Assays for Monitoring Apixaban and Rivaroxaban in Emergency Settings, State-of-the-Art Routine Analysis, and Volumetric Absorptive Microsamples Deliver Discordant Results.

Our aim was to compare the performance of complementary clinical laboratory approaches to monitoring exposure to apixaban and rivaroxaban, the most prescribed direct-acting oral anticoagulants (DOAC's): an automated commercial anti-Xa chromogenic assay suitable for emergency and pre-surgery testing and a laboratory-developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) method employed for non-emergency analysis in plasma and in dried blood volumetric absorptive microsamples (VAMS) collectible by the patients in their homes. The full validation of the LC-MS/MS method was performed. Cross-validation of the methodologies was accomplished by processing 60 specimens collected for whole blood count and DOAC monitoring in a central clinical laboratory.

Therapeutic Drug Monitoring and Pharmacokinetics-Based Individualization of Drug Therapy.

The philosophy, practice, and clinical impact of therapeutic drug monitoring (TDM) has changed profoundly with the appearance of widely available and, in a technical sense, commonly applicable modeling, simulation, and dosing software tools in the past decade [...

Effect of hypercholesterolemia on circulating and cardiomyocyte-derived extracellular vesicles.

Hypercholesterolemia (HC) induces, propagates and exacerbates cardiovascular diseases via various mechanisms that are yet not properly understood. Extracellular vesicles (EVs) are involved in the pathomechanism of these diseases. To understand how circulating or cardiac-derived EVs could affect myocardial functions, we analyzed the metabolomic profile of circulating EVs, and we performed an in-depth analysis of cardiomyocyte (CM)-derived EVs in HC.

Assessment of the practical impact of adjusting beta-lactam dosages based on therapeutic drug monitoring in critically ill adult patients: a systematic review and meta-analysis of randomized clinical trials and observational studies.

An estimated 70% of critically ill patients receive antibiotics, most frequently beta-lactams. The pharmacokinetic properties of these substances in this patient population are poorly predictable. Therapeutic drug monitoring (TDM) is helpful in making personalized decisions in this field, but its overall impact as a clinical decision-supporting tool is debated.

Modeling Pharmacokinetics in Individual Patients Using Therapeutic Drug Monitoring and Artificial Population Quasi-Models: A Study with Piperacillin.

Population pharmacokinetic (pop-PK) models constructed for model-informed precision dosing often have limited utility due to the low number of patients recruited. To augment such models, an approach is presented for generating fully artificial quasi-models which can be employed to make individual estimates of pharmacokinetic parameters. Based on 72 concentrations obtained in 12 patients, one- and two-compartment pop-PK models with or without creatinine clearance as a covariate were generated for piperacillin using the nonparametric adaptive grid algorithm.

Reference data on estrogen metabolome in healthy pregnancy.

Introduction: Estrogen hormones and their metabolites are implicated in the maintenance of healthy pregnancy and adequate fetal development. Abnormal levels were related to increased risk of pregnancy complications, particularly preeclampsia. Our aims were (1) to develop a methodological platform for the comprehensive assessment of estrogen metabolome in pregnancy; (2) to collect healthy reference data for relevant elements of estrogen metabolome in each trimester; (3) to assess unconjugated fractions of the estrogen metabolome, (4) to assess the dominant metabolic pathways of estrogen compounds.

Role of CB1 Cannabinoid Receptors in Vascular Responses and Vascular Remodeling of the Aorta in Female Mice.

Both the endocannabinoid system (ECS) and estrogens have significant roles in cardiovascular control processes. Cannabinoid type 1 receptors (CBRs) mediate acute vasodilator and hypotensive effects, although their role in cardiovascular pathological conditions is still controversial. Estrogens exert cardiovascular protection in females.

Risk Estimation of Gestational Diabetes Mellitus in the First Trimester.

Context: There is no early, first-trimester risk estimation available to predict later (gestational week 24-28) gestational diabetes mellitus (GDM); however, it would be beneficial to start an early treatment to prevent the development of complications.

Objective: We aimed to identify early, first-trimester prediction markers for GDM.

Methods: The present case-control study is based on the study cohort of a Hungarian biobank containing biological samples and follow-up data from 2545 pregnant women.

