A Guinea Pig Model of Pediatric Metabolic Dysfunction-Associated Steatohepatitis: Poor Vitamin C Status May Advance Disease.

Children and teenagers display a distinct metabolic dysfunction-associated steatohepatitis (MASH) phenotype, yet studies of childhood MASH are scarce and validated animal models lacking, limiting the development of treatments. Poor vitamin C (VitC) status may affect MASH progression and often co-occurs with high-fat diets and related metabolic imbalances. As a regulator of DNA methylation, poor VitC status may further contribute to MASH by regulating gene expression This study investigated guinea pigs-a species that, like humans, depends on vitC in the diet-as a model of pediatric MASH, examining the effects of poor VitC status on MASH hallmarks and global DNA methylation levels.

Fixed dosing of alpelisib for children with vascular anomalies: Can we do better?

Severe forms of vascular malformations (VM) can highly impact patients' quality of life and lead to life-threatening organ dysfunction. Numerous VM are caused by somatic activating mutations in the PI3K/AKT/mTOR signalling pathway. Alpelisib, a PIK3CA inhibitor was recently FDA-approved for paediatric PIK3CA-related overgrowth syndrome (PROS).

Population Pharmacokinetic Modelling of Apixaban in End-Stage Kidney Disease Patients with Atrial Fibrillation Receiving Haemodialysis.

Background And Objective: Apixaban is increasingly being used for stroke prevention in patients with end-stage kidney disease with atrial fibrillation undergoing haemodialysis, but no pharmacostatistical model is available for dosage adjustment. This study aimed to develop a population pharmacokinetic model of apixaban in these patients to characterise its dialytic clearance and determine optimal dosing regimens and discontinuation timing before surgery.

Methods: Patients received 2.

Antibody-Based Antigen Delivery to Dendritic Cells as a Vaccination Strategy Against Ebola Virus Disease.

Dendritic cells connect innate and adaptive immune responses. This is a particularly important immune checkpoint in the case of emerging infections against which most of the population does not have preexisting antibody immunity. In this study, we sought to test whether antibody-based delivery of Ebola virus (EBOV) antigens to dendritic cells could be used as a vaccination strategy against Ebola virus disease.

Emoquine-1: A Hybrid Molecule Efficient against Multidrug-Resistant Parasites, Including the Artemisinin-Resistant Quiescent Stage, and Also Active In Vivo.

To challenge the multidrug resistance of malaria parasites, new hybrid compounds were synthesized and evaluated against laboratory strains and multidrug-resistant clinical isolates. Among these hybrids, emoquine-1 was the most active on proliferative , with IC values in the range of 20-55 nM and a high selectivity index with respect to mammalian cells. This drug retained its activity on several multiresistant field isolates from Cambodia and Guiana, exhibited no cross-resistance to artemisinin, and is also very active against the quiescent stage of the artemisinin-resistant parasites, three features that constitute the gold standard for new antimalarial drugs.

Transcriptomic Signatures of Cold Acclimated Adipocytes Reveal CXCL12 as a Brown Autocrine and Paracrine Chemokine.

Besides its thermogenic capacity, brown adipose tissue (BAT) performs important secretory functions that regulate metabolism. However, the BAT microenvironment and factors involved in BAT homeostasis and adaptation to cold remain poorly characterized. We therefore aimed to study brown adipocyte-derived secreted factors that may be involved in adipocyte function and/or may orchestrate intercellular communications.

Lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension.

Vascular inflammation regulates endothelial pathophenotypes, particularly in pulmonary arterial hypertension (PAH). Dysregulated lysosomal activity and cholesterol metabolism activate pathogenic inflammation, but their relevance to PAH is unclear. Nuclear receptor coactivator 7 () deficiency in endothelium produced an oxysterol and bile acid signature through lysosomal dysregulation, promoting endothelial pathophenotypes.

Uncovering a new family of conserved virulence factors that promote the production of host-damaging outer membrane vesicles in gram-negative bacteria.

CprA is a short-chain dehydrogenase/reductase (SDR) that contributes to resistance against colistin and antimicrobial peptides. The cprA gene is conserved across Pseudomonas aeruginosa clades and its expression is directly regulated by the two-component system PmrAB. We have shown that cprA expression leads to the production of outer membrane vesicles (OMVs) that block autophagic flux and have a greater capacity to activate the non-canonical inflammasome pathway.

Variable temocillin protein binding and pharmacokinetics in different clinical conditions: Implications for target attainment.

Aims: The beta-lactam antibiotic temocillin is increasingly used to treat extended-spectrum beta-lactamase (ESBL-producing) strains; however, its protein binding is complex. This study aims to predict unbound temocillin concentrations in various participant groups to determine its impact on the probability of target attainment (PTA) and to improve dosing recommendations.

Methods: The plasma pharmacokinetics were analysed using non-linear mixed-effects modelling.

Ibrutinib pharmacokinetics in B-lymphoproliferative disorders discloses exposure-related incidence of hypertension.

Objective: Ibrutinib has been the first Bruton tyrosine kinase inhibitor (BTKi) authorized for the treatment of B-cell lymphoproliferative disorders (B-LPDs). Numerous publications have confirmed the efficacy of this orally administrated drug in chemo-free regimens for B-LPDs. They also reported several adverse events (AE) associated with ibrutinib treatment.

Dosing and route of administration of clindamycin given in combination with rifampicin.

Objectives: The aim of the present study was to develop a PK interaction model of intravenous (IV) and oral clindamycin when combined with rifampicin, and to determine whether appropriate clindamycin concentrations could be achieved for different doses and administration routes (oral, intermittent and continuous infusion) of clindamycin.

