Étude phénotypique des enzymes du métabolisme des thiopurines (ITPA, IMPDH), lien avec les métabolites thiopuriques et optimisation thérapeutique en gastro-entérologie

The aims of this study are 1) to evaluate inosine triphosphate pyrophosphatase (ITPA) and inosine monophoshate dehydrogenase (IMPDH) activities in red blood cells (RBCs) in relation to the monitoring of thiopurine metabolites and the phenotyping of thiopurine S-methyltransferase (TPMT), 2) to investigate a possible link between ITPA activity and the occurence of adverse effects observed under azathioprine (AZA) treatment.The retrospective study was carried out on a large population of healthy adults and children as well as those suffering from immunological diseases. A quadrimodal distribution of ITPA was identified among the population using a gaussian mixture model. A weak intraindividual variability of ITPA activity was found. In the paediatric population, a low ITPA activity is correlated with increased levels of methyl nucleotides, suggesting a risk of hepatotoxicity. The relationship observed between ITPA activity and both mean corpuscular volume and gammaglobulin levels in IBD children on AZA therapy suggests that the determination of ITPA activity may allow the prediction of a persistent inflammatory process in subjects with elevated ITPA activity.The phenotypic study of IMPDH shows no influence of age, sex and AZA therapy on the activity of IMPDH. Moreover a large interindividual variability in the activity of IMPDH was found. A bimodal distribution of IMPDH activity in RBCs was observed as well as a relation between this activity and the methyl nucleotides.Further study on the combined effect of the three enzymes ITPA, IMPDH and TPMT on the variability of response to thiopurine therapy will be consideredCette étude a pour objectifs 1) d'évaluer l'activité érythrocytaire de l'inosine triphosphate pyrophosphatase (ITPA) et de l'inosine monophosphate deshydrogénase (IMPDH) en lien avec le suivi des métabolites thiopuriques et le phénotypage de la thiopurine S-méthyltransférase (TPMT), 2) d'étudier le lien entre l'activité de l'ITPA et la survenue d'effets indésirables observés sous azathioprine (AZA).L'étude rétrospective réalisée sur une large population de sujets adultes et enfants, sains et atteints de maladies auto-immunes, a permis d'identifier une distribution quadrimodale de l'activité de l'ITPA à l'aide d'un modèle de mélange gaussien ainsi qu'une faible variabilité intra-individuelle de cette activité. Dans la population pédiatrique, une activité de l'ITPA basse est corrélée à une augmentation des dérivés méthylés suggérant un risque d'hépatotoxicité. Le lien observé entre l'activité ITPasique, le volume globulaire moyen et les gammaglobulines chez les enfants atteints de maladie inflammatoire chronique de l'intestin sous AZA suggère que la mesure de l'activité de l'ITPA permettrait d'anticiper la persistance d'un syndrome inflammatoire chez les sujets à activité élevée.L'étude phénotypique de l'IMPDH montre une importante variabilité inter-individuelle de l'activité de cette enzyme et l'absence d'influence de l'âge, du sexe et du traitement par AZA sur cette activité. Une distribution bimodale de l'activité de l'IMPDH érythrocytaire a été observée ainsi qu'un lien entre cette activité et les dérivés méthylés.En perspective, l'étude combinée des activités de l'ITPA, l'IMPDH et de la TPMT sur la variabilité de la réponse aux traitements thiopuriques sera envisagé

Phenotypic study of enzymes involved in thiopurine metabolism (ITPA, IMPDH), relationship with thiopurine metabolites and therapeutic optimization in gastro-enterology

