Advances in Combination Therapy for Asthma and COPD

361 Pages·2011·3.056 MB·English

by  Jan Lötvall(eds.)

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A
DVANCES IN COMBINATION
THERAPY FOR ASTHMA
COPD
AND
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A
DVANCES IN COMBINATION
THERAPY FOR ASTHMA
COPD
AND
Editor
Jan Lo¨tvall
KreftingResearchCentre,UniversityofGothenburg,Go¨teborg,Sweden
A John Wiley & Sons, Ltd., Publication
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Thiseditionfirstpublished2012
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LibraryofCongressCataloguing-in-PublicationData
AdvancesincombinationtherapyforasthmaandCOPD/[editedby]JanLo¨tvall,WilliamBusse.
p. ; cm.
Includesbibliographicalreferencesandindex.
ISBN978-0-470-72702-7(cloth)
1. Lungs–Diseases,Obstructive–Chemotherapy. 2. Asthma–Chemotherapy. 3. Polypharmacy.
4. Chemotherapy,Combination. I. Lo¨tvall,Jan. II. Busse,W.W.(WilliamW.)
[DNLM:1. Asthma–drugtherapy. 2. DrugTherapy,Combination.
3. PulmonaryDisease,ChronicObstructive–drugtherapy.WF553]
RC776.O3A33 2011
616.2’3061–dc23
2011023057
AcataloguerecordforthisbookisavailablefromtheBritishLibrary.
Thisbookispublishedinthefollowingelectronicformat:ePDF:9781119998631;WileyOnlineLibrary:9781119998624;
epub:9781119978466;Mobi:9781119978473
Typesetin10.5/12.5ptTimesbyAptaraInc.,NewDelhi,India
Printedin[Country]by[Printer]
FirstImpression2012
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Contents
Contributors xi
Preface xiii
1 Similarities and differences in the pathophysiology
of asthma and COPD 1
J.ChristianVirchow
1.1 Introduction 1
1.2 PulmonaryfunctionabnormalitiesinasthmaandCOPD 3
1.3 RiskfactorsforasthmaandCOPD 5
1.4 CellularinflammationinasthmaandCOPD 8
1.5 DistributionandconsequencesofinflammationinasthmaandCOPD 9
1.6 PatternsofepithelialinjuryinasthmaandCOPD 10
1.7 Airwayhyperresponsiveness 10
1.8 Beta-receptorblockers 10
1.9 DifferentialdiagnosisofasthmaandCOPD 11
1.10 Overlapsyndrome 12
1.11 Conclusion 12
References 13
2 Glucocorticoids: pharmacology and mechanisms 16
PeterJ.Barnes
2.1 Introduction 16
2.2 Chemicalstructures 16
2.3 Themolecularbasisofinflammation 17
2.4 Cellulareffectsofglucocorticoids 19
2.5 Glucocorticoidreceptors 20
2.6 Glucocorticoidactivationofgenetranscription 22
2.7 Suppressionofinflammatorygenes 23
2.8 Steroidresistance 29
2.9 Interactionwith(cid:2) -adrenergicreceptors 32
2
2.10 Conclusions 33
References 33
3 Inhaled corticosteroids: clinical effects in asthma and COPD 38
PaulM.O’ByrneandDesmondM.Murphy
3.1 Introduction 38
3.2 Anti-inflammatoryactivityofcorticosteroids 38
3.3 Routesofadministration 39
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3.4 Absorptionandfateofcorticosteroids 41
3.5 Currentlyavailableinhaledcorticosteroids 41
3.6 Efficacyinasthma 43
3.7 EfficacyinCOPD 44
3.8 SideeffectsofICS 46
3.9 Conclusions 49
References 49
4 LABAs: pharmacology, mechanisms and interaction
with anti-inflammatory treatments 53
GaryP.Anderson
4.1 GalenicalformsofLABAs:formulations,isomers,enantiomers,
diasteriomersandsalts 55
4.2 Absoluteandfunctional(cid:2) -adrenoceptorselectivity 56
2
4.3 Cellularorganizationofreceptorclusters:functionalstructureofthe
