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Trimetazidine: The Heart Drug You've Never Heard Of

By Carl DeMarco Peer evie!ed "y #te$hen B% #trum& MD

Trimetazidine: The Heart Drug You've Never Heard Of

Over ( million )merican* are a+icted !ith *ome form of cardiova*cular

di*ea*e%, -t remain* the num"er one cau*e of death in the .#%,

/iven thi* 0iller1* $revalence& you !ould thin0 that medical o2cialdom !ould

en*ure maturing individual* have acce** to all availa"le treatment o$tion*%

You !ould "e !rong%

De*$ite over 34 year* of $u"li*hed *tudie*&( a little50no!n& $otentially

life*aving heart drug langui*he* in clinical and regulatory lim"o in thi*

country& a drug that 6ife 78ten*ion9 e*$ou*e* a* a com$elling target for

further re*earch and $otential D) a$$roval%

)vaila"le in more than 4 nation* around the !orld& it i* unli0e any other

conventional $re*cri$tion medication for heart di*ea*e on the )merican

mar0et today%

Thi* drug i* called a* trimetazidine ;TMa*tarel M in 7uro$e& it modulate* mitochondrial

meta"oli*m to energize and revive com$romi*ed heart ti**ue% ) mountain of

*cienti?c re*earch *ho!* it ha* the ca$a"ility to $rotect vulnera"le& o8ygen5

de$rived heart mu*cle "efore a lethal cardiac event ta0e* $lace%

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-n thi* article you !ill di*cover com$elling evidence of trimetazidine1*

cardio$rotective $o!er% You !ill learn of it* ca$acity to rever*e the deadly

im$act of dimini*hed "lood @o! to the heart& the $rinci$al va*cular $athology

"ehind mo*t heart attac0*%

Concern* a"out the lac0 of long5term data on hard end$oint* li0e heart attac0

and cardiac mortality ma0e the regulatory $ath to a$$roval a di2cult one for

thi* novel drug% The arduou* a$$roval $ath for a ne! ty$e of drug to hel$

treat i*chemic heart di*ea*e i* an e8am$le of the need to cut "urden*ome

"ureaucratic mandate* and *timulate the evaluation of "etter medication* for

heart di*ea*e%

To under*tand ho! TM< aAord* additional $rotection for at5ri*0 heart mu*cle&

!e "egin "y outlining the *igni?cant limitation* and danger* of conventional

heart drug*%

Many Medication* But Only One Mode of )ction

Cardiac i*chemia i* the medical condition in !hich "lood @o! and therefore

o8ygen delivery to heart ti**ue i* $rogre**ively limited& ty$ically "y arterial

"loc0age thi* i* the origin of mo*t heart attac0*% )ngina i* it* $rimary

*ym$tomche*t $ain often accom$anied "y a *en*ation of uncomforta"le

$re**ure% )ngina i* the heart mu*cle crying out for more o8ygen in order to$erform it* "lood $um$ing function%

-t may *ur$ri*e you to learn that !hile conventional drug* for cardiac

i*chemia and angina o$erate via diAerent mechani*m* of action& they induce

only one $hy*iological eAect: they lo!er heart mu*cle demand for o8ygen "y

im$roving "lood @o! and reducing cardiac !or0load%

Thi* a$$roach may not "e eAective for all individual* !ith heart di*ea*e% The

$ro"lemE The*e drug* do not re*tore heart ti**ue already damaged or

dy*functional "ac0 to $ea0 e2ciency% The $o!erhou*e* 0no!n a*

mitochondria in com$romi*ed heart mu*cle cell* remain una"le to o$timally

convert fuel into energy for ma8imum out$ut%3

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Thi* may account for a chilling *tati*tic: F of $atient* on conventional

medication* continue to *uAer chronic angina and remain at ri*0 of further

cardiac com$lication*%

Ghile enlightened individual* may *u$$ort heart cell mitochondrial function

u*ing Co,4 ;u"iIuionol=&J 65carnitine&K taurine&L magne*ium& P

;$yrroloIuinoline Iuinone= and other nutrient*&,4&,, mo*t $atient* are not

told a"out them "y their cardiologi*t and o$timal do*ing *eldom occur*%

urthermore& the drug TM< function* via uniIue cyto$rotective mechani*m*

to *u$$ort left ventricular function through enhancing coronary "lood @o!% By

*hifting energy *u"*trate utilization to gluco*e through inhi"ition of fatty acid

