ARITMO

Arrhythmogenic potential of drugs

 Partecipanti

Mappa

 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

 Obiettivo del progetto (Objective)

'The ability of some compounds to prolong the QT interval of the electrocardiogram and to precipitate Torsade de Pointes (TdP, a potentially fatal arrhythmia) has caused several regulatory interventions, including drug withdrawals. Specific guidelines have been implemented to detect QT liability of new compounds as early as possible. However there is growing evidence that an increase in the QT interval does not necessarily lead to TdP which further increased the regulatory and clinical difficulties. This proposal will assess the arrhythmogenic potential of antipsychotics, antihistamines and anti-infectives (> 250 compounds). It will fulfill this aim by: reviewing the literature on in-vitro and in-vivo preclinical evidence; conducting in-silico modeling to predict the arrhythmic potential through target profiling and docking molecules in existing atomistic models and predicting the effects on hERG K, Na, Ca\ channels; analyzing the information in national and international pharmacovigilance DBs of spontaneous reports; conducting prospective case control surveillance on symptomatic QT prolongation; conducting cohort studies in psychiatric and hematology patients; analyzing information from existing studies to assess the association between drug use and various arrhythmia outcomes; and collecting blood samples from cases and drug-matched controls to investigate potential effect modification by candidate genes and a hypothesis generating approach including more than 2000 genes. Healthcare DBs on 27 million persons in 5 countries will be used to calculate rates and relative risks of arrhythmic events during drug use. Predictions on arrhythmic potential will be compared with actual postmarketing risk to assess the predictive value of preclinical markers. All information will be integrated to allow for ranking the arrhythmic potential of all the 250 study drugs and creation of risk charts that will allow for more informed treatment and decision making.'

Introduzione (Teaser)

Many drugs have been taken off the market because they have been linked to a potentially fatal heart arrhythmia. A new project revisits these drugs to determine if there is a link with this serious, though rare, event.

Descrizione progetto (Article)

Concern has been expressed about drugs that prolong the QT interval of the electrocardiogram, precipitating torsade de pointes (Tdp), a potentially fatal arrhythmia. However, a growing body of evidence is showing that an increase in the QT interval does not necessarily lead to TdP, casting doubt on clinical and regulatory decisions that have been made.

The 'Arrhythmogenic potential of drugs' (ARITMO) project was designed to examine the relationship between medications and arrhythmia.

To date, it has assessed three classes of drugs: antipsychotics, antihistamines, and anti-infective agents. Literature reviews, databases with pharmacokinetic parameters, and databases with a cardiac safety profile were used to study the drugs.

In addition, researchers examined the relationship between these drugs and ventricular arrhythmia (VA) and sudden cardiac death (SCD). They also looked at patient profiles to see if they could find new parameters that would predict TdP. Finally, the investigators conducted genetic analyses.

Out of 450 drugs under study, a comparison between literature review and database analysis could be provided for 205 drugs: 26 antihistamines, 36 antipsychotics, and 143 anti-infective agents. ARITMO provided new information for 16 antihistamines and 20 antipsychotics and confirmed that anti-infective agents were generally in the low-risk category.

These and similar results have numerous implications. They can be used to help regulators make decisions about the risk associated with these drugs. They also can be used to prioritise drugs that should be evaluated. Finally, the findings can be used to quantify risk and validate preclinical predictive models.

The integrated evidence that has emerged from the ARITMO project will allow for better regulatory and clinical decision making. Furthermore, an infrastructure has been established that can be used for other drugs. This effort represents a collaborative network for doing research and delivering state-of-the-art results.