10/4/18

1

ManagementofChemotherapyInducedNausea/Vomiting(CINV)

inAdultCancerPatientsByZahraShaghaghi,Pharm-D,BCOP,PhC

Preparedfor2018 NMSHPBalloonFiestaSymposium

10/4/18

2

GoalsandObjectives:

• DescribedifferenttypeofCINV- acutevs.delayedandanticipatoryemesis.• Describepatient’sriskfactorsfordevelopingCINV.• Discusspotentialemetogenicity ofchemotherapyregimens.• DiscusspathophysiologyofCINV&Neurotransmittersinvolved• Recognizeroleof5HT3-RA&NK1-RAinpharmacologicapproachestomanagementofCINV.• Recommendoptimalantiemeticprophylaxisbasedonoverallemesisriskfactors&RecommendationsintheNCCNGuidelinesforAntiemesis.

AudienceQuestion#1

Whichoneisthemostcommonfearedsideeffectofchemotherapy?

1- Immunesuppression

2- Fatigue

3- FebrileNeutropenia

4- Vomiting

10/4/18

3

ChemotherapyInducedNauseaVomiting(CINV)Fewsideeffectsofcancertreatmentaremorefearedbythepatientthannauseaandvomiting.

• Threephasesofemesisinclude:nausea,retching,andVomiting.

• GoalisPrevention.

TypesofEmesis

• ThreedistincttypesofCINVhavebeendefined:acute,delayed,andanticipatory.

• RecognizingthedifferencesbetweenthesetypesofCINVhasimportantimplicationsforbothpreventionandmanagementCINV.

10/4/18

4

AcuteEmesis

• ItisthemostwidelystudiedformofCINV.• Intheabsenceofaneffectiveprophylaxisanti-emeticregimen:• Itoccursduringthefirst24hoursafterchemotherapy• Theonsetisusuallywithin1-2hoursofChemotherapy.• Itpeaksinthefirst4-6hours.•Mosteasilypreventedandtreatedwithcurrentanti-emeticdrugs.

DelayedEmesis

• Anyemesisoccurringafter24hourspostchemotherapy.• UnderlyingPathophysiologynotwellunderstood.• Bestexampleishighdosecisplatin,butcanoccurwithotheragentssuchascyclophosphamide,carboplatin,anthracyclines,andIfosfamide.• Itpeaksat48-72hoursintheabsenceofeffectiveprophylaxis.• Delayedemesisislesscontrolledwithcurrentanti-emetics.• Patientswhohavecompletecontrolofacuteemesisarelesspredisposedtodelayedsymptoms.

10/4/18

5

AnticipatoryEmesis

• Aconditionedreflexinpatientswhohavedevelopedsignificantnauseaandvomitingduringpreviouscycles.• Veryimportanttoprovidemaximalcontrolofemesisearlierintreatment.• Usuallyoccurs24hourspriortotreatment.• Susceptiblepopulation:youngeradults,patientsreceivingchemotherapytreatmentforlongerperiodsoftime.

RiskFactorsforDevelopingCINV

• PatientRiskFactors(mayormaynotincreaseoverallemesisrisk)

• RegimenRiskFactors

OverallEmesisRisk=Patient’sriskfactors+Regimenriskfactors

10/4/18

6

AudienceResponseQuestion#2

JDisa40-yearolddepressedwomanwhoisdiagnosedrecentlywithextensivestagesmallcelllungcancer.Sheisasocialdrinker,stoppedsmoking15yearsago.HerPMHissignificantformorningsicknesswithher2pregnanciesandmotionsickness.Heroncologistwishestousecisplatin75mg/m2IVD1,etoposide100mg/m2IVD1-3ofevery21daystimes6cyclesasherchemotherapytreatment.whatareJD’sspecificriskfactorsfordevelopingN/V?A- femaleB- AgeC- HistoryofmorningSicknessD- Historyofmotionsickness

PatientspecificriskfactorsfordevelopingCINV• Anxiety,expectationofnausea• Women>men• Psychosocialfactors(anxiety,depression,etc.)• Youngerage(i.e.,<50y/o)• Historyofmotionsickness• Pregnancy-inducednausea/vomiting• Historyofmoderatealcoholuse(protective)• Extentofdisease(stage)• Anti-emeticsinconsistentwithguidelines• Priorchemotherapyanddegreeofanti-emeticcontrol

10/4/18

7

RegimenSpecificRiskFactors

• DoseandScheduleofregimen• Single-agentchemotherapyemetogeniccategories:– High– Moderate– Low– Minimal• Formulti-drugregimens:thedrugthathasthehighestlevelofemetogenicitydeterminestheregimen’semeticrisklevel.• Nolonger“calculate”emetogenicityofmultipledrugregimens

EMETOGENICPOTENTIALOFANTICANCERAGENTS

Itisbasedontheproportionofpatientswhoexperienceemesisintheabsenceofeffectiveantiemeticprophylaxis.

