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Goal
Thegoalofthisactivityistodefinetheareaofchronotherapyandcurrentlimitationsinunderstanding,summarize
classesofdrugsforwhichinformationisavailableonoptimaltimeofdosing,andreviewprinciplesofchronotherapy.

LearningObjectives
Uponcompletionofthisactivity,participantswillbeableto:
1.
2.
3.
4.
5.

Definechronotherapy
Identifyfactorsthataffecttheoutcomesoftimingofdrugdosing
Identifythetimeofdaymostsuitedforadministrationofnifedipinegastrointestinaltherapeuticsystem(GITS)
Describeoptimaldosingtimesfordifferentcalciumchannelblockers
Describetheoptimaldosingtimefordifferentantidepressants

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Author(s)
LingLingZhu,MD

DepartmentofGeriatrics,TheSecondAffiliatedHospital,SchoolofMedicine,ZhejiangUniversity,Zhejiang,China
Disclosure:LingLingZhu,MD,hasdisclosednorelevantfinancialrelationships.
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QuanZhou,MD

DepartmentofClinicalPharmacy,TheSecondAffiliatedHospital,SchoolofMedicine,ZhejiangUniversity,Zhejiang,
China
Disclosure:QuanZhou,MD,hasdisclosednorelevantfinancialrelationships.
XiaoFengYan,MD

DepartmentofClinicalPharmacy,TheSecondAffiliatedHospital,SchoolofMedicine,ZhejiangUniversity,Zhejiang,
China
Disclosure:XiaoFengYan,MD,hasdisclosednorelevantfinancialrelationships.
SuZeng,MD

DepartmentofPharmaceuticalAnalysisandDrugMetabolism,CollegeofPharmaceuticalSciences,Zhejiang
University,Zhejiang,China
Disclosure:SuZeng,MD,hasdisclosednorelevantfinancialrelationships.

CMEAuthor(s)
DsireLie,MD,MSEd

ClinicalProfessor,FamilyMedicine,UniversityofCalifornia,OrangeDirector,DivisionofFacultyDevelopment,UCI
MedicalCenter,Orange,California
Disclosure:DsireLie,MD,MSEd,hasdisclosednorelevantfinancialrelationships.

FromInternationalJournalofClinicalPractice

OptimalTimetoTakeOnceDailyOralMedicationsinClinical
Practice
LingLingZhu,MDQuanZhou,MDXiaoFengYan,MDSuZeng,MD
Posted:10/01/2008Updated:12/04/2008IntJClinPractCME.200862(10):15601571.2008

AbstractandIntroduction
Abstract

Currentlyonlyafewpackageinsertsofoncedailymedicationsspeciallydefinethedosingtime,althoughsporadic
studieshavedemonstratedadministrationtimedependenteffectsonthetherapeuticoutcome.Some
chronotherapeuticapproachesaimtodiminishtheoccurrenceofadversedrugreactions(ADRs)andhencebetter
toleranceandmedicationcompliancewhereasmostofthechronotherapiesarerecommendedtoimprovetherapeutic
efficacy.Theadministrationtimedependentefficacyseemsnotacommonfeatureofdrugswithinthesimilar
therapeuticorstructuralclassanditisrelatedtokindsofdrugs,pathophysiologicstatus,clinicalsymptomsand
feedbackfrompatients.Doctors,pharmacistsandnursesshouldknowwhatkindofdrughasrequirementforoptimal
dosingtime,andrealizethatbetterefficacyandlowerincidenceofADRsmaybeachievedbyrationalarrangementof
administrationschedule.Inordertopromotemedicationcompliance,itisessentialtoprovidepatienteducation
regardingdifferencesbetweenconventionalandchronotherapeuticapproachesandpathophysiologicbenefitsof
chronotherapy.
Introduction
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Moreandmoreoncedailyoralmedicationsareemerging.Asmembersofmedicationtherapymanagement(MTM)in
clinicalpractice,doctors,pharmacistsandnursesalwaysfaceacommonproblem,i.e.whatistheoptimaltimeforthe
patientstotakethesedrugs.Isitinthemorning,intheearlyevening,atbedtimeoratanytime?Pitifully,onlyafew
packageinsertsspeciallydefinethedosingtime.Thiscriticalproblemintroducesaconceptofchronotherapy,whichis
theoptimisationofdrugeffectsand/orminimisationofadversedrugreactions(ADRs)bytimingmedicationswith
regardtobiologicalrhythms. [1]Numeroussporadicclinicaltrialshavedemonstratedadministrationtimedependent
effectsofoncedailymedicationsontherapeuticoutcome.So,themembersofMTMhavealottorelearnabouthowto
usebotholdandnewoncedailydrugseffectively.However,asystematicreviewupdateofchronotherapyofoncedaily
medicationsinclinicalpracticeisnotyetavailable.
Meanwhile,apatientwhoisbeingswitchedfromaconventionalregimentoachronotherapeuticregimenmaynotfully
understandthefundamentalsbehindthechange.Thisinturnmayresultinpoormedicationcompliance,or,even
worse,thatthepatientmaydiscontinuetakingthemedicine.SoitisessentialforthemembersofMTMtoremind
themselvestopromotemedicationcompliancebyprovidingeducationtothepatientregardingthedifferencesbetween
conventionalandchronotherapeuticapproaches,andpathophysiologicbenefitsofchronotherapy.Thispaperfocuses
onthisrespectandaimstodescribethatbetterefficacyandlowerincidenceofADRsmaybeachievedbyarranging
optimaldosingtimeofoncedailymedications.

