HL-1 cells express an inwardly rectifying K+ current activated via muscarinic receptors comparable to that in mouse atrial myocytes

An inwardly rectifying K^+ current is present in atrial cardiac myocytes that is activated by acetylcholine (I_{KACh}). Physiologically, activation of the current in the SA node is important in slowing the heart rate with increased parasympathetic tone. It is a paradigm for the direct regulation of signaling effectors by the Gβγ G-protein subunit. Many questions have been addressed in heterologous expression systems with less focus on the behaviour in native myocytes partly because of the technical difficulties in undertaking comparable studies in native cells. In this study, we characterise a potassium current in the atrial-derived cell line HL-1. Using an electrophysiological approach, we compare the characteristics of the potassium current with those in native atrial cells and in a HEK cell line expressing the cloned Kir3.1/3.4 channel. The potassium current recorded in HL-1 is inwardly rectifying and activated by the muscarinic agonist carbachol. Carbachol-activated currents were inhibited by pertussis toxin and tertiapin-Q. The basal current was time-dependently increased when GTP was substituted in the patch-clamp pipette by the non-hydrolysable analogue GTPγS. We compared the kinetics of current modulation in HL-1 with those of freshly isolated atrial mouse cardiomyocytes. The current activation and deactivation kinetics in HL-1 cells are comparable to those measured in atrial cardiomyocytes. Using immunofluorescence, we found GIRK4 at the membrane in HL-1 cells. Real-time RT-PCR confirms the presence of mRNA for the main G-protein subunits, as well as for M2 muscarinic and A1 adenosine receptors. The data suggest HL-1 cells are a good model to study IKAch

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

Antipsychotic Abuse, Dependence, and Withdrawal in the Pediatric Population: A Real-World Disproportionality Analysis

Antipsychotic drugs (APs) aim to treat schizophrenia, bipolar mania, and behavioral symptoms. In child psychiatry, despite limited evidence regarding their efficacy and safety, APs are increasingly subject to off-label use. Studies investigating addictology-related symptoms in young people being scarce, we aimed to characterize the different patterns of AP misuse and withdrawal in children and adolescents relying on the WHO pharmacovigilance database (VigiBase®, Uppsala Monitoring Centre, Sweden). Using the standardized MedDRA Query ‘drug abuse, dependence and withdrawal’, disproportionality for each AP was assessed with the reporting odds ratio and the information component. A signal was detected when the lower end of the 95% confidence interval of the information component was positive. Results revealed mainly withdrawal symptoms in infants (under 2 years), intentional misuse in children (2 to 11 years), and abuse in adolescents (12 to 17 years). Olanzapine, risperidone, aripiprazole, and quetiapine were disproportionately reported in all age groups, with quetiapine being subject to a specific abuse signal in adolescents. Thus, in adolescents, the evocation of possible recreational consumption may lead to addiction-appropriate care. Further, in young patients with a history of AP treatment, a careful anamnesis may allow one to identify misuse and its role in the case of new-onset symptoms

Comparaison de deux protocoles antalgiques utilisés au cours de la ponction folliculaire sur les taux de réussite en fécondation in vitro

Objectives: Analgesic protocols administered before a follicular puncture under local anesthesia are well tolerated when using NSAIDs, but we still do not know their possible impacts on in vitro fertilization (IVF) outcomes. Material and methods: A retrospective monocentric study using two consecutive temporal cohorts of patients was conducted to compare two analgesic protocols: paracetamol/alprazolam (P/A), then nefopam/ketoprofen (N/K). Results: We demonstrated that biochemical pregnancy rate and the others outcomes of IVF are not significantly influenced by the type of analgesic protocol used. Conclusion: The protocol N/K enhances patient comfort without jeopardizing the IVF success rates. © 2010 Elsevier Masson SAS. All rights reserved

New Strategies for Volume Control in Patients with Diabetes Mellitus, a Narrative Review

