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. France is considered one of the leading countries in the research and development of drugs for rare diseases, yet the position of French public and private stakeholders in the research and development of gene therapies for rare diseases at global and European level remains unclear. To answer this question, we used the GENOTRIAL FR database developed by OrphanDev to clarify France's involvement and competitiveness in this field. The results show that France is actively involved in gene therapy clinical trials, with a dense international collaboration network and solid expertise. However, the French medical infrastructure is mainly involved in clinical research on gene therapy candidates sponsored by several foreign countries. To a lesser extent, French public and private entities are also developing their own gene therapy candidates for various rare diseases, some of which have already reached advanced clinical phases. In conclusion, a number of technical and financial challenges need to be overcome if France is to maintain its position as a European and world leader and increase its contribution to reducing the economic and social burden of rare diseases by developing revolutionary and effective new therapies.

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. Creating a network of expert precision-medicine centers and ensuring that precision-medicine procedures are reimbursed by social security would guarantee fair and sustainable access. Finally, training healthcare professionals, creating interfaces between precision-medicine expert centers and primary care professionals as well as patients, and integrating individual patient data into medical records are all key drivers that will enable information from precision-medicine to be made available and guarantee the proper use of these approaches.

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. To illustrate the clinical patterns of these off-target ADRs, we here present data from pharmacovigilance system, through different populations and points of view (worldwide, French population, vulnerable population and individual). These data could help clinicians to better know about CNS ADRs with antibiotics, to better identify risk factors and vulnerable patients and to highlight the importance to set up the right diagnostic explorations in the best timing to avoid complications. Clinicians should request a pharmacological opinion from pharmacologist (biologists and pharmacovigilance clinicians) in front of vulnerable population before or during antibiotics. Pharmacovigilance advice could help clinicians in the diagnosis and the management of an ADR. Therapeutic drug monitoring is particularly contributive to adjust doses of antibiotics administered in vulnerable patients. Pharmacovigilance advice and TDM are essential to perform personalized medicine, and contribute to the proper use of drugs.

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. Chromatographic separation was performed using a Phenomenex Luna Omega Polar C18 column. Detection was performed using a triple-quadrupole mass spectrometer equipped with an electrospray ionization interface. The method was fully validated in plasma according to the European Guidelines on Bioanalytical Method Validation and partially validated in breast milk by determining the intraday precision and accuracy, linearity, lower limit of quantification, and matrix effect. RESULTS: The correlation coefficients of the calibration curves were greater than 0.99. Coefficients of variation ranged from 3.05% to 14.66% and 0.62%-14.90% for internal standard-normalized matrix effect, 1.4%-14.1% and 2.1%-10.4% for intraday precision, and 3.2%-13.9% and 4.1%-9.6% for interday precision, in plasma and milk, respectively. The relative error in accuracy did not exceed ±15% for any analyte. The method was successfully applied clinically to measure the concentrations of psychotropic drugs in 952 plasma samples, among which 43% of the concentrations were out of the therapeutic range, and 13 breast milk samples, with calculated relative infant doses ranging from 0.32% to 8.18%. CONCLUSIONS: To the best of the authors' knowledge, this is the first routine technique validated for the quantification of psychotropic drugs in both plasma and breast milk, allowing for treatment optimization and prevention of adherence issues, including those in breastfeeding patients.

