· to licensure of the varicella vaccine. Routine vaccination against chickenpox has produced...

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).


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.


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


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).


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

sion

or

ice

pack

sn

Do

notu

sev

ineg

ar

n

Patie

nts

rare

lyr

equi

retr

ansp

ortt

oho

spita

lor

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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,


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.


Self-test questionsThe following statements are either true or false

(answers on page 135)

1. Bluebottlestingsshouldbewashedoffwithvinegar.

2. Lacerationsfromstingrayinjuriesshouldbeleftopenfor

delayedprimaryclosure.


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.


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


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.



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


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


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.



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


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),


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.




5. Flowcytometryisausefultechniquefordiagnosing

Hodgkin'sdisease.

6. ImmunosuppressioninpatientswithHIVcanbe

assessedbyflowcytometry.


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


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


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


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.




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


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).


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


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.


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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edITorIAL eXeCuTIVe CoMMITTee

ChairmanJWGtiller–Psychiatrist

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AdVISorY edITorIAL PANeLAustralasianCollegeforEmergencyMedicine JHolmesAustralasianCollegeofDermatologists IDMcCrossinAustralasianChapterofSexualHealthMedicine CCarmodyAustralasianCollegeoftropicalMedicine KWinkelAustralasianFacultyofoccupationalMedicine RHorsleyAustralasianFacultyofRehabilitationMedicine GBashfordAustralasianSocietyforHIVMedicine JZieglerAustralasianSocietyofBloodtransfusion JIsbisterAustralasianSocietyofClinicalandExperimentalPharmacologistsandtoxicologists HKrumAustralasianSocietyofClinicalImmunologyandAllergy CKatelarisAustralianandnewZealandCollegeofAnaesthetists KBrandisAustralianandnewZealandSocietyofnephrology PSnellingAustralianandnewZealandAssociationofneurologists FVajdaAustralianBirthDefectsSociety ttaylorAustralianCollegeofRuralandRemoteMedicine AIannuzziAustralianDentalAssociation MMcCulloughAustralianMedicalAssociation JGullottaAustralianPharmaceuticalPhysiciansAssociation CGittlesonAustralianPostgraduateFederationinMedicine BSweetAustralianRheumatologyAssociation JBertouchAustralianSocietyforGeriatricMedicine RKPenhallAustralianSocietyofotolaryngologyHeadandneckSurgery EPChapmanCardiacSocietyofAustraliaandnewZealand JHnBett

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