Cette étude a pour objectifs 1) d'évaluer l'activité érythrocytaire de l'inosine triphosphate pyrophosphatase (ITPA) et de l'inosine monophosphate deshydrogénase (IMPDH) en lien avec le suivi des métabolites thiopuriques et le phénotypage de la thiopurine S-méthyltransférase (TPMT), 2) d'étudier le lien entre l'activité de l'ITPA et la survenue d'effets indésirables observés sous azathioprine (AZA).L'étude rétrospective réalisée sur une large population de sujets adultes et enfants, sains et atteints de maladies auto-immunes, a permis d'identifier une distribution quadrimodale de l'activité de l'ITPA à l'aide d'un modèle de mélange gaussien ainsi qu'une faible variabilité intra-individuelle de cette activité. Dans la population pédiatrique, une activité de l'ITPA basse est corrélée à une augmentation des dérivés méthylés suggérant un risque d'hépatotoxicité. Le lien observé entre l'activité ITPasique, le volume globulaire moyen et les gammaglobulines chez les enfants atteints de maladie inflammatoire chronique de l'intestin sous AZA suggère que la mesure de l'activité de l'ITPA permettrait d'anticiper la persistance d'un syndrome inflammatoire chez les sujets à activité élevée.L'étude phénotypique de l'IMPDH montre une importante variabilité inter-individuelle de l'activité de cette enzyme et l'absence d'influence de l'âge, du sexe et du traitement par AZA sur cette activité. Une distribution bimodale de l'activité de l'IMPDH érythrocytaire a été observée ainsi qu'un lien entre cette activité et les dérivés méthylés.En perspective, l'étude combinée des activités de l'ITPA, l'IMPDH et de la TPMT sur la variabilité de la réponse aux traitements thiopuriques sera envisagéeThe aims of this study are 1) to evaluate inosine triphosphate pyrophosphatase (ITPA) and inosine monophoshate dehydrogenase (IMPDH) activities in red blood cells (RBCs) in relation to the monitoring of thiopurine metabolites and the phenotyping of thiopurine S-methyltransferase (TPMT), 2) to investigate a possible link between ITPA activity and the occurence of adverse effects observed under azathioprine (AZA) treatment.The retrospective study was carried out on a large population of healthy adults and children as well as those suffering from immunological diseases. A quadrimodal distribution of ITPA was identified among the population using a gaussian mixture model. A weak intraindividual variability of ITPA activity was found. In the paediatric population, a low ITPA activity is correlated with increased levels of methyl nucleotides, suggesting a risk of hepatotoxicity. The relationship observed between ITPA activity and both mean corpuscular volume and gammaglobulin levels in IBD children on AZA therapy suggests that the determination of ITPA activity may allow the prediction of a persistent inflammatory process in subjects with elevated ITPA activity.The phenotypic study of IMPDH shows no influence of age, sex and AZA therapy on the activity of IMPDH. Moreover a large interindividual variability in the activity of IMPDH was found. A bimodal distribution of IMPDH activity in RBCs was observed as well as a relation between this activity and the methyl nucleotides.Further study on the combined effect of the three enzymes ITPA, IMPDH and TPMT on the variability of response to thiopurine therapy will be considere

Mise au point d'une technique de dosage de la pepsine dans les liquides de lavage broncho-alvéolaire de patients atteints de reflux gastro-œsophagien

LYON1-BU Santé (693882101) / SudocSudocFranceF

ITPA Activity in Adults and Children Treated With or Without Azathioprine: Relationship Between TPMT Activity, Thiopurine Metabolites, and Co-medications

International audienceBACKGROUND: The implication of inosine triphosphate pyrophosphatase (ITPA) on thiopurine drug response variability has been investigated but little data are available on its role on thiopurine metabolites. The ability of ITPA to modify the thiopurine metabolite levels is currently used to optimize azathioprine (AZA) therapy in relation to thiopurine S-methyltransferase (TPMT) activity, the aim of this study is to investigate ITPA phenotype in a large population and to evaluate the relation between ITPA and TPMT activities and thiopurine metabolites. METHODS: ITPA activity was determined in 183 adults and 138 children with or without AZA therapy. 6-thioguanine nucleotides (6-TGN), 6-methylmercaptopurine nucleotides (6-MeMPN) levels, and ITPA as well as TPMT activities were measured in red blood cells. Using the Gaussian mixture model, distribution of ITPA activity was evaluated. Intraindividual variability and influence of age, sex, AZA treatment and associated co-medications on ITPA activity were also assessed. RESULTS: This retrospective study shows a quadrimodal distribution in ITPA activity. No influence of age, sex, AZA therapy, and co-medications was found. In adults, ITPA activity was not significantly associated with 6-TGN or 6-MeMPN concentrations, whereas a weak negative correlation was observed with 6-MeMPN levels in pediatric populations (rs = -0.261; P = 0.024). A weak positive correlation was observed between ITPA and TPMT activities in children (rs = 0.289; P = 0.001). CONCLUSIONS: ITPA activity was poorly influenced by nongenetic parameters and has no influence on 6-TGN and 6-MeMPN concentrations in adults and only a weak correlation with 6-MeMPN and TPMT activity in children. These results demonstrate that ITPA is not a rate-limiting enzyme in the formation of 6-TGN but suggest that a decrease in ITPA activity in children may be a risk factor for accumulation of 6-MeMPN in cells