ß-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 ß-lactam antibiotics, their associated covariates, and the impact of dosage adjustment. METHODS: This prospective, observational, cohort study was performed in three ICUs. Four ß-lactams were continuously infused, and therapeutic drug monitoring (TDM) was performed at days 1, 4, and 7. The primary pharmacokinetic/pharmacodynamic target was an unbound ß-lactam plasma concentration four times above the bacteria's minimal inhibitory concentration during the whole dosing interval. The demographic and clinical covariates associated with target attainment were evaluated. RESULTS: A total of 170 patients were included (426 blood samples). The percentages of empirical ß-lactam underdosing at D1 were 66% for cefepime, 43% for cefotaxime, 47% for ceftazidime, and 14% for meropenem. Indexed creatinine clearance was independently associated with treatment underdose if increased (adjusted odds ratio per unit, 1.01; 95% CI, 1.00 to 1.01; p = 0.014) or overdose if decreased (adjusted odds ratio per unit, 0.95; 95% CI, 0.94 to 0.97; p < 0.001). Pharmacokinetic/pharmacodynamic target attainment was significantly increased after ß-lactam dosage adjustment between day 1 and day 4 vs. no adjustment (53.1% vs. 26.2%; p = 0.018). CONCLUSIONS: This study increases our knowledge on the optimization of ß-lactam therapy in ICU patients. A large inter- and intra-patient variability in plasmatic concentrations was observed, leading to inadequate exposure. A combined indexed creatinine clearance and TDM approach enables adequate dosing for better pharmacokinetic/pharmacodynamic target attainment.

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. Furthermore, regardless of the success of a repurposing trial, commercial parties often lack interest in pursuing marketing authorisation for financial reasons, and academic researchers lack the knowledge, time and funding. Therefore, the new indication of a repurposed drug often does not make it 'on label'. We propose a large increase in public funding for generic drug repurposing research, including funds for the marketing authorisation process when a trial is successful, and a reduction in the regulatory burden of the marketing authorisation process for repurposed generic drugs.

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). CBD is almost as widespread as it is poorly understood from a pharmacological point of view and particularly in terms of drug interactions. Drug-drug interactions could lead to clinical complications, and we here gather data currently available on pharmacokinetics (PK) drug-drug interactions with CBD through a narrative review. This review shows that several PK drug-drug interactions exist with different class of medications and aims to help clinicians to better know about CBD for their practice as this product is increasingly used.

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. OBJECTIVE: RILUSCI is a phase 1b-2b trial designed to assess whether riluzole is a safe and biologically effective means of managing spasticity in adult patients with traumatic chronic SCI. METHODS: In this multicenter double-blind trial, adults (aged 18-65 years) suffering from spasticity after SCI (target enrollment: 90 participants) will be randomly assigned to be given either a placebo or a recommended daily oral dose of riluzole for two weeks. The latter dose will be previously determined in phase 1b of the study by performing double-blind dose-finding tests using a Bayesian continuous reassessment method. The primary endpoint of the trial will be an improvement in the Modified Ashworth Score (MAS) or the Numerical Rating Score (NRS) quantifying spasticity. The secondary outcomes will be based on the safety and pharmacokinetics of riluzole as well as its impact on muscle spasms, pain, bladder dysfunction and quality of life. Analyses will be performed before, during and after the treatment and the placebo-controlled period. CONCLUSION: To the best of our knowledge, this clinical trial will be the first to document the safety and efficacy of riluzole as a means of reducing spasticity in patients with chronic SCI. TRIAL REGISTRATION: The clinical trial, which is already in progress, was registered on the ClinicalTrials.gov website on August 9, 2016 under the registration number NCT02859792. TRIAL SPONSOR: Assistance Publique-Hôpitaux de Marseille.

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. Some show benefits on motor symptoms and others on non-motor symptoms and quality of life. Concerning patients' view, several web surveys were collected, highlighting the real use of cannabis to relieve symptoms of neurological disorders, mostly outside a medical pathway. This anarchic use keeps questioning particularly in terms of risks: consumption of street cannabis, drug-drug interactions with usual medical treatment, consideration of medical history, and adverse reactions (psychiatric, respiratory, cardiovascular disorders, etc.), underlining the importance of a medical supervision. To date, most scientific data support the therapeutic potential of cannabis in neurological disorders. As far as patients and patients' associations are calling for it, there is an urgent need to manage clinical studies to provide stronger evidence and secure medical cannabis use.

