Evaluation of the Effect of Loperamide on the Cardiac Repolarization Interval Using Exposure-Response Analysis.

This analysis assessed the relationship between the plasma concentrations of loperamide and its N-desmethyl loperamide meta- bolite (M1) and the potential QT interval prolongation at therapeutic and supratherapeutic doses. The exposure-response analysis was performed using the data from healthy adults participating in a randomized, double-blind, single-dose, four-way (placebo; loperamide 8 mg [therapeutic]; loperamide 48 mg [supratherapeutic]; moxifloxacin 400 mg [positive control]) crossover study. The electrocardiographic measurements extracted from 12-lead digital Holter recordings were time-matched to pharmacokinetic sampling of loperamide/M1.

Drug-Drug Interactions Between HIV Antivirals and Concomitant Drugs in HIV Patients: What We Know and What We Need to Know.

Highly active antiretroviral therapy has led to a significant increase in the life expectancy of people living with HIV. The trade-off is that HIV-infected patients often suffer from comorbidities that require additional treatment, increasing the risk of Drug-Drug Interactions (DDIs), the clinical relevance of which has often not been determined during registration trials of the drugs involved. Therefore, it is important to identify potential clinically relevant DDIs in order to establish the most appropriate therapeutic approaches.

Usefulness of a TDM-Guided Approach for Optimizing Teicoplanin Exposure in the Treatment of Secondary Bloodstream Infections Caused by Glycopeptide-Susceptible .

To assess the clinical usefulness of teicoplanin optimized by means of a therapeutic drug monitoring (TDM)-guided approach for treating secondary bloodstream infections (BSIs) caused by . Hospitalized patients having in the period 1 March 2021-31 October 2024 a documented BSI caused by glycopeptide-susceptible being treated with teicoplanin as definitive targeted therapy optimized by means of a real-time TDM-guided expert clinical pharmacological advice (ECPA) program were retrospectively included. Teicoplanin trough concentrations (C) ranging from 20 to 30 mg/L were defined as the desired target of efficacy based on international guidelines.

Impact of attaining an aggressive PK/PD target with continuous infusion beta-lactams on the clinical efficacy of targeted therapy of early post-transplant Gram-negative infections in critically ill OLT recipients. An interim analysis of a 3-year prospective, observational, study.

Background: To assess the impact of attaining aggressive beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) targets on clinical efficacy in critical orthotopic liver transplant (OLT) recipients with documented early Gram-negative infections.

Methods: OLT recipients admitted to the post-transplant ICU between June 2021 and May 2024 having documented Gram-negative infections treated with targeted therapy continuous infusion (CI) beta-lactams, and undergoing therapeutic drug monitoring (TDM)-guided beta-lactam dosing adjustment in the first 72 hours were prospectively enrolled. Free steady-state concentrations (fCss) of beta-lactams (BL) and/or of beta-lactamase inhibitors (BLI) were calculated, and aggressive PK/PD target attainment was measured.

Characterisation of periorbital mechanical allodynia in the reserpine-induced fibromyalgia model in mice: The role of the Schwann cell TRPA1/NOX1 signalling pathway.

Fibromyalgia (FM) is a complex and multifaceted condition characterized by a range of clinical symptoms, including widespread pain and a strong association with migraine headaches. Recent findings have underscored the role of oxidative stress and transient receptor potential ankyrin 1 (TRPA1) channel in migraine and FM. However, the precise mechanisms underlying the comorbidity between migraine and FM are unclear.

The Hormetic Potential of GDF15 in Skeletal Muscle Health and Regeneration: A Comprehensive Systematic Review.

Background: Growth Differentiation Factor 15 (GDF15) has been described as influencing skeletal physiology. Nevertheless, no systematic appraisal of the effect of GDF15 on skeletal muscle tissues has been developed to the present day.

Objective: The aim of the present work was to review the evidence on the topic.

NLRP3 promoter methylation as a predictive biomarker for glucocorticoid response in patients with inflammatory bowel disease.

Glucocorticoids are used for inflammatory bowel disease (IBD) therapy; however nearly 50 % of IBD patients exhibit resistance or dependence. This study evaluates the relationship between methylation level at two CpG sites (cg21991396 and cg00448525) within NLRP3 promoter and glucocorticoid response of 94 IBD pediatrics (39 with Crohn's disease (40.4 %)) and 47 IBD adults (26 with Crohn's disease (55.

Pharmacological differences and switching among anti-CGRP monoclonal antibodies: A narrative review.