Interférence des métabolites de l’éthylène glycol sur le dosage ampérométrique du lactate sur analyseur ABL 825

Cas clinique : Un homme de 86 ans est retrouvé inconscient à son domicile sans notion d’intoxication. À son admission, il présente une acidose (pH = 7,24) associée à une hyperlactacidémie à 26 mmol/L sur ABL 825® Radiometer, secondairement contrôlée à 4,54 mmol/L sur Dimension R × L® Siemens. En raison d’interférences précédemment décrites sur la mesure du lactate lors d’intoxications à l’éthylène glycol, nous avons suspecté et confirmé une intoxication chez ce patient dont le taux sérique d’éthylène glycol a été retrouvé à 2,40 mmol/L (148,8 mg/L). Méthodes : Afin de tester l’interférence des métabolites de l’éthylène glycol sur ABL 825® nous avons réalisé des surcharges croissantes de 0,1 à 40 mmol/L, correspondant aux concentrations sanguines retrouvées en cas d’intoxication, en éthylène glycol et ses principaux métabolites : acide glycolique, acide oxalique, acide glyoxylique et glyoxal. Résultats : Trois des quatre métabolites testés interfèrent sur l’ABL 825® avec le dosage de l’acide lactique : l’acide glycolique, l’acide glyoxylique et le glyoxal. Le signal d’une mole d’acide glycolique est équivalent au signal de deux moles d’acide lactique. Une mole d’acide glyoxylique semble générer une réponse équivalente à une mole d’acide lactique. Enfin, le glyoxal donne une interférence moindre mais non négligeable. Conclusion : La détermination du lactate sur l’ABL 825® est sujette à des interférences majeures chez des sujets intoxiqués par l’éthylène glycol notamment avec l’acide glycolique qui est le métabolite le plus largement retrouvé en cas d’intoxication. Cette interférence doit être connue des utilisateurs de cet analyseur de gaz du sang

ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response

International audienceAzathioprine (AZA), a thiopurine drug, is widely used in the treatment of children with immunological diseases such as inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH); however, interindividual variability in the occurrence of adverse drug reactions (ADRs) and drug response is observed. This study investigated (i) the relationships between inosine triphosphate pyrophosphatase (ITPA) activity, an enzyme involved in thiopurine metabolism, and the occurrence of ADRs in children with immunological disease on AZA therapy, and (ii) the relationship between ITPA activity and the inflammatory activity observed in children with IBD. ITPA and TPMT activities were determined in 106 children with immunological disease on AZA therapy. Markers of hepatotoxicity, myelotoxicity, pancreatitis and inflammation as well as clinical information were retrospectively collected during regular medical visits. No significant association was found between ITPA activity and hepatotoxicity or clinical ADRs such as cutaneous reactions, arthralgia, flulike symptoms and gastrointestinal disorders. Concerning myelotoxicity, a significant relation was observed between ITPA activity and RBC mean corpuscular volume (MCV; p=0.003). This observation may be related to the significant relationship found between high ITPA activity and the increase in -globulin level reflecting inflammation (p=0.005). In our study, ITPA activity was not associated with occurrence of ADRs, but a relationship between high ITPA activity and -globulin, a marker of inflammation, was found in children with IBD. Therefore, measurement of ITPA activity may help to identify children with IBD predisposed to residual inflammation on AZA therapy. Further prospective studies are needed to confirm this result

