J Pharmacokinet Pharmacodyn
December 2024
Recently, an optimal dosing algorithm (OptiDose) was developed to compute the optimal drug doses for any pharmacometrics model for a given dosing scenario. In the present work, we enhance the OptiDose concept to compute optimal drug dosing with respect to both efficacy and safety targets. Usually, these are not of equal importance, but one is a top priority, that needs to be satisfied, whereas the other is a secondary target and should be achieved as good as possible without failing the top priority target.
View Article and Find Full Text PDFPurpose: This feasibility study aimed to investigate the use of exhaled breath analysis to capture and quantify relative changes of metabolites during resolution of acute diabetic ketoacidosis under insulin and rehydration therapy.
Methods: Breath analysis was conducted on 30 patients of which 5 with DKA. They inflated Nalophan bags, and their metabolic content was subsequently interrogated by secondary electrospray ionization high-resolution mass spectrometry (SESI-HRMS).
Accurate treatment adjustment to physical activity (PA) remains a challenging problem in type 1 diabetes (T1D) management. Exercise-driven effects on glucose metabolism depend strongly on duration and intensity of the activity, and are highly variable between patients. In-silico evaluation can support the development of improved treatment strategies, and can facilitate personalized treatment optimization.
View Article and Find Full Text PDFJ Pharmacokinet Pharmacodyn
June 2023
Determining a drug dosing recommendation with a PKPD model can be a laborious and complex task. Recently, an optimal dosing algorithm (OptiDose) was developed to compute the optimal doses for any pharmacometrics/PKPD model for a given dosing scenario. In the present work, we reformulate the underlying optimal control problem and elaborate how to solve it with standard commands in the software NONMEM.
View Article and Find Full Text PDFDiabetic ketoacidosis (DKA), a frequent complication of type 1 diabetes (T1D), is characterized by hyperosmolar hypovolemia. The response of water-regulating hormones arginine vasopressin (AVP; antidiuretic hormone) and aldosterone to DKA treatment in children is not well understood, although they may have potential as future diagnostic, prognostic, and/or treatment monitoring markers in diabetic patients. We aimed to characterize the dynamics of the response in copeptin (marker for AVP) and aldosterone secretion to rehydration treatment in pediatric patients with DKA.
View Article and Find Full Text PDFIntroduction: Brain tumors are the second most frequent type of all pediatric malignancies. Depending on their localization, patients with brain tumors may present neurological or ophthalmological symptoms, but also weight anomalies and endocrine disorders ranging from growth hormone deficiency, anomalies of puberty, diabetes insipidus to panhypopituitarism. Immediately at diagnosis, all patients with brain tumors require a complete assessment of the hypothalamic-pituitary function in order to address eventual endocrine disorders.
View Article and Find Full Text PDFInherited metabolic disorders (IMDs) comprise a heterogeneous class of genetic disorders characterized by impaired biochemical functions in metabolism. However, incidences and outcomes of patients hospitalized with IMDs are largely unknown. We conducted a population-based cohort study using nationwide in-hospital claims data in Switzerland from 2012 to 2020.
View Article and Find Full Text PDFObjective: Differentiation between central diabetes insipidus (cDI) and primary polydipsia (PP) remains challenging in clinical practice. Although the hypertonic saline infusion test led to high diagnostic accuracy, it is a laborious test requiring close monitoring of plasma sodium levels. As such, we leverage machine learning (ML) to facilitate differential diagnosis of cDI.
View Article and Find Full Text PDFFront Endocrinol (Lausanne)
September 2022
Objective: Diabetic ketoacidosis (DKA) is a life-threatening complication of both type 1 and type 2 diabetes. We aimed to assess population-based rates, trends and outcomes of patients with DKA.
Design And Methods: This is a nationwide cohort study using hospital discharge claims data from 2010 to 2018 in Switzerland.
Introduction: It is crucial to understand psychosocial outcomes in children and adolescents with type 1 diabetes (T1D) and their families to provide optimal family-centered care. Hence, the aim of this study was to explore psychosocial outcomes in young people with T1D and their parents using currently available glucose monitoring devices in a real-life clinic setting.
Methods: Children and adolescents aged 2-18 years with T1D for more than 6 months and their parents were recruited into a cross-sectional study to complete the Hypoglycemia Fear Survey (HFS) and the Pediatric Quality of Life Inventory (PedsQL) Generic Score Scales, Diabetes Module and Family Impact Module.
Background: The differential diagnosis of diabetes insipidus is challenging. The most reliable approaches are copeptin measurements after hypertonic saline infusion or arginine, which is a known growth hormone secretagogue but has recently also been shown to stimulate the neurohypophysis. Similar to arginine, glucagon stimulates growth hormone release, but its effect on the neurohypophysis is poorly studied.
