Cardiotoxicity of Non-Cardiovascular Drugs

352 Pages·5.907 MB·English

Cardiotoxicity of
Non-Cardiovascular Drugs
Cardiotoxicity of Non-Cardiovascular Drugs Edited by Giorgio Minotti
© 2010 John Wiley & Sons Ltd. ISBN: 978-0-470-77274-4
Cardiotoxicity of
Non-Cardiovascular Drugs
Editor
Giorgio Minotti
University Campus Bio-Medico,
CIR and Drug Sciences, and Alberto Sordi
Foundation-Research Institute on Aging, Rome, Italy
A John Wiley and Sons, Ltd, Publication
Thiseditionfirstpublished2010
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LibraryofCongressCataloging-in-PublicationData
Cardiotoxicityofnon-cardiovasculardrugs/editor,GiorgioMinotti.
p. ; cm.
Includesbibliographicalreferencesandindex.
ISBN978-0-470-77274-4(cloth)
1. Cardiovasculartoxicology. I. Minotti,Giorgio.
[DNLM:1. CardiovascularDiseases—chemicallyinduced. 2. Cardiovascular
System—drugeffects. 3. DrugToxicity.
WG120C267152010]
RC677.C3652010
616.1’061—dc22
2009052142
AcataloguerecordforthisbookisavailablefromtheBritishLibrary.
ISBN:978-0-470-77274-4
Setin10.5/13ptsSabonbyIntegraSoftwareServicesPvt.Ltd,Pondicherry,India.
PrintedinGreatBritainbyTJInternational,Padstow,Cornwall.
To Federica, Anna Martina, and Lorenzo, for
supporting my work with understanding and
loving tolerance.
Contents
Preface ix
ListofContributors xi
Abbreviations xv
1 MitochondrialDysfunctioninCellInjuryand
Cardiotoxicity 1
FabioDiLisa,MartinaSemenzato,AndreaCarpi,Sara
Menazza,NinaKaludercic,RobertaMenabo` andMarcella
Canton
2 CardiovascularLiabilitiesofDrugs:RegulatoryAspects 25
ClaudioArrigoni
3 CellularMechanisms,MolecularTargets,and
Structure–FunctionRelationshipsinDrug-Induced
Arrhythmias:Antihistamines,PsychoactiveDrugs,and
AntimicrobialAgents 47
MariaVirginiaSoldovieriandMaurizioTaglialatela
4 CardiovascularToxicityofAntitumorDrugs:Dimensions
oftheProbleminChildren 97
RebeccaScullyandStevenE.Lipshultz
5 CardiovascularToxicityofAntitumorDrugs:Dimensionof
theProbleminAdultSettings 127
JosephR.CarverandChaitaliJ.Desai
6 DiagnosticAspectsofCardiovascularToxicityof
AntitumorDrugs 201
MichaelS.EwerandThomasM.Suter
viii CONTENTS
7 CardiovascularToxicityofAntitumorDrugs:Translating
MolecularMechanismsintoClinicalFacts 223
PierantonioMenna,EmanuelaSalvatorelli,CarloSalsano,
LucaGianniandGiorgioMinotti
8 NSAIDActionandtheFoundationsforCardiovascular
Toxicity 257
AnnaL.BlobaumandLawrenceJ.Marnett
9 CardiovascularToxicitiesofNSAIDS:Epidemiologic
Aspects 287
AntonioGonza´lez-Pe´rezandLuisAlbertoGarc´ıa
Rodriguez
10 CardiovascularToxicitiesofLife-SavingDrugs:Antiviral
Therapy 313
JamesJ.KohlerandWilliamLewis
Index 333
Preface
Somedrugs that have beendeveloped and marketedtotreat noncardio-
vascular diseases have been known to induce a number of untoward
cardiovascular effects (arrhythmias, blood pressure disorders, cardio-
myopathy, thromboembolism, or combinations of one effect with
another). There are cases where such effects can be conceptually recon-
ciledwiththeknownmodeofactionofthedrugsattheirtargettissues;in
othercases,however,thecausativelinkbetweenthemolecularsignature
of the drugs and the clinical manifestations of cardiovascular toxicity
proves much less obvious. Both on-target and off-target mechanisms
contribute to generate cardiovascular toxicities, and such complexity
reflects on the lack of guidelines on how the cardiovascular sequelae of
noncardiovasculardrugsshouldbepreventedortreated.
