Pharmacoépidémiologie et pharmacologie sociale des médicaments du diabète de type 2 : des données pharmacodynamiques de base à l'utilisation des bases de données. Etudes du risque de cancer de la vessie associé à la pioglitazone et du risque de pancréatite aigüe associé aux incrétinomimétiques

Notre travail est basé sur l'étude de deux événements indésirables associés à des médicaments du diabète de type 2. Premièrement, nous étudions le risque de cancer de la vessie lié à l'utilisation de la pioglitazone. Nous montrons que des erreurs dans la caractérisation de ses propriétés pharmacodynamiques, dans l'interprétation des données animales et dans le rapport de données d'un essai clinique ont pu retarder l'évaluation correcte de ce risque. La synthèse des résultats des différentes méthodes d'évaluation permet de montrer l'existence de ce risque. Deuxièmement, nous étudions la survenue de pancréatites aigues liées à l'utilisation des médicaments utilisant l'effet des incrétines (incrétinomimétiques). Après discussion des éléments pharmacodynamiques, nous présentons une étude réalisée à partir de la Base Nationale de Pharmacovigilance française et une étude de cohorte utilisant la base de données britannique du Clinical Practice Research Database dans laquelle risque de pancréatite aiguë associé à l'utilisation d'incrétinomimétique n'était pas été augmenté par rapport à l'utilisation de sulfonylurées. Nous montrons que l'évaluation du risque médicamenteux nécessite un faisceau d'argument issu de l'utilisation des multiples sources disponibles (données pharmacodynamiques de base, essais cliniques, études des bases de notifications spontanées et études observationnelles sur le médicament). L'analyse des limites méthodologiques et des limites liées aux facteurs sociaux impliqués nous permet de discuter l'évaluation du risque médicamenteux.In this thesis, we examine two adverse reactions associated with drugs used in type 2 diabetes. First, we study the risk of bladder cancer with the use of pioglitazone. We show that characterization of its pharmacodynamic properties, interpretation of animal data and results from a clinical trial were mistaken and could have delayed the correct assessment of this risk. The numerous observational studies are also discussed. The review of data from all assessment methods published during the last 15 years demonstrates the existence of this risk. Second, we study the occurrence of acute pancreatitis associated with incretin-based drugs. After discussing pharmacodynamic issues, we present a study showing a signal of pancreatitis associated with incretin-based drugs in the French National Pharmacovigilance Database. Then, the risk of acute pancreatitis was assessed in a cohort study from the UK Clinical Practice Research Database. Adjusted for several important cofactors, the use of incretin-based drugs was not associated with an increased risk of acute pancreatitis compared to sulfonylureas use. However, these results do not exclude potential chronic pancreatic inflammation or acute pancreatic adverse effects in the long term with incretin-based drugs. These examples allow us to emphasize the importance of basic pharmacodynamic data. We show that risk assessment needs the concordance of studies from all sources of data available (pharmacodynamics data, clinical trials, adverse events database studies and observational studies). We discuss the influence of methodological limits and limits related to social factors on the quality of drug risk studies

Diabetes Obes Metab

AIM: Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have been commercialized in France for type 2 diabetes since April 2020 and later for heart and renal diseases. Given the recent developments in treating diabetes and the widening of SGLT-2i indications, we aimed to study changes in the use of glucose-lowering drugs in France and to characterize SGLT-2i new users. METHODS: We performed a nationwide utilization study using the French health insurance database. Trends in incidence and prevalence of glucose-lowering drug use were assessed by a repeated cross-sectional study in 2019 and 2021. A cohort study of incident SGLT-2i users was then conducted to describe patient characteristics and the strategy for treating diabetes. RESULTS: The prevalence of SGLT-2i use gradually reached 0.1% in the third quarter of 2021 and increased more significantly to 0.2% thereafter. SGLT-2i became the second most prescribed glucose-lowering drug class after metformin at the end of 2021 (0.1%). Among the cohort of 125 387 SGLT-2i new users (mean age 65.0 years; 60.1% of men), 87.6% presented a diabetic comorbidity. The patient profile changed over the study period with an increasing proportion of patients with cardiovascular (28.7% in 2020 vs. 40.2% in 2021) or renal (7.7% in 2020 vs. 11.8% in 2021) comorbidities at initiation. The main combinations used at SGLT-2i initiation were metformin (12.5%) and metformin plus dipeptidyl peptidase-4 inhibitors (8.1%). One-year probability of SGLT-2i persistence was estimated to be 55%. CONCLUSION: The expansion of indications for SGLT-2i and the broadening of the target population make it essential to assess the reasons for discontinuation and review their safety profile

