Patterns of medication errors involving pediatric population reported to the French Medication Error Guichet

Background: Medication error is a global threat to patient safety, particularly in pediatrics. Yet, this issue remains understudied in this population, in both hospital and community settings. Objectives: To characterize medication errors involving pediatrics reported to the French Medication Error Guichet, and compare them with medication errors in adults, in each of the hospital and community settings. Methods: This was a retrospective secondary data analysis of medication errors reported throughout 2013-2017. Descriptive and multivariate analyses were performed to compare actual and potential medication error reports between pediatrics (aged 18 and <60 years). Two subanalyses of actual medication errors with adverse drug reaction (ADR), and serious ADR were conducted. Results: We analyzed 4,718 medication error reports. In pediatrics, both in hospital (n=791) and community (n=1,541) settings, antibacterials for systemic use (n=121, 15.7%; n=157, 10.4%, respectively) and wrong dose error type (n=391, 49.6%; n=549, 35.7%, respectively) were frequently reported in medication errors. These characteristics were also significantly more likely to be associated with reported errors in pediatrics compared with adults. In the hospital setting, analgesics (adjusted odds ratio (aOR)=1.59; 95% confidence interval (CI) 1.03:2.45), and blood substitutes and perfusion solutions (aOR=3.74; 95%CI 2.24:6.25) were more likely to be associated with reported medication errors in pediatrics; the latter drug class (aOR=3.02; 95%CI 1.59:5.72) along with wrong technique (aOR=2.28; 95%CI 1.01:5.19) and wrong route (aOR=2.74; 95%CI 1.22:6.15) error types related more to reported medication errors with serious ADR in pediatrics. In the community setting, the most frequently reported pediatric medication errors involved vaccines (n=389, 25.7%). Psycholeptics (aOR=2.42; 95%CI 1.36:4.31) were more likely to be associated with reported medication errors with serious ADR in pediatrics. Wrong technique error type (aOR=2.71; 95%CI 1.47:5.00) related more to reported medication errors with ADR in pediatrics. Conclusions: We identified pediatric-specific medication error patterns in the hospital and community settings. Our findings inform focused error prevention measures, and pave the way for interventional research targeting the needs of this population

EurOP2E – the European Open Platform for Prescribing Education, a consensus study among clinical pharmacology and therapeutics teachers

Purpose Sharing and developing digital educational resources and open educational resources has been proposed as a way to harmonize and improve clinical pharmacology and therapeutics (CPT) education in European medical schools. Previous research, however, has shown that there are barriers to the adoption and implementation of open educational resources. The aim of this study was to determine perceived opportunities and barriers to the use and creation of open educational resources among European CPT teachers and possible solutions for these barriers. Methods CPT teachers of British and EU medical schools completed an online survey. Opportunities and challenges were identified by thematic analyses and subsequently discussed in an international consensus meeting. Results Data from 99 CPT teachers from 95 medical schools were analysed. Thirty teachers (30.3%) shared or collaboratively produced digital educational resources. All teachers foresaw opportunities in the more active use of open educational resources, including improving the quality of their teaching. The challenges reported were language barriers, local differences, lack of time, technological issues, difficulties with quality management, and copyright restrictions. Practical solutions for these challenges were discussed and include a peer review system, clear indexing, and use of copyright licenses that permit adaptation of resources. Conclusion Key challenges to making greater use of CPT open educational resources are a limited applicability of such resources due to language and local differences and quality concerns. These challenges may be resolved by relatively simple measures, such as allowing adaptation and translation of resources and a peer review system

Optimisation de la réponse aux thiopurines par la pharmacogénétique : approches in vitro et cliniques

