Calcium kinetic rates in Caucasian males and females from birth to adulthood.

Calcium plays an important role in bone physiology and its kinetics change over lifetime. The analysis of calcium deposition and release through stable isotope techniques has guided recommendations on nutritional uptake for overall health. In addition, calcium kinetics have great relevance for toxicokinetic studies of bone-seeking elements (e.

Sterol Derivatives Specifically Increase Anti-Inflammatory Oxylipin Formation in M2-like Macrophages by LXR-Mediated Induction of 15-LOX.

The understanding of the role of LXR in the regulation of macrophages during inflammation is emerging. Here, we show that LXR agonist T09 specifically increases 15-LOX abundance in primary human M2 macrophages. In time- and dose-dependent incubations with T09, an increase of 3-fold for ALOX15 and up to 15-fold for 15-LOX-derived oxylipins was observed.

Using Interdisciplinary Teams to Mitigate the Effects of Drug Shortages in Palliative Care: The Case of Lorazepam Injection.

Given the rising frequency of drug shortages in hospitals, interdisciplinary collaboration is necessary to manage medications, modify electronic medical records, and evaluate safety outcomes. One such shortage impacted lorazepam injection, a medication commonly used in palliative care to treat anxiety, agitation, and seizures. In anticipation of the lorazepam shortage in the summer of 2022, pharmacy staff collaborated with palliative care physicians to identify alternative treatment recommendations when providers were prohibited from ordering lorazepam injection.

A prognostic baseline blood biomarker and tumor growth kinetics integrated model in paclitaxel/platinum treated advanced non-small cell lung cancer patients.

Paclitaxel/platinum chemotherapy, the backbone of standard first-line treatment of advanced non-small cell lung cancer (NSCLC), exhibits high interpatient variability in treatment response and high toxicity burden. Baseline blood biomarker concentrations and tumor size (sum of diameters) at week 8 relative to baseline (RS8) are widely investigated prognostic factors. However, joint analysis of data on demographic/clinical characteristics, blood biomarker levels, and chemotherapy exposure-driven early tumor response for improved prediction of overall survival (OS) is clinically not established.

Development of a quantitative proteomics approach for cyclooxygenases and lipoxygenases in parallel to quantitative oxylipin analysis allowing the comprehensive investigation of the arachidonic acid cascade.

Oxylipins derived from the cyclooxygenase (COX) and lipoxygenase (LOX) pathways of the arachidonic acid (ARA) cascade are essential for the regulation of the inflammatory response and many other physiological functions. Comprehensive analytical methods comprised of oxylipin and protein abundance analysis are required to fully understand mechanisms leading to changes within these pathways. Here, we describe the development of a quantitative multi-omics approach combining liquid chromatography tandem mass spectrometry-based targeted oxylipin metabolomics and proteomics.

GC-MS analysis of oxysterols and their formation in cultivated liver cells (HepG2).

Oxysterols play a key role in many (patho)physiological processes and they are potential biomarkers for oxidative stress in several diseases. Here we developed a rapid gas chromatographic-mass spectrometry-based method for the separation and quantification of 11 biologically relevant oxysterols bearing hydroxy, epoxy, and dihydroxy groups. Efficient chromatographic separation (resolution ≥ 1.

A continued learning approach for model-informed precision dosing: Updating models in clinical practice.

Model-informed precision dosing (MIPD) is a quantitative dosing framework that combines prior knowledge on the drug-disease-patient system with patient data from therapeutic drug/ biomarker monitoring (TDM) to support individualized dosing in ongoing treatment. Structural models and prior parameter distributions used in MIPD approaches typically build on prior clinical trials that involve only a limited number of patients selected according to some exclusion/inclusion criteria. Compared to the prior clinical trial population, the patient population in clinical practice can be expected to also include altered behavior and/or increased interindividual variability, the extent of which, however, is typically unknown.

Physiology-based toxicokinetic modelling of aluminium in rat and man.

A sufficient quantitative understanding of aluminium (Al) toxicokinetics (TK) in man is still lacking, although highly desirable for risk assessment of Al exposure. Baseline exposure and the risk of contamination severely limit the feasibility of TK studies administering the naturally occurring isotope Al, both in animals and man. These limitations are absent in studies with Al as a tracer, but tissue data are limited to animal studies.

Nonparametric goodness-of-fit testing for parametric covariate models in pharmacometric analyses.

The characterization of covariate effects on model parameters is a crucial step during pharmacokinetic/pharmacodynamic analyses. Although covariate selection criteria have been studied extensively, the choice of the functional relationship between covariates and parameters, however, has received much less attention. Often, a simple particular class of covariate-to-parameter relationships (linear, exponential, etc.

Reinforcement learning and Bayesian data assimilation for model-informed precision dosing in oncology.

Model-informed precision dosing (MIPD) using therapeutic drug/biomarker monitoring offers the opportunity to significantly improve the efficacy and safety of drug therapies. Current strategies comprise model-informed dosing tables or are based on maximum a posteriori estimates. These approaches, however, lack a quantification of uncertainty and/or consider only part of the available patient-specific information.