Further complexity is introduced by uncertainties about the actual
prevalence of cardiovascular effects induced by noncardiovascular
drugs:someeffectsarecommon,butothersarefelttoberare,unproven,
or suspected at best. The actual incidence of expected or unexpected
cardiovasculareventsalsoseemstovaryfromlowtohighdependingon
whethercardiovascularsafetysignalsaredetectedinprospectiveorretro-
spective analyses. And finally, there is a concern that the canonical
processofdrugdevelopmentmightproveunabletoanticipatethecardi-
otoxic potential of new chemical entities. The study of preclinical tox-
icology may suffer from unavoidable pitfalls in wild type or engineered
cells or laboratory animals; moreover, the conspiring effects of
polymorphisms, comorbidities, and drug-drug interactions cannot be
adequately explored in phase II or III trials as they are designed at the
moment. It follows that defining the cardiovascular safety of a given
noncardiovasculardrugmayonlybecomepossiblewhenthatparticular
drug is used to treat hundreds of thousands patients, with each patient
introducingvariableslikefavourableorunfavourablelifestyle,preexist-
ing cardiovascular or metabolic risk factors, concomitant medications,
x PREFACE
and other culprits that we cannot foresee at this time. In cases where a
non-cardiacblockbusterdrugiswithdrawnfromthemarketorsubjected
to restrictive relabelling because of unexpected or higher than expected
cardiotovasculartoxicity,wecannotescapetheconclusionthatitsdevel-
opment and approval were flawed by the limited predictiveness of
preclinicalandclinicaltrials.
This book provides a collection of contributions on the basic, epide-
miologic,andclinicalaspectsofcardiovasculartoxicityinducedbysome
popularclassesofnoncardiovasculardrugs(antihistamines,psychoactive
drugs, antibiotics, antineoplastics, nonsteroidal anti-inflammatory
drugs, antiretrovirals). Some sections address the concept of cardiovas-
cular liability in regulatory settings and that of mitochondrial dysfunc-
tionasacommonpathwaytocardiotoxicityinducedbydrugsingeneral.
In moving from one section to another the reader may develop a sense
thatsomeinformationisredundant,orthatthereisalackofconsistency
at other points. This is explained by the different backgrounds of the
contributorsandtheconsequentoverlapordiversificationintheirpoints
ofview.Whilstpossiblydetractingfromaneasy-to-readoverviewofthe
problem, such limitations may help the reader to capture the ups and
downsofafieldthatisstillmovinginthesearchforfirmconclusionsand
guidelines.Likewise,thebookisunavoidablyincompleteinitscoverage
oftopics.Reviewingallofthedrugsthatsurfacedintheliteraturebecause
ofunconfirmedwarningsoranecdoticalreportswouldhavebeenbeyond
the aims of the editors: here we wished to call the reader’s attention to
thosepreclinicalandclinicalparadigmsthatbestidentifiedcardiovascu-
lartoxicityofnoncardiovasculardrugsasastandalonediscipline.
In the next few years our perception of drug-induced cardiovascular
toxicity might easily change because of the approval of safer drugs or
refinements of techniques for predicting, managing, or preventing such
toxicity. We therefore hope that this book will be received by both
experts and non experts in this field as a genuine attempt to define
where we are now, and what should be done in the near future in the
interestofpatients’healthandscientificprogress.
IpersonallythanktheteamatJohnWiley&Sons,Ltdforencouraging
theeditingofthisbook,andthecontributorsfortheirinvaluableefforts
whichmadeitallpossible.