A pharmacological analysis of high-affinity sodium transport in barley (Hordeum vulgare L.): a 24Na+/42K+ study

Soil sodium, while toxic to most plants at high concentrations, can be beneficial at low concentrations, particularly when potassium is limiting. However, little is known about Na+ uptake in this ‘high-affinity’ range. New information is provided here with an insight into the transport characteristics, mechanism, and ecological significance of this phenomenon. High-affinity Na+ and K+ fluxes were investigated using the short-lived radiotracers 24Na and 42K, under an extensive range of measuring conditions (variations in external sodium, and in nutritional and pharmacological agents). This work was supported by electrophysiological, compartmental, and growth analyses. Na+ uptake was extremely sensitive to all treatments, displaying properties of high-affinity K+ transporters, K+ channels, animal Na+ channels, and non-selective cation channels. K+, NH4+NH4+, and Ca2+ suppressed Na+ transport biphasically, yielding IC50 values of 30, 10, and <5 μM, respectively. Reciprocal experiments showed that K+ influx is neither inhibited nor stimulated by Na+. Sodium efflux constituted 65% of influx, indicating a futile cycle. The thermodynamic feasibility of passive channel mediation is supported by compartmentation and electrophysiological data. Our study complements recent advances in the molecular biology of high-affinity Na+ transport by uncovering new physiological foundations for this transport phenomenon, while questioning its ecological relevance

Heterologous expression of the yeast HAL5 gene in tomato enhances salt tolerance by reducing shoot Na+accumulation in the long term

[EN] For salt tolerance to be achieved in the long-term plants must regulate Na+/K+ homeostasis over time. In this study, we show that the salt tolerance induced by overexpression of the yeast HAL5 gene in tomato (Solanum lycopersicum) was related to a lower leaf Na+ accumulation in the long term, by reducing Na+ transport from root to shoot over time regardless of the severity of salt stress. Furthermore, maintaining Na+/K+ homeostasis over time was associated with changes in the transcript levels of the Na+ and K+ transporters such as SlHKT1;2 and SlHAK5. The expression of SlHKT1;2 was upregulated in response to salinity in roots of transgenic plants but downregulated in the roots of wild-type (WT) plants, which seems to be related to the lower Na+ transport rate from root to shoot in transgenic plants. The expression of the SlHAK5 increased in roots and leaves of both WT and transgenic plants under salinity. However, this increase was much higher in the leaves of transgenic plants than in those of WT plants, which may be associated with the ability of transgenic leaves to maintain Na+/K+ homeostasis over time. Taken together, the results show that the salt tolerance mechanism induced by HAL5 overexpression in tomato is related to the appropriate regulation of ion transport from root to shoot and maintenance of the leaf Na+/K+ homeostasis through modulation of SlHKT1 and SlHAK5 over time.This work was funded by grant AGL2012-40150-C03 from the Spanish 'Ministerio de Economia y Competitividad' and grant 04553/GERM/06 from the Fundacion SENECA, Murcia (Spain). I. E. and B. P. were supported by a postdoctoral position from the JAE-Doc program of National Research Council (CSIC). We thank Prof. R Serrano (IBMCP-CSCIC, Valencia, Spain) for providing the plasmid vector. We thank Stephen Hasler for his help in editing the English version of the manuscript.García-Abellán, JO.; Egea, I.; Pineda Chaza, BJ.; Sánchez-Bel, P.; Belver, A.; García Sogo, B.; Flores, FB.... (2014). Heterologous expression of the yeast HAL5 gene in tomato enhances salt tolerance by reducing shoot Na+accumulation in the long term. Physiologia Plantarum. 152(4):700-713. https://doi.org/10.1111/ppl.12217S700713152

