Spectroscopy of an AdS Reissner-Nordstrom black hole

In the framework of black hole spectroscopy, we extend the results obtained for a charged black hole in an asymptotically flat spacetime to the scenario with non vanishing negative cosmological constant. In particular, exploiting Hamiltonian techniques, we construct the area spectrum for an AdS Reissner-Nordstrom black hole.Comment: 21 pages, enhanced conclusions, references adde

Relationship between adverse drug reactions to antibacterial agents and the Klebsiella pneumoniae carbapenemase-producing (KPC) Klebsiella pneumoniae outbreak: Insight from a pharmacovigilance study

Background: The management of Klebsiella pneumoniae carbapenemase producing (KPC) infections represents a major challenge. Several safety and efficacy concerns are shared by available antibiotics used in KPC infections, leading to the occurrence of serious adverse drug reactions (ADRs), with ceftazidime-avibactam possibly showing a more favourable risk-benefit profile. We investigated the potential impact of resistance on ADR reports in countries with different prevalence of KPC isolates (Italy vs. United Kingdom [UK]), and described safety profile of newer and older antibiotics used in KPC infections. Methods: Three spontaneous reporting systems (SRSs) with different features (Italy, UK and worldwide FAERS) were used to describe safety profiles of colistin, meropenem, tigecycline, gentamicin and ceftazidime-avibactam in terms of System Organ Class and Preferred Term level. ADRs were plotted with prevalence of KPC isolates in Italy and UK. A comparison between before-after the KPC outbreak period (1999-2008 vs. 2009-2018) of overall and serious ADRs for selected antibiotics in each SRS was performed. Relationship between total and serious number of ADR reports per year and KPC isolates per year after KPC outbreak (2009-2017) was investigated for both Italy and UK. Results: A total of 16,329 ADR reports were collected in the three SRSs, with meropenem (42.6%) and gentamicin (36.9%) having the highest number of reports. Significant increase in total and serious ADR reports after the KPC outbreak compared to previous 10 years was found for colistin, meropenem and gentamicin (p < 0.01). No significant increase in tigecycline ADRs was reported in FAERS and UK database. Unexpected safety signals involving selected antibiotics were not detected. Significant positive relationship between overall and serious ADR reports and KPC isolates per year for both Italy (p < 0.01; p = 0.005) and UK (p = 0.032; p = 0.013) was found. Conclusion: KPC outbreak led to significant increase in ADRs to selected antibiotics, and a close relationship with antimicrobial resistance was found, both in countries with high and low resistance rate. New safety signals were not detected for selected agents. Active surveillance should be maintained to promptly identify unexpected safety issues

The value of case reports and spontaneous reporting systems for pharmacovigilance and clinical practice

Non present

Lessons to be Learnt from Real-World Studies on Immune-Related Adverse Events with Checkpoint Inhibitors: A Clinical Perspective from Pharmacovigilance

The advent of immune checkpoint inhibitors (ICIs) caused a paradigm shift both in drug development and clinical practice; however, by virtue of their mechanism of action, the excessively activated immune system results in a multitude of off-target toxicities, the so-called immune-related adverse events (irAEs), requiring new skills for timely diagnosis and a multidisciplinary approach to successfully manage the patients. In the recent past, a plethora of large-scale pharmacovigilance analyses have characterized various irAEs in terms of spectrum and clinical features in the real world. This review aims to summarize and critically appraise the current landscape of pharmacovigilance studies, thus deriving take-home messages for oncologists. A brief primer to study design, conduction, and data interpretation is also offered. As of February 2020, 30 real-world postmarketing studies have characterized multiple irAEs through international spontaneous reporting systems, namely WHO Vigibase and the US FDA Adverse Event Reporting System. The majority of studies investigated a single irAE and provided new epidemiological evidence about class-specific patterns of irAEs (i.e. anti-cytotoxic T-lymphocyte antigen 4 [CTLA-4] versus anti-programmed cell death 1 [PD-1] receptor, and its ligand [PD-L1]), kinetics of appearance, co-occurrences (overlap) among irAEs, and fatality rate. Oncologists should be aware of both strengths and limitations of these pharmacovigilance analyses, especially in terms of data interpretation. Optimal management (including rechallenge), predictivity of irAEs (as potential biomarkers of effectiveness), and comparative safety of ICIs (also in terms of combination regimens) represent key research priorities for next-generation real-world studies

