NSAIDs and Cardiovascular Diseases: Role of Reactive ......4 OxidativeMedicineandCellularLongevity Naproxen, ibuprofen, ketoprofen (cytosolic/secreted) (induced by thrombin, injury/inflammation,

Review ArticleNSAIDs and Cardiovascular DiseasesRole of Reactive Oxygen Species

Rajeshwary Ghosh1 Azra Alajbegovic1 and Aldrin V Gomes12

1Department of Neurobiology Physiology and Behavior University of California Davis CA 95616 USA2Department of Physiology and Membrane Biology University of California Davis CA 95616 USA

Correspondence should be addressed to Aldrin V Gomes avgomesucdavisedu

Received 22 December 2014 Revised 3 March 2015 Accepted 3 March 2015

Academic Editor Mark J Crabtree

Copyright copy 2015 Rajeshwary Ghosh et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used drugs worldwide NSAIDs are used for a varietyof conditions including pain rheumatoid arthritis and musculoskeletal disorders The beneficial effects of NSAIDs in reducing orrelieving pain are well established and other benefits such as reducing inflammation and anticancer effects are also documentedThe undesirable side effects of NSAIDs include ulcers internal bleeding kidney failure and increased risk of heart attack andstroke Some of these side effects may be due to the oxidative stress induced by NSAIDs in different tissues NSAIDs have beenshown to induce reactive oxygen species (ROS) in different cell types including cardiac and cardiovascular related cells Increasesin ROS result in increased levels of oxidized proteins which alters key intracellular signaling pathways One of these key pathwaysis apoptosis which causes cell death when significantly activated This review discusses the relationship between NSAIDs andcardiovascular diseases (CVD) and the role of NSAID-induced ROS in CVD

1 Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) are themost widely used over-the-counter drugs as well as the mostprescribed class of drugs for a variety of conditions includingpains rheumatoid arthritis osteoarthritis musculoskeletaldisorders and other comorbid conditions [1] Millions ofpeople suffer from pain resulting in the prolonged use ofNSAIDs being common Besides reducing or relieving painNSAIDs have been shown to be useful as anticancer agents invarious kinds of cancers [2ndash4] However NSAIDs also haveundesirable side effects including ulcers [5] bleeding [6] kid-ney failure [7 8] and increased risk of heart attack and stroke[8 9] One of themechanismswhich has been associatedwiththe adverse effects of NSAIDs is the generation of oxidativestress The present review focuses on NSAIDs-induced ROSgeneration leading to cardiovascular diseases (CVD)

2 Types of NSAIDs

NSAIDs may be classified according to their mechanism ofaction Nonselective NSAIDs like ibuprofen and naproxen

which comprise one class inhibit both cyclooxygenase-1(COX-1) and cyclooxygenase-2 (COX-2) enzymes A secondclass of NSAIDs (celecoxib and rofecoxib) targets only theCOX-2 pathway and is termed as COX-2 selective inhibitors(also known as coxibs) COX selectivity is one of thedetermining factors that is considered when administratingNSAIDs to a patient Administration of nonselective NSAIDshas been associated with side effects like peptic ulcer diseaseand gastrointestinal bleeding [10] COX-2 selective NSAIDshave been shown to exhibit gastroprotective effects unlikethe nonselective NSAIDs and are thus useful in patientswith painful gastrointestinal conditions [10ndash12] Anotherclass of semiselective NSAIDs (indomethacin meloxicamand diclofenac) have a higher affinity for COX-2 but tend toinhibit the COX-1 pathway also [13] However irrespectiveof their mechanism of action prolonged exposure to anyclass of NSAIDs has been shown to have potential adverseeffects on cardiovascular events in patients with or withoutpreexisting cardiovascular conditions depending on theduration and dosage of these drugs [14 15] (Table 1) Patientswith preexisting cardiovascular conditions such as coronary

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2015 Article ID 536962 25 pageshttpdxdoiorg1011552015536962

2 Oxidative Medicine and Cellular Longevity

Table1Listof

NSA

IDsw

iththeirrecom

mendeddo

sesa

ndlevelsin

thec

irculation

Genericname

Chem

icalname

Recommendeddo

sages

(may

vary

depend

ingon

thea

geandcond

ition

)

Levelsin

thec

irculation(120583M

and120583gmL)

(dosed

ependent)

Traden

ame

Diclofenac

2-[(26-D

ichlorop

henyl)a

mino]ph

enyl

acetic

acid

25mgndash150m

gday

5120583M

(15120583gmL)

and7120583

M(20120583gmL)

[for5

0mgand75

mgdo

sesrespectiv

ely]

ZorvolexC

ataflam

Cam

biaVo

ltaren

VoltarengelArthrotec

(com

binedwith

miso

prostol)

FlectorZipsor

Penn

said

Indo

methacin

[1-(4-C

hlorob

enzoyl)-5-metho

xy-2-

methyl-1H-in

dol-3

-yl]a

cetic

acid

25mgndash200m

gday

3120583Mndash6120583M

(1to

2120583gmL)