• HighEmeticriskèè over90%frequencyofemesis

• ModerateEmeticRiskèè 30-90%frequencyofemesis

• LowEmeticRiskèè 10-30%frequencyofemesis

• MinimalEmeticRiskèè lessthan10%frequencyofemesis

10/4/18

8

EmetogenicPotentialofIVAnticancerAgentsintheabsenceofeffectiveantiemeticprophylaxis

HighlyEmetogenic- >90%incidenceinacuteanddelayedemesis– Cyclophosphamide/doxorubicincombination– Cisplatin– Higherdosesofspecificchemotherapyagents(e.g.CarboplatinAUC=4&>4)

EmetogenicPotentialofIVAnticancerAgentsintheabsenceofeffectiveantiemeticprophylaxis

ModeratelyEmetogenic- 30-90%riskofacuteanddelayedemesis– Carboplatin,Oxaliplatin– Anthracyclines(relativelylowerdoses)– Nitrogenmustards(e.g.Bendamustine,Ifosfamide,Cyclophosphamide,Irinotecan)

10/4/18

9

EmetogenicPotentialofIVAnticancerAgentsintheabsenceofeffectiveantiemeticprophylaxis

LowEmetogenic- 10-30%riskofacuteemesis- Antimicrotubules (e.g.,Taxanes)- Antimetabolites&antifolates(e.g.Fluorouracil,Methotrexate,Pemetrexed)

EmetogenicPotentialofIVAnticancerAgentsintheabsenceofeffectiveantiemeticprophylaxis

Minimaly Emetogenic- <10%riskofacuteemesis– Monoclonalantibodies,Vinca Alkaloids

SeeNCCNGuidelinesforAntiemesis (availableat:www.nccn.org)forcompletelist

10/4/18

10

EMETOGENICPOTENTIALOFORALANTICANCERAGENTS

Moderatetohighemeticrisk(≥30%frequencyofemesis):• Cytotoxicchemotherapy- Cyclophosphamide≥100mg/m2/d,Temozolomide>75mg/m2/d• Crizotinib• PARPinhibitors- Olaparib,Rucaparib,Niraparib

Minimaltolow(<30%frequencyofemesis):• Capecitabine• Temozolomide<75mg/m2/d• “-nibs”– Gefitinib,Afatinib,Suntinib,Regorafenib• CDK4/6inhibitors- Palbociclib,Ribociclib,AbemaciclibSeeNCCNGuidelinesforAntiemesis (availableat:www.nccn.org)forcompletelist

10/4/18

11

PathophysiologyofCINV

• Vomitingistriggeredbyafferentimpulsestothevomitingcenter,anucleusofcellsinthemedulla.• Impulsesarereceivedfromsensorycenters,suchasthechemoreceptortriggerzone(CTZ),cerebralcortex,andvisceralafferentsfromthepharynxandGItract.• Whenexcited,afferentimpulsesareintegratedbythevomitingcenter,resultinginefferentimpulsestothesalivationcenter,respiratorycenter,andthepharyngeal,GI,andabdominalmuscles,leadingtovomiting.

PathophysiologyofNausea/Vomiting

• Thevomitingreflexistriggeredbyafferentimpulsestothevomitingcenterfromvagus nerveterminalsinthewallofthesmallbowel,thechemoreceptortriggerzone,orthecerebralcortex.• Theactofvomitingoccurswhenefferentimpulsesaresenttoanumberoforgansandtissuessuchastheabdominalmuscles,salivaryglands,cranialnerves,andrespiratorycenter

10/4/18

12

NeurotransmittersInvolvedinCINV

• ManyneurotransmittersarepotentiallyinvolvedinCINV,buttheserotoninreceptors--type3[5-(hydroxytryptamine)HT3]--andthesubstancePreceptors(NK1 receptors)aremostimportant.• DopamineD2 receptorsareoflesserimportancebutprovidedthekeytocurrentunderstandingof5-HT3 receptor.• Otherneurotransmitters(H1,M,GABA,CB)mayhavesomeeffectonnausea,withalessereffectonvomiting.

