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The prevalence and incidence of cardiac pro-arrhythmic disorders are often influenced by sex due to specific effects on the QT interval. Androgens shorten QT, which may be protective against acquired long QT syndromes and their related arrhythmias in men such as torsade de pointes (TdP). On the other hand, androgens can potentiate Brugada and early repolarization syndromes, which are most prevalent in men. In this case series, we highlight four male patients with aborted SCD in the setting of abnormal testosterone status; two patients with TdP in a setting of testosterone deprivation (of which one drug-induced) and 2 patients with ventricular fibrillation associated with exogenous androgenic booster (Tribulus terrestris) intake. From this case series, we review the current available literature of the effects of androgen as a double-edged sword on the QTc interval and emphasize the importance of QTc monitoring in this subset of patients., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: Patients with type 2 diabetes mellitus (T2DM) have a prolonged QT interval and are at high risk of sudden cardiac death. A prolonged QT interval, indicative of impaired ventricular repolarization, is a risk factor for lethal ventricular arrhythmias, such as torsades-de-pointes (TdP)., Aims: To identify key clinical and biochemical covariates associated with Fridericia's corrected QT interval (QTcF) among euthyroid patients with T2DM, and to describe the temporal relationship between these factors and QTcF., Methods: We performed prospective, clinical, biochemical and electrocardiographic measurements among patients with T2DM enrolled in the DIACART study at Pitié-Salpêtrière Hospital, at T1 (baseline) and T2 (follow-up), with a median interval of 2.55 years., Results: Mean age (63.9±8.5 years), sex (22.35% women), drugs with known risk of TdP according to the CredibleMeds website (Cred-drugsTdP) and serum thyroid-stimulating hormone (TSH) concentrations correlated with QTcF in univariate analysis at both T1 and T2. In multivariable analysis, all these covariates except age were significantly associated with QTcF at both T1 (women: standardized β=0.24±0.07, P=0.001; Cred-drugsTdP: β=0.19±0.07, P=0.007; TSH concentration: β=0.18±0.07, P=0.01) and T2 (women: β=0.25±0.08, P=0.002; Cred-drugsTdP: β=0.25±0.08, P=0.001; TSH concentration: β=0.19±0.08, P=0.01). Furthermore, variation in QTcF over the years was associated with variation in TSH concentration (r=0.24, P=0.007) and changes in use of Cred-drugsTdP (r=0.2, P=0.02)., Conclusions: Serum TSH concentration and its variation were associated with QTcF and its variation, even after correcting for the main determinants of QTcF. Interventional optimization of TSH concentration in T2DM warrants further investigation to establish its impact on the risk of TdP and sudden cardiac death., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: Hydroxychloroquine (HCQ) dosage required to reach circulating levels that inhibit SARS-Cov-2 are extrapolated from pharmacokinetic data in non-COVID-19 patients., Methods: We performed a population-pharmacokinetic analysis from 104 consecutive COVID-19 hospitalized patients (31 in intensive care units, 73 in medical wards, n=149 samples). Plasma HCQ concentration were measured using high performance liquid chromatography with fluorometric detection. Modelling used Monolix-2019R2., Results: HCQ doses ranged from 200 to 800mg/day administered for 1 to 11days and median HCQ plasma concentration was 151ng/mL. Among the tested covariates, only bodyweight influenced elimination oral clearance (CL) and apparent volume of distribution (Vd). CL/F (F for unknown bioavailability) and Vd/F (relative standard-error, %) estimates were 45.9L/h (21.2) and 6690L (16.1). The derived elimination half-life (t1/2) was 102h. These parameters in COVID-19 differed from those reported in patients with lupus, where CL/F, Vd/F and t1/2 are reported to be 68L/h, 2440 L and 19.5h, respectively. Within 72h of HCQ initiation, only 16/104 (15.4%) COVID-19 patients had HCQ plasma levels above the in vitro half maximal effective concentration of HCQ against SARS-CoV-2 (240ng/mL). HCQ did not influence inflammation status (assessed by C-reactive protein) or SARS-CoV-2 viral clearance (assessed by real-time reverse transcription-PCR nasopharyngeal swabs)., Conclusion: The interindividual variability of HCQ pharmacokinetic parameters in severe COVID-19 patients was important and differed from that previously reported in non-COVID-19 patients. Loading doses of 1600mg HCQ followed by 600mg daily doses are needed to reach concentrations relevant to SARS-CoV-2 inhibition within 72hours in≥60% (95% confidence interval: 49.5-69.0%) of COVID-19 patients., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Aims: Following the serious adverse events that occurred in January 2016 during the BIA 10-2474 First-in-Human study, the French Ministry of Health asked the Regional Health Agencies to inspect operations at all research sites conducting phase I/II clinical trials of experimental drugs. The aim of this study was to assess the medical relevance of the inspections made in Île-de-France (Paris region) in 2017., Methods: All 30 sites of Île-de-France region fully authorized to perform phase I/II trials were inspected by a public health physician and a public health pharmacist. Their reported list of observations was submitted to three physicians with longstanding experience of early pharmacology studies performed in academic or private research facilities. These physicians were asked to adjudicate each observation according to their perceived medical importance regarding safety. Adjudications were first performed separately and disagreements were later settled during a final adjudication meeting., Results: At least one disagreement occurred initially among the 3 adjudicators for 84 of the 120 observations (70%) reported by the inspectors. Following reconciliation, the 3 physicians agreed that 20% of the observations were likely to have potentially serious medical consequences. These observations mainly concerned the management of emergencies and of serious adverse events and the continuity of care., Conclusions: Maintenance of on-site inspections periodically carried out by regulatory authorities granting authorisations to perform phase I/II trials are justified. However, the medical relevance of these inspections can be improved with more emphasis on factors affecting the safety of research participants than on administrative or purely regulatory issues., (Copyright © 2020 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Over the past decades, assessment of drug safety and of their benefits harms balance has been profoundly modified by the availability of large databases and computerized automated statistical approaches. Improvement of digital data storage capacity has been applied to pharmacovigilance reports. VigiBase, the international pharmacovigilance database, is now aggregating over 21 million individual case safety reports in 2020. Identification and investigation of drug safety signals - concerning notably rare and unknown adverse drug reactions - is one of the major tasks in pharmacovigilance that can be amplified by automated signal detection. Several quantitative statistical methods exist, each with its own strengths and limits. Integrating signal detection, pharmacovigilance databases can be used for a wide variety of retrospective observational studies illustrated here by concrete examples. Confirming these signals by orthogonal validation using pre-clinical platforms and prospective trials is helpful. Pharmacovigilance databases represent a considerable source of information. However, the quality of signal detection and of pharmacoepidemiology studies in the field of adverse drug reaction closely depends on the quality of the individual data recorded., (Copyright © 2020 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: Abiraterone and enzalutamide are recently-approved androgen deprivation therapies (ADTs) for metastatic prostate cancer, with unknown cardiac safety profiles. Abiraterone has a propensity to hypermineralocorticism on top of androgen deprivation, so might carry an additional risk for atrial tachyarrhythmia (AT) and heart failure (HF) compared with other ADTs., Aim: To determine if abiraterone was associated with an increased proportion of AT and HF reports among all suspected adverse drug reactions (ADRs) reported in several pharmacovigilance databases compared with enzalutamide, other ADTs and all other drugs., Methods: In this observational retrospective pharmacovigilance study, we performed a disproportionality analysis of reports of suspected ADRs in men in the French pharmacovigilance database, the European pharmacovigilance database and the international pharmacovigilance database VigiBase, to evaluate the reporting odds ratios (RORs) of AT and HF for abiraterone compared with enzalutamide, other ADTs and all other drugs., Results: In the 5,759,781 ADR reports in men in VigiBase, 55,070 pertained to ADTs. The RORs for AT for abiraterone versus enzalutamide, other ADTs and all other drugs were 4.1 (95% confidence interval 3.1-5.3), 3.7 (3-4.5) and 3.2 (2.7-3.7), respectively (P<0.0001 for all). The corresponding RORs for HF were 2.5 (2-3), 1.5 (1.3-1.7) and 2 (1.7-2.3), respectively (P<0.0001 for all). These results were concordant with the French and European pharmacovigilance databases. Mean times to AT and HF onset were shorter with abiraterone (5.2±0.8 and 4.5±0.6 months, respectively) versus other ADTs (13.3±3.2 and 9.2±1.1 months, respectively) (both P<0.05). Cases on abiraterone versus other ADTs were more frequently associated with at least two ADR terms, including AT, HF, hypokalaemia, hypertension and oedema (13.6% vs 6%; P<0.0001). For abiraterone, age, but not dose, was associated with reporting of AT and HF versus any other ADR., Conclusions: Compared with other ADTs, abiraterone was associated with higher reporting of AT and HF, associated with hypokalaemia, hypertension and oedema. These findings are consistent with the hypermineralocorticism induced by abiraterone, but not by other ADTs., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Long QT syndrome (LQTS) can cause the potentially fatal ventricular tachycardia torsades de pointes (TdP). QT interval corrected for heart rate (QTc) is shorter in men than in women, with testosterone contributing to shorten QTc. We recently described male hypogonadism as a reversible risk factor for acquired LQTS and TdP, but the clinical characteristics of such patients have not been characterized., Aims: To describe the clinical characteristics of men with acquired LQTS or TdP associated with hypogonadism caused by endocrine conditions or androgen deprivation therapy (ADT), and to evaluate the relationship between testosterone concentrations and electrocardiographic changes., Methods: We searched MEDLINE (to 04 January 2019) and the French pharmacovigilance database (to 09 August 2018) to identify male cases of acquired LQTS and TdP associated with endocrine hypogonadism or ADT; their narratives were gathered from reporting collaborators., Results: We identified seven cases of TdP (one fatal) with endocrine hypogonadism, abnormally long QTc and morphologically abnormal T-wave notches. After reversion of low testosterone concentrations in the surviving patients (N=6), QTc shortened, T-wave morphology normalized and there was no TdP recurrence. Among these cases, none had mutation in the LQTS genes, three men required testosterone and three had reversible hypogonadism after resolution of a concurrent acute severe illness. We found an additional 27 reports of men with LQTS (N=6), TdP (N=9; 2/9 fatal) or sudden death (N=12; 10/12 fatal) suspected to be induced or favoured by ADT (24/27 for prostate cancer). Generally, after ADT withdrawal, QTc shortened and no TdP recurred., Conclusion: We propose seeking for hypogonadism caused by endocrine conditions or ADT in men presenting with TdP. Caution is warranted when ADT is used in situations at risk of TdP. Testosterone may be useful to treat or prevent TdP., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: The gold standard method for assessing the QTcF (QT corrected for heart rate by Fridericia's cube root formula) interval is the "QTcF semiautomated triplicate averaging method" (TAM), which consists of measuring three QTcF values semiautomatically, for each 10-second sequence of a triplicate electrocardiogram set, and averaging them to get a global and unique QTcF value. Thus, TAM is time consuming. We have developed a new method, namely the "QTcF semiautomated triplicate concatenation method" (TCM), which consists of concatenating the three 10-second sequences of the triplicate electrocardiogram set as if they were a single 30-second electrocardiogram, and measuring QTcF only once for the triplicate electrocardiogram set., Aim: To compare the TCM method with the TAM method., Methods: Fifty triplicate electrocardiograms were read twice by an expert and a student using both methods (TAM and TCM). We plotted Bland-Altman plots to assess agreement between the two methods, and to compare the student and expert results. The time needed to read a set of 20 consecutive triplicate electrocardiograms was measured., Results: Limits of agreement between TAM and TCM ranged from -8.25 to 6.75ms with the expert reader. TCM was twice as fast as TAM (17.38 versus 34.28min for 20 consecutive triplicate electrocardiograms). Bland-Altman plots comparing student and expert results showed limits of agreement ranging from -4.34 to 11.75ms for TAM, and -1.2 to 8.0ms for TCM., Conclusions: TAM and TCM show good agreement for QT measurement. TCM is less time consuming than TAM. After a learning session, an inexperienced reader can measure the QT interval accurately with both methods., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Several studies have suggested that proton-pump inhibitors (PPIs), mostly omeprazole, interact with clopidogrel efficacy by inhibiting the formation of its active metabolite via CYP2C19 inhibition. Whether this occurs with all PPIs is a matter of debate. As rabeprazole is a less potent CYP2C19 inhibitor than other PPIs, we studied the interaction between rabeprazole and the antiplatelet actions and pharmacokinetics of clopidogrel., Aim: To demonstrate the