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British journal of clinical pharmacology : BJCP 88(12), 5149-5165 (2022). doi:10.1111/bcp.15467 special issue: "Themed Issue: Methodological Consideration in Research and Development of Medicines for Children (C4C / Issue Edited by: Ian Wong, Saskia Dewildt", Published by Wiley-Blackwell, Oxford

Preclinical, epidemiological, and small clinical studies suggest that green tea extract (GTE) and its major active component epigallocatechingallate (EGCG) exhibit antineoplastic effects in the colorectum.A randomized, double-blind trial of GTE standardized to 150 mg of EGCG b.i.d. vs placebo over 3 years was conducted to prevent colorectal adenomas (n = 1,001 with colon adenomas enrolled, 40 German centers). Randomization (1:1, n = 879) was performed after a 4-week run-in with GTE for safety assessment. The primary end point was the presence of adenoma/colorectal cancer at the follow-up colonoscopy 3 years after randomization.The safety profile of GTE was favorable with no major differences in adverse events between the 2 well-balanced groups. Adenoma rate in the modified intention-to-treat set (all randomized participants [intention-to-treat population] and a follow-up colonoscopy 26-44 months after randomization; n = 632) was 55.7% in the placebo and 51.1% in the GTE groups. This 4.6% difference was not statistically significant (adjusted relative risk 0.905; P = 0.1613). The respective figures for the per-protocol population were 54.3% (151/278) in the placebo group and 48.3% (129/267) in the GTE group, indicating a slightly lower adenoma rate in the GTE group, which was not significant (adjusted relative risk 0.883; P = 0.1169).GTE was well tolerated, but there was no statistically significant difference in the adenoma rate between the GTE and the placebo groups in the whole study population.

Background Cancer patients are at risk of secondary therapy–related myeloid neoplasms (t-MNs). Acquired blood-specific mutations in clonal hematopoiesis (CH)–associated genes are t-MN risk factors, and their occurrence associated with cancer therapy and age. Patients with ovarian cancer (OC) showed a particularly high prevalence of CH–associated gene mutations, which may additionally be explained by the high proportion of a hereditary disease cause in this cancer entity. Methods We performed a retrospective analysis of 448 OC patients enrolled in the AGO-TR1 study; 249 were enrolled at primary diagnosis and 199 at platinum-sensitive recurrence. Analyses included the most frequently altered CH–associated genes (ASXL1, DNMT3A, GNAS, JAK2, PPM1D, SF3B1, SH2B3, SRSF2, TET2, TP53). Results were analyzed according to the BRCA1/2 germline (gBRCA1/2) mutation status. All statistical tests were 2-sided. Results Advanced age at blood draw and a high number of prior platinum-based chemotherapy lines were risk factors to acquire CH–associated gene mutations, with gene-specific effects observed. Binomial logistic regression suggested increased probabilities for gBRCA1/2 mutation carriers to acquire CH-associated PPM1D and TP53 gene mutations (PPM1D: odds ratio = 4.30, 95% confidence interval = 1.48 to 12.46, P = .007; TP53: odds ratio = 6.20, 95% confidence interval = 0.98 to 53.9, P = .06). This observation was due to a statistically significantly increased number of platinum-based chemotherapy lines in gBRCA1/2 mutation carriers vs noncarriers (PPM1D: mean [SD] = 2.04 [1.27] vs 1.04 [0.99], P Conclusions A positive gBRCA1/2 mutation status is not a risk factor to acquire CH–associated gene mutations. OC patients may benefit from monitoring CH–associated gene mutations, especially following carboplatin exposure. Future clinical studies are required to assess whether treatment regimen should be adapted according to individual t-MN risks.

Contains fulltext : 238693.pdf (Publisher’s version ) (Open Access) Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient.Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug.Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.

ZusammenfassungDieser Beitrag bietet einen Überblick zu Basiswissen in medikamentöser Schmerztherapie in der Palliativsituation. Schmerz ist eines der führenden Symptome bei 60–90 % aller Krebspatienten. Schmerzen entstehen auch bei neurologischen oder anderen Krankheiten, die am Lebensende auftreten. Um dieses Symptom zu behandeln, ist eine ganzheitliche Strategie vonnöten, die alle körperlichen, psychologischen, sozialen und spirituellen Aspekte der multidimensionalen Schmerzerfahrung („Total Pain“-Konzept) umfasst.Die Behandlung von Krebsschmerzen basierte viele Jahre auf einem Stufenschema, beginnend mit nichtopioiden Analgetika, gefolgt von mittelstarken und starken Opioiden. Im Gegensatz dazu wird die heutige Schmerzbehandlung mehr von der tatsächlichen Intensität dieses aversiven Ereignisses bestimmt.Die Schmerzbeurteilung sollte darauf zugeschnitten sein, eine nozizeptive vs. neuropathische Schmerzkomponente zu identifizieren, die durch die geeignete Arzneimitteltherapie gelindert werden muss. Nichtopioid-Analgetika sind ideale Substanzen zur Linderung nozizeptiver Schmerzen. Antidepressiva und Antikonvulsiva reduzieren die Intensität neuer neuropathischer Schmerzen. Opioide sind für alle Arten von Schmerzen geeignet, sollten jedoch als zweite Wahl eingesetzt werden. Tilidin und Tramadol sind Prodrugs, die erst nach Aktivierung in der Leber schmerzlindernd wirken. Arzneimittelwechselwirkungen können diese Aktivierung blockieren. Schnellwirksame Opioide sollten bei Tumor-Durchbruchschmerzen eingesetzt werden. Transdermale Opioid-Anwendungen werden bei Schluckstörungen empfohlen, normalerweise jedoch nicht, um die Schmerzkontrolle einzuleiten. Wenn Nebenwirkungen wie Halluzinationen für das ausgewählte Opioid auftreten, kann ein Opioid-Wechsel durchgeführt werden.

Bupropion is hydroxylated to its primary active metabolite hydroxybupropion by cytochrome P450 enzyme CYP2B6. In vitro data suggest the existence of alternative hydroxylation pathways mediated by the highly polymorphic enzyme CYP2C19. However, the impact of its genetic variants on bupropion metabolism in vivo is still under investigation. We report the case of a 28-year-old male Caucasian outpatient suffering from major depressive disorder who did not respond to a treatment with bupropion. Therapeutic drug monitoring revealed very low serum concentrations of both bupropion and hydroxybupropion. Genotyping identified a heterozygous status for the gain-of-function allele with the genotype CYP2C19*1/*17 predicting enhanced enzymatic activity. The present case shows a reduced bupropion efficacy, which may be explained by a reduced active moiety of bupropion and its active metabolite hydroxybupropion, due to alternative hydroxylation pathways mediated by CYP2C19 in an individual with CYP2C19 rapid metabolizer status. The case report thus illustrates the clinical relevance of therapeutic drug monitoring in combination with pharmacogenetics diagnostics for a personalized treatment approach.

