· to licensure of the varicella vaccine. routine vaccination against chickenpox has produced...
TRANSCRIPT
114 Turning knowledge into action (Editorial) HBuchan
116 Letters
117 Managing injuries by venomous sea creatures in Australia GKIsbister
122 Consumer Medicine Information conundrums PAslani
125 Antidepressants in pregnancy and breastfeeding ASvedWilliams
128 Abnormal laboratory results.Cell markers KCartwright
130 Prescribing exercise for diabetes BPenny
133 New drugshumanpapillomavirusvaccine,
insulinglulisine,lapatinib
Fulltextwithsearchfacilityonlineatwww.australianprescriber.com
VoLuMe 30 NuMber 5 AN INdePeNdeNT reVIew oCTober 2007 C o n t E n t S
Insert wall chart
Emergencymanagementof
anaphylaxisinthecommunity
114 | VoLuMe 30 | NuMber 5 | oCTober 2007
Editorial
Turning knowledge into actionHeather Buchan, National Institute of Clinical Studies, National Health and Medical Research Council, Melbourne
Keywords:evidence-basedmedicine,guidelines.
(Aust Prescr 2007;30:114–15)
Studiesofhealthcareprovisionshowthatmanypatientsdo
notgetcarethatisconsistentwiththebestavailableevidence.
Astudyofthecareprovidedtoseveralthousandpeoplein
theUnitedStatesusingtelephoneinterviewsandchartaudit
showedthat,forawiderangeofconditions,peoplereceived
careconsistentwithbestpracticerecommendationsonly55%
ofthetime.Whileprescribingshowedhigherratesofadherence
torecommendedcarethaninterventionsrequiringcounselling
andeducation(69%vs18%),substantialnumbersofpeople
werenotreceivingdrugsthatwouldbeofbenefittothem.1
Similarresultshavebeenfoundwhenauditingcareprovided
byprimarycarephysiciansinthenetherlands.2InAustralia,
morelimitedstudiesshowthatthereiswidespreadunderuse
ofmanydrugs,suchasoralanticoagulantsinpeoplewithatrial
fibrillation,andACEinhibitorsandbetablockersinpatients
withheartfailure.Conversely,thereisalsooveruseofdrugsin
Australia,suchasantibioticsforthecommoncoldandacute
bronchitis.3
Pooruptakeofresearchfindingsisnotconfinedtoareaswhere
discoveriesarerecent.Ittookonaverageover15yearsfor
researchfindingsonanumberofclinicalinterventions(suchas
influenzavaccination,thrombolytictherapy,useofbetablockers
aftermyocardialinfarction,anddiabeticfootcare)toreacha
rateofuseof50%ineligiblepatientsseeninclinicalpractice.4
Howcanthegapsbetweenbestevidenceandcurrentpractice
beclosedmorequicklyandmoreeffectively?traditional
approachesaimtoimprovetheknowledgeandskillsof
cliniciansthroughcontinuingeducationandtraining.over
recentyearstherehasalsobeenafocusonmakingresearch
findingseasierforclinicianstoaccessandinterpret.
Evidence-ratingsystems,systematicreviewsofresearch,
evidencesummariesandproductionofguidelinesareallways
oftryingtomaketheenormousresearchoutputmanageable.
However,improvedknowledgedoesnotnecessarilyproduce
alterationsinbehaviourorchangeinlong-establishedhabits.
thisisevidencedbythedifficultythatmanypeoplehave
inchangingtheirdietinordertoloseweightorattaining
recommendedlevelsofexercisedespiteknowingwhatthey
shoulddoandthehealthadvantagesthatcouldresult.
Barriersotherthanlackofknowledgethatpreventbestevidence
beingappliedinpracticevaryaccordingtotheclinicalissue,
theindividualdoctorandtheenvironmentinwhichcareis
delivered.Examplesofbarriersincludealackofrecognition
thatagapexists,beliefsorattitudesthatresearchfindingsare
notimportantorrelevanttopractice,andestablishedsystems
ofcarethatmakeitdifficulttochangecustomaryprocesses.
Insomeinstancespatientbeliefsandpreferencesplayan
importantroleininfluencingprescribingbehaviour.thisis
onereasonforinappropriateprescribingofantibioticsforviral
infections.
oneapproachtoimprovingcareistoagreeonspecificareas
wherepracticeshouldbechanged,identifythebarriersto
changeanddesigninterventionstoovercomethesebarriers.
Forexample,oneoftheaimsofaprograminnorwaywas
toincreaseprescribingofthiazidesforthetreatmentof
uncomplicatedhypertensioningeneralpractice.5Potential
barriersidentifiedwerethatthiazideswereconsidered
old-fashioned,physicianswereworriedaboutpossibleadverse
effectsandlackofantihypertensiveeffect,physicianswere
notfamiliarwiththerelevantbrandnames,andfewother
clinicianswereusingthesedrugs.Establishedhabitsofgeneral
practitionersandadvocacybypharmaceuticalcompanieswere
alsonotedaspotentialbarrierstoincreasedprescribingof
thiazides.Interventionsdesignedtoovercomethesebarriers
In this issue …
Patientsneedinformationtomakethebestuseoftheir
medicines.Whileallprescriptionmedicinesnowhave
ConsumerMedicineInformation,ParisaAslanibelieves
thisresourceisunderused.Sometimesinformation
canbelackingandAnneSvedWilliamssaystheuseof
antidepressantsinpregnancyandlactationhastobelargely
guidedbyclinicalexperience.
Informationisalsorelevantfornon-drugtherapies.
BronwynPennytellsustheimportantcomponentsofan
exerciseprescriptionforpatientswithdiabetes.
Agoodexampleofturningknowledgeintoaction,
discussedbyHeatherBuchan,isthemanagementof
jellyfishstings.GeoffIsbistertellsusthattherehavenow
beenprospectivetrialstoguidetreatment.
| VoLuMe 30 | NuMber 5 | oCTober 2007 115
includededucationaloutreachvisits,useofopinionleaders,
auditandfeedbackandcomputerisedreminderslinkedtothe
medicalrecordsystem.
Identifyingbarriersandincentivestochangeandusing
thisinformationtotailorimplementationstrategiesseems
logicalbut,atpresent,whilesomestudiesshowsuccess
usingthisapproachothersdonot.theinterventionsusedin
thenorwegianstudysignificantlyincreasedprescriptionsof
thiazidesforhypertension.However,theywereineffectivein
improvingtheriskassessmentofpatientsbeforeprescribing
andforachievingtreatmentgoalsinpatientswithhypertension
orhypercholesterolaemia.6
Insomereportedstudiesitisunclearwhetherthemethods
usedtoidentifybarriersproducedaccurateinformationabout
themostimportantbarriersorwhethertheimplementation
strategieswereoptimallytailoredtotheidentifiedbarriers.An
overviewofstudiesofguidelineimplementationconcludedthat
therewasstillanimperfectevidencebasetomakedecisions
aboutimplementationstrategiesbecauseofpoorreportingof
studysettings,barrierstochange,andthecontentandrationale
ofinterventions.7
thekeymessagesthatemergefromexperiencedresearchers
runningprogramstochangeclinicalpracticeemphasisethe
importanceof:
n usingasystematicapproach,withcarefulplanning,concrete
proposalsandtargetsforchange
n ensuringthatongoingpracticedataareprovidedto
practitionersandusedasanintegralpartofthechangeprocess
n providingappropriateleadershipandsufficientsupportfor
anychangeprogram.
references1. McGlynnEA,AschSM,AdamsJ,KeeseyJ,HicksJ,
DeCristofaroA,etal.thequalityofhealthcaredeliveredtoadultsintheUnitedStates.nEnglJMed2003;348:2635-45.
2. SpiestH,MokkinkHG;WerkgroeponderzoekKwaliteit.Quotedin:GrolR,WensingM,EcclesM.Improvingpatientcare:theimplementationofchangeinclinicalpractice.Edinburgh:Elsevier;2005.Chapter1.
3. nationalInstituteofClinicalStudies.Evidencepracticegapsreport.Melbourne:nICS;2003.Vol1.
http://www.nhmrc.gov.au/nics/asp/index.asp?page=knowledge/knowledge_article_type&cid=5212&id=406[cited2007Sep4]
4. BalasEA,BorenSA.Managingclinicalknowledgeforhealthcareimprovement.In:Yearbookofmedicalinformatics.Stuttgart:Schattauer;2000.p.65-70.
5. FretheimA,oxmanAD,FlottorpS.Improvingprescribingofantihypertensiveandcholesterol-loweringdrugs:amethodforidentifyingandaddressingbarrierstochange.BMCHealthServRes2004;4:23.
http://www.biomedcentral.com/1472-6963/4/23[cited2007Sep4]
6. FretheimA,oxmanAD,HavelsrudK,treweekS,KristoffersenDt,BjorndalA.Rationalprescribinginprimarycare(RaPP):aclusterrandomizedtrialofatailoredintervention.PLoSMed2006;3:e134.
7. GrimshawJM,thomasRE,MacLennanG,FraserC,RamsayCR,ValeL,etal.Effectivenessandefficiencyofguidelinedisseminationandimplementationstrategies.HealthtechnolAssess2004;8.
http://www.hta.nhsweb.nhs.uk/fullmono/mon806.pdf[cited2007Sep4]
Conflict of interest: none declared
Anaphylaxis wall chart Accompanyingthisissueisanewversionofthe
Australian Prescriberwallchartontheemergency
managementofanaphylaxis.thisreplacestheprevious
versionpublishedin2001.
thenewversionhasbeenpreparedovermanymonthswith
theassistanceoftheAustralasianCollegeforEmergency
Medicine,theAustralianandnewZealandCollegeof
Anaesthetists,theRoyalAustralasianCollegeofPhysicians,
theAustralasianSocietyofClinicalImmunologyandAllergy,
theRoyalAustralianCollegeofGeneralPractitioners,andthe
RoyalAustralianandnewZealandCollegeofRadiologists.
theEditorialExecutiveCommitteeofAustralian Prescriber
believesthatthewallchartwillassisthealthprofessionals
workinginthecommunity.Whilethereareotherprotocols
formanaginganaphylaxis,theEditorialExecutiveCommittee
considersthattheAustralian Prescriberwallchartwillbe
applicableinmostsituations.Aswithallprotocols,the
keystoneofdrugtreatmentistogivethepatientadrenaline.
Message to all 2007 graduates in medicine, pharmacy and dentistryIfyouaregraduatinginAustraliathisyearandyouwishto
continuereceivingAustralian Prescriber,pleasecomplete
andsendthedistributionformontheinsidebackcoverof
thisissue,orregisteronline(www.australianprescriber.com
atMailinglist).
116 | VoLuMe 30 | NuMber 5 | oCTober 2007
LettersLetters,whichmaynotnecessarilybepublishedinfull,shouldberestrictedtonotmorethan250words.Whenrelevant,commentonthe
letterissoughtfromtheauthor.Duetoproductionschedules,itisnormallynotpossibletopublishlettersreceivedinresponsetomaterial
appearinginaparticularissueearlierthanthesecondorthirdsubsequentissue.
Varicella vaccination
Editor,–Beforetheuniversalvaricellavaccinationprogram,
95%ofadultsintheUSAexperiencednaturalchickenpox
(usuallyasschool-agedchildren).Mostofthesecases
werebenignandresultedinlong-termimmunity.this
highpercentageofindividualswithlong-termimmunity
hasbeencompromisedbymassvaricellavaccinationof
children,whichprovidesatbest70–90%immunitythatis
temporaryandofunknownduration.1,2thisshiftschickenpox
toamorevulnerableadultpopulationinwhichchickenpox
carries20timesmoreriskofdeathand15timesmorerisk
ofhospitalisationcomparedtochildren.thisisinadditionto
theadverseeffectsofthechickenpoxandshinglesvaccines3,
aswellasthepotentialforincreasedriskofshinglesforan
estimated30–50yearsamongadults.
Asearlyas1965DrHope-Simpsonsuggested,'thepeculiar
agedistributionofzostermayinpartreflectthefrequency
withwhichthedifferentagegroupsencountercasesof
chickenpox...'.4Arecentstudyfounda90%overallincrease
inadultshingles,from2.77/1000to5.25/1000,duringa
periodofincreasingvaricellavaccinecoverage,1998–2003.5
IftheoutcomesinthisandotherUKstudiesaredueto
animmunologically-mediatedlink(thatis,lowvaricella
incidenceproducesanincreaseintheincidenceofherpes
zoster),thentheapproximate50%reductioninriskofherpes
zosterachievedinalargetrialofazostervirusvaccine,at
bestreducesshinglesincidencebacktotheprelicensurerate.
theuniversalvaricellavaccinationprogramcurrently
requiresaboostervaccine(recommendedinchildren
4–6yearsold)andashinglesvaccine(recommendedin
adults60yearsandolder).However,thesearelesseffective
thanthenaturalimmunitythatexistedincommunitiesprior
tolicensureofthevaricellavaccine.Routinevaccination
againstchickenpoxhasproducedcontinualcyclesof
treatmentanddisease.
GarySGoldman
MedicalVeritasInternationalInc.
Pearblossom,California
USA
references
1. GoldmanGS.Universalvaricellavaccination:efficacytrendsandeffectonherpeszoster.IntJtoxicol2005;24:205-13.
2. ChavesSS,GargiulloP,ZhangJX,CivenR,GurisD,MascolaL,etal.Lossofvaccine-inducedimmunitytovaricellaovertime.nEnglJMed2007;356:1121-9.