Thiopurines are cytotoxic and immunosuppressive drugs widely prescribed, mainly in inflammatory bowel disease (IBD). They constitute one of the best success story of pharmacogenetic implementation into clinical practice based on the screening of thiopurine S-methyltransferase (TPMT) deficiency, a key enzyme in thiopurine metabolism. Optimization of thiopurine response is challenging because of its large interindividual variability such as inefficacy and toxicities. This thesis has explored, on one hand, the relationships between TPMT activity and metabolite concentrations, and on the other hand, factors associated with thiopurine inefficacy. Using a primary care pharmacogenetic database, we first analyzed TPMT distribution and genotype-phenotype correlation, in relation with thiopurine metabolites in a large population. Using a PheWAS study based on a clinical data warehouse we then reported that a very high TPMT activity (“ultra-rapid” phenotype) was associated with parameters of active IBD and poor response to thiopurines. Furthermore, a retrospective study in pediatric IBD identified factors predicting the occurrence of lymphopenia during thiopurine therapy. Finally, using a lymphoblastoid cell line (LCL) in vitro model, we established a transcriptomic signature, including 32 genes predicting thiopurine cellular resistance. A bioinformatic functional analysis identified metabolic pathways in relation with p53 and cell cycle, as well as molecular mechanisms associated with thiopurine resistance. To conclude, this research work, focusing on the variability of thiopurine response and mainly therapeutic resistance, provides new hypotheses to individualize and optimize therapeutic response to thiopurines.Les thiopurines sont des médicaments cytotoxiques et immunosuppresseurs largement prescrits, notamment dans les maladies inflammatoires chroniques de l’intestin (MICI). Ils représentent l’un des meilleurs exemples d’application clinique de la pharmacogénétique avec le dépistage du déficit en thiopurine S-méthyltransférase (TPMT), enzyme clé du métabolisme des thiopurines. La variabilité interindividuelle de la réponse à ces médicaments rend nécessaire leur optimisation thérapeutique. Ce travail de thèse a d’une part, analysé les relations entre activité TPMT et concentrations des métabolites thiopuriniques, et d’autre part, recherché des facteurs associés à la résistance aux thiopurines. A l’aide d’une base de données pharmacogénétiques hospitalière et d’une étude « PheWAS » à partir d’un entrepôt de données cliniques, nous avons analysé la distribution et la corrélation génotype-phénotype pour la TPMT, en lien avec les concentrations des métabolites thiopuriniques. Nous avons observé qu’une activité TPMT très élevée (phénotype « ultra-rapide ») était associée à des paramètres clinico-biologiques reflétant une maladie évolutive et un traitement inefficace dans les MICI. De plus, une étude clinique rétrospective dans les MICI pédiatriques a permis d’identifier des facteurs associés à la lymphopénie observée sous thiopurines. Enfin, à partir d’un modèle in vitro fondé sur des lignées cellulaires lymphoblastoïdes (LCL) sélectionnées, nous avons établi une signature transcriptomique, incluant 32 gènes, prédictive de la résistance aux thiopurines. Une analyse fonctionnelle bioinformatique a abouti à l’identification de voies métaboliques liées à la protéine p53 et au cycle cellulaire, ainsi que des mécanismes moléculaires associés à la résistance aux thiopurines. En conclusion, ce travail de thèse, qui a exploré la variabilité de réponse aux thiopurines et tout particulièrement la résistance à ces médicaments, propose des hypothèses pour l’individualisation et l’optimisation thérapeutique des thiopurines

Thiopurine response optimization using pharmacogenomics : in vitro and clinical approaches

