Supplemental studies for cardiovascular risk assessment in safety pharmacology: a critical overview

Cardiovascular Toxicology
Sandra PicardRené Rouet

Abstract

Safety Pharmacology studies for the cardiovascular risk assessment, as described in the ICH S7A and S7B guidelines, appear as being far from sufficient. The fact that almost all medicines withdrawn from the market because of life-threatening tachyarrhythmias (torsades-de-pointes) were shown as hERG blockers and QT interval delayers led the authorities to focus mainly on these markers. However, other surrogate biomarkers, e.g., TRIaD (triangulation, reverse-use-dependence, instability and dispersion of ventricular repolarization), have been identified to more accurately estimate the drug-related torsadogenic risk. In addition, more attention should be paid to other arrhythmias, not related to long QT and nevertheless severe and/or not self-extinguishing, e.g., atrial or ventricular fibrillation, resulting from altered electrical conduction or heterogeneous shortening of cardiac repolarization. Moreover, despite numerous clinical cases of drug-induced pulmonary hypertension, orthostatic hypotension, or heart valvular failure, few safety investigations are still conducted on drug interaction with cardiac and regional hemodynamics other than changes in aortic blood pressure evaluated in conscious large animals during the core batte...Continue Reading

References

Nov 1, 1991·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·J A Schoenberger
Apr 1, 1989·Journal of Cardiovascular Pharmacology·S N LedermanH C Strauss
Jan 1, 1983·Human Pathology·R Joselson, M Warnock
Apr 1, 1984·Environmental Health Perspectives·I Y Adamson
Oct 1, 1984·Chest·P J KudenchukG B Trobaugh
Jan 1, 1984·The American Journal of Medicine·S K GoldbergA M Fein
Jan 1, 1982·Journal of Pharmacological Methods·S J Humphrey, R B McCall
Oct 1, 1981·Annals of Internal Medicine·J E Heffner, S A Sahn
Sep 1, 1981·Thorax·B H Bass
Jun 14, 1980·British Medical Journal·D J Gillmer, P Kark
Nov 1, 1993·Journal of Cardiovascular Pharmacology·J E de La CoussayeA Sassine
May 1, 1995·Journal of Cardiovascular Pharmacology·J F AupetitG Faucon
Mar 1, 1994·Clinical and Experimental Hypertension : CHE·M J DePasqualeAnthony A Fossa
Feb 1, 1993·Circulation·S C Krishnan, Charles Antzelevitch
May 1, 1993·British Journal of Clinical Pharmacology·A G JohnsonJ McCallum
Jan 15, 1996·Circulation·Gan-Xin Yan, Charles Antzelevitch
May 1, 1996·Annals of Allergy, Asthma & Immunology : Official Publication of the American College of Allergy, Asthma, & Immunology·J A HeyW Kreutner
Apr 1, 1996·The Journal of Pharmacy and Pharmacology·M J HagertyK A Kane
Aug 1, 1996·Journal of Applied Physiology·P HessJ P Clozel
Dec 1, 1996·Journal of the American College of Cardiology·Charles AntzelevitchGan-Xin Yan
Aug 28, 1997·The New England Journal of Medicine·H M ConnollyH V Schaff
Jan 1, 1997·Ryōikibetsu shōkōgun shirīzu·K Kubo, M Kato
Aug 1, 1997·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·I Verhaeverbeke, T Mets
Jan 1, 1997·Liver Transplantation and Surgery : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society·V J CanzanelloR A Krom
Dec 12, 1997·Journal of Cardiovascular Electrophysiology·S SicouriCharles Antzelevitch
Feb 11, 1998·General Pharmacology·T NatsukawaK Kimura
Sep 3, 1998·The New England Journal of Medicine·Michel HaïssaguerreJacques Clémenty
Sep 11, 1998·Journal of Cardiovascular Pharmacology·Lars EckardtGünter Breithardt
Feb 4, 1999·Hypertension·Y TakedaH Mabuchi
Feb 16, 1999·Archives of Internal Medicine·H LuukinenS L Kivelä
Apr 8, 1999·Journal of the American College of Cardiology·J FeenstraB H Stricker
Apr 14, 1999·Kidney International·J J De LimaJ B Roullet
May 5, 1999·The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation·D O TaylorP VanVeldhuisen
Aug 31, 1999·Journal of Cardiovascular Electrophysiology·Charles AntzelevitchG P Thomas
Oct 12, 1999·Journal of Cardiovascular Electrophysiology·M R RosenR Z Gainullin
Jul 11, 2000·Japanese Journal of Pharmacology·J Tamargo
Sep 27, 2000·Proceedings of the National Academy of Sciences of the United States of America·J S MitchesonMichael Sanguinetti
Dec 16, 2000·The New England Journal of Medicine·W N KernanR I Horwitz
Jan 6, 2001·Lancet·L KøberDanish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) Study Group
Feb 15, 2001·Cardiology·I GussakP Bjerregaard
Jun 19, 2001·Journal of Cardiovascular Electrophysiology·S D Girouard, D S Rosenbaum
Feb 20, 2002·JAMA : the Journal of the American Medical Association·Adelaide M Arruda-OlsonPatricia A Pellikka
Apr 19, 2002·The Journal of Pharmacology and Experimental Therapeutics·Sean EkinsSteven A Wrighton