Aims Older patients in particular suffer from adverse drug reactions (ADR) when presenting in the emergency department. We aimed to characterise the phenotype of those ADRs, to be able to recognise an ADR in older patients. Methods Cases of ADRs in emergency departments collected within the multicentre prospective observational study (ADRED) were analysed (n = 2215). We analysed ADR‐associated diagnoses, symptoms and their risk profiles. We present frequencies and odds ratios (OR) with 95% confidence intervals for adults (18–64 years) compared to older adults (≥65 years; young–old 65–79, old–old ≥80 years) and regression coefficients (B) for each year of age. Results Most prominent differences were seen for drug‐associated confusion, dehydration, and bradycardia (OR 6.70 [1.59–28.27], B .054; OR 6.02 [2.41–15.03], B .081, and 4.82 [2.21–10.54], B .040), more likely seen in older adults. Bleedings were reported in all age groups, but gastrointestinal bleedings occurred with more than doubled chance in older adults (OR 2.46 [1.77–3.41], B .030), likewise did other bleedings such as haemorrhage from respiratory passages (OR 2.89 [1.37–6.11], B.036). Falls were more likely in older adults (OR 2.84 [1.77–4.53], B .030), while dizziness was frequent in both age groups. Conclusion Our data point to differences in symptoms of ADRs between adults and older individuals, with dangerous drug‐associated phenomena in the older adult such as bleedings or falls. Physicians should consider drug‐associated origins of symptoms in older adults with an increased risk for serious health problems., publishedVersion

Background For treatment with psychotropic drugs during pregnancy, extended therapeutic drug monitoring is recommended for individual therapy adjustment. We measured venlafaxine (VEN), O-desmethylvenlafaxine (ODV) and active moiety, AM (sum of VEN+ODV) concentrations in maternal serum, amniotic fluid and umbilical cord blood. Methods Concentrations of VEN, ODVEN and AM were measured in nine mother-infant pairs at time of delivery; in five cases, amniotic fluid samples were available. Concentrations are reported as median values, first (Q1) and third (Q3) quartiles and ranges. Penetration ratio was calculated by dividing concentrations of VEN, ODVEN and AM in amniotic fluid and umbilical cord blood by maternal serum concentrations. Results Median daily dosage of venlafaxine was 75 mg (range 37.5–225 mg). There were no significant correlations between daily dose, maternal serum, umbilical cord blood and amniotic fluid concentrations. Median penetration ratio into amniotic fluid was 2.5 (range 0.56–4.48). Median penetration ratio into fetal circulation was 1.05 (range 0.62–2.08). Median concentration of AM was 223.8 ng/mL, range 33.9–338.0 ng/mL (maternal serum), 789.0 ng/mL, range 309-1052.5 ng/mL (amniotic fluid) and 291.0 ng/mL, range 21.1–448.4 ng/mL (cord blood). Discussion VEN, ODVEN and AM concentrations in maternal serum, amniotic fluid and umbilical cord blood indicate that the fetus might have been exposed to relatively high concentrations throughout pregnancy. High concentrations in amniotic fluid indicate an increased penetration into and/or accumulation within amniotic fluid and a decreased elimination out of amniotic fluid. Findings indicate that fetal in-utero exposition to venlafaxine is higher compared to other antidepressants.

Ingmar Bergs,1 Katja S Just,2 Annegret Müller,1 Julia C Stingl,2,&ast; Michael Dreher1,&ast; 1Department of Pneumology and Internal Intensive Care Medicine, University Hospital RWTH Aachen, Aachen, Germany; 2Institute of Clinical Pharmacology, University Hospital RWTH Aachen, Aachen, Germany&ast;These authors contributed equally to this workCorrespondence: Ingmar Bergs, Department of Pneumology and Internal Intensive Care Medicine, University Hospital RWTH Aachen, Pauwelsstr. 30, Aachen, 52074, Germany, Tel +49 241/80 35443, Email ibergs@ukaachen.dePurpose: Dyspnea is a leading symptom of COPD that causes presentations in emergency departments or negatively impacts on them. Guideline-based inhalation therapies are intended to reduce dyspnea in COPD patients. This study analyzed how common guideline recommended inhalation therapy regimens are occurring in clinical practice among COPD patients presenting to emergency departments due to adverse drug reactions in polytherapy using data of the German ADRED database.Patients and Methods: In total, 269 COPD cases were identified. In a further analysis, all cases were analyzed for documented GOLD stage and guideline-recommended inhalation therapy for COPD. Dyspnea and other symptoms identified during ED presentation were analyzed and compared between patients who did and did not receive the guideline’s recommended inhalation therapy.Results: In this observation, 41% (n = 46) of all 112 cases with a documented COPD and GOLD stage received an underdosed therapy according to current guidelines. Dyspnea was the most common identified symptom (32%, n = 36) in this cohort and occurred more often in patients who received an underdosage of inhalation therapy (p < 0.01).Conclusion: Patients with COPD presenting to ED with ADRs show a high rate of non-guideline-recommended inhalation therapy and present more often with dyspnea compared to those COPD patients who received an adequate dosing of inhalation therapy.Keywords: emergency department, dyspnea, guideline therapy, chronic obstructive pulmonary disease, adverse drug events

Recent meta-analytic studies of social cognition and the functional imaging of empathy have exposed the overlap between their neural substrates and heteromodal association areas. The 'gradient model' of cortical organization proposes a close relationship between these areas and highly connected hubs in the default mode network, a set of cortical areas deactivated by demanding tasks. Here, we used a decision-making task and representational similarity analysis with classic 'empathy for pain' visual stimuli to probe the relationship between high-level representations of imminent pain in others and the high end of the gradient of this model. High-level representations were found to co-localize with task deactivations or the transitions from activations to deactivations. These loci belonged to two groups: those that loaded on the high end of the principal cortical gradient and were associated by meta-analytic decoding with the default mode network, and those that appeared to accompany functional repurposing of somatosensory cortex in the presence of visual stimuli. In contrast to the nonspecific meta-analytic decoding of these loci, low-level representations, such as those of body parts involved in pain or of pain itself, were decoded with matching topics terms. These findings suggest that that task deactivations may set out cortical areas that host high-level representations, but whose functional characterization in terms of simple mappings is unlikely. We anticipate that an increased understanding of the cortical correlates of high-level representations may improve neurobiological models of social interactions and psychopathology.

