CYP1A2 expression rather than genotype is associated with olanzapine concentration in psychiatric patients.

Olanzapine is a commonly prescribed atypical antipsychotic agent for treatment of patients with schizophrenia and bipolar disorders. Previous in vitro studies using human liver microsomes identified CYP1A2 and CYP2D6 enzymes being responsible for CYP-mediated metabolism of olanzapine. The present work focused on the impact of CYP1A2 and CYP2D6 genetic polymorphisms as well as of CYP1A2 metabolizing capacity influenced by non-genetic factors (sex, age, smoking) on olanzapine blood concentration in patients with psychiatric disorders (N = 139).

Selection and Evaluation of mRNA and miRNA Reference Genes for Expression Studies (qPCR) in Archived Formalin-Fixed and Paraffin-Embedded (FFPE) Colon Samples of DSS-Induced Colitis Mouse Model.

The choice of appropriate reference genes is essential for correctly interpreting qPCR data and results. However, the majority of animal studies use a single reference gene without any prior evaluation. Therefore, many qPCR results from rodent studies can be misleading, affecting not only reproducibility but also translatability.

Optimization of process conditions for mammalian fed-batch cell culture in automated micro-bioreactor system using genetic algorithm.

Recombinant proteins produced by mammalian cell culture technology represent an important segment of therapeutic molecules. Development of their manufacturing processes is a time- and resource-consuming task. A wide array of process conditions, e.

Phenoconversion of CYP2D6 by inhibitors modifies aripiprazole exposure.

The efficacy of aripiprazole therapy and the risk of adverse reactions are influenced by substantial inter-individual variability in aripiprazole metabolizing capacity. In vitro studies assigned the potential role in aripiprazole metabolism to CYP2D6 and CYP3A enzymes; therefore, the association between the steady-state aripiprazole plasma concentrations and patients' CYP2D6 and CYP3A statuses (CYP2D6, CYP3A4, and CYP3A5 genotypes, and CYP3A4 expression) and/or co-medication with CYP function modifying medications has been investigated in 93 psychiatric patients on stable aripiprazole therapy. The patients' CYP2D6 genotype had a major effect on aripiprazole plasma concentrations, whereas contribution of CYP3A genotypes and CYP3A4 expression to aripiprazole clearance were considered to be minor or negligible.

Modular Serial Flow Through device for pulsed electric field treatment of the liquid samples.

In biotechnology, medicine, and food processing, simple and reliable methods for cell membrane permeabilization are required for drug/gene delivery into the cells or for the inactivation of undesired microorganisms. Pulsed electric field treatment is among the most promising methods enabling both aims. The drawback in current technology is controllable large volume operation.

Potential Role of Patients' CYP3A-Status in Clozapine Pharmacokinetics.

Background: The atypical antipsychotic clozapine is effective in treatment-resistant schizophrenia; however, the success or failure of clozapine therapy is substantially affected by the variables that impact the clozapine blood concentration. Thus, elucidating the inter-individual differences in clozapine pharmacokinetics can facilitate the personalized therapy.

Methods: Since a potential role in clozapine metabolism is assigned to CYP1A2, CYP2C19, CYP2D6 and CYP3A enzymes, the association between the patients' CYP status (CYP genotypes, CYP expression) and clozapine clearance was evaluated in 92 psychiatric patients.

Optimization of Clonazepam Therapy Adjusted to Patient's CYP3A Status and NAT2 Genotype.

Background: The shortcomings of clonazepam therapy include tolerance, withdrawal symptoms, and adverse effects such as drowsiness, dizziness, and confusion leading to increased risk of falls. Inter-individual variability in the incidence of adverse events in patients partly originates from the differences in clonazepam metabolism due to genetic and nongenetic factors.

Methods: Since the prominent role in clonazepam nitro-reduction and acetylation of 7-amino-clonazepam is assigned to CYP3A and N-acetyl transferase 2 enzymes, respectively, the association between the patients' CYP3A status (CYP3A5 genotype, CYP3A4 expression) or N-acetyl transferase 2 acetylator phenotype and clonazepam metabolism (plasma concentrations of clonazepam and 7-amino-clonazepam) was evaluated in 98 psychiatric patients suffering from schizophrenia or bipolar disorders.

Beyond aphasia: Altered EEG connectivity in Broca's patients during working memory task.

