (CRIB), University Hospital Basel, University of Basel, Spitalstrasse 2, 4056 Basel, Switzerland.

Most studies investigating early risk predictors in coronavirus disease 19 (COVID-19) lacked comparison with controls. We aimed to assess and directly compare outcomes and risk predictors at time of emergency department (ED) presentation in COVID-19 and controls. Consecutive patients presenting to the ED with suspected COVID-19 were prospectively enrolled. COVID-19-patients were compared with (i) patients tested negative (overall controls) and (ii) patients tested negative, who had a respiratory infection (respiratory controls). Primary outcome was the composite of intensive care unit (ICU) admission and death at 30 days. Among 1081 consecutive cases, 191 (18%) were tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and 890 (82%) were tested negative (overall controls), of which 323 (30%) had a respiratory infection (respiratory controls). Incidence of the composite outcome was significantly higher in COVID-19 (23%) as compared with the overall control group (10%, adjusted-HR 2.45 (95%CI, 1.61-3.74), < 0.001) or the respiratory control group (10%, adjusted-HR 2.93 (95%CI, 1.66-5.17), < 0.001). Blood oxygen saturation, age, high-sensitivity troponin, c-reactive protein, and lactate dehydrogenase were identified as the strongest predictors of poor outcome available at time of ED presentation in COVID-19 with highly comparable prognostic utility in overall and respiratory controls. In conclusion, patients presenting to the ED with COVID-19 have a worse outcome than controls, even after adjustment for differences in baseline characteristics. Most predictors of poor outcome in COVID-19 were not restricted to COVID-19, but of comparable prognostic utility in controls and therefore generalizable to unselected patients with suspected COVID-19.
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http://dx.doi.org/10.3390/jcm10122672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234319PMC
June 2021

Comparison of Acute Kidney Injury in Patients with COVID-19 and Other Respiratory Infections: A Prospective Cohort Study.

J Clin Med 2021 May 25;10(11). Epub 2021 May 25.

Department of Cardiology, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.

Previous studies have indicated an association between coronavirus disease 2019 (COVID-19) and acute kidney injury (AKI) but lacked a control group. The prospective observational COronaVIrus-surviVAl (COVIVA) study performed at the University Hospital, Basel, Switzerland consecutively enrolled patients with symptoms suggestive of COVID-19. We compared patients who tested positive for SARS-CoV-2 with patients who tested negative but with an adjudicated diagnosis of a respiratory tract infection, including pneumonia. The primary outcome measure was death at 30 days, and the secondary outcomes were AKI incidence and a composite endpoint of death, intensive care treatment or rehospitalization at 30 days. Five hundred and seven patients were diagnosed with respiratory tract infections, and of those, 183 (36%) had a positive PCR swab test for SARS-CoV-2. The incidence of AKI was higher in patients with COVID-19 (30% versus 12%, < 0.001), more severe (KDIGO stage 3, 22% versus 13%, = 0.009) and more often required renal replacement therapy (4.4% versus 0.93%; = 0.03). The risk of 30-day mortality and a composite endpoint was higher in patients with COVID-19-associated AKI (adjusted hazard ratio (aHR) mortality 3.98, 95% confidence interval (CI) 1.10-14.46, = 0.036; composite endpoint aHR 1.84, 95% CI 1.02-3.31, = 0.042). The mortality risk was attenuated when adjusting for disease severity (aHR 3.60, 95% CI 0.93-13.96, = 0.062). AKI occurs more frequently and with a higher severity in patients with COVID-19 and is associated with worse outcomes.
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http://dx.doi.org/10.3390/jcm10112288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197451PMC
May 2021

Regular Caffeine Intake Delays REM Sleep Promotion and Attenuates Sleep Quality in Healthy Men.

J Biol Rhythms 2021 08 23;36(4):384-394. Epub 2021 May 23.

Centre for Chronobiology, Psychiatric Hospital of the University of Basel, Basel, Switzerland.

Acute caffeine intake can attenuate homeostatic sleep pressure and worsen sleep quality. Caffeine intake-particularly in high doses and close to bedtime-may also affect circadian-regulated rapid eye movement (REM) sleep promotion, an important determinant of subjective sleep quality. However, it is not known whether such changes persist under chronic caffeine consumption during daytime. Twenty male caffeine consumers (26.4 ± 4 years old, habitual caffeine intake 478.1 ± 102.8 mg/day) participated in a double-blind crossover study. Each volunteer completed a caffeine (3 × 150 mg caffeine daily for 10 days), a withdrawal (3 × 150 mg caffeine for 8 days then placebo), and a placebo condition. After 10 days of controlled intake and a fixed sleep-wake cycle, we recorded electroencephalography for 8 h starting 5 h after habitual bedtime (i.e., start on average at 04:22 h which is around the peak of circadian REM sleep promotion). A 60-min evening nap preceded each sleep episode and reduced high sleep pressure levels. While total sleep time and sleep architecture did not significantly differ between the three conditions, REM sleep latency was longer after daily caffeine intake compared with both placebo and withdrawal. Moreover, the accumulation of REM sleep proportion was delayed, and volunteers reported more difficulties with awakening after sleep and feeling more tired upon wake-up in the caffeine condition compared with placebo. Our data indicate that besides acute intake, also regular daytime caffeine intake affects REM sleep regulation in men, such that it delays circadian REM sleep promotion when compared with placebo. Moreover, the observed caffeine-induced deterioration in the quality of awakening may suggest a potential motive to reinstate caffeine intake after sleep.
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http://dx.doi.org/10.1177/07487304211013995DOI Listing
August 2021

Probability of pharmacological target attainment with flucloxacillin in Staphylococcus aureus bloodstream infection: a prospective cohort study of unbound plasma and individual MICs.

J Antimicrob Chemother 2021 06;76(7):1845-1854

Division of Internal Medicine, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.

Objectives: MSSA bloodstream infections (BSIs) are associated with considerable mortality. Data regarding therapeutic drug monitoring (TDM) and pharmacological target attainment of the β-lactam flucloxacillin are scarce.

Patients And Methods: We determined the achievement of pharmacokinetic/pharmacodynamic targets and its association with clinical outcome and potential toxicity in a prospective cohort of 50 patients with MSSA-BSI. Strain-specific MICs and unbound plasma flucloxacillin concentrations (at five different timepoints) were determined by broth microdilution and HPLC-MS, respectively.

Results: In our study population, 48% were critically ill and the 30 day mortality rate was 16%. The median flucloxacillin MIC was 0.125 mg/L. The median unbound trough concentration was 1.7 (IQR 0.4-9.3), 1.9 (IQR 0.4-6.2) and 1.0 (IQR 0.6-3.4) mg/L on study day 1, 3 and 7, respectively. Optimal (100% fT>MIC) and maximum (100% fT>4×MIC) target attainment was achieved in 45 (90%) and 34 (68%) patients, respectively, throughout the study period. Conversely, when using the EUCAST epidemiological cut-off value instead of strain-specific MICs, target attainment was achieved in only 13 (26%) patients. The mean unbound flucloxacillin trough concentration per patient was associated with neurotoxicity (OR 1.12 per 1 mg/L increase, P = 0.02) and significantly higher in deceased patients (median 14.8 versus 1.7 mg/L, P = 0.01).