AntigastricsecretionDrugs
Protonpumpinhibitor(PPI)andH2receptorantagonists(H2RAs)aretwomajoracidsuppressingdrugsusedfor
symptomrelief,healingoferosiveoesophagitis,resolutionofpepticulceration,reducingriskfornonsteroidalanti
inflammatorydrug(NSAID)inducedmucosaldamageandpreventionofdiseaserecurrence.
Itwasfoundthattheoptimaltimeofmorningvs.eveningadministrationofPPIsdependedonthekindofPPI,clinical
symptomsandfeedbackfromthepatients.Morningdosingofpantoprazolewassignificantlysuperiortoeveningdosing
withregardto24hintragastricpHanditshouldberecommendedforthetreatmentofacidrelateddiseases. [2]This
administrationscheduleisalsospeciallydefinedinprescribinginformationforPANTOLOC(pantoprazoletablets
ALTANAPharma,Konstanz,Germany).However,dosingtimeisnotyetdefinedinthepackageinsertsofLOSEC
MUPS (omeprazolemagnesiumtabletsAstraZenecaAB,Sdertlje,Sweden),Pariet (rabeprazoletabletsEsaiCo
Ltd,Tokyo,Japan),Prevacid(lansoprazolecapsulesTAPPharmaceuticalProducts,LakeForest,IL,USA)and
Nexium(esomeprazolemagnesiumtabletsAstraZenecaPharmaceuticalCoLtd,Wilminton,DE,USA).Morning
dosingofomeprazoleispreferableforpatientswithrefluxinducedbyphysicalactivitywhereaseveningdosingisclearly
preferableforpatientswithnocturnalreflux. [3]Lansoprazoleisroutinelyadministeredinthemorning,butpatientswith
mainlynocturnalsymptomsmaybebesttreatedbyeveningdosing. [4]Eveningdosingofrabeprazole(20mg)
normalisesmoreeffectivelythetotaloesophagealexposureandprovidessignificantlybettercontrolofnocturnalgastro
oesophagealrefluxdiseasethanmorningdosing. [5]Onepotentialreasonforthebetterefficacyoftheeveningdosing
ofPPIcouldbethehighercaloricintakeatdinnercomparedwithbreakfastandthetheorythatthemorepotentthe
stimulus,themoreprotonpumpsthatwillbeexposedforconsecutiveinhibitionbythePPI.
AsforoncedailyH2RAssuchasranitidine,famotidineandroxatidine,earlyeveningdosing(18:00h)providesbetter
controlofnocturnalacidityandmoresatisfactorycontrolof24haciditythandosingatbedtime(22:00h)andhenceis
suggestedforoptimisationoftherapeuticefficacy. [69]Apossibleexplanationfortheimprovedefficacyisthathigh
plasmaconcentrationsoforalH2RAsarepresentwhenstimulitoacidsecretionarehighafterdinner.

DrugsActingonCardiovascularSystem
Inthecardiovascularpatient,thefocusofchronotherapywouldbetooptimallyimprovethepreventionandtreatmentof
diseasesaccordingtocircadianvariationsandthekineticanddynamicpropertiesofdrugs.Table1liststheoptimal
dosingtimeofcommondrugsactingoncardiovascularsystem.
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Table1.

Drugs

Optimaldosing
time

Patients

Calciumchannelblockers
Isradipinesustainedrelease
formulation

Evening

Hypertensivepatientswithchronicrenalfailure

Isradipinesustainedrelease
formulation

Regardlessof
time

Patientswithuncomplicatedessentialhypertension

NifedipineGITS

Bedtime

Patientswhoarenonresponderstotheinitial30mg/day
doseandinturnreceive60mg/daydoseorpatientswho
wanttoavoidADRs(e.g.oedema)

NifedipineGITS

Regardlessof
time

Hypertensivepatientsreceiving30mg/daynifedipine
GITS

Amlodipine

Morning

Patientswithmildtomoderateessentialhypertension

Nisoldipineextendedrelease

Morning

Patientswithmildtomoderateessentialhypertension

Cilnidipine

Bedtime

Patientswithuncontrollablemorninghypertension

Verapamilextendedrelease
(marketedasCoveraHS)

Bedtime

Anginaorhypertensivepatients

Diltiazemextendedrelease
(marketedasCardizemLA)

Bedtime

Anginaorhypertensivepatients

Losartan

Uncertain

Ibesartan

Regardlessof
time

Patientswithuncomplicated,mildtomoderateessential
hypertension

Olmesartanmedoxomil

Regardlessof
time

Patientswithuncomplicated,mildtomoderateessential
hypertension

Valsartan

Bedtime

Nondipperhypertensivepatients

Telmisartan

Bedtime

Nondipperhypertensivepatients

Telmisartan

Morning

Youngmenwithmildormoderateessentialhypertension

Candesartancilexetil

Awakening

Patientswithmildtomoderateessentialhypertension

AngiotensinIIreceptorblockers

Angiotensinconvertingenzymeinhibitors
Benazepril

Morning

Patientswithprimarymildtomoderatehypertension

Perindopril

Morning

Patientswithprimarymildtomoderatehypertension

Quinapril

Evening

Patientswithprimarymildtomoderatehypertension

Ramipril

Bedtime

Patientswithprimarymildtomoderatehypertension

Trandolapril

Bedtime

Patientswithprimarymildtomoderatehypertension

Lisinopril

Bedtime

Patientswithprimarymildtomoderatehypertension

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Enalapril

Bedtime

Patientswithprimarymildtomoderatehypertension

Morning

Patientswithhypertension,anginapectorisorheartfailure

Carvedilol

Evening

Patientswhohavebeentreatedwithfirstline
antihypertensivedrugsbutstillhadhighBPinthe
morning

Carvedilolphosphateextended
release

Morning

Patientswithheartfailure,leftventriculardysfunction
followingmyocardialinfarctionorhypertension

Propranololextendedrelease

Bedtime

Patientswithhypertension

Betablocker
Metoprololsuccinatesustained
release

Antihyperlipidaemicdrugs
Statinswithashorterhalf
life(i.e.lovastatin,simvastatinand Evening
fluvastatin)

Patientswithhypercholesterolaemia

Statinswithlongerhalflives(i.e.
fluvastatinextendedrelease,
rosuvastatinandatorvastatin)

Regardlessof
time

Patientswithhypercholesterolaemia

Pravastatin

Evening

Patientswithhypercholesterolaemia

Atorvastatin

Evening

PatientsundergoingPCI

Ezetimibe

Morning

Patientswithprimaryhypercholesterolaemia

Ezetimibe/simvastatintablet

Evening

Patientswithprimaryhypercholesterolaemia

Fenofibrateretard

Regardlessof
time

Patientswithhypertriglyceridaemia

Bezafibrateretard

Morning

Patientswithhypertriglyceridaemia

DoxazosinGITS

Morning

Patientswithgrade12essentialhypertension

Regardlessof
time

Patientswithbenignprostatichyperplasia

Lowdoseaspirin

Bedtime

Patientswhoareatriskforacardiovascularand/or
cerebrovascularevent

Isosorbidemononitratesustained
releaseformulation(e.g.Elantan
LA,IMDUR)

Awakening

Patientswithanginapectoris

Indapamide,hydrochlorothiazide

Morning

Patientswithessentialhypertension

Torasemide

Bedtime

Patientswithessentialhypertension

Oncedailyhydrochlorothiazide
basedfixeddosecombination

Before6PM
and
preferablyin
themorning

Patientswithessentialhypertension

Diuretics

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OptimalDosingTimeofCommonDrugsActingonCardiovascularSystem
GITS=gastrointestinaltherapeuticsystemADRs=adversedrugreactionsPCI=percutaneouscoronaryintervention
BP=bloodpressure.

