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Background: Arterial hypertension has been recently reported from randomized controlled trials (RCTs) assessing poly (ADP‐ribose) polymerase inhibitor (PARPi). Objective: In a context of increasing use of PARPi, it is crucial to properly assess risk and incidence of this adverse event for clinical practice. Methods: We performed a systematic review and meta‐analysis in MEDLINE, Cochrane CENTRAL and ClinicalTrials.gov up to January 4, 2023 with an ongoing surveillance up to June 7, 2023. RCTs comparing PARPi to placebo in adult patients with solid tumors were included if hypertension was reported. The primary outcome was the summary risk ratio (RR, with 95% CIs) of any hypertension of PARPi class in placebo RCTs. Secondary outcomes were the summary risk and incidence of hypertension of each individual PARPi. To provide clinical features of PARPi‐associated hypertension, we independently queried the WHO's pharmacovigilance database, up to September 1, 2022. Results: In total, 41 placebo RCTs (n = 15 264 adult patients) were included. PARPi class was not associated with an increased risk of hypertension compared with placebo. In individual analyses, the risk of hypertension was lower with olaparib than placebo (RR 0.77 [95% CI: 0.68–0.86], P < 0.01; I2 = 19%, χ2P = 0.26). Niraparib monotherapy increased the risk of any (RR 2.84 [95% CI: 1.76–4.57], P < 0.01; I2 = 66%, χ2P = 0.01) hypertension with a summary incidence of 19.87% (95% CI: 15.23–25.50). In real‐life setting, niraparib‐associated hypertension occurs within 20 days and was serious in 66%. Co‐prescription of at least one antihypertensive or therapy‐induced hypertension was reported in 20.5% or 14.4% of cases, respectively. Conclusions: In a context of extensive assessment of niraparib in combination, these data reinforce the need of a close monitoring of this adverse event to preserve its clinical benefit on patients' survival. [ABSTRACT FROM AUTHOR]

Due to their negative effects on hypoxic pulmonary vasoconstriction, dihydropyridine calcium channel inhibitors (DCCIs) can lead to hypoxia in patients with a pulmonary shunt. To date, only preclinical studies and case reports have focused on this potential adverse drug reaction. We aimed to assess the reporting association between DCCIs and hypoxia using the World Health Organization pharmacovigilance database (VigiBase). We performed a disproportionality analysis to evaluate the strength of the reporting association between i.v. clevidipine and nicardipine, thought to be a surrogate of patients in the intensive care unit, and hypoxia. The information component and the lower end of its 95% credibility interval were used to evaluate disproportionality. A description of the cases was made. Secondary outcomes included the association between all DCCIs and hypoxia compared with other treatments with similar indications, urapidil and labetalol, regardless of the route of administration. Association between oral nicardipine and hypoxia was also searched. A statistically significant signal of hypoxia was found for intravenous clevidipine and nicardipine. The time to onset was reported with a median of 2 days (interquartile range 1.5–4.5). Four dechallenges were performed with intravenous nicardipine, leading to the resolution of the symptoms. Regardless of the route of administration, a signal of hypoxia was also found for nimodipine but not for other drugs, including comparators. For nicardipine no signal of hypoxia was found with the oral route of administration. Our pharmacovigilance database analysis showed a significant association between the use of intravenous DCCIs and hypoxia. [ABSTRACT FROM AUTHOR]

Aims: Due to their central mechanism of action, antiseizure medications (ASMs) could lead to adverse effects likely to impair driving skills. Their extended use to neuropsychiatric disorders makes it a class of drugs to monitor for their road traffic accidental (RTA) potential. We aimed to assess the reporting association between ASMs and RTAs using the World Health Organization pharmacovigilance database (VigiBase). Methods: We performed a disproportionality analysis to compute adjusted reporting odds ratios to evaluate the strength of reporting association between ASMs and RTAs. A univariate analysis using the reporting odds‐ratio was used to assess drug–drug interactions between ASMs and RTAs. Results: There were 1 341 509 reports associated with at least 1 ASM in VigiBase of whom 2.91‰ were RTAs reports. Eight ASMs were associated with higher reporting of RTAs compared to others (ranging from 1.35 [95% confidence interval 1.11–1.64] for lamotrigine to 4.36 [95% confidence interval 3.56–5.32] for cannabis). Eight significant drug–drug interactions were found between ASMs and the onset of RTA, mainly involving CYP450 induction. Conclusion: A significant safety signal between RTAs and some ASMs was identified. Association of several ASMs might further increase the occurrence of RTA. ASMs prescription in patients with identified risk factors of RTA should be considered with caution. Study number: ClinicalTrials.gov, NCT04480996. [ABSTRACT FROM AUTHOR]