Antibodies targeting either the calcitonin gene-related peptide (CGRP), such as galcanezumab, fremanezumab, and eptinezumab, or the receptor (erenumab) have been approved for the prevention of episodic and chronic migraine. Although widely used and generally effective, a proportion of patients discontinue treatment due to lack of efficacy. In both randomized controlled trials and observational studies, all anti-CGRP monoclonal antibodies (mAbs) have consistently demonstrated comparable efficacy and tolerability, suggesting a pharmacological class effect.

Pharmacokinetic/pharmacodynamic issues for optimizing treatment with beta-lactams of Gram-negative infections in critically ill orthotopic liver transplant recipients: a comprehensive review.

Orthotopic liver transplant (OLT) represents the standard of care for managing patients affected by end-stage and life-threatening liver diseases. Although a significant improvement in surgical techniques, immunosuppressant regimens, and prompt identification of early post-transplant complications resulted in better clinical outcome and survival in OLT recipients, the occurrence of early bacterial infections still represents a remarkable cause of morbidity and mortality. In this scenario, beta-lactams are the most frequent antimicrobials used in critical OLT recipients.

Abnormal p53 High-Grade Endometrioid Endometrial Cancer: A Systematic Review and Meta-Analysis.

Objective: Our primary objective was to evaluate the oncologic outcomes of patients with abnormal p53 FIGO grade 3 (high-grade) endometrioid endometrial cancer. As secondary objectives, we determined the global prevalence of abnormal p53 in grade 3 endometrioid endometrial carcinomas and the geographical variations.

Methods: The following electronic databases were searched: PubMed/Medline, EMBASE, Cochrane Library, Scopus, and Web of Science.

6-Nitrodopamine is an endogenous mediator of rat seminal vesicles contractility.

Background: 6-Nitrodopamine (6-ND) released from rat vas deferens acts an endogenous modulator of vas deferens contractility.

Objectives: To investigate whether rat isolated seminal vesicles (RISV) releases 6-ND, the mechanisms involved in the release, and the modulatory role of 6-ND on tissue contractility.

Methods: Rat seminal vesicles were removed and placed in Krebs-Henseleit's solution at 37°C for 30 min, and an aliquot was used to analyze the concentrations of 6-ND, dopamine, noradrenaline, and adrenaline by liquid chromatography with tandem mass spectrometry (LC-MS/MS).

Pharmacokinetic Boosting of Calcineurin Inhibitors in Transplantation: Pros, Cons, and Perspectives.

The concept of pharmacokinetic (PK) boosting of calcineurin inhibitors (CNI) emerged after the FDA approval of cyclosporine-A. Several studies followed, and the proof of concept was well established by the late 1990s. This also continued for the next blockbuster immunosuppressant, tacrolimus.

Centenarians-the way to healthy vascular ageing and longevity: a review from VascAgeNet.

The prevalence of centenarians, people who lived 100 years and longer, is steadily growing in the last decades. This exceptional longevity is based on multifaceted processes influenced by a combination of intrinsic and extrinsic factors such as sex, (epi-)genetic factors, gut microbiota, cellular metabolism, exposure to oxidative stress, immune status, cardiovascular risk factors, environmental factors, and lifestyle behavior. Epidemiologically, the incidence rate of cardiovascular diseases is reduced in healthy centenarians along with late onset of age-related diseases compared with the general aged population.

Monitoring opioid analgesic misuse, abuse and dependence: What to the data from addictovigilance tell us about the situation in France?

The opioid epidemic has emerged in the USA in the late 1990s and widespread to Canada, Australia, and the UK to a lesser extent in the more recent years. At the European level, several studies performed in different European countries have highlighted that prescription opioid use increased substantially over the last decade, and several proxies for misuse show a parallel increasing trend. The French addictovigilance experience on opioid analgesics is a good example of a specific dedicated monitoring, taking into account in a global and multisource perspective, patterns of utilization, population involved in problematic use, ways of acquisition and health complications.

Health disparities in diabetes treatment: The challenge of G6PD deficiency.

Aims: To assess the impact of Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an enzymatic deficiency prevalent in individuals of African or Asian descent, on Hemoglobin A1c (HbA1c) levels, diabetes medication purchases, and the cumulative incidence of diabetes related complications.

Methods: A large cohort study was conducted within a national health organization, comparing 3,913 G6PD-deficient patients to a matched control group without G6PD deficiency over two decades. The main measures and outcomes were the HbA1c levels, patterns of diabetes medication purchases, and the incidence of severe diabetes-related complications.

