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Purpose Ivabradine has been approved for the treatment of chronic heart failure and chronic stable angina pectoris in Europe. Based on adverse outcomes of reproductive animal studies and the lack of human data, ivabradine is considered contraindicated during pregnancy. The aim of this observational study is to analyse ivabradine use before and during pregnancy. Methods We evaluated all ivabradine-related requests to the German Embryotox Institute from 2007 to 2019. Exposed pregnancies were analysed as to their outcome. Results Off-label use for supraventricular tachycardia was frequent in women of childbearing age. Of 38 prospectively ascertained pregnancies with ivabradine exposure and completed follow-up, 32 resulted in live births, 3 in spontaneous abortions, and 3 were electively terminated. One neonate presented with major birth defects (atrial septal defect and cleft palate). In 33/38 patients, ivabradine was discontinued after confirmation of pregnancy without cardiac deterioration and 5/38 women continued ivabradine throughout pregnancy. In addition, there were 3 retrospectively reported pregnancies including one major birth defect (tracheal atresia). Conclusion This case series represents the largest cohort of ivabradine-exposed pregnancies, published so far. According to our findings, ivabradine appears not to be a major teratogen. However, established drugs of choice with strong evidence of low risk for the unborn should be preferred in women planning pregnancy. After inadvertent exposure during pregnancy or lack of treatment alternatives, fetal ultrasound for structural anomalies and growth restriction is recommended. In addition, close monitoring is necessary in pregnant women with supraventricular arrhythmias or cardiac disease.

Aims Using 3 different perpetrators the impact of voriconazole, cobicistat and rifampicin (single dose), we evaluated the suitability of a microdose cocktail of factor Xa inhibitors (FXaI; rivaroxaban, apixaban and edoxaban; 100 μg in total) to study drug-drug interactions. Methods Three cohorts of 6 healthy volunteers received 2 treatments with microdoses of rivaroxaban, apixaban and edoxaban alone and with coadministration of 1 of the perpetrators. Plasma and urine concentrations of microdosed apixaban, edoxaban and rivaroxaban were quantified using a validated ultra-performance liquid chromatography-tandem mass spectrometry with a lower limit of quantification of 2.5 pg/mL. Results Voriconazole caused only a minor interaction with apixaban and rivaroxaban, none with edoxaban. Cobicistat significantly increased exposure of all 3 FXaI with area under the plasma concentration-time curve ratios of 1.67 (apixaban), 1.74 (edoxaban) and 2.0 (rivaroxaban). A single dose of rifampicin decreased the volume of distribution and elimination half-life of all 3 FXaI. Conclusions The microdosed FXaI cocktail approach is able to generate drug interaction data and can help elucidating the mechanism involved in the clearance of the different victim drugs. This is a safe approach to concurrently study drug-drug interactions with a drug class. (EudraCT 2016-003024-23).

Aims Rivaroxaban exposure is considerably increased by drugs that are combined P-glycoprotein (P-gp) and strong cytochrome P450 (CYP) 3A inhibitors (e.g. ketoconazole). The aim of the present study was to investigate the effects of the potent P-gp inhibitor ciclosporin and its combination with the moderate CYP3A inhibitor fluconazole on rivaroxaban pharmacokinetics and on CYP3A activity. Methods Twelve healthy volunteers received 20 mg rivaroxaban orally alone, in combination with ciclosporin (dose-individualized oral regimen), and in combination with ciclosporin and fluconazole (400 mg day-1 orally). CYP3A4 activity was estimated using a midazolam microdose. Pharmacokinetics was analysed using noncompartmental and compartmental methods. Results Compared to baseline, ciclosporin increased rivaroxaban average exposure by 47% (90% confidence interval 28-68%), maximum concentration by 104% (70-146%), and decreased CYP3A4 activity by 34% (25-42%). Ciclosporin combined with fluconazole increased rivaroxaban average exposure by 86% (58-119%) and maximum concentration by 115% (83-153%), which was considerably stronger than observed in historical controls receiving rivaroxaban with fluconazole alone, and decreased CYP3A4 activity by 79% (76-82%). Conclusion Patients treated with rivaroxaban in combination with single modulators of multiple elimination pathways or multiple modulators of single elimination pathways (CYP3A, P-gp) require particular care.

