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d al w s eif Gr ?t sit er v ni U ?r ert f si n e z Li d al w s eif Gr ?t sit er v ni U ?r ert f si n e z Li Angioedema Congress Book Edited by Murat Bas Thomas K. Hoffmann Georg Kojda 19figures 3tables d al w s eif Gr ?t sit er v ni U ?r ert f si n e z Li GeorgThiemeVerlag Stuttgart·NewYork IV BibliographicInformationpublishedby ImportantNote:Medicineisanever-changingscienceun- dieDeutscheNationalbibliothek dergoingcontinualdevelopment.Researchandclinicalex- periencearecontinuallyexpandingourknowledge,inpar- DieDeutscheNationalbibliothekliststhispublication ticular our knowledge of proper treatment and drug intheDeutscheNationalbibliografie; therapy.Insofarasthisbookmentionsanydosageorappli- detailedbibliographicdataisavailableon cation,readersmayrestassuredthattheauthors,editors, theinternetathttp://dnb.d-nb.de. andpublishershavemadeeveryefforttoensurethatsuch referencesareinaccordancewiththestateofknowledge atthetimeofproductionofthebook. Nevertheless,thisdoesnotinvolve,imply,orexpressany guaranteeorresponsibilityonthepartofthepublishersin respecttoanydosageinstructionsandformsofapplications stated in the book. Every user is requested to examine carefully the manufacturers’ leaflets accompanying each drugandtocheck,ifnecessaryinconsultationwithaphysi- cianorspecialist,whetherthedosageschedulesmentioned thereinorthecontraindicationsstatedbythemanufactur- ersdifferfromthestatementsmadeinthepresentbook. Suchexaminationisparticularlyimportantwithdrugsthat areeitherrarelyusedorhavebeennewlyreleasedonthe market.Everydosagescheduleoreveryformofapplication usedisentirelyattheuser’sownriskandresponsibility.The Thispublicationhasbeensponsored authorsandpublishersrequesteveryusertoreporttothe byJereni/ShireHGT. publishersanydiscrepanciesorinaccuraciesnoticed. ©2009GeorgThiemeVerlagKG Someoftheproductnames,patents,andregistereddesigns d al Rüdigerstraße14 referredtointhisbookareinfactregisteredtrademarksor sw 70469Stuttgart,Germany proprietary names even though specific reference tothis eif http://www.thieme.de factisnotalwaysmadeinthetext.Therefore,theappear- Gr ThiemeNewYork,333SeventhAvenue anceofanamewithoutdesignationasproprietaryisnotto ?t NewYork,NY10001,USA beconstruedasarepresentationbythepublisherthatitis ersit http://www.thieme.com inthepublicdomain. niv Thisbook,includingallpartsthereof,islegallyprotected U PrintedinGermany bycopyright.Anyuse, exploitation,orcommercialization ?r outsidethenarrowlimitssetbycopyrightlegislation,with- ert f CoverdesignbyThiemeVerlagsgruppe outthepublisher’sconsent,isillegalandliabletoprosecu- si FiguresbyZiegler+Müller,Kirchentellinsfurt tion.Thisapplies inparticulartophotostat reproduction, n ze TypesettingbyZiegler+Müller,Kirchentellinsfurt copying,mimeographingorduplicationofanykind,trans- Li PrintingandBookbindingbyGrafischesCentrumCuno, lating,preparationofmicrofilms,andelectronicdataproc- Calbe essingandstorage. ISBN978-3-13-147421-6 1 2 3 4 5 6 V Preface Hereditary angioedema and other forms of non- Anotherimportantaimofthisbookistodraw allergicangioedemaarelongknownandwerede- attention to bradykinin-induced angioedema scribed firstbyQuinckein1882andbyOssler in whichiscausedbycertaindrugssuchasACE-in- 1888.Bothdescribeswellingsofthemucosaand/ hibitorsand/orsartans.Someoftheseangioedema or submucosa of the skin which may impair arepresentinthelarynxandmaycausedeathas breathing and are potentially