Introduction: Acquired hemophilia A (AHA) is a rare autoimmune hemorrhagic disease occurring in several underlying conditions. Drug‐associated AHA (D‐AHA) is poorly addressed nowadays. Aim: This work aims to identify and characterize which drugs are associated with AHA using the WHO global database of reported potential effects of medicinal products (VigiBase). Methods: First, we realized a disproportionality analysis using the information component (IC) to identify D‐AHA in VigiBase. IC compares observed‐ and expected‐values in order to find associations between drugs and adverse drug reactions (ADRs) using disproportionate Bayesian reporting. IC025 is the lower end of a 95% credibility interval for the IC. Then, we collected cases of drugs significantly associated with AHA from July 2004 to November 2021. Results: 14 drugs with IC025 > 0 were identified representing a total of 185 cases. D‐AHA occurred more frequently in men (59%) than women (41%). The median (min–max) age at onset was 75 years (8–98). The median [Q1–Q3] time to onset of D‐AHA from the start of the suspected drug was 30 days [9.5–73.75] and 10% of cases resulted in a fatality. The drugs associated with the highest IC025 (IC025 > 2) were Clopidogrel, Alemtuzumab, Omalizumab. This study retrieved for the first time three usually used drugs (3/14) that exhibit a significant pharmacovigilance signal for D‐AHA. Conclusion: This worldwide pharmaco‐epidemiologic study updates the list of the drugs associated with AHA. The clinician should be aware of these possible severe ADR, which might require larger epidemiological and pathophysiologic studies. [ABSTRACT FROM AUTHOR]

Background: Transverse myelitis (TM) has recently been associated by health authorities with Ad26.COV2.S (Janssen/Johnson & Johnson), one of the 5 US Food and Drug Administration (FDA) or European Medicines Agency (EMA) labeled severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) vaccines. It is unknown whether a similar association exists for the other FDA or EMA labeled SARS‐CoV‐2 vaccines (BNT162b2 [Pfizer/BioNTech], mRNA‐1273 [Moderna], ChAdOx1nCov‐19 [Oxford–AstraZeneca], and NVX‐CoV2373 [Novavax]). This study aimed to evaluate the association between SARS‐CoV‐2 vaccine class and TM. Methods: This observational, cross‐sectional, pharmacovigilance cohort study examined individual case safety reports from VigiBase, the World Health Organization's pharmacovigilance database. We first conducted a disproportionality analysis with the information component (IC) using the reports of TM that occurred within 28 days following exposure to the FDA or EMA labeled SARS‐CoV‐2 vaccines, from December 1, 2020 (first adverse event related to a SARS‐CoV‐2 vaccine) to March 27, 2022. Second, we analyzed the clinical features of SARS‐CoV‐2 vaccine‐associated TM cases reported in VigiBase. Results: TM was significantly associated both with the messenger ribonucleic acid (mRNA)‐based (n = 364; IC025 = 0.62) and vector‐based (n = 136; IC025 = 0.52) SARS‐CoV‐2 vaccines that are authorized by the FDA or the EMA. Conclusions: Findings from this observational, cross‐sectional pharmacovigilance study showed that mRNA‐based and vector‐based FDA/EMA labeled SARS‐CoV‐2 vaccines can be associated with TM. However, because TM remains a rare event, with a previously reported rate of 0.28 cases per 1 million vaccine doses, the risk–benefit ratio in favor of vaccination against SARS‐CoV‐2 virus remains unchallenged. Rather, this study suggests that clinicians should consider the diagnosis of TM in patients presenting with early signs of spinal cord dysfunction after SARS‐CoV‐2 vaccination. ANN NEUROL 2022;92:1080–1089 [ABSTRACT FROM AUTHOR]