CalciumChannelBlockers
Severalstudiescomparedtheefficaciesofmorningvs.eveningadministrationofcalciumchannelblockers(CCBs)in
patientswithessentialhypertension.Administrationtimedependenteffectonbloodpressure(BP)seemsnota
commonfeatureofCCBs.ItisrelatedtothekindsofCCBs.
IsradipineSustainedRelease

OncedailydosingtimeisnotyetdefinedinthecurrentpackageinsertofDynaCircCR(isradipinecontrolledrelease
tabletsReliantPharmaceuticals,Inc.,LibertyCorner,NJ,USA).Arandomised,doubleblind,placebocontrolledstudy
revealedthattheBPloweringeffectofisradipinesustainedreleasein18patientswithuncomplicatedessential
hypertension(meanage556years)wasregardlessofdosingtime. [10]However,aneveningregimenseemsmoreapt
thanamorningregimentoobtainthetherapeuticgoalinhypertensivepatientswithchronicrenalfailure.Onlythe
eveningadministrationresetthenormalsynchronisationofthe24hBPandheartrate(HR)profiles.Thenondipper
BPprofilecouldbenormalisedwitheveningbutnotmorningdosing. [11]Thedifferenceintheresultsofthesetwo
studiesimpliesthatthecomorbidityfactor(i.e.chronicrenalfailure)exertsdifferentadministrationtimedependent
effectofisradipinesustainedreleaseonBPinhypertensivepatients.Itmaybeexplainedbythesystolicanddiastolic
BPfallinthenight,whichattenuatedinchronicrenalfailurepatients,incontrasttotheessentialhypertensioninwhich
thenocturnalBPfallwaspreserved.
NifedipineGITS

Inpreviouslyuntreatedessentialhypertensionpatientswithgrade12,theefficacyof60mg/daynifedipine
gastrointestinaltherapeuticsystem(GITS)innonresponderstotheinitial30mg/daydosewastwiceasgreatwith
bedtimewhencomparedwithmorningdosing.Bedtimeadministrationsignificantlyreducestheincidenceofoedemaas
anADRby91%andthetotalnumberofallADRsby74%whencomparedwithmorningdosing.Interestingly,dosing
timeeffectontheefficacywascloselyrelatedtothedosageofnifedipineGITS.Thedosingtimeof30mg/day
nifedipineGITShasnoimpactonthetherapeuticefficacy. [12,13]Althoughoncedailydosingtimeisnotyetdefinedin
prescribinginformationforAdalatXL(nifedipineGITS),thedosedependentenhancedefficacyandthemarkedly
improvedsafetyprofileofbedtimeascomparedwithmorningdosingshouldbetakenintoaccountwhenprescribing
nifedipineGITSinthetreatmentofessentialhypertension.
Amlodipine

Anopen,randomisedcrossoverstudyin12patientswithmildtomoderateessentialhypertensionfor3weeksshowed
thatmorningdosingofamlodipinelowereddaytimeBPslightlymorethaneveningdosing,butthisdidnotachieve
statisticalsignificance. [14]However,aperspective,doubleblind,randomised,crossoverstudy,in62Chinesepatients
withmildtomoderateessentialhypertensionfor6weeks,revealedthat24hdiastolicBPloadandnighttimeBPload
weresignificantlygreaterwitheveningdosingcomparedwithmorningdosing.NocturnalfallofBPwasgreaterwith
morningdosingthanwitheveningdosing. [15]Thus,althoughoncedailydosingtimeisnotyetspeciallydefinedinthe
currentpackageinsertofNorvasc(amlodipinetabletsPfizer,NewYork,NY,USA),theoptimaldosingtimeof
amlodipinemaybemorning.
NisoldipineExtendedRelease

Arandomised,crossoverstudyin85patientswithmildtomoderatehypertensionrevealedthatthetimingofnisoldipine
extendedreleaseadministrationhadnoeffectonthemeanchangesinBPandHRovera24hperiod.However,a
significantlygreatereffectonawakediastolicBPfollowing4week20mgoncedailytherapywasobservedwithmorning
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dosingcomparedwitheveningdosing.Inaddition,smallincreasesinsleepandearlymorningHRwereseenwith
eveningcomparedwithmorningadministrationofnisoldipine. [16]So,morningdosingmaybepreferredfornisoldipine
extendedrelease.
Cilnidipine

Anopenrandomisedcrossoverstudyin13essentialhypertensionpatientsconcludedthatcilnidipineefficacywas
regardlessofadministrationtime. [17]However,bedtimebutnotmorningdosingsignificantlyreducesnocturnalBPand
isusefulforpatientswithuncontrollablemorninghypertension. [18]Largesample,doubleblindrandomisedcrossover
studyisessentialfortheevaluationofthedosingtimedependentefficacyofcilnidipine.
VerapamilExtendedrelease(CoveraHS )

CoveraHS(Pfizer)usesthecontrolledonset,extendedreleasedeliverysystem.Thetabletconsistsofmultiplecoats.
Theoutermostcoatiscomposedofasemipermeablemembranethatregulatestheamountofwaterthatcan
penetrateintothetablet.WaterfromtheGItractwillcontinuetosaturatethislayeratafixedrateuntilthesecondcoat
isreached.Thesecondcoatwillcontinuetoabsorbwaterbuttemporarilyimpedesanyfluidfromreachingtheinner
coreofactivedrug.After45h,fluideventuallypenetratesintothethirdcoat,whichosmoticallyexpands,pushing
verapamiloutofthetabletataconstant,fixedrate.Accordingtothisdesignprinciple,CoveraHSshouldbegivenat
bedtimesothatthebedtimedosingcanachieveamaximumplasmaconcentrationofverapamilintheearlymorning
andtheextendedreleaseoverthe24htimeperiod. [19]
DiltiazemExtendedRelease(CardizemLA )

Comparedwithmorningadministration,bedtimedosingofCardizemLA (Biovail,Mississauga,ON,Canada)provides
enhanced24hcontrol,optimalmorningprotectionandanadditional3.3mmHgdiastolicBPreductioninthecritical
morninghours,whenanginaorhypertensivepatientsareatthegreatestrisk. [20]Apossibleexplanationforthe
improvedefficacyisthatbedtimeadministrationexhibited22%greaterbioavailabilitycomparedwithmorning
administrationundersteadystateconditionsandalsoprovidedmorethantwofoldhigherplasmadiltiazemlevelsinthe
criticalmorninghours. [21]