meta"oli*m& TM< oAer* the $otential to enhance cardiac mu*cle cell )TP

level* through $ath!ay* that may not "e attaina"le !ith nutrient* alone%

Conventional Drug* .*ed in Treating )ngina and -*chemic Heart Di*ea*e&,(

Drug Cla** 78am$le* Mechani*m of )ction i*0* and #ide 7Aect*

)nti$latelet )gent* )*$irin& clo$idogrel Clot $revention "y

reduction of "lood $latelet adhe*ion to ve**el !all* /a*trointe*tinal "leeding

Beta Bloc0er* Meto$rolol& atenolol educe cardiac !or0load "y

reduction in heart rate& "lood $re**ure& contractility ;*Iueeze= 6o! "lood

$re**ure& dizzine**& !heezing may increa*e dia"ete* ri*0&, erectile

dy*function

)ngioten*in5Converting 7nzyme ;)C7= -nhi"itor* Ca$to$ril& enala$rileduce cardiac !or0load "y limiting activity of 0ey enzyme in

maintaining "lood $re**ure 6o! "lood $re**ure& 0idney im$airment

Calcium Channel Bloc0er* Nifedi$ine& amlodi$ine educe cardiac

!or0load "y reducing contractility ;*Iueeze= #lo! heart rate& ra$id

heart rate& dizzine**

Nitrate* Nitroglycerin -ncrea*e cardiac "lood @o! "y dilating

coronary arterie* 6o! "lood $re**ure& dizzine**& fainting

Heart Protection Through a .niIue and Po!erful Mechani*m

By contra*t to e8i*ting cardiac drug*& TM< render* heart mu*cle o$timally

functional "y enhancing energy out$ut& a* o$$o*ed to reducing !or0load%,3

Thi* fundamentally di*tinct mode of action oAer* aging individual* a

com$lementary and $otentially more eAective !ay to !ard oA heart attac0

"y enhancing the heart1* energy $roducing function rather than !ea0ening

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the heart%

Thi* outcome i* achieved via a novel mechani*m of action: the meta"olic

$ath!ay "y !hich the heart convert* fuel into energy i* favora"ly altered%

Here1* ho! it !or0*:

The mitochondria !ithin your heart cell* utilize fatty acid* to generate the

"ul0 of the energy that fuel* heart function in the $re*ence of di*ea*e& the

u*e of fatty acid* increa*e*%,J TM< ena"le* the mitochondria to utilize more

gluco*e a* a fuel *ource%,K5,

Thi* *hift in heart cell meta"oli*m aAord* "ene?t*%

To "urn fatty acid*& mitochondria reIuire much more o8ygen and $roduce

more !a*te $roduct* than they do !hen gluco*e i* the energy

*ource%,K&,&(4 .nder normal condition* that $o*e* no $ro"lem& "ut

i*chemic heart ti**ue ra$idly lo*e* e2ciency and accumulate* acid a* it

continue* to try to $o!er it*elf from fat%(,

By converting the $referred fuel *ource to gluco*e& fe!er damaging acid* are

$roduced%,K&(4&(( #tudie* *ho! that in the $re*ence of TM

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Of eIual im$ortance& TM< induce* the*e "ene?cial eAect* !ith no negative

im$act on *o5called hemodynamic*& the delicate "alance of heart rate&

"lood $re**ure& and heart mu*cle contractility that ultimately determine*

"lood @o!%,K&K Thi* i* in mar0ed contra*t to virtually all conventional drug*

for angina and i*chemia& !hich may $roduce $otentially *eriou*

hemodynamic im"alance*%

-n addition to the*e life*aving eAect*& TM< increa*e* $la*ma level* of the

heart5$rotecting com$ound adeno*ine in $atient* !ith angina% )deno*ine i*

e**ential for cellular energy tran*fer% The re*ult i* called $reconditioning:

heart mu*cle develo$* a tolerance for limited "lood @o! in*tead of dying

from it%,K&L

TM< al*o $o*itively in@uence* gene e8$re**ion& increa*ing $roduction of

*everal *ignaling molecule* involved in regulation of heart mu*cle

contractility%,K& Other *ignaling molecule* involved in endothelial function

are al*o favora"ly in@uenced "y TM

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infarction* !ithout the !arning of angina%