Objective: The literature supporting the role of a specific drug in the onset of drug‐induced antineutrophil cytoplasmic antibody–associated vasculitis (AAV) mainly relies on case reports or short series and implicates old treatments. The advent of new treatments may have modified the epidemiology of these adverse drug reactions. This study was undertaken to update the list of drugs associated with AAV by using a pharmacovigilance‐based data mining approach. Methods: We collected data on adverse drug reactions reported using the Medical Dictionary for Regulatory Activities preferred term "anti‐neutrophil cytoplasmic antibody positive vasculitis" up to November 2020 from the World Health Organization pharmacovigilance database (VigiBase). For each retrieved drug, a case–noncase analysis was performed, and disproportionate reporting was calculated by using the information component (IC). A positive IC025 value, which is the lower end of the 95% credibility interval, was considered significant. Results: A total of 483 deduplicated individual case safety reports of drug‐induced AAV involving 15 drugs with an IC025 >0 were retrieved. Of the individuals with drug‐induced AAV for whom data on sex were available (n = 371), 264 (71.2%) were women. The median age at onset of drug‐induced AAV was 62 years (quartile 1 [Q1]–Q3 45–72 years), and the median time from the introduction of the suspected drug to the onset of drug‐induced AAV was 9 months (Q1–Q3 1–36 months). Drug‐induced AAV was considered serious in 472 (98.1%), and was fatal in 43 (8.9%), of 481 cases. The drugs associated with the highest disproportionate reporting were hydralazine, propylthiouracil, thiamazole, sofosbuvir, minocycline, carbimazole, mirabegron, and nintedanib. Conclusion: Our findings strengthen the evidence of an association of AAV with previously suspected drugs, but also identify 3 new drugs that may cause drug‐induced AAV. Particular attention should be given to these drugs by prescribers and in experimental studies. [ABSTRACT FROM AUTHOR]

Aims: Drug repositioning aims to propose new indications for marketed drugs. Although several methods exist, the utility of pharmacovigilance databases for this purpose is unclear. We conducted a disproportionality analysis in the World Health Organization pharmacovigilance database VigiBase to identify potential anticholinesterase drug candidates for repositioning in Alzheimer's disease (AD). Methods: Disproportionality analysis is a validated method for detecting significant associations between drugs and adverse events (AEs) in pharmacovigilance databases. We applied this approach in VigiBase to establish the safety profile displayed by the anticholinesterase drugs used in AD and searched the database for drugs with similar safety profiles. The detected drugs with potential activity against acetylcholinesterase and butyrylcholinesterases (BuChEs) were then evaluated to confirm their anticholinesterase potential. Results: We identified 22 drugs with safety profiles similar to AD medicines. Among these drugs, 4 (clozapine, aripiprazole, sertraline and S‐duloxetine) showed a human BuChE inhibition rate of over 70% at 10−5 M. Their human BuChE half maximal inhibitory concentration values were compatible with clinical anticholinesterase action in humans at their normal doses. The most active human BuChE inhibitor in our study was S‐duloxetine, with a half maximal inhibitory concentration of 1.2 μM. Combined with its ability to inhibit serotonin (5‐HT) reuptake, the use of this drug could represent a novel multitarget directed ligand therapeutic strategy for AD. Conclusion: We identified 4 drugs with repositioning potential in AD using drug safety profiles derived from a pharmacovigilance database. This method could be useful for future drug repositioning efforts. [ABSTRACT FROM AUTHOR]

Clozapine is an atypical antipsychotic indicated in patients with treatment‐resistant schizophrenia which remains underused due to safety issues. Mechanisms behind these adverse effects are complex and not fully understood. They may involve immune‐related mechanisms, direct toxic effects and oxidative stress. Clozapine‐induced oxidative stress might indeed notably be involved in the onset of neutropenia, agranulocytosis, myocarditis, sialorrhea, and metabolic alterations. Therefore, the association of N‐acetylcysteine (NAC), an easily accessible, low‐cost and well tolerated antioxidant drug could be of interest in clozapine‐treated patients to improve clozapine safety. Furthermore, according to recent studies NAC could help to improve schizophrenia symptoms. We believe that the use of NAC in the context of clozapine prescribing merits further study, as it could improve clozapine safety which may lead to a wider use and ultimately improve the healthcare of thousands of patients. NAC could also secondarily show positive knock‐on effects for the patients by improving clinical symptoms of schizophrenia in synergy with clozapine, and by reducing substance abuse and thus by improving the patient's overall condition. However, given the rarity of clozapine‐induced severe adverse effects, only a large volume of data (e.g., National adverse events monitoring) could assess the benefits of NAC on clozapine safety. [ABSTRACT FROM AUTHOR]