Introduction The prevalence of psychotropic drug use in our society is increasing especially in older adults, thereby provoking severe adverse drug reactions (ADR). To identify specific patient risk profiles associated with psychotropic drug use in the situation of polymedication. Methods Cases of ADRs in general emergency departments (ED) collected within the multi-center prospective observational study (ADRED) were analyzed (n=2215). We compared cases with use of psychotropic drugs and without concerning their clinical presentation at the ED. Results A third of patients (n=731, 33%) presenting to the ED with an ADR took at least 1 psychotropic drug. Patients with psychotropic drug use tended to be older, more often female, and took a higher number of drugs (all p Discussion The association of psychotropic drug use with fall and syncope in combination with polymedication and older age leads to the suspicion that psychotropic drugs might be potentially harmful in specific risk populations such as older adults. It may lead us to thoroughly weigh the benefit against risk in a patient-oriented way, leading to an integrative personalized therapy approach.

OBJECTIVE Gastrointestinal adverse effects occur in 20–30% of patients with metformin-treated type 2 diabetes, leading to premature discontinuation in 5–10% of the cases. Gastrointestinal intolerance may reflect localized high concentrations of metformin in the gut. We hypothesized that reduced transport of metformin via the plasma membrane monoamine transporter (PMAT) and organic cation transporter 1 (OCT1) could increase the risk of severe gastrointestinal adverse effects. RESEARCH DESIGN AND METHODS The study included 286 severe metformin-intolerant and 1,128 metformin-tolerant individuals from the IMI DIRECT (Innovative Medicines Initiative: DIabetes REsearCh on patient straTification) consortium. We assessed the association of patient characteristics, concomitant medication, and the burden of mutations in the SLC29A4 and SLC22A1 genes on odds of intolerance. RESULTS Women (P < 0.001) and older people (P < 0.001) were more likely to develop metformin intolerance. Concomitant use of transporter-inhibiting drugs increased the odds of intolerance (odds ratio [OR] 1.72, P < 0.001). In an adjusted logistic regression model, the G allele at rs3889348 (SLC29A4) was associated with gastrointestinal intolerance (OR 1.34, P = 0.005). rs3889348 is the top cis-expression quantitative trait locus for SLC29A4 in gut tissue where carriers of the G allele had reduced expression. Homozygous carriers of the G allele treated with transporter-inhibiting drugs had more than three times higher odds of intolerance compared with carriers of no G allele and not treated with inhibiting drugs (OR 3.23, P < 0.001). Use of a genetic risk score derived from rs3889348 and SLC22A1 variants found that the odds of intolerance were more than twice as high in individuals who carry three or more risk alleles compared with those carrying none (OR 2.15, P = 0.01). CONCLUSIONS These results suggest that intestinal metformin transporters and concomitant medications play an important role in the gastrointestinal adverse effects of metformin.

Cytochrome P450 (CYP) 2D6 is a polymorphic enzyme expressed in the central nervous system (CNS), important in drug metabolism and with a potentially constitutive role in CNS function such as vigilance. This study aimed to analyze variability in CYP2D6 activity linked to vigilance-related adverse drug reactions (ADRs) in the CNS. A dataset of N = 2939 ADR cases of the prospective multicenter observational trial in emergency departments (EDs) (ADRED; trial registration: DRKS-ID: DRKS00008979) was analyzed. Dizziness as the most frequent reported CNS ADR symptom (12.7% of patients, n = 372) related to vigilance was chosen as the outcome. The association of dizziness with CYP2D6 activity markers was analyzed. The number of CYP2D6 substrates taken, a CYP2D6 saturation score (no, moderate, and strong saturation), a CYP2D6 saturation/inhibition score (no, weak, moderate, and strong), and composed CYP2D6 activity using a genotyped subsample (n = 740) calculating additive effects of genotype and CYP2D6 saturation by drug exposure were used as CYP2D6 activity markers. Effects were compared to other frequent nonvigilance-related CNS ADR symptoms (syncope and headache). Secondary analyses were conducted to control for other ADR symptoms frequently associated with dizziness (syncope, nausea, and falls). The majority of all patients (64.5%, n = 1895) took at least one drug metabolized by CYP2D6. Around a third took a CNS drug (32.5%, n = 955). The chance to present with drug-related dizziness to the ED increased with each CYP2D6 substrate taken by OR 1.11 [1.01–1.23]. Presenting with drug-related dizziness was more likely with CYP2D6 saturation and saturation/inhibition (both OR 1.27 [1.00–1.60]). The composed CYP2D6 activity was positively associated with dizziness (p = 0.028), while poorer activity affected patients more often with dizziness as an ADR. In contrast, nonvigilance-related ADR symptoms such as syncope and nausea were not consistently significantly associated with CYP2D6 activity markers. This study shows an association between the number of CYP2D6 substrates, the predicted CYP2D6 activity, and the occurrence of dizziness as a CNS ADR symptom. As dizziness is a vigilance-related CNS symptom, patients with low CYP2D6 activity might be more vulnerable to drug-related dizziness. This study underlines the need for understanding individual drug metabolism activity and individual risks for ADRs.

Hypoglycemia is a potentially life-threatening drug event under antidiabetic treatment. The aim of the study was to examine time trends in severe hypoglycemia in older adults with type 2 diabetes mellitus (T2DM) and antidiabetic treatment.Multicenter prospective diabetes patient follow-up registry (DPV).Patients aged ≥75 years with T2DM and documented treatment between 2005 and 2019.Outcomes of interest were rates of severe hypoglycemia, diabetes therapy, body mass index, HbA1c, and estimated glomerular filtration rate. Time trends of outcomes were analyzed in the whole cohort and compared between age groups (75-80, 80-85, ≥85 years).A total of 136,931 patients from 188 diabetes centers were included. The adjusted HbA1c decreased from 7.3% (95% confidence interval 7.3-7.4) in 2005 to 7.2% (7.2-7.2) in 2019 (P.001), with no significant difference between age groups (P = .47). Rates of severe hypoglycemia decreased from 6.7 (6.0-7.4) to 4.1 of 100 person-years (3.7-4.5) (P.001) in the entire population. Patients aged ≥85 years had constantly lower HbA1c levels compared with younger groups (P.001). Although severe hypoglycemia decreased the most in the ≥85 age group (P.001), severe hypoglycemia remained consistently higher in this group compared with the 75 to80 years group (P.001).During the analyzed time, the risk for severe hypoglycemia decreased. Although drugs with intrinsic risk for hypoglycemia were used less frequently, antidiabetic treatment in older adults should be further improved to continue reducing severe hypoglycemia in this age group, potentially accepting less strict metabolic control and age-specific target ranges.

In patient care, diagnostics of genetic variants may lead to improved drug safety and efficacy. Both clinicians and drug regulatory agencies are making efforts to disseminate knowledge of pharmacogenetic diagnostics and validate the benefit for patients. More than 150 drug labels have been extended with information on pharmacogenetics or other biomarkers that should be determined during the course of drug therapy. In this chapter, pharmacogenetics as a tool for improving individual drug therapy is discussed for some major diseases and drugs used to treat them.

