1,721,168 research outputs found
Antipsychotics and Torsadogenic Risk: Signals Emerging from the US FDA Adverse Event Reporting System Database
Full text linkBackground: Drug-induced torsades de pointes (TdP) and related clinical entities represent a current regulatory and clinical burden. Objective: As part of the FP7 ARITMO (Arrhythmogenic Potential of Drugs) project, we explored the publicly available US FDA Adverse Event Reporting System (FAERS) database to detect signals of torsadogenicity for antipsychotics (APs). Methods: Four groups of events in decreasing order of drug-attributable risk were identified: (1) TdP, (2) QT-interval abnormalities, (3) ventricular fibrillation/tachycardia, and (4) sudden cardiac death. The reporting odds ratio (ROR) with 95 % confidence interval (CI) was calculated through a cumulative analysis from group 1 to 4. For groups 1+2, ROR was adjusted for age, gender, and concomitant drugs (e.g., antiarrhythmics) and stratified for AZCERT drugs, lists I and II (http://www.azcert.org, as of June 2011). A potential signal of torsadogenicity was defined if a drug met all the following criteria: (a) four or more cases in group 1+2; (b) significant ROR in group 1+2 that persists through the cumulative approach; (c) significant adjusted ROR for group 1+2 in the stratum without AZCERT drugs; (d) not included in AZCERT lists (as of June 2011). Results: Over the 7-year period, 37 APs were reported in 4,794 cases of arrhythmia: 140 (group 1), 883 (group 2), 1,651 (group 3), and 2,120 (group 4). Based on our criteria, the following potential signals of torsadogenicity were found: amisulpride (25 cases; adjusted ROR in the stratum without AZCERT drugs = 43.94, 95 % CI 22.82-84.60), cyamemazine (11; 15.48, 6.87-34.91), and olanzapine (189; 7.74, 6.45-9.30). Conclusions: This pharmacovigilance analysis on the FAERS found 3 potential signals of torsadogenicity for drugs previously unknown for this risk
Reduced neuropsychiatric events as “beneficial reactions” to drugs: Seek associations with caution
No full textDapagliflozin and cardiovascular outcomes: anything else to DECLARE?
Full text linkIntroduction: Individuals with type 2 diabetes mellitus (T2DM) have increased cardiovascular risk with regulatory agencies requiring cardiovascular outcome trials (CVOTs) for the approval of new antidiabetic drugs. Areas covered: In this paper, the authors critically discuss the background, trial design, results and implications of a recent CVOT [NCT01730534; DECLARE-TIMI 58 study], which demonstrated that dapagliflozin was non-inferior to placebo in terms of major adverse cardiovascular events, and superior for the occurrence of hospitalization for heart failure (HF) and composite renal endpoints, thus confirming the cardiovascular benefit of sodium-glucose co-transporter-2 (SGLT2) inhibitors. No statistically-significant effects were found for amputations, fractures, and stroke (debated safety issues having emerged in previous CVOTs). Expert opinion: DECLARE-TIMI 58 is the longest (4.2 years of follow up), largest (>17,000 participants) and most inclusive (only 41% of individuals with established atherosclerotic cardiovascular disease) CVOT raising the debate towards SGLT2 inhibitor therapy in primary prevention and the potential use of these drugs also in patients with HF without T2DM and other subpopulations
The value of case reports and spontaneous reporting systems for pharmacovigilance and clinical practice
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Direct Oral Anticoagulants and Interstitial Lung Disease: Emerging Clues from Pharmacovigilance
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The evolving role of disproportionality analysis in pharmacovigilance
No full textIntroduction: From 2009 to 2015, the IMI PROTECT conducted rigorous studies addressing questions about optimal implementation and significance of disproportionality analyses, leading to the development of Good Signal Detection Practices. The ensuing period witnessed the independent exploration of research paths proposed by IMI PROTECT, accumulating valuable experience and insights that have yet to be seamlessly integrated. Areas covered: This state-of-the-art review integrates IMI PROTECT recommendations with recent acquisitions and evolving challenges. It deals with defining the object of study, disproportionality methods, subgrouping, masking, drug-drug interaction, duplication, expectedness, the debated use of disproportionality results as risk measures, integration with other types of data. Expert opinion: Despite the ongoing skepticism regarding the usefulness of disproportionality analyses and individual case safety reports, their ability to timely detect safety signals regarding rare and unpredictable adverse reactions remains unparalleled. Moreover, recent exploration into their potential for characterizing safety signals revealed valuable insights concerning potential risk factors and the patient’s perspective. To fully realize their potential beyond hypothesis generation and achieve a comprehensive evidence synthesis with other kinds of data and studies, each with their unique limitations and contributions, we need to investigate methods for more transparently communicating disproportionality results and mapping and addressing pharmacovigilance biases
Drug-induced torsades de pointes: data mining of the public version of the FDA Adverse Event Reporting System (AERS)