Conclusions: Flucloxacillin pharmacological target attainment in MSSA-BSI patients is frequently achieved when unbound flucloxacillin concentrations and strain-specific MICs are considered. However, currently recommended dosing regimens may expose patients to excessive flucloxacillin concentrations, potentially resulting in drug-related organ damage.
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http://dx.doi.org/10.1093/jac/dkab089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212765PMC
June 2021

Disposition Decision Support by Laboratory Based Outcome Prediction.

J Clin Med 2021 Mar 1;10(5). Epub 2021 Mar 1.

Emergency Department, University Hospital Basel, 4031 Basel, Switzerland.

Disposition is one of the main tasks in the emergency department. However, there is a lack of objective and reliable disposition criteria, and diagnosis-based risk prediction is not feasible at early time points. The aim was to derive a risk score (TRIAL) based on routinely collected baseline (TRIage level and Age) and Laboratory data-supporting disposition decisions by risk stratification based on mortality. We prospectively included consecutive patients presenting to the emergency department over 18 weeks. Data sets of routinely collected baseline (triage level and age) and laboratory data were used for multivariable logistic regression to develop the TRIAL risk score predicting mortality. Routine laboratory variables and disposition cut-offs were chosen beforehand by expert consensus. Risk stratification was based on low risk (<1%), intermediate risk (1-10%), and high risk (>10%) of in-hospital mortality. In total, 8687 data sets were analyzed. Variables identified to develop the TRIAL risk score were triage level (Emergency Severity Index), age, lactate dehydrogenase, creatinine, albumin, bilirubin, and leukocyte count. The area under the ROC curve for in-hospital mortality was 0.93. Stratification according to the TRIAL score showed that 67.5% of all patients were in the low-risk category. Mortality was 0.1% in low-risk, 3.5% in intermediate-risk, and 26.2% in high-risk patients. The TRIAL risk score based on routinely available baseline and laboratory data provides prognostic information for disposition decisions. TRIAL could be used to minimize admission in low-risk and to maximize observation in high-risk patients.
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http://dx.doi.org/10.3390/jcm10050939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957752PMC
March 2021

Systematic screening on admission for SARS-CoV-2 to detect asymptomatic infections.

Antimicrob Resist Infect Control 2021 02 27;10(1):44. Epub 2021 Feb 27.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, University of Basel, Petersgraben 4, 4031, Basel, Switzerland.

The proportion of asymptomatic carriers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains elusive and the potential benefit of systematic screening during the SARS-CoV-2-pandemic is controversial. We investigated the proportion of asymptomatic inpatients who were identified by systematic screening for SARS-CoV-2 upon hospital admission. Our analysis revealed that systematic screening of asymptomatic inpatients detects a low total number of SARS-CoV-2 infections (0.1%), questioning the cost-benefit ratio of this intervention. Even when the population-wide prevalence was low, the proportion of asymptomatic carriers remained stable, supporting the need for universal infection prevention and control strategies to avoid onward transmission by undetected SARS-CoV-2-carriers during the pandemic.
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http://dx.doi.org/10.1186/s13756-021-00912-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912536PMC
February 2021

The impact of daily caffeine intake on nighttime sleep in young adult men.

Sci Rep 2021 Feb 25;11(1):4668. Epub 2021 Feb 25.

Centre for Chronobiology, Psychiatric Hospital of the University of Basel, Basel, Switzerland.

Acute caffeine intake can delay sleep initiation and reduce sleep intensity, particularly when consumed in the evening. However, it is not clear whether these sleep disturbances disappear when caffeine is continuously consumed during daytime, which is common for most coffee drinkers. To address this question, we investigated the sleep of twenty male young habitual caffeine consumers during a double-blind, randomized, crossover study including three 10-day conditions: caffeine (3 × 150 mg caffeine daily), withdrawal (3 × 150 mg caffeine for 8 days, then switch to placebo), and placebo (3 × placebo daily). After 9 days of continuous treatment, electroencephalographically (EEG)-derived sleep structure and intensity were recorded during a scheduled 8-h nighttime sleep episode starting 8 (caffeine condition) and 15 h (withdrawal condition) after the last caffeine intake. Upon scheduled wake-up time, subjective sleep quality and caffeine withdrawal symptoms were assessed. Unexpectedly, neither polysomnography-derived total sleep time, sleep latency, sleep architecture nor subjective sleep quality differed among placebo, caffeine, and withdrawal conditions. Nevertheless, EEG power density in the sigma frequencies (12-16 Hz) during non-rapid eye movement sleep was reduced in both caffeine and withdrawal conditions when compared to placebo. These results indicate that daily caffeine intake in the morning and afternoon hours does not strongly impair nighttime sleep structure nor subjective sleep quality in healthy good sleepers who regularly consume caffeine. The reduced EEG power density in the sigma range might represent early signs of overnight withdrawal from the continuous presence of the stimulant during the day.
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http://dx.doi.org/10.1038/s41598-021-84088-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907384PMC
February 2021

LC-MS/MS method for nine different antibiotics.

Clin Chim Acta 2020 Dec 5;511:360-367. Epub 2020 Nov 5.

Laboratory Medicine, University Hospital Basel, University Basel, Petersgraben 4, 4031 Basel, Switzerland. Electronic address:

Background And Aims: TDM of antibiotics can bring benefits to patients and healthcare systems by providing better treatment and saving healthcare resources. We aimed to develop a multi-analyte method for several diverse antibiotics using LC-MS/MS.

Materials And Methods: Sample preparation consisted of protein precipitation with methanol, dilution and online extraction using a Turboflow Cyclone column. Separation was performed on a Synergi 4 µm Max RP column and deuterated forms of three antibiotics were used as internal standards.

Results: We present a LC-MS/MS method for the quantitative determination of nine antibiotics, including five cephalosporins, the carbapenem ertapenem, the fluoroquinolone ciprofloxacin as well as the combination drug trimethoprim-sulfamethoxazole from plasma. Additionally, unbound ertapenem and cefazolin were analyzed in plasma water after ultrafiltration using plasma calibrators. Results from routine TDM show the applicability of the method.

Conclusion: The presented method is precise and accurate and was introduced in a university hospital, permitting fast TDM of all nine analytes. It was also used in a clinical study for measuring cefazolin free and total concentrations.
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http://dx.doi.org/10.1016/j.cca.2020.11.001DOI Listing
December 2020

HILIC LC-MS/MS method for the quantification of cefepime, imipenem and meropenem.

J Pharm Biomed Anal 2020 Jul 2;186:113289. Epub 2020 Apr 2.

