Population Pharmacokinetics and Pharmacodynamics of Sotalol Following Expedited Intravenous Loading in Patients With Atrial Arrhythmias.

Sotalol, a class III antiarrhythmic agent, is used to maintain sinus rhythm in patients with atrial fibrillation or atrial flutter (AFIB/AFL). Despite its efficacy, sotalol's use is limited by its potential to cause life-threatening ventricular arrhythmias due to QT interval prolongation. Traditionally, sotalol administration required hospitalization to monitor these risks.

Interaction of milrinone with extracorporeal life support.

Background: Milrinone is commonly prescribed to critically ill patients who need extracorporeal life support such as extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). Currently, the effect of ECMO and CRRT on the disposition of milrinone is unknown.

Methods: Ex vivo ECMO and CRRT circuits were primed with human blood and then dosed with milrinone to study drug extraction by the circuits.

Interaction of azithromycin and methylprednisolone with ex-vivo extracorporeal membrane oxygenation circuits (ECMO).

Background: Azithromycin and methylprednisolone are two medications that are commonly used in patients who require ECMO support. Unfortunately, ECMO support can decrease drug concentrations through adsorption to circuit components. Such interactions have not been well described for either azithromycin or methylprednisolone.

Umbilical cord blood gentamicin concentrations following maternally-administered intrapartum exposures.

We identified cord blood gentamicin concentrations that were higher than anticipated, and above clinical targets for immediate gentamicin re-dosing after birth. Incorporation of gentamicin levels at birth may aid in optimizing postnatal gentamicin dosing among infants exposed to intrapartum gentamicin.

Pharmacokinetic Research in Pediatric Extracorporeal Therapies: Current State and Future Directions.

Extracorporeal life support (ECLS), including extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT), are life-saving therapies for critically ill children. Despite this, these modalities carry frustratingly high mortality rates. One driver of mortality may be altered drug disposition due to a combination of underlying illness, patient-circuit interactions, and drug-circuit interactions.

Hepatic retinol dehydrogenase 11 dampens stress associated with the maintenance of cellular cholesterol levels.

Objective: Dysregulation of hepatic cholesterol metabolism can contribute to elevated circulating cholesterol levels, which is a significant risk factor for cardiovascular disease. Cholesterol homeostasis in mammalian cells is tightly regulated by an integrated network of transcriptional and post-transcriptional signalling pathways. Whilst prior studies have identified many of the central regulators of these pathways, the extended supporting networks remain to be fully elucidated.

Decorin, an exercise-induced secretory protein, is associated with improved prognosis in breast cancer patients but does not mediate anti-tumorigenic tissue crosstalk in mice.

Background: Regular exercise can reduce incidence and progression of breast cancer, but the mechanisms for such effects are not fully understood.

Methods: We used a variety of rodent and human experimental model systems to determine whether exercise training can reduce tumor burden in breast cancer and to identify mechanism associated with any exercise training effects on tumor burden.

Results: We show that voluntary wheel running slows tumor development in the mammary specific polyomavirus middle T antigen overexpression (MMTV-PyMT) mouse model of breast cancer but only when mice are not housed alone.

Extraction of ketamine and dexmedetomidine by extracorporeal life support circuits★.

Background: Patients supported with extracorporeal life support (ECLS) circuits such as ECMO and CRRT often require high doses of sedatives and analgesics, including ketamine and dexmedetomidine. Concentrations of many medications are affected by ECLS circuits through adsorption to the circuit components, dialysis, as well as the large volume of blood used to prime the circuits. However, the impact of ECLS circuits on ketamine and dexmedetomidine pharmacokinetics has not been well described.

A physiologically-based pharmacokinetic modeling approach for dosing amiodarone in children on ECMO.

Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary bypass device commonly used to treat cardiac arrest in children. The American Heart Association guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care recommend using amiodarone as a first-line agent to treat ventricular arrhythmias in children with cardiac arrest. However, there are no dosing recommendations for amiodarone to treat ventricular arrhythmias in pediatric patients on ECMO.

Priorities for Clinical Research in Pediatric Extracorporeal Membrane Oxygenation Anticoagulation From the Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

Objectives: To identify and prioritize research questions for anticoagulation and hemostasis management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus.

Data Sources: Systematic review was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial consensus conferences of international, interprofessional experts in the management of ECMO for critically ill neonates and children.

Study Selection: The management of ECMO anticoagulation for critically ill neonates and children.

Antifibrinolytic and Adjunct Hemostatic Agents: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

Objectives: To derive systematic-review informed, modified Delphi consensus regarding antifibrinolytic and adjunct hemostatic agents in neonates and children supported with extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE consensus conference.