[Challenge in modern intensive care: chronic critical illness - pathophysiology and therapeutic options].

The recent developments in intensive care have resulted in improved survival rates of patients treated with acute organ deficiency. As a consequence, the rate of those who survive the acute phase and subsequently require protracted organ support due to persisting organ dysfunction has been growing. Several survivors display chronic health status deterioration leading to prolonged rehabilitation or nursing, and repeated hospitalizations.

Therapeutic Monitoring of Orally Administered, Small-Molecule Anticancer Medications with Tumor-Specific Cellular Protein Targets in Peripheral Fluid Spaces-A Review.

Orally administered, small-molecule anticancer drugs with tumor-specific cellular protein targets (OACD) have revolutionized oncological pharmacotherapy. Nevertheless, the differences in exposure to these drugs in the systemic circulation and extravascular fluid compartments have led to several cases of therapeutic failure, in addition to posing unknown risks of toxicity. The therapeutic drug monitoring (TDM) of OACDs in therapeutically relevant peripheral fluid compartments is therefore essential.

A High-Throughput Clinical Laboratory Methodology for the Therapeutic Monitoring of Ibrutinib and Dihydrodiol Ibrutinib.

Ibrutinib (IBR) is an oral anticancer medication that inhibits Bruton tyrosine kinase irreversibly. Due to the high risk of adverse effects and its pharmacokinetic variability, the safe and effective use of IBR is expected to be facilitated by precision dosing. Delivering suitable clinical laboratory information on IBR is a prerequisite of constructing fit-for-purpose population and individual pharmacokinetic models.

Assessment of Antibiotic Pharmacokinetics, Molecular Biomarkers and Clinical Status in Critically Ill Adults Diagnosed with Community-Acquired Pneumonia and Receiving Intravenous Piperacillin/Tazobactam and Hydrocortisone over the First Five Days of Intensive Care: An Observational Study (STROBE Compliant).

Severe community-acquired pneumonia (CAP) is a condition that frequently requires intensive care and, eventually, can cause to death. Piperacillin/tazobactam antibiotic therapy is employed as an empiric intravenous regimen, in many cases supplemented with intravenous bolus hydrocortisone treatment. The individual and condition-dependent pharmacokinetic properties of these drugs may lead to therapeutic failure.

[Clinical and diagnostic relevance of asymmetric and symmetric dimethyl arginine (ADMA/SDMA)].

Összefoglaló. Régóta folynak kutatások olyan újabb biomarkerek azonosítására, amelyek segítik a krónikusan progrediáló, úgynevezett civilizációs betegségek - például cardiovascularis kórképek, vesefunkció-beszűkülés - korai felismerését. Az aszimmetrikus és a szimmetrikus dimetil-arginin (ADMA és SDMA) kettő azon paraméterek közül, amelyek biológiai hatásai évtizedek óta ismertek ugyan, ám biomarkerként egyelőre nem terjedtek el a humán orvosi-diagnosztikai gyakorlatban.

Adrenal, Gonadal and Peripherally Steroid Changes in Response to Extreme Physical Stress for Characterizing Load Capacity in Athletes.

Athletes are often exposed to extreme physical stress during training or competitions. The consequent activation of the hypothalamus-hypophysis-adrenal (HPA) axis results in intensified steroid hormone production in the adrenal cortex. We determined the impact of an acute extreme physical stress on adrenal and gonadal steroidogenesis in healthy male professional athletes ( = 40).

Sex-related differences of early cardiac functional and proteomic alterations in a rat model of myocardial ischemia.

Background: Reduced cardiovascular risk in premenopausal women has been the focus of research in recent decades. Previous hypothesis-driven experiments have highlighted the role of sex hormones on distinct inflammatory responses, mitochondrial proteins, extracellular remodeling and estrogen-mediated cardioprotective signaling pathways related to post-ischemic recovery, which were associated with better cardiac functional outcomes in females. We aimed to investigate the early, sex-specific functional and proteomic changes following myocardial ischemia in an unbiased approach.

Identification of disease- and headache-specific mediators and pathways in migraine using blood transcriptomic and metabolomic analysis.