Laboratory Medicine, University Hospital Basel, University of Basel, Petersgraben 4, 4031 Basel, Switzerland. Electronic address:

A high performance hydrophilic interaction chromatography method combined with tandem-mass spectrometry for the quantification of cefepime, meropenem and imipenem in plasma and cerebrospinal fluid is presented. A solution of 0.5 M 3-Morpholinopropanesulfonic acid and ethylene glycol (1:1) was added to the samples before analysis to ensure stability of analytes during work up and storage. Deuterated forms of cefepime and meropenem were used as internal standards. Protein precipitation prior to injection into the LC-MS/MS system provided a fast and easy sample preparation. For online extraction, a Turboflow Cyclone-MCX column was used and the chromatographic separation was carried out on a Hypersil GOLD HILIC column. Linear calibration curves were obtained in the concentration range of 0.4-40 mg/l, 0.6-60 mg/l and 1-100 mg/l for meropenem, imipenem and cefepime, respectively. The intra- and interday imprecision and inaccuracy values were below 10 % for plasma and 13 % for cerebrospinal fluid using a calibration in plasma. The method was employed for therapeutic drug measurements in a university hospital.
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http://dx.doi.org/10.1016/j.jpba.2020.113289DOI Listing
July 2020

Drug Exposure in Newborns: Effect of Selected Drugs Prescribed to Mothers During Pregnancy and Lactation.

Ther Drug Monit 2020 04;42(2):255-263

Laboratory Medicine, University Hospital Basel, University Basel, Basel, Switzerland.

The number of newborns exposed to therapeutic drugs during pregnancy is growing because of the increased use of drugs during pregnancy. In recent years, advances in our understanding of drug placental transfer have augmented the likelihood of a healthy baby in mothers with chronic diseases needing drug therapy. Globally, for example, more than 1.4 million pregnancies in 2015 have been burdened with antiretroviral drugs due to an increasing number of HIV-positive women treated with these drugs, particularly in low- and middle-income countries. In most cases, the fetus is exposed to much higher drug doses in utero than the newborn nursed by the mother. Drug transfer through the placenta takes place by passive diffusion, active transport, or facilitated transport, and drug concentrations in the fetal circulation may be comparable to that in the mother's blood concentration. The excretion of drugs into breastmilk predominantly occurs by passive diffusion, allowing only the non-protein-bound fraction of the blood drug concentration to penetrate. Drug agencies in the United States and Europe highly recommend performing clinical trials in pregnant or breastfeeding women. However, only a few drugs have reported statistically sound data in these patient groups. Most available results concerning pregnancy are obtained from observational studies after birth, assessing outcomes in the newborn or by measuring drug concentrations in the mother and umbilical cord blood. In the case of the lactation period, some studies have evaluated drug concentrations in breastmilk and blood of the mother and/or infant. In this review, exposure to antiretrovirals, immunosuppressants used after solid organ transplantation, and antiepileptics during pregnancy and lactation has been discussed in detail.
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http://dx.doi.org/10.1097/FTD.0000000000000747DOI Listing
April 2020

A 2D HPLC-MS/MS method for several antibiotics in blood plasma, plasma water, and diverse tissue samples.

Anal Bioanal Chem 2020 Jan 3;412(3):715-725. Epub 2020 Jan 3.

Laboratory Medicine, University Hospital Basel, University of Basel, Petersgraben 4, 4031, Basel, Switzerland.

An analytical method using 2D high-performance liquid chromatography followed by tandem mass spectrometry for the quantification of the beta-lactam antibiotics amoxicillin, flucloxacillin, piperacillin, benzylpenicillin, the beta-lactamase inhibitors clavulanic acid, and tazobactam, as well as the macrolide antibiotic clindamycin, is presented. All analytes were measured in human plasma, while amoxicillin, clavulanic acid, flucloxacillin, and clindamycin were also analyzed in human tissue samples. Because of its high-protein binding, additionally, the free fraction of flucloxacillin was measured after ultrafiltration. As internal standards, deuterated forms of the beta-lactams were used. Sample preparation for all matrices was protein precipitation followed by online extraction on a TurboFlow MAX column, while sample separation was performed on an Accucore XL C18 column. Calibration curves were linear over 0.2-25 mg/kg for the tissue samples and 0.05-20 mg/l for the free fraction of flucloxacillin. In plasma, the calibration curves for amoxicillin and piperacillin were linear over 3.125-125 mg/l, for clavulanic acid and tazobactam over 1-40 mg/l, for benzylpenicillin 0.25-40 mg/l, and for flucloxacillin and clindamycin over 1.5-60 mg/l and 0.05-8 mg/l respectively. In plasma and plasma ultrafiltrate, inaccuracy and imprecision for any analyte were always less than 15%. In tissue, the accuracy and precision varied up to 16%, respectively, 20%, when various tissues were analyzed using a calibration in water. Graphical abstract.
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http://dx.doi.org/10.1007/s00216-019-02285-0DOI Listing
January 2020

Danger of Herbal Tea: A Case of Acute Cholestatic Hepatitis Due to Tea.

Front Med (Lausanne) 2019 11;6:221. Epub 2019 Oct 11.

University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland.

is a Chinese medicinal herb. Artemisinin-derivatives are recommended as part of a combination treatment for uncomplicated malaria. Herbal and dietary supplements (HDS) are increasingly used worldwide and HDS-induced liver injury is becoming a growing concern. We present the first case of severe acute cholestatic hepatitis due to the intake of tea as chemoprophylaxis for malaria in a patient returning from Ethiopia. The patients presented with jaundice, elevated transaminases, and parameters of cholestasis (total bilirubin 186.6 μmol/L, conjugated bilirubin 168.5 μmol/L). A liver biopsy showed a portal hepatitis with lymphocytic infiltration of the bile ducts and diffuse intra-canalicular and intra-cytoplasmic bilirubinostasis. The toxicologic analysis of the Artemisia tea revealed the ingredients arteannuin b, deoxyartemisin, campher, and scopoletin. There were no other identifiable etiologies of liver disease. The Roussel Uclaf Causality Assessment Method (RUCAM) score assessed a "probably" causal relationship. Sequencing of genes encoding for hepatic transporters for bile acid homeostasis (BSEP, MDR3, and FIC1) found no genetic variants typically associated with hereditary cholestasis syndromes. Normalization of bilirubin occurred 3 months after the onset of disease. The use of artemisinin-derivatives for malaria prevention is ineffective and potentially harmful and should thus be discouraged. Moreover, the case demonstrates our as yet inadequate understanding of the pathophysiology and susceptibility to HDS induced liver injury.
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http://dx.doi.org/10.3389/fmed.2019.00221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798169PMC
October 2019

Development and validation of an LC-MS/MS method to quantify lysergic acid diethylamide (LSD), iso-LSD, 2-oxo-3-hydroxy-LSD, and nor-LSD and identify novel metabolites in plasma samples in a controlled clinical trial.