On March 16, 2020, the French Society of Pharmacology and Therapeutics put online a national Question and Answer (Q&A) website, https://sfpt-fr.org/covid19 on the proper use of drugs during the COVID‐19 pandemic. The working group 'Drugs and COVID‐19' was composed of a scientific council, an editorial team, and experts in the field. The first questions were posted online during the first evening of home‐confinement in France, March 17, 2020. Six weeks later, 140 Q&As have been posted. Questions on the controversial use of hydroxychloroquine and to a lesser extent concerning azithromycin have been the most consulted Q&As. Q&As have been consulted 226 014 times in 41 days. This large visibility was obtained through an early communication on Twitter, Facebook, traditional print, and web media. In addition, an early communication through the French Ministry of Health and the French National Agency for Medicines and Health Products Safety ANSM had a large impact in terms of daily number of views. There is a pressing need to sustain a public drug information service combining the expertise of scholarly pharmacology societies, pharmacovigilance network, and the Ministry of Health to quickly provide understandable, clear, expert answers to the general population's concerns regarding COVID‐19 and drug use and to counter fake news. [ABSTRACT FROM AUTHOR]

Drug‐induced hypertension was described with several pharmacological classes, especially with serotonin reuptake inhibitors (SRIs). However, this link has remained controversial: the French summary of product characteristics specify a risk of hypertension only with paroxetine and sertraline. To identify a possible class effect common to all SRIs, our study investigated the reports of hypertension associated with SRIs in two pharmacovigilance databases. Two different types of investigations were performed: (i) a comparative study in VigiBase®, which is the World Health Organization (WHO) pharmacovigilance database (PVDB), from where notifications of hypertension with six SRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) were extracted. The relationship between the suspected SRIs and the occurrence of hypertension was assessed by calculating reporting odds ratio (ROR) in a case/non‐case design; (ii) a descriptive study of hypertension reports associated with SRIs in the French pharmacovigilance database (FPVDB). In VigiBase®, 14 824 notifications of SRI‐induced hypertension (2.5%) were identified (mean age 54.3 years, mainly women 69.1%). Among them, 3 879 (26.2%) were associated to sertraline; 3 118 (21.0%) to fluoxetine; 2 725 (18.4%) to paroxetine; 2 570 (17.3%) to citalopram; 2 295 (15.5%) to escitalopram; and 237 (1.6%) to fluvoxamine. A significant ROR value was found with all six SRIs (ROR range from 1.16 to 1.92). In the FPVDB, 24 reports of hypertension were found with all six SRIs used at standard doses, mainly in women (66.7%) with a mean age of 57.8 years and a median time of onset of 6 days. In 10 cases (42%), patients had a history of hypertension. This study, performed in real conditions of life, shows a significant pharmacovigilance safety signal between the use of SRIs and the development or worsening of hypertension. [ABSTRACT FROM AUTHOR]

Abstract: Whether oral anticoagulants, vitamin K antagonists (VKAs), and nonvitamin K oral anticoagulant (NOACs) frequently prescribed to atrial fibrillation (AF) patients, do themselves have a pro‐ or anti‐arrhythmic effect have never been addressed. Transmembrane action potentials were recorded in an acute rabbit model of superfused pulmonary veins (PVs) sleeves preparations using standard microelectrode technique. Fluindione 10 μ m (n = 6) increased the AP (action potential) duration (APD), induced a significantly Vmax depression (from 95 ± 14 to 53 ± 5 V/s, P < 0.05), and 2 : 1 blocks during rapid atrial pacing thus evoking class I anti‐arrhythmic properties, and prevented spontaneous trigger APs. Apixaban 10 μ m (n = 6) increased the APD, significantly prolonged the effective refractory period (from 56.3 ± 4.2 to 72.0 ± 8.6 ms, P < 0.05), and prevented triggered APs occurrence. Fluindione and apixaban effects were suppressed with the addition of the protease‐activated receptors 1 (PAR 1) agonist SFLLR‐NH2. Warfarin 10 μ m (n = 6) significantly abbreviated the early refractory period (from 56.3 ± 4.2 to 45.0 ± 2.2 ms, P < 0.05) and increased triggered APs occurrence that were successfully prevented by nifedipine but not by the addition of the protease‐activated receptors 1 agonist SFLLR‐NH2. In this acute rabbit PVs model, VKAs and NOACs, at physiological concentrations, exhibited very different pharmacological properties that influence PVs electrophysiology, implying PAR1, with fluindione and apixaban which exhibited more anti‐arrhythmic properties, whereas warfarin exhibited more pro‐arrhythmic properties. [ABSTRACT FROM AUTHOR]