3. GoldmanGS.thecaseagainstuniversalvaricellavaccination.IntJtoxicol2006;25:313-7.
4. Hope-SimpsonRE.thenatureofherpeszoster:along-termstudyandanewhypothesis.ProcRSocMed1965;58:9-20.
5. YihWK,BrooksDR,LettSM,JumaanAo,ZhangZ,ClementsKM,etal.theincidenceofvaricellaandherpeszosterinMassachusettsasmeasuredbytheBehavioralRiskFactorSurveillanceSystem(BRFSS)duringaperiodofincreasingvaricellavaccinecoverage,1998–2003.BMCPublicHealth2005;5:68.
Influenza vaccination
Editor,–Ihaveanunansweredquestionafterreadingthe
articlebyPaulDugdale(AustPrescr2007;30:35–7).
Ihavetendedtodiscouragevaccinatingyounghealthyadults
withinfluenzavaccineasIwasundertheimpressionthatan
occasionalboutofinfluenzaintheiryoungeryearswould
primetheimmunesystemandproducemuchbetterimmune
responsesforfutureattacksthatwouldkeepthemingood
steadintheirlateryears.
Isthereanyevidenceforthis?Isitareasonableapproach?
LouZaninovich
Generalpractitioner
WestPerth
Dr Paul Dugdale, author of the article, comments:
thereisahealthbenefitofinfectionwithonesubtypeof
influenzabecause,likevaccinationwiththatsubtype,it
willproduceimmunitytothatsubtypeandcanproduce
partialimmunitytoothersubtypes.However,comparedto
vaccination,anypossibleincreasedefficacyofwildinfection
inpreventingfutureinfectionwouldbemorethanoffset
bythehealthcostofactuallyhavingtheboutofinfluenza.
thereforechoosingnottobevaccinatedonthegroundsof
possiblenetfuturebenefitisnotreasonable.
Itmayofcoursebequitereasonableforahealthyadultto
declinevaccinationonthegroundsthatitisnotworththeir
whiletoreducetheirchanceofgettingwildinfluenza.A
discussionoftheirparticularlifecircumstanceswillassist
suchadecision.
| VoLuMe 30 | NuMber 5 | oCTober 2007 117
Managing injuries by venomous sea creatures in AustraliaGeoffrey K Isbister, Senior Research Fellow, Tropical Toxinology Unit, Menzies School of Health Research, Charles Darwin University, Northern Territory, Clinical Toxicologist and Emergency Physician, Calvary Mater Newcastle Hospital, New South Wales, and Clinical Toxicologist, New South Wales and Queensland Poison Information Centres
Summary
Marine injuries or stings are common, but
the majority cause only minor effects and do
not require medical intervention. Injuries from
venomous marine creatures can be divided into
jellyfish stings due to contact with nematocysts,
and penetrating injuries from spiny fish, stingrays
and sea urchins. box jellyfish are the most
dangerous and may cause severe and potentially
life-threatening effects. First aid for jellyfish stings
includes removal of the tentacles, and hot water
immersion for bluebottles or vinegar for major
box jellyfish. In addition to vinegar, major box
jellyfish stings are treated with analgesia and
local dressings. early resuscitation is required
in the rare severe cases. Irukandji syndrome
causes severe generalised pain associated
with autonomic effects with little local pain or
reaction. Treatment is symptomatic but may
require large amounts of analgesia. Spiny fish
and stingrays cause a combination of traumatic
injury and venom-mediated effects. First aid is
hot water immersion and treatment includes
analgesia, thorough wound cleaning and regular
review for secondary infection. Stingray injuries
can be associated with significant trauma and
sometimes result in penetrating abdominal or
thoracic injury.
Keywords:antivenoms,jellyfish,stingray,stonefish.
(Aust Prescr 2007;30:117–21)
Introduction
Injuriesfromvenomousmarinecreaturesareanincreasing
problemseenbyhealthcareworkersincoastalregions.the
majorityofinjuriesarerelativelyminorandmaynotrequire
medicalintervention.themostfrequentmarinestingsarefrom
jellyfish,mainlybluebottles.Boxjellyfish(taxonomicclass
Cubozoa)aremoredangerousandmaycausesevereand
potentiallylife-threateningenvenominginnorthernAustralia.
Injuriesfromspinyfishandstingraysmakeupmostofthe
remaininginjuriesandareacombinationoftraumaticinjury
andenvenoming.Injuriesfromseaurchinspines,contactwith
marinespongesandbitesfromblue-ringedoctopiorseasnakes
arelesscommoninAustralia.1,2
Jellyfish stingsthereareover100medicallyimportantspeciesofjellyfish
belongingtothephylumCnidaria.InAustralia,theimportant
groupsinclude:
n Physalia(bluebottlesorPortugueseMan-of-War)
n Chironex fleckeri(majorboxjellyfish)
n Carukia barnesiandotherboxjellyfishcausingIrukandji
syndrome.
Bluebottle (Physalia species) stingsBluebottlestingsarecommoninmanypartsofAustralia.Many
thousandsofstingsoccureachsummerandasignificant
proportionofthepopulationhasbeenstungatleastonce.
Stingsusuallyoccurinshallowwatersinthesurfwhenswarms
arewashedashore,solargenumbersofcasesoccurforashort
periodbeforethebeachisclosed.themainclinicaleffectis
immediateandintenselocalpainwhichlastsforaboutanhour,
oroccasionallylongerinmoreseverecases.thisisassociated
withcharacteristiclinearerythematousraisederuptions.Arash
orlocalisedrednessatthestingsitemayremainforhoursto
days.Uncommonlyadelayedlocalisedvesicularreactionoccurs
within48hours,butscarringisrare.onlyafewpatientsdevelop
systemicsymptomssuchasnausea,vomiting,abdominalpain,
myalgiaandrarelyrespiratorydistress.3
Treatment of bluebottle stingsthebluebottleshouldbewashedoffwithseawaterorcarefully
removedandthenthestingsiteimmersedinhotwater.there
isnowgoodevidencetosupportthisfirstaid.Anopen-labelled
randomisedcontrolledtrialfoundthatimmersioninhotwater
at45°Cfor20minutescausedaclinicallyimportantreduction
inpainin87%ofpatientscomparedtoonly33%treatedwith
118 | VoLuMe 30 | NuMber 5 | oCTober 2007
icepacks.3thevenomisheatlabileandimmersionofthesting
inhotwateristhoughttoinactivatethevenomandtherefore
relievethepain.Ifhotwaterimmersionisnotpossiblethena
constantflowofhotwateronthestingsiteorahotshowerisan
alternative.Vinegarisnotrecommendedforbluebottlestings.
Major box jellyfishChironex fleckeriisourmostdangerousjellyfish.Itisfoundin
watersnorthofthetropicofCapricorn(fromaboutGladstonein
theeasttoExmouthinthewest).Atleast65deathshavebeen
attributedtoC. fleckeriandfatalcasesinchildrenoccurevery
fewyears.Fatalitiesinthelast15yearshavefollowedrapid
envenomingwithdeathduetocardiovascularcollapse
occurringwithin20–30minutesatremotebeaches.4Severe
envenomingrequiresskincontactwithseveralmetresof
tentacleinanadult,butadeathhasbeenreportedwith
1.2metresofcontactinachild.4
Inthevastmajorityofcasesthereisseverelocalpainand
erythematouswhealformationatthestingsiteswhichappear
asdarkredorpurplewhip-likelesions.Inmoreseverecases
superficialnecrosisoccursalongthestinglesions.thisrarely
causespermanentscarring.Delayedhypersensitivityreactions
characterisedbypapularurticarialreactionsalongthestingsites
occurinoverhalfofcases.4
Confirmationofjellyfishstingsbyskinscrapingsor'sticky
tapetesting'ishelpfulinpatientsseeninhospital,particularly
afterboxjellyfishstings.thetestisbestfortentaclestings
suchasthoseofC. fleckeri.Stickytapeisplacedoverthe
stingsite,removedandthenplacedonamicroscopeslidefor
identificationofthestingingcells(nematocysts).5
Treatment of Chironex fleckeri stingsFirstaidconsistsofimmediateremovalofanytentacles
andgenerousapplicationofvinegar.Vinegardeactivates
theremainingnematocystsandthereforepreventsfurther
envenoming.Localpaincaninitiallybetreatedwithicepacks,
butmayrequireoralorparenteralanalgesia.Mostskinlesions
willhealwithoutanyinterventions,butmoresevereand
necroticlesionsneedlocaldressings.Delayedhypersensitivity
reactionscanbetreatedwithtopicalcorticosteroids.
therapidonsetandthealmost'allornone'characteristicof
systemicenvenominghasmeantthatalmostno-onewith
severeenvenomingarrivesinhospitalaliveunlessearly
basicresuscitationhasbeensuccessful.SevereC. fleckeri
envenomingismanagedasamedicalemergencywith
immediatebasiclifesupportandinterventiontomanageairway,
breathingandcirculation.Cardiovascularcollapseshouldbe
managedwithfluidresuscitation,intravenousantivenom(large
initialdoseofsixvials)andadjunctivetreatmentwithinotropes
ormagnesiuminunresponsivecases.4
thesheep-derivedantivenomspecificforC. fleckerihasnever
beentestedincontrolledtrialsanditsefficacyinhumans
isunclear.6Intramuscularantivenomisnotrecommended
duetodelayedandpartialabsorption,particularlyin
haemodynamicallycompromisedpatients.
Irukandji syndrome
Irukandjisyndromeismostcommonlyreportedinnorthern
Australia.5,7,8MostclinicalstudiesareofstingsbyCarukia
barnesi,butotherboxjellyfishcancausethesyndrome.7,9
theseincludeCarybdea xaymacana,Alatinanrmordens,
Malo maximaandanunnamed'firejelly'.9
Irukandjisyndromeischaracterisedbyminorlocaleffects,
butseveregeneralisedpainandautonomiceffects.thesting
maybepainlessorcauseonlymildirritationwithapatch
oferythema.over20–30minutes,severegeneralisedback,
abdominal,chestandmusclepaindevelopwhichareassociated
withtachycardia,hypertension,nauseaandvomiting,anxiety,
agitationandsweating.Inmoreseverecasestherecanbe
cardiacinvolvementwithECGchanges(twaveinversionand
Stsegmentdepression),progressingtomyocardialdepression
withelevatedtroponinandthencardiogenicpulmonaryoedema
andcardiogenicshock.Atleastonedeathhasbeenattributed
toIrukandjisyndrome.7thegeneralisedpainusuallytakes
6–12hourstoresolve,butcardiacinvolvementmayrequire
supportivecarefor2–3days.
Skinscrapingsarerequiredfornematocystidentification.
theseareplacedin1–4%formalinandthenexaminedunder
themicroscope.7
Treatment of Irukandji syndromethemainstayoftreatmentforIrukandjisyndromeissupportive
careandpainrelief.titratedintravenousopioidanalgesiais
recommended(fentanylormorphine).Largeandrepeatdoses
areoftenrequired.Pulmonaryoedemashouldbetreatedwith
supportivecare,includingoxygen,positivepressureventilation
andinotropes.
MagnesiumhasrecentlybeenusedinIrukandjisyndrome
asaninitialbolusandtheninfusiontotreatthepainand
hypertension.8therehasnotbeenuniversalsuccessand
adverseeffectsduetohypermagnesaemiahavebeen
reported.8Furtherstudyisrequiredbeforemagnesiumcanbe
recommendedasfirst-linetherapy.
Other jellyfish
InformationonotherjellyfishinAustraliaisbasedon
isolatedcasereportsandexpertopinionduetothelackof
epidemiologicalstudiesofdefinitelyidentifiedjellyfishstings.
Inmanycasestheclinicaleffectsoflocalpainandirritation
makeparticularjellyfishstingsimpossibletodistinguishfrom
eachotherwithoutidentificationofthejellyfish.treatmentis
similartobluebottlestingsalthoughthereislittledirectevidence
forthis(table1).
| VoLuMe 30 | NuMber 5 | oCTober 2007 119
Tabl
e 1
Firs
t ai
d an
d tr
eatm
ent
of je
llyfis
h st
ings
and
ven
omou
s fis
h in
jurie
s
Type
Firs
t ai
dM
edic
al t
reat
men
t
Blu
ebot
tles
(Phy
salia
spe
cies
)n
Was
hth
est
ing
site
with
sea
wat
era
ndr
emov
ean
yte
ntac
les
n
Imm
erse
inh
otw
ater
at4
5ºC
for
20m
inut
eso
rho
tsho
wer
n
Do
notu
sev
ineg
ar
n
the
patie
ntr
arel
yre
quir
estr
ansp
ortt
oho
spita
lor
med
ical
inte
rven
tion
n
Sev
ere
loca
lstin
gso
rbu
llous
wou
nds
may
nee
ddr
essi
ng
Maj
orb
oxje
llyfis
h(C
hiro
nex
fleck
eri)
n
Imm
edia
tely
rem
ove
any
tent
acle
sn
App
lyv
ineg
arim
med
iate
lya
ndli
bera
llyn
App
lyic
epa
cks
n
Res
usci
tate
(air
way
,bre
athi
nga
ndc
ircu
latio
n)p
atie
nts
who
are
unco
nsci
ous
orh
ave
card
iova
scul
arc
olla
pse
n
All
butv
ery
min
ors
tings
req
uire
tran
spor
tto
hosp
ital
n
Giv
eor
ala
ndp
aren
tera
lana
lges
iafo
rst
ing
site
pai
nn
For
seve
reli
fe-t
hrea
teni
nge
nven
omin
g:
–gi
vefi
rsta
id
–re
susc
itate
–
adm
inis
ter
intr
aven
ous
antiv
enom
–
cons
ider
mag
nesi
umth
erap
y
Iruk
andj
isyn
drom
en
App
lyv
ineg
arim
med
iate
lya
ndli
bera
llyn
Rem
ove
any
tent
acle
sif
pres
ent
n
Ifvi
nega
ris
not
ava
ilabl
ew
ash
the
area
with
sea
wat
er
n
tran
spor
tto
hosp
italf
or:
–
pare
nter
ala
nalg
esia
with
titr
ated
intr
aven
ous
fent
anyl
or
mor
phin
e
–ca
rdia
cm
onito
ring
,EC
Ga
ndc
ardi
ace
nzym
esn
Car
diac
invo
lvem
enta
ndp
ulm
onar
yoe
dem
aw
illr
equi
re
su
ppor
tive
care
and
man
agem
ento
fbre
athi
nga
ndc
ircul
atio
n
oth
erje
llyfis
h:–
mau
ves
tinge
r(P
elag
ia s
peci
es)
–ha
irje
llyfis
h(C
yane
a sp
ecie
s)–
jimbl
e(C
aryb
dea
rast
oni)
–ot
her
box
jelly
fish
(Chi
rops
alm
us
br
onze
ii)
n
Was
hth
est
ing
site
with
sea
wat
era
ndr
emov
ean
yte
ntac
les
n
Con
side
rho
twat
erim
mer
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120 | VoLuMe 30 | NuMber 5 | oCTober 2007
Mauvestingers(Pelagiaspecies)causelocalpainandskin
irritationandhavebeenconfusedwithbluebottlestingsin
southernwaters.3Hairjellyfish(Cyaneaspecies)alsooccurin
southernwatersandarenamedfortheirhair-liketentacles.