May 3, 2002·Clinical and Experimental Pharmacology & Physiology·R A L DampneyT Tagawa
May 17, 2002·The New England Journal of Medicine·Dany Goldgran-ToledanoJean-Philippe Kevorkian
Jul 20, 2002·Journal of Cardiovascular Pharmacology·A SugiyamaKeitaro Hashimoto
Jun 27, 2003·Journal of Cardiovascular Pharmacology·Volker KühlkampLudger Seipel
Aug 20, 2003·Circulation·Fiorenzo GaitaMartin Borggrefe
Nov 5, 2003·Heart·Yee Guan Yap, A John Camm
Nov 6, 2003·Toxicological Sciences : an Official Journal of the Society of Toxicology·Robert L HamlinDavid M Hamlin
Jan 28, 2004·British Journal of Pharmacology·S M GardinerT Bennett
Feb 21, 2004·European Journal of Pharmacology·Anthony A FossaBernard Fermini
Apr 20, 2004·Journal of Cardiovascular Electrophysiology·Robert R FenichelIndependent Academic Task Force
Apr 28, 2004·Experimental Physiology·Edmund J CrampinMerryn Tawhai
Jun 3, 2004·Journal of Pharmacological and Toxicological Methods·Alan BassPatricia Williams
Jun 24, 2004·Molecular Pharmacology·Eckhard FickerArthur M Brown
Jul 10, 2004·The Journal of Physiology·Jonathan SatinLior Gepstein
Aug 12, 2004·Physiology·Denis Noble
Sep 2, 2004·The Journal of Pharmacology and Experimental Therapeutics·Yuri A KuryshevDavid Rampe
Jan 19, 2005·British Journal of Pharmacology·Pascal ChamperouxSerge Richard
Jan 22, 2005·European Journal of Pharmacology·Akira TakaharaKeitaro Hashimoto
Feb 16, 2005·British Journal of Pharmacology·L L EckhardtC T January
Mar 23, 2005·Circulation·Björn I GustafssonHelge Waldum
Apr 9, 2005·Journal of Cardiovascular Electrophysiology·Philip AouateJamal Seoud
Apr 27, 2005·Heart Rhythm : the Official Journal of the Heart Rhythm Society·Jeffrey M Fish, Charles Antzelevitch
Apr 27, 2005·Heart Rhythm : the Official Journal of the Heart Rhythm Society·Sami ViskinBernard Belhassen
May 14, 2005·Cardiovascular Research·Rainer SchimpfMartin Borggrefe
Jun 7, 2005·Journal of the American College of Cardiology·Sunny S PoEugene Patterson
Jun 18, 2005·Journal of Pharmacological and Toxicological Methods·Daniela S HauserGuido Hanauer
Jul 5, 2005·Heart Rhythm : the Official Journal of the Heart Rhythm Society·Rashmi R Shah, Luc M Hondeghem
Jul 5, 2005·Heart Rhythm : the Official Journal of the Heart Rhythm Society·Marek Malik
Sep 6, 2005·The Journal of Toxicological Sciences·Motohiro ShiotaniIkuo Horii
Oct 12, 2005·Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology·Andrea SarkozyPedro Brugada
Dec 13, 2005·Journal of Internal Medicine·Leif Carlsson
Mar 10, 2006·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·Marion AubertEric A Ertel
Mar 15, 2006·CNS Drugs·David Murdoch, Gillian M Keating
Apr 12, 2006·Pacing and Clinical Electrophysiology : PACE·Alexander Burashnikov, Charles Antzelevitch
May 9, 2006·Journal of Pharmacological and Toxicological Methods·Anthony A FossaJun Zhou
Aug 1, 2006·Heart Rhythm : the Official Journal of the Heart Rhythm Society·Tengxian LiuGan-Xin Yan
Aug 24, 2006·European Heart Journal·Carla GiustettoFiorenzo Gaita
Oct 3, 2006·Expert Review of Molecular Diagnostics·Peter James O'Brien
Oct 28, 2006·Drugs & Aging·Vincent M Santillo, Franklin C Lowe
Nov 11, 2006·The Journal of Pharmacology and Experimental Therapeutics·Lu WangEckhard Ficker
Nov 30, 2006·Journal of Pharmacological Sciences·Guray SoydanMeral Tuncer
Mar 7, 2007·Clinical Pharmacology and Therapeutics·B K MalhotraP Wicker
Apr 3, 2007·Human Psychopharmacology·Patrick MbayaDavid Bennett
Jun 20, 2007·Basic & Clinical Pharmacology & Toxicology·Akira TakaharaKeitaro Hashimoto
Jun 26, 2007·American Journal of Physiology. Heart and Circulatory Physiology·Charles Antzelevitch
Apr 2, 2008·Pharmacology & Therapeutics·Chinmay Patel, Charles Antzelevitch
May 9, 2008·The New England Journal of Medicine·Michel HaïssaguerreJacques Clémenty
Jun 17, 2008·British Journal of Pharmacology·Dan M Roden
Jul 9, 2008·The American Journal of Emergency Medicine·Jérôme FichetDominique Babuty
Jul 21, 2009·Journal of Pharmacological and Toxicological Methods·O AdeyemiM Dewhurst
Sep 23, 2009·Circulation·Satish R RajDan M Roden
Jan 1, 2010·Heart Rhythm : the Official Journal of the Heart Rhythm Society·Eyal NofCharles Antzelevitch
Jan 5, 2011·European Journal of Echocardiography : the Journal of the Working Group on Echocardiography of the European Society of Cardiology·Florent Le VenYves Etienne
Jan 19, 2011·Fundamental & Clinical Pharmacology·Paolo Emilio PudduJoffrey Ducroq
Nov 1, 2002·Current Protocols in Pharmacology·Pierre Lacroix
Mar 1, 2008·Current Protocols in Pharmacology·Philippe GuillaumePierre Lacroix
Mar 1, 2009·Current Protocols in Pharmacology·Philippe GuillaumePierre Lacroix

