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Arrhythmogenic potential of drugs

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.

Field of science

  • /humanities/languages and literature/literature - general
  • /medical and health sciences/clinical medicine/hematology

Call for proposal

FP7-HEALTH-2009-single-stage
See other projects for this call

Funding Scheme

CP-FP - Small or medium-scale focused research project

Coordinator

ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Address
Dr Molewaterplein 40
3015 GD Rotterdam
Netherlands
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 537 804
Administrative Contact
Miriam Cjm Sturkenboom (Prof.)

Participants (19)

FUNDACIO INSTITUT MAR D INVESTIGACIONS MEDIQUES IMIM
Spain
EU contribution
€ 194 974
Address
Doctor Aiguader 88
08003 Barcelona
Activity type
Research Organisations
Administrative Contact
Andreu Fort (Mr.)
LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE ROYAL CHARTER
United Kingdom
EU contribution
€ 148 600
Address
Keppel Street
WC1E 7HT London
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Penny Ireland (Ms.)
ALMA MATER STUDIORUM - UNIVERSITA DI BOLOGNA
Italy
EU contribution
€ 272 470
Address
Via Zamboni 33
40126 Bologna
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Verdiana Bandini (Ms.)
UNIVERSITAET BREMEN

Participation ended

Germany
EU contribution
€ 83 614,78
Address
Bibliothekstrasse 1
28359 Bremen
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Sven Petersen (Mr.)
UNIVERSITY OF NEWCASTLE UPON TYNE
United Kingdom
EU contribution
€ 157 800
Address
Kings Gate
NE1 7RU Newcastle Upon Tyne
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Aleona Blinova (Ms.)
UNIVERSITE VICTOR SEGALEN BORDEAUX II
France
EU contribution
€ 120 780
Address
Rue Leo Saignat 146
33076 Bordeaux Cedex
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Nicholas Moore (Prof.)
FONDAZIONE SALVATORE MAUGERI CLINICA DEL LAVORO E DELLA RIABILITAZIONE
Italy
EU contribution
€ 48 960
Address
Via Salvatore Maugeri 4
27100 Pavia
Activity type
Research Organisations
Administrative Contact
Silvia Giuliana Priori (Prof.)
CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Germany
EU contribution
€ 97 440
Address
Chariteplatz 1
10117 Berlin
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Wilhelm Haverkamp (Prof.)
UNIVERSITA DEGLI STUDI DI VERONA
Italy
EU contribution
€ 54 720
Address
Via Dell Artigliere 8
37129 Verona
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Susanna Montalto (Dr.)
ST GEORGE'S HOSPITAL MEDICAL SCHOOL
United Kingdom
EU contribution
€ 293 200
Address
Cranmer Terrace
SW17 0RE London
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Paul Craven (Dr.)
ASTRAZENECA AB
Sweden
EU contribution
€ 101 465
Address
Vastra Maelarhamnen
151 85 Sodertaelje
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Scott Boyer (Dr.)
Stichting Informatievoorziening voor Zorg en Onderzoek
Netherlands
EU contribution
€ 84 600
Address
Van Deventerlaan
3528AE Utrecht
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Ron Mc Herings (Dr.)
Fondazione Scientifica SIMG-ONLUS
Italy
EU contribution
€ 50 400
Address
Via Del Pignoncino 9-11
50142 Firenze
Activity type
Research Organisations
Administrative Contact
Mazzaglia Giampiero (Dr.)
AARHUS UNIVERSITETSHOSPITAL
Denmark
EU contribution
€ 84 600
Address
Palle Juul-jensens Boulevard 99
8200 Aarhus
Activity type
Research Organisations
Administrative Contact
Jesper Dambo Nielsen (Mr.)
ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Netherlands
EU contribution
€ 52 800
Address
Meibergdreef 15
1105AZ Amsterdam
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Hanno L. Tan (Dr.)
Drug Safety Research Trust
United Kingdom
EU contribution
€ 217 600
Address
Blundell Lane, Bursledon Hal
SO31 1AA Southampton
Activity type
Research Organisations
Administrative Contact
Chris Atkinson (Mr.)
LEIBNIZ-INSTITUT FUR PRAVENTIONSFORSCHUNG UND EPIDEMIOLOGIE - BIPS GMBH
Germany
EU contribution
€ 65 905,22
Address
Achterstrasse 30
28359 Bremen
Activity type
Other
Administrative Contact
Xiaogang Gerns
SYNAPSE RESEARCH MANAGEMENT PARTNERS SL
Spain
EU contribution
€ 80 586
Address
Calle Velazquez 94 Planta 1
28006 Madrid
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Eva Molero (Ms.)
PHARMO Institute N.V.
Netherlands
Address
Van Deventerlaan 30-40
3528 AE Utrecht
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Heleen Van Engeland (Ms.)