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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.

European journal of clinical pharmacology 79(2), 219-227 (2023). doi:10.1007/s00228-022-03433-9, Published by Springer, New York

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.

Translational Psychiatry 11(1), 467 (2021). doi:10.1038/s41398-021-01591-5, Published by Nature Publishing Group, London

Background and aims The Hepatitis E virus hijacks the endosomal system for its release. These structures are highly dependent on cholesterol. Hence, this study investigates the impact of HEV on cholesterol-metabolism, the effect of intracellular cholesterol content on HEV-release and the potential of cholesterol-modulators to serve as antivirals. Methods Intracellular cholesterol-content of cells was modulated and impacts on HEV were monitored using qPCR, Western blot, microscopy, virus-titration and density-gradient centrifugation. Blood-lipids and HEV-RNA were routinely quantified in chronically infected patients during follow-up visits. Results In HEV-infected cells, decreased levels of cholesterol are found. In patients, HEV infection decreases serum-lipid concentrations. Importantly, statin treatment herein increases viral titers. Similarly, reduction of intracellular cholesterol via simvastatin treatment increases viral release in vitro. On the contrary, elevating intracellular cholesterol via LDL or 25-hydroxycholesterol strongly reduces viral release due to enhanced lysosomal degradation of HEV. Drug-induced elevation of intracellular cholesterol via fenofibrate or PSC833 impairs HEV release via the same mechanism. Conclusions This study analyses the crosstalk between HEV and intracellular cholesterol. The results highlight the importance of an intact cholesterol homeostasis for HEV-release and thereby identify a potential target for antiviral strategies. Especially fenofibrate is considered a promising novel antiviral against HEV. Beyond this, the study may help clinicians evaluating co-treatments of HEV-infected patients with statins, as this may be counter indicated., Graphical abstract

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.

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

The polymorphic drug-metabolizing enzyme CYP2D6, which is responsible for the metabolism of most psychoactive compounds, is expressed not only in the liver, but also in the brain. The effects of its marked genetic polymorphism on the individual capacity to metabolize drugs are well known, but its role in metabolism of neural substrates affecting behavior personality or cognition, suggested by its CNS expression, is a long-standing unresolved issue. To verify earlier findings suggesting a potential effect on attentional processes, we collected functional imaging data, while N = 415 participants performed a simple task in which the reward for correct responses varied. CYP2D6 allelic variants predicting higher levels of enzymatic activity level were positively associated with cortical activity in occipito-parietal areas as well as in a right lateralized network known to be activated by spatial attentional tasks. Reward-related modulation of activity in cortical areas was more pronounced in poor metabolizers. In conjunction with effects on reaction times, our findings provide evidence for reduced cognitive efficiency in rapid metabolizers compared to poor metabolizers in on-task attentional processes manifested through differential recruitment of a specific neural substrate.

Resumen Objetivo La Monitorizacion Terapeutica de Drogas (llamada en ingles TDM: therapeutic drug monitoring) combina la cuantificacion de las concentraciones de medicamentos en la sangre, la interpretacion farmacologica y las directrices de tratamiento. La TDM introduce una herramienta de medicina de precision en una ipoca de gran conciencia de la necesidad de tratamientos personalizados en neurologia y psiquiatria. Las indicaciones claras de la TDM incluyen la ausencia de respuesta clinica en el rango de dosis terapeuticas, la evaluacion de la adherencia farmacologica, problemas de tolerancia e interacciones medicamentosas. Metodos Basandose en la literatura existente, se describieron los rangos de referencia terapeutica recomendables, los valores criticos de laboratorio y los niveles de recomendacion para usar la TDM para la optimizacion de dosis sin indicaciones especificas, se calcularon los factores de conversion, los factores para el calculo de concentraciones medicamentosas relacionadas con la dosis (en ingles DRC dose-to-ratio concentration) y el cociente entre el metabolito y el compuesto original (en ingles se llama MPR: metabolite-to-parent ratio). Resultados Este resumen de las guias actualizadas del consenso por la Task Force del TDM del Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie, ofrece el conocimiento practico y teorico para la integracion de la TDM como parte de la farmacoterapia con medicamentos neuropsiquiatricos en la practica clinica rutinaria. Conclusiones La presente traduccion en espanol, de la guia para la aplicacion del TDM en medicamentos neuropsiquiatricos, tiene como objetivo ayudar a los clinicos a mejorar la seguridad y la eficacia de los tratamientos.

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.

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.

Basic & clinical pharmacology & toxicology : BCPT 130(1), 132-140 (2022). doi:10.1111/bcpt.13681, Published by Wiley-Blackwell, Oxford

British journal of clinical pharmacology : BJCP 88(5), 2380-2395 (2022). doi:10.1111/bcp.15175, Published by Wiley-Blackwell, Oxford

Vaccines : open access journal 9(12), 1419 (2021). doi:10.3390/vaccines9121419 special issue: "COVID-19 vaccines and vaccination / editors: Ralph A. Tripp [und 15 weitere]", Published by MDPI, Basel

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.

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.

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.

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.

PLOS ONE 16(3), e0247446 (2021). doi:10.1371/journal.pone.0247446, Published by PLOS, San Francisco, California, US

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.

BJPsych Open 8(1), e20 (2021). doi:10.1192/bjo.2021.1075, Published by Cambridge University Press, Cambridge

BMC pharmacology & toxicology 22(1), 56 (2021). doi:10.1186/s40360-021-00520-y, Published by BioMed Central, London

Allergy : European journal of allergy and clinical immunology 77(7), 2080-2089 (2022). doi:10.1111/all.15189, Published by Wiley, Oxford

Objectives ABCB1 gene polymorphisms can modify P-glycoprotein function with clinical consequences. Methods The 3435C>T polymorphism prevalence was analyzed using oligonucleotide probes and next-generation sequencing in 421 unrelated healthy individuals living in Cuba. Data were stratified by gender, ethnic background and residence. The genotype and allelic frequencies were determined. Results The genotype distribution met the Hardy–Weinberg equilibrium assumption. The allelic frequency was 63.5% for the 3435C variant. The genotype frequencies were 41.1% for CC, 44.9% for CT and 14.0% for TT. The allele and genotype distributions differed between individuals living in La Habana and Santiago de Cuba (p Conclusions This is the first report on allele and genotype frequencies of the 3435C>T polymorphism in Cuba, which may support personalized medicine programs.

We conducted a clinical study to determine the effect of efavirenz and ritonavir on the pharmacokinetics of R‐ and S‐PZQ in healthy male participants. This was toward evaluating the risk of drug‐drug interactions, which may occur after PZQ administration to HIV patients on efavirenz or ritonavir containing regimens. A non‐randomized, open‐label, single‐dose, one sequence crossover study with 2 arms was conducted. We gave 26 healthy volunteers a single oral dose of 40 mg/kg PZQ followed by a daily oral dose of either 400 mg efavirenz or 100 mg ritonavir for 14 consecutive days. On day 14, they ingested a single 40 mg/kg dose of PZQ. We measured plasma levels up to 12 h on day 1 and day 14. Samples were analyzed by LC‐MS. Pharmacokinetic analysis was conducted in WinNonlin to determine the primary endpoints (plasma T 1/2, C min, and AUC). Efavirenz had a significant effect on the pharmacokinetics of PZQ (p, The effect of efavirenz and ritonavir on the pharmacokinetics of praziquantel (PZQ) were investigated. An open label, single dose one sequence crossover clinical study with 26 healthy male volunteers was conducted. Efavirenz decreased the AUC of PZQ 4‐fold (p