Les thiopurines sont des médicaments cytotoxiques et immunosuppresseurs largement prescrits, notamment dans les maladies inflammatoires chroniques de l’intestin (MICI). Ils représentent l’un des meilleurs exemples d’application clinique de la pharmacogénétique avec le dépistage du déficit en thiopurine S-méthyltransférase (TPMT), enzyme clé du métabolisme des thiopurines. La variabilité interindividuelle de la réponse à ces médicaments rend nécessaire leur optimisation thérapeutique. Ce travail de thèse a d’une part, analysé les relations entre activité TPMT et concentrations des métabolites thiopuriniques, et d’autre part, recherché des facteurs associés à la résistance aux thiopurines. A l’aide d’une base de données pharmacogénétiques hospitalière et d’une étude « PheWAS » à partir d’un entrepôt de données cliniques, nous avons analysé la distribution et la corrélation génotype-phénotype pour la TPMT, en lien avec les concentrations des métabolites thiopuriniques. Nous avons observé qu’une activité TPMT très élevée (phénotype « ultra-rapide ») était associée à des paramètres clinico-biologiques reflétant une maladie évolutive et un traitement inefficace dans les MICI. De plus, une étude clinique rétrospective dans les MICI pédiatriques a permis d’identifier des facteurs associés à la lymphopénie observée sous thiopurines. Enfin, à partir d’un modèle in vitro fondé sur des lignées cellulaires lymphoblastoïdes (LCL) sélectionnées, nous avons établi une signature transcriptomique, incluant 32 gènes, prédictive de la résistance aux thiopurines. Une analyse fonctionnelle bioinformatique a abouti à l’identification de voies métaboliques liées à la protéine p53 et au cycle cellulaire, ainsi que des mécanismes moléculaires associés à la résistance aux thiopurines. En conclusion, ce travail de thèse, qui a exploré la variabilité de réponse aux thiopurines et tout particulièrement la résistance à ces médicaments, propose des hypothèses pour l’individualisation et l’optimisation thérapeutique des thiopurines.Thiopurines are cytotoxic and immunosuppressive drugs widely prescribed, mainly in inflammatory bowel disease (IBD). They constitute one of the best success story of pharmacogenetic implementation into clinical practice based on the screening of thiopurine S-methyltransferase (TPMT) deficiency, a key enzyme in thiopurine metabolism. Optimization of thiopurine response is challenging because of its large interindividual variability such as inefficacy and toxicities. This thesis has explored, on one hand, the relationships between TPMT activity and metabolite concentrations, and on the other hand, factors associated with thiopurine inefficacy. Using a primary care pharmacogenetic database, we first analyzed TPMT distribution and genotype-phenotype correlation, in relation with thiopurine metabolites in a large population. Using a PheWAS study based on a clinical data warehouse we then reported that a very high TPMT activity (“ultra-rapid” phenotype) was associated with parameters of active IBD and poor response to thiopurines. Furthermore, a retrospective study in pediatric IBD identified factors predicting the occurrence of lymphopenia during thiopurine therapy. Finally, using a lymphoblastoid cell line (LCL) in vitro model, we established a transcriptomic signature, including 32 genes predicting thiopurine cellular resistance. A bioinformatic functional analysis identified metabolic pathways in relation with p53 and cell cycle, as well as molecular mechanisms associated with thiopurine resistance. To conclude, this research work, focusing on the variability of thiopurine response and mainly therapeutic resistance, provides new hypotheses to individualize and optimize therapeutic response to thiopurines

Conséquences de l'insuffisance hépatique sur la prise en charge thérapeutique des patients cirrhotiques post-hépatite C (étude rétrospective sur une cohorte de patients du service maladies infectieuses et tropicales de l'Hôpital Tenon)

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Twitter

Contexte et problématique : La formation médicale continue sur le médicament constitue, à l’heure actuelle, un vrai challenge, notamment dans le contexte de l’avènement des réseaux sociaux, et plus particulièrement de Twitter®, qui ont révolutionné l’accès à l’information. Exégèse : Le compte Twitter® @Reseau_CRPV a été créé par le Réseau français des centres régionaux de pharmacovigilance (RFCRPV) regroupant l’ensemble des 31 centres régionaux de pharmacovigilance (CRPV) en France et dont une des missions est l’information sur le médicament. Outre la diffusion d’information des agences officielles et une veille bibliographique, ce compte propose tous les vendredis un questionnaire à réponse unique (le #PharmacoQuiz), en lien avec les médicaments, et comportant quatre propositions. Les thématiques abordées sont vastes, des effets indésirables au bon usage des médicaments en passant par l’addictovigilance. La difficulté des quiz est établie grâce à un système de gradation par étoiles. La réponse détaillée est publiée le lundi suivant, associée à la diffusion d’informations provenant de la littérature scientifique en référence au quiz. Comme tout tweet, c’est également l’occasion pour la communauté scientifique d’échanger et de débattre sur une problématique spécifique liée au médicament. Par rapport aux méthodes traditionnelles de diffusion d’information ou d’enseignement, les médias sociaux offrent une flexibilité importante et facilitent les interactions entre celui qui diffuse l’information et les pairs ou étudiants. Conclusion : Le #PharmacoQuiz constitue le premier exemple français d’évaluation des connaissances dans le domaine de la pharmacologie via un réseau social. C’est un outil novateur et ludique de formation médicale continue qui contribue pleinement aux missions de formation et d’information des CRPV

Les recommandations INCa/HAS pour prévenir les toxicités au 5-FU et analogues sont-elles utiles ou futiles ? La question ne se pose plus

Suite à la publication de l’éditorial du Pr Pierre Michel (paru dans le numéro de septembre 2019), nous, biologistes pharmacologues, exerçant une activité de pharmacogénétique, de suivi thérapeutique pharmacologique, ou de pharmacovigilance, souhaitons apporter des précisions et corrections au texte publié qui met en cause l’intégrité des professionnels et la pertinence scientifique de nos disciplines. La [...