7ven $eo$le !ho *urvive heart attac0* have $ermanently !ea0ened heart

mu*cle% Thi* can lead to a"normal heart"eat* ;arrhythmia*= and the chronic

ina"ility of the heart to $um$ enough "lood ;heart failure=%

#ucce** in Clinical #tudie* )cro** Multi$le Heart Health -ndicator*

TM< "oa*t* an im$re**ive trac0 record in the acute management of "oth

i*chemic heart di*ea*e ;the event* leading u$ to a heart attac0= and

conge*tive heart failure ;a maor con*eIuence of a heart attac0=%&3,

One of the earlie*t *ign* of i*chemic heart di*ea*e i* a change in

electrocardiogram reading* conducted during mild e8erci*e% One *uch

mea*ure& 0no!n a* #T5*egment de$re**ion& indicate* heart mu*cle lac0ing

an adeIuate *u$$ly of o8ygen to meet the demand of increa*ed cardiac

!or0load ;i*chemia=% #everal dou"le5"lind& $lace"o5controlled 7uro$ean

*tudie* *ho!ed that the addition of TM< to a *tandard drug *uch a* a "eta

"loc0er could $rolong the time that $atient* could e8erci*e "efore #T5

*egment de$re**ion a$$eared%3(533

7ection raction

.nli0e #T5*egment de$re**ion!hich i* a*ym$tomatic and goe* unnoticed in

aging individual* !ith heart di*ea*ethe ?r*t noticea"le *ign of i*chemia i*

che*t $ain or angina& !hich occur* !hen the heart mu*cle i* under *tre** due

to $hy*ical e8ertion& *trong emotion* or other factor*% Multi$le *tudie* reveal

that $atient* treated !ith TM< e8$erience fe!er e$i*ode* of angina and a

longer interval "efore angina on*et in e8erci*e te*t* com$ared to $atient*

given $lace"o or other anti5angina drug*%3(&3J -n one $articularly im$re**ive

*tudy& J4 $atient* !ith *ta"le angina !ere treated !ith the calcium "loc0er

diltiazem !ith or !ithout the addition of TM

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$eri$heral artery di*ea*e ;claudication=%33&3K53