(cid:2) -adrenoceptorandmodeofsignalling 58
2
4.4 Dimersandoligomers:homo-andheterodimerism/oligoism 60
4.5 Pharmacogenomicsofthe(cid:2) -adrenoceptorandadenylatecyclase
2
polymorphisminrelationtoLABAs 61
4.6 Understandingthe‘reassertion’paradox,‘exosites’andrelativespeedof
onset:themembranediffusionmicrokineticmodelofLABAaction 61
4.7 Regulationanddesensitization 63
4.8 Fullversuspartialagonism(pharmacologicalefficacy) 64
4.9 Beta-blockersnotLABAs? 67
4.10 Non-receptor-mediatedeffects? 68
4.11 BiochemicalbasisoffunctionalantagonismanditscriticalroleinLABA
actionindiseaseandexacerbations 68
4.12 MolecularcooperativitybetweenLABAsandsteroids 69
4.13 Perspective 73
References 73
5 Long- and ultra-long-acting (cid:2) -agonists 81
2
MarioCazzolaandMariaGabriellaMatera
5.1 Introduction 81
5.2 Long-acting(cid:2) -agonists 82
2
5.3 Novelultra-long-acting(cid:2) -agonists 86
2
5.4 Conclusion 95
References 95
6 The safety of long-acting beta-agonists and the development
of combination therapies for asthma and COPD 102
VictorE.OrtegaandEugeneR.Bleecker
6.1 Introduction 102
6.2 Asthma-relatedmortalityandbeta-agonistexposure 103
6.3 Long-actingbeta-agonistsandincreasedasthma-relatedmortality 105
6.4 SafetyandefficacyofLABAtherapyinasthma:retrospectiveanalyses 107
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6.5 EfficacyofLABAtherapyasacomponentofcombinationtherapy
withICSforthemanagementofasthma 110
6.6 Scientificbasisofthebeneficialandadverseeffectsofbeta-agonist
therapy:invitrodataandthebeta-agonistparadox 113
6.7 ConclusionsregardingthesafetyofLABAtherapyasacomponent
ofcombinationtherapywithICSforthemanagementofasthma 114
6.8 Beta-agonisttherapyandadverseeventsinCOPD 115
6.9 SafetyandefficacyofLABAtherapyinthemanagementofCOPD:
theclinicalevidence 116
6.10 RoleofLABAtherapyasacomponentofcombinationtherapywithICS
forthemanagementofCOPD 117
6.11 ConclusionsregardingthesafetyofLABAtherapyasacomponent
ofcombinationtherapyforthemanagementofCOPD 120
6.12 PharmacogeneticsofLABAsandcombinationtherapy 120
6.13 SafetyandefficacyofLABAtherapyandthedevelopmentofcombination
therapiesforthemanagementofasthmaandCOPD 126
6.14 Summaryandfuturedirections 127
Acknowledgement 128
References 128
7 Inhaled combination therapy with glucocorticoids
and long-acting (cid:2) -agonists in asthma and COPD, current
2
and future perspectives 135
JanLo¨tvall
7.1 PharmacologicalmanagementguidelinesofasthmaandCOPD 135
7.2 Steroidtreatmentinasthma 136
7.3 EffectsofaddingLABAtoinhaledglucocorticoidsinasthma 137
7.4 SteroidtreatmentinCOPD 140
7.5 EffectsofLABAsinCOPD 140
7.6 Combinationinhalersversustwoseparateinhalersforinhaled
GCSandLABAs 141
7.7 Regulartreatmentaloneversusadditionalformoterol-containing
combinationsasrelievertherapy 143
7.8 Currentlyavailablecombinationinhalers 145
7.9 UpcomingandalternativecombinationsofinhaledGCSandLABAs 146
7.10 Futureofcombinedinhalationtherapyinrespiratorydisease 148
References 149
8 Novel anti-inflammatory treatments for asthma and COPD 154
PaulA.Kirkham,GaetanoCaramori,K.FanChungandIanM.Adcock
8.1 Introduction 154
8.2 CurrentasthmaandCOPDtherapies 158
8.3 Theneedfornewtherapies 160
8.4 Improvingcurrenttherapies 162