Association study between herpes zoster reporting and mRNA COVID‐19 vaccines (BNT162b2 and mRNA‐1273)

Several cases of herpes zoster (HZ) following mRNA COVID-19 vaccination (BNT162b2 and mRNA-1273) have been reported, and the first epidemiological evidence suggests an increased risk. We used the worldwide pharmacovigilance database VigiBase to describe HZ cases following mRNA COVID-19 vaccination. We performed disproportionality analyses (case/non-case statistical approach) to assess the relative risk of HZ reporting in mRNA COVID-19 vaccine recipients compared to influenza vaccine recipients and according to patient age. To 30 June 2021, of 716 928 reports with mRNA COVID-19 vaccines, we found 7728 HZ cases. When compared to influenza vaccines, mRNA COVID-19 vaccines were associated with a significantly higher reporting of HZ (reporting odds ratio 1.9, 95% CI 1.8–2.1). Furthermore, we found a reduced risk of reporting HZ among under 40-year-old persons compared to older persons (reporting odds ratio 0.39, 95% CI 0.36–0.41). Mild and infrequent HZ reactions may occur shortly after mRNA COVID-19 vaccination, at higher frequency than reported with influenza vaccination, especially in patients over 40 years old. Further analyses are needed to confirm this risk

Mining electronic health records for drugs associated with 28-days mortality in COVID-19: a pharmacopoeia wide association study (PharmWAS)

International audienceBackground Patients hospitalized for a given condition may be receiving other treatments for other contemporary conditions or comorbidities. The use of such observational clinical data for pharmacological hypothesis generation is appealing in the context of an emerging disease but particularly challenging due to the presence of drug indication bias. Objective With this study, our main objective was the development and validation of a fully data-driven pipeline that would address this challenge. Our secondary objective was to generate pharmacological hypotheses in patients with COVID-19 and demonstrate the clinical relevance of the pipeline. Methods We developed a pharmacopeia-wide association study (PharmWAS) pipeline inspired from the PheWAS methodology, which systematically screens for associations between the whole pharmacopeia and a clinical phenotype. First, a fully data-driven procedure based on adaptive least absolute shrinkage and selection operator (LASSO) determined drug-specific adjustment sets. Second, we computed several measures of association, including robust methods based on propensity scores (PSs) to control indication bias. Finally, we applied the Benjamini and Hochberg procedure of the false discovery rate (FDR). We applied this method in a multicenter retrospective cohort study using electronic medical records from 16 university hospitals of the Greater Paris area. We included all adult patients between 18 and 95 years old hospitalized in conventional wards for COVID-19 between February 1, 2020, and June 15, 2021. We investigated the association between drug prescription within 48 hours from admission and 28-day mortality. We validated our data-driven pipeline against a knowledge-based pipeline on 3 treatments of reference, for which experts agreed on the expected association with mortality. We then demonstrated its clinical relevance by screening all drugs prescribed in more than 100 patients to generate pharmacological hypotheses. Results A total of 5783 patients were included in the analysis. The median age at admission was 69.2 (IQR 56.7-81.1) years, and 3390 (58.62%) of the patients were male. The performance of our automated pipeline was comparable or better for controlling bias than the knowledge-based adjustment set for 3 reference drugs: dexamethasone, phloroglucinol, and paracetamol. After correction for multiple testing, 4 drugs were associated with increased in-hospital mortality. Among these, diazepam and tramadol were the only ones not discarded by automated diagnostics, with adjusted odds ratios of 2.51 (95% CI 1.52-4.16, Q=.1) and 1.94 (95% CI 1.32-2.85, Q=.02), respectively. Conclusions Our innovative approach proved useful in generating pharmacological hypotheses in an outbreak setting, without requiring a priori knowledge of the disease. Our systematic analysis of early prescribed treatments from patients hospitalized for COVID-19 showed that diazepam and tramadol are associated with increased 28-day mortality. Whether these drugs could worsen COVID-19 needs to be further assessed