Journal ArticleDOI
Drug-induced Proarrhythmia and Torsade de Pointes: A Primer for Students and Practitioners of Medicine and Pharmacy
J. Rick Turner,Ignacio Rodriguez,Emily H Mantovani,Gary Gintant,Peter R. Kowey,Ralph J Klotzbaugh,Krishna Prasad,Philip T. Sager,Norman Stockbridge,Colette Strnadova +9 more
TLDR
This primer reviews the clinical implications of a drug's identified proarrhythmic liability, the issues associated with these safety‐related withdrawals, and the actions taken by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and by regulatory agencies in terms of changing drug development practices and introducing new nonclinical and clinical tests to asses proarrhalic liability.Abstract:
Multiple marketing withdrawals due to proarrhythmic concerns occurred in the United States, Canada, and the United Kingdom in the late 1980s to early 2000s. This primer reviews the clinical implications of a drug's identified proarrhythmic liability, the issues associated with these safety-related withdrawals, and the actions taken by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and by regulatory agencies in terms of changing drug development practices and introducing new nonclinical and clinical tests to asses proarrhythmic liability. ICH Guidelines S7B and E14 were released in 2005. Since then, they have been adopted by many regional regulatory authorities and have guided nonclinical and clinical proarrhythmic cardiac safety assessments during drug development. While this regulatory paradigm has been successful in preventing drugs with unanticipated potential for inducing the rare but potentially fatal polymorphic ventricular arrhythmia torsade de pointes from entering the market, it has led to the termination of drug development programs for other potentially useful medicines because of isolated results from studies with limited predictive value. Research efforts are now exploring alternative approaches to better predict potential proarrhythmic liabilities. For example, in the domain of human electrocardiographic assessments, concentration-response modeling conducted during phase 1 clinical development has recently become an accepted alternate primary methodology to the ICH E14 "thorough QT/QTc" study for defining a drug's corrected QT interval prolongation liability under certain conditions. When a drug's therapeutic benefit is considered important at a public health level but there is also an identified proarrhythmic liability that may result from administration of the single drug in certain individuals and/or drug-drug interactions, marketing approval will be accompanied by appropriate directions in the drug's prescribing information. Health-care professionals in the fields of medicine and pharmacy need to consider the prescribing information in conjunction with individual patients' clinical characteristics and concomitant medications when prescribing and dispensing such drugs.read more
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Journal ArticleDOI
Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet
Miguel A. Sanz,Miguel A. Sanz,Pierre Fenaux,Martin S. Tallman,Elihu H. Estey,Bob Löwenberg,Tomoki Naoe,Eva Lengfelder,Hartmut Döhner,Alan K. Burnett,Sai Juan Chen,Vikram Mathews,Harry J. Iland,Eduardo Magalhães Rego,Hagop M. Kantarjian,Lionel Adès,Giuseppe Avvisati,Pau Montesinos,Uwe Platzbecker,Farhad Ravandi,Nigel H. Russell,Francesco Lo-Coco +21 more
TL;DR: This review contains specific recommendations for the identification and management of the most important complications such as the bleeding disorder APL differentiation syndrome, QT prolongation, and other all-trans retinoic acid- and ATO-related toxicities.
Journal ArticleDOI
Comparative Cardiac Safety of Selective Serotonin Reuptake Inhibitors among Individuals Receiving Maintenance Hemodialysis
TL;DR: The heterogeneous QT-prolonging potential of SSRIs may differentially affect cardiac outcomes in the hemodialysis population, and this association was more pronounced among elderly individuals, females, patients with conduction disorders, and those treated with other non-SSRI QT.
Journal ArticleDOI
Pathogenesis-directed therapy of 2019 novel coronavirus disease.
TL;DR: A narrative review linking CO VID‐19 therapies with pathogenic mechanisms of SARS‐CoV‐2 has resulted in six major therapeutic goals for COVID‐19 therapy based on the pathogenic mechanism of Sars‐Cov‐2.
Journal ArticleDOI
Mechanobiology Assays with Applications in Cardiomyocyte Biology and Cardiotoxicity.
Cheavar A. Blair,Beth L. Pruitt +1 more
TL;DR: A brief overview of techniques that can be used to quantify changes in the active force that cardiomyocytes generate and variations in their inherent stiffness in response to cardiotoxic drugs is provided.
Journal ArticleDOI
Genetic and Molecular Aspects of Drug-Induced QT Interval Prolongation
Daniela Baracaldo-Santamaría,Kevin Llinás-Caballero,Julián Miguel Corso-Ramirez,Carlos Martín Restrepo,Camilo Alberto Dominguez-Dominguez,Dora Janeth Fonseca-Mendoza,Carlos Alberto Calderón-Ospina +6 more
TL;DR: In this paper, the application of personalized medicine in long QT syndromes has been discussed, in order to evaluate the risk of every individual from a pharmacogenetic standpoint.
References
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Journal ArticleDOI
Rechanneling the cardiac proarrhythmia safety paradigm: a meeting report from the Cardiac Safety Research Consortium.
TL;DR: The Comprehensive In Vitro Proarrhythmia Assay (CIPA) as discussed by the authors is a non-clinical in vitro/in silico assessment of risk of arrhythmic risk.
Journal ArticleDOI
The Rotterdam Study: 2018 update on objectives, design and main results.
M. Arfan Ikram,Guy Brusselle,Guy Brusselle,Sarwa Darwish Murad,Cornelia M. van Duijn,Oscar H. Franco,André Goedegebure,Caroline C W Klaver,Tamar Nijsten,Robin P. Peeters,Bruno H. Stricker,Henning Tiemeier,André G. Uitterlinden,Meike W. Vernooij,Albert Hofman,Albert Hofman +15 more
TL;DR: The rationale of the study and its design is given, a summary of the major findings and an update of the objectives and methods are presented and the cohort is being expanded by persons aged 40 years and over.
A Meeting Report from the Cardiac Safety Research Consortium
Philip T. Sager,Jonathan H. Seltzer,J. Rick Turner,Jeffrey L. Anderson,William R. Hiatt,Peter R. Kowey,Judith J. Prochaska,Norman Stockbridge,William B. White +8 more
TL;DR: This white paper provides a summary of a scientific proposal presented at a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/Food and Drug Administration-sponsored Think Tank, with the intention of moving toward consensus on defining a new paradigm in the field of cardiac safety.
Journal ArticleDOI
The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative — Update on progress
Thomas Colatsky,Bernard Fermini,Gary Gintant,Jennifer B. Pierson,Philip T. Sager,Yuko Sekino,David G. Strauss,Norman Stockbridge +7 more
TL;DR: An international multi-disciplinary team of regulatory, industry and academic scientists are working together to develop and validate a set of predominantly nonclinical assays and methods that eliminate the need for the thorough-QT study and enable a more precise prediction of clinical proarrhythmia risk.