A Pooled Analysis of Three Randomized Phase I/IIa Clinical Trials Confirms Absence of a Clinically Relevant Effect on the QTc Interval by Umibecestat.

Umibecestat, an orally active β-secretase inhibitor, reduces the production of amyloid beta-peptide that accumulates in the brain of patients with Alzheimer's disease. The echocardiogram effects of umibecestat, on QTcF (Fridericia-corrected QT), on PR and QRS and heart rate (HR), were estimated by concentration-effect modeling. Three phase I/II studies with durations up to 3 months, with 372 healthy subjects over a wide age range, including both sexes and 2 ethnicities, were pooled, providing a large data set with good statistical power.

Highly Variable Pharmacokinetics of Tyramine in Humans and Polymorphisms in OCT1, CYP2D6, and MAO-A.

Tyramine, formed by the decarboxylation of tyrosine, is a natural constituent of numerous food products. As an indirect sympathomimetic, it can have potentially dangerous hypertensive effects. data indicated that the pharmacokinetics of tyramine possibly depend on the organic cation transporter OCT1 genotype and on the CYP2D6 genotype.

Two studies in one: A propensity-score-matched comparison of fingolimod versus interferons and glatiramer acetate using real-world data from the independent German studies, PANGAEA and PEARL.

Background: This study compared outcomes following fingolimod or BRACE treatments (beta-interferons/glatiramer acetate) in patients with active MS (≥ 1 relapse in the previous year) following previous BRACE treatment.

Methods And Findings: Patients with active MS who previously received BRACE were identified from German prospective, observational studies, PANGAEA and PEARL. A novel methodology was developed to compare outcomes between propensity-score-matched cohorts (3:1 ratio) from the independent single-arm studies.

Combination treatment of fingolimod with antidepressants in relapsing-remitting multiple sclerosis patients with depression: a multicentre, open-label study - REGAIN.

Objectives: Approximately one in two patients with multiple sclerosis (MS) suffer from comorbid depression. The primary objective of this study was to evaluate the safety and tolerability of fingolimod and antidepressant combination in relapsing-remitting MS patients with mild-to-moderate depression. Efficacy outcome variables were quality of life (QoL), fatigue, disability and depression.

Multiple Sclerosis Therapy With Disease-Modifying Treatments in Germany: The PEARL (ProspEctive phArmacoeconomic cohoRt evaluation) Noninterventional Study Protocol.

Background: Patients with multiple sclerosis (MS) require long-term therapy and have a wide variety of needs for health-related support. The efficacy and safety of MS therapy, as assessed by both clinicians and patients, are important parameters that need to be considered. However, few studies combine data on efficacy and safety outcomes with pharmacoeconomic data.

Impact of mineralocorticoid receptor polymorphisms on urinary electrolyte excretion with and without diuretic drugs.

Aim: Polymorphisms in the mineralocorticoid receptor may affect urinary sodium and potassium excretion. We investigated polymorphisms in the MR gene in relation to urinary electrolyte excretion in two separate studies.

Patients & Methods: The genotype-phenotype association was studied in healthy volunteers after single doses of bumetanide, furosemide, torsemide, hydrochlorothiazide, triamterene and after NaCl restriction.

Educating orally anticoagulated patients in drug safety: a cluster-randomized study in general practice.

Background: Orally anticoagulated patients with insufficient knowledge about their treatment have a higher risk of complications. Standardized patient education could raise their level of knowledge and improve time spent within target INR range.

Methods: This cluster randomized trial included 319 anticoagulated patients drawn from 22 general medical practices.

Safety relevant knowledge of orally anticoagulated patients without self-monitoring: a baseline survey in primary care.

Background: Effective and safe management of oral anticoagulant treatment (OAT) requires a high level of patient knowledge and adherence. The aim of this study was to assess patient knowledge about OAT and factors associated with patient knowledge.

Methods: This is a baseline survey of a cluster-randomized controlled trial in 22 general practices with an educational intervention for patients or their caregivers.

Practice nursed-based, individual and video-assisted patient education in oral anticoagulation--protocol of a cluster-randomized controlled trial.

Background: Managing oral anticoagulant treatment (OAT) is a challenge for patients and primary care providers. It requires a high level of patient knowledge and adherence. Studies have shown that insufficient adherence and a low level of patient knowledge about OAT are primary causes for complications.

Amelogenin-based sex identification as a strategy to control the identity of DNA samples in genetic association studies.

Misassignment between DNA samples and clinical or epidemiological data may compromise the results of genetic association studies. Genotyping in replicates or controlling for Hardy-Weinberg equilibrium cannot identify misassignments caused by sample mix-ups. DNA-based sex identification (sex typing) is currently the best strategy to identify mix-ups.

Implementing the cross-disciplinary subject of palliative medicine (Q13) against the backdrop of recent changes of the legal framework using University Medical School Göttingen as an example.

