administered

ChugaiPharmaceuticalCo.,Ltd.1

Revid:March2010(10thversion)n

872171

-DRUGFORTREATMENTOFUNSTABLEANGINAPECTORISANDACUTEHEARTFAILURE-

SIGMART®

Injection2mg

SIGMART®

Injection12mg

SIGMART®

Injection48mg

prescriptiondrugNote1)

StorageBrandnameSIGMARTInjection

Storeattemperatures10°Corbelow.2mg12mg48mg

ApprovalNo.20500AMZ00

348

20500AMZ00

349

20800AMZ10

235

ShelfLife

Indicatedonthelabelandthepackage

(twoyearsfromthedateof

production).

DateoflistingintheNHI

reimburmentprice

Aug1993Aug1993June1997

DateofinitialmarketinginJapanSept1993Sept1993June1997

Dateoflatestreexamination

(Unstableanginapectoris)

Aug2002Aug2002Aug2002

AdditionalindicationOct2007Oct2007Oct2007

Note1)Caution-Uonlypursuanttotheprescriptionofaphysician,etc.

CONTRAINDICATIONS(SIGMARTInjectionis

contraindicatedinthefollowingpatients.)

tswithverehepaticorrenaldysfunction.(Since

metabolicandexcretoryfunctionsareimpaired,the

bloodconcentrationofSIGMARTmaybecomehigh).

tswithverecerebraldysfunction.(SIGMART

maynegativelyaffectcerebralfunctionwhenblood

pressureisloweredexcessively.)

tswithverehypotensionorcardiogenicshock.

(SinceSIGMARTlowersbloodpressure,the

symptomsmaybeexacerbated.)

tswithEinmenger'ssyndromeorprimary

pulmonaryhypertension.(SinceSIGMARTreduces

venousreturn,itmayintensifyreducedbloodpressure

andreducedcardiacoutput.)

tswithrightventricularinfarction.(Since

SIGMARTreducesvenousreturn,itmayinduce

cardiogenicshock.)

tshavingsymptomsofdehydration.(Since

SIGMARTreducesvenousreturnandlowerscardiac

output,itmayinducecardiogenicshock.)

tswithneurocirculatoryasthenia.(Sincethis

conditioniscaudbyneurologicalfactors,theeffectsof

SIGMARTareunstable.)

tswithclodangleglaucoma.(Intraocular

pressuremayincrea.)

tswithahistoryofhypernsitivitytoSIGMART

ornitrate/nitritederivatives.

tsreceivingdrugswithPDE5(phosphodiestera

type5)-inhibitingeffect(sildenafilcitrate,vardenafil

hydrochloridehydrate,ortadalafil).(See“

Interactions.”)

DESCRIPTION

BrandnameSIGMARTInjection

2mg12mg48mg

Ingredient/

content(content

pervial)

Nicorandil

2mg,JP

Nicorandil

12mg,JP

Nicorandil

48mg,JP

Inactive

ingredient

(contentper

vial)

D-mannitol,

3mg

D-mannitol,

18mg

D-mannitol,

72mg

Sodiumcitratehydrate

DosageformColorless,transparentvial(lyophilized

injection)

Color,

description

Whitemassorpowder

pHandosmoticpressureratiofollowingreconstitution

Diluent

Isotonicsodium

chloridesolution

5%glucosolution

forinjection

Concentration

(%)

0.010.020.030.010.020.03

pH6.6±

1.0

6.8±

1.0

6.9±

1.0

6.7±

1.0

7.0±

1.0

7.1±

1.0

Osmotic

pressureratio

Note2)

ca.1ca.1

Note2)ratiotoisotonicsodiumchloridesolution

2ChugaiPharmaceuticalCo.,Ltd.

INDICATIONS

Unstableanginapectoris

Acuteheartfailure(includingacutedecompensationofchronic

heartfailure)

DOSAGEANDADMINISTRATION

Unstableanginapectoris

SIGMARTisdissolvedinisotonicsodiumchloridesolution

or5%glucoinjectiontopreparea0.01%-0.03%solution.