Impulse Control Disorders by Dopamine Partial Agonists: A Pharmacovigilance-Pharmacodynamic Assessment Through the FDA Adverse Event Reporting System

BACKGROUND: The dopaminergic partial agonism of the so-called third-generation antipsychotics (TGAs; aripiprazole, brexpiprazole, cariprazine) is hypothesized to cause impulse control disorders (ICDs). Relevant warnings by the Food and Drug Administration (FDA) were posted on aripiprazole (2016) and brexpiprazole (2018). Our study investigated the FDA Adverse Event Reporting System and the pharmacodynamic CHEMBL database to further characterize TGA-induced ICDs. METHODS: We downloaded and pre-processed the FDA Adverse Event Reporting System up to December 2020. We adapted Bradford Hill criteria to assess each TGA's -and secondarily other antipsychotics'-causal role in inducing ICDs (pathological gambling, compulsive shopping, hyperphagia, hypersexuality), accounting for literature and disproportionality. ICD clinical features were analyzed, and their pathogenesis was investigated using receptor affinities. RESULTS: A total of 2708 reports of TGA-related ICDs were found, primarily recording aripiprazole (2545 reports, 94%) among the drugs, and gambling (2018 reports, 75%) among the events. Bradford-Hill criteria displayed evidence for a causal role of each TGA consistent across subpopulations and when correcting for biases. Significant disproportionalities also emerged for lurasidone with compulsive shopping, hyperphagia, and hypersexuality, and olanzapine and ziprasidone with hyperphagia. Time to onset varied between days and years, and positive dechallenge was observed in 20% of cases. Frequently, co-reported events were economic (50%), obsessive-compulsive (44%), and emotional conditions (34%). 5-Hydroxytryptamine receptor type 1a agonism emerged as an additional plausible pathogenetic mechanism. CONCLUSIONS: We detected an association between TGAs and ICDs and identified a new signal for lurasidone. ICD characteristics are behavior specific and may heavily impact on life. The role of 5-Hydroxytryptamine receptor type 1a agonism should be further explored

Bone fracture as a novel immune-related adverse event with immune checkpoint inhibitors: Case series and large-scale pharmacovigilance analysis

Although immune checkpoint inhibitors (ICIs) are associated with different immune-related adverse events (irAEs), the potential effect on the skeleton is poorly defined albeit biologically plausible and assessable through pharmacovigilance. We described a case series of patients experiencing skeletal fractures while on ICIs at the National Cancer Institute of Milan. To better characterize the clinical features of skeletal irAEs reported with ICIs, we queried the FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis by means of reporting odds ratios (RORs), deemed significant by a lower limit of the 95% confidence interval (LL95% CI) > 1. Bone AEs emerging as significant were scrutinized in terms of demographic and clinical data, including concomitant irAEs or drugs affecting bone resorption or causing bone damage. Four patients with skeletal events while on ICIs were included in our case series, of which three exhibited vertebral fractures. In FAERS, 650 patients with bone and joint injuries and treated with ICIs were retrieved, accounting for 822 drug-event pairs. Statistically significant ROR was found for eight, two and one bone AEs respectively with PD-1, PD-L1 and CTLA-4 inhibitors, being pathological fracture (N = 46; ROR = 3.17; LL95%CI = 2.37), spinal compression fracture (42; 2.51; 1.91), and femoral neck fracture (26; 2.38; 1.62) the most common. Concomitant irAEs or drugs affecting bone metabolism were poorly reported. The increased reporting of serious vertebral fractures in patients without concomitant irAEs and no apparent preexisting risk factors could suggest a possible cause-effect relationship and calls for close clinical monitoring and implementation of dedicated guidelines

The environmental impact of pharmaceuticals in Italy: Integrating healthcare and eco-toxicological data to assess and potentially mitigate their diffusion to water supplies