PathophysiologyofEmesis

• Fear,Dread,Anticipationè Higherlevelofcortexè5HT3,NK1,D2,GABAèEmeticCenterInMedullaè Vomiting

• InnerEar,Motionè CerebellumèH1,Mè EmeticCenterInMedulla(NK1)èVomiting

• BloodBornEmeticsèChemoreceptorTriggerZone(CTZ)è5HT,D2,M,CB,Opioidè EmeticCenterInMedulla(NK1)è Vomiting

• Vagal,sympatheticstimulationsè 5HT3,NK1,D2,M,CB,H1è EmeticCenterInMedulla(NK1)è Vomiting

10/4/18

13

Anti-emeticsDrugClasses- basedontargetingreceptor

• Histamine(H1)• Diphenhydramine(++++)• Promethazine(++++)• Prochlorperazine(++)

• Dopamine(D2)• Haloperidol(++++)•Metoclopramide(+++)• Olanzapine(++++)• Prochlorperazine(++++)• Promethazine(++)

Anti-emeticsDrugClasses- basedontargetingreceptor

• Muscarinicacetylcholinereceptors(M)• Scopolamine(++++)• Diphenhydramine(++)• Promethazine(++)

• Cannabinoid(CB)• Dronabinol• Nabilone

• GABA• Lorazepam

10/4/18

14

Corticosteroids:Dexamethasone

• CornerstoneofAntiemetictherapy(bothAcute&DelayedN/V)

• MOAnotwellunderstood,possiblyprostaglandinblockingactivityinthecerebralcortexandchangesincellularpermeability.

• Notrecommendedassingleagentforhigh/moderateCINV• Notrecommendedwithimmunotherapiesandcellulartherapies.• SE:insomnia,agitation,increasedenergy,increasedappetite,agitation,moodchanges,Hyperglycemiaw/prolongeduse,dyspepsia&abdominaldiscomfort.

• Clinicalpearl:considerextendingthecourseforpatientssufferingfromextendeddelayedCINV

• NK1receptorantagonists(withtheexceptionofRolapitant)inhibitmetabolismofDexamethasone,reducedoseofdexamethasone.

SerotoninReceptorAntagonists

• TherevolutionincontrolofCINVhappenedwhenrecognizedtheroleof5-HT3receptorsubtype.• Developmentofselective5-HT3antagonistledtosignificantsuccessincontrolofCINV.• The5-HT3receptorsarelocatedbothcentrally(NTSandAP)andintheperiphery(GI)vomitingreflexarc.• Oralandintravenousserotoninreceptorantagonists(5-HT3RA)haveequivalentefficacywhenusedattheappropriatedosesandintervals.• Clinicalpearl:Afterreceivingpalonosetron,granisetron transdermalpatch,orextended-releaseinjection,breakthrough5-HT3RAsplayalimitedroleinthedelayedinfusionperiodandbreakthroughantiemeticshouldfocusonadifferentmechanismofaction.

10/4/18

15

5HT3ReceptorAntagonists

• Dolasetron 100mgPOonce.• Granisetron 10mgSQonceor2mgPOonce,or0.01mg/kg(max1mg)IVonce,or3.1mg/24-htransdermalpatchapplied24–48hpriortofirstdoseofchemotherapy.• Ondansetron16–24mgPOonce,or8-16mgIVonce• Palonosetron0.25mgIVonce

Neurokinin-1(NK1)receptorantagonistsPlaceintherapyisforpreventionandnottreatmentofCINV.LargestbenefitseenindelayedCINVsetting.• Aprepitant- 125mgPOD1,then80mgD2&3;Aprepitantinjectableemulsion130mgIVonce.Fosaprepitant- 150mgIVonce.• Netupitant300mg/palonosetron0.5mg(availableasfixedcombinationproductonly)POonce.• Rolapitant- 180mgPOonce(hasanextendedhalf-lifeandshouldnotbeadministeredatlessthan2-weekintervals)