Objective Epidermal growth factor receptor inhibitors (EGFRI) are used as targeted cancer therapy. On average 70% of patients treated with EGFRIs suffer from skin toxicity. Studies showed a correlation between overall survival and the appearance of a skin rash, which is used as a biomarker for therapy efficacy. Micro RNAs (miRNA) as tumor or resistance biomarkers for cancer therapy are also highly investigated. In our study, we searched for associations of miRNA expression profiles in serum, with the severity of skin rash, in order to identify tentative therapy predictive biomarkers. Materials and methods Five candidate miRNAs were selected, based on an earlier in vitro next-generation-sequencing-experiment and after literature search. MiR-21, miR-31, miR-17, miR-106b and miR-520e were investigated in serum samples from patients (n = 254) treated with EGFRI. The quantitative expression of miRNA was tested for association with the occurrence/severity of the rash. Results In our cohort of patients treated with EGFR inhibiting monoclonal antibodies, miR-21 and miR-520e serum concentrations were negatively correlated with severity of skin rash (p-value 0.000582 and 1.53e-07 linear-trend-test) whereas for miR-31, a positive correlation was observed (p-value 9.01e-06 linear-trend-test). Conclusions This suggests that miR-21, miR-31 and miR-520e expression might be a treatment dependent marker for EGFRI induced skin rash.

British journal of clinical pharmacology : BJCP 87(7), 2732-2756 (2021). doi:10.1111/bcp.14671, Published by Wiley-Blackwell, Oxford

Objective Data regarding the ability of antidepressants to enter fetal, newborn and infant fluids have become gradually available, but mechanisms of antidepressant transfer remain poorly understood. Here we calculated penetration ratios in an array of matrices from combined samples of pregnant/breastfeeding women taking antidepressants. Method We performed a systematic literature search of PubMed and EMBASE to identify studies with concentrations of antidepressants from maternal blood, amniotic fluid, umbilical cord blood and/or breast milk. Penetration ratios were calculated by dividing the concentrations in amniotic fluid, umbilical cord plasma or breast milk by the maternal plasma concentration. When data from multiple studies were available, we calculated combined penetration ratios, weighting the study mean by study size. Results Eighty-five eligible studies were identified. For amniotic fluid, the highest penetration ratios were estimated for venlafaxine (mean 2.77, range 0.43-4.70 for the active moiety) and citalopram (mean 2.03, range 0.35-6.97), while the lowest ratios were for fluvoxamine (mean 0.10) and fluoxetine (mean 0.11, range 0.02-0.20 for the active moiety). For umbilical cord plasma, nortriptyline had the highest ratio (mean 2.97, range 0.25-26.43) followed by bupropion (mean 1.14, range 0.3-5.08). For breast milk, the highest ratios were observed for venlafaxine (mean 2.59, range 0.85-4.85), mianserin (mean 2.22, range 0.80-3.64) and escitalopram (mean 2.19, range 1.68-3.00). Conclusion We observed considerable variability across antidepressants regarding their ability to enter fetal, newborn and infant fluids. Measuring antidepressant concentrations in a maternal blood sample can provide a reliable estimate of fetal/infant exposure, although further evidence for concentration-dependent effects is required.

Pharmacoepidemiology and drug safety 28(3), 377-388 (2019). doi:10.1002/pds.4726, Published by Wiley, Chichester [u.a.]

Aim: The need for pharmacogenomic education is becoming more and more urgent. Our aim was to evaluate the progress in pharmacogenomics education since then, and to put forward further recommendations. Methods: A survey was sent to 248 schools of medicine, pharmacy, nursing and health professions around the world. Results: The majority of the study programs (87%) include pharmacogenomics education, which is generally taught as part of the pharmacology curriculum. On average, educators and teachers have selected appropriate and highly relevant pharmacogenomics biomarkers to include in their teaching programs. Conclusions: Based on the results, we can conclude that the state of pharmacogenomics education at the surveyed universities has improved substantially since 2005. ispartof: PHARMACOGENOMICS vol:20 issue:9 pages:643-657 ispartof: location:England status: published

Selective serotonin reuptake inhibitors (SSRIs) are first-line antidepressants for the treatment of major depressive disorder (MDD). However, treatment response during an initial therapeutic trial is often poor and is difficult to predict. Heterogeneity of response to SSRIs in depressed patients is partly driven by co-occurring somatic disorders such as coronary artery disease (CAD) and obesity. CAD and obesity may also be associated with metabolic side effects of SSRIs. In this study, we assessed the association of CAD and obesity with treatment response to SSRIs in patients with MDD using a polygenic score (PGS) approach. Additionally, we performed cross-trait meta-analyses to pinpoint genetic variants underpinnings the relationship of CAD and obesity with SSRIs treatment response. First, PGSs were calculated at different p value thresholds (PT) for obesity and CAD. Next, binary logistic regression was applied to evaluate the association of the PGSs to SSRIs treatment response in a discovery sample (ISPC, N = 865), and in a replication cohort (STAR*D, N = 1,878). Finally, a cross-trait GWAS meta-analysis was performed by combining summary statistics. We show that the PGSs for CAD and obesity were inversely associated with SSRIs treatment response. At the most significant thresholds, the PGS for CAD and body mass index accounted 1.3%, and 0.8% of the observed variability in treatment response to SSRIs, respectively. In the cross-trait meta-analyses, we identified (1) 14 genetic loci (including NEGR1, CADM2, PMAIP1, PARK2) that are associated with both obesity and SSRIs treatment response; (2) five genetic loci (LINC01412, PHACTR1, CDKN2B, ATXN2, KCNE2) with effects on CAD and SSRIs treatment response. Our findings implicate that the genetic variants of CAD and obesity are linked to SSRIs treatment response in MDD. A better SSRIs treatment response might be achieved through a stratified allocation of treatment for MDD patients with a genetic risk for obesity or CAD.

Theoretical models of dopamine function stemming from reinforcement learning theory have emphasized the importance of prediction errors, which signal changes in the expectation of impending rewards. Much less is known about the effects of mean reward rates, which may be of motivational significance due to their role in computing the optimal effort put into exploiting reward opportunities. Here, we used a reinforcement learning model to design three functional neuroimaging studies and disentangle the effects of changes in reward expectations and mean reward rates, showing recruitment of specific regions in the brainstem regardless of prediction errors. While changes in reward expectations activated ventral striatal areas as in previous studies, mean reward rates preferentially modulated the substantia nigra/ventral tegmental area, deep layers of the superior colliculi, and a posterior pontomesencephalic region. These brainstem structures may work together to set motivation and attentional efforts levels according to perceived reward opportunities.