J Clin Lab Anal 2018 Feb 26;32(2). Epub 2017 May 26.

Laboratory Medicine, University Hospital and University of Basel, Basel, Switzerland.

Background: Lysergic acid diethylamide (LSD) is a widely used recreational drug. The aim of this study was to develop and validate a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the quantification of LSD, iso-LSD, 2-oxo-3-hydroxy LSD (O-H-LSD), and nor-LSD in plasma samples from 24 healthy subjects after controlled administration of 100 μg LSD in a clinical trial. In addition, metabolites that have been recently described in in vitro studies, including lysergic acid monoethylamide (LAE), lysergic acid ethyl-2-hydroxyethylamide (LEO), 2-oxo-LSD, trioxylated-LSD, and 13/14-hydroxy-LSD, should be identified.

Methods: Separation of LSD and its metabolites was achieved on a reversed phase chromatography column after turbulent-flow online extraction. For the identification and quantification, a triple-stage quadrupole LC-MS/MS instrument was used.

Results: The validation data showed slight matrix effects for LSD, iso-LSD, O-H-LSD, or nor-LSD. Mean intraday and interday accuracy and precision were 105%/4.81% and 105%/4.35% for LSD, 98.7%/5.75% and 99.4%/7.21% for iso-LSD, 106%/4.54% and 99.4%/7.21% for O-H-LSD, and 107%/5.82% and 102%/5.88% for nor-LSD, respectively. The limit of quantification was 0.05 ng/mL for LSD, iso-LSD, and nor-LSD and 0.1 ng/mL for O-H-LSD. The limit of detection was 0.01 ng/mL for all compounds.

Conclusion: The method described herein was accurate, precise, and the calibration range within the range of expected plasma concentrations. LSD was quantified in the plasma samples of the 24 subjects of the clinical trial, whereas iso-LSD, O-H-LSD, nor-LSD, LAE, LEO, 13/14-hydroxy-LSD, and 2-oxo-LSD could only sporadically be detected but were too low for quantification.
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http://dx.doi.org/10.1002/jcla.22265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817285PMC
February 2018

Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide in Healthy Subjects.

Clin Pharmacokinet 2017 Oct;56(10):1219-1230

Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Hebelstrasse 2, 4031, Basel, Switzerland.

Background And Objective: Lysergic acid diethylamide (LSD) is used recreationally and in clinical research. The aim of the present study was to characterize the pharmacokinetics and exposure-response relationship of oral LSD.

Methods: We analyzed pharmacokinetic data from two published placebo-controlled, double-blind, cross-over studies using oral administration of LSD 100 and 200 µg in 24 and 16 subjects, respectively. The pharmacokinetics of the 100-µg dose is shown for the first time and data for the 200-µg dose were reanalyzed and included. Plasma concentrations of LSD, subjective effects, and vital signs were repeatedly assessed. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-effect relationships were described using pharmacokinetic-pharmacodynamic modeling.

Results: Geometric mean (95% confidence interval) maximum plasma concentration values of 1.3 (1.2-1.9) and 3.1 (2.6-4.0) ng/mL were reached 1.4 and 1.5 h after administration of 100 and 200 µg LSD, respectively. The plasma half-life was 2.6 h (2.2-3.4 h). The subjective effects lasted (mean ± standard deviation) 8.2 ± 2.1 and 11.6 ± 1.7 h for the 100- and 200-µg LSD doses, respectively. Subjective peak effects were reached 2.8 and 2.5 h after administration of LSD 100 and 200 µg, respectively. A close relationship was observed between the LSD concentration and subjective response within subjects, with moderate counterclockwise hysteresis. Half-maximal effective concentration values were in the range of 1 ng/mL. No correlations were found between plasma LSD concentrations and the effects of LSD across subjects at or near maximum plasma concentration and within dose groups.

Conclusions: The present pharmacokinetic data are important for the evaluation of clinical study findings (e.g., functional magnetic resonance imaging studies) and the interpretation of LSD intoxication. Oral LSD presented dose-proportional pharmacokinetics and first-order elimination up to 12 h. The effects of LSD were related to changes in plasma concentrations over time, with no evidence of acute tolerance.

Trial Registration: NCT02308969, NCT01878942.
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http://dx.doi.org/10.1007/s40262-017-0513-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591798PMC
October 2017

Evaluation of two novel chemiluminescence immunoassays for the detection of Clostridium difficile glutamate dehydrogenase and toxin A&B.

J Microbiol Methods 2017 04 10;135:63-65. Epub 2017 Feb 10.

Division of Clinical Microbiology, University Hospital Basel, Basel, Switzerland.

A novel immunoassay for Clostridium difficile glutamate dehydrogenase (GDH) and toxin A&B (LIAISON, DiaSorin) was compared to another GDH assay (Alere), PCR and toxigenic culture. The GDH-DiaSorin is slightly more sensitive than the GDH-Alere. Sensitivity of the Toxin-Diasorin test is in accordance to the sensitivity of other immunoassays in literature.
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http://dx.doi.org/10.1016/j.mimet.2017.02.004DOI Listing
April 2017

Mistaking 2C-P for 2C-B: What a Difference a Letter Makes.

J Anal Toxicol 2017 Jan 6;41(1):77-79. Epub 2016 Oct 6.

Department of Nephrology, Hypertension and Clinical Pharmacology, Inselspital, Bern University Hospital, University of Bern, Switzerland

2,5-Dimethoxy-4(n)-propylphenethylamine (2C-P) is a synthetic phenethylamine derivative belonging to the large family of the so-called 2C drugs. These compounds can differ significantly in receptor affinity, potency and duration of action, and an important structural difference is the ligand in the 4 position of the phenyl ring, such as propyl in 2C-P or bromine in 2,5-dimethoxy-4-bromophenethylamine (2C-B). The 2C drugs are known for their hallucinogenic properties. We present a case of a 19-year-old male admitted to the emergency department with severe hallucinations, mydriasis, tachycardia, agitation and confusion following the use of a substance sold as 2C-B. By using liquid chromatography-mass spectrometry, the more potent substance 2C-P was detected and quantified. On the basis of two blood sample concentrations, the estimated elimination half-life was 19 h. This case report illustrates and discusses the differences in potency and duration of action of 2C drugs.
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http://dx.doi.org/10.1093/jat/bkw108DOI Listing
January 2017

Characteristics of autoantibodies targeting 14-3-3 proteins and their association with clinical features in newly diagnosed giant cell arteritis.

Rheumatology (Oxford) 2017 05;56(5):829-834

Translational Immunology, Department of Biomedicine.

Objectives: Autoantibodies are useful biomarkers for diagnosing and monitoring treatment in some autoimmune diseases. Antibodies against isoforms of 14-3-3 protein have been proposed as biomarkers for the presence of aortic aneurysm in large-vessel vasculitis (LVV). Here, we aimed to evaluate the diagnostic role and potential immunopathological involvement of anti-14-3-3 antibodies in newly diagnosed LVV patients.