Sodium is reabsorbed all along the renal tubules. The positive impacts of sodium-glucose cotransporter-2 inhibitors (SGLT2i), angiotensin receptor neprilysin inhibitor (ARNI) and mineralocorticoid receptor antagonists (MRA) on hard renal and/or cardiac endpoints calls for the role of diuretics in nephroprotection and cardioprotection in patients with diabetes mellitus to be reviewed. Here, we review: (a) the mechanisms of action of the available natriuretics; (b) the physiological adaptations to chronic loop diuretic usage that lead to increased sodium reabsorption in the proximal and distal convoluted tubules; (c) the physiology of sodium retention in patients with diabetes mellitus; and (d) the mechanisms of aldosterone breakthrough. We show the rationale for combined diuretics to target not only the loop of Henle, but also the proximal and distal convoluted tubules. Indeed, higher residual proteinuria in patients treated with renin-angiotensin-aldosterone system (RAAS) blockers portends poorer renal and cardiovascular outcomes. Diuretics are known to optimize the reduction of proteinuria, in addition to RAAS blockers, but may favor aldosterone breakthrough in the absence of MRA. The aim of our study is to support a combined diuretics strategy to improve the management of patients with diabetes mellitus and chronic kidney disease or heart failure

Adverse Drug Reactions of Olanzapine, Clozapine and Loxapine in Children and Youth: A Systematic Pharmacogenetic Review

Children and youth treated with antipsychotic drugs (APs) are particularly vulnerable to adverse drug reactions (ADRs) and prone to poor treatment response. In particular, interindividual variations in drug exposure can result from differential metabolism of APs by cytochromes, subject to genetic polymorphism. CYP1A2 is pivotal in the metabolism of the APs olanzapine, clozapine, and loxapine, whose safety profile warrants caution. We aimed to shed some light on the pharmacogenetic profiles possibly associated with these drugs’ ADRs and loss of efficacy in children and youth. We conducted a systematic review relying on four databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 recommendations and checklist, with a quality assessment. Our research yielded 32 publications. The most frequent ADRs were weight gain and metabolic syndrome (18; 56.3%), followed by lack of therapeutic effect (8; 25%) and neurological ADRs (7; 21.8%). The overall mean quality score was 11.3/24 (±2.7). In 11 studies (34.3%), genotyping focused on the study of cytochromes. Findings regarding possible associations were sometimes conflicting. Nonetheless, cases of major clinical improvement were fostered by genotyping. Yet, CYP1A2 remains poorly investigated. Further studies are required to improve the assessment of the risk–benefit balance of prescription for children and youth treated with olanzapine, clozapine, and/or loxapine

Medications as a Trigger of Sleep-Related Eating Disorder: A Disproportionality Analysis

Sleep-related eating disorder (SRED) is a parasomnia with recurrent, involuntary, amnestic eating episodes during sleep. There is growing evidence of the association between SRED and medications. Therefore, we aimed to rank drugs showing the strongest association. VigiBase® (WHO pharmacovigilance database) was queried for all reports of “Sleep-related eating disorder”. Disproportionality analysis relied on the Reporting Odds Ratio, with its 95% Confidence Interval (CI), and the Information Component. Our VigiBase® query yielded 676 cases of drug-associated SRED. Reports mostly involved zolpidem (243, 35.9%), sodium oxybate (185, 27.4%), and quetiapine (97, 14.3%). Significant disproportionality was found for 35 medications, including zolpidem (387.6; 95%CI 331.2–453.7), sodium oxybate (204.2; 95%CI 172.4–241.8), suvorexant (67.3; 95%CI 38.0–119.2), quetiapine (53.3; 95%CI 43.0–66.1), and several psychostimulants and serotonin-norepinephrine reuptake inhibitors (SNRIs). Patients treated with nonbenzodiazepines or SNRIs were significantly older (mean age: 49.0 vs. 37.5; p < 0.001) and their SRED were more likely to be serious (62.6% vs. 51.4%; p = 0.014) than patients treated with sodium oxybate or psychostimulants. Psychotropic drugs are involved in almost all reports. In patients with SRED, an iatrogenic trigger should be searched for