Therapeutisches Drug-Monitoring (TDM) umfasst die Quantifizierung und die Interpretation von Serum- oder Plasmakonzentrationen von Arzneistoffen im Blut, um die Pharmakotherapie zu optimieren. TDM ist ein Werkzeug, mit dem sich die hohe interindividuelle Variabilitat der Pharmakokinetik von Patienten identifizieren lasst und es ermoglicht somit eine personalisierte Pharmakotherapie. Im September 2017 veroffentlichte die Arbeitsgruppe Therapeutisches Drug-Monitoring der Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) ein Update der TDM-Konsensusleitlinien. In diesem Artikel sollen die wesentlichen Inhalte fur die klinische Praxis in der Psychiatrie und Neurologie zusammengefasst werden.

The Li-Fraumeni cancer predisposition syndrome (LFS1) presents with a variety of tumor types and the TP53 gene is covered by most diagnostic cancer gene panels. We demonstrate that deleterious TP53 variants identified in blood-derived DNA of 523 patients with ovarian cancer (AGO-TR1 trial) were not causal for the patients' ovarian cancer in three out of six TP53-positive cases. In three out of six patients, deleterious TP53 mutations were identified with low variant fractions in blood-derived DNA but not in the tumor of the patient seeking advice. The analysis of the TP53 and PPM1D genes, both intimately involved in chemotherapy-induced and/or age-related clonal hematopoiesis (CH), in 523 patients and 1,053 age-matched female control individuals revealed that CH represents a frequent event following chemotherapy, affecting 26 of the 523 patients enrolled (5.0%). Considering that TP53 mutations may arise from chemotherapy-induced CH, our findings help to avoid false-positive genetic diagnoses of LFS1.

Purpose To investigate the impact of accelerated, single-shot 3D-GRASE acquisition on quantitative arterial spin labeling (ASL) with multiple and single post-labeling delay (PLD) in terms of perfusion-weighted SNR per unit scan time (TSNRPW ) and quantification accuracy. Methods Five subjects were scanned on a 3T MRI scanner using the pseudo-continuous arterial spin labeling (PCASL) technique with a 3D-GRASE imaging sequence capable of parallel imaging acceleration. A 3-inversion pulse background suppression was simulated and implemented in the sequence. Three time-matched single PLD measurements, a segmented one without acceleration, 1 with conventional GRAPPA, and 1 with CAIPIRINHA sampling, were used to compare TSNRPW . Three time-matched multiple PLD measurements with the identical imaging parameters were additionally evaluated (no acceleration vs. CAIPIRINHA sampling vs. CAIPIRINHA sampling with doubled number of PLDs). Cerebral blood flow and arterial transit time fit uncertainties were compared and used as a quality measure. Results The single PLD measurements show an 11% TSNRPW increase using CAIPIRINHA sampling instead of GRAPPA sampling, while the non-accelerated scan exhibits 35% higher TSNRPW compared to the GRAPPA scan. However, taking advantage of the increased number of averages for multiple PLD acquisitions, a 14%/16% (gray matter) and 34%/36% (white matter) reduction of CBF fit uncertainty is observed with CAIPIRINHA sampling (6 PLDs/12 PLDs) compared to no acceleration. Conclusion Accelerated single-shot 3D-GRASE with PCASL allows for smaller quantification uncertainties than time-matched segmented acquisitions. Corresponding single-shot acquisitions with acceptable blurring and no intra-volume motion render state-of-the-art ASL methods in a clinically feasible time possible.

Introduction Drug–drug interactions (DDIs) are an important risk factor for adverse drug reactions. Older, polymedicated patients are particularly affected. Although antithrombotics have been detected as high-risk drugs for DDIs, data on older patients exposed to them are scarce. Methods Baseline data of 365 IDrug study outpatients (≥ 60 years, use of an antithrombotic and one or more additional long-term drug) were analyzed regarding potential drug–drug interactions (pDDIs) with a clinical decision support system. Data included prescription and self-medication drugs. Results The prevalence of having one or more pDDI was 85.2%. The median number of alerts per patient was three (range 0–17). For 58.4% of the patients, potential severe/contraindicated interactions were detected. Antiplatelets and non-steroidal anti-inflammatory drugs (NSAIDs) showed the highest number of average pDDI alert involvements per use (2.9 and 2.2, respectively). For NSAIDs, also the highest average number of severe/contraindicated alert involvements per use (1.2) was observed. 91.8% of all pDDI involvements concerned the 25 most frequently used drug classes. 97.5% of the severe/contraindicated pDDIs were attributed to only nine different potential clinical manifestations. The most common management recommendation for severe/contraindicated pDDIs was to intensify monitoring. Number of drugs was the only detected factor significantly associated with increased number of pDDIs (p

Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalized treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities and forensic patients. Clear indications for TDM include lack of clinical response in the therapeutic dose range, assessment of drug adherence, tolerability issues and drug-drug interactions.Based upon existing literature, recommended therapeutic reference ranges, laboratory alert levels, and levels of recommendation to use TDM for dosage optimization without specific indications, conversion factors, factors for calculation of dose-related drug concentrations and metabolite-to-parent ratios were calculated.This summary of the updated consensus guidelines by the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie offers the practical and theoretical knowledge for the integration of TDM as part of pharmacotherapy with neuropsychiatric agents into clinical routine.The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment.

Erratum zu: Nervenarzt 2018 https://doi.org/10.1007/s00115-018-0643-9 Im Originalbeitrag ist Tab. 2 leider fehlerhaft. Fur die Substanzen Carbamazepin und Valproat wurde im Originalbeitrag ein Empfehlungsgrad zur Anwendung des therapeutischen Drug-Monitorings (TDM) von 2 (empfohlen) angegeben. …

Pharmaceuticals 14(10), 1056 (2021). doi:10.3390/ph14101056 special issue: "Special Issue "Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives" / Special Issue Editors: Dr. Charlotte Vermehren, Guest Editor; Dr. Niels Westergaard, Guest Editor", Published by MDPI, Basel

Objectives Many studies describing an association of drugs with falls focus mostly on drugs acting in the central nervous system. We aim to analyze the association of all drugs taken with falls in older adults. Design Prospective population-based study (ActiFE study). Setting and Participants A total of 1377 community-dwelling older adults with complete recording of falls and baseline information on drug intake. Methods Negative binomial regression was used to analyze the association of 34 drug classes with a 12-month incidence rate ratio (IRR) of falls adjusting for age, sex, comorbidities, gait speed, balance, chair rise, kidney function, liver disease, and smoking. Results Participants took a median 3 drugs (interquartile range 1, 5), with 34.5% (n = 469) having ≥5 drugs. The median IRR for a fall per person-year was overall 0.72 [95% confidence interval (CI) 0.60–0.83] and 2.22 (95% CI 1.90–2.53) among those who experienced ≥1 fall. The following drug classes showed significant associations: antiparkinsonian medication [IRR 2.68 (95% CI 1.59–4.51)], thyroid therapy [IRR 1.40 (95% CI 1.08–1.81)], and systemic corticosteroids [IRR 0.33 (95% CI 0.13–0.81)]. Among fall-risk-increasing drugs only antiepileptics [IRR 2.16 (95% CI 1.10–4.24)] and urologicals [IRR 2.47 (95% CI 1.33–4.59)] were associated with falls in those participants without a prior fall history at baseline. Conclusion and Implications Additional drug classes, such as antiparkinsonian medication, thyroid therapy, and systemic corticosteroids, might be associated with falls in older adults, possibly representing pharmacological effects on the musculoskeletal and central nervous systems. Further evaluations in larger study populations are recommended.