Theusualadultdosageforintravenousdripinfusionis2mg

agemaybeadjusted

accordingtosymptoms,whilenotexceeding6mgperhour.

Acuteheartfailure(includingacutedecompensationof

chronicheartfailure)

SIGMARTisdissolvedinisotonicsodiumchloridesolution

or5%glucoinjectiontopreparea0.04%-0.25%solution.

Theusualadultdosageis0.2mg/kgofnicorandiltobegiven

byintravenousadministrationoverabout5minutes,followed

by0.2mg/kg/hrofnicorandiltobegivenbycontinuous

agemaybeadjustedinthe

rangeof0.05-0.2mg/kg/hraccordingtochangesinblood

pressureandsymptoms.

PRECAUTIONS

lAdministration(SIGMARTInjectionshouldbe

administeredwithcareinthefollowingpatients.)

(1)Elderly(e4,"UintheElderly".)

(2)Patientswithhypotension(SinceSIGMARTlowers

bloodpressure,thissymptommaybeexacerbated.)

(3)Patientswithhepaticorrenaldysfunction(Since

metabolicandexcretoryfunctionsareimpaired,the

bloodconcentrationofSIGMARTmaybecomehigh).

(4)Patientswithleftventricularoutflowstenosis,

hypertrophicobstructivecardiomyopathy,oraortic

stenosisduetoacuteheartfailure(Differencein

pressuremaybeincreadandleadtoaggravationof

symptoms.)

antPrecautions

(1)WhileSIGMARTisbeingadministered,bloodpressure

andhemodynamicsshouldbemonitoredfrequently.

Dosageshouldbeadjustedgraduallyaccordingto

patient'shemodynamicsandsymptoms.

(2)Whenabnormalitiessuchashypotensionareobrved

whileSIGMARTisbeingadministeredorwhen

patientsmaysufferfromhypotension,dosageshouldbe

ssary,

appropriatemeasuressuchalevationoflower

extremitiesoradministrationofvasopressors

(catecholaminepreparations)shouldbetaken.

(3)Sincecoadministrationwithdrugswith

PDE5-inhibitingeffect(sildenafilcitrate,vardenafil

hydrochloridehydrate,ortadalafil)mayenhancethe

hypotensiveeffectofSIGMARTandexcessively

decreabloodpressure,confirmationshouldbemade

beforeadministeringSIGMARTthatthedrugsare

er,thepatientshouldbe

cautionedagainstusingthedrugsduringorafter

takingSIGMART.

(4)Whenudinpatientswithacuteheartfailure,

SIGMARTshouldbeadministeredwithsufficient

managementofthepatient’sgeneralcondition

includingbloodpressure,heartrate,urinaryoutput,

bodyfluidsandelectrolytes,aswellaspulmonary

arterialwedgepressure,cardiacoutputandbloodgas

ifpossible.

(5)Whenudinpatientswithacuteheartfailure,

SIGMARTmaycauariousdecreainblood

ore,bloodpressureshouldbe

frequentlymeasuredduringtreatmentwithSIGMART.

Ifanyabnormalityisobrved,treatmentshouldbe

discontinuedandappropriatemeasurestaken.

(6)Ifexpectedimprovementisnotachievedfollowing

treatmentwithSIGMARTinpatientswithacuteheart

failure,appropriatemeasuressuchaschangeof

treatmenttoanothershouldbetaken.

(7)Inpatientswithacuteheartfailure,ifhemodynamics

andclinicalsymptomsimproveandthepatient’s

conditionbecomesstabilized(recoverfromtheacute

stage)followingtreatmentwithSIGMART,treatment

Thasrarely

beenudformorethan48hoursinpatientswithacute

ore,ifitisnecessarytou

SIGMARTformorethan48hours,thedrugshouldbe

administeredwithsufficientmanagementofthe

patient’sbloodcirculationandgeneralcondition.

teractions

Contraindicationsforcoadministration(SIGMART

shouldnotbecoadministeredwiththefollowingdrugs).