Methods: Antibodies against three isoforms of 14-3-3 (γ, ɛ and ζ) were measured in 90 subjects: 48 GCA and 3 Takayasu's arteritis (TA) patients, and 39 controls (non-inflammatory and inflammatory diseases), using a multiplexed bead-based immunoassay and immunoprecipitation studies. The positive cut-off value was defined based on young healthy controls. Anti-14-3-3 IgG antibodies in LVV patients were compared with those in controls in order to assess their diagnostic performance, and the relationship of anti-14-3-3 IgG antibodies to the immunohistopathology of artery explants was assessed.

Results: Antibodies against all three 14-3-3 isoforms were detected in LVV patients as well as in age-matched inflammatory and non-inflammatory controls. Among LVV patients, detection of antibodies targeting 14-3-3 ɛ and ζ was associated with more severe disease. Detection of antibodies against 14-3-3 γ was linked to latent Toxoplasma gondii infection, a parasite that secrets a 14-3-3 homologue, suggesting potential cross-reactivity.

Conclusion: Detection of antibodies against 14-3-3 proteins at the time of LVV diagnosis is not disease-specific. Their presence at high levels in LVV patients with stroke, aortitis and-in a previous study-aneurysm formation may indicate an association with extensive tissue destruction. The relevance of 14-3-3 antibodies in non-LVV patients needs to be investigated in larger cohorts.
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http://dx.doi.org/10.1093/rheumatology/kew469DOI Listing
May 2017

Presentations due to acute toxicity of psychoactive substances in an urban emergency department in Switzerland: a case series.

BMC Pharmacol Toxicol 2016 05 26;17(1):25. Epub 2016 May 26.

Division of Clinical Pharmacology and Toxicology, University Hospital Basel, Hebelstrasse 2, CH-4031, Basel, Switzerland.

Background: Although the recreational use of psychoactive substances is common there is only limited systematic collection of data on acute drug toxicity or hospital presentations, in particular regarding novel psychoactive substances (NPS) that have emerged on the illicit market in the last years.

Methods: We included all cases presenting at the emergency department (ED) of the University Hospital of Basel, Switzerland, between October 2014 and September 2015 with acute toxicity due to self-reported recreational drug use or with symptoms/signs consistent with acute toxicity. Intoxications were confirmed using immunoassays and LC-MS/MS, detecting also novel psychoactive substances.

Results: Among the 50'624 attendances at the ED, 210 were directly related to acute toxicity of recreational drugs. The mean patient age was 33 years and 73 % were male. Analytical drug confirmation was available in 136 cases. Most presentations were reportedly related to cocaine (33 %), cannabis (32 %), and heroin (14 %). The most commonly analytically detected substances were cannabis (33 %), cocaine (27 %), and opioids excluding methadone (19 %). There were only two NPS cases; a severe intoxication with paramethoxymethamphetamine (PMMA) in combination with other substances and an intoxication of minor severity with 2,5-dimethoxy-4-propylphenethylamine (2C-P). The most frequent symptoms were tachycardia (28 %), anxiety (23 %), nausea or vomiting (18 %), and agitation (17 %). Severe complications included two fatalities, two acute myocardial infarctions, seizures (13 cases), and psychosis (six cases). Most patients (76 %) were discharged home, 10 % were admitted to intensive care, and 2 % were referred to psychiatric care.

Conclusion: Most medical problems related to illicit drugs concerned cocaine and cannabis and mainly included sympathomimetic toxicity and/or psychiatric disorders confirming data from the prior year. Importantly, despite the dramatic increase in various NPS being detected in the last years, these substances were infrequently associated with ED presentations compared with classic recreational drugs.
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http://dx.doi.org/10.1186/s40360-016-0068-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882845PMC
May 2016

Clinical benefit of high-sensitivity cardiac troponin I in the detection of exercise-induced myocardial ischemia.

Am Heart J 2016 Mar 2;173:8-17. Epub 2015 Dec 2.

Department of Cardiology, University Hospital, Basel, Switzerland; Cardiovascular Research Institute Basel (CRIB), University Hospital, Basel, Switzerland. Electronic address:

Background: A pilot study using a novel high-sensitivity cardiac troponin I (hs-cTnI) assay suggested that cTnI might be released into blood during exercise-induced myocardial ischemia. We investigated the potential clinical value of this signal.

Methods: We included 819 patients with suspected exercise-induced myocardial ischemia referred for rest/bicycle myocardial perfusion single-photon emission computed tomography. The treating cardiologist used all available clinical information to quantify clinical judgment regarding the presence of myocardial ischemia using a visual analog scale twice: prior and after stress testing. High-sensitivity cTnI measurements were obtained before, immediately after peak stress, and 2 hours after stress testing in a blinded manner. Myocardial ischemia was adjudicated using perfusion single-photon emission computed tomography and coronary angiography findings.

Results: Exercise-induced myocardial ischemia was detected in 278 (34%) patients. High-sensitivity cTnI levels were significantly higher at all time points in patients with myocardial ischemia as compared with those without (P < .001 for all). Combining clinical judgment prior exercise testing with baseline hs-cTnI levels increased diagnostic accuracy as quantified by the area under the receiver operating characteristics curve (AUC) from 0.672 to 0.757 (P < .001). Combining clinical judgment after exercise testing (AUC 0.704) with baseline or poststress hs-cTnI levels also increased the diagnostic accuracy (AUC 0.761-0.771, P < .001 for all). In contrast, exercise-induced changes in hs-cTnI during exercise did not seem useful, as they were small and similar in patients with or without myocardial ischemia.

Conclusions: High-sensitivity cTnI concentrations at rest and after exercise, but not its exercise-induced changes, provide substantial incremental value to clinical judgment including exercise electrocardiography regarding the presence of myocardial ischemia.
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http://dx.doi.org/10.1016/j.ahj.2015.11.010DOI Listing
March 2016

Direct comparison of cardiac troponin I and cardiac troponin T in the detection of exercise-induced myocardial ischemia.

Clin Biochem 2016 Apr 17;49(6):421-432. Epub 2015 Dec 17.

Department of Cardiology, University Hospital Basel, Switzerland; Cardiovascular Research Institute Basel (CRIB), University Hospital Basel, Switzerland. Electronic address:

Background: It is unknown, whether cardiac troponin (cTn) I or cTnT is the preferred biomarker in the detection of exercise-induced myocardial ischemia.

Methods: We investigated patients with suspected myocardial ischemia referred for exercise or pharmacological rest/stress myocardial perfusion single-photon emission computed tomography (SPECT) to directly compare the diagnostic accuracy of high-sensitivity cTnI (hs-cTnI) and hs-cTnT. Diagnostic performance was analyzed separately according to stress modality. Hs-cTnI and hs-cTnT were measured before, immediately after, as well as 2h and 4h after maximal exercise in a blinded fashion. Further, all clinical information available to the treating cardiologist was used to quantify the clinical judgment regarding the presence of myocardial ischemia using a visual analog scale twice: once prior and once after stress-testing. The presence of stress-induced myocardial ischemia was adjudicated using SPECT combined with coronary angiography findings.