Broca's region and adjacent cortex presumably take part in working memory (WM) processes. Electrophysiologically, these processes are reflected in synchronized oscillations. We present the first study exploring the effects of a stroke causing Broca's aphasia on these processes and specifically on synchronized functional WM networks.

Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis.

Cholesterol synthesis is among the oldest metabolic pathways, consisting of the Bloch and Kandutch-Russell branches. Following lanosterol, sterols of both branches are proposed to be dedicated to cholesterol. We challenge this dogma by mathematical modeling and with experimental evidence.

Clinical-pharmacist intervention reduces clinically relevant drug-drug interactions in patients with heart failure: A randomized, double-blind, controlled trial.

Background: Incidence of drug-drug interactions (DDIs) increases with complexity of treatment and comorbidities, as in heart failure (HF). This randomized, double-blind study evaluated the intervention of the pharmacist on prevalence of clinically relevant DDIs (NCT01855165).

Methods: Patients admitted with HF were screened for clinically relevant DDIs, and randomized to control or intervention.

Transcriptome study and identification of potential marker genes related to the stable expression of recombinant proteins in CHO clones.

Background: Chinese hamster ovary (CHO) cells have become the host of choice for the production of recombinant proteins, due to their capacity for correct protein folding, assembly, and posttranslational modifications. The most widely used system for recombinant proteins is the gene amplification procedure that uses the CHO-Dhfr expression system. However, CHO cells are known to have a very unstable karyotype.

The electrophysiological correlates of the working memory subcomponents: evidence from high-density EEG and coherence analysis.

Synchronization between prefrontal (executive) and posterior (association) cortices seems a plausible mechanism for temporary maintenance of information. However, while EEG studies reported involvement of (pre)frontal midline structures in synchronization, functional neuroimaging elucidated the importance of lateral prefrontal cortex (PFC) in working memory (WM). Verbal and spatial WM rely on lateralized subsystems (phonological loop and visuospatial sketchpad, respectively), yet only trends for hemispheric dissociation of networks supporting rehearsal of verbal and spatial information were identified by EEG.

SteatoNet: the first integrated human metabolic model with multi-layered regulation to investigate liver-associated pathologies.

Current state-of-the-art mathematical models to investigate complex biological processes, in particular liver-associated pathologies, have limited expansiveness, flexibility, representation of integrated regulation and rely on the availability of detailed kinetic data. We generated the SteatoNet, a multi-pathway, multi-tissue model and in silico platform to investigate hepatic metabolism and its associated deregulations. SteatoNet is based on object-oriented modelling, an approach most commonly applied in automotive and process industries, whereby individual objects correspond to functional entities.

Dehydroepiandrosterone post-transcriptionally modifies CYP1A2 induction involving androgen receptor.

The pharmacological dosage of dehydroepiandrosterone (DHEA) protects against chemically induced carcinogenesis. The chemoprotective activity of DHEA is attributed to its inhibitory potential for the expression of CYP1A enzymes, which are highly responsible for metabolic activation of several mutagenic and carcinogenic chemicals. The present work investigated whether the chemoprevention by DHEA was due to diminished transcriptional activation of CYP1A genes or to the post-transcriptional modulation of CYP1A expression.

An algorithm for rapid computational construction of metabolic networks: a cholesterol biosynthesis example.

Alternative pathways of metabolic networks represent the escape routes that can reduce drug efficacy and can cause severe adverse effects. In this paper we introduce a mathematical algorithm and a coding system for rapid computational construction of metabolic networks. The initial data for the algorithm are the source substrate code and the enzyme/metabolite interaction tables.

Assessment of the haptic robot as a new tool for the study of the neural control of reaching.

Current experimental methods for the study of reaching in the MRI environment do not exactly mimic actual reaching, due to constrains in movement which are imposed by the MRI machine itself. We tested a haptic robot (HR) as such a tool. Positive results would also be promising for combined use of fMRI and EEG to study reaching.

Molecular Interactions between NAFLD and Xenobiotic Metabolism.

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, is a complex multifactorial disease characterized by metabolic deregulations that include accumulation of lipids in the liver, lipotoxicity, and insulin resistance. The progression of NAFLD to non-alcoholic steatohepatitis and cirrhosis, and ultimately to carcinomas, is governed by interplay of pro-inflammatory pathways, oxidative stress, as well as fibrogenic and apoptotic cues. As the liver is the major organ of biotransformation, deregulations in hepatic signaling pathways have effects on both, xenobiotic and endobiotic metabolism.

