A Modeling Approach towards Identifying Potential Bivalent Sensitizers of Neuromuscular Blocking Agents

ABSTRACT Objective: Anaphylactic reactions induced by neuromuscular blocking agents (NMBAs) can occur at first contact and might be due to cross-sensitization by other drugs or chemicals. Our aim was to investigate whether divalent molecules sharing chemical features with NMBAs might potentially cause cross-sensitization. Methods: We constructed a pharmacophore key from chemical features common to all NMBAs (two positive or ionizable features 1.0807 nm apart) and used the key to screen FDA-approved small drug molecules of the Drug Bank® database (1541 molecules). The selected molecules were categorized on the basis of the values for three main parameters (fit value, relative energy and mean polar surface area). Results: Screening from the pharmacophore key selected 13 NMBAs and 88 non-NMBA drugs. Of these 88 drugs, 42 had high-ranking parameter values and were considered preferential cross-sensitizers. These included the dopamine D2 receptor ligands aripiprazole and domperidone. Pholcodine, as well as nizatidine, ranitidine, antrafenine, cabergoline and, to some extent, chlorhexidine best fulfilled the required criteria of apolar character, bioavailability and ionization rate. Conclusion: Our data support the hypothesis that pholcodine might be a potential NMBA cross-sensitizer. They confirmed the results of inhibition tests on patient serum suggesting that dopamine D2 receptor ligands might be cross-sensitizers. They also identified chlorhexidine, a widely used disinfectant incriminated in several cases of immediate hypersensitivity reactions, as a potential cross-sensitizer. Pharmacophore modelling is an inexpensive, straightforward approach that can be used to identify potential NMBA cross-sensitizing agents

Investigating ADR mechanisms with Explainable AI: a feasibility study with knowledge graph mining

National audienceAdverse drug reactions (ADRs) are statistically characterized within randomized clinical trials or by postmarketing pharmacovigilance. However, the molecular mechanisms causing ADRs remain unknown in most cases. This is true even for common toxicities that are classically monitored during trials such as hepatic or skin toxicities. Interestingly, many elements of knowledge about drugs and drug ingredients are available beside clinical trials. In particular, open-access knowledge graphs describe their properties, interactions, and involvements in pathways. Expert classifications have also been manually established by experts and label drugs either as causative or not for several types of ADRs. In our paper, we propose to mine biomedical knowledge graphs to identify biomolecular features that enable to automatically reproduce such expert classifications, distinguishing drugs causative or not for a given type of ADR. In an Explainable AI perspective, we explore simple classification techniques such as Decision Trees and Classification Rules because they provide human-readable models which explain the classification itself. We also evaluate the assumption that biomolecular features mined from knowledge graphs might provide elements of explanation for the molecular mechanisms behind ADRs

Le paracétamol : connaissance, usage et risque de surdosage en patientèle urbaine de médecine générale. Étude prospective descriptive transversale

International audienceIntroduction: Acetaminophen is the most involved active substance in both unintentional and intentional drug poisoning. However, its availability outside community pharmacies is being debated in France.Methods: We made, via a self-administered questionnaire, a prospective assessment of knowledge, use and acetaminophen overdose risk in patients consulting their general practitioner, in the Metz Métropole urban area, between May 2015 and February 2016. We estimated the prevalence of potential unintentional overdosage by capture-recapture method.Results: Among 819 responding patients, only 17.9 % had a sufficient knowledge and 20.3 % were at risk for potential unintentional overdose. The risk was higher for patients aged over 55 years or belonging to socioprofessional categories of laborers and inactive. A good knowledge score was a protective factor for overdose risk (P < 0.0001). The liver toxicity of acetaminophen was particularly unknown. The prevalence of potential unintentional acetaminophen overdose was estimated at 1 to2 % of the population.Conclusion:Proposing acetaminophen outside of pharmacies cannot be recommended in France in such conditions. Information campaigns are needed to limit the risk of unintentional overdose and its consequences on liver toxicity.Introduction: Le paracétamol est la substance active la plus impliquée dans les intoxications médicamenteuses volontaires et involontaires. Néanmoins, sa mise à disposition hors officine, via la grande distribution, est actuellement débattue en France.Méthode: Nous avons réalisé une évaluation prospective de la connaissance, de l’usage et du risque de surdosage en paracétamol à l’aide d’un questionnaire autoadministré dans la patientèle de cabinets de médecine générale de la zone urbaine de Metz Métropole, entre mai 2015 et février 2016. La prévalence des patients en risque potentiel de surdosage involontaire a été estimée par méthode de capture-recapture.Résultats: Parmi les 819 patients ayant répondu, 17,9 % avaient une connaissance satisfaisante et 20,3 % étaient à risque de surdosage potentiel, majoritairement des patients âgés de plus de 55 ans ou appartenant aux catégories socioprofessionnelles des ouvriers et des inactifs. Un bon score de connaissance était un facteur protecteur du risque de surdosage (p < 0,0001). Le risque de toxicité hépatique était particulièrement méconnu. La prévalence des patients à risque potentiel de surdosage involontaire était estimée entre 1 et 2 % de la population.Conclusion: La dispensation du paracétamol hors des pharmacies d’officine ne saurait être recommandée en l’état. Des campagnes d’information sont nécessaires pour limiter le risque de surdosage involontaire et de ses conséquences hépatotoxiques

Hypertrigyceridemia during infliximab therapy

International audienceno abstrac

Nicorandil-induced ulcerations: A 10-year observational study of spontaneously reported cases to the French pharmacovigilance network

International audienc