Result: A total of 403 consecutive patients were enrolled in our study, of which 229 underwent exercise stress and 174 patients pharmacological stress. Exercise-stress-induced myocardial ischemia was detected in 90 patients (39.3% of 229). Levels of hs-cTnI and hs-cTnT were both significantly higher at all time-points examined in patients with exercise-induced myocardial ischemia as compared to patients without myocardial ischemia (all p<0.001). Correlation of hs-cTnI and hs-cTnT was high in direct comparison of time-points (Spearman's rho all ≥0.7). The AUCs for baseline/peak/2h/4h for hs-cTnI and hs-cTnT were 0.71/0.71/0.72/0.69 vs. 0.74/0.73/0.71/0.72, respectively (all p=ns for hs-cTnI versus hs-cTnT). In patients undergoing pharmacological stress, the AUCs for baseline/peak/2h/4h for hs-cTnI and hs-cTnT were 0.66/0.66/0.68/0.67 and 0.61/0.62/0.64/0.59, respectively (all p=ns for hs-cTnI versus hs-cTnT). Also the combinations including clinical judgment or changes during serial sampling were similar for hs-cTnI and hs-cTnT (all p=ns).

Conclusions: Hs-cTnI and hs-cTnT provide comparable diagnostic information regarding exercise-induced myocardial ischemia. Overall, their diagnostic accuracy seems moderate.

Unique Identifier: NCT01838148.
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http://dx.doi.org/10.1016/j.clinbiochem.2015.12.005DOI Listing
April 2016

Does Fentanyl Lead to Opioid-induced Hyperalgesia in Healthy Volunteers?: A Double-blind, Randomized, Crossover Trial.

Anesthesiology 2016 Feb;124(2):453-63

From the Department for Anesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital of Basel, Basel, Switzerland (E.M., O.B., W.R.); Department of Anesthesiology, University Hospital Hannover, Hannover, Germany (J.F.); and Department of Laboratory Medicine, University Hospital of Basel, Basel, Switzerland (P.D., K.M.R.).

Background: Although opioids in general and remifentanil in particular have been shown to induce hyperalgesia, data regarding fentanyl are scarce. Thus, the authors investigated the effect of fentanyl dosing on pain perception and central sensitization in healthy volunteers using established pain models.

Methods: Twenty-one healthy, male volunteers were included in this randomized, double-blind, crossover study and received either intravenous low-dose (1 μg/kg) or high-dose (10 μg/kg) fentanyl. Pain intensities and hyperalgesia were assessed by intracutaneous electrical stimulation, and cold pressor pain was used as an additional measure of acute pain. The primary outcome was hyperalgesia from 4.5 to 6.5 h after fentanyl administration.

Results: A higher dose of fentanyl led to significantly decreased pain scores as measured by the numeric rating scale (0.83 units lower [95% CI, 0.63 to 1.02]; P < 0.001) but increased areas of hyperalgesia (+30.5% [95% CI, 16.6 to 44.4%]; P < 0.001) from 4.5 to 6.5 h after fentanyl administration. Allodynia did not differ between groups (+4.0% [95% CI, -15.4 to 23.5%]; P = 0.682).The high dose also led to both increased cold pressor pain threshold (+43.0% [95% CI, 29.7 to 56.3%]; P < 0.001) and tolerance (+32.5% [95% CI, 21.7 to 43.4%]; P < 0.001) at 4.5 to 6.5h. In the high-dose group, 19 volunteers (90%) required reminders to breathe, 8 (38%) required supplemental oxygen, and 12 (57%) experienced nausea.

Conclusions: A higher dose of fentanyl increased hyperalgesia from 4.5 to 6.5 h in healthy volunteers while simultaneously decreasing pain scores.
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http://dx.doi.org/10.1097/ALN.0000000000000976DOI Listing
February 2016

Pharmacokinetics and Concentration-Effect Relationship of Oral LSD in Humans.

Int J Neuropsychopharmacol 2015 Jun 24;19(1). Epub 2015 Jun 24.

Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research (Mr Dolder, and Drs Schmid, Haschke, and Liechti), and Laboratory Medicine (Mr Dolder and Dr Rentsch), University Hospital and University of Basel, Basel, Switzerland.

Background: The pharmacokinetics of oral lysergic acid diethylamide are unknown despite its common recreational use and renewed interest in its use in psychiatric research and practice.

Methods: We characterized the pharmacokinetic profile, pharmacokinetic-pharmacodynamic relationship, and urine recovery of lysergic acid diethylamide and its main metabolite after administration of a single oral dose of lysergic acid diethylamide (200 μg) in 8 male and 8 female healthy subjects.

Results: Plasma lysergic acid diethylamide concentrations were quantifiable (>0.1 ng/mL) in all the subjects up to 12 hours after administration. Maximal concentrations of lysergic acid diethylamide (mean±SD: 4.5±1.4 ng/mL) were reached (median, range) 1.5 (0.5-4) hours after administration. Concentrations then decreased following first-order kinetics with a half-life of 3.6±0.9 hours up to 12 hours and slower elimination thereafter with a terminal half-life of 8.9±5.9 hours. One percent of the orally administered lysergic acid diethylamide was eliminated in urine as lysergic acid diethylamide, and 13% was eliminated as 2-oxo-3-hydroxy-lysergic acid diethylamide within 24 hours. No sex differences were observed in the pharmacokinetic profiles of lysergic acid diethylamide. The acute subjective and sympathomimetic responses to lysergic acid diethylamide lasted up to 12 hours and were closely associated with the concentrations in plasma over time and exhibited no acute tolerance.

Conclusions: These first data on the pharmacokinetics and concentration-effect relationship of oral lysergic acid diethylamide are relevant for further clinical studies and serve as a reference for the assessment of intoxication with lysergic acid diethylamide.
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http://dx.doi.org/10.1093/ijnp/pyv072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772267PMC
June 2015

Development and validation of a rapid turboflow LC-MS/MS method for the quantification of LSD and 2-oxo-3-hydroxy LSD in serum and urine samples of emergency toxicological cases.

Anal Bioanal Chem 2015 Feb 27;407(6):1577-84. Epub 2014 Dec 27.

Laboratory Medicine, University Hospital, Petersgraben 4, 4031, Basel, Switzerland.