Falls is a frequent type of adverse drug reactions causing significant morbidity and mortality in the elderly. We reviewed, with which drugs the risk of falls is relevant and might depend on genomic variation. Pharmacogenetic variability may contribute to drug-induced falls for instance mediated by impaired drug elimination due to inherited deficiency in enzymes like CYP2C9, CYP2C19 and CYP2D6. The relative role of specific genes and polymorphisms in old age may differ from younger people. Biomarkers for frailty, but also genomic biomarkers might help identifying patients at high risk for drug-induced falls. Many other factors including disease and drug–drug interactions also contribute to risk of falls. Further studies analyzing the impact of genomic variation on the medication-related fall risk in the older adult are urgently needed.

The MR signal from gray matter has been long known to present small differences in intensity that have been attributed to variations in cortical myelin content. Previous studies have shown that the T1-, T2-weighted signal and their ratio are sensitive to these variations. Here, we investigated different combinations of signal from MPRAGE and FLAIR images in multimodal segmentation with parametric models of signal intensity to identify a procedure for the identification of contrast in cortical gray matter and the segmentation of different cortical components at 3T. We show that a three-modal combination of these signals delivers a stable segmentation of the cortical mantle in which two distinct components are reliably identified. The resulting intensity maps correspond well to known regional myeloarchitectural differences between cortical regions. These results confirm that widely available MR sequences contain signal that may be used to reliably detect subtle differences in the composition of gray matter with a segmentation approach.

Introduction: Pregnancy-related physiological changes exert a crucial impact on the pharmacokinetics of antidepressants; however, the current evidence presents inconsistencies. A clearer understanding of pregnancy-related effects on antidepressant disposition may facilitate the development of guidelines for appropriate dose adjustments during the course of pregnancy based on therapeutic drug monitoring. Areas covered: We systematically reviewed studies comparing antidepressant levels in the same individuals during pregnant and non-pregnant states. Using dose-adjusted plasma concentration measurements, we estimated alteration ratios between the 3rd trimester and baseline (before or after pregnancy). Additionally, we performed a meta-analysis for changes in dose-adjusted concentrations to estimate mean differences. Expert opinion: Data for several antidepressants display clear alteration patterns during pregnancy. On the basis of the alteration ratios trimipramine, fluvoxamine, and nortriptyline show a prominent decrease in dose-adjusted levels, especially in the 3rd trimester. Clomipramine, imipramine, citalopram, and paroxetine show smaller decreases in dose-adjusted concentrations in the third trimester. For escitalopram, venlafaxine and fluoxetine, changes are considered negligible. For sertraline, there was a tendency toward increased dose-adjusted concentrations in pregnancy. Available evidence suffers from major limitations and factors affecting pharmacokinetics have been insufficiently addressed. Further research is required to promote knowledge on pregnancy effects on antidepressant pharmacokinetics.

Background Older adults are more prone to develop adverse drug reactions (ADRs) since they exhibit numerous risk factors. The first aim was to analyse the number of spontaneous ADR reports regarding older adults (> 65) in the ADR database of the German Federal Institute for Drugs and Medical Devices (BfArM) and to set them in relation to i) the number of ADR reports concerning younger adults (19–65), and ii) the number of inhabitants and assumed drug-exposed inhabitants. The second aim was to analyse, if reported characteristics occurred more often in older vs. younger adults. Methods All spontaneous ADR reports involving older or younger adults within the period 01/01/2000–10/31/2017 were identified in the ADR database. Ratios concerning the number of ADR reports/number of inhabitants and ADR reports/drug-exposed inhabitants were calculated. The reports for older (n = 69,914) and younger adults (n = 111,463) were compared using descriptive and inferential statistics. Results The absolute number of ADR reports involving older adults increased from 1615 (2000) up to 5367 ADR reports (2016). The age groups 76–84 and 70–79 had the highest number of ADR reports with 25 ADR reports per 100,000 inhabitants and 27 ADR reports per 100,000 assumed drug-exposed inhabitants. For both ratios, the number of reports was higher for males (26 and 28 ADR reports) than for females (24 and 26 ADR reports). Fatal outcome was reported almost three times more often in older vs. younger adults. Six out of ten drug substances most frequently suspected were antithrombotics (vs. 1/10 in younger adults). For some drug substances (e.g. rivaroxaban) the ADRs reported most frequently differed between older (epistaxis) and younger adults (menorrhagia). Conclusions There is a need to further investigate ADRs in older adults since they occurred more frequently in older vs. younger adults and will likely increase in future. Physicians should be aware of different ADRs being attributed to the same drug substances which may be more prominent in older adults. Regular monitoring of older adults taking antithrombotics is recommended.

Adverse drug reactions (ADR) account for 5 to 7% of emergency department (ED) consultations. We aimed to assess medication risk profiles for ADRs leading to ED visits. We analysed medication intake and patient demographics in a prospective multi-centre observational study collecting ADR cases in four large EDs in Germany. Odds ratios (OR) were calculated to relate drug classes taken to those suspicious for an ADR after a causality assessment. A total of 2215 cases of ED visits due to ADRs were collected. The median age of the cohort was 73 years; in median, six co-morbidities and an intake of seven drugs were documented. Antineoplastic/immunomodulating agents had the highest OR for being suspected for an ADR (OR 20.45, 95% CI 14.54–28.77), followed by antithrombotics (OR 2.94, 95% CI 2.49–3.47), antibiotics (OR 2.65, 95% CI 1.78–3.95), systemic glucocorticoids (OR 2.43, 95% CI 1.54–3.82) and drugs affecting the central nervous system (CNS), such as antipsychotics (OR 2.36, 95% CI 1.46–3.81), antidepressants (OR 2.10, 95% CI 1.57–2.83), antiparkinsonian medication (OR 2.11, 95% CI 1.15–3.84), opioids (OR 1.79, 95% CI 1.26–2.54) and non-opioid analgesics (OR 1.32, 95% CI 1.01–1.72). Patients experiencing ADRs leading to ED visits are commonly old, multi-morbid and multi-medicated. CNS drugs may be more relevant than prior expected. With calculating ORs, we could replicate involvement of antineoplastic agents, antithrombotics, antibiotics, systemic glucocorticoids and non-opioid analgesics as frequently suspected for ADRs in EDs. DRKS-ID: DRKS00008979.