GiorgioMinotti
Editor
List of Contributors
ClaudioArrigoni,AcceleraS.r.l.,VialePasterur10,P.O.box11,20014
Nerviano(MI),Italy.
Anna L. Blobaum, A.B. Hancock Jr. Memorial Laboratory for Cancer
Research, Departments of Biochemistry, Chemistry and Pharmacology,
VanderbiltInstituteofChemicalBiology,CenterinMolecularToxicology
and Vanderbilt Ingram Cancer Center, Vanderbilt University School of
Medicine,Nashville,TN37232,USA.
Marcella Canton, Dipartimento di Scienze Biomediche Sperimentali,
Universita` degliStudidiPadova,VialeG.Colombo3,35121Padova,Italy.
Andrea Carpi, Dipartimento di Scienze Biomediche Sperimentali,
Universita` degliStudidiPadova,VialeG.Colombo3,35121Padova,Italy.
JosephR.Carver,UniversityoftheSciencesinPhiladelphia,Hospitalof
the University of Pennsylvania, 1600 Penn Twr, 3400 Spruce St., Phila-
delphia,PA19104,USA.
Chaitali J. Desai, University of the Sciences in Philadelphia, Hospital of
the University of Pennsylvania, 1600 Penn Twr, 3400 Spruce St., Phila-
delphia,PA19104,USA.
Fabio Di Lisa, Dipartimento di Scienze Biomediche Sperimentali,
Universita` degliStudidiPadova,VialeG.Colombo3,35121Padova,Italy.
Michael S. Ewer, The University of Texas, M. D. Anderson Cancer
Center,1515HolcombeBlvd.,Houston,TX77030-4009,USA.
xii LIST OF CONTRIBUTORS
LucaGianni,IstitutoNazionaleTumori,ViaVenezian1,20133Milan,
Italy.
Antonio Gonza´lez-Pe´rez, Centro Espan˜ol de Investigacio´n Farmacoepi-
demiolo´gica (CEIFE), Almirante 28, 2(cid:2), 28004 Madrid, and Departa-
mentodeGene´ticaEstructural.NeoCodexSL,CharlesDarwin6,41092
Sevilla,Spain.
Nina Kaludercic, Dipartimento di Scienze Biomediche Sperimentali,
Universita` degliStudidiPadova,VialeG.Colombo3,35121Padova,Italy.
JamesJ.Kohler,EmoryUniversity,DepartmentofPathology,WMB,101
WoodruffCircle,Atlanta,GA30322,USA.
WilliamLewis,EmoryUniversity,DepartmentofPathology,WMB,101
WoodruffCircle,Atlanta,GA30322,USA.
Steven E. Lipshultz, University of Miami, Leonard M. Miller School of
Medicine,HoltzChildren’sHospitaloftheUniversityofMiami/Jackson
MemorialMedicalCenterandtheSylvesterComprehensiveCancerCen-
ter,DepartmentofPediatrics,P.O.Box016820,Miami,FL33101,USA.
LawrenceJ.Marnett,A.B.HancockJr.MemorialLaboratoryforCancer
Research, Departments of Biochemistry, Chemistry and Pharmacology,
Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicol-
ogyandVanderbiltIngramCancerCenter,VanderbiltUniversitySchool
ofMedicine,Nashville,TN37232,USA.
Roberta Menabo`, Sezione Biomembrane, Istituto di Neuroscienze del
CNR,Universita` diPadova,35121Padova,Italy.
Sara Menazza, Dipartimento di Scienze Biomediche Sperimentali,
Universita` degliStudidiPadova,VialeG.Colombo3,35121Padova,Italy.
Pierantonio Menna, University Campus Bio-Medico, CIR and Drug
Sciences, and Alberto Sordi Foundation-Research Institute on Aging,
ViaAlvarodelPortillo21,00128Rome,Italy.
GiorgioMinotti,UniversityCampusBio-Medico,CIRandDrugSciences,
andAlbertoSordiFoundation-ResearchInstituteonAging,ViaAlvarodel
Portillo21,00128Rome,Italy.