8.5 TargetingchemokinesandtheirreceptorsinasthmaandCOPD 166
8.6 TargetingT-cell-derivedandproinflammatorycytokinesinasthma
andCOPD 169
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8.7 TargetingadhesionmoleculesinasthmaandCOPD 172
8.8 GrowthfactorblockersinasthmaandCOPD 173
8.9 Mucouscells,submucosalglandsandmucusproductioninasthma
andCOPD 173
8.10 InfectionsinasthmaandCOPD 174
8.11 Intracellularsignallingpathways 175
8.12 InhibitionoftranscriptionfactorsinasthmaandCOPD 178
8.13 AntioxidantsinasthmaandCOPD 181
8.14 Immunomodulationandanti-allergytreatmentsinasthmaandCOPD 182
8.15 Conclusions 185
Acknowledgements 186
References 186
9 Novel biologicals alone and in combination
in asthma and allergy 203
SharmileeM.NyenhuisandWilliamW.Busse
9.1 Introduction 203
9.2 Targetsoftherapy 204
9.3 Interleukin-4 204
9.4 Interleukin-5 207
9.5 Interleukin-13 211
9.6 Tumornecrosisfactor-(cid:3) 212
9.7 ImmunoglobulinE 215
9.8 DNAvaccines 220
9.9 Futuredirections 222
9.10 Conclusion 224
References 225
10 Anti-infective treatments in asthma and COPD 232
JonathanD.R.MacintyreandSebastianL.Johnston
10.1 Introduction 232
10.2 Currentguidelines 234
10.3 Acuteexacerbationsofasthma 236
10.4 Increasedsusceptibilitytoinfectioninasthmatics 236
10.5 Roleofatypicalbacteriainasthma 237
10.6 Roleofvirusesinasthmaexacerbations 244
10.7 Anti-infectivesinCOPDexacerbations 250
10.8 UseofantibioticsinstableCOPD 256
10.9 Roleofvaccination 257
10.10 Conclusion 259
References 260
11 Long-acting muscarinic antagonists in asthma and COPD 268
M.DianeLougheed,JosuelOraandDenisE.O’Donnell
11.1 Introduction 268
11.2 Innervationoftheairways 268
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11.3 CholinergicmechanismsinasthmaandCOPD 270
11.4 Roleoflong-actinganticholinergicbronchodilatorsinobstructive
lungdisease 271
11.5 Summary 287
References 288
12 Phosphodiesterase inhibitors in obstructive lung disease 296
JanLo¨tvallandBoLundba¨ck
12.1 Introduction 296
12.2 Phosphodiesteraseenzymes 297
12.3 DifferentpharmacologicalagentsblockingPDE4 298
12.4 BiologicaleffectsofPDE4inhibition,preclinicalinformation 300
12.5 ClinicaleffectsofPDE4inhibitioninCOPD 302
12.6 EffectsofPDE4inhibitorsonsystemicprocessesinCOPD 304
12.7 SideeffectsofPDE4inhibitors 304
12.8 PDE4inhibitorsinCOPDmanagementplans 305
12.9 FutureprospectswithPDE4inhibitorsinobstructiveairwaysdisease 305
12.10 Summary 306
References 306
13 Biological therapies in development for COPD 311
J.MorjariaandR.Polosa
13.1 Introduction 311
13.2 InflammatorycellsinvolvedinthepathogenesisofCOPD 312
13.3 CytokinesandchemokinesinCOPD 315
13.4 DevelopmentofbiologicalagentsinCOPD 320
13.5 Conclusions 323
References 323
14 ‘Triple therapy’ in the management of COPD: inhaled steroid,
long-acting anticholinergic and long-acting (cid:2) -agonist 333
2
RonaldDahl
14.1 Introduction 333
14.2 Long-actinginhaledanticholinergic(LAMA)and(cid:2) -agonist(LABA)
2
bronchodilators 333
14.3 TreatmentstrategiesforCOPD 334
14.4 InhaledcorticosteroidsandCOPD 334
14.5 CombinationtreatmentwithICS,LAMAandLABA:‘tripletherapy’ 335
14.6 ExtracteddatafromTORCHandUPLIFTstudies 337
14.7 Conclusions 340
References 341
Index 343
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Contributors