life-threatening. In well. Currently, there is no published algorithm particular,swellingsofthepharynxandthelarynx fordiagnosisandtreatment.Likewise,thereisno often require emergency treatment and several evidence-based treatment at all. In more severe daysofhospitalization.Thedifferentiationofbra- cases, such patients are usually hospitalized and dykinin-induced angioedema to allergic angio- receiveglucocorticoidsandantihistamines.Fortu- edemaiscrucialforsuccessfultherapy. nately,newdrugs havebeen developed in recent Eventoday,manypatientswithhereditaryan- yearswhicharebasedonentirelynewmolecular gioedema are notcorrectlydiagnosed in the first mechanisms and which are subcutaneously ap- place.Furthermore,pharmacotherapyisoftenmis- plied. This appears to be a considerable advance. directedifpatientsaretreatedinhospitalswhere Forthefirsttime,thesenewdrugsofferthepossi- noorminorexperienceexistswithsuchpatients. bility of on-demand self-administration even in Forexample,itstillhappensthatphysiciansrefuse children. toprovide effectivebutexpensive antibradykinin pharmacotherapyevenforpatientshavingacard Düsseldorf, GeorgKojda identifying them as having hereditary angioede- September2009 ma.Thus, itis oneimportantaimof thisbookto alertphysiciansandotherhealthcareprovidersto the course of this disease, its diagnosis and its pharmacotherapy. d al w s eif Gr ?t sit er v ni U ?r ert f si n e z Li VI Addresses Prof.Dr.VolkerAdams PDDr.med.KarinHartmann HerzzentrumLeipzigGmbH KlinikumderUniversitätzuKöln Strümpellstraße39 KlinikundPoliklinikfürDermatologie 04289Leipzig undVenerologie e-mail:[email protected] KerpenerStraße62 50937Köln Dr.MuratBas e-mail:[email protected] Hals-Nasen-OhrenklinikundPoliklinik KlinikumrechtsderIsar PDDr.med.ThomasK.Hoffmann derTechnischenUniversitätMünchen UniversitätsklinikumDüsseldorf IsmaningerStraße22 Hals-Nasen-Ohren-Klinik 81675München Gebäude-Nr.:13.76 e-mail:[email protected] Moorenstraße5 40225Düsseldorf Prof.Dr.KonradBork e-mail:Thomas.Hoffmann@ Universitäts-HautklinikMainz med.uni-duesseldorf.de Johannes-Gutenberg-Universität Langenbeckstraße1 PDDr.WolfhartKreuz 55101Mainz KlinikumJ.WolfgangGoethe-Universität e-mail:[email protected] ZentrumfürKinderheilkundeIII Hämostaseologie Prof.Dr.IngridFleming Theodor-Stern-Kai7 KlinikumJ.WolfgangGoethe-Universität 60596Frankfurt Theodor-Stern-Kai7 60596Frankfurt Dr.med.JanRamakers e-mail:[email protected] UniversitätsklinikumDüsseldorf Moorenstraße5 d Prof.Dr.PeterGohlke 40225Düsseldorf al w UniversitätsklinikumSchleswig-Holstein e-mail:[email protected] s eif InstitutfürPharmakologie Gr Hospitalstraße4 Prof.Dr.BerndRosenkranz sit?t 24105Kiel ViaDr.med.JensZimmermann er e-mail:[email protected] JeriniAG v ni Invalidenstraße130 U ?r 10115Berlin ert f e-mail:[email protected] si n e z Li VII Table of Contents 1 TreatmentofAllergicAngioedema . . . . . .. . . . . . .. . . . . . .. . . . . . . .. . . . . . .. . . . . . . . 1 K.Hartmann Introduction.. . . . . . .. . . . . . . .. . . . . . .. . . . 1 TherapyforChronicAngioedema. . . .. . . . . . . . 2 TherapyforAcuteAngioedema . .. . . . . . .. . . . 2 2 EmergencyTherapyforAngioedemaoftheUpperAirway . . . . . . . .. . . . . . .. . . . . . . . 4 T.K.Hoffmann,H.Bier,G.Kojda,M.Bas Introduction.. . . . . . .. . . . . . . .. . . . . . .. . . . 4 Therapy . . . . . . .. . . . . . . .. . . . . . .. . . . . . . . 5 Symptoms . .. . . . . . .. . . . . . . .. . . . . . .. . . . 