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.

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.

Towards precision dosing in psychiatry: Population pharmacokinetics meta-modelling of clozapine and lithium.

Background: Treatment optimization is mandatory in psychiatric diseases and the use of population pharmacokinetics (popPK) models through model informed precision dosing (MIPD) has the potential to improve patient medical care. In this perspective, meta-modelling methods could provide popPK models with improved predictive performances and most of covariates of interest. The aims of this study were to develop meta-models of clozapine and lithium, assess their predictability and propose optimized dosing regimens for both drugs.

Artificial intelligence in drug repurposing for rare diseases: a mini-review.

Drug repurposing, the process of identifying new uses for existing drugs beyond their original indications, offers significant advantages in terms of reduced development time and costs, particularly in addressing unmet medical needs in rare diseases. Artificial intelligence (AI) has emerged as a transformative force in healthcare, and by leveraging AI technologies, researchers aim to overcome some of the challenges associated with rare diseases. This review presents concrete case studies, as well as pre-existing platforms, initiatives, and companies that demonstrate the application of AI for drug repurposing in rare diseases.

Does gene therapies clinical research in rare diseases reflects the competitivity of the country: Example of France.

Rare diseases are chronic, serious and generally genetic conditions affecting a small number of people, and their therapeutic management is a real challenge. They represent a considerable burden for patients, caregivers and society alike. Compared with existing symptomatic treatments, gene therapies represent a promising new approach aimed at treating these diseases by replacing a defective gene, or by abolishing or reviving a gene-derived function.

Can precision medicine be integrated into routine therapeutic decisions at the bedside of patients?

Therapeutic strategies are shifting from a "one-size-fits-all" population-based approach to a stratified approach targeting groups with similar characteristics, or even individuals, tailoring treatments to the unique characteristics of each patient. Since such strategies rely on increasingly complex knowledge and healthcare technologies, along with an understanding of the tools of precision medicine, the appropriate dissemination and use of these strategies involves a number of challenges for the medical community. Having evaluation methodologies that have been jointly designed with the institutional, industrial, academic stakeholders, and also patients, like streamlining the processes and externally validating performances, could enhance the relevance of the "evaluation" aspect of precision medicine.

Antibiotic-induced neurological adverse drug reactions.

Antibiotics are drugs widely used all around the world. Central nervous system adverse drug reactions (CNS ADRs) are mostly under-suspected with antibiotics. Nevertheless, these ADRs could lead to severe complications such as encephalopathy.

Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning.

Background: Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences.

Simultaneous Quantification of Psychotropic Drugs in Human Plasma and Breast Milk and Its Application in Therapeutic Drug Monitoring and Peripartum Treatment Optimization.

Background: Therapeutic drug monitoring is recommended for several psychotropic drugs, particularly in sensitive situations such as the peripartum period. This study aimed to develop an ultra-high-performance liquid chromatography-tandem spectrometry method for the simultaneous quantification of 14 psychotropic drugs in human plasma and 4 in breast milk.

Methods: The samples were precipitated with methanol containing the stable isotope-labeled analogs.

-Lactam Pharmacokinetic/Pharmacodynamic Target Attainment in Intensive Care Unit Patients: A Prospective, Observational, Cohort Study.

Background: The aims of this study were to describe pharmacokinetic/pharmacodynamic target attainment in intensive care unit (ICU) patients treated with continuously infused -lactam antibiotics, their associated covariates, and the impact of dosage adjustment.

Methods: This prospective, observational, cohort study was performed in three ICUs. Four -lactams were continuously infused, and therapeutic drug monitoring (TDM) was performed at days 1, 4, and 7.

Cannabis for the treatment of amyotrophic lateral sclerosis: What is the patients' view?

Cannabis may have therapeutic benefits to relieve symptoms of amyotrophic lateral sclerosis (ALS) thanks to its pleiotropic pharmacological activity. This study is the first to present a large questionnaire-based survey about the "real-life" situation regarding cannabis use in the medical context in ALS patients in France. There were 129 respondents and 28 reported the use of cannabis (21.

Drug Repurposing of Generic Drugs: Challenges and the Potential Role for Government.

Drug repurposing is the process of identifying a new use for an existing drug or active substance in an indication outside the scope of the original indication. Drug repurposing has important advantages including reduced development time and costs, and potentially large societal healthcare cost savings. However, current generic drug repurposing research faces a number of challenges in obtaining research funds.

Cannabidiol and pharmacokinetics drug-drug interactions: Pharmacological toolbox.

Cannabidiol (CBD) is one of the most important components of the Cannabis sativa plant with delta9-tetrahydrocannabinol (THC). CBD is used both for medical and recreational purposes. It can be of pharmaceutical grade (Epidyolex®), and also self-service purchased in pharmacy, CBD shops and on the internet (non-pharmaceutical).

Riluzole for treating spasticity in patients with chronic traumatic spinal cord injury: Study protocol in the phase ib/iib adaptive multicenter randomized controlled RILUSCI trial.

Background: Satisfactory treatment is often lacking for spasticity, a highly prevalent motor disorder in patients with spinal cord injury (SCI). Low concentrations of riluzole potently reduce the persistent sodium current, the post-SCI increase in which contributes to spasticity. The repurposing of this drug may therefore constitute a useful potential therapeutic option for relieving SCI patients suffering from chronic traumatic spasticity.

What Do We Know About Medical Cannabis in Neurological Disorders and What Are the Next Steps?

Medical use of cannabis has been receiving growing attention over the last few decades in modern medicine. As we know that the endocannabinoid system is largely involved in neurological disorders, we focused on the scientific rationale of medical cannabis in three neurological disorders: amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease through pharmacological plausibility, clinical studies, and patients' view. Clinical studies (randomized controlled trials, open-label studies, cohorts, and case reports) exploring medical cannabis in these disorders show different results depending on the methods and outcomes.

Local Anesthetic Plasma Concentrations as a Valuable Tool to Confirm the Diagnosis of Local Anesthetic Systemic Toxicity? A Report of 10 Years of Experience.

Background: Local anesthetic systemic toxicity (LAST) has been reported as a serious complication of local anesthetic (LA) peripheral injection. The signs and symptoms of LAST are highly variable, and the challenge remains to confirm its diagnosis. In this context, the determination of LA plasma concentration appears as a valuable tool to confirm LAST diagnosis.

Towards Precision Dosing of Clozapine in Schizophrenia: External Evaluation of Population Pharmacokinetic Models and Bayesian Forecasting.

Background: Therapeutic drug monitoring and treatment optimization of clozapine are recommended, owing to its narrow therapeutic range and pharmacokinetic (PK) variability. This study aims to assess the clinical applicability of published population PK models by testing their predictive performance in an external data set and to determine the effectiveness of Bayesian forecasting (BF) for clozapine treatment optimization.

Methods: Available models of clozapine were identified, and their predictive performance was determined using an external data set (53 patients, 151 samples).

Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer's disease CSF profile of neuronal injury and inflammation.

Alzheimer's disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as amyloid pathology. We performed an exome-wide rare variant analysis of six AD biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and Neurogranin) to discover genes associated with these markers. Genetic and biomarker information was available for 480 participants from two studies: EMIF-AD and ADNI.