Lysergic acid diethylamide (LSD) is a widely used recreational drug. The aim of the present study is to develop a quantitative turboflow LC-MS/MS method that can be used for rapid quantification of LSD and its main metabolite 2-oxo-3-hydroxy LSD (O-H-LSD) in serum and urine in emergency toxicological cases without time-consuming extraction steps. The method was developed on an ion-trap LC-MS/MS instrument coupled to a turbulent-flow extraction system. The validation data showed no significant matrix effects and no ion suppression has been observed in serum and urine. Mean intraday accuracy and precision for LSD were 101 and 6.84%, in urine samples and 97.40 and 5.89% in serum, respectively. For O-H-LSD, the respective values were 97.50 and 4.99% in urine and 107 and 4.70% in serum. Mean interday accuracy and precision for LSD were 100 and 8.26% in urine and 101 and 6.56% in serum, respectively. For O-H-LSD, the respective values were 101 and 8.11% in urine and 99.8 and 8.35% in serum, respectively. The lower limit of quantification for LSD was determined to be 0.1 ng/ml. LSD concentrations in serum were expected to be up to 8 ng/ml. 2-Oxo-3-hydroxy LSD concentrations in urine up to 250 ng/ml. The new method was accurate and precise in the range of expected serum and urine concentrations in patients with a suspected LSD intoxication. Until now, the method has been applied in five cases with suspected LSD intoxication where the intake of the drug has been verified four times with LSD concentrations in serum in the range of 1.80-14.70 ng/ml and once with a LSD concentration of 1.25 ng/ml in urine. In serum of two patients, the O-H-LSD concentration was determined to be 0.99 and 0.45 ng/ml. In the urine of a third patient, the O-H-LSD concentration was 9.70 ng/ml.
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http://dx.doi.org/10.1007/s00216-014-8388-1DOI Listing
February 2015

Evaluation of the effect of short-term treatment with the integrase inhibitor raltegravir (Isentress) on the course of progressive feline leukemia virus infection.

Vet Microbiol 2015 Feb 3;175(2-4):167-78. Epub 2014 Nov 3.

Clinical Laboratory, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260, 8057 Zurich, Switzerland. Electronic address:

Cats persistently infected with the gammaretrovirus feline leukemia virus (FeLV) are at risk to die within months to years from FeLV-associated disease, such as immunosuppression, anemia or lymphoma/leukemia. The integrase inhibitor raltegravir has been demonstrated to reduce FeLV replication in vitro. The aim of the present study was to investigate raltegravir in vivo for its safety and efficacy to suppress FeLV replication. The safety was tested in three naïve specified pathogen-free (SPF) cats during a 15 weeks treatment period (initially 20mg then 40mg orally b.i.d.). No adverse effects were noted. The efficacy was tested in seven persistently FeLV-infected SPF cats attained from 18 cats experimentally exposed to FeLV-A/Glasgow-1. The seven cats were treated during nine weeks (40mg then 80mg b.i.d.). Raltegravir was well tolerated even at the higher dose. A significant decrease in plasma viral RNA loads (∼5×) was found; however, after treatment termination a rebound effect was observed. Only one cat developed anti-FeLV antibodies and viral RNA loads remained decreased after treatment termination. Of note, one of the untreated FeLV-A infected cats developed fatal FeLV-C associated anemia within 5 weeks of FeLV-A infection. Moreover, progressive FeLV infection was associated with significantly lower enFeLV loads prior to infection supporting that FeLV susceptibility may be related to the genetic background of the cat. Overall, our data demonstrate the ability of raltegravir to reduce viral replication also in vivo. However, no complete control of viremia was achieved. Further investigations are needed to find an optimized treatment against FeLV. (250 words).
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http://dx.doi.org/10.1016/j.vetmic.2014.10.031DOI Listing
February 2015

[Sense and nonsense of toxicological analyses in the daily clinical routine].

Ther Umsch 2013 Aug;70(8):491-7

Universitätsklinik für Allgemeine Innere Medizin, Inselspital Bern und Pharmacoepidemiology Unit, Spitalpharmazie, Universitätsspital Basel.

Screening tests for drugs of abuse are regularly used in the clinical routine. These tests identify the targeted substances very differently if tests from different manufacturers are used and sometimes also react positive after the intake of drugs which are not intended to be detected. Therefore, implausible results have to be questioned. A test result can be falsely negative, if a patient has taken a compound which is not detected by the antibody used in the test system. Chromatographic confirmation and screening assays are more laborious to perform and more demanding for the interpretation and are therefore only offered by several specialized clinical laboratories. However, their specificity is excellent and many different compounds can be detected depending on the number of compounds which are part of the mass spectra library used. If the clinical evaluation results in the differential diagnosis of an acute intoxication, screening tests for drugs of abuse can help to identify a single compound or a group of substances. The clinical picture, however, can usually not been explained by a qualitative test result. In addition, there are no published data demonstrating that these tests meaningfully influence triage, treatment, diagnosis or further therapy of a poisoned patient. The quantitative determination of specific compounds in the blood allows for example an appraisal of the prognosis and helps to indicate a specific therapy after intake of acetaminophen or methanol. New designer drugs can not at all be detected by the classic screening tests for drugs of abuse. The have to be identified by chromatographic methods.
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http://dx.doi.org/10.1024/0040-5930/a000436DOI Listing
August 2013

Low allopurinol doses are sufficient to optimize azathioprine therapy in inflammatory bowel disease patients with inadequate thiopurine metabolite concentrations.

Eur J Clin Pharmacol 2013 Aug 16;69(8):1521-31. Epub 2013 Apr 16.

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

Purpose: Recent studies in patients with inflammatory bowel diseases (IBD) on thiopurine therapy suggest that too low 6-thioguanine nucleotide concentrations (6-TGN) and too high methylmercaptopurine nucleotide concentrations (MMPN) can be reversed by a combination therapy of allopurinol and low-dose thiopurines. To date, however, optimal dosing has not been established. The aim of this study was to evaluate the minimal allopurinol doses necessary to achieve adequate 6-TGN concentrations in combination with low-dose azathioprine.

Methods: A stepwise dose-escalation of allopurinol was performed in 11 azathioprine-pretreated IBD patients with inadequately low 6-TGN concentrations (<235 pmol/8 × 10(8) erythrocytes) and/or elevated MMPN concentrations (>5,000 pmol/8 × 10(8) erythrocytes) and/or elevated liver enzymes (alanine aminotransferase and/or aspartate aminotransferase levels one- to threefold the upper limit of normal). Six patients were recruited into an open study, and five were treated in the context of an individualized therapeutic approach. Adverse effects, azathioprine metabolites, liver enzymes and whole blood counts were monitored two to three times per month.

Results: Adequate 6-TGN concentrations were achieved with a combination of 25 mg allopurinol and 50 mg azathioprine in one patient and with 50 mg allopurinol and 50 mg azathioprine in nine patients. Median 6-TGN concentrations (range) were 336 (290-488) pmol/8 × 10(8) erythrocytes after an 8-week-long intake of the final dose combination. One patient dropped out due to nausea after the first intake. MMPN concentrations and liver enzymes normalized immediately in all affected patients. All patients finishing the dose-escalation regimen tolerated the treatment without toxicity.