non-inferiority of rabeprazole over placebo using change in platelet reactivity index (PRI; vasodilator-stimulated phosphoprotein [VASP] assay) in a predefined population of good clopidogrel responders. Omeprazole was used as the positive control., Methods: In this randomized three-period crossover study in healthy volunteers, 36 healthy men received clopidogrel (75 mg/day for 7 days) with placebo, omeprazole (20mg/day) or rabeprazole (20mg/day). Clopidogrel antiplatelet effects and disposition kinetics were assessed on day 7 of combination therapy. Non-inferiority threshold was predefined as an upper limit of the 90% confidence interval for the difference in change in PRI between placebo and rabeprazole of<10% in good clopidogrel responders., Results: In good clopidogrel responders (inhibition of VASP index>30%), the clopidogrel antiplatelet effect remained non-inferior to placebo during rabeprazole (difference 3.4% [-1.7; 8.5]) but not omeprazole (difference 7.5% [2.5; 12.6]) co-administration. The AUC0-24 and Cmax of active clopidogrel metabolite decreased with both omeprazole and rabeprazole, and conditions of bioequivalence were not met, except for AUC0-24 with rabeprazole., Conclusions: Rabeprazole does not interact with clopidogrel to the same extent as omeprazole. However, under our experimental conditions and proton-pump inhibitor doses, there was no significant pharmacodynamic interaction between rabeprazole or omeprazole and clopidogrel, despite a significant decrease in the formation of clopidogrel active metabolite., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

The development of medicinal products is subject to quality standards aimed at guaranteeing that database contents accurately reflect the source documents. Paradoxically, these standards hardly address the quality of the source data itself. The objective of this work was to propose recommendations to improve data quality in three fields (pharmacovigilance, pharmacoepidemiology and clinical studies). The analysis was focused on the data and on the critical stages presenting critical quality problems, for which the current guidelines are insufficiently detailed, unsuitable and/or poorly applied. Finally, recommendations have been proposed, mainly focused on the origin of the data and its transcription., (© 2013 Société Française de Pharmacologie et de Thérapeutique.)

The handling of conflicts of interest in the area of healthcare products and technology has become a major issue for all of those involved in healthcare. Round Table N°4 at the Giens Workshops 2011 has put forward concrete proposals to clarify and optimise the handling of conflicts of interest. Conflicts of interest cannot be defined by the individuals consulted or applying for funds since each institution, whether public or private, that puts out a call for projects or that requests advice, analyses or expert testimony in the healthcare field has different degrees of what it defines as a conflict of interest, depending on the context of the proposal or specific request that it puts out. In contrast, each individual has ties of personal interest that can and must be openly disclosed. The ties are much more diverse than what is commonly found in the conflict of interest statements of large institutions operating in the healthcare field and are not limited to financial and operational ties between companies and individuals. In addition, the statements are difficult to manage because of their sheer number. The Round Table recommends that each individual should openly disclose all of his or her ties of personal interest in a Single Statement of Ties of personal Interest (SSTI). The SSTI would be updated regularly and accessible on line. Each institution could then determine whether or not the reported ties represent a conflict in the context of the mission proposed. Each institution could publish in advance the conditions that would give rise to a conflict and, in this way, an individual could refrain from applying for the mission. Other practical approaches to handling conflicts of interest were put forward., (© 2012 Société Française de Pharmacologie et de Thérapeutique.)

Three cases of intoxication by flecainide acetate were characterized by cardiovascular collapse with widening of the QRS complex at electrocardiography. In two of these patients, impairment of liver or renal function probably played a facilitating role. Infusion of molar sodium lactate in high doses resulted in rapid and durable clinical and electrocardiographic improvement. This effect of molar sodium lactate may tentatively be attributed to either displacement of flecainide from its tissue receptor sites, or to a decrease in the effect of flecainide by alteration of its action on the fast sodium channel, or to the beneficial effects of vascular filling.