)nother mea*ure of the *everity of angina i* the need for $atient* to u*e

medication* *uch a* nitrate* to relieve *ym$tom*% Patient* ta0ing TM< are

often a"le to *igni?cantly reduce their nitrate inta0e%3 Ghen !e reduce the

num"er of drug* a $atient u*e* !e al*o decrea*e the chance of adver*e *ide

eAect* a* !ell a* healthcare co*t*%

-*chemic cardiomyo$athy i* the term for im$aired heart mu*cle ti**ue !ith a

reduced ca$acity to $um$ "lood eAectively% Through it* "ene?cial *hift* in

cardiac meta"oli*m& TM< increa*e* the amount of "lood $um$ed "y heart* of

$atient* !ith *evere i*chemic cardiomyo$athy& at the *ame time reducing the

dy*functional dilation of the heart1* $um$ing cham"er* ;ventricle*=%34&3L&J4

)fter a heart attac0 and the accom$anying lo** of heart mu*cle& there i* a

*har$ decrea*e in "lood $um$ing a"ility that often $er*i*t* after *ucce**ful

intervention% Ghen TM< i* added to the drug regimen of $atient* undergoing

common intervention* *uch a* cardiac catheterization and coronary artery

"y$a** grafting& *tudie* *ho! im$rovement* in left ventricular function%J,5J

;#ee gra$h "elo!%= 6eft ventricular function i* in e**ence a mea*urement of

the heart1* hor*e $o!er i%e%& it* a"ility to ?re on all cyclinder*% TM< al*o

reduce* the freIuency of angina attac0* during cardiac catheterization

$rocedure* and lo!er* mar0er* of heart mu*cle damage during *urgery%J(&J3

/lco*ylated hemoglo"in ;Hemoglo"in ),C=

Heart failure often follo!* a heart attac0& though it may develo$ a* the re*ult

of chronic i*chemia !ithout an actual myocardial infarction% Heart failure

occur* !hen the heart mu*cle i* una"le to meet the "ody1* meta"olic

demand for "lood @o!% -t* *ym$tom* include lo** of e8erci*e tolerance&

di2culty "reathing& and @uid "uildu$% The failing heart1* $um$ing cham"er*

are enlarged and e8hi"it $oor mu*cle contractility%

#tudie* *ho! that TM< can im$rove the*e and other $arameter* of heart

failure% Patient* treated !ith TM< e8hi"it enhanced left ventricular function

a**ociated !ith an increa*e in their heart mu*cle1* energy content%,3

Patient* !ith coronary artery di*ea*e !ho are given TM< al*o e8$erience

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the*e $atient* recovered normal function after going oA TM

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Over the $a*t fe! year*& ho!ever& concern* have "een rai*ed a"out one

$articular 0ind of drug reaction that1* common "oth to trimetazidine and to a

ho*t of other drug* !ith *imilar chemical *tructure*% The molecular core of all

of the*e drug* ;!hich include many $o$ular anti5*eizure& anti5hy$erten*ion&and antide$re**ant agent*= can interact !ith "rain rece$tor* for the

neurotran*mitter do$amine%K,&K(

That interaction can cau*e *o5called e8tra$yramidal *ym$tom*& many of

!hich are remar0a"ly *imilar to tho*e *een in Par0in*on1* di*ea*e: *lo! or

*tiA movement*& *$eech di*tur"ance*& and a cla**ical hand tremor at re*t%

/ait di*tur"ance* and lo** of eIuili"rium are al*o $o**i"le%K

#uch reaction* are more than inconvenient in older $eo$le e*$ecially& they

can increa*e the ri*0* of fall* and therefore of fracture*%K3

The $reci*e incidence of the*e reaction* i* a* yet unclear& though it a$$ear*

to "e lo! and com$ara"le to other drug* that can cau*e tho*e *ym$tom*%K,

T!o *tudie* *hed *ome light on the *u"ect& "oth involving $atient* !ho came

to a neurology clinic for their *ym$tom*%

The ?r*t *tudy& $u"li*hed in (44J& !a* conducted to "etter Iuanitfy the ri*0

of drug5induced movement di*order* related to trimetazidine%KJ The

re*earcher* trac0ed the incidence of trimetazidine u*e and movement

$ro"lem* li0e drug5induced Par0in*on1* and tremor* in ,4&(J $atient*

treated at a neurology clinic in 7uro$e% Of the*e ,4&(J $atient*& ,4 !ere

treated !ith trimetazidine& and JK of the*e $atient* ;3F= e8$erienced an

adver*e eAect on motor function% Drug5induced Par0in*oni*m !a* o"*erved

in ,4 $atient* ;L%KF= treated !ith trimetazidine only& !ith an additional ,4

$atient* ;L%KF= *imultaneou*ly receiving other drug* $otentially ca$a"le of

inducing movement di*order*% Treatment !ith trimetazidine !or*ened$reviou*ly diagno*ed Par0in*on1* di*ea*e in ,( $atient*& and trimetazidine

induced tremor* in $atient*% ) (4,, *tudy& al*o of $atient* coming to a

neurology clinic& re$ort* on a *erie* of (, ca*e* of e8tra$yramidal *ym$tom*

in $eo$le ta0ing trimetazidine& all "ut one of !hom had "een ta0ing the drug

for *everal year*%K, #eventeen of the (, *u"ect* had ty$ical Par0in*on1*5li0e

*ym$tom*& three had gait di*order*& and one had re*tle** leg *yndrome%

Di*continuation of the trimetazidine led to com$lete re*olution of *ym$tom*

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in ,K $atient*& and *igni?cant reduction in the other ?ve%