DrugsSigns,Symptoms,

and

Treatment

MechanismandRisk

Factors

Drugswith

PDE5-inhibit

ingeffect

Sildenafil

citrate

(VIAGRA)

Vardenafil

hydrochloride

hydrate

(LEVITRA)

tadalafil

(CIALIS)

Coadministration

mayenhance

hypotensiveeffect

WhileSIGMART

promotescGMP

production,drugswith

PDE5-inhibitingeffect

decreacGMP

degradation,andtherefore,

thehypotensiveeffectof

SIGMART,which

mediatestheincreain

cGMP,maybeenhanced

bycoadministrationwith

thedrugs..

ChugaiPharmaceuticalCo.,Ltd.3

eReactions

Unstableanginapectoris

Thefollowingadverreactionstothisdrugwerereportedin

227patients(6.64%)and301eventsof3,420patients

oradverreactionswere

headache(53events,1.55%),hepaticfunctiondisorder(37

events,1.08%),increadALT(GPT)(29events,0.85%),

decreadbloodpressure(24events,0.70%),increadAST

(GOT)(19events,0.56%),increadAl-P(15events,

0.44%),thrombocytopenia(15events,0.44%),incread

totalbilirubin(13events,0.38%),increadLDH(9events,

0.26%),anemia(9events,0.26%),andincreadγ-GTP(8

events,0.23%)(attheendofthereexaminationperiod).

Acuteheartfailure(includingacutedecompensationof

chronicheartfailure)

Thefollowingadverreactionstothisdrugwerereportedin

50of193patients(25.9%,79events),whowerethesubjects

nadverreactionswerethrom-

bocytopenia(11events,5.7%),headache(10events,5.2%),

decreadbloodpressure(7events,3.6%),increadtotal

bilirubin(7events,3.6%),decreadrumtotalprotein(5

events,2.6%),increadAST(GOT)(3events,1.6%),

increadALT(GPT)(3events,1.6%),increadblood

creatinine(3events,1.6%),leucocytosis(3events,1.6%),

urinaryproteinpositive(3events,1.6%),increadLDH(2

events,1.0%),increadCK(CPK)(2events,1.0%),

ventriculartachycardia(2events,1.0%),increadblood

potassium(2events,1.0%)anddecreadHDLcholesterol

(2events,1.0%)(atthetimeofapproval).

(1)ClinicallySignificantAdverReactions

1)Hepaticdysfunctionandjaundice(incidenceunknown):

cdysfunction,within-

creadAST(GOT),ALT(GPT)andγ-GTPmayoccur.

Patientsshouldbecarefullymonitored,andadministra-

tionofthedrugshouldbediscontinuedandappropriate

therapeuticmeasurestaken,ifsuch

abnormalitiesareobrved.

2)Thrombocytopenia(incidenceunknown):Thrombocy-

bnormalitiesareobrved,

thedrugshouldbediscontinuedimmediatelyandap-

propriatetherapeuticmeasuresmustbetaken.

(2)Otheradverreactions

Ifanyofthefollowingadverreactionsareobrved,

appropriatemeasuressuchasdosagereductionor

temporarydiscontinuationshouldbetaken.

5%>≥1%<1%

CardiovascularHypotensionNote3),

increadheartrate,

ventricular

tachycardia,etc.

Psychoneuro-

logic

HeadacheLight-headedness,

numbnessoflimbs,

etc.

Gastrointestin-

al

Naua,vomiting,

upperabdominal

discomfort,etc.

HepaticIncreadAST

(GOT),incread

ALT(GPT),incread

totalbilirubin,

increadγ-GTP,

increadAl-P,

increadLDH,etc.

HematologicAnemia,thrombocy-

topenia,leucocytosis,

etc.