AngiotensinIIReceptorBlockers
AlthoughoncedailydosingtimeisnotyetspeciallydefinedinthecurrentpackageinsertsofAprovel(irbesartan
tabletsSanofiWinthropIndustrie,Ambares,France),Diovan(valsartancapsulesNovartis,EastHanover,NJ,USA),
Micardis(telmisartantabletsBoehringerIngelheim,Ridgefield,NJ,USA),Blopress(candesartancilexetiltablets
TakedaPharmaceutical,Osaka,Japan)andBenicar(olmesartanmedoxomiltabletsSankyo,Tokyo,Japan),the
efficaciesofmorningvs.eveningadministrationofangiotensinIIreceptorblockers(ARBs)inessentialhypertension
patientswerecomparedinseveralstudies.Inconsistentfindingswereidentified.Theadministrationtimedependent
efficacyseemsnotacommonfeatureofARBs.ItisrelatedtothekindsofARBsandthedipperstatusofpatients.
Administrationtimedependenteffectsoflosartanhavenotbeendocumented.Therewasnosignificantdifferencein
antihypertensiveefficacybetweenadministrationschedules(morningvs.evening)followinga6weektherapywith
100mgirbesartanin20patientswithuncomplicated,mildtomoderateessentialhypertension. [22]Dosingtimedidnot
exertstatisticallysignificantdifferencesontheefficacyofolmesartanmedoxomil(2040mg)after12weeksofmorning
vs.eveningdosingin18diurnallyactivesubjectswithuncomplicated,mildtomoderate,essentialhypertension. [23]
Theoptimaltimeofvalsartanisbedtime.Bedtimeadministrationasopposedtoadministrationduringwakening
improvesthesleeptimerelativeBPdeclinetowardsamoredipperpatternwithoutlossin24hefficacy.Italsoresults
inasignificantincreaseinthepercentageofcontrolledpatientsaftertreatment,andasignificantreductioninurinary
albuminexcretion.Timeoftreatmentcanbechosenaccordingtothedipperstatusofapatient. [24,25]
Astudyin42youngmenwithmildormoderateessentialhypertensionconcludedthattelmisartan(40or80mg)should
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begiveninthemorning,inthatastatisticallysignificantreductionofmorningdiastolicBPwasonlyfoundinpatients
treatedwithtelmisartaninthemorning,asopposedtobedtimedosing,althoughthesystolicBPvaluesinallthetime
intervalswerecomparable. [26]Morerecently,bedtimedosingoftelmisartanwasrecommended.Asopposedto
morningdosing,bedtimedosingimprovedthesleeptimerelativeBPdeclinetowardsamoredipperpatternwithout
lossin24hefficacy,andachievesignificantlybetternocturnalBPregulationfollowinga12weektherapywith80mg
telmisartanin215patients,meanage46.412.0,withessentialhypertension. [27]Thefindingsindicatethatthedosing
timeoftelmisartancanbechosenaccordingtothedipperstatusofapatient.Furtherstudiesareneededtoaddress
whetheragestatusmayinfluenceadministrationtimedependenteffectsoftelmisartanonBPcontrolinhypertensive
patients.
Asforcandesartancilexetil,theoptimaldosingtimeisduringawakening.Theefficacyofcandesartancilexetil(8mg
oncedaily)wasevaluatedafter3monthantihypertensivetherapyin60patients,meanage606years,withmildto
moderateessentialhypertension.Administrationuponawakening,asopposedtoatbedtime,seemstoprovidea
superiorcontrolofmean24handmeandaytimeBP. [28]

AngiotensinconvertingEnzymeInhibitors
AlthoughoncedailydosingtimeisnotyetdefinedinthecurrentpackageinsertsofLotensin(benazeprilhydrochloride
tablets),Accupril(quinaprilhydrochloridetablets),Tritace(ramipriltablets)andMAVIK (trandolapriltablets),the
efficaciesofmorningvs.eveningadministrationofangiotensinconvertingenzymeinhibitors(ACEIs)inessential
hypertensionpatientswerecomparedinseveralstudies.
Asingleblindcrossoverstudyin10hypertensivepatientsreceivingasingledoseof10mgbenazeprilconcludedthat
morningadministrationmoreeffectivelycoveredthewhole24hthananeveningdose. [29]Itisworthytostudywhether
chronologicaleffectstillexistsduringmaintenancetherapywithbenazepril.Asforperindopril(4mg),theeffectof
reducingtheearlymorningpeakBPrisetendedtobegreaterwiththe21:00hdose.However,the09:00hdosehadan
effectthatpersistedfor>24hbuttheeffectofthe21:00hdosehaddissipated18hafterthedose. [30]Itindicatesthat
theresponseprofileobtainedwithperindoprilcannotbetransformedfromonedosetimetoanotherautomaticallyand
thatchronobiologyhasimportanteffectsonthedrug'saction.Currently,morningdosingisrecommendedinprescribing
informationforAcertil(Servier,Orlans,France).Inclinicalpractice,the21:00hdoseshouldbetitratedtothenext
doserange.
Eveningadministrationofquinapril(20mg)seemspreferable,becauseitproducesamoresustainedandstable24h
BPcontrolcomparedwiththemorningdosing,probablythroughamorefavourablemodulationoftissueangiotensin
convertingenzymeinhibitionoreffectontheadrenergicinducedriseinBPthatoccursduringearlymorninghours.A
partiallossofeffectivenesswasobservedduringnightifquinaprilwasgiveninthemorning. [31]
Theoptimaldosingtimeoframipriliseveningorbedtime.Eveningintakeof5mgramiprilhadasignificantlymore
favourableeffectonhaemodynamicsthanmorningdosingin30patientswithessentialhypertensionstageII. [32]
BeneficialeffectsoncardiovascularmorbidityandmortalityseenwithramiprilintheHeartOutcomesPrevention
Evaluationstudywererelatedtoitsimprovedeffect(i.e.increaseinthediurnal/nocturnalBPratio)onthenondipping
BPpatternoftheparticipatingcohortofpatientsreceivingramiprilatbedtime. [33]
Theoptimaldosingtimeoftrandolaprilisbedtime.Inthebedtimeadministeredgroup,prewakingandmorningsystolic
BPweresignificantlydecreasedby11mmHgandby8.4mmHgrespectively.Ontheotherhand,inthemorning
administeredgroup,thereductionofprewakingandmorningsystolicBPdidnotreachthelevelofstatistical
significance.BedtimeadministrationresultsinasafeandeffectivemeansofcontrollingmorningBPwithoutthe
inductionofexcessiveBPreductionnocturnally. [34]
Bloodpressurechangesasaresultofoncedailyadministration20mglisinoprilatthreedifferenttimes(8:00,16:00and
22:00h)wereassessedin40patientswithprimarymildtomoderatehypertension.Thechronobiologicalanalysis
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showedagreaterreductionofsystolicanddiastolicmorningBPafterdosingat22:00h,althoughBPcircadianrhythm
wasunmodified.Apossibleexplanationfortheimprovedefficacyofadministrationat22:00hthatpeakserum
concentrationsoflisinopriloccurwithinabout7hwhencardiovasculareventsaremostfrequent. [35]
DrycoughasanADRisobservedin12%ormorepatientstreatedwithenalapril.ThisADRmightbediminishedor
eliminatedbyaswitchtonighttimeadministrationinpatientswhocomplainofcoughduringtreatmentwithenalaprilin
themorning. [36,37]Plasmabradykinin,whichislikelytobeinvolvedinthemechanismofenalaprilinducedcough,was
foundtobeaffectedbythedosingtime.Ittendedtoincreasefollowingenalapriladministrationat10:00h,butnotat
22:00h.Inaddition,BPwasstillsignificantlyreduced24hafteradministrationofenalaprilat22:00h,butnotat10:00h,
indicatingtheprolongedantihypertensiveactionofenalaprilafteradministrationat22:00h.Thus,nighttimedosingis
preferredforenalapril.