10/4/18

16

D2- DOPAMINETYPE2RECEPTORANTAGONIST(METOCLOPROMIDE)

• Itwasthe1stgroupofantiemeticthatwasusedforthepreventionofCINV.• InitialAntiemetictherapywerefocusedondopamineD2receptorsanddopaminergicantagonistsuchasmetoclopramide• ThreeproposedMOAcontributingtoitsantiemeticproperties:

• Blocksdopamineatthechemoreceptortriggerzone(CTZ)• Stimulatescholinergicactivityinthegut,causingincreasedgutmotility• BlocksperipheralserotoninreceptorsintheGI&CTZ(high- doseonly)

• MetoclopramidehadlimitedefficacyincontrollingCINVevenwhenusedinhighdoseandwassignificantlyassociatedwithsideeffectmainlyextrapyramidalsymptoms.

Olanzapine- Atypicalantipsychotic

• Olanzapine5-10mgPOoncedailyX4days.• SE:sedation,EPS,QTcprolongation• CNSdepression/sedationmostnotableonday2&improvesovertime• Consider5mgdoseforelderlyorover-sedatedpatients• MayincreasetheriskofdevelopingQTcprolongation,whenusedincombinationwithotherQT-prolongingagents.

10/4/18

17

NEPA-Netupitant+Palonosetron

• Netupitanthashalf-lifeof80hours(vs.aprepitant half-life9-13hours)• InhibitsCYP3A4upto4daysfollowingdose• Phase3studiesinhighly- andmoderately- emetogenicchemotherapyregimensdemonstratedimprovedcontrolofCINVinacute,delayedandoverallphases

• UsewithcautioninpatientsreceivingconcomitantmedicationsprimarilymetabolizedbyCYP3A4.TheplasmaconcentrationsofCYP3A4substratescanincreasewhenco-administered.TheinhibitoryeffectonCYP3A4canlastformultipledays.• Atwo-foldincreaseinthesystemicexposureofdexamethasonewasobserved4daysaftersingledoseofNetupitant,reduceddoseofDexamethasoneshouldbegiven.

• ConsiderthepotentialeffectsofincreasedplasmaconcentrationsofmidazolamorotherbenzodiazepinesmetabolizedviaCYP3A4(alprazolam,triazolam).whenadministeringwithNetupitant,thesystemicexposuretomidazolamwassignificantlyincreased

• AvoidconcomitantusewithastrongCYP3A4inducersuchasrifampin.

PRINCIPLESOFEMESISCONTROLinCANCERPATIENT

Preventionofnausea/vomitingisthegoal

• Evaluatetheriskfornausea/vomiting.• Considerotherpotentialcausesofemesis:brainmetastasis,gastroparesis,etc.• Reviewconcomitantdrugsincludingopioids• Multidrugregimenvssingledrugregimen• Acute≤24hoursvs.delayednausea>24hours.• Highemetogenicpotentialchemotherapyvs.moderateemeticrisk.• Beawareofthepotentialfortheoveruseofprophylacticantiemetics• UnwantedpotentialAdverseeffects&poseundueeconomicburden

10/4/18

18

NCCNGuidelineForAnti-emesisRecommendation- SingleDayHighlyEmetogenicRegimens,Acute• NK1-RA+5HT3-RA+DexamethasoneORPalonosetron0.25mgIV+Olanzapine10mgPO+Dexamethasone12OROlanzapine+NK1-RA+5H3-RA+Dexamethasone

NCCNGuidelinesforAntiemesis:RecommendationsforDelayed,Highly EmetogenicofsingledayregimenUsedD1forAcuteN/V UseforDelayedN/V

Aprepitant125+5HT3+Dex12 Aprepitant80Days2-3+Dexamethasone8Days2-4

Olanzapine10PO+Dex12PO/IV+Palonosetron0.25IV

Olanzapine10mgPOdailyondays2,3,4

Olanzapine10+5HT3+NK1+Dex Olanzapine10mgPOdailyondays2,3,4.Aprepitant80mgPOdailyondays2,3(ifAprepitantPOusedonday1)Dexamethasone8mgPO/IVdailyondays2,3,4

10/4/18

19

NCCNGuidelinesforAntiemesis :RecommendationsforAcute&Delayed, ModeratelyEmetogenic