Hypernsiti-

VityNote4)

Rash

Renal

Increadblood

creatinine,urinary

proteinpositive,etc.

OthersDecreadrumtotal

protein,increadCK

(CPK),incread

bloodpotassium,

decreadHDL

cholesterol,etc.

Note3)SeeSection2,"ImportantPrecautions".

Note4)

Intheeventofsuchsymptom,administrationshould

bediscontinued.

heElderly

Sincetheelderlyoftenhavereducedphysiologicalfunction

andaremorelikelytoexperienceadverreactions,

SIGMARTshouldbeadministeredwhileclolyand

frequentlymonitoringbloodpressureandhemodynamics.

Thedosageshouldbecarefullyandgraduallyadjustedin

viewofthepatient’shemodynamicsandsymptoms.(See

"ImportantPrecautions".)

Inparticular,cautionshouldbetakenfordecreainblood

pressure,whichisapttooccurinelderlypatientswithacute

heartfailure.

ingPregnancy,DeliveryorLactation

SincethesafetyofSIGMARTinpregnantwomenhasnot

beenestablished,uofSIGMARTinpregnantwomenor

womenwhomaypossiblybepregnantisnotrecommended.

ricU

ThesafetyofSIGMARTinchildrenhasnotbeen

established(noclinicalexperience).

tionsconcerningU

Preparationmethod

SIGMARTshouldbedissolvedinphysiologicalsalineor

5%glucosolutionforinjectionandudwithin24hours

ofpreparation.

PHARMACOKINETICS

oncentration

(1)Singleadministration

1)

Tofivehealthyvolunteers,2mgofSIGMARTInjection

wasadministeredonceoveratwominuteperiod

Note5).

Theresultswereasfollows:

Cokel(hr-1)t

1/2

Cl

total

AUCVd(L)

4ChugaiPharmaceuticalCo.,Ltd.

(ng/mL)(hr)(L/hr)(ng⋅hr/

mL)

Average103.86.500.109126.016.2319.6

Co:Plasmaconcentrationofnicorandilimmediatelyafter

administration

Note5)Thisisdifferentfromtheapproveddosageand

administrationofSIGMART.(See"DOSAGEAND

ADMINISTRATION”.)

(2)Continuousadministration

2),3)

Tofivehealthyvolunteers,SIGMARTInjectionwas

intravenouslyadministeredforsixhourscontinuously

Note6).Theresultswereasfollows:

Rateof

admin-

istration

(mg/hr)

C

6h

(ng/mL)

t

1/2

Cl

total

(L/hr)

AUC

(ng⋅hr/

mL)

Cl

renal

(L/hr)α

pha

β

pha

2310.141.56621940.113

4840.171.98445590.131

61520.141.32399580.111

C

6h

:Plasmaconcentrationofnicorandilimmediatelyafterthe

completionofcontinuousintravenousadministration

(3)Long-termadministration(inpatientswithacuteheart

failure)4)

SIGMARTInjectionwasintravenouslyadministeredto

14patientswithacuteheartfailureatadoof0.2mg/kg

for5minutes,andthenatarateof0.2mg/kg/hrfor48

ecourofplasmanicorandil

concentrationisshownbelow.

Timeafterthestartofadministration(hr)

Timecourofplasmanicorandilconcentrationinpatients

withacuteheartfailure(mean±SE)

lismandexcretion

3),5)

ThemetabolismandexcretionofSIGMARTwere

investigatedbyintravenouslyadministering2,4or6mg/hr

ofSIGMARTInjection(asnicorandil)tofivehealthymen

Note6)and6mg/hrofnicorandillabelledwithdeuteriumto

fourhealthymenforsixhours,

nicorandilwassubjectedtoadenitrationreactionand

metabolizedtoN-(2-hydroxyethyl)

metabolite,N-(2-hydroxyethyl)nicotinamide,was

detectableintheplasma0.25-0.5hoursafterthestartof

continuousintravenousadministration,andreacheda

ulative

urinaryexcretionofnicorandilandthemetabolite

[N-(2-hydroxyethyl)nicotinamide]24hoursafter

administrationwas0.2%to0.4%and2%to5%,

respectively.