Skincontactresultsinminorandtransientpainassociatedwith
spreadingerythema.therehavebeennumerousreportsof
cornealstingsbythisjellyfish.theeyeshouldbeirrigatedwith
largeamountsoffluidandtopicalsteroidsinstilled.
otherspeciesofboxjellyfishoccurinAustraliabutcauseless
severeeffectsandmaypresentsimilarlytootherjellyfishstings.
onelargeboxjellyfish,Chiropsalmus bronzeii,occursinfar
northQueenslandandcausesonlylocalpainandskinreactions.
thejimble(Carybdea rastoni)iswell-knowninsouthernand
westernwatersandwillcauselocalpainanderythema.
Venomous fish theimportantgroupsoffishwithvenomousspinesinclude
catfish,stonefishandscorpionfish.2,10theycausepuncture
woundswithlocalisedpain,whichcanbesevereandpersistent
withsignificantenvenomingsuchaswithstonefish,bullroutor
marinecatfish.thereisusuallyassociatederythemaandoedema
occursinmoreseverecases.Uncommonlythefishspinemay
breakoffandrequireremoval.themostimportantcomplication
issecondaryinfectionwithmarineoraquaticorganisms.
Stonefishcamouflagethemselvesontheseafloorandmost
commonlycauseinjurieswhentroddenon.thespinesare
coveredbysheathsthatpushbackasthespinecoveredin
venomentersthetissues.thiscausesimmediateseverepain
whichmayradiatefromtheinjurysitewithassociatedswelling
anderythema.Althoughsystemiceffectsareoftendescribed
thesearemorelikelysecondarytopainratherthansystemic
envenoming.Bullroutoccurintidalestuariesandslow-moving
streamsofeasternAustralia.theyarealsobottom-dwellers
whichcommonlycauseinjuriestothefeetwithsimilarseverity
tothoseofstonefish.
Catfishareacommoncauseofspinyinjuriesalthoughmany
catfishdonothavevenomassociatedwiththespinesintheir
dorsalandpectoralfins.Moresevereinjuriesoccurwiththe
orientalorstripedcatfish(Plotosus lineatus),whichpossesses
potenttoxins.Mostinjuriesoccurinfishermentryingtopullthe
fishofflines.
therearenumerousothervenomousorspinyfish,suchasred
rockcodinnewSouthWales,andsoldierfishandcobblersin
southernAustralia.Mostofthesecauseinjurieswhentheyare
handled,forexamplebyfishermen.Scatsarelesswellknown
butoccurintheIndo-Pacificocean.theycauseimmediatesevere
painthatlastsforuptoanhourwithminimalothereffects.
TreatmentFirstaidforvenomousfishstingsishotwater(45ºC)immersion
oftheaffectedlimbforupto90minutes.1thetemperaturemust
betestedwithanunaffectedlimbfirst.Anecdotallyhotwater
providessymptomaticrelief,butthepainmayrecurwhenthe
affectedlimbisremovedfromthewater.10Withmoresevereor
non-responsivepain,oralandoccasionallyparenteralanalgesia
isrequired.Infiltrationofthewoundwithlocalanaestheticor
aregionalnerveblockisoftenmoreeffective.However,the
patientmustbewarnedthathotwatertreatmentshouldnot
beusedafterthelimbisanaesthetisedbecauseoftherisk
ofthermalinjury.Allwoundsmustbethoroughlycleaned
andirrigated.Anypiecesofspineshouldberemovedand
radiographicorultrasoundimagingmayassistinidentifying
foreignbodies.
Stonefishantivenomshouldbeusedinanystonefishsting
thatdoesnotrespondtohotwaterimmersionandadequate
analgesia.thishorse-derivedantivenomislikelytobemore
effectiveifgivenintravenouslyandsoonaftertheinjury.
Swabsfromobviouslyinfectedwoundsshouldbeculturedand
antibioticsprescribed.theroleofprophylacticantibiotics
isunclear.Largeseriesofcasesandexperienceintheaquarium
andcatfishindustriessuggestthatprophylacticantibiotics
arenotrequired.10However,allpenetratingmarineinjuries
mustberegularlyreviewedsothatanyemerginginfection
canbetreatedearly.Confirmedinfectionrequiresantibiotic
therapyandtheopinionofaninfectiousdiseasesspecialist
shouldbesought.
Stingrays
Althoughstingrayshavevenomintheirtail,thetraumaofthe
injuryisusuallymoreimportantthanvenom-mediatedeffects.
Stingraysusuallyrestonthebottomofthewaterandmost
commonlycauseaninjurywhentheyareunwittinglytrodden
on.thismakesthestingrayreflexivelywhipitstailupwardand
intotheperson'sfootorankle.Injuriestothehandscanoccurif
thefisharehandledandrarelydiverscansustaininjuriestothe
chestorabdomenthatcauseserioustraumaordeath.thesharp
bonyspineproducesalacerationandsimultaneouslyleaves
venominthewound.themajoreffectsofthevenomareintense
localpainandslowlydevelopingnecrosis.Systemiceffects
areuncommonandmostlikelysecondarytoseverepain.the
mostimportantcomplicationissecondaryinfection,especially
inwoundsthatpenetrateajointspaceortendonsheaths,or
woundsthatarenotcleanedordebridedwhenappropriate.
Treatment
thetreatmentofstingrayinjuriesissimilartospinyfishinjuries
(table1)exceptthereisoftenmoretrauma.Firstaidmay
requirecontrolofhaemorrhageaswellashotwaterimmersion.
Lacerationsshouldbeleftopenfordelayedprimaryclosure,
ensuringadequatedrainage.Woundscontainingforeign
material,orwhichentersterilebodycavities,orpresentlate,
usuallyrequiresurgicalexplorationanddebridement.Again,
| VoLuMe 30 | NuMber 5 | oCTober 2007 121
thereiscontroversyoverprophylacticantibioticsandthey
shouldbeconsideredwithlargewounds,retainedforeign
materialordelayedpresentation.10
Sea urchinsMostseaurchininjuriesarefromnon-venomousspinesandthe
mainproblemisremovalofbroken-offspines.Venomousspines
arelesscommonbutcausemoreintenselypainfulpuncture
wounds.Hotwaterimmersionisappropriatefirstaid.treatment
consistsofradiographicorultrasoundexaminationtolocate
retainedspines.Somespinesareachalkymaterialthatbreaks
easily,makingremovaldifficult,whileothersarestronger.It
isreasonabletoremovespinesclosetothesurfaceandthen
followthepatientuntilthesymptomsresolve.Patientswith
persistentpainmayrequiresurgicalremovaloftheremaining
spines.
SpongesSpongecontactreactionsareuncommonandmaybedifficult
todiagnoseiftheyaredelayed.onlyafewAustralianspecies
producetoxicsecretions,includingfiresponges(Tedania
species)andNeofibulariaspecies.11Initiallytheremayonlybea
mildsensationwithlocaliseditchinessandstingingdeveloping
afterminutestohours.Insomecasesthissensationincreases
andcancauseintensesymptomsfor2–3days.Usuallythere
isonlyerythema,butoccasionallyvesiclesandbullae,local
swellingandjointstiffnessdevelop.Firespongesarereported
tocausedelayedreactionsanddesquamationcanoccurafter
2–3weeks.11
nospecifictreatmenthasbeenrecommendedexcept
washingthestingsite.theeffectsresolveoverdaystoweeks
irrespectiveoftreatment.Symptomaticreliefwithanalgesiaor
antihistaminescanbeused.
blue-ringed octopus bitesAnumberofspeciesofblue-ringedoctopioccurintidalareas
aroundAustralia.theirsalivacontainstetrodotoxin,apotent
sodiumchannelblocker.theywillonlybitewhendisturbedor
handled.thebiteisoftenpainlessandassociatedwithsmall
puncturemarks.Generalisedparaesthesia,nausea,dizziness
andmalaisemaydevelop,butthemajorityofcasesdonot
progress.Inseverecasesthereisrapidprogressiontoaflaccid
paralysisandrespiratoryfailure.Earlybasicresuscitationto
provideventilatorysupportisessentialinsevereenvenoming.
Medicalmanagementissupportiveandtheeffectsusuallylast
2–5days.Pressureimmobilisationisrecommendedforfirstaid.
ConclusionMinorinjuriesfromvenomousmarinecreaturesarecommon
butmostpeopledonotseekmedicalattention.thisistypified
bythethousandsofbluebottlestingsthatoccurannuallywhich
aretreatedbyfirstaidstationsandwherehotwaterimmersion
hasnowbeenshowntobeeffective.Majorinjuriesareless
commonandrangefromsevereboxjellyfishstingsthatoccur
mainlyinnorthernAustraliatotraumaandsecondaryinfections
frompenetratinginjuriesfromfishsuchasstingrays.
references1. IsbisterGK.Marineenvenomationandpoisoning.In:
DartRC,editor.Medicaltoxicology.3rded.Philadelphia:Lippincott,Williams&Wilkins;2004.p.1621-44.
2. WilliamsonJA,FennerPJ,BurnettJW,RifkinJF.Venomousandpoisonousmarineanimals:amedicalandbiologicalhandbook.1sted.Sydney:UniversityofnewSouthWalesPress;1996.
3. LotenC,StokesB,WorsleyD,SeymourJE,JiangS,IsbisterGK.Arandomisedcontrolledtrialofhotwater(45degreesC)immersionversusicepacksforpainreliefinbluebottlestings.MedJAust2006;184:329-33.
4. CurrieBJ,JacupsSP.ProspectivestudyofChironexfleckeriandotherboxjellyfishstingsinthe'topEnd'ofAustralia'snorthernterritory.MedJAust2005;183:631-6.
5. o'ReillyGM,IsbisterGK,LawriePM,trestonGt,CurrieBJ.ProspectivestudyofjellyfishstingsfromtropicalAustralia,includingthemajorboxjellyfishChironexfleckeri.MedJAust2001;175:652-5.
6. CurrieBJ.Marineantivenoms.JtoxicolClintoxicol2003;41:301-8.
7. Huynhtt,SeymourJ,PereiraP,MulcahyR,CullenP,Carrettet,etal.SeverityofIrukandjisyndromeandnematocystidentificationfromskinscrapings.MedJAust2003;178:38-41.
8. CorkeronM,PereiraP,MakrocanisC.EarlyexperiencewithmagnesiumadministrationinIrukandjisyndrome.AnaesthIntensiveCare2004;32:666-9.
9. LittleM,PereiraP,Carrettet,SeymourJ.JellyfishresponsibleforIrukandjisyndrome.QJM2006;99:425-7.
10. IsbisterGK.VenomousfishstingsintropicalnorthernAustralia.AmJEmergMed2001;19:561-5.
11. IsbisterGK,HooperJn.Clinicaleffectsofstingsbyspongesofthegenustedaniaandareviewofspongestingsworldwide.toxicon2005;46:782-5.
Conflict of interest: none declared
Self-test questionsThe following statements are either true or false
(answers on page 135)
1. Bluebottlestingsshouldbewashedoffwithvinegar.
2. Lacerationsfromstingrayinjuriesshouldbeleftopenfor
delayedprimaryclosure.
122 | VoLuMe 30 | NuMber 5 | oCTober 2007
Consumer Medicine Information conundrumsParisa Aslani, Senior Lecturer in Pharmacy Practice, Faculty of Pharmacy, The University of Sydney
Summary
People have a right to receive accurate and up-to-date information about their medicines from their health professionals. Providing written and verbal medicine information can improve consumers' use of medicines, but it can also have a negative impact. Consumer Medicine Information is standardised written information about prescription and pharmacist-only medicines in Australia. It is a tool which can be used by health professionals during their consultations to explain about the treatment they are recommending, including its harms and benefits. If used effectively and appropriately, Consumer Medicine Information could become an important vehicle in ensuring the quality use of medicines. Although some consumers are receiving Consumer Medicine Information from their health professionals, the documents are generally underutilised.
Keywords:druginformation,drugtherapy,patientinformation.
