[COVID-19 and adenovirus vaccines: French experience of enhanced pharmacovigilance].

As part of the COVID-19 vaccination campaign, the National Agency for the Safety of Medicines and Health Products and all 31 regional pharmacovigilance centers were mobilized in an exceptional reinforced vaccine pharmacovigilance surveillance system. Concerning adenovirus vaccines, Vaxzévria® and Jcovden®, this national system, based on the daily analysis of notified cases of adverse events, has allowed the early identification of safety signals, some of which have been validated, others still under analysis, common to mRNA vaccines or more specific of adenovirus vaccines such as Vaccine Induced Immune Thrombocytopenia. Complementing european and international actions, this follow-up has contributed to a better definition of the safety profile of these vaccines and has led to redefine the vaccine strategy in our country.

Platform trials.

For the past few years, platform trials have experienced a significant increase, recently amplified by the COVID-19 pandemic. The implementation of a platform trial is particularly useful in certain pathologies, particularly when there is a significant number of drug candidates to be assessed, a rapid evolution of the standard of care or in situations of urgent need for evaluation, during which the pooling of protocols and infrastructure optimizes the number of patients to be enrolled, the costs, and the deadlines for carrying out the investigation. However, the specificity of platform trials raises methodological, ethical, and regulatory issues, which have been the subject of the round table and which are presented in this article.

[HLA-B58.01 and allopurinol hypersensitivity renal vasculitis in a Chinese patient].

Introduction: Allopurinol, widely used in the treatment of hyperuricemia and gout, has been shown to cause severe cutaneous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, as well as systemic reactions such as DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms). The HLA-B*5801 allele is known to be a risk factor for severe cutaneous manifestations of hypersensitivity to allopurinol, mostly in Asian populations.

Observation: We report the observation of a 47-year-old Chinese patient, with no previous medical history, carrying the HLA-B*5801 allele, who developed an isolated allopurinol hypersensitivity necrotizing renal vasculitis without cutaneous manifestations.

Validation of Artificial Intelligence to Support the Automatic Coding of Patient Adverse Drug Reaction Reports, Using Nationwide Pharmacovigilance Data.

Introduction: Adverse drug reaction reports are usually manually assessed by pharmacovigilance experts to detect safety signals associated with drugs. With the recent extension of reporting to patients and the emergence of mass media-related sanitary crises, adverse drug reaction reports currently frequently overwhelm pharmacovigilance networks. Artificial intelligence could help support the work of pharmacovigilance experts during such crises, by automatically coding reports, allowing them to prioritise or accelerate their manual assessment.

Artificial Intelligence for Unstructured Healthcare Data: Application to Coding of Patient Reporting of Adverse Drug Reactions.

Adverse drug reaction (ADR) reporting is a major component of drug safety monitoring; its input will, however, only be optimized if systems can manage to deal with its tremendous flow of information, based primarily on unstructured text fields. The aim of this study was to develop an automated system allowing to code ADRs from patient reports. Our system was based on a knowledge base about drugs, enriched by supervised machine learning (ML) models trained on patients reporting data.

Spontaneous Reports of Serious Adverse Drug Reactions Resulting From Drug-Drug Interactions: An Analysis From the French Pharmacovigilance Database.

Few data are available on the clinical impact of drug-drug interactions (DDIs). Most of the studies are limited to the analysis of exposure to potential DDI or the targeted impact of the combination of a few drugs or therapeutic classes. The analysis of adverse drug reaction (ADR) reports could be a mean to study generally the adverse effects identified due to a DDI.

Safety of immune checkpoint inhibitor rechallenge after discontinuation for grade ≥2 immune-related adverse events in patients with cancer.

Background: Safety of rechallenge of immune checkpoint inhibitor (ICI) after grade ≥2 immune-related adverse events (irAEs) leading to ICI discontinuation remains unclear.

Methods: All adverse drug reactions involving at least one ICI reported up to December 31, 2019 were extracted from the French pharmacovigilance database. Patients were included if they experienced at least one grade ≥2 irAE resulting in ICI discontinuation, with subsequent ICI rechallenge.

French Pharmacovigilance Public System and COVID-19 Pandemic.

The current COVID-19 pandemic is an exceptional health situation including for drug use. As there was no known effective drug for COVID-19 at the beginning of the pandemic, different candidates were proposed. In this short article, we present the French public pharmacovigilance activities during this health crisis.

Drug interactions related to self-medication: a French pharmacovigilance database study.

Self-medication (SM) is a common practice perceived by patients as harmless which can, however, entail health risks. The aim of the study was to identify drug-drug interactions (DDIs) involving SM drugs leading to adverse drug reactions (ADRs) in the National French Pharmacovigilance Database. All ADR reports from 1 January 1985 to 31 July 312018, coded as 'interaction' and 'self-medication', were selected and studied.

[In vitro protection of cerebral mitochondrial function by E-resveratrol in anoxia followed by re-oxygenation].

Using an experimental model of anoxia-reoxygenation applied to suspensions of mitochondria isolated from rat cortex, we have searched the effects of resveratrol added to the suspension or previously injected to rats from which mitochondria were extracted. With this model, we observe that resveratrol counteracts decoupling effects induced by anoxia-reoxygenation. It also fully inhibits intermembrane cytochrome c release, initial step of mitochondrial apoptosis and blocks ATP generation which achieves it.

[The pharmacologic basis of pain treatment].

The treatment of chronic pain uses drugs from different pharmacological classes. Analgesics are the common basis of these treatments. Peripheral analgesics (or minor analgesics such as paracetamol) and non-steroidal anti-inflammatory drugs are used for moderate pain (grade I of WHO).

[Effects of trimetazidine on altered functions of rat kidney induced by cyclosporine].