Background: Recent data suggest that gene expression profiles of peripheral white blood cells can reflect changes in the brain. We aimed to analyze the transcriptome of peripheral blood mononuclear cells (PBMC) and changes of plasma metabolite levels of migraineurs in a self-controlled manner during and between attacks.

Methods: Twenty-four patients with migraine were recruited and blood samples were collected in a headache-free (interictal) period and during headache (ictal) to investigate disease- and headache-specific alterations.

A pharmacokinetics-based approach to the monitoring of patient adherence to atorvastatin therapy.

The inadequate adherence of patients whose hyperlipidemia is treated with atorvastatin (ATR) to medical instructions presents a serious health risk. Our aim was to develop a flexible approach based on therapeutic drug monitoring (TDM), nonparametric population pharmacokinetic modeling, and Monte Carlo simulation to differentiate adherent patients from partially and nonadherent individuals in a nonrandomized, unicentric, observational study. Sixty-five subjects were enrolled.

Sensitive, High-Throughput Liquid Chromatography-Tandem Mass Spectrometry Analysis of Atorvastatin and Its Pharmacologically Active Metabolites in Serum for Supporting Precision Pharmacotherapy.

The antihyerlipidemic drug atorvastatin (ATR) is used worldwide as part of the strategy to prevent cardiovascular events. The high prevalence of patient nonadherence remains an important challenge which could be addressed efficiently by precision pharmacotherapy based on therapeutic drug monitoring (TDM). ATR is metabolized to pharmacologically active metabolites, and evidence shows that the sums of ATR acid and lactone form concentrations (ATR + ATRL), or of ATR and hydroxylated metabolites (ATR + MET) should be assayed.

[Therapeutic drug monitoring of atypical antipsychotics and antidepressants: conclusions of the first year at Semmelweis University].

Introduction: Pharmacotherapy supported by therapeutic drug monitoring (TDM) has a tradition in psy - chiatry. Novel diagnostic infrastructure based on mass spectrometry has been developed at Semmelweis University, allowing the renewal of psychiatric treatments supported by TDM. In a cooperation of the Department of Laboratory Medicine, and the Department of Psychiatry and Psychotherapy 13 drugs were assayed in a routine setting.

Analysis of 14 drugs in dried blood microsamples in a single workflow using whole blood and serum calibrators.

Multiplexed, high-throughput analysis facilitates therapeutic drug monitoring. 14 drugs with various physico-chemical properties were quantitated in dried blood microsamples. Analytes were extracted employing eight solvent compositions and seven extraction methods.

Pharmacokinetics of Two Chlorine-Substituted Bis-Pyridinium Mono-Aldoximes with Regenerating Effect on Butyrylcholinesterase.

Our aim was to find chlorine-substituted antidotes against organophosphate poisoning and compare their pharmacokinetics to their parent compound, K-203. White male Wistar rats were intramuscularly injected with K-203, K-867 or K-870. Serum, brain, kidneys, liver, lung, eyes, and testes tissues were taken after 5, 15, 30, 60, and 120 min and analyzed using reversed-phase high-performance liquid chromatography.

Development of a methodology to make individual estimates of the precision of liquid chromatography-tandem mass spectrometry drug assay results for use in population pharmacokinetic modeling and the optimization of dosage regimens.

Background: The clinical value of therapeutic drug monitoring can be increased most significantly by integrating assay results into clinical pharmacokinetic models for optimal dosing. The correct weighting in the modeling process is 1/variance, therefore, knowledge of the standard deviations (SD) of each measured concentration is important. Because bioanalytical methods are heteroscedastic, the concentration-SD relationship must be modeled using assay error equations (AEE).

Metabolic and catecholamine response to sympathetic stimulation in early-treated adult male patients with phenylketonuria.

Purpose: Defective function of phenylalanine hydroxylase in phenylketonuria (PKU) results in the accumulation of phenylalanine (Phe) and the reduction of tyrosine (Tyr) in the blood, interfering in the normal development and function of organs and tissues in the body. Tyr is the precursor of catecholamines, secreted in response to stress by the adrenal medulla and paraganglia. The aim of this study was to evaluate plasma catecholamine and amino acid response to an escalating series of sympathetic stress tests in PKU patients.