A New Drug–Drug Interaction Between Hydroxychloroquine and Metformin? A Signal Detection Study

Introduction Hydroxychloroquine was recently promoted in patients infected with COVID-19 infection. A recent experimental study has suggested an increased toxicity of hydroxychloroquine in association with metformin in mice. Objective The present study was undertaken to investigate the reality of this putative drug–drug interaction between hydroxychloroquine and metformin using pharmacovigilance data. Methods Using VigiBase®, the WHO pharmacovigilance database, we performed a disproportionality analysis (case/non-case study). Cases were reports of fatal outcomes with the drugs of interest and non-cases were all other reports for these drugs registered between 1 January 2000 and 31 December 2019. Data with hydroxychloroquine (or metformin) alone were compared with the association hydroxychloroquine + metformin. Results are reported as ROR (reporting odds ratio) with their 95% confidence interval. Results Of the 10,771 Individual Case Safety Reports (ICSR) involving hydroxychloroquine, 52 were recorded as ‘fatal outcomes’. In comparison with hydroxychloroquine alone, hydroxychloroquine + metformin was associated with an ROR value of 57.7 (23.9–139.3). In comparison with metformin alone, hydroxychloroquine + metformin was associated with an ROR value of 6.0 (2.6–13.8). Conclusion Our study identified a signal for the association hydroxychloroquine + metformin that appears to be more at risk of fatal outcomes (particularly by completed suicides) than one of the two drugs when given alone

Incretin-based therapies and risk of pancreatic cancer in patients with type 2 diabetes : A meta-analysis of randomized controlled trials

Aims: To perform a meta-analysis of randomized controlled trials (RCTs), including 6 recently published large-scale cardiovascular outcome trials (CVOTs), to evaluate the risk of pancreatic cancer with incretin-based therapies in patients with type 2 diabetes (T2DM). Materials and Methods: For the period January 1, 2007 to May 1, 2017, the PubMed, Embase, Cochrane Central Register and databases were searched for RCTs in people with T2DM that compared incretin drugs with placebo or other antidiabetic drugs, with treatment and follow-up durations of >= 52 weeks. Two reviewers screened the studies, extracted the data and assessed the risk of bias independently and in duplicate. Results: A total of 33 studies (n = 79971), including the 6 CVOTs, with 87 pancreatic cancer events were identified. Overall, the pancreatic cancer risk was not increased in patients administered incretin drugs compared with controls (Peto odds ratio [OR] 0.67, 95% confidence interval [CI] 0.44-1.02). In the 6 CVOTs, 79 pancreatic cancer events were identified in 55248 participants. Pooled estimates of the 6 CVOTs showed an identical tendency (Peto OR 0.65, 95% CI 0.42-1.01). Notably, in the subgroup of participants who received treatment and follow-up for >= 104 weeks, 84 pancreatic cancer events were identified in 59919 participants, and a lower risk of pancreatic cancer was associated with incretin-based therapies (Peto OR 0.62, 95% CI 0.41-0.95). Conclusions: Treatment with incretin drugs was not associated with an increased risk of pancreatic cancer in people with T2DM. Instead, it might protect against pancreatic malignancy in patients treated for 104 weeks.Peer reviewe