IanM.Adcock K.FanChung
AirwaysDiseaseSection,NationalHeart AirwaysDiseaseSection,NationalHeart
andLungInstitute,ImperialCollegeLondon, andLungInstitute,ImperialCollegeLondon,
DovehouseStreet,LondonSW36LY,UK DovehouseStreet,LondonSW36LY,UK
GaryP.Anderson RonaldDahl
LungDiseaseResearchGroup,Departments DepartmentofRespiratoryDiseases,
ofPharmacologyandMedicine,University AarhusUniversityHospital,NBG,
ofMelbourne,Parkville,3010VIC,Australia DK8000AarhusC,Denmark
PeterJBarnes SebastianL.Johnston
SectionofAirwayDisease,NationalHeart DepartmentofRespiratoryMedicine,
andLungInstitute,ImperialCollegeLondon, NationalHeartandLungInstitute,
DovehouseStreet,LondonSW36LY,UK MRCandAsthmaUKCentreinAllergic
MechanismsofAsthma,ImperialCollege
London,NorfolkPlace,London
EugeneR.Bleecker
W21PG,UK
WakeForestUniversityHealthSciences,
CenterforHumanGenomicsand
PersonalizedMedicine,MedicalCenter PaulA.Kirkham
Boulevard,Winston-Salem,NC27157,USA AirwaysDiseaseSection,NationalHeart
andLungInstitute,ImperialCollege
London,DovehouseStreet,London
WilliamW.Busse
SW36LY,UK
DivisionofAllergyandImmunology,
DepartmentofMedicine,Universityof
Wisconsin,600HighlandAvenue,Madison, JanLo¨tvall
WI53792,USA KreftingResearchCentre,Universityof
Gothenburg,Go¨teborg,Sweden
GaetanoCaramori
CentreofResearchonAsthmaandCOPD, M.DianeLougheed
UniversityofFerrara,Ferrara,Italy DepartmentofMedicine,Divisionof
Respirology,Queen’sUniversity,102Stuart
Street,Kingston,Ontario,Canada,K7L2V6
MarioCazzola
UnitofRespiratoryDiseases,Departmentof
InternalMedicine,UniversityofRome‘Tor BoLundba¨ck
Vergata’,ViaMontpellier1,Rome00133, KreftingResearchCentre,Universityof
Italy Gothenburg,Sweden
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xii CONTRIBUTORS
JonathanD.R.Macintyre DenisE.O’Donnell
DepartmentofRespiratoryMedicine, DepartmentofMedicine,Divisionof
NationalHeartandLungInstitute,MRCand Respirology,Queen’sUniversity,
AsthmaUKCentreinAllergicMechanisms 102StuartStreet,Kingston,
ofAsthma,ImperialCollegeLondon, OntarioK7L2V6,Canada
NorfolkPlace,LondonW21PG,UK
JosuelOra
MariaGabriellaMatera ClinicalResearchFellow,Respiratory
UnitofPharmacology,Departmentof InvestigationUnit,KingstonGeneral
ExperimentalMedicine,SecondUniversity HospitalandQueen’sUniversity,
ofNaples,Naples,Italy 102StuartStreet,Kingston,
OntarioK7L2V6,Canada
J.Morjaria
DepartmentofInfection,Inflammationand VictorE.Ortega
Repair,UniversityofSouthampton, WakeForestUniversityHealthSciences,
Southampton,UK CenterforHumanGenomicsand
PersonalizedMedicine,Medical
CenterBoulevard,Winston-Salem,NC
DesmondM.Murphy
27157,USA
McMasterUniversityMedicalCenter,1200
MainSt.West,Hamilton,OntarioL9G4R7,
Canada RiccardoPolosa
OspedaleSantaMarta,U.O.CdiMedicina
InternaeMedicinad’Urgenza,Via
SharmileeM.Nyenhuis
GesualdoClementi36,95124Catania,Italy
DivisionofAllergyandImmunology,
DepartmentofMedicine,Universityof
Wisconsin,600HighlandAvenue,Madison, J.ChristianVirchow
WI53792,USA DepartmentofPneumology/IntensiveCare
MedicineKlinikI/Zentrumfu¨rInnere
MedizinUniversita¨tsklinikum,Universityof
PaulM.O’Byrne
RostockErnst-Heydemann-Str.6,D-18055
Rm3W10,McMasterUniversityMedical
Rostok,Germany
Center,1200MainSt.West,Hamilton,
OntarioL9G4R7,Canada