Betablockers
Betablockersarestillrecommendedasfirstlinetherapyinmanyhypertensivepatients,particularlythoseathighrisk
forcardiovasculardisease.Theyarealsoindicatedforothercardiovasculardisorderssuchascongestiveheartfailure
andpostmyocardialinfarction.
ClinicalusefulnessofchronotherapywithcarvedilolwasobservedbyKogaetal. [38]Carvedilol,asasingledoseinthe
morningoreveninginarandomisedcrossoveropenlabelprotocol,wasaddedtotherapyregimeninninepatientswho
hadbeentreatedwithfirstlineantihypertensivedrugsfor4weeksbutstillhadhighBPinthemorning.Evening
carvediloladministrationafter4weekssignificantlysuppressedthemorningsurgewhilemorningadministrationlackeda
significantantisurgeeffect.Theadditionofchronotherapywithcarvedilolmaybeaneffectivewaytosuppressmorning
surgesofhypertension.Carvedilolphosphateextendedreleasecapsule(COREGCRGlaxoSmithKline,Research
TrianglePark,NC,USA)utilisesproprietarymicropumptechnologythatcontrolsthedeliveryofcarvedilolandhelpsto
maintainappropriateconcentrationsinthebodyovera24hspanwithoncedailydosing.Itshouldbetakenoncedaily
inthemorningwithfood,asdescribedinitscurrentpackageinsert.AphaseIclinicaltrial(studyID:SK&F
105517/906)sponsoredbyGlaxoSmithKlinemayprovideevidenceforfavouringmorningdosingofCOREGCR. [39]In
thatclinicaltrial,eveningadministrationofcarvedilolCR(80mg)resultedinanapproximate10%decreaseinthearea
underthecurveofbothR(+)andS()carvedilol,a1519%decreaseinC maxofbothR(+)andS()carvedilolanda
decreaseintherateofabsorptionofbothR(+)andS()carvedilol(t maxdelayedapproximately1.5h)comparedwith
morningadministration.Asformetoprololsuccinatesustainedrelease(BetalocZOKAstraZenecaPharmaceuticalCo
Ltd),itisrecommendedforoncedailytreatmentandispreferablytakentogetherwiththemorningmealaccordingto
itsprescribinginformation.Moreover,morninghypotensionanddaytimefatiguecanbeavoidedwhenmetoprolol
succinateisprescribedwiththebreakfast. [40]Achronotherapeuticformulationofpropranololextendedrelease
(InnopranXLReliantPharmaceuticals,Inc.)wasapprovedforthetreatmentofhypertensionbecauseofits
appropriatepharmacokinetics.Multipledosestudyofthismedicationshowedthatbedtimedosingwaspreferablein
thatitresultedintroughdrugbloodconcentrationduringthenightbecauseoftheintentionaldelayofpropranolol
releasefor45h,peakdrugconcentrationbetween4and10AM,andanelevatedplateauofdrugconcentrationinthe
afternoonandearlyevening. [41]

AntihyperlipidaemicDrugs
3hydroxy3methylglutarylcoenzymeA(HMGCoA)reductaseinhibitors,alsoknownasstatins,areeffectiveinprimary
andsecondarypreventionofcardiovasculareventsinpatientswithhyperlipidaemia.Therateofcholesterolbiosynthesis
isatitshighestaftermidnightandlowestduringthemorningandearlyafternoon.Thecircadianrhythmiscausedby
diurnalchangesintheactivityofhydroxymethylglutarylcoenzymeAreductase.Ingeneral,statinswithashorterhalf
life(i.e.lovastatin,simvastatinandfluvastatin)aremoreeffectiveinloweringlowdensitylipoproteincholesterol(LDL
C)whentakenintheevening,whereasstatinswithlongerhalflives(i.e.fluvastatinextendedrelease,rosuvastatinand
atorvastatin)havesimilarlipidloweringeffectswhentakenduringanytimeoftheday. [4246]
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Thesystemicbioavailabilityofpravastatinadministeredatbedtimewas60%decreasedcomparedwiththatfollowinga
morningdose.However,theefficacyofpravastatinadministeredintheeveningwasmarginallymoreeffectivethanthat
afteramorningdose.Chronophysiologiceffectoutweighingchronopharmacokineticeffectmaybetheunderlying
mechanism.InthecurrentpackageinsertofMevalotin(Sankyo),itisalsorecommendedtobetakenoncedailyat
bedtime.Newevidencehasshownsignificantadministrationtimedependentinfluenceonlipidandnonlipidrelated
effectsofatorvastatinin152patientsundergoingPCI.Oneyearclinicalfollowupdatainthesepatientsshowed
eveningintakeofatorvastatin(40mg/dayforthefirstmonthand10mg/daythereafter)wasassociatedwithless
frequentoccurrenceofmajorcardiacevents,alowrestenosisrate,atrendtowardslowpreandpostproceduralhigh
sensitivityCreactiveproteinlevels,amorepronounceddecreaseintotalcholesterol,LDLCandtriglyceridevalues,an
increaseinhighdensitylipoproteincholesterol(HDLC)levelsandbetterimprovementofendothelialdysfunction
comparedwithmorningdosing. [47]
Asforezetimibe,morningintakewasequallyeffectivefortotalandLDLC,buttherewasabenefitwithmorningintake
consideringtheincreaseinHDLC. [48]However,dosingtimeisnotyetdefinedintheprescribinginformationforZetia
(ezetimibetabletsScheringPlough,Kenilworth,NJ,USA).Vytorin(ezetimibe/simvastatintabletMerck/Schering
Plough,Kenilworth,NJ,USA)ismoreeffectivewhentakenintheeveningaccordingtoitsprescribinginformation.As
tobezafibrateextendedrelease,totalcholesterolloweringefficacywasregardlessofdosingtimebutHDLCincreased
morewithmorningdosing. [49]Fenofibrateextendedreleasemorningintakewasequallyeffectiveaseveningintake. [50]