Note6)Thisisdifferentfromtheapproveddosageand

administrationofSIGMARTforacuteheartfailure

(includingacutedecompensationofchronicheart

failure).(See"DOSAGEAND

ADMINISTRATION".)

roteinbindingrate6)

Inaninvitrotestusinghumanrum,therumprotein

bindingraterangedfrom34.2%to41.5%(nicorandil

concentration:1-100µg/mL)

CLINICALSTUDIES

fulnessofSIGMARTInjectionwasconfirmedbya

double-blindcomparativestudyonpatientswithunstable

anginapectoris

7)

.

icalstudiesincludingdouble-blindstudyonpatients

withunstableanginapectoris,overallimprovementrates

rangedfrom68.4%to75.0%7,8)inatotalof134asssable

patients.

icalstudiesincludingadouble-blindstudyofpatients

withacuteheartfailure(includingacutedecompensationof

chronicheartfailure,withapulmonaryarterialwedge

pressureof18mmHgormore),SIGMARTInjectionwas

intravenouslyadministeredto54patientsatadoof0.2

mg/kgfor5minutes,andthenatarateof0.2mg/kg/hr

ult,theirpulmonaryarterialwedge

pressuredecreadby21.2%9-11).

PHARMACOLOGY

cologicalaction

(1)Coronaryvasodilatingactivity

1)InacanineLangendorffpreparation,nicorandil

dilatedrelativelysmallcoronaryarteriesunder

normal-pressureperfusion,whereasunder

low-pressureperfusionduringischemia,itdilated

esthetizeddogs,

intravenousadministrationofnicorandildilatedlarge

coronaryarteriesinado-dependentmanner

irrespectiveofcoronarybloodflow12,13).

2)WhenSIGMARTInjection(2mgto6mgor

0.05-0.1mg/kgofnicorandil)wasadministered

intravenouslyoncetopatientswithcoronaryartery

diaNote7),coronaryangiographyshowed

0

200

400

600

800

1000

1200

1400

1600

012243648

Timeafterthestartofadministration(hr)

Timecourofplasmanicorandilconcentration(mean±SE)

stration

Pl

a

s

m

a

c

o

n

c

e

n

t

r

a

t

i

o

n

(

n

g

/

m

L

)

Pl

a

s

m

a

c

o

n

c

e

n

t

r

a

t

i

o

n

(

n

g

/

m

L

)

ChugaiPharmaceuticalCo.,Ltd.5

significantcoronaryvasodilationinado-dependent

eofdilation(inrelationtothe

internaldiameterofnon-stenoticvesls)rangedfrom

108%to127%

14-16)

.

(2)Effectsoncoronarybloodflow

1)Nicorandilproducedado-dependent,sustained

increaincoronarybloodflowfollowingintravenous

orintraduodenaladministrationinopen-chested

eresponswereshown

inconsciousdogs,isolatedcanineheart-lung

preparations,andcanineLangendorff's

preparations

13,17-20)

.

2)SIGMARTInjection(0.1mg/kgofnicorandil)was

administeredintravenouslyonceNote7)topatientswith

anginapectorishavingnosignificantstenosisoran

organicstenosisof75%orgreaterintheleftcoronary

arteryandtopeoplewithnosignificantstenosis.

Thegreatcardiacveinflowwasthenmeasuredthree

tofiveminutesafteradministration(continuous

thermaldilutionmethod).Inthenon-stenosisgroup

(n=5),theaveragevolumeincreadfrom115to187

mL/min.,andinthestenosisgroup(n=4),itincread

from38to69mL/min.,thusconfirmingsignificant

increasincoronarybloodflow

16)

.