Sniffing-related motor cortical potential: topography and possible generators.

This study estimated the whole-scalp topography and possible generators of the cortical potential associated with volitional self-paced inspirations (sniffs). In 17 healthy subjects we recorded a 32-channel electroencephalogram (EEG) during sniffing, for comparison during finger flexions. We averaged the EEG with respect to movement onset, and performed current source density and principal component analysis on the grand averaged data.

Estimation of drug-metabolizing capacity by cytochrome P450 genotyping and expression.

Many undesired side effects or therapeutic failures of drugs are the result of differences or changes in drug metabolism, primarily depending on the levels and activities of cytochrome P450 (P450) enzymes. To assess whether P450 expression profiles can reflect hepatic drug metabolism, we compared P450 mRNA levels in the liver or peripheral leukocytes with the corresponding hepatic P450 activities. A preliminary P450 genotyping for the most frequent polymorphisms in white populations (CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP2D6*3, CYP2D6*4, CYP2D6*6, and CYP3A5*3) was carried out before P450 phenotyping, excluding the donors with nonfunctional alleles of CYP2C9, CYP2C19, and CYP2D6 and those with a functional CYP3A5*1 allele from a correlation analysis.

Brain-computer interface analysis of a dynamic visuo-motor task.

Background: The area of brain-computer interfaces (BCIs) represents one of the more interesting fields in neurophysiological research, since it investigates the development of the machines that perform different transformations of the brain's "thoughts" to certain pre-defined actions. Experimental studies have reported some successful implementations of BCIs; however, much of the field still remains unexplored. According to some recent reports the phase coding of informational content is an important mechanism in the brain's function and cognition, and has the potential to explain various mechanisms of the brain's data transfer, but it has yet to be scrutinized in the context of brain-computer interface.

Inhibition of human sterol Δ7-reductase and other postlanosterol enzymes by LK-980, a novel inhibitor of cholesterol synthesis.

Novel potential inhibitors of the postsqualene portion of cholesterol synthesis were screened in HepG2 cells. 2-(4-Phenethylpiperazin-1-yl)-1-(pyridine-3-yl)ethanol (LK-980) was identified as a prospective compound and was characterized further in cultures of human primary hepatocytes from seven donors. In vitro kinetic measurements show that the half-life of LK-980 is at least 4.

Investigation of the CYP2C9 induction profile in human hepatocytes by combining experimental and modelling approaches.

The goal of the present review is to characterise the induction profile of CYP2C9, a member of the cytochrome P450 superfamily. Since the mechanism of CYP2C9 induction is fairly complex, with parallel processes triggered by various inducers, an evaluation of the experimental results is often a great challenge. At least three nuclear receptors, the glucocrticoid receptor (GR), the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), are known to mediate the CYP2C9 gene induction in man.

Tableting process optimisation with the application of fuzzy models.

A quality-by-design (QbD) principle, including process analytical technology, is becoming the principal idea in drug development and manufacturing. The implementation of QbD into product development and manufacturing requires larger resources, both human and financial, however, large-scale production can be established in a more cost-effective manner and with improved product quality. The objective of the present work was to study the influence of particle size distribution in powder mixture for tableting, and the settings of the compression parameters on the tablet quality described by the capping coefficient, standard deviations of mass and crushing strength of compressed tablets.

Minimisation of the capping tendency by tableting process optimisation with the application of artificial neural networks and fuzzy models.

The pharmaceutical industry is increasingly aware of the advantages of implementing a quality-by-design (QbD) principle, including process analytical technology, in drug development and manufacturing. Although the implementation of QbD into product development and manufacturing inevitably requires larger resources, both human and financial, large-scale production can be established in a more cost-effective manner and with improved efficiency and product quality. The objective of the present work was to study the influence of particle size (and indirectly, the influence of dry granulation process) and the settings of the tableting parameters on the tablet capping tendency.

Identification of the phase code in an EEG during gripping-force tasks: a possible alternative approach to the development of the brain-computer interfaces.

Background: The subject of brain-computer interfaces (BCIs) represents a vast and still mainly undiscovered land, but perhaps the most interesting part of BCIs is trying to understand the information exchange and coding in the brain itself. According to some recent reports, the phase characteristics of the signals play an important role in the information transfer and coding. The mechanism of phase shifts, regarding the information processing, is also known as the phase coding of information.