DoxazosinGITS
DoxazosinGITS(CarduraXLPfizer)isusuallytakenonceadayinthemorningwithbreakfastaccordingtoits
prescribinginformation.However,arandomisedstudyin91patientswithgrade12essentialhypertension(meanage
56.711.2years)demonstratedthatdoxazosinGITS(4mg)therapyuponawakeningfor3monthsfailedtoprovidefull
24htherapeuticcoveragewhereasbedtimedosingsignificantlyreducedBPthroughoutthe24h. [51]Interestingly,
dosingtimedidnotappeartoinfluencetheefficacyandsafetyofdoxazosininpatientswithbenignprostatic
hyperplasia(BPH)after24weeksoftreatment,suggestingthatthereisnoneedtorestricttheadministrationof
doxazosintotheeveninginBPHpatients. [52]

Aspirin
Lowdoseaspiriniscommonlyprescribedfortheprimaryandsecondarypreventionofcardiovascularand
cerebrovascularevents.DosingtimeisnotyetdefinedinthecurrentpackageinsertofBayaspirinBayer,Leverkusen,
Germany.However,recentevidenceshowedthat100mgaspirinadministeredatbedtime,butnotonawakening,hasa
beneficialeffectonambulatoryBP.BPwasslightlyelevatedafterdosingonawakeningwhereasasignificantBP
reduction(decreaseof7.2/4.9mmHginsystolic/diastolicBP)wasobservedinpatientswhowasreceivingaspirinbefore
bedtime. [53]ThereductioninnocturnalBPmeanwasdoubleinnondippers(11.0/7.1mmHg)comparedwithdippers
(5.5/3.3mmHgp<0.001).Thestudycorroboratessignificantadministrationtimedependenteffectoflowdoseaspirin
onBP,mainlyinnondipperhypertensivepatients. [54]Morningdosingofaspirinhasitslowestprotectivevalueagainst
cardiovasculareventsduringthenightandearlymorning.Incontrast,highestplasmalevelofaspirintakenlateevening
(22:00h)wouldbereachedpriortothepeakincidenceofthromboembolicdisorders.Bedtimedosingwouldthusfit
betterinthecircadianschemeoftheoccurrenceofstroke,thusresultinginasignificantlymoreeffectiveprevention. [55]

IsosorbideMononitrateSustainedreleaseFormulation
ElantanLA (SchwarzPharma,Monheim,Germany),alongactingisosorbidemononitrateformulation,shouldbe
givenuponawakening.About30%ofitsdoseisavailableforimmediatereleaseandtheremaining70%isgradually
releasedovertime.Ithasaquickonsetofactionandeffectsareevidentforupto17h.Itspharmacokineticprofile
accordswiththecircadianvariationincardiovasculardiseaseandhencemaximisedprotectionagainstthemorning
surgeinmyocardialischaemia.AsforIMDUR(AstraZenecaPharmaceuticalCoLtd),oncedailyadministrationinthe
morning,afterawakening,isrecommendedinitspackageinsertsothatitproducesaplasmanitrateprofilethatishigh
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enoughtogiveantianginalprotectionduringthedaytime,butlowenoughduringthelatterpartofthedosageinterval
toavoidthedevelopmentoftolerance.

Diuretics
Diureticsarecurrentlyrecommendedasfirstlinetherapyforthetreatmentofhypertension.Inaddition,theyremainan
importantcomponentinthetreatmentofheartfailure.Indapamideandhydrochlorothiazideshouldbegiveninthe
morning.TheurinaryNa/Kratiointhepatientsisincreasedsignificantlyandthusfewersideeffectsbyaswitchto
morningtimeadministration.Efficacyoftorasemide(5mg/day)in58patientswithgrade12essentialhypertension
wassignificantlyhigherwithbedtimedosingascomparedwiththeadministrationofthedrugonawakening.The
percentageofpatientswithcontrolledambulatoryBPafter6weekstreatmentwasalsohigherafterbedtimetreatment
(54%vs.27%).Inaddition,afull24htherapeuticcoveragewasobservedonlywhentorasemidewasgivenbefore
bedtime. [56]Withregardtothesafetyprofile,twopatientspresentedsecondaryeffects(abdominalpain,diarrhoea)in
morningdose,andfourpatientstakingthedrugatbedtimereportednicturia.Thedifferencesinefficacyand
therapeuticdurationshouldbetakenintoaccountwhenprescribingtorasemideforthetreatmentofessential
hypertension.Toreducenighttimeurination,taketheoncedailyhydrochlorothiazidebasedfixeddosecombination
before6PMandpreferablyinthemorning.Thesemedicationsincludebetablocker/hydrochlorothiazide,ARB
hydrochlorothiazideandACEIhydrochlorothiazide.