The structure of the KtrAB potassium transporter

In bacteria, archaea, fungi and plants the Trk, Ktr and HKT ion transporters are key components of osmotic regulation, pH homeostasis and resistance to drought and high salinity. These ion transporters are functionally diverse: they can function as Na+ or K+ channels and possibly as cation/K+ symporters. They are closely related to potassium channels both at the level of the membrane protein and at the level of the cytosolic regulatory domains. Here we describe the crystal structure of a Ktr K+ transporter, the KtrAB complex from Bacillus subtilis. The structure shows the dimeric membrane protein KtrB assembled with a cytosolic octameric KtrA ring bound to ATP, an activating ligand. A comparison between the structure of KtrAB-ATP and the structures of the isolated full-length KtrA protein with ATP or ADP reveals a ligand-dependent conformational change in the octameric ring, raising new ideas about the mechanism of activation in these transporters.We are grateful for access to ID14-1/ID14-4/ID-29 at ESRF (through the Portuguese BAG), PXII at SLS, XRD1 at ELETTRA and PROXIMA1 at SOLEIL and thank the respective support staff. A.S. was supported by FEBS (Long term fellowship). This work was funded by EMBO (Installation grant), by FEDER funds through the Operational Competitiveness Program-COMPETE and by National Funds through FCT-Fundacao para a Ciencia e a Tecnologia under the projects FCOMP-01-0124-FEDER-022718 (PEst-C/SAU/LA0002/2011), FCOMP-01-0124-FEDER-009028 (PTDC/BIA-PRO/099861/2008) and FCOMP-01-0124-FEDER-010781 (PTDC/QUI-BIQ/105342/2008). We also thank G. Gabant and M. Cadene at the 'Plateforme de Spectrometrie de Masse' at CBM, CNRS, Orleans for mass spectrometry analysis, and C. Harley for critical reading of the manuscript

Plant High-Affinity Potassium (HKT) transporters involved in salinity tolerance: structural insights to probe differences in ion selectivity

High-affinity Potassium Transporters (HKTs) belong to an important class of integral membrane proteins (IMPs) that facilitate cation transport across the plasma membranes of plant cells. Some members of the HKT protein family have been shown to be critical for salinity tolerance in commercially important crop species, particularly in grains, through exclusion of Na+ ions from sensitive shoot tissues in plants. However, given the number of different HKT proteins expressed in plants, it is likely that different members of this protein family perform in a range of functions. Plant breeders and biotechnologists have attempted to manipulate HKT gene expression through genetic engineering and more conventional plant breeding methods to improve the salinity tolerance of commercially important crop plants. Successful manipulation of a biological trait is more likely to be effective after a thorough understanding of how the trait, genes and proteins are interconnected at the whole plant level. This article examines the current structural and functional knowledge relating to plant HKTs and how their structural features may explain their transport selectivity. We also highlight specific areas where new knowledge of plant HKT transporters is needed. Our goal is to present how knowledge of the structure of HKT proteins is helpful in understanding their function and how this understanding can be an invaluable experimental tool. As such, we assert that accurate structural information of plant IMPs will greatly inform functional studies and will lead to a deeper understanding of plant nutrition, signalling and stress tolerance, all of which represent factors that can be manipulated to improve agricultural productivity.Shane Waters, Matthew Gilliham and Maria Hrmov

Harmonizing and improving European education in prescribing: An overview of digital educational resources used in clinical pharmacology and therapeutics

Aim: Improvement and harmonization of European clinical pharmacology and therapeutics (CPT) education is urgently required. Because digital educational resources can be easily shared, adapted to local situations and re-used widely across a variety of educational systems, they may be ideally suited for this purpose. Methods: With a cross-sectional survey among principal CPT teachers in 279 out of 304 European medical schools, an overview and classification of digital resources was compiled. Results: Teachers from 95 (34%) medical schools in 26 of 28 EU countries responded, 66 (70%) of whom used digital educational resources in their CPT curriculum. A total of 89 of such resources were described in detail, including e-learning (24%), simulators to teach pharmacokinetics and/or pharmacodynamics (10%), virtual patients (8%), and serious games (5%). Together, these resources covered 235 knowledge-based learning objectives, 88 skills, and 13 attitudes. Only one third (27) of the resources were in-part or totally free and only two were licensed open educational resources (free to use, distribute and adapt). A narrative overview of the largest, free and most novel resources is given. Conclusion: Digital educational resources, ranging from e-learning to virtual patients and games, are widely used for CPT education in EU medical schools. Learning objectives are based largely on knowledge rather than skills or attitudes. This may be improved by including more real-life clinical case scenarios. Moreover, the majority of resources are neither free nor open. Therefore, with a view to harmonizing international CPT education, more needs to be learned about why CPT teachers are not currently sharing their educational materials