The gold standard of saving fresh tissue in liquid nitrogen has some serious disadvantages in that this process is not available in daily medical routine practices even in many tumor centers. Our approach of a new minimally invasive technique is obtaining urothelial cells via micro-brushing the urinary bladder on the occasion of urological routine methods such as transurethral resection (TUR). Urothelial cells were obtained from 25 patients via two different micro-brushes from tumor tissue and from macroscopically healthy tissue during TUR. These cells were immediately transferred into RNA stabilization reagent and stored at -20°C. Later, mRNA was isolated, transcribed into cDNA, and amplified. cDNA was stored at -20°C until analysis. The mean RNA quantity was 99.5 ng/μl from tumor tissues and 66.3 ng/μl from macroscopically tumor-free tissue, enabling a considerable number of analyses. The quality of the gained cDNA allowed semi-quantitative PCR analysis of GSTM1 expression as well as quantitative PCR analysis of c-Myc expression. The new technique presents several important advantages. First, staging and grading of the stained tumor sample can be examined immediately, whereas fresh frozen sample is not examined until some days later. Further, this method can be applied in hospitals with no access to liquid nitrogen or without capability to provide an additional examination of frozen tumor sample by a pathologist. This presented minimally invasive method enables investigation of gene expression in the urinary bladder without disadvantages of the need for storage of fresh tissues in liquid nitrogen.

Sensory irritation is an acute adverse effect caused by chemicals that stimulate chemoreceptors of the upper respiratory tract or the mucous membranes of the outer eye. The avoidance of this end point is of uttermost importance in regulatory toxicology. In this study, repeated exposures to ethyl acrylate were analyzed to investigate possible carryover effects from day to day for different markers of sensory irritation. Thirty healthy subjects were exposed for 4 h on five subsequent days to ethyl acrylate at concentrations permitted by the German occupational exposure limit at the time of study. Ratings of eye irritation as well as eye blinking frequencies indicate the elicitation of sensory irritation. These markers of sensory irritation showed a distinct time course on every single day. However, cumulative carryover effects could not be identified across the week for any marker. The rhinological and biochemical markers could not reveal hints for more pronounced sensory irritation. Neither increased markers of neurogenic inflammation nor markers of immune response could be identified. Furthermore, the performance on neurobehavioral tests was not affected by ethyl acrylate and despite the strong odor of ethyl acrylate the participants improved their performances from day to day. While the affected physiological marker, the increased eye blinking frequency stays roughly on the same level across the week, subjective markers like perception of eye irritation decrease slightly from day to day though the temporal pattern of, i.e., eye irritation perception stays the same on each day. A hypothetical model of eye irritation time course derived from PK/PD modeling of the rabbit eye could explain the within-day time course of eye irritation ratings repeatedly found in this study more precisely.

The aim of this study was to prove the suitability of simultaneously administered microdoses of the factor Xa inhibitors (FXaIs) rivaroxaban, apixaban and edoxaban (100 µg in total). To evaluate drug–drug interactions, the impact of ketoconazole, a known strong inhibitor of cytochrome P450 3A4 and P-glycoprotein, was studied. In a crossover clinical trial, 18 healthy volunteers were randomized to the two treatments using microdoses of rivaroxaban, apixaban and edoxaban alone and when coadministered with ketoconazole. Plasma and urine concentrations of microdosed apixaban, edoxaban and rivaroxaban were quantified using a validated ultra-performance liquid chromatography–tandem mass spectrometry assay with a lower limit of quantification of 2.5 pg/ml. The microdosed FXaI cocktail showed similar pharmacokinetic parameters compared with published data, using normal therapeutic doses of each FXaI. Ketoconazole significantly increased exposure, with geometric mean AUC ratios of 1.90 (apixaban), 2.35 (edoxaban) and 2.27 (rivaroxaban). The microdosed FXaI cocktail approach was able to precisely predict the drug interaction with ketoconazole. This is the first study that has been conducted to evaluate drug–drug interactions with a drug class, and the low administered doses also allow evaluation in vulnerable target populations. EudraCT 2016-003024-23.