Antidepressants
Chronotherapieswithantidepressantsmaybringadditionaltherapeuticadvantages.Clomipramine(150mg)oncedaily
wasgivento30patientswithdepressionatthreedifferenttimesoftheday(morning,noon,orbeforebedtime),usinga
doubleblindmethodovera4weekperiod.Beneficialeffectswerecloselyrelatedtotheadministrationtime,withthe
mosteffectiveresultbeingobservedwiththenoonadministration. [57]
Onthecontrary,dosingtimehasnoinfluenceontheefficaciesofcitalopram,sertralineandvenlafaxinesustained
releaseformulations,asindicatedinstandarddruginformation.Fluoxetineisrecommendedtobeadministeredinthe
morningaccordingtothepackageinsertofProzac(fluoxetinecapsulesEliLilly&Co,Indianapolis,IN,USA),
althoughUsheretal. [58]revealedthattheefficacyandtolerationwereregardlessofthedosingtime.Fluvoxamineis
bettertoleratedwithbedtimedosing.Mirtazapineisapotentblockerofthehistaminereceptorsandittendstohavea
somewhatsedativeeffect,thusfavouringadministrationatbedtime.Fluvoxaminemaleateandmirtazapinearealso
recommendedtobegivenatbedtimeaccordingtotheirprescribinginformation.Paroxetineisusuallyadministeredin
themorning.MorningdosingcandecreasetheoccurrenceofinsomniaasanADR,whereasbedtimedosingis
preferableifpatientsfeeldrowsyaftermorningdosing.Theolanzapine/fluoxetinecombinationhasdemonstrated
effectivenessinthetreatmentresistantdepression.Administrationoncedailyintheeveningisspeciallydefinedinthe
packageinsertofSYMBYAX (olanzapineandfluoxetinecapsulesEliLilly&Co).

DrugsActingonMetabolismandEndocrineSystem
LevothyroxineSodium

Levothyroxinesodiumisagoodtherapeuticchoiceforhypothyroidism.Standarddruginformationresources
recommendthatlevothyroxinesodiumbetakenhalfanhourbeforebreakfast.However,apilotstudyin12patients
withprimaryhypothyroidismdemonstratedthattakingthesamedoseoflevothyroxineatbedtime,whencomparedwith
thatduringmorning,mightbebetter.Bedtimedosingwasassociatedwithhigherthyroidhormoneconcentrationsand
lowerthyroidstimulatinghormoneconcentrationscomparedwithmorningdosing.Alargedoubleblindedrandomised
studywillneedtobeperformedtoconfirmtheseresults.AbetterGIuptakeoflevothyroxinesodiumduringnightmay
betheunderlyingmechanismforthefindingsofthisstudy. [59]Takingmedicationatbedtimeinsteadofinthemorning
couldhavemajorimplicationsformanythyroidpatients.
HypoglycaemicDrugs
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Patientswithdiabetesmellitusshouldbeofferedindividualisedtherapy.Hypoglycaemiceffectsofglimepiride,
pioglitazoneandrosiglitazoneareregardlessoftheadministrationtime. [60]However,GlucotrolXL(glipizidecontrolled
releasetabletPfizer),Avandaryl(rosiglitazonemaleateandglimepiridetabletsGlaxoSmithKline)andDiamicron
MR(gliclazidemodifiedreleasetabletsLesLaboratoiresServier,Gidy,France)shouldbegivenoncedailywith
breakfast.Disturbancesofthegutsuchasdiarrhoea,constipation,indigestionandnauseacanbeavoidedor
minimisedifgliclazidemodifiedreleasetabletistakenwiththebreakfast.
AntiasthmaDrugs

Appropriateantiasthmatherapycanalleviatesymptomsandreducemorbidity.Optimaldosingtimeisrequiredfor
someantiasthmadrugs.Bambuterol(terbutalineprodrug)andmontelukastarerecommendedtobetakenatbedtime,
asdefinedinthecurrentpackageinsertsofBambec(bambuteroltabletAstraZenecaPharmaceuticalCoLtd)and
Singulair(montelukastsodiumtabletsMerck&Co,Cramlington,UK).Eveningadministrationofbambuterolin
comparisonwithmorningadministrationproducedenhancedbronchodilatoreffectat7AM,whichseeminglywas
becauseoftheelevatedterbutalinelevelmaintainedduringthemorninghoursfollowingeveningadministration.The
mean7AMplasmaterbutalineconcentrationwas15.6nmol/lwitheveningbambuterol,whileitwasonly10.5nmol/lwith
morningadministration. [61]Eveningdosingseemstobepreferableforpranlukastandoncedailytheophylline
preparationsothatitcanachievehighertherapeuticallevelsatnightandinthemorningwhenasthmaticsareatthe
greatestriskofdevelopingbronchospasm. [62,63]
NonsteroidalAntiinflammatoryDrugs

Nonsteroidalantiinflammatorydrugsarenecessaryincommonailmentssuchasosteoarthritisanddegenerativejoint
disease.PotentialtherapeuticbenefitofNSAIDsmightbegainedbyarrangingoptimaldosingtime.Eveningdosingof
indomethacinsustainedreleasewasmosteffectiveinosteoarthritispatientswithpredominantnocturnalormorning
painwhereasmorningornooningestionwasthemosteffectiveinpatientswithmaximumafternoonoreveningpain.
Theanalgesiceffectwasincreasedbyabout60%whentheNSAIDwastakenatthepreferredtime(about6hpriorto
theusualtimeofdayofworseosteoarthriticpain)comparedwithwhenitwasingestedatthenonpreferredtimesof
theday. [64,65]Withregardtothesafetyprofile,adoubleblind,crossovertrialofa3weekdurationinvolving66
patientsconcludedthatadverseeffectswereconsistentlygreaterinoccurrenceandinseveritywhenindomethacin
sustainedreleasewasingestedat8AMthanatanyothertimeoftheday. [66]Morningdosingofketoprofencontrolled
release(200mg)increasedtheefficacywithoutreducingthetolerabilityinpatientswithosteoarthrosiswhencompared
witheveningdosing.Thereductioninthedegreeofpainintheafternoonandintheeveningwassignificantlyhigherfor
themorningdose. [66]However,totalandGIsideeffectsweretwofoldgreaterinpatientstakingketoprofeninthe
morningthanatnight,asdescribedinadoubleblindtrialwith118osteoarthritisoutpatientsreceivinga200mg
ketoprofenslowreleasetablet. [67]BruguerolleaconcludedthateveningdosingofNSAIDswouldbebettertoleratedby
diurnallyactivepersonscomparedwiththemorningdosingandpatientswithhighriskofGIirritationshouldbeadvised
toavoidtakingNSAIDearlyinthemorning. [68]Asforcelecoxib(acyclooxygenase2specificinhibitor),theefficacyof
regimen(200mgoncedaily)inthemanagementofosteoarthritisofthekneeorhipisregardlessofthedosingtime. [69]