#ome 7uro$ean authoritie* no! advocate for removal of trimetazidine from

the mar0et entirely& claiming that the ri*05"ene?t ratio i* unacce$ta"ly

high%K3 Other* are more circum*$ect& recommending in*tead that $atient*

and their $hy*ician* monitor for *ide eAect*& and di*continue the drug only if

and !hen *ym$tom* occur%K, ortunately& in the va*t maority of ca*e*

re$orted& !ithdra!al of the drug lead* to ra$id re*olution of the*e

*ym$tom*%K, -t may "e that TM< *hould only "e $re*cri"ed for *everal

month* to re*tore cardiac out$ut in tho*e !ith *evere heart mu*cle damage%

The*e $atient* could then initiate or continue ta0ing nutrient* li0e u"iIuinol

Co,4& carnitine& taurine& and P for long term maintenance of heart

mu*cle cell mitochondrial out$ut%

-f you have any Iue*tion* on the *cienti?c content of thi* article& $lea*e call a

6ife 78ten*ion9 Health )dvi*or at ,5KK5K354(L%

eference*

,% oger >6& /o )#& 6loyd5Rone* DM& et al% Heart Di*ea*e and #tro0e

#tati*tic*55(4,( .$date: ) e$ort rom the )merican Heart )**ociation%

Circulation% (4,( Ran ,(J;,=:e(5e((4%

(% Brod"in P& O1Connor C)% Trimetazidine in the treatment of angina $ectori*%

Br R Clin Pract% ,K #e$((;=:J5K%

% #ac0 M% Clinical -m$lication*: ) evie! of the Data% )dvanced #tudie* in

Medicine% (443 Novem"er3;,4=:#,K5#(,%

3% .**her R& 6o$a*chu0 /D% Targeting malonyl Co) inhi"ition of mitochondrial

fatty acid u$ta0e a* an a$$roach to treat cardiac i*chemiaSre$erfu*ion% Ba*ic

e* Cardiol% (44 Mar,43;(=:(45,4%

J% o*enfeldt 6& Pe$e #& 6innane )& et al% Coenzyme ,4 $rotect* the aging

heart again*t *tre**: *tudie* in rat*& human ti**ue*& and $atient*% )nn N Y

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)cad #ci% (44( )$rJ:JJ5 di*cu**ion 3K5J%

K% 6ango & #molen*0i T& Nar0ie!icz M& #uchorze!*0a R& 6y*ia05#zydlo!*0a

G% -n@uence of 65carnitine and it* derivative* on myocardial meta"oli*m and

function in i*chemic heart di*ea*e and during cardio$ulmonary "y$a**%

Cardiova*c e*% (44, RulJ,;,=:(,5%

L% Reeee"hoy & eith M& reeman M& et al% Nutritional *u$$lementation !ith

Myo>ive re$lete* e**ential cardiac myocyte nutrient* and reduce* left

ventricular *ize in $atient* !ith left ventricular dy*function% )m Heart R% (44(

Run,3;K=:,4(5,44%

% Cohen N& )lon -& )lmoznino5#ara?an D&et al% Meta"olic and clinical eAect*

of oral magne*ium *u$$lementation in furo*emide5treated $atient* !ith

*evere conge*tive heart failure% Clin Cardiol (444 (;K=:35K%

% Cho!anadi*ai G& Bauerly )& Tcha$arian 7& Gong )& Corto$a**i /)& uc0er

B% PyrroloIuinoline Iuinone *timulate* mitochondrial "iogene*i* through

c)MP re*$on*e element5"inding $rotein $ho*$horylation and increa*ed P/C5,

al$ha e8$re**ion% R Biol Chem% (4,4 Ran ,(J:,3(5J(%

,4% 6i CR&

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,4,(;,=:e3(K5JL%

,% 7lliott GR& Meyer PM% -ncident dia"ete* in clinical trial* of antihy$erten*ive

drug*: a net!or0 meta5analy*i*% 6ancet% (44L Ran (4K;JJL=:(4,5L%

,3% raga**o /& Per*eghin /& De Co"elli & et al% 7Aect* of meta"olic

modulation "y trimetazidine on left ventricular function and

$ho*$hocreatineSadeno*ine tri$ho*$hate ratio in $atient* !ith heart failure%

7ur Heart R% (44K )$r(L;=:3(5%

,J% Onay5Be*i0ci )& /uner #& )rioglu 7& Oza0ca -& Ozceli0ay )T& )ltan >M% The

eAect* of chronic trimetazidine treatment on mechanical function and fattyacid o8idation in dia"etic rat heart*% Can R Phy*iol Pharmacol% (44L