Perceptions that arise from stimulation of olfactory and trigeminal receptors in the nasal cavity guide the evaluation of chemical environment in humans. Strong interindividual differences in these assessments may be attributed to nonsensory factors such as gender, anxiety, and chemical sensitivity. Knowledge regarding the influence of these factors originates mainly from basic odor research using short-term exposure scenarios. In situations with continuous chemical exposures—common in the working environment—their impact is less clear. To investigate their role during the exposure to workplace chemicals, 4-hour experimental exposure studies (total N = 105) using nine different airborne chemicals were summarized. In each study, subjects evaluated a single chemical in a controlled environment by rating five chemosensory perceptions, including odor intensity, disgust, annoyance, pungency, and burning, several times during occupational limit and low exposures. It was investigated whether the effects of trait-like modulators, such as anxiety and self-reported chemical sensitivity, depend on exposure-related factors and gender. Trait-like modulators markedly affected ratings by women, but not men. Highly anxious women reported more intense annoyance and disgust than less anxious women. Stronger self-reported chemical sensitivity was associated with increased ratings of pungency and burning in women exposed to occupational limit concentrations. This study demonstrates that a complex interplay of exposure-related factors, gender, and trait-like individual differences affects perceptual ratings during continuous chemical exposure. It seems necessary to incorporate the assessment of specific as well as general trait-like modulators into future experimental exposure studies.

Aim: The identification of antidepressant drugs (ADs) response biomarkers in depression is of high clinical importance. We explored CHL1 and ITGB3 expression as tentative response biomarkers. Materials & methods: In vitro sensitivity to ADs, as well as gene expression and genetic variants of the candidate genes CHL1, ITGB3 and SLC6A4 were measured in lymphoblastoid cell lines (LCLs) of 58 depressed patients. Results: An association between the clinical remission of depression and the basal expression of CHL1 and ITGB3 was discovered. Individuals whose LCLs expressed higher levels of CHL1 or ITGB3 showed a significantly better remission upon AD treatment. In addition individuals with the CHL1 rs1516338 TT genotype showed a significantly better remission after 5 weeks AD treatment than those carrying a CC genotype. No association between the in vitro sensitivity of LCLs toward AD and the clinical remission could be detected. Conclusion: CHL1 expression in patient-derived LCLs correlated with the clinical outcome. Thus, it could be a valid biomarker to predict the success of an antidepressant therapy. Original submitted 8 December 2014; Revision submitted 2 March 2015

Because of the large variation in the response to psychoactive medication, many studies have attempted to uncover genetic factors that determine response. While considerable knowledge exists on the large effects of genetic polymorphisms on pharmacokinetics and plasma concentrations of drugs, effects of the concentration at the target site and pharmacodynamic effects on brain functions in disease are much less known. This article reviews the role of magnetic resonance imaging (MRI) to visualize response to medication in brain behaviour circuits in vivo in humans and assess the influence of pharmacogenetic factors. Two types of studies have been used to characterize effects of medication and genetic variation. In task-related activation studies the focus is on changes in the activity of a neural circuit associated with a specific psychological process. The second type of study investigates resting state perfusion. These studies provide an assessment of vascular changes associated with bioavailability of drugs in the brain, but may also assess changes in neural activity after binding of centrally active agents. Task-related pharmacogenetic studies of cognitive function have characterized the effects in the prefrontal cortex of genetic polymorphisms of dopamine receptors (DRD2), metabolic enzymes (COMT) and in the post-synaptic signalling cascade under the administration of dopamine agonists and antagonists. In contrast, pharmacogenetic imaging with resting state perfusion is still in its infancy. However, the quantitative nature of perfusion imaging, its non-invasive character and its repeatability might be crucial assets in visualizing the effects of medication in vivo in man during therapy.