(Aust Prescr 2007;30:122–4)
Introductiontherehavebeenincreasingdemandsforinformationabout
medicinesfromconsumerswhoconsiderwritteninformation
tobeuseful1,2andhavebeeninfavourofreceivingit.3,4In
Australiaconsumerorganisationsdrovethedevelopmentof
ConsumerMedicineInformation(CMI)whichisnowavailable
forallprescriptionmedicines.Someconsumerspreferto
receivethisinformationfromtheirdoctors5whileothersprefer
pharmacists3,5,howevermanyhealthprofessionalshavebeen
doubtfulaboutthevalueofCMI.
Researchshowsthatthereislimitedinteractionbetween
consumersandhealthprofessionalswhenwrittenmedicine
informationisprovided.2,5thisisunfortunatebecause,when
receivedwithverbaladvice,writteninformationhasmany
positiveimpactsonconsumers6,includingimprovedadherence
totherapy.7,8,9Medicinesinformationspecificallywritten
forconsumersshouldthereforehaveanimportantrolein
consultationsandsupportthequalityuseofmedicines.
what is a CMI and how is it distributed?ItisalegalrequirementthatCMIisavailableforallprescription
(S4andS8)andpharmacist-only(S3)medicines,andthatitis
consistentwiththeapprovedproductinformation.thecontent
ofaCMIisdefinedbylegislationandincludesheadingssuch
ashowtotakeyourmedicines,sideeffectsandadescription
oftheproduct.AustralianCMIsareuniquebecausetheywere
developedtoenableconsumerstoeasilylocatetheinformation
theyneedandthecurrentdesignandcontenthavebeentested
toensurethis.
thename'ConsumerMedicineInformation'isintendedtoshow
clearlythattheinformationisaboutmedicines.Itistherefore
aconcernthattheconsumersectionofthePharmaceutical
BenefitsSchemewebsite(PBSonline)usestheterm'Consumer
factsheet'todescribeCMIs.Pharmaceuticalindustry,health
professionalandconsumerorganisationshavebeenbattlingto
increaseconsumerawarenessof'CMIs'.theuseofanadditional
termthatdoesnotspecificallyrefertomedicinesmaycreate
confusion.
Healthprofessionalshaveadutyofcaretoprovideinformation,
whetherverbal,writtenorboth,toensurethatconsumers
canusetheirmedicinescorrectlyandsafely.Whilethey
arenotlegallyobligedtoprovideCMIwitheverymedicine
prescribedorsupplied,Box1showshowCMIcanbeusedwith
consumers.10
In2003,andaspartoftheMedicinesInformationfor
Consumersprogram,communitypharmacistsinAustralia
begantoreceivefinancialincentivesfordistributingCMI.11
Participatingpharmaciststhereforehaveanobligationto
provideCMIfollowingtheguidelinesofthePharmaceutical
SocietyofAustralia.12
Box 1
using Consumer Medicine Information 10
CMIcanbeusedto:
n educateconsumersandtheircarersaboutthemedicine
andhowtotakeiteffectively
n supportverbalinformation
n informandreassureaboutadverseeffects,andmonitor
adverseevents
n improveadherencetotherapy.
| VoLuMe 30 | NuMber 5 | oCTober 2007 123
thevastmajorityofCMIsaredistributedfromhealth
professionals'computers.Currentlymorethan1200(about
88%ofallCMIs)areavailableelectronically.thewebsites
ofpharmaceuticalcompaniesandhealthprofessionaland
consumerorganisationsareincreasinglyincludingCMIs(Box2).
The consumer experienceAnecdotally,veryfewAustralianconsumersarereceiving
CMIwiththeirprescriptionmedicines.Moreover,whenCMIis
given,ittendsnottobediscussedaspartoftheconsultation.
thoseconsumerswhoareawareofCMI,whoreceiveitfrom
pharmacistsandwhoreadit5,11,donotknowhowitdiffersfrom
otherformsofwritteninformation.13
Inasurveyof226consumersincommunitypharmaciesin
metropolitanSydney,58%reportedreceivingCMIontheday
oftheinterview,and82%saidthattheyhadreceivedCMIin
thepast.5theirmainreasonsforreadingCMIweretogain
knowledgeabouttheirmedicines,andconcernsaboutadverse
effects.themostcommonlycitedimpactofreadingtheCMI
wasbeinginformed,followedbybeingmoreconfidentabout
themedicineanditsimportance.Fearofexperiencingadverse
effectsmade11consumers(5%)stoptakingtheirmedicine.
Afurther20reportedhavingconcerns,themajorityofwhom
contactedtheirhealthprofessional.onlytwoofthe20ceased
takingtheirmedicine,andthreereportedchangingit.5
theMedicinesInformationforConsumersprogramwas
evaluatedin2003and2004.11thefirstsurveyof200consumers
showedthat94%hadreceivedacomputer-generatedCMIfrom
theirpharmacistonatleastoneoccasion.twolatertelephone
surveysof1000consumersindicatedthat24%and29%ofthe
respondentshadrememberedreceivingacomputer-generated
CMIfromtheirpharmacist,sometimeinthepast.Some
reportedthattheCMIcausedthemtobeanxiousabouttheir
medicines.
thereiscontradictoryevidenceregardingtheimpactofwritten
medicineinformationontheadverseeffectsexperiencedby
consumerswhoreadtheinformation.Somestudiesshowa
directrelationshipbetweenfearofadverseeffectsandstopping
medicinesafterreadingwritteninformation.14,15otherstudies
haveshownnorelationship.7,16,17thereluctanceofsome
healthprofessionalstoprovideCMItoconsumersforfearthat
theinformationcanleadtoperceivedoractualexperienceof
adverseeffectsandconsequentnon-adherencetotherapymay
notbefullyjustified.However,thenegativeimpactisrealand
thisiswhyitispreferabletodiscussCMIwiththeconsumer
ratherthanjusthandingitout.
Althoughthereissomediscrepancybetweentheactual
researchandtheanecdotalevidence,thereisconfusionamong
consumersaboutwhataCMIleafletisandwhatitcontains.
CMIisnotmeanttobeastand-alonedocument,butan
importanttoolthatshouldbepartoftheinteractionbetween
healthprofessionalsandconsumers.Healthprofessionalshave
theresponsibilitytoensurethatconsumersunderstandthe
informationintheCMIandknowwhatactiontotakeshould
theyexperienceadverseeffects.
use by health professionalsConsumerswanttoreceiveinformationfromtheirhealth
professionals,somefromtheirdoctors5andothersfromtheir
pharmacists.3,5Itisthereforeinthebestinterestsofconsumers
ifhealthprofessionalsareawareofCMIandhowtouseit.
thefirstguidelinesforhealthprofessionalswerepublished
in1995.18theycontainedrecommendationsontheprovision
ofCMIs,theiruseincounsellingaboutthetreatmentand
theactiontobetakeninspecialcircumstances,suchas
emergencies.theguidelinessuggestedthathealthprofessionals
provideCMIstonon-Englishspeakingpeople,buttake
reasonablestepstoensurethattheyunderstandtheinformation
Box 2
Some websites with Consumer Medicine Information
website urL and navigation to CMI
nationalPrescribingService,consumerssection www.nps.org.au/consumers Goto:ConsumerMedicineInformation
RoyalAustralianCollegeofGeneralPractitioners, www.racgp.org.au/patientspatientssection Goto:ConsumerMedicineInformation
AustralianPrescriptionProductsGuide www.appco.com.au/appguide Goto:ConsumerMedicineInformation
BetterHealthChannel(Victoria) www.betterhealth.vic.gov.au Goto:Medicinesguide
PharmaceuticalBenefitsScheme,consumerssection www.pbs.gov.au/html/consumer/home Goto:(nameofdrug)thengotoConsumerFactSheet
Healthinsite www.healthinsite.gov.au Goto:(nameofdrug)thengotoHealthinsiteInformation PartnerResults
124 | VoLuMe 30 | NuMber 5 | oCTober 2007
content,suchasseekingassistancefromafamilymember,
friendorinterpreterwhocanreadandtranslatetheCMIforthe
consumer.
Pharmacyandnursingspecificguidelineshavesincebeen
developedtoencouragetheuseofCMIsbytheseprofessionals.
thereisalsoaguideforconsumersandhealthprofessionals
whichprovidesinformationaboutCMIs,howtheycanimprove
healthcareandhowtheycanbeused.10
Despiteallthisactivity,thereislimitedknowledgeamong
healthprofessionalsofwhatCMIsare(withtheexceptionof
pharmacistswhoarepaidafeetodistributethem)andhow
theycanbeusedforthebenefitofconsumers.Pharmacists
anddoctorsmayfeelthattheyaretoobusytoincludeCMIin
theirconsultationsortheymaynotprovideitbecausetheyare
uncertainwhattodowithit.
How can a CMI be used in practice?InusingCMIwithconsumers(Box1),itisimportantthathealth
professionalsarefamiliarwithitsstructureandcontent.10It
isalsoimportanttonotethatwhileareaswithinaCMIcanbe
highlightedforincreasedconsumerattention,nosectionsofa
CMIshouldbedeletedorcrossedoutasthisde-emphasising
ofinformationmightincreasethehealthprofessional'sliability
shouldanyproblemsoccur.12
HealthprofessionalscanincreaseconsumerawarenessofCMI
byencouragingtheirpatientstoaskforCMIfortheircurrentand
newmedicines.
ConclusionConsumershavearighttoreceiveinformationaboutthe
medicinestheyaretaking.Althoughsomeconsumersare
receivingCMI,thereisaneedtoincreaseitsprovision.the
challengeforallhealthprofessionalsistointegratetheCMIinto
theirconsultations.Consumers,too,shouldbemadeawareof
CMIandthattheycanaskforaCMIabouttheirmedicine.
thereisalsoaneedtoevaluateCMIreceiptanduseby
consumers,andtoassesstheimpactofCMIonthehealthcare
system.thereisanexpectationthatCMIwillpromotethe
qualityuseofmedicines,butthereisnoevidencecurrently
availabletoconfirmthis.
Acknowledgement: The author thanks the following for their time
and valuable contributions to this manuscript: Diana Aspinall,
Trish Dunning, Mary Emanuel, Deborah Monk, Susan Parker,
David Pearson, Sylvia Roins, Gillian Shenfield and David Sless.
references1. MottramDR,ReedC.Comparativeevaluationofpatient
informationleafletsbypharmacists,doctorsandthegeneralpublic.JClinPharmther1997;22:127-34.
2. KooM,KrassI,AslaniP.Consumeropinionsonmedicinesinformationandfactorsaffectingitsuse–anAustralianexperience.IntJPharmPract2002;10:107-14.
3. LivingstoneCR,PughAL,WinnS,WilliamsonVK.Developingcommunitypharmacyserviceswantedbylocalpeople:informationandadviceaboutprescriptionmedicines.IntJPharmPract1996;4:94-102.
4. SleathB,WurstK.Patientreceiptof,andpreferencesforreceiving,antidepressantinformation.IntJPharmPract2002;10:235-42.
5. KooM,KrassI,AslaniP.ConsumeruseofConsumerMedicineInformation–apilotstudy.JPharmPractRes2005;35:94-8.
6. RaynorDK.theinfluenceofwritteninformationonpatientknowledgeandadherencetotreatment.In:MyersLB,MidenceK,editors.Adherencetotreatmentinmedicalconditions.Amsterdam:HarwoodAcademicPublishers;1998.p.83-111.
7. MyersED,CalvertEJ.Information,complianceandside-effects:astudyofpatientsonantidepressantmedication.BrJClinPharmacol1984;17:21-5.
8. MachucaM,EspejoJ,GutierrezL,MachucaMP,HerreraJ.theeffectofwritteninformationprovidedbypharmacistsoncompliancewithantibiotherapy.ArsPharmaceutica2003;44:141-57.
9. Al-Saffarn,DeshmukhAA,CarterP,AdibSM.Effectofinformationleafletsandcounsellingonantidepressantadherence:openrandomisedcontrolledtrialinapsychiatrichospitalinKuwait.IntJPharmPract2005;13:123-32.
10. PHARMConsumerSub-Committee.UsingConsumerMedicineInformation(CMI)–aguideforconsumersandhealthprofessionals.Canberra:CommonwealthDepartmentofHealthandAgedCare;2000.http://www.health.gov.au/internet/wcms/publishing.nsf/content/nmp-pdf-cmi-cnt.htm[cited2007Sep4]
11. BentonM,SnowK,ParrV.EvaluationoftheMedicinesInformationforConsumers(MIC)program(report).Canberra:PharmacyGuildofAustralia;2004.
12. PharmaceuticalSocietyofAustralia.Guidelines:ConsumerMedicineInformationandthepharmacist.In:AustralianPharmaceuticalFormularyandHandbook.20thed.Canberra:PSA;2006.p.369-70.
13. KooM,KrassI,AslaniP.Patientcharacteristicsinfluencingevaluationofwrittenmedicineinformation:lessonsforpatienteducation.AnnPharmacother2005;39:1434-40.
14. BandeshaG,RaynorDK,tealeC.Preliminaryinvestigationofpatientinformationleafletsaspackageinserts.IntJPharmPract1996;4:246-8.
15. SandsCD,RobinsonJD,orlandoJB.theoralcontraceptivePPI:itseffectonpatientknowledge,feelings,andbehavior.DrugIntellClinPharm1984;18:730-5.
16. GeorgeCF,WatersWE,nicholasJA.Prescriptioninformationleaflets:apilotstudyingeneralpractice.BMJ1983;287:1193-6.
17. GibbsS,WatersWE,GeorgeCF.thebenefitsofprescriptioninformationleaflets(2).BrJClinPharmacol1989;28:345-51.
18. CommonwealthDepartmentofHumanServicesandHealth.Generalguidelinesforhealthprofessionalsonconsumerproductinformation.Canberra:AustralianGovernmentPublishingService;1995.