(3)Coronaryvasospasmolyticactivity

1)Indogswithpartiallyconstrictedcoronaryarteries,

nicorandilinhibitedcyclicalreductionsofcoronary

ry

vasoconstrictioninducedbytheintracoronary

injectionofmethacholineornorepinephrinein

miniaturepigswasalsosuppresdbynicorandil

21,22)

.

2)In10patientswithcoronaryspasticanginapectoris,

0.1mg/kgofnicorandilwasadministered

intravenouslytotreatcoronaryspasmsinducedby

ergonovineloadtestornaturallyoccuringcoronary

spasmsNote7).Theresultsshowedthatnicorandil

attenuatedcoronaryspasms23).

(4)Effectsoncardio-hemodynamics

1)Nicorandilslightlydecreadsystemicbloodpressure

do-dependentlywheninjectedintravenouslyin

werenoappreciableeffectsonheartrate,myocardial

contractility,myocardialoxygenconsumptionand

atrioventricularconductiontimeatdoscausinga

significantdecreaincoronaryvascularresistance

17,

18,24)

.

2)WhenSIGMARTInjection(2to6mgor

0.05-0.1mg/kgofnicorandil)wasadministered

intravenouslyoncetopatientswithcoronaryangina

pectorisatrestNote7),heartrateincread,andBP

dynamicsindex(e.g.,systolicaorticpressure),

systemicvascularresistance,andpressure-rate

productdecreadinado-dependentmanner.

However,therangeofthefluctuationswereslight

tomild

14-16)

.Whilerightintraventricularpacingwas

utilized,SIGMARTInjection(0.05mg/kgof

nicorandil)wasadministeredintravenouslyonceNote

7)toeightpatientswithanginapectoriswith75%or

sofleftventricularfunction,

nicorandilsuppresdincreasintheleftventricular

end-diastolicpressureandincreadthecardiac

index

25)

.

Note7)Thisisdifferentfromtheapproveddosage

andadministrationofSIGMART.(See

"DOSAGEANDADMINISTRATION”.)

(5)Effectsonheartfailure

1)Inacaninemodelofacuteheartfailure,treatmentwith

nicorandildecreadrightatrialpressureandleft

ventricularpressureinthelatediastolicpha(a

decreainthepreload),withaconcurrentdecreain

thetotalperipheralvascularresistance(adecreain

theafterload).Conquently,byimprovingtheleft

ventricularcontractilityandincreasingthecardiac

output,thetreatmentimprovedthehemodynamicsin

heartfailure26).

2)Patientswithacuteheartfailure(includingacute

decompensationofchronicheartfailure)received

intravenousadministrationofSIGMARTatadoof

0.2mg/kg/5minfollowedbya2-hourcontinuous

intravenousinfusionatarateof0.2mg/kg/

result,asignificantdecreawasfoundinthe

pulmonaryarterialwedgepressure,diastolicpressure,

systolicpulmonaryarterialpressure,diastolic

pulmonaryarterialpressure,andtotalperipheral

vascularresistance,whileasignificantincreawas

eninthecardiacindex,cardiacoutput,outputper

stroke,ificant

changewasfoundintheheartrate,systolicblood

pressure,meanrightatrialpressure,orpressure-rate

Product11).

3)Inpatientswithcongestiveheartfailurewhoreceived

along-termcontinuousintravenousinfusionof

SIGMART,adecreainthepulmonaryarterial

wedgepressurewasmaintained,whichsuggestedthat

drugresistancewouldhardlyoccur27).

latingeffectanditsmechanism

Thevasohypotoniceffectofnicorandilonextractedblood

veslsissuppresdbyATP-nsitiveKchannelinhibitors

orguanylatecyclainhibitors28).Moreover,inacanine

modelofacuteheartfailure,thecardiac

hemodynamics-improvingeffectofthedrug(of

increasingtheaorticbloodflow)wassuppresdby

ATP-nsitiveKchannelinhibitors29).Furthermore,thedrug

caudanincreainthecGMPcontentinextractedblood

vesls30).Thefactssuggestthatthevasodilatingeffectof

thedrugisrelatedtotheeffectofopeningtheATP-nsitive

Kchannel,aswellastotheeffectofincreasingproduction

ofcGMP.