The cytochrome P450 enzyme 2D6 is involved in the metabolism of 20% of all commonly used drugs, including many psychotropic drugs and CNS-active substances. CYP2D6 is among the CYP enzymes with the highest expression levels in the brain, suggesting a role in the local brain metabolism of psychotropic drugs and the existence of endogenous substrates. The genetic polymorphism of CYP2D6, which causes individual differences in activity levels of the enzyme, has also been characterized functionally in human brain imaging studies. Here we explore the feasibility of predicting CYP2D6 phenotype using component-wise gradient boosting on fMRI resting brain perfusion images. The images belonged to subjects showing a range of genetic CYP2D6 variants. We achieved sensitivity and specificity values between 85% and 87% for the classification of ultrarapid metabolisers, and between 71% and 79% for poor metabolisers. An extension of the boosting algorithm, developed to improve the clinical plausibility of the inherently sparse models, produced enhanced models in agreement with the results of previous studies, showing some brain regions as positively associated with genotypic variation, most prominently in the prefrontal white matter and the corpus callosum. With further development, such a probabilistic method might constitute a valuable, non-invasive alternative to actual genotyping.

The goals of this German guideline are the improvement of diagnosis and therapy of scabies, the implementation of a coordinated action in outbreaks of scabies, and the control of this infestation in large migration or refugee flows.Sarcoptes scabiei var. hominis is transmitted by direct skin-to-skin contact of sufficient duration. The infectivity of female mites when removed from patients does not exceed 48 hours at room temperature (21°C) and relative humidity of 40-80%. The risk of infection rises proportionally to the number of mites on the skin and is particularly high in crusted scabies. As elderly persons tend to develop crusted scabies due to disease- or medication-related immunosuppression, there is an increased risk for outbreaks of scabies at nursing homes and extended-care facilities. The guideline contains detailed recommendations for management of such outbreaks. In refugees the prevalence of scabies is higher than in the general population in Germany, but the risk for outbreaks is not high. Scabies infestation should be considered when a recent onset of itching is associated with eczema and presence of burrows or comma-like papules at predilection sites. It is confirmed by dermatoscopic detection of mites or by microscopic identification of mites, mite eggs or fecal matter (scybala) from skin scrapings.The treatment of choice for common scabies is topical permethrin 5% cream applied for 8-12 hours. Permethrin can be considered for off-label use also in infants of less than 3 months of age and pregnant women. For this group crotamiton is another option, which, besides benzyl benzoate, presents a good second line therapy for the other indications. Indications for oral ivermectin, which has just been licensed in Germany, include patients with immunosuppression, severe dermatitis, and low adherence.Crusted scabies is preferentially treated by a combination of topical permethrin and oral ivermectin. Affected patients should be isolated, and all contact persons should be treated. The guideline contains lists for additional measures, including possible treatment of contact persons, clothes, linen and other possibly infested articles.

Aim The aim of this study was to investigate if biomarkers of individual drug metabolism, respectively, the erlotinib/O-desmethyl-erlotinib metabolic ratio, may be a predictive factor for the severity of erlotinib-mediated skin rash in epidermal growth factor receptor (EGFR) inhibitor-treated patients suffering from epithelial cancers. This is especially important since it is known that the severity of skin rash has a prognostic value on outcome and survival in cancer patients experiencing skin rash under treatment with EGFR inhibitors. Methods From 2008 to 2014, 96 patients, n = 63 suffering from histologically confirmed non-small-cell lung cancer and n = 33 from pancreatic adenocarcinoma were observed for the occurrence and severity of skin rash after the onset of treatment with erlotinib. The primary end-points (occurrence and severity of skin rash, progression-free survival [PFS] and overall survival [OS]) were analysed with regard to erlotinib and its metabolite O-desmethyl-erlotinib trough serum concentrations measured at 4 weeks after onset of therapy by the use of correlation, multiple regression and survival analysis. Results Occurrence of skin rash was associated with PFS (p = 0.0042) and OS (p = 0.017) in the overall cohort of erlotinib-treated cancer patients. Drug-metabolising activity assessed by the erlotinib/O-desmethyl-erlotinib metabolic ratio was correlated with severity of skin rash (p = 0.023) and as well highly associated with both PFS (p = 2.1 × 10 −4 ) and OS (p = 5.8 × 10 −5 ). Conclusion The erlotinib/O-desmethyl-erlotinib metabolic ratio reflecting the individual metabolic activity of erlotinib correlated with the severity of skin rash and outcome in patients treated with EGFR tyrosine kinase inhibitors. The metabolic ratio determined in serum may be used for therapeutic monitoring in erlotinib treatment and decisions on individual dosing to rash in rash-negative patients.

1551 Background: Prevention of colorectal adenomas (CA) can reduce colorectal cancers (CRC). Epidemiological and experimental data suggest that the green tea catechin epigallocatechingallate has an antineoplastic effect in the large bowel. MIRACLE is the largest trial so far to examine the effect of three-year daily intake of green tea extract (GTE) on the incidence of metachronous CA in a Caucasian population. Methods: Prospective, parallel group, double-blinded, placebo-controlled, randomized multicenter trial (40 German centers, recruitment 11/2011-6/2015). Patients (n = 1001, age 50-80y), polypectomy ≤ 6 months and tolerating GTE well (one-month run-in) were randomized to receive decaffeinated GTE standardized to EGCG (150 mg bid, capsules) or placebo (P) for 3 years. Primary endpoint: Incidence of metachronous CA at the 3-year follow-up colonoscopy. Secondary endpoints: Occurrence, number, localization, size, histological subtype of CA, frequency of CRC, biomarker and safety. Strata: study center, low-dose aspirin (≤100 mg/d). Results: Clinical parameters were well balanced. CA incidence at the 3-year follow-up colonoscopy was analyzed in the modified ITT set (modITT; n = 309 patients (GTE), n = 323 (placebo), timely follow up colonoscopy) and the per protocol set (PP, modITT set without major protocol violations). Incidence of CA was 55.7 % (P) and 51.1% (GTE), (modITT, adj. RR 0.905, one sided, p = 0.081), respectively 54.3 % (P) and 48.3% (GTE) (PP, adj. RR 0.883, one sided, p = 0.058). These differences did not reach statistical significance. In the preplanned exploratory analysis regarding gender incidence of CA in females was 47.9% (P) and 47.6% (GTE) in the modITT-set (adj. RR 0.989; 95%-CI: 0.753,1.299; p = 0.935), respectively 45.4% (P) and 46.9% (GTE) in the PP-set (adj. RR 1.014; 95%-CI: 0.748, 1.373; p = 0.930). In contrast, in the male population incidence of CA in the follow-up colonoscopy was 60.4% (P) and 52.9% (GTE) in the modITT-set (adj. RR 0.846; 95% CI 0.717, 0.999); p = 0.048), respectively 59.1% (P) and 49.1% (GTE) in the PP-set (RR 0.803, 95% CI: 0.666, 0.969; p = 0.022). Thus, GTE intake was associated with a significant, 12.4 relative and 7.5% absolute reduction of metachronous CA in the male modITT population. There were no differences with respect to safety between the groups. Conclusions: GTE reduced the incidence of metachronous CA. However, a significant effect was only observed in the in the male population whereas there was no effect in the female population. Clinical trial information: NCT 01360320.

