Milestones in Drug Therapy Series Editors Michael J. Parnham, University Hospital for Infectious Diseases, Zagreb, Croatia Jacques Bruinvels, Bilthoven, The Netherlands Advisory Board J.C. Buckingham, Imperial College School of Medicine, London, UK R.J. Flower, The William Harvey Research Institute, London, UK A.G. Herman, Universiteit Antwerpen, Antwerp, Belgium P. Skolnick, National Institute on Drug Abuse, Bethesda, MD, USA Forfurther volumes: http://www.springer.com/series/4991 . Henry M. Staines Sanjeev Krishna l Editors Treatment and Prevention of Malaria Antimalarial Drug Chemistry, Action and Use VolumeEditors DrHenryM.Staines Prof.SanjeevKrishna CentreforInfectionandImmunology CentreforInfectionandImmunology DivisionofClinicalSciences DivisionofClinicalSciences StGeorge’s,UniversityofLondon StGeorge’s,UniversityofLondon CranmerTerrace CranmerTerrace LondonSW170RE LondonSW170RE UnitedKingdom UnitedKingdom [email protected] [email protected] SeriesEditors Prof.MichaelJ.Parnham,Ph.D. VisitingScientist Research&ClinicalImmunologyUnit UniversityHospitalforInfectiousDiseases“Dr.FranMihaljevic´” Mirogojska8 HR-10000Zagreb Croatia Prof.Dr.JacquesBruinvels Sweelincklaan75 NL-3723JCBilthoven TheNetherlands ISBN978-3-0346-0479-6 e-ISBN978-3-0346-0480-2 DOI10.1007/978-3-0346-0480-2 #SpringerBaselAG2012 Thisworkissubjecttocopyright.Allrightsarereserved,whetherthewholeorpartofthematerialis concerned,specificallytherightsoftranslation,reprinting,re-useofillustrations,recitation,broadcast- ing, reproduction on microfilms or in other ways, and storage in data banks. For any kind of use, permissionofthecopyrightownermustbeobtained. Theuseofgeneraldescriptivenames,registerednames,trademarks,etc.inthispublicationdoesnot imply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevantprotec- tivelawsandregulationsandthereforefreeforgeneraluse. Productliability:Thepublisherscannotguaranteetheaccuracyofanyinformationaboutdosageand applicationcontainedinthisbook.Ineveryindividualcasetheusermustchecksuchinformationby consultingtherelevantliterature. Printedonacid-freepaper SpringerBaselAGispartofSpringerScienceþBusinessMedia(www.springer.com) HMSdedicatesthisbooktohiswife,Zoe¨,andchildren, Talia,LucaandOrenandSKtoYasmin’smemory andKarim,andtotherestofhisexceptionalfamily. . Preface Malariaisadevastatingdiseasethatextractshugehealthandeconomiccostsfrom the poorestcountriesin endemicregions. Malariaiscaused by single celled para- sites, belonging to the genus Plasmodium that have infected humans (and related primates)forthousandsofyears.Initsdifferentspecificandclinicalguises,malaria isoneofthestrongestselective forcestohaveshapedourrecentevolution.These parasites have already evaded one attempt at eradication in the mid twentieth century. Now, there are renewed attempts to control and eventually eradicate whatremainsoneoftheworld’sbiggestkillers. Withambitiousnewtargetssettoreducetheglobalburdenofmalaria,wemust urgently develop new tools for disease control, as well as optimising and re- evaluating our current tools. An indispensable part of controlling malaria is the capability of treating the disease effectively, despite the ability of this highly mutableparasitetodevelopresistancesoonerorlatertoallclassesofantimalarials. Understandingofhowantimalarialdrugsmightwork,howbesttousethemandhow toassessforresistancetothemhasexpandedconsiderablyinthepastfewyears.This bookaimstocapturetheserecentadvancesinourunderstandingofallantimalarial classes,anddiscusshowthisinformationispertinentfortreatingpatients. The introductory chapter details the disease, its current political, financial and technical context, alongside the policies and tools required to make eradication a possibility.Subsequentchapterscoverthehistory,chemistry,mechanismsofaction andresistance,preclinicalandclinicaluse,pharmacokineticsandsafetyandtolerabil- ityofourcurrentantimalarialdrugarmamentarium.Eachchapterreflectstheunique perspectives of its expert authors, and often describes new ideas and directions for study. There is particular emphasis on artemisinins (and related next generation peroxides)thathavebecomethefrontlinetreatmentformalaria,aspartofartemisi- nin-basedcombinationtherapies(ACTs).Theartemisininsmayhavebecomeestab- lishedinACTsinthepastdecade,buttheyarenowbeingchallengedbythepotential forresistancethathasrecentlybeendescribedandisonlyjustbeingdefined. Other chapters authoritatively discuss our antimalarial drug development pipe- lineandhowthisisbeingshapedbypublic/privatepartnerships;molecularmarkers vii viii Preface of antimalarial drug resistance, their use in monitoring treatment failures and the insights they provide into the action of these drugs; malaria prevention strategies, includingchemoprophylaxis,wheretheriskofcatchingmalariaisbalancedagainst the risk of side effects of drugs and the critical use of diagnostics to improve the identificationofmalariaandtorefinetreatmentstrategies. Thetreatmentandpreventionofmalariaisafascinatingandcomplexsubject– made all the more interesting now that malaria eradication is back on the global agenda.Wehopethatreaderswillbestimulatedbythisvolumeandthattheymay finditscontentsusefulindealingwithmalaria. London,UnitedKingdom HenryM.Staines SanjeevKrishna Contents AntimalarialDrugsandtheControlandEliminationofMalaria ......... 1 KarenI.Barnes 4-Aminoquinolines:Chloroquine,Amodiaquine andNext-GenerationAnalogues ............................................. 19 PaulM.O’Neill,VictoriaE.Barton,StephenA.Ward, andJamesChadwick CinchonaAlkaloids:QuinineandQuinidine ............................... 45 DavidJ.Sullivan 8-Aminoquinolines:PrimaquineandTafenoquine ......................... 69 NormanC.WatersandMichaelD.Edstein Other4-Methanolquinolines,AmylAlcoholsandPhentathrenes: Mefloquine,LumefantrineandHalofantrine ............................... 95 FrancoisNosten,PenelopeA.Phillips-Howard, andFeikoO.terKuile Antifolates:Pyrimethamine,Proguanil,Sulphadoxine andDapsone .................................................................. 113 AlexisNzila Naphthoquinones:Atovaquone,andOtherAntimalarials TargetingMitochondrialFunctions ........................................ 127 AkhilB.Vaidya Non-AntifolateAntibiotics:Clindamycin,Doxycycline, AzithromycinandFosmidomycin ........................................... 141 SanjeevKrishnaandHenryM.Staines ix