Background Elderly patients are particularly vulnerable to adverse drug reactions, especially if they are affected by additional risk factors such as multimorbidity, polypharmacy, impaired renal function and intake of drugs with high risk potential. Apart from these clinical parameters, drug safety and efficacy can be influenced by pharmacogenetic factors. Evidence-based recommendations concerning drug-gene-combinations have been issued by international consortia and in drug labels. However, clinical benefit of providing information on individual patient factors in a comprehensive risk assessment aiming to reduce the occurrence and severity of adverse drug reactions is not evident. Purpose of this randomized controlled trial is to compare the effect of a concise individual risk information leaflet with standard information on risk factors for side effects. Methods/Design The trial was designed as a prospective, two-arm, randomized, controlled, multicenter, pragmatic study. 960 elderly, multimorbid outpatients in general medicine are included if they take at least one high risk and one other long-term drug (polymedication). As high risk “index drugs” oral anticoagulants and antiplatelets were chosen because of their specific, objectively assessable side effects. Following randomization, test group patients receive an individualized risk assessment leaflet evaluating their personal data concerning bleeding- and thromboembolic-risk-scores, potential drug-drug-interactions, age, renal function and pharmacogenetic factors. Control group patients obtain a standardized leaflet only containing general information on these criteria. Follow-up period is 9 months for each patient. Primary endpoint is the occurrence of a thromboembolic/bleeding event or death. Secondary endpoints are other adverse drug reactions, hospital admissions, specialist referrals and medication changes due to adverse drug reactions, the patients’ adherence to medication regimen as well as health related quality of life, mortality and resulting costs. Discussion Despite extensive evidence of risk factors for adverse drug reactions, there are few prospective trial data about an individualized risk assessment including pharmacogenetic information to increase patient safety. By conducting a health economic analysis, we will evaluate if the application of an individualized drug therapy in daily routine is cost-effective. Trial registration German Clinical Trials Register: DRKS00006256, date of registration 09/01/15.

In the 1990s, an uncommonly high percentage of glutathione S-transferase M1 (GSTM1) negative bladder cancer cases (70%) was reported in the greater Dortmund area. The question arose as to whether this uncommonly high percentage of GSTM1 negative bladder cancer cases was due to environmental and/or occupational exposure decades ago. Thus, 15 years later, another study on bladder cancer was performed in the same area after the coal, iron, and steel industries had finally closed in the 1990s. In total 196 bladder cancer patients from the St.-Josefs-Hospital Dortmund-Hörde and 235 controls with benign urological diseases were assessed by questionnaire and genotyped for GSTM1, glutathione S-transferase T1 (GSTT1), and the N-acetyltransferase 2 (NAT2) tag SNP rs1495741. The frequency of the GSTM1 negative genotype was 52% in bladder cancer cases and thus lower compared to a previous study performed from 1992 to 1995 in the same area (70%). NAT2 genotypes were distributed equally among cases and controls (63% slow acetylators). Fewer GSTT1 negative genotypes were present in cases (17%) than in controls (20%).

In recent years, genome-wide association studies (GWAS) have identified more than 300 validated associations between genetic variants and risk of approximately 70 common diseases. A small number of rare variants with a frequency of usually less than 1% are associated with a strongly enhanced risk, such as genetic variants of TP53, RB1, BRCA1, and BRCA2. Only a very small number of SNPs (with a frequency of more that 1% of the rare allele) have effects of a factor of two or higher. Examples include APOE4 in Alzheimer's disease, LOXL1 in exfoliative glaucoma, and CFH in age-related macular degeneration. However, the majority of all identified SNPs have odds ratios between 1.1 and 1.5. In the case of urinary bladder cancer, all known SNPs that have been validated in sufficiently large populations are associated with odds ratios smaller than 1.5. These SNPs are located next to the following genes: MYC, TP63, PSCA, the TERT-CLPTM1L locus, FGFR3, TACC3, NAT2, CBX6, APOBEC3A, CCNE1, and UGT1A. It is likely that these moderate risk or "wimp SNPs" interact, and because of their high number, collectively have a strong influence on whether an individual will develop cancer or not. It should be considered that variants identified so far explain only approximately 5-10% of the overall inherited risk. Possibly, the remaining variance is due to an even higher number of SNPs with odds ratios smaller than 1.1. Recent studies have provided the following information: (1) The functions of genes identified as relevant for bladder cancer focus on detoxification of carcinogens, control of the cell cycle and apoptosis, as well as maintenance of DNA integrity. (2) Many novel SNPs are far away from the protein coding regions, suggesting that these SNPs are located on distant-acting transcriptional enhancers. (3) The low odds ratio of each individual bladder cancer-associated SNP is too low to justify reasonable preventive measures. However, if the recently identified SNPs interact, they may collectively result in a substantial risk that is of preventive relevance. In addition to the "novel SNPs" identified by the recent GWAS, at least 163 further variants have been reported in relation to bladder cancer, although they have not been consistently validated in independent case-control series. Moreover, given that only 60 of these 163 "old SNPs" are covered by the SNP chips used in the recent GWAS, there are in principle 103 published variants still awaiting validation or disproval. In future, besides identifying novel disease-associated rare variants by deep sequencing, it will also be important to understand how the already identified variants interact.