Conflict of interest: none declared
| VoLuMe 30 | NuMber 5 | oCTober 2007 125
Antidepressants in pregnancy and breastfeedingAnne Sved Williams, Psychiatrist, Clinical Senior Lecturer, University of Adelaide, and Director, Perinatal and Infant Mental Health Services, Children, Youth and Women's Health Services, South Australia
Summary
Maternal depression and anxiety during pregnancy and the early years of an infant's life cause substantial problems to the mother, her infant and her family. Suicide is an ever-present risk with depression along with adverse effects on infant growth and birth weight. balancing these risks against accumulating evidence of the effects of selective serotonin reuptake inhibitors on the fetus and infant presents a challenge to the treating doctor. Careful explanation to the woman and her partner of the risks of both the condition and the treatment, using a biological, psychological and social treatment approach, is likely to provide the most benefit.
Keywords:depression,infants,lactation,selectiveserotonin
reuptakeinhibitors.
(Aust Prescr 2007;30:125–7)
IntroductionDepressioninpregnantandlactatingwomenisacommon
problem.Inattemptingtofindthebesttreatmentoptionsfor
thesewomen,doctorsworkwithlessknowledgeandmorerisks
thanwithotherpatients.Drugtrialsalwaysexcludepregnant
andlactatingwomenandthereforepracticeisguidedbydata
accumulatedfromclinicalexperience.Cliniciansmustconsider
theriskofdamagefromthemedicationsandtheeffectsofthe
illnessitselfonboththemotherandthebaby.
Harmful effects of maternal depressionthereisincreasingevidencethatantenatalandpostnatal
anxietyanddepressionpotentiallyhaveenduringeffectson
offspring.
PregnancyAlthoughsomestudiesdiffer,mostdocumentmaternal
antenataldepressionascausingslightlyshortergestational
lengthandlowerbirthweightinnewborns.1Antenatalanxiety
hasshownastrongassociationwithraisedcortisollevelsin
10-year-oldoffspring,withthepotentialforincreased
vulnerabilitytopsychopathologyinthesechildren.2Boyswhose
depressedmothersshowambivalencetotheminearlymonths
haveincreasedratesofbehaviouralproblemsandlearning
difficultiesbytheageoffiveyears.3
Lactationtherelationshipbetweenpostnataldepressionand
breastfeedingisemergingascomplex.Womenwhodevelop
postnataldepressionaremorelikelytostopbreastfeedingthan
womenwhoarenotdepressed.Likewise,womenwhoestablish
andmaintainbreastfeedingarelesslikelytodevelopdepression
thanwomenwhohavedifficultieswithbreastfeeding.
Harmful effects of antidepressants AntidepressantuseinAustraliahaschangedinthelasttwo
decades.tricyclicantidepressantshavefallenfromfavourand
manyhavebeenwithdrawn.theiradverseeffectsandrisk
offatalityfromoverdosemakethemhazardous.However,
somedoctorscontinuetoprescribethemafterconsidering
therisksandthebenefits.therehavebeenfewdocumented
problemsarisingfromtheiruse,butthisisperhapsduetolack
ofextensiveresearch.Asmallstudyontheuseofdothiepinin
lactationsuggestedbetteroutcomesforchildrenofdepressed
motherstakingthedrugcomparedtothosewhosemothers
chosenomedication.4Casereportssuggestthatdoxepinmay
beharmfultoinfantsandshouldbeavoidedinbreastfeeding.5
Dataonmirtazapinearesparseandthereforethisdrugshould
notbeusedasafirst-linetreatmentinpregnancy.Recent
workcautiouslysuggeststhatlevelsofmirtazapinearelowin
breastfedinfants.
Venlafaxineuseinearlypregnancyhasbeenassociated
withincreasedratesofspontaneousabortionbutnotfetal
abnormality.therearealsonowmanycasereportsofneonatal
effectssoitshouldbeusedwithgreatcautioninpregnancy.
Venlafaxinehasthepotentialtoaccumulateinthebreastfed
babywithprolongedtreatment.6
Drugsusedtotreatbipolardepressionincludesodiumvalproate
whichishighlyteratogenicandisbestavoidedinthefirst
trimester.However,itisprobablysafetouseduringlactation.
Lithiummayalsocausefetalabnormalitiesandisgenerally
advisedagainstinearlypregnancyandduringlactation.
However,arecentreviewofitsuseinthefirsttrimesterhas
shownlowerratesofcardiacabnormalitiesthanpreviously
documented.Itsuseinlactationhassuggesteditisrelatively
safeincompliantmotherswithhealthybabies.7Infantsmustbe
monitoredforlithiumconcentrationsinserumaswellasrenal
126 | VoLuMe 30 | NuMber 5 | oCTober 2007
andthyroidfunction.Specialistadviceishighlyrecommended
withlithium.thisisalsothecaseforlamotrigine.
SSRIs during pregnancy
First trimester:EarlyprospectivetrialsonSSRIssuggestedthey
weresafewithnoteratogeniceffects.However,recentdatahave
challengedthisandsuggestasmallincreaseinbirthdefects.
theseresultswerenotstatisticallysignificantandshouldbe
interpretedwithcaution.8,9Paroxetinehasbeenassociated
withcardiovascularabnormalities10,althoughrecentanalysis
suggeststhisriskisonlyatdosesgreaterthan25mgperday.11
Second and third trimesters:Recentstudiesshowasmallbut
significantriskofshortergestationallengthandlowerbirth
weightininfantsofmotherswhousedSSRIsinlaterpregnancy
evencomparedtobabiesofuntreatedmotherswithdepression.1
Third trimester:Increasesinmildrespiratorydistress,irritability
andfeedingproblemshavebeenobservedininfantsofmothers
takingSSRIsinlatepregnancy.Somebutnotallresearch
suggeststhatparoxetinemaycausemoreneonataldifficulties.12
theseeffectsareself-limitingandhavegenerallysettledby14
days.Itisunclearwhethertheseneonataleffectsarewithdrawal
ortoxiceffects.13therehavealsobeenreportsofpersistent
pulmonaryhypertensionofthenewborn14andpossibly
intraventricularhaemorrhage.12
SSRIs during lactationManySSRIsarehighlyproteinboundandlittledrugis
transferredfromthemothertotheinfantduringlactation.
WecanthereforebemoreconfidentinprescribingSSRIsin
lactation.5However,thereisindividualvariabilityininfant
levelsofSSRIsandthereareoccasionalcasereportsdescribing
adverseeffects.15Lessdataareavailableontheuseofother
antidepressantdrugsduringlactation.
So what is a doctor to do?
Whenawomanpresentsearlyinpregnancywithdepression
averycarefulassessmentshouldbemade,preferablywith
herpartnerorotherfamilymemberasadditionalhistorian.An
assessmentofriskofself-harmorsuicideisvital.otherrisks
suchaspoorantenatalcareareincreasedwithdepression.
oncesafetyissuesandgeneralself-carehavebeenaddressed,
abiological,psychologicalandsocialtreatmentplanshould
beexploredrelatingtothepatient'sneedsandwishes,and
theseverityofthedepression.Sufficientinformationshould
beprovidedtothepatientsotheycanmakeaninformed
decisionabouttheirtreatment.Carefuldocumentationofthese
discussionsisimportantformedicolegalreasons.
Pre-conceptioncounsellingforwomenalreadytaking
antidepressantsmustexploretherelativerisksofthedepression
itselfcomparedtotherisksofusingantidepressantsin
pregnancy.Anxietyaboutmedicationuseinpregnancymay
behigh.Forawomanwhosedepressionhasreceded,atrial
ofslowcessationofmedicationbeforeconceptionmaybe
successful,buthermentalstateshouldbemonitoredincase
ofarelapse.
Unplannedconceptionsforwomenonantidepressantscan
causealarmandsomewomenwillabruptlyceasetheir
medication.Unfortunately,upto75%ofwomenwhodoso
maydeveloparecurrenceoftheirdepressionbeforedelivery.13
Carefulreassessmentofrelativeriskswillreassuremany
womenthatcontinuationoftheirmedicationisappropriate.
Ifapregnantwomandecidestocontinuetakingthedrug,
doctorsshouldbeawarethatpharmacokineticschangeduring
pregnancy.Intheeventofarelapse,awomanmightneed
higherdosesofmanydrugsincludingSSRIstomaintainclinical
improvement.
Laterinpregnancy,concernsoverneonataltoxicityand
withdrawalsguidesomedoctorstolowerSSRIdosesuntil
afterdelivery.Anecdotally,manywomencanmanagethiswell,
providedgoodpsychosocialsupportisavailable.Somewomen
willchoosetocontinueoncurrentdoseswithsupport,and
appropriatemanagementoftheneonate.
Which antidepressant to use?Expertsdifferintheirassessmentsoftherelativerisksofthe
antidepressants,butingeneral,SSRIsarepreferredtotricyclic
antidepressants,combinedserotoninandnoradrenaline
reuptakeinhibitorsandmirtazapine.Everyantidepressant
hasbeenassociatedwithsomeneonataleffects,anddifferent
studiesshowdifferingresults.thedataonparoxetineinhigher
dosescauseconcern.11Whilesomeperinatalpsychiatrists
preferfluoxetinewithitslongerhalf-lifeandpotentialforslower
neonatalwithdrawaleffects,manyprefertheshorter-acting
SSRIs,eithercitalopram,fluvoxamineorsertralineasthe
maternalresponsemaybefaster.
useful sources of information Itisessentialtofrequentlyupdateinformationaboutbest
practiceinthisareaasnewinformationrapidlychanges
practice.Reliablewebsitessuchastheorganisationof
teratologyInformationSpecialists(otIS)(www.otispregnancy.
org)andtheCanadianwww.motherisk.orgarevaluabletoboth
doctorsandpatients.MostlargeAustralianobstetricfacilities
alsoprovideapharmacyinformationservice(seebox),andif
indoubt,atelephonecallisappropriate.telephoneadvice
fromapsychiatristcanbeobtainedprivatelyorthrough
GPPsychSupporton1800200588.Pharmaceuticalcompanies
mayhaveadditionaldataabouttheeffectsofantidepressants
onpregnancyandlactation.
Conclusiontherisksofthedepressionanditsconsequencesmustbe
weighedagainsttherisksofthemedicationstobothmotherand
| VoLuMe 30 | NuMber 5 | oCTober 2007 127
infantduringthedifferentphasesofpregnancyandlactation.
Carefulhistorytaking,closemonitoringandgoodpsychosocial
caremaybesufficientformanywomenwithdepression
duringpregnancy.Whenantidepressantsareneeded,thebaby
shouldbemonitoredpostnatallyforfeeding,neurologicaland
respiratorydifficulties.PrescriptionofSSRIspostnatallyappears
lesshazardousthaninantenataluse,andpotentiallyofbenefit
tomotherandchild.
Acknowledgement: Thanks to Mr Neil Hotham, Pharmacist,
Children, Youth and Women's Health Service, South Australia,
and Associate Professor Marie-Paule Austin, University of
New South Wales.
references1. oberlandertF,WarburtonW,MisriS,AghajanianJ,
HertzmanC.neonataloutcomesafterprenatalexposuretoselectiveserotoninreuptakeinhibitorantidepressantsandmaternaldepressionusingpopulation-basedlinkedhealthdata.ArchGenPsychiatry2006;63:898-906.
2. vandenBerghBR,MulderEJ,MennesM,GloverV.Antenatalmaternalanxietyandstressandtheneurobehaviouraldevelopmentofthefetusandchild:linksandpossiblemechanisms.Areview.neurosciBiobehavRev2005;29:237-58.
3. WeinbergK,tronickE.Emotionalcharacteristicsofinfantsassociatedwithmaternaldepressionandanxiety.Pediatrics1998;102Suppl5:1298-304.
4. BuistA,JansonH.Effectofexposuretodothiepinandnorthiadeninbreastmilkonchilddevelopment.BrJPsychiatry1995;167:370-3.
5. Eberhard-GranM,EskildA,opjordsmoenS.Useofpsychotropicmedicationsintreatingmooddisordersduringlactation:practicalrecommendations.CnSDrugs2006;20:187-98.
6. IlettKF,KristensenJH,HackettLP,PaechM,KohanR,RamponoJ.Distributionofvenlafaxineanditso-desmethylmetaboliteinhumanmilkandtheireffectsinbreastfedinfants.BrJClinPharmacol2002;53:17-22.
7. VigueraAC,newportDJ,RitchieJ,StoweZ,Whitfieldt,MogielnickiJ,etal.Lithiuminbreastmilkandnursinginfants:clinicalimplications.AmJPsychiatry2007;164:342-5.
8. AlwanS,ReefhuisJ,RasmussenSA,olneyRS,FriedmanJM;nationalBirthDefectsPreventionStudy.Useofselectiveserotonin-reuptakeinhibitorsinpregnancyandtheriskofbirthdefects.nEnglJMed2007;356:2684-92.
9. LouikC,LinAE,WerlerMM,Hernandez-DiazS,MitchellAA.First-trimesteruseofselectiveserotonin-reuptakeinhibitorsandtheriskofbirthdefects.nEnglJMed2007;356:2675-83.
10. WogeliusP,norgaardM,GislumM,PedersenL,MunkE,MortensenPB,etal.Maternaluseofselectiveserotoninreuptakeinhibitorsandriskofcongenitalmalformations.Epidemiology2006;17:701-4.
11. BerardA,RamosE,ReyE,BlaisL,St-AndreM,oraichiD.Firsttrimesterexposuretoparoxetineandriskofcardiacmalformationsininfants:theimportanceofdosage.BirthDefectsResBDevReprodtoxicol2007;80:18-27.