MayJ;J=:J(L5J%

,K% Onay5Be*i0ci )& Oz0an #)% Trimetazidine revi*ited: a com$rehen*ive

revie! of the $harmacological eAect* and analytical techniIue* for the

determination of trimetazidine% Cardiova*c Ther% (44 #ummer(K;(=:,3L5KJ%

,L% raga**o /& #$oladore & Cu0o )& Pallo*hi )% Modulation of fatty acid*o8idation in heart failure "y *elective $harmacological inhi"ition of 50etoacyl

coenzyme5) thiola*e% Curr Clin Pharmacol% (44L #e$(;=:,45K%

,% /ryn"erg )% 7Aector* of fatty acid o8idation reduction: $romi*ing ne!

anti5i*chaemic agent*% Curr Pharm De*% (44J,,;3=:35J4%

,% )vaila"le at: !!!%mim*%comS.#)SdrugSinfoStrimetazidine

F(4hydrochlorideSEIUanti5anginalF(4drug*Vty$eUfull % )cce**ed Novem"er

,J& (4,,%

(4% antor P& 6ucien )& oza0 & 6o$a*chu0 /D% The antianginal drug

trimetazidine *hift* cardiac energy meta"oli*m from fatty acid o8idation to

gluco*e o8idation "y inhi"iting mitochondrial long5chain 50etoacyl coenzyme

http://var/www/apps/conversion/tmp/scratch_4/www.mims.com%2FUSA%2Fdrug%2Finfo%2Ftrimetazidine%20hydrochloride%2F%3Fq=anti-anginal%20drugs&type=fullhttp://var/www/apps/conversion/tmp/scratch_4/www.mims.com%2FUSA%2Fdrug%2Finfo%2Ftrimetazidine%20hydrochloride%2F%3Fq=anti-anginal%20drugs&type=fullhttp://var/www/apps/conversion/tmp/scratch_4/www.mims.com%2FUSA%2Fdrug%2Finfo%2Ftrimetazidine%20hydrochloride%2F%3Fq=anti-anginal%20drugs&type=fullhttp://var/www/apps/conversion/tmp/scratch_4/www.mims.com%2FUSA%2Fdrug%2Finfo%2Ftrimetazidine%20hydrochloride%2F%3Fq=anti-anginal%20drugs&type=full

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) thiola*e% Circ e*% (444 Mar ,LK;J=:J45%

(,% olme* CD& Clanachan )#& 6o$a*chu0 /D% atty acid o8idation inhi"itor* in

the management of chronic com$lication* of athero*clero*i*% Curr )thero*cler

e$% (44J e"L;,=:K5L4%

((% Mody >& #ingh BN& Mohiuddin -H& et al% Trimetazidine5induced

enhancement of myocardial gluco*e utilization in normal and i*chemic

myocardial ti**ue: an evaluation "y $o*itron emi**ion tomogra$hy% )m R

Cardiol% , #e$ (;J)=:3(53%

(% 6avanchy N& Martin R& o**i )% )nti5i*chemic eAect* of trimetazidine: ,P5NM *$ectro*co$y in the i*olated rat heart% )rch -nt Pharmacodyn Ther% ,L

Mar(K;,=:L5,,4%

(3% enaud R% -nternal $H& NaW& and Ca(W regulation "y trimetazidine during

cardiac cell acido*i*% Cardiova*c Drug* Ther% , Mar,;K=:KLL5K%

(J% 7l Banani H& Bernard M& Cozzone P& Rame* & euvray D% -onic and

meta"olic im"alance a* $otential factor* of i*chemia re$erfu*ion inury% )m RCardiol% , #e$ (;J)=:(J5(%