In the European Union (EU), responsibilities for medicines and companion diagnostics (CDxs) are divided. The European Medicines Agency (EMA) and national agencies approve medicines, whereas notified bodies (NBs) certify CDx. The EU regulation on in vitro diagnostic medical devices of 2017 mandates NBs to consult regulatory authorities, usually the EMA, during the certification of a CDx. This consultation is required for an innovative CDx based on a new biomarker and introduced together with an innovative medicine, as well as for any new “generic” CDx for the same well-known biomarker and using the same methodological approach as an established reference CDx. EMA’s view how the CDx affect the benefit–risk balance of the corresponding medicines may well change NBs’ certification decisions. This chapter delineates EMA’s current and possible future principles in the assessment of the impact of CDx on the benefit–risk balance of medicines.

PLOS ONE 15(3), e0230632 (2020). doi:10.1371/journal.pone.0230632, Published by PLOS, San Francisco, California, US

Gastrointestinal adverse effects occur in 20-30% of patients with metformin-treated type 2 diabetes, leading to premature discontinuation in 5-10% of the cases. Gastrointestinal intolerance may reflect localized high concentrations of metformin in the gut. We hypothesized that reduced transport of metformin via the plasma membrane monoamine transporter (PMAT) and organic cation transporter 1 (OCT1) could increase the risk of severe gastrointestinal adverse effects.The study included 286 severe metformin-intolerant and 1,128 metformin-tolerant individuals from the IMI DIRECT (Innovative Medicines Initiative: DIabetes REsearCh on patient straTification) consortium. We assessed the association of patient characteristics, concomitant medication, and the burden of mutations in theWomen (These results suggest that intestinal metformin transporters and concomitant medications play an important role in the gastrointestinal adverse effects of metformin.

The aim of this study was to measure and investigate correlations of lamotrigine concentrations in maternal as well as umbilical cord blood, amniotic fluid, and breast milk to account for the distribution of the drug. Concentrations of lamotrigine were measured in 19 mother–infant pairs at the time of delivery. To account for the penetration ratio into amniotic fluid, cord blood and breast milk, the concentration of lamotrigine in the particular environment was divided by the concentration in maternal serum. A no-intercept model was applied for associations between maternal serum concentrations, amniotic fluid, umbilical cord blood, and breast milk concentrations. The mean daily dosage of lamotrigine was 351.32 mg (range 50–650 mg). We detected associations between maternal serum and amniotic fluid (β = 0.088, p

Background The adverse drug reaction database of the German Federal Institute for Drugs and Medical Devices (Bundesinstitut fur Arzneimittel und Medizinprodukte, BfArM) contains reports of suspected adverse drug reactions (ADRs) that are spon- taneously submitted by physicians, pharmacists, or patients. The aim of the present study was a descriptive analysis of all of these spontaneous reports. Methods 345 662 spontaneously submitted reports were analyzed with respect to the number of reports per year, the sources of the reports, demographic variables, the most commonly reported ADRs, and the drug classes most commonly suspected. Results The number of reports submitted spontaneously each year has grown steadily since 1978. At the least detailed level of analysis, "drugs for the treatment of nervous system disorders" were the most common class of drugs under suspicion of causing the reported adverse drug reactions (23.1%). In a more detailed analysis by therapeutic subgroup, the three subgroups most commonly reported as suspected of causing side effects were antithrombotic agents, systemic antibiotics, and psycholeptics-causing thrombocytopenia, diarrhea, and drug dependency as the most frequently reported ADRs, respectively. The order of drug classes most commonly causing ADRs differed markedly between the physicians' reports (diazepines, fluoroquinolones, heparins) and the patients' reports (interferons, anti- thrombotic drugs, selective immunosuppressant drugs). Patients more commonly reported subjectively perceived ADRs, while physicians more commonly reported findings or diagnoses that require medical expertise. Conclusion The increasing number of spontaneous reports is mainly due to reports forwarded from pharmaceutical companies to the BfArM. This, in turn, is probably a result of increasingly strict legal reporting requirements in Germany. The detected differences between physicians' and patients' ADR reports can be taken to indicate that patients should be more specifically informed and questioned about potential ADRs. By reporting adverse drug reactions, physicians may improve drug safety.

Background Adverse drug reactions (ADR) are a common reason for emergency room visits and for hospitalization. An ADR is said to have occurred when the patient's symptoms and signs are considered to be possibly, probably, or definitely related to the intake of a drug. Methods In four large hospital emergency departments, one in each of four German cities ( Ulm, Furth, Bonn, and Stuttgart), the percentage of suspected ADR cases among all patients presenting to the emergency room was determined during a 30-day period of observation. ADRs were ascertained by screening the digital records of all patients seen in the emergency room; causality was assessed as specified by the WHO-UMC (Uppsala Monitoring Center). Results ADR were sought in a total of 10 174 emergency department visits. 665 cases of suspected ADR were found, yielding a prevalence of 6.5%. The prevalence of ADR among patients with documented drug intake was 11.6%. Among the patients with documented suspected ADRs, 89% were hospitalized (in contrast to the 43.7% hospitalization rate in the entire group of 10 174 emergency department visits). A possible causal relationship between the patient's symptoms and signs and the intake of a drug was found in 74-84% of cases. Patients with ADR were found to be taking a median of 7 different drugs simultaneously. Conclusion Adverse drug reactions are a relevant cause of emergency department visits, accounting for 6.5% of the total visits in this study, and often lead to hospital admission. The ADRED (Adverse Drug Reactions in Emergency Departments) study, which is now being conducted, is intended to shed further light on their causes, patient risk factors, and potential avoidability.