Pharmaceuticals can reach the environment at all stages of their lifecycle and accumulate in the ecosystem, potentially reaching toxic levels for animals and plants. In recent years, efforts have been made to map and control this hazard. Assessing country-specific environmental risks could drive regulatory actions towards eco-friendlier drug utilization and disposal practices. By starting from a list of 25 environmentally hazardous pharmaceuticals developed by Region Stockholm, we integrated eco-toxicological and 2019-2021 Italian drug utilization data to estimate the environmental impact of pharmaceuticals in Italy. We calculated the risk as the ratio between the predicted environmental concentration (PEC) and the predicted no-effect concentration (PNEC). We found a high risk for levonorgestrel, ciprofloxacin, amoxicillin, azithromycin, venlafaxine, sertraline and diclofenac and a moderate risk for ethinyloestradiol, oestradiol and clarithromycin. This analysis can be periodically performed to identify the pharmaceuticals with the highest risk for the environment and ascertain if containment measures should be implemented

Breakthrough invasive fungal infections in liver transplant recipients exposed to prophylaxis with echinocandins vs other antifungal agents: A systematic review and meta-analysis

Introduction: Although echinocandins are recommended as first-line prophylaxis for high-risk orthotopic liver transplant (OLT) recipients, occurrence of breakthrough-invasive fungal infections (IFIs) remains a serious concern. We aim to assess the risk of breakthrough IFIs among OLT recipients exposed to prophylaxis with echinocandins compared to other antifungals. Materials and methods: Two authors independently searched PubMed-MEDLINE, Embase, study registries and reference lists from inception to March 2021, to retrieve randomised controlled trials (RCTs) or observational studies comparing efficacy and safety of echinocandins vs other antifungals for prophylaxis in OLT recipients. Data were independently extracted from two authors, and the quality of included studies was independently assessed according to ROB 2.0 tool for RCTs and ROBINS-I tool for observational studies. The primary outcome was occurrence of breakthrough IFI at the end of prophylaxis (EOP). Results: 698 articles were screened, and ten studies (3 RCTs and 7 observational) were included. No difference between echinocandins and other antifungals in terms of breakthrough IFIs at the EOP emerged both from RCTs (odds ratio [OR] 0.85, 95% CI 0.24–2.99) and observational studies (OR 1.43, 95% CI 0.28–7.40). No difference emerged also for secondary outcomes. In the subgroup comparison between echinocandins and polyenes, a trend for higher risk of breakthrough IFI at the EOP (OR 4.82, 95% CI 0.97–24.03) was noted. Conclusions: Echinocandins do not seem to be associated with increased risk of breakthrough IFIs in OLT recipients. However, the large diversity in the comparator group hinders a definitive interpretation. Further studies exploring the relationship between echinocandin use and breakthrough IFIs according to specific comparators are warranted

Post-Marketing Surveillance of CAR-T-Cell Therapies: Analysis of the FDA Adverse Event Reporting System (FAERS) Database

Introduction As chimeric antigen receptor T-cell therapies are becoming increasingly available in the armamentarium of the hematologist, there is an emerging need to monitor post-marketing safety. Objective We aimed to better characterize their safety profile by focusing on cytokine release syndrome and identifying emerging signals. Methods We queried the US Food and Drug Administration Adverse Event Reporting System (October 2017-September 2020) to analyze suspected adverse drug reactions to tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel). Disproportionality analyses (reporting odds ratio) were performed by comparing chimeric antigen receptor T-cell therapies with (a) all other drugs (reference group 1) and (b) other onco-hematological drugs with a similar indication, irrespective of age (reference group 2), or (c) restricted to adults (reference group 3). Notoriety was assessed through package inserts and risk management plans. Adverse drug reaction time to onset and cytokine release syndrome features were investigated. Results Overall, 3225 reports (1793 axi-cel; 1433 tisa-cel) were identified. The reported toxicities were mainly: cytokine release syndrome (52.2%), febrile disorders (27.7%), and neurotoxicity (27.2%). Cytokine release syndrome and neurotoxicity were often co-reported and 75% of the events occurred in the first 10 days. Disproportionalities confirmed known adverse drug reactions and showed unexpected associations: for example, axi-cel with cardiomyopathies (reporting odds ratio = 2.3; 95% confidence interval 1.2-4.4) and gastrointestinal perforations (2.9; 1.2-7.3), tisa-cel with hepatotoxicity (2.5; 1.1-5.7) and pupil disorders (15.3; 6-39.1). Conclusions Our study confirms the well-known adverse drug reactions and detects potentially emerging safety issues specific for each chimeric antigen receptor T-cell therapy, also providing insights into a stronger role for tisa-cel in inducing some immunodeficiency-related events (e.g., hypogammaglobulinemia, infections) and coagulopathies, and for axi-cel in neurotoxicity