(K% 7l Banani H& Bernard M& Baetz D& et al% Change* in intracellular *odium

and $H during i*chaemia5re$erfu*ion are attenuated "y trimetazidine%

Com$ari*on "et!een lo!5 and zero5@o! i*chaemia% Cardiova*c e*% (444

#e$3L;3=:K5K%

(L% )u**edat R& ay )& ay 6& >erdy* M& Har$ey C& o**i )% -m$rovement of

long5term $re*ervation of i*olated arre*ted rat heart: "ene?cial eAect of the

antii*chemic agent trimetazidine% R Cardiova*c Pharmacol% ,

Ran(,;,=:,(5J%

(% ay 6& inelli C& )u**edat R& /uarnieri C& o**i )% -m$rovement of long5

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term $re*ervation of the i*olated arre*ted rat heart "y trimetazidine: eAect*

on the energy *tate and mitochondrial function% )m R Cardiol% ,J )ug

(3LK;K=:3JB53B%

(% Dra0e5Holland )R& Belcher P& Hynd R& No"le M-% -nfarct *ize in ra""it*: a

modi?ed method illu*trated "y the eAect* of $ro$ranolol and trimetazidine%

Ba*ic e* Cardiol% , May5Run;=:(J45%

4% )lli"ardi #& Chierchia #6& Margonato >& et al% 7Aect* of trimetazidine on

meta"olic and functional recovery of $o*ti*chemic rat heart*% Cardiova*c

Drug* Ther% , Dec,(;K=:J35%

,% Boucher & Hear*e DR& O$ie 6H% 7Aect* of trimetazidine on i*chemic

contracture in i*olated $erfu*ed rat heart*% R Cardiova*c Pharmacol% ,3

Rul(3;,=:3J5%

(% Di Pa*Iuale P& 6o >er*o P& Bucca >& et al% 7Aect* of trimetazidine

admini*tration "efore throm"oly*i* in $atient* !ith anterior myocardial

infarction: *hort5term and long5term re*ult*% Cardiova*c Drug* Ther% ,

#e$,;J=:3(5%

% ara )& Demiryure0 #& Celi0 )& Tara0cioglu M& Demiryure0 )T% 7Aect* of

chronic trimetazidine treatment on myocardial $reconditioning in

ane*thetized rat*% undam Clin Pharmacol% (44K Oct(4;J=:335J%

3% ara )& Demiryure0 #& Celi0 )& Tara0cioglu M& Demiryure0 )T% 7Aect* of

trimetazidine on myocardial $reconditioning in ane*thetized rat*% 7ur R

Pharmacol% (443 Oct (JJ4;,5=:,J53J%

J% Pa$ado$oulo* C6& anonidi* -7& otridi* P#& et al% The eAect of

trimetazidine on re$erfu*ion arrhythmia* in acute myocardial infarction% -nt R

Cardiol% ,K Rul (KJJ;(=:,L53(%

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K% Belcher P& Dra0e5Holland )R& Hynd RG& No"le M-% 7Aect* of trimetazidine

on in vivo coronary arterial $latelet throm"o*i*% Cardiova*c Drug* Ther% ,

e"L;,=:,35JL%

L% Blardi P& de 6alla )& >ol$i 6& )uteri )& Di Perri T% -ncrea*e of adeno*ine

$la*ma level* after oral trimetazidine: a $harmacological $reconditioningE

Pharmacol e*% (44( Ran3J;,=:K5L(%

% Morgan 77& Young M7& Mc7lfre*h T)& et al% Chronic treatment !ith

trimetazidine reduce* the u$regulation of atrial natriuretic $e$tide in heart

failure% undam Clin Pharmacol% (44K Oct(4;J=:J45J%

% Monti 6D& )lli"ardi #& Piatti PM& et al% Triglyceride* im$air $o*ti*chemic

recovery in i*olated heart*: role* of endothelin5, and trimetazidine% )m R

Phy*iol Heart Circ Phy*iol% (44, #e$(,;=:H,,((54%

34% raga**o /& Piatti Md PM& Monti 6& et al% #hort5 and long5term "ene?cial

eAect* of trimetazidine in $atient* !ith dia"ete* and i*chemic

cardiomyo$athy% )m Heart R% (44 Nov,3K;J=:7,%

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endothelial dy*function in chronic heart failure: an antio8idant eAect% 7ur

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33% Manchanda #C% Treatment of *ta"le angina !ith lo! do*e diltiazem in

com"ination !ith the meta"olic agent trimetazidine% -nt R Cardiol% (44

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K4% Ma*moudi & Ma**on H& /ra* >& )ndrea0 M% 78tra$yramidal adver*e drug

reaction* a**ociated !ith trimetazidine: a *erie* of (, ca*e*% undam Clin

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reaction* a**ociated !ith trimetazidine: a *erie* of (, ca*e*% undam Clin

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