12. nordengH,Spigseto.treatmentwithselectiveserotoninreuptakeinhibitorsinthethirdtrimesterofpregnancy:effectsontheinfant.DrugSaf2005;28:565-81.
13. AustinMP.totreatornottotreat:maternaldepression,SSRIuseinpregnancyandadverseneonataleffects.PsycholMed2006;36:1663-70.
14. ChambersCD,Hernandez-DiazS,VanMarterLJ,WerlerMM,LouikC,JonesLK,etal.Selectiveserotonin-reuptakeinhibitorsandriskofpersistentpulmonaryhypertensionofthenewborn.nEnglJMed2006;354:579-87.
15. LattimoreKA,DonnSM,Kacirotin,KemperAR,nealCR,VazquezDM.Selectiveserotoninreuptakeinhibitor(SSRI)useduringpregnancyandeffectsonthefetusandnewborn:ameta-analysis.JPerinatology2005;25:595-604.
Further readingMaternalSSRIuseandneonataleffects.AustAdvDrugReactBull2003;22:14.
Dr Sved Williams has received financial assistance for
educational activities from Pfizer, Wyeth, Bristol-Myers Squibb,
Solvay, Eli Lilly, GlaxoSmithKline and Lundbeck.
Self-test questionsThe following statements are either true or false
(answers on page 135)
3. Itissafetoprescribesodiumvalproateduringearly
pregnancy.
4. Generally,SSRIsaresafetouseduringlactation.
Pregnancy drug information centres
New South wales
MotherSafe
tel:(02)93826539/1800647848(tollfreefornSWcallers)
Queensland
QueenslandDrugInformationCentre(healthprofessionals)
tel:(07)36367098
South Australia
Women'sandChildren'sHospital
tel:(08)81617222
Victoria
RoyalWomen'sHospital
tel:(03)93442277
western Australia
Women's&newbornHealthService
tel:(08)93402723
128 | VoLuMe 30 | NuMber 5 | oCTober 2007
Cell markersKimberly Cartwright, Consultant Haematologist, Wollongong Hospital, New South Wales
Summary
Cell markers serve as a monogram to help identify and classify cells. The majority are molecules or antigens within the plasma membrane of cells. Specific combinations of markers are unique to different cell types. These molecules are not merely markers, but also have important functional roles. Knowing which molecules are present can help in the diagnosis of disease or in directing treatment.
Keywords:flowcytometry,immunocytochemistry,
immunophenotyping.
(Aust Prescr 2007;30:128–9)
IntroductionMostcellmarkersaremoleculesinthecellmembranewhich
canbeusedtoidentifycelltypes.theyareclassifiedbytheir
clustersofdifferentiation(CD)whicharerecognisedbyspecific
antibodies.
How does the laboratory analyse cell surface markers?therearetwocommonimmunophenotypingmethods
usedtoanalysecellmarkers.theseareflowcytometry,
whichisperformedonfresh,unfixedcellsuspensions,and
immunohistochemistrywhichisperformedonfixedspecimens.
thesetestscanbeperformedonblood,bonemarrow,lymph
nodesandothertissues.
Anunderstandingofthesetestsandthenecessaryspecimen
preparationisimportantforpractitionerscollectingfineneedle
aspiratesandsurgicalbiopsies,toensureoptimalprocessing
andinterpretation.
Flow cytometryFlowcytometryusesalaserlightsourcetoanalysethe
size,complexityandphysicalpropertiesoffreshviablecells
insuspensionafterlabellingwithfluorescentmonoclonal
antibodies.onetotwothousandcellscanbeanalysedper
second.
theadvantagesofflowcytometryincludetheabilitytorapidly
andsimultaneouslyanalysemultiplecellparameters.the
Abnormallaboratoryresults
disadvantageistheinabilitytodirectlyassessthecellular
morphologyofthecellpopulationunderanalysis.Asmearof
thespecimenmustbestainedandreviewedmicroscopicallyin
correlationwithflowcytometrytoensureanalysisofthecorrect
cellpopulation,toassesscellviabilityandtoguidetheselection
ofantibodiestobetested.Flowcytometricanalysismaybe
severelycompromisedifthesamplescontaininsufficient
materialortoomanydeadcells.
Althoughtheacquisitionofdatacanbeautomated,the
interpretationoftheresultsandtheirclinicalsignificance
requiressubstantialinputandcriticaljudgementfromtrained
haematologistsorpathologists.Resultsshouldbeanalysedin
conjunctionwiththeclinicalpresentation,cellularmorphology
andcytogeneticswhenappropriate.
ImmunohistochemistryImmunohistochemistryisthephenotypingmethodofchoice
fortissuebiopsiesandisanintegralcomponentofroutine
diagnostichistopathology.Itallowsdirectvisualisationof
labelledcellsurfaceantigensandcellularmorphologyvia
lightmicroscopy.theselectionofantibodiesavailablefor
useonparaffinsectionismorelimitedandtheturnaround
timeisslowerthanforflowcytometry.Resultsmaybe
severelycompromisedifthesamplesaretoosmallor
inadequatelyfixed.
when are these tests useful?
To assess abnormal cell populationsGenerallythisanalysisisrequestedbyhaematologistsor
pathologiststofurtherinvestigateaberrantcellpopulations
foundduringmicroscopyofblood,marrow,lymphnodesor
othertissues.Flowcytometryisnowanessentialtoolinthe
diagnosisofhaematologicalmalignanciessuchasleukaemia
andlymphoma.
Forexample,immunophenotypingmayberecommended
toinvestigatepersistentperipheralbloodlymphocytosis.
Lymphocytosismaybeduetoareactivestatesuchasresolving
viralinfection,priorsplenectomyorduetoanunderlying
lymphoproliferativedisordersuchaschroniclymphocytic
leukaemia.CD8tlymphocytespredominateinreactive
lymphocytosiswhereasB-chroniclymphocyticleukaemia
hasadistinctiveimmunophenotypecharacterisedbythe
expressionofmatureBcellmarkers(CD19,CD20andCD23),
| VoLuMe 30 | NuMber 5 | oCTober 2007 129
weakexpressionofmonoclonalsurfaceimmunoglobulinand
co-expressionofthetcellmarker,CD5.Recentstudiessuggest
thatexpressionofothermarkerssuchasCD38,ZAP70and
p53correlateswithapoorprognosis.theroutineuseofthese
assaysrequiresfurtherstudyandstandardisation.1
FlowcytometryisnotusefulinthediagnosisofHodgkin's
lymphomaandotherfibrotictumours.thisisbecausethereare
alownumberofviablemalignantcellsinthesamplecompared
tothenumeroussurroundingreactivecells.
To monitor for minimal residual diseaseFlowcytometryisoneofseveralmethodsusedtodetect
minimalresidualdiseaseinpatientswithnoclinicalor
morphologicalevidenceofdisease.Inpatientswithaknown
haematologicalmalignancysuchasacutelymphoblastic
leukaemia,flowcytometrymaybeusefultodetectlowlevels
ofpersistentdiseasefollowingtherapy.
To quantify cell populations Cliniciansmayalsorequesttheanalysisofspecificmarkers
tohelpguidetherapy,forexampleusingflowcytometryto
measureCD4lymphocytecountsinimmunosuppressedor
HIVpositivepatients.PatientswithlowCD4countsareat
greaterriskofopportunisticinfections.thisisparticularlytrue
whentheCD4lymphocytecountinperipheralbloodfallsbelow
200cells/microlitreor0.2x109/L.
To assess cell proliferationKi-67(MIB1)isanimportantmarkerofcellproliferationwhich
canbeassessedbyimmunohistochemistryorflowcytometry
toassistdiagnosisandguidetherapy.1Forexample,Burkitt's
lymphomaischaracterisedbyaveryhighgrowthfractionwith
nearly100%ofcellspositiveforKi-67.thisismuchhigherthan
seeninotherlymphomas.Becauseofthishighproliferative
index,Burkitt'slymphomacanfrequentlybecuredwith
intensivechemotherapy.
To identify disease-specific targets for therapyRituximab,anantibodyspecifictoCD20,isanimportant
advanceinthetreatmentofnon-Hodgkin'slymphoma.Similarly,
trastuzumab,whichtargetsthehumanepidermalgrowthfactor
receptor2protein(HER2),isanewtherapyforbreastcancer.
testingappropriatepatientspecimensfortheseantigenshelps
todeterminewhetherpatientsmaybenefitfromtheuseof
thesetargetedtherapies.CD20maybefoundonBlymphocytes
byeitherimmunophenotypingorimmunohistochemistry.
HER2isfoundbyimmunohistochemistryorbytheDnA-based
techniquefluorescentin situ hybridisation.
To identify foreign cell populationsInsomelaboratoriestheKleihauerassay,usedtodetect
fetomaternalhaemorrhage,isnowperformedbyflow
cytometry.Similarmethodologieshavebeendevelopedto
detectblooddopinginathletesbyidentifyinghomologous
bloodcellantigens.2
To detect paroxysmal nocturnal haemoglobinuriaParoxysmalnocturnalhaemoglobinuriaisararehaematological
disordercharacterisedbymarrowaplasia,intravascular
haemolysisandanincreasedriskofvenousthrombosis.It
isduetoanacquiredinabilitytoproduceamoleculewhich
anchorscertaincellmembraneproteins.thisleadstoa
deficiencyinspecificmembraneproteins.Flowcytometric
analysiscandetectclonalpopulationsofbloodcellsdeficientin
theseproteins,greatlysimplifyingthediagnosis.
ConclusionAnalysisofbloodandtissueforcellsurfacemarkersisawidely
acceptedandusefultool.Itassistscliniciansindiagnosingand
managingavarietyofconditions,particularlyhaematological
malignancies.
references 1. GudginEJ,ErberWn.Immunophenotypingof
lymphoproliferativedisorders:stateoftheart.Pathology2005;37:457-78.
2. nelsonM,PoppH,SharpeK,AshendenM.Proofofhomologousbloodtransfusionthroughquantificationofbloodgroupantigens.Haematologica2003;88:1284-95.
Further readingLeisnerRJ,GoldstoneAH.ABCofclinicalhaematology:theacuteleukaemias.BMJ1997;314:733.
HerdsonPB,ScolyerRA,McGregorAR.Definingmomentsinmedicine:pathology.MedJAust2001;174:11-12.
FleishertA,tomarRH.Introductiontodiagnosticlaboratoryimmunology.JAMA1997;278:1823-34.
Conflict of interest: none declared
Self-test questionsThe following statements are either true or false
(answers on page 135)
5. Flowcytometryisausefultechniquefordiagnosing
Hodgkin'sdisease.
6. ImmunosuppressioninpatientswithHIVcanbe
assessedbyflowcytometry.
130 | VoLuMe 30 | NuMber 5 | oCTober 2007
Prescribing exercise for diabetesBronwyn Penny, Exercise Physiologist, Diabetes Australia – NSW, Sydney
Summary
Prescribed effectively, regular exercise is extremely safe, effective and essential in managing diabetes and its complications. It can play a significant role in reducing associated cardiovascular and lifestyle risk factors. The cornerstone of effective exercise prescription lies in the consideration of the various barriers, motivators and medical concerns that face people with diabetes and understanding how exercise may impact both positively and negatively upon these factors.
Keywords:cardiovasculardisease,stresstesting.
(Aust Prescr 2007;30:130–3)
IntroductionRegularphysicalactivityhasbeenshowntosignificantlyimprove
thehealthoutcomesforpeoplewithdiabetes.Physicallyactive
patientswithdiabeteshavelowerratesofallcausemortality
andcardiovascularheartdisease.1Regularexerciseassistsin
maintaininggoodbloodglucosecontrolwhichinturnhelpsto
decreasetheriskofdevelopingdiabetescomplicationssuchas
neuropathyandnephropathy.2,3,4Itcanalsoenhancequalityof
lifeandreducestress,anxietyanddepression.5
Prescribingexerciseshouldbeconsideredoneoftheessential
componentsofdiabetescare.Unfortunately,itisstilllargely
underused.4
Pre-exercise screening and testingCertainexerciseintensitiesandmodalitiesmaybe
contraindicatedorinappropriateforsomepeople.3,4,6Before
prescribinganexerciseprogramforapersonwithdiabetes
itisimperativethatthepatientisscreenedandassessedfor
cardiovasculardiseaseriskfactorsorotherconditionsthat
mayposesignificanthealthrisks.3,6thepatientshouldbe
askedaboutanysymptomsofcardiovasculardiseaseincluding
unusualshortnessofbreath,chestpainwithexertion,dizziness,
light-headedness,swellingoftheanklesandpaininthecalves
thatisnotassociatedwithmusclepain.Ifthesesymptomsare
present,furtherinvestigationisneededbeforethepatientcan
beginanexerciseroutine.7othercardiovascularriskfactors
thatshouldbeassessedincludebloodpressure,cholesteroland
lipidprofiles,restingheartrate,weight,bodymassindex,waist
circumference,familyhistoryandpreviouscardiachistory.6
thepresenceofcardiovascularriskfactorsandother
complicationsdoesnotprecludeapersonwithdiabetesfrom
undertakinganexerciseprogram.6Screeningprovidesauseful
riskstratificationtooltoguideexerciseprescriptionoridentify
thosewhoshouldundergocardiacstresstestingbeforestarting
toexercise.3,6Currentlytherearenoclear-cutguidelines.
Stresstestingallowsdefinitivemanagementofpatients
withcardiovasculardiseasebeforeexerciseisprescribed.
