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Il rischio di torsione di punta da farmaci antibatterici: un approccio farmaco-epidemiologico
Full text linkWHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
1. Torsades de pointes (TdP) is a potentially fatal event caused by several drugs (some used as antiarrhythmics some for non-cardiovascular indications), which block hERG K+ channels.
2. During the last decade, a number of regulatory measures have regarded medicinal products carrying this pro-arrhythmic risk in humans (TdP liability).
3. Previous epidemiological studies showed significant exposure of the general population to drugs, with TdP liability, with similar consumption pattern in several European countries.
WHAT THIS STUDY ADDS
1. A structured analysis of the existing literature documente TdP liability for several antibacterial agents.
2. Notwithstanding stringent regulatory measures taken over the past few years on these agents, population exposure to antibacterials with TdP-liability is still significant in several countries.
3. The magnitude of the problem is heterogeneous with remarkable diversity between Northern and Southern European countries (lower and higher exposure, respectively).
4. Data mining of the largest pharmacovigilance database (FDA_AERS) identified several antimicrobial agents with suspected TdP liability (i.e. signals) that deserve further investigations: linezolid, caspofungin, posaconazole, indinavir and nelfinavir.
SUMMARY
Drug-induced TdP associated with QT prolongation represents a matter of concern both for basic researchers and physicians. Currently, an integrated and multidimensional approach represents the best strategy for a correct risk-benefit assessment, not only during the drug development process, but also for already marketed drugs. Although TdP is usually a self-limiting arrhythmia, under certain circumstances, it may degenerate into ventricular fibrillation and sudden cardiac death. Thus, even a low risk is not justified for drugs with uncertain benefits, providing only symptomatic improvement of a mild disease or whenever safer therapeutic analogues are available.
The aim of this thesis was to critically evaluate the risk of TdP associated with antibacterials using a pharmaco-epidemiological approach. This therapeutic class was chosen taking into account the impact and relevant implications deriving from proper use. Unfortunately, antibiotics are frequently abused or overused, thus several national and international authorities have recently implemented campaigns to promote awareness and appropriate prescription.
In the first part of the thesis (Chapter 1. Introduction), pharmacological and regulatory aspects of drug-induced TdP will be overviewed. The need for a multidimensional strategy in the process of risk assessment will be especially emphasized. Comprehension of molecular mechanisms and complexity of factors subtending TdP is of primary importance to appreciate the rational basis of this research.
In the second part of the thesis (Chapter 2. The magnitude of the problem), the impact of TdP in the general population will be studied by analyzing antibacterial exposure. Public literature has been collected, evaluated and classified on the basis of previous criteria, with the aim of creating a list of antibacterial drugs with a risk of TdP. Drug-utilization study has been performed to evaluate drug consumption over an 8-year period (1998-2005) in 14 European Countries that were enrolled in the ESAC (European Surveillance of Antibacterial Consumption) project.
In the third part of the thesis (Chapter 3. The contribution of pharmacovigilance), international databases of spontaneous reports have been analyzed to test whether a significant consumption would reflect into significant number of TdP reports. Because the FDA Adverse Event Reporting System (AERS) is publicly accessible and is considered the largest source of pharmacovigilance data, it was used to identify spontaneous reports of TdP. We test the feasibility of an already validated method (the case/non case methodology) to early detect signals of TdP that deserve further investigation.
In the fourth part of the thesis (Chapter 4. Signal refinement), the therapeutic class of anti-infectives has been focused and thoroughly investigated. A qualitative approach has been proposed to individually analyze spontaneous reports of TdP. Notably, this strategy has been integrated with the quantitative approach (case/non case method) in order to detect signals of TdP that have been discussed on the basis of current knowledge.
In the final part of the thesis (General comment and perspectives), main results will be overviewed emphasizing potential implications and long-term perspectives of the project. Implementation of this research is mandatory, but certainly this pharmaco-epidemiological research represents the basis to refine integrated strategies of risk assessment and actually delineate the cardiac safety profile of each antibacterial agents.SOMMARIO
La Torsione di Punta (TdP) conseguente al prolungamento dell’intervallo QT dell’elettrocardiogramma è una delle reazioni avverse a farmaci di maggior interesse nel campo della ricerca clinica e di base. Un approccio multidimensionale volto ad integrare le diverse competenze è oramai riconosciuto e condiviso a livello internazionale per una corretta valutazione del rischio, sia per le molecole in fase di sviluppo che per i farmaci già in commercio. Nonostante la TdP sia in gene un fenomeno autolimitantesi, in talune circostanze, essa può sfociare in fibrillazione ventricolare e conseguente morte cardiaca improvvisa. Pertanto, anche un medicinale che abbia un rischio estremamente basso può non essere accettabile qualora i suoi benefici non siano ben studiati o esistano alternative terapeutiche più sicure.