4 Conclusion . . . . .. . . . . . . .. . . . . . .. . . . . . . . 7 Diagnostics. .. . . . . . .. . . . . . . .. . . . . . .. . . . 4 3 HereditaryAngioedema:ClinicalManifestationandTherapy . . . . . .. . . . . . .. . . . . . . . 8 W.Kreuz,E.Aygören-Pürsün,I.MartinezSaguer,E.Rusicke Introduction.. . . . . . .. . . . . . . .. . . . . . .. . . . 8 EpidemiologyandGenetics BiologicalCharacteristicsofC1-INH. . . . . .. . . . 8 ofC1-INHDeficiency. . . . . .. . . . . . .. . . . . . . 9 DiagnosisandClassification ClinicalSymptomsofHereditaryAngioedema . 10 ofC1-INHDeficiency. .. . . . . . . .. . . . . . .. . . . 8 CurrentTreatmentofHereditaryAngioedema . 12 Conclusion . . . . .. . . . . . . .. . . . . . .. . . . . . . 13 d al w 4 SpecialAspectsoftheTreatmentofHereditaryAngioedemainChildren . . .. . . . . . . 15 s eif Gr J.Ramakers,T.Niehues ?t sit Introduction.. . . . . . .. . . . . . . .. . . . . . .. . . 15 DifferentialDiagnoses. . . . .. . . . . . .. . . . . . . 16 er v ClinicalPicture . . . . . .. . . . . . . .. . . . . . .. . . 15 Therapy . . . . . . .. . . . . . . .. . . . . . .. . . . . . . 16 ni U Diagnosis . . .. . . . . . .. . . . . . . .. . . . . . .. . . 16 PatientInformationandPsychosocialAspects . 17 ?r ert f si n e z Li VIII TableofContents 5 AcutePhaseProteinsinKinin-InducedAngioedema . . . .. . . . . . . .. . . . . . .. . . . . . . . 19 M.Bas,H.Bier,M.Oppermann,T.K.Hoffmann,G.Kojda Introduction . . . . . .. . . . . . . .. . . . . . .. . . . 19 AcutePhaseProteinsin TheRoleofBradykininin Bradykinin-InducedAngioedema. .. . . . . . . . 21 Non-AllergicAngioedema . . . .. . . . . . .. . . . 20 Conclusion . . .. . . . . . . .. . . . . . .. . . . . . . . 22 6 BradykininandtheKallikrein-KininSystem: Kallikreins,BradykininandVascularSignalTransduction . . . . . . . .. . . . . . .. . . . . . . . 23 V.Adams TheKallikrein-KininSystem. . .. . . . . . .. . . . 23 AnimalModelswithParticipation oftheKallikrein-KininSystems . . .. . . . . . . . 24 7 DrugsAffectingtheKallikrein-KininSystem . . . .. . . . . . .. . . . . . . .. . . . . . .. . . . . . . . 28 B.Rosenkranz,W.Fan,J.Zimmermann TheKallikrein-KininSystem. . .. . . . . . .. . . . 28 AntagonistsoftheKallikrein-KininSystem. . . 28 8 RAASBlockerandBradykininMetabolism: TheRoleofBradykininforClinicalEfficacy . . . . .. . . . . . .. . . . . . . .. . . . . . .. . . . . . . . 32 P.Gohlke Introduction . . . . . .. . . . . . . .. . . . . . .. . . . 32 AT ReceptorAntagonists 1 TheKallikrein-KininSystem. . .. . . . . . .. . . . 33 andBradykinin . . . . . . . .. . . . . . .. . . . . . . . 36 ACEInhibitorandKinins . . . . .. . . . . . .. . . . 34 Conclusions. . .. . . . . . . .. . . . . . .. . . . . . . . 36 9 ANewLookattheTherapeuticEffectsofACEInhibitors: d ACEasSignalTransductionMolecule . . .. . . . . . .. . . . . . .. . . . . . . .. . . . . . .. . . . . . . . 38 al w eifs K.Kohlstedt,I.Fleming Gr ?t AngiotensinConvertingEnzyme(ACE). .. . . . 38 Perspective:NewViewpoint sit ACEInhibitorsandACESignalling . . . . .. . . . 39 withRegardtoRAS . . . . .. . . . . . .. . . . . . . . 40 er v ni U ?r ert f 10 CurrentandFutureTreatmentOptionsforHereditaryAngioedema. . . . . .. . . . . . . . 42 nsi K.Bork e z Li Index. . . . . . .. . . . . . . .. . . . . . .. . . . . . . .. . . . . . .. . . . . . .. . . . . . . .. . . . . . .. . . . . . . . 