Because of the large variation in the response to psychoactive medication, many studies have attempted to uncover genetic factors that determine response. While considerable knowledge exists on the large effects of genetic polymorphisms on pharmacokinetics and plasma concentrations of drugs, effects of the concentration at the target site and pharmacodynamic effects on brain functions in disease are much less known. This article reviews the role of magnetic resonance imaging (MRI) to visualize response to medication in brain behaviour circuits in vivo in humans and assess the influence of pharmacogenetic factors. Two types of studies have been used to characterize effects of medication and genetic variation. In task-related activation studies the focus is on changes in the activity of a neural circuit associated with a specific psychological process. The second type of study investigates resting state perfusion. These studies provide an assessment of vascular changes associated with bioavailability of drugs in the brain, but may also assess changes in neural activity after binding of centrally active agents. Task-related pharmacogenetic studies of cognitive function have characterized the effects in the prefrontal cortex of genetic polymorphisms of dopamine receptors (DRD2), metabolic enzymes (COMT) and in the post-synaptic signalling cascade under the administration of dopamine agonists and antagonists. In contrast, pharmacogenetic imaging with resting state perfusion is still in its infancy. However, the quantitative nature of perfusion imaging, its non-invasive character and its repeatability might be crucial assets in visualizing the effects of medication in vivo in man during therapy.

Recently, rs11892031[A] has been identified in a genome-wide association study (GWAS) to confer increased risk of urinary bladder cancer (UBC). To confirm this association and additionally study a possible relevance of exposure to urinary bladder carcinogens, we investigated the IfADo UBC study group, consisting of eight case–control series from different regions including 1,805 cases and 2,141 controls. This analysis was supplemented by a meta-analysis of all published data, including 13,395 cases and 54,876 controls. Rs11892031 A/A was significantly associated with UBC risk in the IfADo case–control series adjusted to cigarette smoking, gender, age and ethnicity (OR = 1.18; 95% CI = 1.02–1.37; P = 0.026). In the meta-analysis, a convincing association with UBC risk was obtained (OR = 1.19; 95% Cl = 1.12–1.26; P < 0.0001). Interestingly, the highest odds ratios were obtained for individual case–control series with a high degree of occupational exposure to polycyclic aromatic hydrocarbons and aromatic amines: cases with suspected occupational UBC (OR = 1.41) and cases from the highly industrialized Ruhr area (OR = 1.98) compared with Ruhr area controls (all combined OR = 1.46). Odds ratios were lower for study groups with no or a lower degree of occupational exposure to bladder carcinogens, such as the Hungary (OR = 1.02) or the ongoing West German case–control series (OR = 1.06). However, the possible association of rs11892031[A] with exposure to bladder carcinogens still should be interpreted with caution, because in contrast to the differences between the individual study groups, interview-based data on occupational exposure were not significantly associated with rs11892031. In conclusion, the association of rs11892031[A] with UBC risk could be confirmed in independent study groups.