Considerate le premesse, il progetto di ricerca presentato in questa tesi si è prefisso l’obiettivo di valutare criticamente, tramite un approccio farmaco-epidemiologico, le dimensioni ed il rischio di TdP da farmaci antibatterici. La scelta di questa classe terapeutica nasce dalla rilevanza e dalle implicazioni pratiche di una classe farmacologica da tempo nota per un utilizzo non sempre corretto, sia a livello nazionale che internazionale. Recentemente l’Agenzia Italiana del FArmaco (AIFA) ha intrapreso una campagna di sensibilizzazione all’uso consapevole e razionale degli antibiotici. Inoltre, anche a livello Europeo, attività di sorveglianza e campagne mediatiche hanno raggiunto ampia diffusione.
Nella prima parte della tesi (Capitolo 1. Introduzione), verranno descritti gli aspetti farmacologici e regolatori della TdP indotta da farmaci, delineando l’importanza di una strategia multidisciplinare nella valutazione globale del rischio. La comprensione dei meccanismi molecolari e della complessità di fattori che entrano in gioco nella genesi della TdP sono di fondamentale importanza per comprendere il razionale scientifico alla base del percorso di ricerca.
Nella seconda parte della tesi (Capitolo 2. Le dimensioni del problema), verrà approfondito l’impatto della TdP nella popolazione generale, analizzando l’esposizione a farmaci antibatterici. La letteratura scientifica è stata raccolta, analizzata e strutturata sulla base di criteri predefiniti che hanno portato a stilare un elenco di composti a rischio. Tali farmaci sono stati successivamente oggetto di indagini di farmaco-utilizzazione, tramite l’impiego di metodiche ad hoc per confrontare il trend temporale nei consumi tra popolazioni numericamente differenti. Più precisamente, è stata analizzata la finestra temporale 1998-2005 in 14 paesi dell’Unione Europea partecipanti al progetto ESAC (European Surveillance of Antibacterial Consumption).
Nella terza parte della tesi (Capitolo 3. Il contributo della farmacovigilanza), sono state analizzate le banche-dati internazionali contenenti segnalazioni spontanee di reazioni avverse a farmaci. Come fonte di informazioni è stato scelto il database dell’Agenzia Regolatoria Americana Food and Drug Administration (FDA). Tale archivio, noto come Adverse Event Reporting System (AERS), è pubblicamente accessibile e rappresenta, nel campo della farmacovigilanza, la fonte più ampia oggi disponibile. Inizialmente, è stata saggiata l’applicabilità alla banca-dati AERS di un metodo già validato in letteratura: il metodo caso/non-caso. Tale metodica ha consentito di identificare, da un punto di vista quantitativo, alcuni segnali precoci di rischio che devono necessariamente essere approfonditi ampliando la casistica ed i metodi di analisi.
Una volta verificata l’applicabilità del metodo, nella quarta parte della tesi (Capitolo 4. Perfezionamento del segnale) ho focalizzato l’attenzione sulla classe farmacologica degli anti-infettivi. Per migliorare l’identificazione del segnale, è stato proposto un metodo qualitativo per l’analisi delle singole segnalazioni spontanee. L’integrazione dei due metodi ha portato a definire diversi segnali che sono stati discussi sulla base delle evidenze scientifiche disponibili.
Nella parte conclusiva della tesi (Commento finale e prospettive), verranno sommariamente ripercorsi i principali risultati, discutendo le implicazioni e le prospettive a lungo termine del progetto di ricerca. L’approccio intrapreso e descritto nella tesi rappresenta, a sua volta, il punto di partenza per sviluppare modelli integrati di valutazione del rischio definendo, in ultima istanza, il profilo di sicurezza cardiaca dei diversi farmaci antibatterici
Letter to the editor: RECAM for the diagnosis of DILI-Is it time to incorporate additional pharmacological criteria?
No full textLubiprostone: pharmacokinetic, pharmacodynamic, safety and regulatory aspects in the treatment of constipation-predominant irritable bowel syndrome
No full textINTRODUCTION: Lubiprostone acts locally (apical membrane of human intestinal epithelial cells) as a highly selective type-2 chloride channel activator. It was approved in the USA for chronic idiopathic constipation (January 2006) and in women aged ≥ 18 years suffering from irritable bowel syndrome with constipation (IBS-C) (April 2008). So far, the only other pro-secretory medication approved in IBS-C and currently available in USA and Europe (since August and November 2012, respectively) is linaclotide.
AREAS COVERED: This review outlines the regulatory history, pharmacokinetic, pharmacodynamic and safety data in the treatment of IBS-C with a European perspective. It is based on publicly available data, namely, published literature, drug labels and the FDA's spontaneous reporting system.
EXPERT OPINION: Although interesting pharmacodynamic data suggest that lubiprostone may have additional mechanisms of action, its beneficial effects in IBS-C must be confirmed in the actual clinical scenario taking into account the new version of European Medicines Agency's guideline. This is especially important with regard to duration of studies (recommended to be at least 6 months) to adequately assess long-term sustained efficacy, withdrawal, rebound and safety. Further research is warranted in uncertain areas (i.e., males, pediatric and elderly patients). On the basis of current data, it is still too early to draw definite conclusions on the overall risk-benefit balance for IBS-C
Disproportionality Analysis From World Health Organization Data on Semaglutide, Liraglutide, and Suicidality.