A mitochondrial dysfunction has been suggested to explain chronic renal toxicity observed in ciclosporine A therapy. Our study has investigated whether trimetazidine allows inhibition of mitochondrial alteration induced by ciclosporine A. Oxidative phosphorylation was measured by polarography, calcium fluxes by a specific calcium electrode and the mitochondrial swelling by determination of the optical density at 520 nm, using a spectrophotometer.

[The risk of falling due to benzodiazepine administration, alone or in combination, in elderly subjects].

Benzodiazepines are well tolerated by young adults whereas in elderly people they are less safe and globally induce more central nervous system side-effects and falls. Falls result from a decrease of vigilance and an alteration of postural reflex. This latter includes the reception of sensory information and central integration modulated mainly by dopaminergic D2 receptors and motor stimulation.

S15176 and S16950 interaction with Cyclosporin A antiproliferative effect on cultured human lymphocytes.

S15176 and S16950 are trimetazidine derivatives that antagonize more strongly than the parent drug mitochondrial toxicity, which leads to cellular hypoxia and nephrotoxicity in kidneys experimentally exposed to cyclosporin A. We have investigated whether every derivative might interact or not with the inhibitory effect of Cyclosporin A on the proliferation of cultured human lymphocytes. S15176 significantly increased the antilymphoproliferative effect of Cyclosporin A, whereas S15176 by itself neither displayed any antilymphoproliferative effect, nor did it induce any apoptotic process in cultured human lymphocytes.

[Allergen potential of drugs and ex vivo demonstration of an immune response].

Drugs are able to activate the immune system, which may generate hypersensitivity states in individuals. In a first part, this article deals with the critical processes that are involved in drug sensitizations: what are the specific features of drugs as immunogens; how drugs are recognized as non-self by immunocompetent cells; what is the spontaneous outcome of drug allergic states, does a genetic predisposition regulate the immune response. The second part is mostly devoted to the biological investigation of drug sensitizations: what are we looking for and why, are all the available methods equally suitable for routine diagnosis, what are the major methological problems that we have to face at and how to escape them.

Expression of the genetic variants of human alpha-1-acid glycoprotein in cancer.

Objectives: We have investigated the AAG and its genetic variants concentrations in plasma samples of 61 patients suffering from different types of cancers.

Design And Methods: The patients were shared out in three groups, breast, lung, and ovary cancers groups. AAG concentration was measured by an immunonephelometric method and the phenotype was determined, after desialylation of plasma by analytical isoelectric focusing.

[Pharmacologic and biologic basis of drug allergies].

Drugs are able to activate the immune system, which may generate hypersensitivity states in individuals. This article first deals with the critical processes that are involved in drug sensitizations: what are the specific features of drugs as immunogens; how are drugs recognized as non-self by activated immune cells; what is the spontaneous outcome of an immune response to drugs in individuals; does a genetic predisposition regulate the immune response to drug antigens; how much are biotransformation processes involved in the immunogenicity of drugs? The second part is mostly devoted to the biological investigation of drug sensitizations: what are we looking for and why; are all the available methods equally suitable for routine diagnosis; what are the major methological problems that we have to deal with in investigating patients who have presented with symptoms which are clinically suspected to be of immuno-allergic origin?

Lack of relevance of the acetylator status on dapsone response in chronic autoimmune thrombocytopenic purpura.

Dapsone provides an alternative treatment for patients with chronic autoimmune thrombocytopenic purpura (AITP) who had inadequate response to conventional therapy. However, the efficacy of this treatment is achieved in only 50% of patients. Dapsone is partly metabolized by the polymorphic N-acetyltransferase 2% and 50% of Caucasian patients show a genetically determined slow acetylator phenotype.

Study of the expression of the genetic variants of human alpha1-acid glycoprotein in healthy subjects using isoelectric focusing and immunoblotting.

Human alpha1-acid glycoprotein (AAG) exists as an heterogeneous population of two or three genetic variants (ORM1 F1 and/or S and ORM2 A) in the plasma of most individuals. The ORM1 and ORM2 variants have a separate genetic origin. AAG belongs to the acute-phase proteins, which, under conditions of inflammation, increase several-fold in concentration.

Plasma coenzyme Q10 concentrations in breast cancer: prognosis and therapeutic consequences.

Background: Coenzyme Q10 or ubiquinone is a redox component of the respiratory chain, which may be involved in the pathogenesis of cancer.

Methods: In order to better understand the role of this vitamin in the pathogenesis of breast cancer, a clinical trial including 200 women hospitalized for the biopsy and/or the ablation of a breast tumor was conducted. Ubiquinone plasma concentrations were determined simultaneously with vitamin E plasma concentrations (as antioxidant reference) by HPLC.

Ligand specificity of the genetic variants of human alpha1-acid glycoprotein: generation of a three-dimensional quantitative structure-activity relationship model for drug binding to the A variant.

Human alpha1-acid glycoprotein (AAG) is a mixture of at least two genetic variants: the A variant and the F1 and/or S variant or variants, which are encoded by two different genes. In a continuation of previous studies indicating specific drug transport roles for each AAG variant according to its separate genetic origin, this work was designed to (1) determine the affinities of the two main gene products of AAG (i.e.

[Mediators involved in the nephrotoxicity of cyclosporin A].

Cyclosporin A-induced nephrotoxicity is a well known adverse effect but its mechanism remains unclear. The understanding of the toxicity mechanism is necessary since the new generation of immunosuppressant drugs (cyclosporin G, FK 506, rapamycin) demonstrates renal toxicity. A renal vasoconstriction occurs with the first administration of cyclosporin and involves several mediators (prostaglandins, renal sympathetic nerves, dopamine.