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). The median prediction error (PE) and median absolute PE were used to assess bias and inaccuracy. The potential factors influencing model predictability were also investigated. The final concentration was reestimated for all patients using covariates or previously observed concentrations. RESULTS: The 7 included models presented limited predictive performance. Only 1 model met the acceptability criteria (median PE ≤ ±20% and median absolute PE ≤30%). There was no difference between the data used for building the models (therapeutic drug monitoring or PK study) or the number of compartments in the models. A tendency for higher inaccuracy at low concentrations during treatment initiation was observed. Heterogeneities were observed in the predictive performances between the subpopulations, especially in terms of smoking status and sex. For the models included, BF significantly improved their predictive performance. CONCLUSIONS: Our study showed that upon external evaluation, clozapine models provide limited predictive performance, especially in subpopulations such as nonsmokers. From the perspective of model-informed prediction dosing, model predictability should be improved using updating or metamodeling methods. Moreover, BF substantially improved model predictability and could be used for clozapine treatment optimization.

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. The aims of this study were to describe observed LA concentrations in patients suspected with LAST and their contribution to diagnostic confirmation. METHODS: We retrospectively reported suspected LAST in patients for which at least one plasma LA concentration was determined to confirm diagnosis of LAST. Data collection came from our pharmacological laboratory's database. Clinical signs and symptoms of toxicity, their onset time and observed LA concentrations were used to confirm LAST diagnosis. RESULTS: 33 patients who presented with suspected LAST after ropivacaine and/or lidocaine administration were included. Prodromal symptoms were observed in 13 patients. Isolated central nervous system (CNS) toxicity occurred in 11 patients, and combined CNS and cardiovascular toxicity occurred in 12. One, two or three venous plasma samples were performed in 11, 3 and 19 patients, respectively. Toxic plasma LA concentrations were observed in three patients, receiving peripheral LA injection using lidocaine (16.1 µg/mL) and ropivacaine (4.2 and 4.8 µg/mL). CONCLUSION: This study presents an important biological and clinical dataset of patients who presented with suspected LAST. Plasma LA concentrations could bring valuable information in the diagnosis of LAST but requires rigorous sample protocols.

Genome-Wide Association Study of Alzheimer's Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Dataset.

Alzheimer's disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e., case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline.

BDNF Val66Met gene polymorphism modulates brain activity following rTMS-induced memory impairment.

The BDNF Val66Met gene polymorphism is a relevant factor explaining inter-individual differences to TMS responses in studies of the motor system. However, whether this variant also contributes to TMS-induced memory effects, as well as their underlying brain mechanisms, remains unexplored. In this investigation, we applied rTMS during encoding of a visual memory task either over the left frontal cortex (LFC; experimental condition) or the cranial vertex (control condition). Subsequently, individuals underwent a recognition memory phase during a functional MRI acquisition. We included 43 young volunteers and classified them as 19 Met allele carriers and 24 as Val/Val individuals. The results revealed that rTMS delivered over LFC compared to vertex stimulation resulted in reduced memory performance only amongst Val/Val allele carriers. This genetic group also exhibited greater fMRI brain activity during memory recognition, mainly over frontal regions, which was positively associated with cognitive performance. We concluded that BDNF Val66Met gene polymorphism, known to exert a significant effect on neuroplasticity, modulates the impact of rTMS both at the cognitive as well as at the associated brain networks expression levels. This data provides new insights on the brain mechanisms explaining cognitive inter-individual differences to TMS, and may inform future, more individually-tailored rTMS interventions.

Sex-Specific Metabolic Pathways Were Associated with Alzheimer's Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort.

BACKGROUND: physiological differences between males and females could contribute to the development of Alzheimer's Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives. METHODS: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cerebrospinal fluid (CSF) biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites' discriminatory performance in AD. RESULTS: In females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (area under curve (AUC) = 0.83, standard error (SE) = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046). CONCLUSIONS: metabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, were associated to females, paving the way to personalised treatment.

Dosing antipsychotics in special populations of patients with schizophrenia: severe psychotic agitation, first psychotic episode and elderly patients.

