Ruwen Böhm

A European spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics

Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes. Our data show significant inter-population pharmacogenomic biomarker allele frequency differences, particularly in 7 clinically actionable pharmacogenomic biomarkers in 7 European populations, affecting drug efficacy and/or toxicity of 51 medication treatment modalities. These data also reflect on the differences observed in the prevalence of high-risk genotypes in these populations, as far as common markers in the CYP2C9, CYP2C19, CYP3A5, VKORC1, SLCO1B1 and TPMT pharmacogenes are concerned. Also, our data demonstrate notable differences in predicted genotype-based warfarin dosing among these populations. Our findings can be exploited not only to develop guidelines for medical prioritization, but most importantly to facilitate integration of pharmacogenomics and to support pre-emptive pharmacogenomic testing. This may subsequently contribute towards significant cost-savings in the overall healthcare expenditure in the participating countries, where pharmacogenomics implementation proves to be cost-effective.

Correlation, accuracy, precision and practicability of perioperative measurement of sublingual temperature in comparison with tympanic membrane temperature in awake and anaesthetised patients.

Background and objective The prevention of inadvertent perioperative hypothermia requires precise, reliable and practical methods of temperature measurement in both awake and anaesthetised patients. Different methods and sites of monitoring have been evaluated, but many are imprecise, unusable in awake patients, difficult to apply or too invasive, especially for minor surgery. The aim of this study was to evaluate the performance of perioperative sublingual and tympanic temperature measurement in awake and anaesthetised patients. Methods We enrolled 171 patients, aged 18–75 years, scheduled for surgery with duration less than 1 h under general anaesthesia. Spearmans rank correlation and Bland–Altman analysis for assessment of correlation, accuracy and precision of both methods were determined analysing 171 independent paired values at three different measurement times. Results Sublingual temperatures were significantly higher than tympanic temperatures by 0.1–0.2°C. The coefficient of determination (r2) of both methods was between 0.50 and 0.59, and Bland–Altman analysis revealed a bias (SD) of between −0.09 (0.21) and −0.15 (0.24)°C. Conclusion The accuracy and precision of sublingual temperature measurement were adequate for clinical use, and there was a high correlation with tympanic temperature monitoring. Sublingual temperature measurement has been demonstrated as a good and practical modality for perioperative temperature monitoring in both awake and anaesthetised patients. Trial registration Clinicaltrials.gov NCT01234233.

OpenVigil FDA – Inspection of U.S. American Adverse Drug Events Pharmacovigilance Data and Novel Clinical Applications

Pharmacovigilance contributes to health care. However, direct access to the underlying data for academic institutions and individual physicians or pharmacists is intricate, and easily employable analysis modes for everyday clinical situations are missing. This underlines the need for a tool to bring pharmacovigilance to the clinics. To address these issues, we have developed OpenVigil FDA, a novel web-based pharmacovigilance analysis tool which uses the openFDA online interface of the Food and Drug Administration (FDA) to access U.S. American and international pharmacovigilance data from the Adverse Event Reporting System (AERS). OpenVigil FDA provides disproportionality analyses to (i) identify the drug most likely evoking a new adverse event, (ii) compare two drugs concerning their safety profile, (iii) check arbitrary combinations of two drugs for unknown drug-drug interactions and (iv) enhance the relevance of results by identifying confounding factors and eliminating them using background correction. We present examples for these applications and discuss the promises and limits of pharmacovigilance, openFDA and OpenVigil FDA. OpenVigil FDA is the first public available tool to apply pharmacovigilance findings directly to real-life clinical problems. OpenVigil FDA does not require special licenses or statistical programs.

Intraoperative temperature monitoring with zero heat flux technology (3M SpotOn sensor) in comparison with sublingual and nasopharyngeal temperature: An observational study.

BACKGROUND Perioperative hypothermia is common in patients undergoing general anaesthesia and is associated with important adverse events. The ‘gold standard’ for monitoring body core temperature – the pulmonary artery catheter – is invasive and unsuitable for most patients. For routine clinical practice, other sites and methods of temperature monitoring are commonly used. OBJECTIVE The aim of this study was to evaluate a new temperature sensor (3M SpotOn) using the ’zero heat flux’ method attached to the forehead, and compare it to sublingual and nasopharyngeal sensors in terms of correlation, accuracy and precision. DESIGN An observational study. SETTING University Medical Center Schleswig Holstein, Campus Kiel, Germany from October 2013 to January 2014. PATIENTS One hundred and twenty patients scheduled for elective gynaecological or trauma surgery undergoing general anaesthesia were enrolled into this study. Data of 83 patients were finally analysed. Patients with unexpected blood loss, haemodynamic instability determined by the need for continuous norepinephrine infusion and/or need for postoperative ventilation were excluded from this study. INTERVENTION Temperature monitoring was established after induction of anaesthesia with sublingual and nasopharyngeal probes, and the SpotOn sensor. MAIN OUTCOME MEASURES Body temperature was measured 15, 45 and 75 min after induction of anaesthesia from sublingual and nasopharyngeal probes and the 3M SpotOn sensor at precisely the same moment. RESULTS Analysis of 83 data sets revealed that 3M SpotOn temperatures were almost identical with nasopharyngeal temperatures (mean difference 0.07°C; P = 0.1424) and slightly lower than sublingual temperatures by 0.35°C (P < 0.0001). Coefficients of determination (r) for both methods were between 0.87 (SpotOn vs. nasopharyngeal measurement) and 0.77 (SpotOn vs. sublingual measurement). Bland–Altman analysis revealed a bias (SD) between 0.07°C (0.21) (SpotOn vs. nasopharyngeal) and −0.35°C (0.29) (SpotOn vs. sublingual measurement). CONCLUSION With respect to correlation, accuracy and precision, the 3M SpotOn sensor provides a good measurement of body temperature in comparison to the nasopharyngeal probe and an acceptable measurement in comparison with sublingual thermometry. It is adequate for clinical use. TRIAL REGISTRATION Clinicaltrials.gov identifier: NCT02031159