However,thereisnoevidencethatstresstestingshouldbe
routinelyperformedbeforeexerciseofmoderateintensity
ifcardiovasculardiseaseriskislow.Stresstestingmay
beimpracticalandexpensive.3Conversely,ECGstress
testingisrecommendedforsedentaryindividualswithhigh
cardiovasculardiseaserisk(greaterthanorequalto10%riskof
cardiovasculardiseaseover10years)whowishtoparticipate
inaerobicactivitiesthatexceeddemandsofdailyliving,or
patientswithseveralcardiovasculardiseaseriskfactors.3,6
otherconditionsthatshouldbescreenedforinclude
proliferativeandnon-proliferativeretinopathy,peripheral
neuropathy,autonomicneuropathy,nephropathyand
microalbuminuriaaswellasmusculoskeletallimitationssuch
asrheumatoidarthritis,severeosteoarthritis,osteoporosisand
otherjointproblems.
Highintensityexerciseiscontraindicatedinpeoplewith
proliferativeretinopathyduetotheriskofretinalhaemorrhage.3
Highintensityexercise,whilenotcontraindicated,is
notrecommendedforpeoplewithnephropathyand
microalbuminuria.Highimpactandweight-bearingmodalities
suchasrunningandjumpingareinappropriateandnot
recommendedforpeoplewithperipheralneuropathy,arthritis
andosteoporosisastheyareatgreaterriskoffalls,injuriesand
footdamageduetopoorperipheralsensation.3
todevelopanindividualisedprogram,simpleeasilyperformed
exercisetestsrequiringlittlespecialisedequipment,suchasthe
six-minutewalktestorone-minutesit-to-stand,mayprovide
aninsightintothepatient'scurrentphysicalcapacity.thiswill
assistthepractitionertosuccessfullydevelopaprogramthat
matchestheneedsofthepatienttotheprescribedexercise
intervention.6Exercisetestingisalsousefulforassessingthe
efficacyoftheexerciseprogram.Itisimportanttoconsider
theappropriatenessofanyexercisetestusedasitneedsto
accommodatethepatient'sphysicalabilitiesandlimitations.7
exercise prescriptionVariousmedicalandphysicalconcernswillgovernthetype,
intensityanddurationofexerciseanindividualiscapableof
performingsafely.3,4,6Severallifestyleandsocio-economic
issuessuchasmotivation,personalgoalsandpreferences,
stageofchangeandculturalinfluenceswillalsoaffectthetype
| VoLuMe 29 | NuMber 5 | oCTober 2006 131
ofexerciseinterventiondevelopedanditsimplementation.2,4,5
Finally,availabilityandaccesstoservicesandfacilitiessuchas
exerciseprofessionals,exercisefacilitiesandsafeexercising
optionswillvastlyinfluencethedesignandimplementationof
anexerciseprogram.4Itisimportantthatanyexerciseprogram
betailoredtowardstheindividual.
Writtenexerciseinstructionsmayhelpwithadherencetoan
exerciseprogram.However,ofmoreimportanceisthelevelof
supportthephysiciangivestothepatientregardingtheuptakeof
physicalactivity.Physiciansupport,patientconsultation,specific
adviceregardingthetype,timeandintensityoftheexercise
programandthesettingofappropriateandrealisticgoals
appeartobethestrongestpredictorsofadherencealongwith
thepatient'sreadinesstochangeaperceivedlimitation.Regular
monitoring,assessmentandgoalsettingwillgreatlyassistthe
patient'sabilitytoachievelong-termbehaviourchange.8
Aerobic activityRegularaerobicexerciseimprovesbloodlipidprofiles,blood
pressureandrestingheartrates,bodycompositionand
glycaemiccontrolaswellasreducingcholesterol.Inaddition,it
helpspatientstoloseweight.3,4
Forhealthbenefits,currentguidelinesrecommendthat
aerobicactivityshouldbeperformedforatleast30minutes
atamoderateintensityonmost,ifnotalldaysoftheweek
withnomorethan72hoursbetweenexercisesessions.If
weightlossisdesired,then60minutesofexerciseormore
isrecommended.3,4,6Itisoftendifficultformostpeopleto
beginatthislevel,thereforetheexerciseprescriptionshould
initiallybeginatalevelthepatientcanmanage,withtheaim
ofgraduallyincreasingexercisedurationandintensityasthe
patientprogresses.4
Exerciseshouldbecontinuousinnatureandcouldinclude
activitiessuchaswalking,swimmingorcycling.3,4,6However,
thetypeofexercisewilldependonthepatient'ssafetyand
physicalactivitypreferences.6
Exerciseintensityshouldbeatleastmoderatetovigorousin
nature.Moderateintensityexerciseisdescribedasalevelof
activitythatelicitsaheartrateresponseof55–70%maximal
heartrateor12–13ona20pointratingofperceivedexertion
usingtheBorgscale(seeBox1).3,6,9Whilemoderateintensity
ispreferred,somepatients,especiallyveryobesepatients,
maybeunabletocopeforsustainedperiodsofexercise.Inthis
scenario,intervaltypetrainingandalternatingperiodsofhigh
andlowexerciseintensitiesmaybemoreuseful.Withregardto
monitoringexerciseintensity,whileheartratemonitoringhas
itsbenefits,ratingofperceivedexertionrequiresnoadditional
equipment,iseasytouseandteachtopatientsandcorrelates
stronglywithexercisingheartrates.theBorgscaleisuseful
inmonitoringexerciseintensityforthosewithautonomic
neuropathywhereheartrateresponsesmaybedisproportionate
toactualexerciseintensities.6
Resistance trainingResistancetrainingisanothervitalcomponentofanyexercise
programforpeoplewithdiabetes.thisreferstoexercisethat
requiresthebody'smusculoskeletalsystemtoworkagainstan
opposingforce,suchasgravityorweight.Resistancetraining
haspositiveeffectsoninsulinresistance,glycaemiccontrol,
weightlossandmanagement,maintenanceofleanbodymass,
strength,balanceandfunctionalcapabilities.2,3
Veryobeseindividuals,thosewithbalanceandmobilityissues,
foothealthproblemsandperipheralvasculardiseaseoftenfind
thisformoftrainingeasiertocopewithandmaybemorelikely
toadheretotheprogram.2
Currentresearchandguidelinesrecommendresistancetraining
beperformedatleast2–3timesaweekinconjunctionwithan
aerobictrainingprogramtoobtainthegreatestbenefits.2,3,4,6
Heavyresistancetrainingprovidesthebiggestimpacton
glycaemiccontrolandinsulinsensitivity.Previously,onlylight
weightresistancetrainingwasrecommendedbecauseof
safetyconcernsforthepatient.themajorconcernwaspossible
harmfuleffectsfromlargeacutespikesinbloodpressure
associatedwithheavyresistanceexercise.However,recent
evidencesuggeststhemyocardialdemandsofheavyresistance
trainingarecomparabletothecardiovasculardemandsplaced
onthebodywhenperformingsomeoccasionalactivitiesof
dailylivingsuchasstairclimbing.3Recentresearchhasalso
shownthesafetyandefficacyofheavyresistancestrength
trainingevenforolderadults.2,3
Providedtherearenocontraindications,heavyresistance
trainingtargetingallmajormusclegroupsshouldbeincluded
andconsistofheavyloadslifted8–10times,progressingto
2–3setsforeachexercise.Whiletherearenosetguidelines,a
1–2minutebreakbetweensetswillgivebetterstrengthbenefits.
Box 1
borg's ratings of perceived exertion scale9
6
7 very,verylight
8
9 verylight
10
11 fairlylight
12
13 somewhatlight
14
15 hard
16
17 veryhard
18
19 very,veryhard
20
132 | VoLuMe 30 | NuMber 5 | oCTober 2007
vegetation
theloadshouldnotbeabletobeliftedmorethan8–10times
eachset(thatis8–10repetitionsmaximumstrength).2,3
Regardlessofexerciseintensity,itisimperativethatgood
exercisetechniqueisemphasisedthroughouttheprogramto
reducetheriskofinjuryandmaximisehealthoutcomes.3,4
Exercise programstherearespecificexerciseprogramsforpeoplewith
diabetes(seeBox2).YoucanalsocontactDiabetesAustralia
(phone1300136588)forinformationonexerciseprogramsin
yourlocalarea.
Special considerationstheeffectsofexerciseonpatientswhoareinsulindependent,
takingoralmedicationsorsufferingfromoneofthemany
comorbidconditionsassociatedwithdiabetesalsoneedtobe
consideredwhenprescribingexercise.
HypoglycaemiaExercisehasaninsulin-typeeffectwhichposespotential
hazardsforthosewhoareinsulindependentortakeoral
hypoglycaemicmedications.Exercisecancausehypoglycaemia
ifmedicationdosagesorcarbohydrateintakearenotmodified
withincreasesinlevelsofphysicalactivity.3,4,6Bloodglucose
levelswillresponddifferentlydependingontheindividual,
exerciseintensityandduration.6Asageneralrulethough,
extracarbohydrateshouldbeingestedbeforeexerciseifthe
sessionistolastlongerthan30minutesorifpre-exerciseblood
glucoselevelsarelessthan5.6mmol/L.3,6Asexercise-induced
hypoglycaemiamayoccurmanyhourspostexercise,regular
bloodglucosemonitoringbefore,duringandafterexercise
isrecommendedtoestablishbloodglucoseresponsesto
exercise.3,4,6Alternatively,insulindosagemaybeadjusted.3,6
Referraltoadiabeteseducatortodiscussthesestrategiesis
stronglyrecommendedasisthecarryingofemergencyglucose
suppliesatalltimesduringandafterexercisetotreatpotential
hypoglycaemia.
Diabetic retinopathythepresenceofdiabeticretinopathymayalsoimpactonexercise
prescription.Exercisemayhaveadverseeffectsonthosewith
proliferativeorseverenon-proliferativeretinopathy.Untilthe
retinopathyhasbeenstabilised,highintensityresistanceand
aerobictrainingshouldbeavoidedduetotheriskofretinal
haemorrhaging.3,4,6nevertheless,patientswitheitherofthese
conditionscanstillbenefitfromregularmoderateexercise.
Peripheral neuropathy and vascular diseaseBothperipheralneuropathyandvasculardiseasecanincrease
theriskofinjuryandinfectioninthefeet.Peripheralneuropathy
canalsoaffectbalance,placingthepatientatgreaterriskof
falls.Sometypesofexercisesuchastreadmillwalkingshould
beavoided.Adequatefootwearandregularscreeningfor
blistersisamustfortheseindividuals,especiallywithweight-
bearingactivities.3,4,6non-weight-bearingexercisessuchas
cycling,andupperlimbresistancetrainingmayminimise
damageorinfection.
ConclusionExercisecanplayamajorroleinpreventionandmanagement
ofdiabetes.Itcanimproveglycaemiccontrol,reduce
cardiovascularriskandimprovequalityoflife.Bothaerobicand
resistancetrainingmodalitiesshouldformthecornerstoneof
anyexerciseprogram.Prescribedcorrectlyandwithadequate
considerationsofthebarriers,motivatorsandmedicalconcerns
facingpeoplewithdiabetes,exercisecanbeanextremelysafe
andeffectivetreatmentstrategy.
references1. DiLoretoC,FanelliC,LucidiP,MurdoloG,DeCiccoA,
Parlantin,etal.Makeyourdiabeticpatientswalk:long-termimpactofdifferentamountsofphysicalactivityontype2diabetes.DiabetesCare2005;28:1295-302.
2. DunstanDW,DalyRM,owenn,JolleyD,DeCourternM,ShawJ,etal.High-intensityresistancetrainingimprovesglycemiccontrolinolderpatientswithtype2diabetes.DiabetesCare 2002;25:1729-36.
3. SigalRJ,KennyGP,WassermanDH,Castaneda-SceppaC,WhiteRD.Physicalactivity/exerciseandtype2diabetes:aconsensusstatementfromtheAmericanDiabetesAssociation.DiabetesCare2006;29:1433-8.
4. AlbrightA,FranzM,HornsbyG,KriskaA,MarreroD,UllrichI,etal.AmericanCollegeofSportsMedicinepositionstand.Exerciseandtype2diabetes.MedSciSportsExerc2000;32:1345-60.
5. CohenSt,JacobsonAM.Psychologicalbenefitsofexercise.In:RudermannB,DevlinJt,SchneiderSH,KriskaA,editors.Handbookofexerciseindiabetes. 2nded.Alexandria,VA:AmericanDiabetesAssociation;2002.
6. GordonnF.theexerciseprescription.In:RudermannB,DevlinJt,SchneiderSH,KriskaA,editors.Handbookofexerciseindiabetes.2nded.Alexandria,VA:AmericanDiabetesAssociation;2002.
Box 2
exercise programs for people with diabetes
Livinglonger,livingstronger(Victoria,WesternAustralia)Strengthforlife(SouthAustralia)CouncilontheAgeingwww.cota.org.auPhone1800182324
LiftforLifewww.liftforlife.com.auPhone1300733143
Heartmoveswww.heartfoundation.org.au/Professional_Information/Lifestyle_Risk/Physical_Activity/Heartmoves.htmPhone1300362787
| VoLuMe 30 | NuMber 5 | oCTober 2007 133
7. Clinicalexercisetesting.In:FranklinBA,editor.Guidelinesforexercisetestingandprescription.AmericanCollegeofSportsMedicine.6thed.Philadelphia:Lippincott,Williams&Wilkins;2000.
8. Generalprinciplesofexerciseprescription.In:FranklinBA,editor.Guidelinesforexercisetestingandprescription.AmericanCollegeofSportsMedicine.6thed.Philadelphia:Lippincott,Williams&Wilkins;2000.
9. BorgGA.Psychophysicalbasesofperceivedexertion.MedSciSportsExerc1982;14:377-81.
Further readingBowenK.Managingfootinfectionsinpatientswithdiabetes.AustPrescr2007;30:21-4.