Combined Therapeutic Strategies Based on the Inhibition of Non-Oncogene Addiction to Improve Tumor Response in EGFR- and KRAS-Mutant Non-Small-Cell Lung Cancer.

Background: Oncogene-driven NSCLC is usually treated with targeted therapies using tyrosine kinase inhibitors (TKIs) to inhibit oncogene downstream signaling pathways, affecting tumor survival and proliferation. EGFR- and KRAS-mutant NSCLCs are the most represented subtypes, and they are treated in clinical practice with oncogene-targeting drugs in the first and second line, respectively. Unfortunately, the development of oncogene-independent resistant clones limits TKI efficacy.

Stealth-Engineered Albumin-Coated Nanoparticles for Targeted Therapy: Effective Drug Delivery and Tumor Suppression in Xenograft-Zebrafish Model.

Purpose: In the bloodstream, nanoparticles (NPs) interact with serum proteins to form the protein corona, which includes both opsonins, promoting NP recognition and elimination, and dysopsonins, which can inhibit opsonin activity. Albumin, the most abundant serum protein, is part of this corona and can act as a dysopsonin, potentially hiding NPs from the immune system. This study aims to investigate how a covalently bound layer of human serum albumin (HSA) on polymeric NPs affects the protein corona and their behavior in the immune system.

An evolving machine-learning-based algorithm to early predict response to anti-CGRP monoclonal antibodies in patients with migraine.

Background: The present study aimed to determine whether machine-learning (ML)-based models can predict 3-, 6, and 12-month responses to the monoclonal antibodies (mAbs) against the calcitonin gene-related peptide (CGRP) or its receptor (anti-CGRPmAbs) in patients with migraine using early predictors (up to one month) and to create an evolving prediction tool.

Methods: In this prospective cohort study data from patients with migraine who had received anti-CGRP mAbs for 12 months were collected. Demographic and monthly clinical variables were collected, including monthly headache days (MHDs), days with acute medication use, number of analgesics and Headache Impact Test-6.

Endothelium-derived 6-nitrodopamine is the major mechanism by which nitric oxide relaxes the rabbit isolated aorta.

6-Nitrodopamine (6-ND) is the predominant catecholamine released from isolated vascular tissues in both mammals and reptiles, with its release being significantly reduced by the NO synthesis inhibitor, N-nitro-L-arginine methyl ester (L-NAME). The vasorelaxation induced by 6-ND is unaffected by either L-NAME or the soluble guanylate cyclase (sGC) inhibitor, ODQ, indicating an alternative mechanism of action. The vasorelaxant effect appears to be mediated through selective antagonism of dopamine D receptors rather than traditional nitric oxide (NO)-mediated pathways.

The anti-glypican 1 AT101 antibody as targeting agent to effectively deliver chitosan nanobubbles to glioblastoma cells.

Background: Recently, we developed AT101, an IgM-class mouse monoclonal antibody directed against glypican-1 (GPC1), a proteoglycan that can be considered as useful target for glioblastoma multiforme (GBM) treatment being specifically and highly expressed on GBM cell surface. Here, we proposed the use of AT101 as targeting agent in a drug delivery nanoplatfom to effectively deliver chitosan nanobubbles (NBs) for GBM treatment.

Methods: Chitosan NBs were prepared and conjugated with AT101 or left unconjugated as control.

MIR27A rs895819 CC Genotype Severely Reduces miR-27a Plasma Expression Levels.

rs895819 polymorphism has emerged as a potential additional pharmacogenomic marker of fluoropyrimidine response. Current evidence on its potential effect on miR-27a expression, which represses DPD activity, leading to DPD deficiency and increased fluoropyrimidine-associated toxicity risk, is scarce and inconsistent. We have analyzed the effect of rs895819 polymorphism on miR-27a-3p plasma expression levels under different models of inheritance to contribute further evidence on its plausible biological role in miR-27a expression.

Coupling Pre- and Postnatal Infant Exposures with Physiologically Based Pharmacokinetic Modeling to Predict Cumulative Maternal Levetiracetam Exposure During Breastfeeding.

Background And Objective: Although breastfeeding ensures optimal infant development and maternal health, mothers taking medications may abandon breastfeeding because of uncertainties regarding toxicity to infants. Current methods in predicting infant risk to maternal medication exposure do not account for breastfeeding-related variability or in utero exposure via the umbilical cord (UC). Previously, our workflow integrated variability in infant anatomy and physiology, breast milk intake volume, and drug concentrations in breast milk using physiologically based pharmacokinetic (PBPK) modeling.