Antipsychotic (AP) dosing is well established in nonelderly patients with acute exacerbations of schizophrenia, but not in special populations.This review describes the AP dosing procedures that have been used in clinical studies for acute psychotic agitation, a first episode of psychosis (FEP), and elderly patients. AP dosing data was extracted from the databases of drug regulatory authorities, and from clinical studies available in the medical literature. In acute psychotic agitation, intramuscular and oral APs are frequently prescribed in higher doses than those that saturate D2 receptors. Supersaturating doses of APs should be avoided due to an increased risk of adverse effects. In FEP, many studies showed efficacy of low doses of APs. Studies with risperidone and haloperidol suggested a dose reduction of approximately one third. Titration with a lower starting dose is recommended in elderly patients, due to possible decreases in pharmacokinetic clearance, and due to the risk of concomitant diseases and drug interactions. Exposure to some APs has been associated with QTc prolongation and arrhythmias, and a small but significant increase in the risk of stroke and mortality with APs has been seen, particularly in older people with dementia-related psychosis.

Convergent and Discriminant Validity of Default Mode Network and Limbic Network Perfusion in Amnestic Mild Cognitive Impairment Patients.

BACKGROUND: Previous studies reported default mode network (DMN) and limbic network (LIN) brain perfusion deficits in patients with amnestic mild cognitive impairment (aMCI), frequently a prodromal stage of Alzheimer's disease (AD). However, the validity of these measures as AD markers has not yet been tested using MRI arterial spin labeling (ASL). OBJECTIVE: To investigate the convergent and discriminant validity of DMN and LIN perfusion in aMCI. METHODS: We collected core AD markers (amyloid-ß 42 [Aß42], phosphorylated tau 181 levels in cerebrospinal fluid [CSF]), neurodegenerative (hippocampal volumes and CSF total tau), vascular (white matter hyperintensities), genetic (apolipoprotein E [APOE] status), and cognitive features (memory functioning on Paired Associate Learning test [PAL]) in 14 aMCI patients. Cerebral blood flow (CBF) was extracted from DMN and LIN using ASL and correlated with AD features to assess convergent validity. Discriminant validity was assessed carrying out the same analysis with AD-unrelated features, i.e., somatomotor and visual networks' perfusion, cerebellar volume, and processing speed. RESULTS: Perfusion was reduced in the DMN (F = 5.486, p = 0.039) and LIN (F = 12.678, p = 0.004) in APOE ɛ4 carriers compared to non-carriers. LIN perfusion correlated with CSF Aß42 levels (r = 0.678, p = 0.022) and memory impairment (PAL, number of errors, r = -0.779, p = 0.002). No significant correlation was detected with tau, neurodegeneration, and vascular features, nor with AD-unrelated features. CONCLUSION: Our results support the validity of DMN and LIN ASL perfusion as AD markers in aMCI, indicating a significant correlation between CBF and amyloidosis, APOE ɛ4, and memory impairment.

RNA therapeutics for mood disorders: current evidence toward clinical trials.

INTRODUCTION: Mood disorders are severe yet frequent psychiatric disorders worldwide, comprising major depressive disorder (MDD) and bipolar disorders (BD). Their treatment remains poorly effective. Recently, growing evidence for epigenetic mechanisms has emerged. Consequently, a great interest in a novel pharmacological class arose: RNA therapeutics. AREAS COVERED: We conducted a systematic review of RNA therapeutics -antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), short hairpin RNAs (shRNAs), and micro-RNA (miRNA) therapeutics- for the treatment of mood disorders studied in pre-clinical animal models listed in PubMed, in clinical trials registered in ClinicalTrials.gov and available on the market by combining literature search and Food and Drug Administration and European Medicine Agency online databases. Eighteen pre-clinical studies investigated the antidepressant effects of RNA therapeutics. However, even though there is an increasing number of marketing authorizations and clinical trials for the past twenty years, no RNA therapeutic has reached the clinical development pipeline for the treatment of psychiatric disorders yet. EXPERT OPINION: Several promising RNA therapeutics have been tested in pre-clinical studies for MDD, whereas no molecule has been developed for BD. There are several issues to address before reaching clinical development and new challenges include stratifying patient population and predicting therapeutic response.