Conclusions: Combination therapy with only 50 mg allopurinol and 50 mg azathioprine daily is sufficient, efficacious and safe in most IBD patients with inadequate thiopurine metabolite concentrations to optimize azathioprine-based IBD therapy.
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http://dx.doi.org/10.1007/s00228-013-1500-1DOI Listing
August 2013

Ketamine-like effects after recreational use of methoxetamine.

Ann Emerg Med 2012 Jul 10;60(1):97-9. Epub 2012 Jan 10.

Swiss Toxicological Information Centre, Associated Institute of the University of Zurich, Zurich, Switzerland.

Methoxetamine, the N-ethyl derivative of ketamine, is a novel recreational drug that is not at present subject to restrictive regulations in most countries. To our knowledge, no case of methoxetamine abuse has been published to date in the scientific literature, and the only sources of information are illegal drug users' Web discussion forums. We report the first case of analytically confirmed intravenous methoxetamine abuse in a 19-year-old man. Observed signs and symptoms such as tachycardia, hypertension, confusion, agitation, stupor, ataxia, mydriasis, and nystagmus were consistent with ketamine-induced adverse effects and resolved with symptomatic treatment. According to this case report, user Web reports, and the chemical structure, methoxetamine produces ketamine-like effects. Complete recovery can be expected with supportive care.
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http://dx.doi.org/10.1016/j.annemergmed.2011.11.018DOI Listing
July 2012

Generation of metabolites by an automated online metabolism method using human liver microsomes with subsequent identification by LC-MS(n), and metabolism of 11 cathinones.

Anal Bioanal Chem 2012 Feb 10;402(6):2141-51. Epub 2012 Jan 10.

Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland.

Human liver microsomes (HLMs) are used to simulate human xenobiotic metabolism in vitro. In forensic and clinical toxicology, HLMs are popularly used to study the metabolism of new designer drugs for example. In this work, we present an automated online extraction system we developed for HLM experiments, which was compared to a classical offline approach. Furthermore, we present studies on the metabolism of 11 cathinones; for eight of these, the metabolism has not previously been reported. Metabolites were identified based on MS(2) and MS(3) scans. Fifty-three substances encompassing various classes of drugs were employed to compare the established offline and the new online methods. The metabolism of each of the following 11 cathinones was studied using the new method: 3,4-methylenedioxy-N-benzylcathinone, benzedrone, butylone, dimethylcathinone, ethylone, flephedrone, methedrone, methylone, methylethylcathinone, naphyrone, and pentylone. The agreement between the offline and the online methods was good; a total of 158 metabolites were identified. Using only the offline method, 156 (98.7%) metabolites were identified, while 151 (95.6%) were identified using only the online method. The metabolic pathways identified for the 11 cathinones included the reduction of the keto group, desalkylation, hydroxylation, and desmethylenation in cathinones containing a methylenedioxy moiety. Our method provides a straightforward approach to identifying metabolites which can then be added to the library utilized by our clinical toxicological screening method. The performance of our method compares well with that of an established offline HLM procedure, but is as automated as possible.
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http://dx.doi.org/10.1007/s00216-011-5678-8DOI Listing
February 2012

Effect of twice-daily oral administration of hydrocortisone on the bile acids composition of gallbladder bile in dogs.

Am J Vet Res 2011 Dec;72(12):1607-12

Clinic for Small Animal Internal Medicine, Vetsuisse Faculty, University of Zurich, CH-8057 Zurich, Switzerland.

Objective: To investigate the effects of twice-daily oral administration of hydrocortisone on the bile acids composition of gallbladder bile in dogs.

Animals: 6 placebo-treated control dogs and 6 hydrocortisone-treated dogs.

Procedures: Dogs received hydrocortisone (median dose, 8.5 mg/kg) or a gelatin capsule (control group) orally every 12 hours for 84 days. Gallbladder bile samples were obtained via percutaneous ultrasound-guided cholecystocentesis from each dog before (day 0 [baseline]), during (days 28, 56, and 84), and after (days 28p, 56p, and 84p) treatment for differentiated quantification of unconjugated bile acids and taurine-conjugated and glycine-conjugated bile acids via high-performance liquid chromatography-tandem mass spectrometry.

Results: Treatment with hydrocortisone for 84 days resulted in significant and reversible increases in the concentrations of unconjugated bile acids (ie, cholic, chenodeoxycholic, and deoxycholic acids) and a significant and reversible decrease in the concentration of total taurine-conjugated bile acids, compared with baseline or control group values. Treatment with hydrocortisone had no effect on bile concentrations of glycine-conjugated bile acids.

Conclusions And Clinical Relevance: In dogs, hydrocortisone administration caused reversible shifts toward higher concentrations of the more hydrophobic unconjugated bile acids (chenodeoxycholic acid and deoxycholic acid) and toward lower concentrations of the amphipathic taurine-conjugated bile acids in gallbladder bile. These data suggest that similar bile acids changes could cause major alterations in gallbladder structure or function over time in hypercortisolemic dogs.
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http://dx.doi.org/10.2460/ajvr.72.12.1607DOI Listing
December 2011

The antineoplastic antibiotic taurolidine promotes lung and liver metastasis in two syngeneic osteosarcoma mouse models and exhibits severe liver toxicity.

Int J Cancer 2012 Sep 11;131(5):E804-12. Epub 2012 Jan 11.

Department of Orthopedics, Laboratory for Orthopedic Research, Balgrist University Hospital, and Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.

Osteosarcoma (OS) is the most frequent primary bone tumor. Despite multiagent neoadjuvant chemotherapy, patients with metastatic disease have a poor prognosis. Moreover, currently used chemotherapeutics have severe toxic side effects. Thus, novel agents with improved antimetastatic activity and reduced toxicity are needed. Taurolidine, a broad-spectrum antimicrobial, has recently been shown to have antineoplastic properties against a variety of tumors and low systemic toxicity. Consequently, we investigated in our study the antineoplastic potential of taurolidine against OS in two different mouse models. Although both OS cell lines, K7M2 and LM8, were sensitive for the compound in vitro, intraperitoneal application of taurolidine failed to inhibit primary tumor growth. Moreover, it enhanced the metastatic load in both models 1.7- to 20-fold and caused severe liver deformations and up to 40% mortality. Thus, systemic toxicity was further investigated in tumor-free mice histologically, by electron microscopy and by measurements of representative liver enzymes. Taurolidine dose-dependent fibrous thickening of the liver capsule and adhesions and atrophies of the liver lobes were comparable in healthy and tumor-bearing mice. Liver toxicity was further indicated by up to eightfold elevated levels of the liver enzymes alanine transaminase, aspartate transaminase and GLDH in the circulation. Ultrastructural analysis of affected liver tissue showed swollen mitochondria with cristolysis and numerous lipid vacuoles in the cytoplasm of hepatocytes. The findings of our study question the applicability of taurolidine for OS treatment and may suggest the need for caution regarding the widespread clinical use of taurolidine as an antineoplastic agent.
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http://dx.doi.org/10.1002/ijc.27378DOI Listing
September 2012
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