UsedforAcuteN/VDay1 UseforDelayedN/VDays2-3

5HT3 +Dex(Palonosetron0.25mgIVoncepreferred)

• Dex8mgPO/IVDays2&3• NothingifPalonosetronwasusedin

acutesetting

NK1-RA+5HT3+Dexamethasone Aprepitant80D2-3+/- DexamethasoneD2,D3

Olanzapine+Palonosetron+Dex Olanzapine10mgPOdailyondays2,3

NCCNGuidelinesforAntiemesis:RecommendationsforpreventionofemesiswithLOW ANDMINIMAL emeticriskagents

Low EmeticRisk- Startbeforechemotherapy,Repeatdailyformultidaydosesofchemotherapy.Selectone:• Dexamethasone8–12mgPO/IVonce• Metoclopramide10–20mgPO/IVonce• 5-HT3RAMinimal EmetogenicRisk:• NoRoutineProphylaxis

10/4/18

20

ORALCHEMOTHERAPY- EMESISPREVENTION

Hightomoderateemeticrisk:• Selectoneofthe5-HT3RA• Startbeforechemotherapyandcontinuedaily.

Lowtominimalemeticrisk:PrnRecommendationonly,unlessN/Voccurs,thenselectanyagent&continuedaily

MultidayRegimens

• MultidaychemotherapyregimensarecommonandintroduceachallengeinthemanagementofCINVbecauseoftheoverlapbetweenacuteanddelayedCINV.• Afterchemotherapyadministrationconcludes,theperiodofriskfordelayedemesisalsodependsonthespecificregimenandtheemetogenicpotentialofthelastchemotherapyagentadministeredintheregimen.• Practicalissues:takeintoaccounttheadministrationsetting(eg,inpatientversusoutpatient),preferredrouteofadministration(parenteral,oral,ortransdermal),durationofactionofthe5-HT3RAandappropriateassociateddosingintervals,tolerabilityofdailyantiemetics(eg,steroids),adherence/complianceissues,andindividualriskfactor(s).• Dexamethasonedosemaybemodifiedoromittedwhenthechemotherapyregimenalreadyincludesasteroid• Ifpatientscannottoleratedexamethasone,considerreplacingwitholanzapine.

10/4/18

21

BreakthroughCINV- OccursdespiteProperprophylaxis,Measuresbymeansof“prn”medications

Thegeneralprincipleofbreakthroughtreatmentistoaddoneagentfromadifferentdrugclasstothecurrentregimen• Addanxiolytic• AddH2-blocker/PPI• AddAprepitant• Addolanzapine• Adddopamineantagonist• Changedose/scheduleofserotoninantagonist• Ifpalliative,changechemotherapy• IfcontrolledN/V,thencontinuebreakthroughmedications,onaschedule&PRN

• IfN/Vnotcontrolled:Re-evaluateandconsiderdoseadjustmentsand/orsequentiallyaddoneagentfromadifferentdrugclass

AudienceResponseQuestion#3

JDisa40-yearolddepressedwomanwhowasrecentlydiagnosedwithextensivestagesmallcelllungcancer.Sheisasocialdrinker,stoppedsmoking15yearsago.HerPMHissignificantformorningsicknesswithher2pregnanciesandmotionsickness.Heroncologistwishestousecisplatin75mg/m2IVD1,etoposide100mg/m2IVD1-3ofevery28daysfor6cycles.WhatshouldshereceiveforpreventionofacuteCINV?A- Fosaprepitant150mgIVpluspalonosetron0.25mgIVplusdexamethasone20mgPOB- Fosaprepitant150mgIVpluspalonosetron0.25mgIVplusdexamethasone12mgPOC- Fosaprepitant150mgIVplusondansetron8mgPOplusdexamethasone20mgPOD- Fosaprepitant150mgIVplusondansetron8mgPOplusdexamethasone12mgPO

10/4/18

22

AnswertoAudienceQuestion#3

CorrectanswerisB• CurrentNCCNGuidelines:3drugs(NK1antagonist,5HT3agonist&dexamethasone)forthepreventionofacuteemesisduetohighlyemetogenicchemotherapy.• Fosaprepitant150mgIVissingledoseonD1.• DuetoaninteractionbetweenAprepitant/Fosaprepitantanddexamethasone,itisrecommendedthatthedoseofdexamethasonebedecreasedfrom20mgto12mgpriortochemotherapy.• ThecorrectdoseforPOondansetronis16to24mg.Note:Olanzapineregimensmayalsobeusedforhighlyemeticchemotherapy(itwasnotlistedasoneofthechoices)