No full textAims: To investigate spontaneous reports of TdP present in the public version of the FDA Adverse Event Reporting System (AERS) in the light of what is already known on their TdP-liability. Methods: Reports of TdP from January 2004 through December 2007 were retrieved from the public version of the AERS database. All reports were selected from REACTION files and the relevant suspected and/or interacting drugs were identified from DRUG files. Qualitative analysis was performed by the case/non-case method. Cases were represented by TdP reports, whereas non-cases were all reports of adverse drug reactions other than TdP. Quantitative analysis was assessed by calculating the crude and adjusted reporting odds ratio (ROR), as a measure of disproportionality, with the 95% confidence interval. Results: Reports of TdP were 1665 over a 4-year period, involving 376 active substances. Thirty-five drugs with at least 10 reports were identified: amiodarone and methadone were associated with the highest number of cases (113 and 83 respectively) and most of the other reports were ascribable to antibacterials, antidepressants and antipsychotics; remarkable differences in number of cases and ROR were present among agents within each therapeutic class. A disproportionate reporting was also observed for other compounds such as donepezil, famotidine and mitoxantrone. Conclusions: Large spontaneous reporting databases represent an important source for signal detection of rare adverse drug reactions (ADR), such as TdP. The number of reports associated to donepezil, famotidine and mitoxantrone could be considered unexpected on the basis of current evidence and needs further investigations on their true TdP-liability
Toward a pharmacophore for drugs inducing the long QT syndrome: Insights from a CoMFA study of HERG K+ channel blockers
No full textIn this paper, we present a pharmacophore for QT-prolonging drugs, along with a 3D QSAR (CoMFA) study for a series of very structurally variegate HERG K+ channel blockers. The blockade of HERG K+ channels is one of the most important molecular mechanisms through which QT-prolonging drugs increase cardiac action potential duration. Since QT prolongation is one of the most undesirable side effects of drugs, we first tried to identify the minimum set of molecular features responsible for this action and then we attempted to develop a quantitative model correlating the 3D stereoelectronic characteristics of the molecules with their HERG blocking potency. Having considered an initial set of 31 QT-prolonging drugs for which the HERG K+ channel blocking activity was measured on mammalian transfected cells, we started the construction of a theoretical screening tool able to predict whether a new molecule can interact with the HERG channel and eventually induce the long QT syndrome. This in silico tool might be useful in the design of new drug candidates devoid of the physicochemical features likely to cause the above-mentioned side effect
PV-OWL-Pharmacovigilance surveillance through semantic web-based platform for continuous and integrated monitoring of drug-related adverse effects in open data sources and social media
No full textThe recent EU regulation on Pharmacovigilance [Regulation (EU) 1235/2010, Directive 2010/84/EU] imposes both to Pharmaceutical companies and Public health agencies to maintain updated safety information of drugs, monitoring all available data sources. Here, we present our project aiming to develop a web platform for continuous monitoring of adverse effects of medicines (pharmacovigilance), by integrating information from public databases, scientific literature and social media. The project will start by scanning all available data sources concerning drug adverse events, both open (e.g., FAERS-FDA Adverse Event Reporting Systems, medical literature, social media, etc.) and proprietary data (e.g., discharge hospital records, drug prescription archives, electronic health records), that require agreement with respective data owners. Subsequent, pharmacovigilance experts will perform a semi-Automatic mapping of codes identifying drugs and adverse events, to build the thesaurus of the web based platform. After these preliminary activities, signal generation and prioritization will be the core of the project. This task will result in risk confidence scores for each included data source and a comprehensive global score, indicating the possible association between a specific drug and an adverse event. The software framework MOMIS, an open source data integration system, will allow semi-Automatic virtual integration of heterogeneous and distributed data sources. A web platform, based on MOMIS, able to merge many heterogeneous data sets concerning adverse events will be developed. The platform will be tested by external specialized subjects (clinical researchers, public or private employees in pharmacovigilance field). The project will provide a) an innovative way to link, for the first time in Italy, different databases to obtain novel safety indicators; b) a web platform for a fast and easy integration of all available data, useful to verify and validate hypothesis generated in signal detection. Finally, the development of the unified safety indicator (global risk score) will result in a compelling, easy-To-understand, visual format for a broad range of professional and not professional users like patients, regulatory authorities, clinicians, lawyers, human scientists
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