Discussion
Itisparticularlynoteworthythatadifferencebetweenadministrationschedules(morningvs.evening)hasbeenfound
whereitisnotexpected,i.e.withamlodipine,adrugwithalonghalflifeof3545h.Thus,itindicatesthatalllong
lastingagentsshouldbeproperlystudiedtoevaluatethesafetyandefficacywhentheyareadministratedinthe
morningorintheevening.
Chronopharmacokineticsreferstotimedependentchangesinkinetics,whichmayproceedfromcircadianvariationsat
eachstep,e.g.absorption,distribution,metabolismandexcretion.Interestingly,theoptimaldosingtimesometimesis
notthetimeexpectedfromtheperspectiveofchronopharmacokinetics.Aspirinisarepresentativeexample.Its
bioavailabilityinthemorningistwiceashighasintheafternoon. [70]Takingintoaccountthischronopharmacokinetic
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characteristic,researchesinearlyyearsrecommendedmorningdosingofaspirin.However,recentevidencebaseddata
favourbedtimedosingoflowdoseaspirin. [5355]
Theadministrationtimedependentefficacyseemsnotacommonfeaturefordrugswithinthesimilartherapeuticor
structuralclass.Itisrelatedtokindsofdrugs,pathophysiologicstatus,clinicalsymptomsandfeedbackfrompatients.
TypicalcaseswereobservedwithPPIs,CCBs,ARBs,ACEIsandbetablockers.Furtherstudiesareneededto
determinewhetheradministrationtimedependenteffectswillbeobservedwithdrugsofwhichmorningandevening
dosinghavenotbeencompared.Forexample,whetheradministrationtimedependenteffectsoflosartanexisthasnot
beendocumented,althoughtherelevantstudieshavebeenconductedfortheotherARBs(i.e.irbesartan,valsartan,
telmisartan,olmesartanmedoxomilandcandesartancilexetil).
Inclinicalpractice,membersofMTMneedtoknowthebasisforchronotherapyofdiseases.Forexample,thenon
dippercircadianBPpatternrepresentsariskfactorforleftventricularhypertrophy,microalbuminuria,cerebrovascular
disease,congestiveheartfailure,vasculardementiaandmyocardialinfarction.ThenormalisationofthecircadianBP
patterntoadipperprofileisanoveltherapeuticgoal. [71]Thus,ifadrugadministeredatbedtimeasopposedto
morningdosingimprovedthesleeptimerelativeBPdeclinetowardsamoredipperpatternwithoutlossin24h
efficacy,optimumdosingtimeofthisdrugisatbedtime.
Therapeuticstrategiesinresistantdiseases(e.g.resistanthypertension)includeaddinganotherdrugorchangingdrugs
forabettersynergiccombination.However,thesituationmightbeimprovedifchronotherapeuticapproachis
introduced.Forinstance,Hermidaetal. [72]evaluatedtheimpactonthecircadianpatternofBPbymodifyingthedosing
timewithoutincreasingthenumberofprescribeddrugs.Resultsindicatethat,inpatientswithresistanthypertension,
dosingtimemaybemoreimportantforBPcontrolandforthepropermodellingofthecircadianBPpatternratherthan
justchangingthedrugcombination.
Biologicalrhythmdependentdifferencesinthepharmacokineticsandpharmacodynamicsofoncedailymedications
maybealteredwithotherfactorssuchascomorbidityconditionsandaging.Forexample,chronicrenalfailuremight
resultindifferentadministrationtimedependenteffectsofisradipinesustainedreleaseonBPinhypertensivepatients.
[10,11]Chronopharmacologicalvariationsmayberelatedtoageing.Forexample,administrationtimeeffectsof
telmisartanweredetectedonlyinmidagedbutnotinyoungsubjects. [26,27]

Conclusions
MembersofMTMshouldknowwhatkindofdrughasrequirementforoptimaldosingtime,andrealizethatbetter
efficacyandlowerincidenceofADRsmaybeachievedbyrationalarrangementofadministrationschedule.Inorderto
promotemedicationcompliance,itisessentialtoprovidepatienteducationregardingdifferencesbetweenconventional
andchronotherapeuticapproachesandpathophysiologicbenefitsofchronotherapy.Forthoseoncedailymedications
withoutspecificrequirementsfordosingtime,theyshouldbetakenatthesametimeeveryday.Itshouldalsobeborne
inmindthatmedicationcomplianceisamatterofcourseconcernevenifthereisoptimaltimetotakeoncedaily
medicationsaccordingtothechronotherapyprinciples.

Sidebar:ReviewCriteria
RelevantliteraturewasidentifiedbyperformingPubmedandGoogleScholarsearchesuntilendof2007.TheMeSH
termsusedinvolvedrugadministrationschedule,chronotherapy,chronopharmacology,circadianrhythm,morningand
eveningdosingandclinicaltrials.Otherkeywordsincludechronopharmacokinetics,chronopharmacodynamics,morning
vs.eveningadministration,morningandbedtimedosingandadministrationtimedependenteffects.Availablerelated
packageinsertsandprescribinginformationwerealsoreferenced.
MessagefortheClinic

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Betterefficacyandlowerincidenceofadversedrugreactionsmaybeachievedbyoptimaltimingofoncedaily
medicines.Doctors,pharmacistsandnurseshavealottorelearnabouthowtousebotholdandnewoncedailydrugs
effectively,andpromotemedicationcompliancebyprovidingeducationtothepatientregardingthedifferences
betweenconventionalandchronotherapeuticapproaches,andpathophysiologicbenefitsofchronotherapy.
Acknowledgements

WealsothankH.Grassosfordataonadministrationtimedependenteffectsofcandesartan.DrH.Grassosisfrom
Hypertensionunit,WesternAtticaGeneralHospital,Athens,Greece.
FundingInformation

FundingforthearticleisprovidedbyZhejiangProvincialBureauofEducation(No.20070227),ZhejiangMedical
Association(No.2007ZYC18)andAssociationofZhejiangHospitalAdministration(No.2007AZHAKEB312).
AuthorContributions

L.L.ZhuandQ.ZhouputforwardtheviewpointanddesignedthisstudyQ.Zhou,X.F.Yanperformedtheliterature
reviewanddataanalysis/interpretationL.L.ZhuandQ.ZhouwrotethepaperandS.Zengwasinvolvedinthecritical
revisionofthearticle.
ReprintAddress

QuanZhou,PharmacistClinicalSpecialist,DepartmentofClinicalPharmacy,The2ndAffiliatedHospital,Schoolof
Medicine,ZhejiangUniversity,Zhejiang310009,ChinaTel.:+8657187783891Fax:+8657187213864
Email:zhouquan142602@zju.edu.cn

CLICKHEREforsubscriptioninformationaboutthisjournal.

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ContentsofOptimalTimetoTakeOnceDailyOralMedicationsinClinicalPractice
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1. OptimalTimetoTakeOnceDailyOralMedicationsinClinicalPractice
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