Full text linkIMPORTANCE
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have gained use primarily due to their weight-reduction effects, although a regulatory review was undertaken for potential suicidality concern.
OBJECTIVES
To evaluate potential signals for suicidal and self-injurious adverse drug reactions (ADRs) associated with the GLP-1 RAs semaglutide and liraglutide.
DESIGN, SETTING, AND PARTICIPANTS
Disproportionality analysis through the case-control design using the World Health Organization (WHO) global database of suspected ADRs. Participants were clinical patients worldwide experiencing an ADR suspectedly attributable to semaglutide or liraglutide in the database from inception to August 30, 2023. Data were analyzed from September to December 2023.
EXPOSURE
Treatment with semaglutide or liraglutide regardless of indication or treatment duration.
MAIN OUTCOMES AND MEASURES
Reporting odds ratio (ROR) and the bayesian information component (IC) with 95% CIs were calculated as measures of disproportionate reporting of suicidal and self-injurious ADRs associated with semaglutide and liraglutide compared with all other medications. Sensitivity analyses were conducted including patients with coreported use of antidepressants and benzodiazepines and using dapagliflozin, metformin, and orlistat as comparators. A disproportionality signal was considered when the lower limits of the ROR and IC were above 1 and 0, respectively.
RESULTS
A total of 107 (median [IQR] age 48 [40-56] years; 59 female patients [55%]) and 162 (median [IQR] age 47 [38-60] years; 100 female patients [61%]) cases of suicidal and/or self-injurious ADRs were reported between November 2000 and August 2023 with semaglutide and liraglutide, respectively. Significant disproportionality was detected only for semaglutide-associated suicidal ideation (ROR, 1.45; 95% CI, 1.18-1.77; IC, 0.53; 95% CI, 0.19-0.78), which remained significant in patients with coreported use of antidepressants (ROR, 4.45; 95% CI, 2.52-7.86; IC, 1.96; 95% CI, 0.98-2.63) and benzodiazepines (ROR, 4.07; 95% CI, 1.69-9.82; IC, 1.67; 95% CI, 0.11-2.65), when compared with dapagliflozin (ROR, 5.56; 95% CI, 3.23-9.60; IC, 0.70; 95% CI, 0.36-0.95), metformin (ROR, 3.86; 95% CI, 2.91-5.12; IC, 1.20; 95% CI, 0.94-1.53) and orlistat (ROR, 4.24; 95% CI, 2.69-6.69; IC, 0.70; 95% CI, 0.36-0.95).
CONCLUSIONS AND RELEVANCE
This study using the WHO database found a signal of semaglutide-associated suicidal ideation, which warrants urgent clarification
Drug- and herb-induced liver injury: Progress, current challenges and emerging signals of post-marketing risk
Full text linkDrug-induced liver injury (DILI) and herb-induced liver injury is a hot topic for clinicians, academia, drug companies and regulators, as shown by the steadily increasing number of publications in the past 15 years. This review will first provide clues for clinicians to suspect idiosyncratic (unpredictable) DILI and succeed in diagnosis. Causality assessment remains challenging and requires careful medical history as well as awareness of multifaceted aspects, especially for herbs. Drug discontinuation and therapy reconciliation remain the mainstay in patent's management to minimize occurrence of acute liver failure. The second section will address novel agents associated with liver injury in 2014 (referred to as "signals"), especially in terms of clinical, research and drug development implications. Insights will be provided into recent trends by highlighting the contribution of different post-marketing data, especially registries and spontaneous reporting systems. This literature scrutiny suggests: (1) the importance of post-marketing databases as tools of clinical evidence to detect signals of DILI risk; and (2) the need for joining efforts in improving predictivity of pre-clinical assays, continuing post-marketing surveillance and design ad hoc post-authorization safety studies. In this context, ongoing European/United States research consortia and novel pharmaco-epidemiological tools (e.g. , specialist prescription event monitoring) will support innovation in this field. Direct oral anticoagulants and herbal/dietary supplements appear as key research priorities
Drug-induced liver injury: Towards early prediction and risk stratification
No full textDrug-induced liver injury (DILI) is a hot topic for clinicians, academia, drug companies and regulators, as shown by the steadily increasing number of publications and agents listed as causing liver damage (http:// livertox.nih.gov/). As it was the case in the past decade with drug-induced QT prolongation/arrhythmia, there is an urgent unmet clinical need to develop tools for risk assessment and stratification in clinical practice and, in parallel, to improve prediction of pre-clinical models to support regulatory steps and facilitate early detection of liver-specific adverse drug events. Although drug discontinuation and therapy reconciliation still remain the mainstay in patient management to minimize occurrence of DILI, especially acute liver failure events, different multidisciplinary attempts have been proposed in 2016 to predict and assess drug-related risk in individual patients; these promising, albeit preliminary, results strongly support the need to pursue this innovative pathway
Comment on: “Pharmacokinetics in Patients with Chronic Liver Disease and Hepatic Safety of Incretin-Based Therapies for the Management of Type 2 Diabetes Mellitus”
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