A mechanistic framework for a priori pharmacokinetic predictions of orally inhaled drugs.

The fate of orally inhaled drugs is determined by pulmonary pharmacokinetic processes such as particle deposition, pulmonary drug dissolution, and mucociliary clearance. Even though each single process has been systematically investigated, a quantitative understanding on the interaction of processes remains limited and therefore identifying optimal drug and formulation characteristics for orally inhaled drugs is still challenging. To investigate this complex interplay, the pulmonary processes can be integrated into mathematical models.

Time-to-Event Analysis of Paclitaxel-Associated Peripheral Neuropathy in Advanced Non-Small-Cell Lung Cancer Highlighting Key Influential Treatment/Patient Factors.

Paclitaxel-associated peripheral neuropathy (PN), a major dose-limiting toxicity, significantly impacts patients' quality of life/treatment outcome. Evaluation of risk factors often ignores time of PN onset, precluding the impact of time-dependent factors, e.g.

Simple Targeted Assays for Metabolic Pathways and Signaling: A Powerful Tool for Targeted Proteomics.

We introduce STAMPS, a pathway-centric web service for the development of targeted proteomics assays. STAMPS guides the user by providing several intuitive interfaces for a rapid and simplified method design. Applying our curated framework to signaling and metabolic pathways, we reduced the average assay development time by a factor of ∼150 and revealed that the insulin signaling is actively controlled by protein abundance changes in insulin-sensitive and -resistance states.

Pharmacokinetic/Pharmacodynamic Evaluation of Hydrocortisone Therapy in Pediatric Patients with Congenital Adrenal Hyperplasia.

Objectives: Patients with congenital adrenal hyperplasia (CAH) require lifelong replacement therapy with glucocorticoids. Optimizing hydrocortisone therapy is challenging, since there are no established cortisol concentration targets other than the cortisol circadian rhythm profile. 17-hydroxyprogesterone (17-OHP) concentrations are elevated in these patients and commonly used to monitor therapy.

Effects of chronic low-dose aspirin treatment on tumor prevention in three mouse models of intestinal tumorigenesis.

Although early detection and treatment of colorectal cancer (CRC) have improved, it remains a significant health-care problem with high morbidity and mortality. Data indicate that long-term intake of low-dose aspirin reduces the risk of CRC; however, the mechanisms underlying this chemopreventive effect are still unclear. Different mouse models for inflammation-associated, sporadic, and hereditary CRC were applied to assess the efficacy and mechanism of low-dose aspirin on tumor prevention.

Genetic and chemical diversity of the toxic herb Jacobaea vulgaris Gaertn. (syn. Senecio jacobaea L.) in Northern Germany.

Tansy ragwort, Jacobaea vulgaris Gaertn. (syn. Senecio jacobaea L.

Bayesian Data Assimilation to Support Informed Decision Making in Individualized Chemotherapy.

An essential component of therapeutic drug/biomarker monitoring (TDM) is to combine patient data with prior knowledge for model-based predictions of therapy outcomes. Current Bayesian forecasting tools typically rely only on the most probable model parameters (maximum a posteriori (MAP) estimate). This MAP-based approach, however, does neither necessarily predict the most probable outcome nor does it quantify the risks of treatment inefficacy or toxicity.

The circadian rhythm of corticosteroid-binding globulin has little impact on cortisol exposure after hydrocortisone dosing.

Context: Optimization of hydrocortisone replacement therapy is important to prevent under- and over dosing. Hydrocortisone pharmacokinetics is complex as circulating cortisol is protein bound mainly to corticosteroid-binding globulin (CBG) that has a circadian rhythm.

Objective: A detailed analysis of the CBG circadian rhythm and its impact on cortisol exposure after hydrocortisone administration.

Stochastic and Deterministic Models for the Metastatic Emission Process: Formalisms and Crosslinks.

Although the detection of metastases radically changes prognosis of and treatment decisions for a cancer patient, clinically undetectable micrometastases hamper a consistent classification into localized or metastatic disease. This chapter discusses mathematical modeling efforts that could help to estimate the metastatic risk in such a situation. We focus on two approaches: (1) a stochastic framework describing metastatic emission events at random times, formalized via Poisson processes, and (2) a deterministic framework describing the micrometastatic state through a size-structured density function in a partial differential equation model.

Role of renal function in risk assessment of target non-attainment after standard dosing of meropenem in critically ill patients: a prospective observational study.

Background: Severe bacterial infections remain a major challenge in intensive care units because of their high prevalence and mortality. Adequate antibiotic exposure has been associated with clinical success in critically ill patients. The objective of this study was to investigate the target attainment of standard meropenem dosing in a heterogeneous critically ill population, to quantify the impact of the full renal function spectrum on meropenem exposure and target attainment, and ultimately to translate the findings into a tool for practical application.