Palliative care for patients with advanced and progressive diseases has recently become an integrated and compulsory part of undergraduate training in Germany. Up until now, undergraduate teaching in this cross-disciplinary medical field varied and therefore problems during the implementation process with regard to formal aspects and teaching content are to be expected. This contribution summarizes the new legislative framework for palliative care as an independent specialty in undergraduate medical training and describes format, content and problems of the current implementation process at the University Medical School Göttingen, in order to provide advice and support for other faculties.

[SOPHO-NET - a research network on psychotherapy for social phobia].

This paper presents the Social Phobia Psychotherapy Research Network (SOPHO-NET). SOPHO-NET is among the five research networks on psychotherapy funded by "Bundesministerium für Bildung und Forschung". The research program encompasses a coordinated group of studies of social phobia.

Dimensions of personality--relationship between DSM-IV personality disorder symptoms, the five-factor model, and the biosocial model of personality.

Dimensional approaches regard personality disorders as extreme or maladaptive variants of traits that are commonly used to describe normal personality. Previous clinical and nonclinical studies identified four factors interpreted as Antisocial, Asocial, Asthenic, and Anankastic. To investigate the validity of this four-factor structure in healthy volunteers, 97 male and 98 female students completed versions of the NEO-PI-R and TPQ.

Torsemide renal clearance and genetic variation in luminal and basolateral organic anion transporters.

Aims: To investigate the association between torsemide renal clearance and genetic variation in the basolaterally expressed renal organic anion transporters OAT1 and OAT3 and in the luminally situated OAT4.

Methods: We analysed 22 polymorphisms in the OAT coding genes SLC22A6, SLC22A8 and SLC22A11 and their haplotypes and measured torsemide renal clearance in 95 healthy men. In addition, the effect of torsemide on the OAT-mediated transport was studied in vitro.

Hydrochlorothiazide efficacy and polymorphisms in ACE, ADD1 and GNB3 in healthy, male volunteers.

Objective: The antihypertensive effect of thiazide diuretics has recently been associated with genetic variation in the angiotensin I-converting enzyme (ACE), alpha-adducin (ADD1) and the G protein subunit beta3 (GNB3). Analysis of short-term diuretic effects may provide insight into the mechanisms behind these findings.

Methods: A total of 103 male volunteers took 25 and 100 mg hydrochlorothiazide (HCT) after a placebo day, each.

Anxiety- and novelty seeking-related personality traits and serotonin transporter gene polymorphisms.

The affection of human personality by the promoter and the intron 2 polymorphism in the serotonin transporter gene (SERT) is inconsistently reported. We aimed to clarify this situation by gender-specific haplotype-phenotype association. 98 women and 97 men completed the personality inventories NEO-PI-R and TPQ.

CYP2C9 polymorphisms and the interindividual variability in pharmacokinetics and pharmacodynamics of the loop diuretic drug torsemide.

Introduction: According to in vitro data, torsemide (INN, torasemide) is a substrate of the genetically polymorphic enzyme cytochrome P450 (CYP) 2C9, but the impact of CYP2C9 polymorphisms on torsemide pharmacokinetics and pharmacodynamics has not been studied in humans.

Methods: A total of 36 healthy volunteers (12, 9, 1, 9, 3, and 2 carriers of CYP2C9 genotypes *1/*1 , *1/*2 , *2/*2 , *1/*3 , *2/*3 , and *3/*3 , respectively) received a single oral dose of 10 mg torsemide for pharmacokinetic and pharmacodynamic analysis. The effects of the CYP2C9 polymorphism on torsemide-induced urine volume and urinary elimination of sodium, potassium, chloride, and uric acid were measured during a salt-restricted diet.

Pharmacogenomics of diuretic drugs: data on rare monogenic disorders and on polymorphisms and requirements for further research.

This review summarizes the current status of our knowledge about the role of pharmacogenetic variation in response to diuretics and suggests future research topics for the field. Genes with a role in the pharmacokinetics of most diuretics are renal drug transporters, especially OAT1, OAT3 and OCT2 (genes SLC22A6, SLC22A8 and SLC22A2) whereas variants in carbonic anhydrase (CA), cytochrome P450 enzymes and sulfotransferases are relevant only for specific substances. Genes on the pharmacodynamic side include the primary targets of thiazide, loop, K(+)-sparing and aldosterone antagonistic diuretics: NCC, NKCC2, ENaC and the mineralocorticoid receptor (genes SLC12A3, SLC12A1, SCNN1A, B, G and NR3C2).

Affinities of dihydrocodeine and its metabolites to opioid receptors.

Dihydrocodeine is metabolized to dihydromorphine, dihydrocodeine-6-O-, dihydromorphine-3-O- and dihydromorphine-6-O-glucuronide, and nordihydrocodeine. The current study was conducted to evaluate the affinities of dihydrocodeine and its metabolites to mu-, delta- and kappa-opioid receptors. Codeine, morphine, d,1-methadone and levomethadone were used as controls.