Key points The transient receptor potential melastatin 4 (TRPM4) inhibitor 9-phenanthrol reduces action potential duration in rabbit Purkinje fibres but not in ventricle., TRPM4-like single channel activity is observed in isolated rabbit Purkinje cells but not in ventricular cells., The TRPM4-like current develops during the notch and early repolarization phases of the action potential in Purkinje cells., Abstract Transient receptor potential melastatin 4 (TRPM4) Ca2+-activated non-selective cation channel activity has been recorded in cardiomyocytes and sinus node cells from mammals. In addition, TRPM4 gene mutations are associated with human diseases of cardiac conduction, suggesting that TRPM4 plays a role in this aspect of cardiac function. Here we evaluate the TRPM4 contribution to cardiac electrophysiology of Purkinje fibres. Ventricular strips with Purkinje fibres were isolated from rabbit hearts. Intracellular microelectrodes recorded Purkinje fibre activity and the TRPM4 inhibitor 9-phenanthrol was applied to unmask potential TRPM4 contributions to the action potential. 9-Phenanthrol reduced action potential duration measured at the point of 50 and 90% repolarization with an EC50 of 32.8 and 36.1×10−6 mol l−1, respectively, but did not modulate ventricular action potentials. Inside-out patch-clamp recordings were used to monitor TRPM4 activity in isolated Purkinje cells. TRPM4-like single channel activity (conductance = 23.8 pS; equal permeability for Na+ and K+; sensitivity to voltage, Ca2+ and 9-phenanthrol) was observed in 43% of patches from Purkinje cells but not from ventricular cells (0/16). Action potential clamp experiments performed in the whole-cell configuration revealed a transient inward 9-phenanthrol-sensitive current (peak density = −0.65 ± 0.15 pA pF-1; n = 5) during the plateau phases of the Purkinje fibre action potential. These results show that TRPM4 influences action potential characteristics in rabbit Purkinje fibres and thus could modulate cardiac conduction and be involved in triggering arrhythmias. [ABSTRACT FROM AUTHOR]

Steroid hormones appear to be a key factor in the gender differences in the rates and severity of cardiovascular diseases. Aldosterone and testosterone have typical steroid ring structure, but despite this, they demonstrate very different properties. During acute myocardial ischemia-reperfusion, the deleterious impact of aldosterone is now well established. Conversely, the electrophysiological impact of testosterone in this context remained unknown. We used female rabbit in vitro models and standard microelectrode technique including right ventricle mimicking the 'border zone' existing between normal and ischemic/reperfused areas and isolated right ventricle experiments to assess the acute electrophysiological impact of both aldosterone and testosterone. During ischemia-reperfusion, acute superfusion of 10 and 100 nmol/L testosterone decreased normoxic and reperfused action potential duration at 90% ( APD90), systematically induced conduction blocks, and decreased APD90 dispersion between ischemic and nonischemic areas (from 98 ± 4 to 57 ± 7 ms and 66 ± 3 ms, for, respectively, testosterone 10 and 100 nmol/L, P < 0.05). Testosterone 10 and 100 nmol/L concomitantly decreased sustained premature ventricular contraction ( PVC) occurrence (from 55 to 0%, P < 0.05). Conversely, aldosterone 10 and 100 nmol/L increased normoxic and reperfused APD90, APD90 dispersion, and reperfusion-induced PVCs. Furthermore, testosterone demonstrated cycle length-dependent effects on APD90 for high heart rate, whereas aldosterone did not exhibit any significant effect compared with controls. During acute myocardial ischemia-reperfusion, acute superfusion of physiological concentrations of testosterone seemed to be anti-arrhythmic by removing a pro-arrhythmic substrate ( APD90 dispersion), inducing conduction blocks and decreasing triggered activities ( PVC occurrence). Further experiments are warranted to confirm our results. [ABSTRACT FROM AUTHOR]

Outcome of patients hospitalized for Covid-19 and exposure to angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers in France: Results of the ACECoV study During the spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), early reports indicated that certain groups of patients were at risk of developing severe COVID-19 infections. 4 Vaduganathan M., Vardeny O., Michel T., McMurray J.J.V., Pfeffer M.A., Solomon S.D. Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. [Extracted from the article]

The article inform Endocrine therapy (ET) remains the mainstay treatment for patients with Hormone Receptor-positive (HR+) and HER2-negative (HER2−) metastatic Breast Cancer (BC) without extensive visceral involvement. Topic include describe the case of a metastatic BC patient treated with abemaciclib who developed grade 4 acute kidney injury (AKI) requiring hemodialysis.

The article presents a case study of an 82-year-old female patient admitted for congestive heart failure and exacerbation of her dyspnea. It states she was treated with concomitant bisoprolol and verapamil and following diuretic therapy which initially improved symptoms the patient suffered severe sepsis starting in the urinary tract. It reports urine cytobacteriological testing found non-drug-resistant Escherichia coli, and after ceasing treatment she suffered cardiac arrest with asysstole.