AudienceResponseQuestion#4

BasedonyouranswerforantiemeticregimenforacuteN/VonD1,whatshouldJDreceiveforpreventionofdelayednauseaandvomiting?A- Dexamethasone8mgPOQDondays2to4B- Dexamethasone8mgPOQDdays2to4plusondansetron8mgPOdays2to4C- Aprepitant80mgPOondays2and3plusdexamethasone8mgPOQDondays2to4D- Aprepitant80mgPOondays2and3plusdexamethasone8mgPOQDdays2to4plusondansetron8mgPOdays2to4

10/4/18

23

AnswertoAudienceResponseQuestion#4

• CorrectanswerisA.• SinceJDreceivedfosaprepitant150mgonday1,noadditionalAprepitantisnecessaryforthiscycle.Therefore,singledexamethasone8mgPOQDondays2to4isthecorrectanswer.• 5HT3notrecommendedingeneralforpreventionofdelayednauseaandvomitingduetohighlyemetogenicchemotherapies

Conclusion

• CINVcansignificantlyaffectpatient’squalityoflife,compliance,andprovider’sabilitytoadministerfurtherchemotherapytreatment.• Appropriateuseofantiemetics&adherencetoevidencebasedconsensusguidelinesdecreasesincidenceofCINV.• Theadventof5-HT3andNK1antagoniststhatspecificallytargetneuroreceptorsimplicatedinCINVhasdramaticallyimprovedthepreventionandacutecontrolofsymptoms.• However,delayedCINVremainsdifficulttocontrolandposesasubstantialburdenforpatients.• ProperassessmentofCINVriskanditsmanagementallowpharmaciststheopportunitiestobecomemoredirectlyinvolvedinthecareofcancerpatientsreceivingchemotherapy• Pharmacists&Pharmacytechnicianscanensurethatpatientsaregivenappropriateprescriptionsandcanfacilitatepatientsobtainingthemedications.

10/4/18

24

Questions?

References

• ReferencedwithpermissionfromtheNCCNClinicalPracticeGuidelinesinOncology(NCCNGuidelines®)forAntiemesis V.3.2018©NationalComprehensiveCancerNetwork,Inc 2018.Allrightsreserved.AccessedSeptember,2018.• Hesketh PJ,Aapro M,StreetJC,CaridesAD.Evaluationofriskfactorspredictiveofnauseaandvomitingwithcurrentstandard-of-careantiemetictreatment:analysisoftwophaseIIItrialsofaprepitant inpatientsreceivingcisplatin-basedchemotherapy.SupportiveCareinCancer2010;18:1171-7• Yanai T,Iwasa S,HashimotoH,etal.Adouble-blindrandomizedphaseIIdose-findingstudyofolanzapine10mgor5mgfortheprophylaxisofemesisinducedbyhighlyemetogeniccisplatin-basedchemotherapy.Int JClin Oncol2018;23:382-388

10/4/18

25

Refrences

• Molassiotis A,Aapro M,Dicato M,etal.JPainSymptomManage.2013Sep24

• ClinicalGate,Schematicrepresentationofpathwaysinvolvedinnauseaandvomiting• RosenR.ManagementofCINV,JournalofPharmacyPractice2002(15:1),32-41

• Navari RM,etal.Olanzapineforpreventionofchemotherapyinducednauseaandvomiting.NEngl JMed.2016;375:134-142

• Antiemetics:AmericanSocietyofClinicalOncologyClinicalPracticeGuidelineUpdate,www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki.

• PieterH.M.etal.AMulticenter,Randomized,Double-Blind,CrossoverStudyofOndansetronComparedwithHigh-DoseMetoclopramideinProphylaxisofAcute&DelayedCisplatinInducedNausea/Vomiting.AnnalsofInternalMedicineDecember1990;Volume113:834-840

• Cunningham,D.etal.PreventionofemesisinpatientsreceivingcytotoxicdrugsbyGR38032F,Aselective5-HT,ReceptorAntagonist.TheLancet,June27,1987.