Intoxication volontaire au vérapamil et au bisoprolol : à propos d’un cas

Objectif : Le traitement de l’hypertension artérielle primaire fait appel à différents médicaments cardiotropes aux effets toxiques comparables. Notre travail relate, chez un patient traité pour hypertension, une double intoxication au vérapamil et au bisoprolol initialement étiquetée bisoprolol seul, lors d’un premier screening toxicologique large. Matériel et méthodes : Le diagnostic de cette intoxication a été obtenu par la répétition de recherches larges par une méthode CLHP/UV/BD. Résultats : La découverte de l’intoxication double au bisoprolol et au vérapamil a été permise grâce à deux screening toxicologiques successifs. Les concentrations toxiques de vérapamil sont apparues après la décroissance des concentrations toxiques de bisoprolol, expliquant la persistance, dans le temps, des symptômes cardio-vasculaires. Cette intoxication a conduit le patient à séjourner en service de réanimation médicale pendant plusieurs jours. Les concentrations de vérapamil sont restées toxiques pendant 6 jours. Conclusion : Devant l’absence de modification des signes cliniques et la présence de forme galénique à libération prolongée, la répétition d’un screening toxicologique large plutôt qu’un dosage spécifique du toxique initialement suspecté, a permis le dépistage et le suivi d’une intoxication poly-médicamenteuse à molécules cardiotropes

Trends in Fatal Poisoning Among Drug Users in France From 2011 to 2021

Importance The DRAMES (Décès en Relation avec l’Abus de Médicaments Et de Substances) register is a database of drug-related deaths with the aim of identifying the psychoactive substances associated with and estimating the trends in these deaths. Our novel approach is based on the collection of data on all deaths for which toxicology experts have performed analyses. Objective To describe drug-related deaths in France and report trends over an 11-year period. Design, Setting, and Participants This case series used a national register to assess 4460 drug-related deaths that occurred from 2011 to 2021 in France. Data analyses were performed from January 1, 2012, to December 31, 2022. Main Outcomes and Measures Demographic characteristics; medical and substance abuse history; forensic autopsy findings; and toxicology reports. Results Among the 4460 deceased individuals (mean [SD] age, 37.8 [10.5] years), the mortality rate was highest among men (sex ratio, 4.4:1). Of the deaths involving a single or predominant drug, the legal substitution product, methadone, was the leading cause of death during the entire study period, ahead of heroin—44.7% and 35.9% for methadone vs 15.8% and 21.8% for heroin in 2011 and 2021, respectively. Between 2011 and 2021, most of the drug-related deaths shifted from licit to illicit drugs, and statistically significant variations were found for buprenorphine, cocaine, heroin, methadone, and other licit opioids. Deaths related to polydrug use increased from 23.2% in 2011 to 30.6% in 2021. In this context, opioids remained associated with most deaths, with at least 1 opioid being involved in approximately 9 of 10 cases (85.9%) in 2021. However, the main trend was the dramatic increase in drug combinations with cocaine, from less than one-third of cases in 2011 (30.8%) to more than half in 2021 (57.8%). Conclusions and Relevance This case series assessment of 4460 drug-related deaths found that opioids used alone or in combination were the main contributor to drug-related deaths, despite having a lower prevalence than other drugs. This finding is similar to that of other countries; however, in France licit methadone was the leading cause of opioid-related deaths (ahead of heroin) during the study period. Deaths associated with use of cannabis, new psychoactive substances, and stimulants (including amphetamine-type stimulants and cocaine, especially in combination) have increased and should be closely monitored

Search for the dimuon decay of the Higgs boson in pppp collisions at s\sqrt{s} = 13 TeV with the ATLAS detector

International audienceA search for the dimuon decay of the Higgs boson was performed using data corresponding to an integrated luminosity of 36.1  fb-1 collected with the ATLAS detector in pp collisions at s=13  TeV at the Large Hadron Collider. No significant excess is observed above the expected background. The observed (expected) upper limit on the cross section times branching ratio is 3.0 (3.1) times the Standard Model prediction at the 95% confidence level for a Higgs boson mass of 125 GeV. When combined with the pp collision data at s=7  TeV and s=8  TeV, the observed (expected) upper limit is 2.8 (2.9) times the Standard Model prediction