Interaction of morphine but not fentanyl with cerebral α2-adrenoceptors in α2-adrenoceptor knockout mice

Objectives α2‐Adrenergic and μ‐opioid receptors belong to the rhodopsin family of G‐protein coupled receptors and mediate antinociceptive effects via similar signal transduction pathways. Previous studies have revealed direct functional interactions between both receptor systems including synergistic and additive effects. To evaluate underlying mechanisms, we have studied whether morphine and fentanyl interacted with α2‐adrenoceptor‐subtypes in mice lacking one individual α2‐adrenoceptor‐subtype (α2‐adrenoceptor knockout).

Warming before and after epidural block before general anaesthesia for major abdominal surgery prevents perioperative hypothermia: A randomised controlled trial.

BACKGROUND Epidural analgesia (EDA) is known to be an independent risk factor for perioperative hypothermia and its many known adverse effects. Combined general and epidural anaesthesia decreases intraoperative core temperature more rapidly than general anaesthesia alone. Hence, adequate warming procedures are needed for these patients. OBJECTIVE We evaluated the effects of active skin-surface warming before and/or after initiation of EDA during general anaesthesia as a procedure to prevent perioperative hypothermia. DESIGN A randomised controlled trial. SETTING Department of Anaesthesiology in a general hospital in Germany from January 2013 until August 2014. PATIENTS After obtaining written informed consent, we included 99 adult patients undergoing elective major abdominal surgery under combined general anaesthesia and EDA with an expected duration of surgery of at least 120 min. Patients were excluded if they were under 18 years of age, classified as American Society of Anesthesiologists’ physical status 4 or higher or if patients refused EDA. INTERVENTIONS Patients were randomly assigned to one of three groups and received either only passive insulation, 15 min of active air-forced warming after EDA and before induction of general anaesthesia, or two periods, each of 15 min, of active air-forced warming before and after EDA. Core and skin temperatures were measured at several time points throughout the study. MAIN OUTCOME MEASURES The primary outcome measure was the incidence of hypothermia on arrival in the ICU. The secondary outcome measure was the incidence of postoperative shivering. In addition, the perioperative change in body core temperature was recorded. RESULTS Without prewarming (n = 32), 72% of patients became hypothermic (<36°C) at the end of anaesthesia. Fifteen minutes of warming after insertion of the epidural catheter and before initiation of general anaesthesia reduced the incidence of postoperative hypothermia to 6% (n = 33). After two periods of 15 min of warming before and after insertion of the epidural catheter, no patient became hypothermic (n = 34). Prewarming in either ‘warming’ group prevents the initial temperature drop which was observed in the control group. CONCLUSION Warming for 15 min before and after initiation of EDA in patients receiving combined anaesthesia is effective in preventing postoperative hypothermia. TRIAL REGISTRATION This trial was registered with ClinicalTrials.gov (identifier: NCT01795482).

Pharmacogenetics and Predictive Testing of Drug Hypersensitivity Reactions.

Adverse drug reactions adverse drug reaction (ADR) occur in approximately 17% of patients. Avoiding ADR is thus mandatory from both an ethical and an economic point of view. Whereas, pharmacogenetics changes of the pharmacokinetics may contribute to the explanation of some type A reactions, strong relationships of genetic markers has also been shown for drug hypersensitivity belonging to type B reactions. We present the classifications of ADR, discuss genetic influences and focus on delayed-onset hypersensitivity reactions, i.e., drug-induced liver injury, drug-induced agranulocytosis, and severe cutaneous ADR. A guidance how to read and interpret the contingency table is provided as well as an algorithm whether and how a test for a pharmacogenetic biomarker should be conducted.

Correction: A European Spectrum of Pharmacogenomic Biomarkers: Implications for Clinical Pharmacogenomics.

[This corrects the article DOI: 10.1371/journal.pone.0162866.].

Reply to: Zero-heat flux thermometry.

Perhaps, the most striking aspect of Iden et al. is that 37 of 120 enrolled patients, very nearly a third, were excluded from analysis. Granted, two patients were switched to spinal anaesthesia and the SpotOn thermometer malfunctioned in four others. But 19 patients were eliminated because of ‘calibration failure of the sublingual probe’. That an electronic sublingual probe would fail in more than 15% of cases seems remarkable. After all, oral thermometers are standard hospital equipment and rarely fail in normal use. Twelve additional patients were excluded because surgery did not last long enough to obtain the final planned temperature measurement at 75 min.