Methods: Five hundred and eighteen plasma samples were prospectively obtained from 124 patients treated for bone and joint infections. Population PK analysis was performed using Monolix software.

Incomplete reporting of adverse events in duloxetine trials: a meta-research survey of randomized controlled trials versus placebo.

Objective: Relying on published data alone might be insufficient for meta-analyses to be reliable and trustworthy since selective outcome reporting is common, especially for adverse events. We investigated the existence of selective reporting and its potential for bias in a case study exploring adverse events of duloxetine in adults.

Study Design And Setting: We systematically searched all previous meta-analyses/pooled analyses on duloxetine published on PubMed for 7 indications approved by the American and European health authorities.

Unraveling Chemical Profile, Antioxidant, Antialzheimer and Antimicrobial Potentials of Three Propolis from Northeastern Regions of Algeria: In Vitro and in Silico Evaluation.

This study investigates the pharmaceutical potential both in vitro and in silico of ethanolic propolis extract from three Algerian regions namely TAH (Tahir-Jijel), ATH (Oued Athmania-Mila) and OZ (Oued Zhor-skikda). Twenty-three compounds were identified via HPLC‒DAD, with key constituents including caffeic acid, cynarin, chrysin, naringin, and hesperetin. Moreover, Antioxidant and anti-Alzheimer activities were assessed by multiple assays.

[Teratovigilance. Antiepileptics during pregnancy and paternal use].

The 2023-2024 updates on teratovigilance, with a focus on antiseizure medications, highlight several key points. American medical societies have revised their recommendations: maintaining effective seizure control is essential for both maternal and fetal health; lamotrigine, levetiracetam, and oxcarbazepine are preferred first-line treatments, whereas valproic acid and topiramate should be avoided if possible. In March 2024, an update on topiramate indicated an increased risk of neurodevelopmental disorders with prenatal exposure.

Birth defects reporting and the use of dydrogesterone: a disproportionality analysis from the World Health Organization pharmacovigilance database (VigiBase).

Study Question: Is there an association between dydrogesterone exposure during early pregnancy and the reporting of birth defects?

Summary Answer: This observational analysis based on global safety data showed an increased reporting of birth defects, mainly hypospadias and congenital heart defects (CHD), in pregnancies exposed to dydrogesterone, especially when comparing to progesterone.

What Is Known Already: Intravaginal administration of progesterone is the standard of care to overcome luteal phase progesterone deficiency induced by ovarian stimulation in ART. In recent years, randomized controlled clinical trials demonstrated that oral dydrogesterone was non-inferior for pregnancy rate at 12 weeks of gestation and could be an alternative to micronized vaginal progesterone.

A phase II double-blind multicentre, placebo-controlled trial to assess the efficacy and safety of alpelisib (BYL719) in paediatric and adult patients with Megalencephaly-CApillary malformation Polymicrogyria syndrome (MCAP): the SESAM study protocol.

Introduction: The megalencephaly capillary malformation polymicrogyria (MCAP syndrome) results from mosaic gain-of-function variants. The main clinical features are macrocephaly, somatic overgrowth, neurodevelopmental delay and brain anomalies. Alpelisib (Vijoice) is a recently FDA-approved PI3Kα-specific inhibitor for patients with PIK3CA-related overgrowth spectrum (PROS).

A lipidated peptide derived from the C-terminal tail of the vasopressin 2 receptor shows promise as a new β-arrestin inhibitor.

β-arrestins play pivotal roles in seven transmembrane receptor (7TMR) signalling and trafficking. To study their functional role in regulating specific receptor systems, current research relies mainly on genetic tools, as few pharmacological options are available. To address this issue, we designed and synthesised a novel lipidated phosphomimetic peptide inhibitor targeting β-arrestins, called ARIP, which was developed based on the C-terminal tail (A343-S371) of the vasopressin V2 receptor.

Cathinone metabolism and biliary excretion in an ex-vivo pig liver model: Example of 4-Cl-PVP and eutylone.

Objective: Recently, the pig liver model perfused ex vivo using a normothermic machine perfusion (NMP) has been proposed as a suitable model to study xenobiotic metabolism and biliary excretion. The aim of our study is to describe the metabolism of NPS such as cathinones (with a focus on 4-Cl-PVP and eutylone) in blood and bile, using a normothermic perfused pig liver model.

Methods: Livers (n = 4) from male large white pigs, 3-4 months of age and weighing approximately 75-80 kg, were harvested and reperfused onto an NMP (LiverAssist®, XVIVO) using autologous whole blood at 38 °C.

How to facilitate the wider use of pharmacogenetic tests?

4P medicine (personalized, preventive, predictive, and participatory) is experiencing a remarkable rise, and pharmacogenetics is an essential part of it. However, several obstacles are hindering its deployment. This round table brought together a group of experts to take stock of the situation, reflecting on ways to facilitate the prescription of these tests and the dissemination of the results on a national scale.

Investigating 3-CMC metabolism: Insights from liver microsomes and postmortem biological matrix.

3-Chloromethcathinone (3-CMC) is a synthetic cathinone that has been identified as a new psychoactive substance (NPS) by the European Monitoring Centre for Drugs and Drug Addiction. Despite its increasing prevalence in the recreational drug market since 2014, scientific literature on 3-CMC remains limited. This study employed a multi-step approach to investigate 3-CMC metabolism.

Physiologically Based Pharmacokinetic Model of Cefotaxime in Patients with Impaired Renal Function.

Background: Cefotaxime is a widely prescribed cephalosporin antibiotic used to treat various infections. It is mainly eliminated unchanged by the kidney through tubular secretion and glomerular filtration. Therefore, a reduction of kidney function may increase exposure to the drug and induce toxic side effects.