PHYSICOCHEMISTRY

Nonproprietaryname:

Nicorandil(JAN)

Chemicalname:

N-[2-(Nitrooxy)ethyl]pyridine-3-carboxamide

Structuralformula:

6ChugaiPharmaceuticalCo.,Ltd.

Molecularformula:

C

8

H

9

N

3

O

4

Molecularweight:

211.17

Description:

Nicorandiloccursaswhitecrystals.

Itisfreelysolubleinmethanol,ethanol(99.5),aceticacid

(100);solubleinaceticanhydride;sparinglysolublein

water.

Meltingpoint:

About92°C(tobedecompod)

PACKAGING

2mgInjection

Boxesof10vials.

12mgInjection

Boxesof10vials.

48mgInjection

Boxesof10vials.

REFERENCES

1).:YakuriToChiryo(col.&

Ther.),15(11),4779,1987

2).:YakuriToChiryo(col.&

Ther.),18(9),3479,1990

3)Internaldocument:.:Pharmacokinetics

followingintravenouscontinuousadministrationof

nicorandilinhealthyadults(1990)

4)Internaldocument:PhaIIIstudyinpatientswithacute

heartfailure(long-termadministration)

5)Internaldocument:.:Investigationon

urinarymetabolitesfollowingcontinuousintravenous

administrationofnicorandilinhealthyadults(1990)

6)Internaldocument:.:invivoandinvitro

rumproteinbingingofnicorandil(1991)

7).:RinshoIyaku(icalTher.&

Medicines),7(9),2031,1991

8).:RinshoToKenkyu(icaland

ne),68(11),3480,1991

9)Internaldocument:EarlyphaIIstudyinpatientswith

acuteheartfailure(single+continuousadministration)

10)Internaldocument:LatephaIIstudyinpatientswith

acuteheartfailure

11)Internaldocument:PhaIIIstudyinpatientswith

acuteheartfailure(placebo-controlled)

12).:Arzneim.-Forsch.(DrugRes.),37

(11),1252,1987

13).:.,20(6),881,1979

14).:Myakkangaku(Vesls),31(4),333,

1991

15).:TherapeuticRearch,10(4),1615,

1989

16).:TherapeuticRearch,10(4),1307,

1989

17).:.,19(1),112,1978

18).:Shinzo(Heart),12(4),371,1980

19).:Arzneim-Forsch.(DrugRes.),31

(2),1244,1981

20).:OyoYakuri(Pharmacotrics),15

(3),385,1978

21).:.,19(6),904,1978

22).:.,227(1),220,

1983

23).:TherapeuticRearch,11(5),

1448,1990

24).:col.,3(1),139,

1981

25).:l.,63,56J,1989

26)Kamijo,.:col.,33:93

(1999)

27)Larn,.:.,134:435(1997)

28)Internaldocument:.:

Pharmacologicalstudyusingextractedbloodveslsof

rats(2001)

29)Kamijo,.:col.,11:141

(1996)

30)Internaldocument:.:Influenceon

cAMPandcGMPinaortasofrats(2000)

REQUESTFORLITERATURESHOULDBE

MADETO:

Requestsforanyoftheinternaldocumentslistedinthe

“REFERENCES”ctioncanalsobemadetothefollowing:

DrugInformationCenter

ChugaiPharmaceuticalCo.,Ltd.

1-1Nihonbashi-Muromachi2-chome,Chuo-ku,Tokyo

103-8324,Japan

TEL:0120-189706

FAX:0120-189705

ManufacturedandDistributedby:

ChugaiPharmaceuticalCo.,Ltd.,RocheGroup.

1-1Nihonbashi-Muromachi2-chome,Chuo-ku,Tokyo

103-8324,Japan

BRANDNAMESINOTHERCOUNTRIES

SigmartInjection(Korea)