Citations

May 23, 2012·Expert Opinion on Drug Discovery·Lars SundstromLuc Stoppini
Jun 14, 2012·Journal of Pharmacological and Toxicological Methods·Sonia GoineauGuillaume Froget
Sep 27, 2015·Basic & Clinical Pharmacology & Toxicology·Takashi NagayamaMasato Fujiyoshi
Apr 30, 2013·Journal of Pharmacological and Toxicological Methods·Kylie A BeattieGary R Mirams
Oct 15, 2013·Regulatory Toxicology and Pharmacology : RTP·Sonia GoineauVincent Castagné
Aug 2, 2016·Journal of Pharmacological and Toxicological Methods·Sonia Goineau, Vincent Castagné
Jun 8, 2013·Current Protocols in Pharmacology·Philippe GuillaumeGuillaume Froget
May 16, 2017·Green Chemistry : an International Journal and Green Chemistry Resource : GC·Vinicius AlvesAlexander Tropsha
Aug 11, 2018·Journal of Cardiovascular Pharmacology and Therapeutics·Bo QiuYanfang Xu
Feb 11, 2014·Current Protocols in Pharmacology·Sonia GoineauGuillaume Froget
Aug 5, 2016·Molecular Informatics·Rodolpho C BragaCarolina H Andrade

Related Concepts

Cardiac Arrhythmia
In Silico
Medicinal Plants Testing, Preclinical
Electrocardiographic Recorders
Heart Function Tests
Hemodynamics
Benefit-Risk Assessment
Computational Molecular Biology
His Bundle Electrogram
Attention

Related Feeds

Cardiac Conduction System

The cardiac conduction system is a specialized tract of myocardial cells responsible for maintaining normal cardiac rhythm. Discover the latest research on the cardiac conduction system here.

Atrial Filbrillation

Atrial fibrillation refers to the abnormal heart rhythm characterized by rapid and irregular beating of the atria. Here is the latest research.

Arrhythmia

Arrhythmias are abnormalities in heart rhythms, which can be either too fast or too slow. They can result from abnormalities of the initiation of an impulse or impulse conduction or a combination of both. Here is the latest research on arrhythmias.

Atrial Fibrillation

Atrial fibrillation is a common arrhythmia that is associated with substantial morbidity and mortality, particularly due to stroke and thromboembolism. Here is the latest research.