Data Sources: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021.

Study Selection: Use of antifibrinolytics (epsilon-aminocaproic acid [EACA] or tranexamic acid), recombinant factor VII activated (rFVIIa), or topical hemostatic agents (THAs).

Recommendations on Monitoring and Replacement of Antithrombin, Fibrinogen, and Von Willebrand Factor in Pediatric Patients on Extracorporeal Membrane Oxygenation: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

Objectives: To derive systematic review informed, modified Delphi consensus regarding monitoring and replacement of specific coagulation factors during pediatric extracorporeal membrane oxygenation (ECMO) support for the Pediatric ECMO Anticoagulation CollaborativE.

Data Sources: A structured literature search was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2020, with an update in May 2021.

Study Selection: Included studies assessed monitoring and replacement of antithrombin, fibrinogen, and von Willebrand factor in pediatric ECMO support.

Executive Summary: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE (PEACE) Consensus Conference.

Objectives: To present recommendations and consensus statements with supporting literature for the clinical management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus conference.

Data Sources: Systematic review was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial meetings of international, interprofessional experts in the management ECMO for critically ill children.

Study Selection: The management of ECMO anticoagulation for critically ill children.

Reducing hydrophobic drug adsorption in an in-vitro extracorporeal membrane oxygenation model.

Extracorporeal membrane oxygenation (ECMO) is a life-saving cardiopulmonary bypass technology for critically ill patients with heart and lung failure. Patients treated with ECMO receive a range of drugs that are used to treat underlying diseases and critical illnesses. However, the dosing guidelines for these drugs used in ECMO patients are unclear.

Maximum likelihood estimation of renal transporter ontogeny profiles for pediatric PBPK modeling.

Optimal treatment of infants with many renally cleared drugs must account for maturational differences in renal transporter (RT) activity. Pediatric physiologically-based pharmacokinetic (PBPK) models may incorporate RT activity, but this requires ontogeny profiles for RT activity in children, especially neonates, to predict drug disposition. Therefore, RT expression measurements from human kidney postmortem cortical tissue samples were normalized to represent a fraction of mature RT activity.

Anakinra Removal by Continuous Renal Replacement Therapy: An Ex Vivo Analysis.

Objectives: Patients with sepsis are at significant risk for multiple organ dysfunction, including the lungs and kidneys. To manage the morbidity associated with kidney impairment, continuous renal replacement therapy (CRRT) may be required. The extent of anakinra pharmacokinetics in CRRT remains unknown.

Direct and continuous dosing of propofol can saturate Ex vivo ECMO circuit to improve propofol recovery.

Background: Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary bypass device that provides life-saving complete respiratory and cardiac support in patients with cardiorespiratory failure. The majority of drugs prescribed to patients on ECMO lack a dosing strategy optimized for ECMO patients. Several studies demonstrated that dosing is different in this population because the ECMO circuit components can adsorb drugs and affect drug exposure substantially.

Meropenem extraction by ex vivo extracorporeal life support circuits.

Background: Meropenem is a broad-spectrum carbapenem-type antibiotic commonly used to treat critically ill patients infected with extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae. As many of these patients require extracorporeal membrane oxygenation (ECMO) and/or continuous renal replacement therapy (CRRT), it is important to understand how these extracorporeal life support circuits impact meropenem pharmacokinetics. Based on the physicochemical properties of meropenem, it is expected that ECMO circuits will minimally extract meropenem, while CRRT circuits will rapidly clear meropenem.

Medication patterns and dosing guidance in pediatric patients supported with intermittent hemodialysis or continuous kidney replacement therapy.

Background: Hemodialysis is a life-saving technology used during periods of acute or chronic kidney failure to remove toxins, and maintain fluid, electrolyte and metabolic balance. While this technology plays an important role for pediatric patients with kidney dysfunction, it can alter the pharmacokinetic behavior of medications placing patients at risk for suboptimal dosing and drug toxicity. The ability to directly translate pharmacokinetic alterations into dosing recommendations has thus far been limited and dosing guidance specific to pediatric hemodialysis patients is rare.

Streamlining the Detection of Human Thyroid Receptor Ligand Interactions with XL1-Blue Cell-Free Protein Synthesis and Beta-Galactosidase Fusion Protein Biosensors.

Thyroid receptor signaling controls major physiological processes and disrupted signaling can cause severe disorders that negatively impact human life. Consequently, methods to detect thyroid receptor ligands are of great toxicologic and pharmacologic importance. Previously, we reported thyroid receptor ligand detection with cell-free protein synthesis of a chimeric fusion protein composed of the human thyroid receptor beta (hTRβ) receptor activator and a β-lactamase reporter.