Currently, twelve validated genetic variants have been identified that are associated with urinary bladder cancer (UBC) risk. However, those validated variants explain only 5–10% of the overall inherited risk. In addition, there are more than 100 published polymorphisms still awaiting validation or disproval. A particularly promising of the latter unconfirmed polymorphisms is rs2854744 that recently has been published to be associated with UBC risk. The [A] allele of rs2854744 has been reported to be associated with a higher promoter activity of the insulin-like growth factor-binding protein-3 (IGFBP3) gene, which may lead to increased IGFBP-3 plasma levels and cancer risk. Therefore, we investigated the association of rs2854744 with UBC in the IfADo case–control series consisting of 1,450 cases and 1,725 controls from Germany, Hungary, Venezuela and Pakistan. No significant association of rs2854744 with UBC risk was obtained (all study groups combined: unadjusted P = 0.4446; adjusted for age, gender and smoking habits P = 0.6510), besides a small effect of the [A] allele in the Pakistani study group opposed to the original findings (unadjusted P = 0.0508, odds ratio (OR) = 1.43 for the multiplicative model) that diminished after adjustment for age, gender and smoking habits (P = 0.7871; OR = 0.93). Associations of rs2854744 with occupational exposure to urinary bladder carcinogens and smoking habits were also not present. A meta-analysis of all available case–control series including the original discovery study resulted in an OR of 1.00 (P = 0.9562). In conclusion, we could not confirm the recently published hypothesis that rs2854744 in the IGFBP3 gene is associated with UBC risk.

Genotyping N-acetyltransferase 2 (NAT2) is of high relevance for individualized dosing of antituberculosis drugs and bladder cancer epidemiology. In this study we compared a recently published tagging single nucleotide polymorphism (SNP) (rs1495741) to the conventional 7-SNP genotype (G191A, C282T, T341C, C481T, G590A, A803G and G857A haplotype pairs) and systematically analysed if novel SNP combinations outperform the latter. For this purpose, we studied 3177 individuals by PCR and phenotyped 344 individuals by the caffeine test. Although the tagSNP and the 7-SNP genotype showed a high degree of correlation (R=0.933, P0.0001) the 7-SNP genotype nevertheless outperformed the tagging SNP with respect to specificity (1.0 vs. 0.9444, P=0.0065). Considering all possible SNP combinations in a receiver operating characteristic analysis we identified a 2-SNP genotype (C282T, T341C) that outperformed the tagging SNP and was equivalent to the 7-SNP genotype. The 2-SNP genotype predicted the correct phenotype with a sensitivity of 0.8643 and a specificity of 1.0. In addition, it predicted the 7-SNP genotype with sensitivity and specificity of 0.9993 and 0.9880, respectively. The prediction of the NAT2 genotype by the 2-SNP genotype performed similar in populations of Caucasian, Venezuelan and Pakistani background. A 2-SNP genotype predicts NAT2 phenotypes with similar sensitivity and specificity as the conventional 7-SNP genotype. This procedure represents a facilitation in individualized dosing of NAT2 substrates without losing sensitivity or specificity.

Single nucleotide polymorphism (SNP) rs710521[A], located near TP63 on chromosome 3q28, was identified to be significantly associated with increased bladder cancer risk. To investigate the association of rs710521[A] and bladder cancer by new data and by meta-analysis including all published data, rs710521 was studied in 1,425 bladder cancer cases and 1,740 controls that had not been included in previous studies. Blood samples were collected from 1995 to 2010 in Germany (n = 948/1,258), Hungary (n = 262/65), Venezuela (n = 112/190) and Pakistan (n = 103/227) supplemented by a meta-analysis of 5,695 cases and 40,187 controls. Detection of a A/G substitution (rs710521) on chromosome 3q28, position 191128627 was done via fast real-time polymerase chain reaction (rt–PCR). Rs710521[A] is associated with increased risk in the unadjusted analysis (OR = 1.21; 95% Cl = 1.04–1.40; P = 0.011) and in the recessive model adjusted for age, gender, smoking habits and ethnicity (OR = 1.23; 95% Cl = 1.05–1.44; P = 0.010). No difference between individuals occupationally exposed versus not occupationally exposed to urinary bladder carcinogens was observed concerning the relevance of rs710521[A]. Similarly, rs710521[A] did not confer different susceptibility in smokers and non-smokers. Performing a meta-analysis of 5,695 cases and 40,187 controls including all published studies on rs710521, a convincing association with bladder cancer risk was obtained (OR = 1.18; 95% Cl = 1.12–1.25; P < 0.0001). However, the odds ratio is relatively small.