46 1 1 Treatment of Allergic Angioedema K.Hartmann DepartmentofDermatology,UniversityofCologne,Cologne,Germany Abstract Angioedemasarecharacterizedbyasuddenonsetofswellinginthedeepdermisandsubcutis.Forsimplicity, angioedemasareclassifiedintothosewithgeneticcausesandacquiredforms.Causesofacquiredangioedemas includeallergicreactions,autoimmunemechanisms,infectionsandnon-allergic/pseudo-allergichypersensitiv- ityreactions.Often,acquiredangioedemasareaccompaniedbyurticaria.Asinthecaseofspontaneousurtica- ria,itisreasonabletodistinguishbetweenacuteacquiredangioedemawithacourseoflessthansixweeksand chronicacquiredangioedemathatexistsformorethansixweeks.Forbothforms,possibletriggeringfactors suchasdrugsandinfectionsshouldfirstbeexcluded.Acuteangioedemasaretreatedwithglucocorticoidsand H1-antihistamines.Forchronicangioedemas,non-sedativeH1-antihistaminesarerecommendedasfirst-line therapy.Insomecases,higherdosagesofantihistamines–uptofourtimestheapproveddose–arerequired. Insevereforms,cyclosporinAcanbeconsidered,whereasglucocorticoidsarenotrecommendedforlonger use.Somepatientswithautoimmuneangioedemamayalsorespondtodapsoneorhydroxychloroquine. Introduction cretehistamineandmanyothermediatorsthat,for example,leadtovasodilatationandedemaofthe Angioedemas (synonyms: angioneurotic edema, tissues.Acuteangioedemasareoftentriggeredby Quincke’sedema)arecharacterizedbysuddenon- IgE-mediated allergies, e.g., food allergies, viral setofswellinginthedeepdermisorsubcutis.The infectionsanddrugs.Chronicangioedemas,incon- variousformsofangioedemaincludeacquiredan- trast, are mostly caused by pseudo-allergic reac- gioedemas, angioedemas due to ACE inhibitors, tions,chronicbacterialinfections,e.g.,Helicobacter hereditary angioedemas, angioedemas with eosi- pylori, autoreactive processes and non-steroidal nophilia(Gleichsyndrome)andotherrareangio- antirheumaticdrugs[3]. edemasinassociationwith,e.g.,alpha-1-antitryp- Morethanhalfofallpatientswithacquiredan- sindeficiencyorcarcinoid[1].Therapydiffersfor gioedema suffer concomitantly from urticaria. thevariousforms.Inthischapter,thetherapyfor Whileisolatedhiveslastforlessthan24hours,an- d acquiredangioedemasofallergicandnon-allergic gioedemasexistforupto72hours.Asarule,an- al w originswillbediscussed.Sincemanyacquiredan- gioedemas are not associated with pruritus but s eif gioedemas occur in combination with urticaria, are accompanied by pain or burning sensations. Gr the therapy recommendations are comparable to Theyaffectabovealltheeyelids,lips,tongue,oral sit?t the guidelines for the treatment of spontaneous and pharyngeal mucosa and the genital region er urticaria [2]. Asin cases of spontaneous urticaria (Figs.1.1 and 1.2). Dangerous forms, especially of v ni oneshoulddistinguishbetweenacuteangioedema acuteangioedemas,arelaryngealedemaandana- U ?r thatlastsforlessthansixweeksandchronican- phylacticreactions.Chronicangioedemaoftenex- ert f gioedema that lastsfor morethan six weeks and istformanyyearsorevendecadesandareassoci- si occuratleasttwotimesperweek. ated with decreased quality of life and working n e Causes and pathomechanisms of acquired an- ability[4]. z Li gioedemasaremanifold.Forexample,allergicpro- Forthediagnosisofacuteangioedema,empha- cesses,pseudo-allergichypersensitivityreactions, sisisplacedonthecasehistoryandspecificlabora- autoimmune mechanisms or infections can lead torytestsaccordingtothehistory,e.g.,allergytests toactivationofmastcells.Activatedmastcellsse- for angioedema after consumption of food or in-

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