Conflict of interest: none declared
Self-test questionsThe following statements are either true or false
(answers on page 135)
7. Highintensityexercisemaycausehaemorrhagein
patientswithdiabeticretinopathy.
8. Patientswithdiabeteswhohavecardiovasculardisease
areprecludedfromundertakinganexerciseprogram.
New drugsSomeoftheviewsexpressedinthefollowingnotesonnewlyapprovedproductsshouldberegardedastentative,astheremayhavebeenlittleexperienceinAustraliaoftheirsafetyorefficacy.However,theEditorialExecutiveCommitteebelievesthatcommentsmadeingoodfaithatanearlystagemaystillbeofvalue.Asaresultoffullerexperience,initialcommentsmayneedtobemodified.theCommitteeispreparedtodothis.Beforenewdrugsareprescribed,theCommitteebelievesitisimportantthatfullinformationisobtainedeitherfromthemanufacturer'sapprovedproduct
information,adruginformationcentreorsomeotherappropriatesource.
Human papillomavirus vaccineCervarix(GlaxoSmithKline)
vialorsyringecontaining0.5mLliquid
Approvedindication:preventionofhumanpapillomavirus
infectionandassociatedgenitaldisease
AustralianMedicinesHandbooksection20.1
thisisthesecondvaccinetoberegisteredinAustraliaagainst
humanpapillomavirusinfection.Likethefirstvaccine(seenew
drugs,AustPrescr2006;29:138–43),thisproductisnotalive
vaccinebutismadeupofvirus-likeparticlesderivedfromthe
majorcapsid(L1)protein.Itisabivalentvaccine,designedto
protectagainsthumanpapillomavirustypes16and18.these
virustypesareresponsibleforaround70%ofinvasivecervical
cancersworldwideandarethemostcommononcogenic
papillomavirustypesisolatedfromAustralianwomen.
thebivalentvaccinehasbeencomparedtoplaceboina
randomisedtrialof1113northAmericanandBrazilianwomen
aged15–25years.thesewomenwerenegativefortype16or
18DnA(bythepolymerasechainreaction)andseronegative
forvirustypes16and18atscreening.threedosesofthe
vaccineorplaceboweregiven,at0,1and6months.Cervical
andcervicovaginalspecimens(takenat3or6monthintervals)
wereanalysedforhumanpapillomavirusDnAandabnormal
cytologyforupto27monthsafterthefirstinjection.1
After27months,therewerefourcasesofpersistentinfection
withtype16or18humanpapillomavirusinthevaccinated
group(560women)comparedto31casesintheplacebogroup
(553women).twowomeninthevaccinegrouphadcytological
abnormalitiesassociatedwithvirustype16or18comparedto
27womenintheplacebogroup.1theseabnormalitiesincluded
atypicalsquamouscellsofundeterminedsignificanceandlow-
andhigh-gradesquamousintraepitheliallesions.
Afollow-upstudycontinuedtomonitorthewomen.Someof
themwerefollowedintotalforapproximately48months.these
womenhadreceivedallthreedosesofthevaccineorplacebo
andtheirtreatmentallocationwasstilldoubleblind.Inthe
follow-upphase,10outof340womenhadpersistenthuman
papillomavirustype16or18infection(for10monthsorlonger)
intheplacebogroupcomparedwithnoneofthe357womenin
thevaccinegroup.2
Duringthecombinedinitialandfollow-upphasesofthetrial,
therewerefourcasesofabnormalcytologyorhistology
associatedwithtype16or18virusinthevaccinegroupand
83casesintheplacebogroup.therewerenocasesofcervical
intraepithelialneoplasiainthevaccinegroup.2
thereseemedtobesomecross-protectionofthevaccine
againstinfectionwithotherhumanpapillomavirustypes,
particularlytypes45and31.thiscorrespondedtofewercasesof
cytologicalandhistologicalabnormalitiesinthevaccinegroup
comparedtotheplacebogroup.2
therewerenovaccine-relatedseriousadverseeventsreported.
However,thereweremoreinjection-sitesymptoms(pain,
swelling,redness)inthevaccinegroupcomparedtotheplacebo
group.1,2
thevaccineshouldbegivenintramuscularlyinthedeltoid
regionat0,1and6months.theseconddosecanbedelayedfor
upto2.5monthsafterthefirstdoseifnecessary.theneedfor
boosterdosesiscurrentlyunknown.
thisbivalentvaccineappearstobeeffectiveinproviding
long-termprotectionagainsthumanpapillomavirustypes16
134 | VoLuMe 30 | NuMber 5 | oCTober 2007
Insulinglulisinehasthesameadversereactionsasotherinsulin
preparations,butlong-termexperienceismorelimited.Ithas
notbeenapprovedforuseinchildrenlessthan12years,butthe
reasonsarenotclear.
manufacturerprovidedonlytheproductinformation
reference *†
1. PhillipsP.Insulinsin2002.AustPrescr2002;25:29-31.
Lapatinibtykerb(GlaxoSmithKline)
250mgtablets
Approvedindication:breastcancer
AustralianMedicinesHandbooksection14.3.9
Lapatinibisanewdrugforuseincombinationchemotherapy
withcapecitabineforpatientswithmetastaticbreastcancer.
ItisindicatedforpatientswithtumoursoverexpressingHER2
(humanepidermalgrowthfactorreceptortype2)thathave
progressedaftertreatmentwithananthracycline,ataxaneand
trastuzumab.Lapatinibcausesgrowtharrestorcelldeathof
tumourcellsbyreversiblyinhibitingtheintracellulartyrosine
kinasedomainofHER1(humanepidermalgrowthfactor
receptortype1)andHER2.
Followingoraladministrationoflapatinib,peakplasma
concentrationsarereachedafterapproximatelyfourhours.Itis
extensivelymetabolised,primarilybyCYP3A4andCYP3A5,then
eliminatedinthefaeces.
ConcomitantuseofdrugsthatinhibitorinduceCYP3A4,
suchasketoconazoleorcarbamazepine,affectslapatinib's
pharmacokineticssodoseadjustmentoflapatinibwiththese
drugsmaybeneeded.thesystemicexposureoflapatinib
isincreasedinpatientswithmoderatetoseverehepatic
impairment.Asthebioavailabilityoflapatinibisincreasedwith
food,itshouldbetakenatleastonehourbeforeoraftereating.
Preliminarystudieshaveindicatedthatlapatinibhasbiological
andclinicalactivityagainstvarioussolidtumours(including
breast,ovarianandlung)thatoverexpressHER1andHER2.1,2
Aninterimanalysisoftheefficacyandsafetyoflapatinibin
combinationwithcapecitabinehasbeenfurtherevaluated
inanopenlabelphaseIIItrial.Inthestudy,324womenwith
progressiveHER2positivelocallyadvancedormetastaticbreast
cancerwhohadalreadytriedothertreatments(includingan
anthracycline,ataxaneandtrastuzumab)wererandomised
(ina1:1ratio)toreceiveeitheralapatinibpluscapecitabine
combinationorcapecitabinealone.Lapatinibwasgivenasa
1250mgcontinuousdailydoseandcapecitabinewasgivenas
2000mg(whenincombination)or2500mg(asmonotherapy)
persquaremetreofbodysurfaceintwodivideddosesfor14
daysofa21-daycycle.3
Clinicaldatawerecollectedfor20monthsaftertheenrolment
ofthefirstpatient.Duringthisperiod,datafrom274ofthe324
enrolledwomenwerecollectedforevaluation.
T
and18infectionsandtheprecancerouslesionsassociated
withthem.thepreviouslyapprovedvaccineisquadrivalent
andcontainsantigensfromvirustypes6,11,16and18.As
humanpapillomavirustypes6and11causegenitalwarts,the
quadrivalentvaccineisindicatedformalesandfemaleswhereas
thebivalentvaccineisonlyindicatedforfemales,butforawider
agerange(10–45years).
manufacturerprovidedonlytheproductinformation
references1. HarperDM,FrancoEL,WheelerC,FerrisDG,JenkinsD,
SchuindA,etal.EfficacyofabivalentL1virus-likeparticlevaccineinpreventionofinfectionwithhumanpapillomavirustypes16and18inyoungwomen:arandomisedcontrolledtrial.Lancet2004;364:1757-65.
2. HarperDM,FrancoEL,WheelerCM,MoscickiAB,RomanowskiB,Roteli-MartinsCM,etal.Sustainedefficacyupto4.5yearsofabivalentL1virus-likeparticlevaccineagainsthumanpapillomavirustypes16and18:follow-upfromarandomisedcontroltrial.Lancet2006;367:1247-55.
Insulin glulisineApidraSoloStar(sanofi-aventis)
100IU/mLin3mLcartridgesforuseinreusableinsulininjection
device
Approvedindication:diabetesmellitus
AustralianMedicinesHandbooksection10.1.1
Insulinanaloguesaregeneticallyengineeredtotryandimprove
thecontrolofbloodglucoseinpatientswithdiabetes.1Insulin
glulisinediffersfromhumaninsulinbyonlytwoaminoacids.
thisdifferenceresultsinamorerapidandshort-actingeffecton
bloodglucose.
Patientscaninjectinsulinglulisineinthe15minutesbefore,
orimmediatelyafter,ameal.theanaloguereachesahigher
maximumconcentrationfasterthanasubcutaneousinjectionof
regularhumaninsulin(55vs82minutes)intype1diabetes.
Intype2diabetes,themediantimetomaximumconcentrationis
89minuteswithinsulinglulisineand94minuteswithinsulin.
Insulinglulisineisalsoeliminatedmorerapidlywithahalf-lifeof
42minutescomparedwith86minutesforregularinsulin.Although
themaximumconcentrationofinsulinglulisineisapproximately
twicethatofregularinsulin,oneunitofinsulinglulisinehasthe
sameglucose-loweringeffectasoneunitofregularinsulin.
Insulinglulisineneedstobeusedwithalonger-actinginsulinto
providethepatient'sbasalrequirements.Itshouldnotbemixed
withotherinsulins(exceptnPHinsulins)beforeinjection.
Acomparativestudy,inpatientswithtype1diabetesusing
insulinglarginefortheirbasalrequirements,foundthatthe
efficacyofinsulinglulisinewassimilartothatofinsulinlispro
(anotherquicklyabsorbedanalogue).Inpatientswithtype2
diabetesusingnPHinsulin,injectinginsulinglulisine15minutes
orlessbeforemealshadasimilareffectonglycaemiccontrolto
injectingregularinsulin30–45minutesbeforemeals.
T
| VoLuMe 30 | NuMber 5 | oCTober 2007 135
T
Answers to self-test questions1. False
2. true
3. False
4. true
* Atthetimethecommentwasprepared,informationaboutthisdrugwasavailableonthewebsiteoftheFoodandDrugAdministrationintheUSA(www.fda.gov).
† Atthetimethecommentwasprepared,ascientificdiscussionaboutthisdrugwasavailableonthewebsiteoftheEuropeanMedicinesAgency(www.emea.eu).
thet-score()isexplainedin'two-waytransparency',AustPrescr2005;28:103.
T
overallsurvivalratesweresimilarinbothgroups,with36
deathsinthelapatinibpluscapecitabinegroupand35inthe
capecitabinegroup.theoverallresponseratewas22%inthe
combinationgroupand14%inthemonotherapygroup.Patients
oncombinationtherapyhadalongermediantimetodisease
progressionordeathcomparedtothosetakingcapecitabine
alone(8.4monthsvs4.4months).3
Diarrhoeawasmorecommoninwomentakinglapatinibplus
capecitabinecomparedtothosetakingcapecitabinealone
(60%vs39%).Dyspepsiaandrashwerealsomorecommonin
thecombinationtreatmentgroup.Hand-footsyndrome,nausea
andvomitingoccurredtoasimilardegreeinbothgroups.
therewerefivefataladverseeventsinthestudy–twowomen
oncombinationtreatmentandthreewomenonmonotherapy.
thedeathofapatientwithdiarrhoea,vomitingandsmall-bowel
obstructioninthemonotherapygroupwasdeemedtoberelated
tothestudydrug.3
Lapatinibhasbeenassociatedwithdecreasesinleftventricular
ejectionfraction,andasymptomaticcardiaceventswere
detectedin2%ofpatientstakingcombinationtherapyinthe
trial.3Patientsshouldthereforebeevaluatedbeforestarting
therapyandat8–12weekintervalsduringtreatmenttoensure
thatcardiacfunctiondoesnotdecline.
Althoughlapatinibincombinationwithcapecitabineprolongs
thetimetodiseaseprogressioninwomenwithmetastatic
breastcancer,itdoesnotactuallyimproveoverallsurvivalrates
comparedtocapecitabineonitsown.
manufacturerprovidedonlytheproductinformation
references *1. SpectornL,XiaW,BurrisH,HurwitzH,DeesEC,DowlatiA,
etal.Studyofthebiologiceffectsoflapatinib,areversibleinhibitorofErbB1andErbB2tyrosinekinases,ontumorgrowthandsurvivalpathwaysinpatientswithadvancedmalignancies.JClinoncol2005;23:2502-12.
2. BurrisHA,HurwitzHI,DeesEC,DowlatiA,BlackwellKL,o'neilB,etal.PhaseIsafety,pharmacokinetics,andclinicalactivitystudyoflapatinib(GW572016),areversibledualinhibitorofepidermalgrowthfactorreceptortyrosinekinases,inheavilypretreatedpatientswithmetastaticcarcinomas.JClinoncol2005;23:5305-13.
3. GeyerCE,ForsterJ,LindquistD,ChanS,RomieuCG,Pienkowskit,etal.LapatinibpluscapecitabineforHER2-positiveadvancedbreastcancer.nEnglJMed2006;355:2733-43.
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