View Article and Find Full Text PDFBackground: Kinetics of copeptin and mid regional proadrenomedullin (MR-proADM) during febrile pediatric lower respiratory tract infections (LRTI) are unknown. We aimed to analyze kinetic profiles of copeptin and MR-proADM and the impact of clinical and laboratory factors on those biomarkers.
Methods: This is a retrospective post-hoc analysis of a randomized controlled trial, evaluating procalcitonin guidance for antibiotic treatment of LRTI (ProPAED-study).
Providing the optimal dosing strategy of a drug for an individual patient is an important task in pharmaceutical sciences and daily clinical application. We developed and validated an optimal dosing algorithm (OptiDose) that computes the optimal individualized dosing regimen for pharmacokinetic-pharmacodynamic models in substantially different scenarios with various routes of administration by solving an optimal control problem. The aim is to compute a control that brings the underlying system as closely as possible to a desired reference function by minimizing a cost functional.
View Article and Find Full Text PDFBackground: Hypoglycemia is the most common complication in insulin treated diabetes. Though mostly mild, it can be fatal in rare cases: It is hypothesized that hypoglycemia related QTc prolongation contributes to cardiac arrhythmia.
Objective: To evaluate influence of nocturnal hypoglycemia on QTc and heart rate variability (HRV) in children with T1D.
Front Endocrinol (Lausanne)
February 2022
Regular exercise is beneficial and recommended for people with type 1 diabetes, but increased glucose demand and changes in insulin sensitivity require treatment adjustments to prevent exercise-induced hypoglycemia. Several different adjustment strategies based on insulin bolus reductions and additional carbohydrate intake have been proposed, but large inter- and intraindividual variability and studies using different exercise duration, intensity, and timing impede a direct comparison of their effects. In this study, we use a mathematical model of the glucoregulatory system and implement published guidelines and strategies to provide a direct comparison on a single 'typical' person on a standard day with three meals.
View Article and Find Full Text PDFModeling of retrospectively collected multi-center data of a rare disease in pediatrics is challenging because laboratory data can stem from several decades measured with different assays. Here we present a retrospective pharmacometrics (PMX) based data analysis of the rare disease congenital hypothyroidism (CH) in newborns and infants. Our overall aim is to develop a model that can be applied to optimize dosing in this pediatric patient population since suboptimal treatment of CH during the first 2 years of life is associated with a reduced intelligence quotient between 10 and 14 years.
View Article and Find Full Text PDFObjective: To elucidate the molecular cause in a well-characterized cohort of patients with Congenital Hypothyroidism (CH) and Dyshormonogenesis (DH) by using targeted next-generation sequencing (TNGS).
Study Design: We studied 19 well-characterized patients diagnosed with CH and DH by targeted NGS including genes involved in thyroid hormone production. The pathogenicity of novel mutations was assessed based on prediction tool results, functional studies when possible, variant location in important protein domains, and a review of the recent literature.
Arts syndrome or phosphoribosyl-pyrophosphate-synthetase-1 (PRPS1) deficiency is caused by loss-of-function mutations in the gene (Xq22.3). PRPS1 is an initial and essential step for the synthesis of the nucleotides of purines, pyrimidines, and nicotinamide.
View Article and Find Full Text PDFAn ENDO-European Reference Network (ERN) initiative was launched that was endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology with 22 participants from the ENDO-ERN and the two societies. The aim was to update the practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). A systematic literature search was conducted to identify key articles on neonatal screening, diagnosis, and management of primary and central CH.
View Article and Find Full Text PDFContext: Copeptin is a surrogate marker for arginine vasopressin (AVP) release in response to hyperosmolal stimuli such as diabetic ketoacidosis (DKA).
Objective: The objective of this work is to characterize kinetics of copeptin and osmolality, and their dynamic relationship during rehydration and insulin therapy in children with type 1 diabetes (T1D) and DKA.
Design And Setting: A prospective, observational, multicenter study was conducted.
Terminal thyroid gland differentiation - the last developmental step needed to enable thyroid hormone (T4) synthesis - involves profound structural and biochemical changes in the thyroid follicular cells (TFCs). We aimed to develop an ex vivo thyroid model of embryonic mouse thyroid that would replicate the in vivo TFC differentiation program. E13.
View Article and Find Full Text PDFJ Pediatr Endocrinol Metab
November 2019
Thyroid dyshormonogenesis (TDH) is characterized by the defective synthesis of thyroid hormones. We present a patient with congenital hypothyroidism (CH) who presented in newborn screening with elevated serum thyroid-stimulating hormone (TSH), decreased free thyroxine (fT4) and increased thyroglobulin (Tg) concentrations. Ultrasound scan revealed a properly structured thyroid gland.
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