TivorbexInd

ocinInd

ocin

SR

Indo

-Lem

mon

Ind

omethagan

Ketoprofen

2-(3-Benzoylph

enyl)p

ropano

icacid

25mgndash300m

gday

2120583

Mto

22120583M

(043to

562120583gmL)

[50m

gdo

se]

OruvailNexcede

Ibup

rofen

2-(4-Isobu

tylphenyl)prop

anoica

cid

100m

gndash800m

gday

97120583

Mndash291120583M

(20ndash

60120583gmL)

[400

mg

dose]

AdvilMotrin

andNurofenV

icop

rofen

(com

binedwith

hydrocod

one)D

uexis

(com

binedwith

famotidine)

Naproxen

(2S)-2-(6-Metho

xy-2-naphthyl)prop

anoic

acid

250m

gndash1000

mgday

(bothoralandIV

)

377120583M

(95120583

gmL)

[500

mgdo

seon

ceevery12hor

1000

mg

dose

for5

days]

Naprosyn

EC-N

aprosyn

Naprapac

(cop

ackagedwith

lansop

razole)Aleve

AccordA

naprox

DSAn

aproxAntalgin

ApranaxTrexim

et(com

binedwith

sumatrip

tansuccinate)andVimovo

(com

binedwith

esom

eprazolemagnesiu

m)

Sulin

dac

(1Z)-5-Fluo

ro-2-m

ethyl-1-[4-

(methylsu

lfinyl)b

enzylid

ene]-1H-in

den-3-

ylacetic

acid

200m

gndash40

0mgday

14120583Mndash6120583M

(05ndash20120583gmL)[con

stant

fora

lldo

ses]

Clinoril

Ketorolac

5-Be

nzoyl-2

3-dihydro-1H-pyrrolizine-1-

carboxylic

acid

10mgndash40

mgday

39120583M

(10120583

gmL)

Torado

lSprix

Piroxicam

4-Hydroxy-2-m

ethyl-N

-(2-pyrid

inyl)-2H

-12

-benzothiazine-3-carbo

xamide11-

dioxide

02m

gndash20

mgday

5120583M

to6120583

M(15to

2120583gmL)

[single

20mgdo

se]9120583M

to24120583M

(3ndash8120583gmL)

[for2

0mgrepeated

doses]

Feldene

Oxidative Medicine and Cellular Longevity 3

Table1Con

tinued

Genericname

Chem

icalname

Recommendeddo

sages

(may

vary

depend

ingon

thea

geandcond

ition

)

Levelsin

thec

irculation(120583M

and120583gmL)

(dosed

ependent)

Traden

ame

Nim

esulide

N-(4-Nitro-2-

phenoxyphenyl)m

ethanesulfo

namide

100m

gtwiced

aily

10120583M

to20120583M

(286to

458)m

gL

[100

mg]

[175]

Sulid

eNim

aloxM

esulidX

iloxNise

Nexen

Nidolon

Diflun

isal

2101584041015840-D

ifluo

ro-4-hydroxy-3-

biph

enylcarboxylic

acid

250m

gndash1000

mg

164120583

M(41120583

gmL)

[250

mgdo

ses]

348120583

M(87120583

gmL)

[500

mgdo

ses]and

496120583

M(124120583gmL)

[single100

0mgd

ose]

Dolob

id

Flurbiprofen

2-(2-Fluoro-4-biph

enylyl)propano

icacid

50mgndash300m

gday

60120583M

(14mgL)

[065m

gkg

offlu

rbiprofenIV

][176]

Ansaid

Mefenam

icacid

2-[(23-

Dim

ethylphenyl)a

mino]benzoicacid

250m

gfollo

wed

by500m

gevery6ho

urs

83120583

M(20120583

gmL)

[250

mgsin

gled

oses]

Ponstel

Tolm

etin

[1-Methyl-5

-(4-methylbenzoyl)-1H

-pyrrol-

2-yl]acetic

acid

5mgndash1800

mgday

156120583

M(40120583

gmL)

[400

mgoraldo

se]

TolectinTolectin

DSTo

lectin

600

Thetablelistson

lythoseNSA

IDsthath

avebeen

mentio

nedin

Table3alon

gwith

theirrecom

mendeddo

sesa

ndrespectiv

econcentrations

inthecirculation

Mosto

fthe

inform

ationregardingthedo

sagesa

ndlevelsin

serum

orplasmaof

theNSA

IDsh

asbeen

takenfro

mtheFD

Aapproved

sitehttpwwwdrugsc

omN

imesulideistheon

lyNSA

IDin

thelistthatisn

otavailablein

theUSA

Referencesfor

theplasma

concentrations

offlu

rbiprofenandnimesulidea

regivenin

thetable

Serum

concentrations

Plasm

acon

centratio

ns


Naproxen ibuprofen ketoprofen

(cytosolicsecreted) (induced by thrombin injuryinflammation

hormones like epinephrine angiotensin II)

Cyclooxygenase pathway

COX-1(constitutive)

COX-2(inducible)

Valdecoxib celecoxib rofecoxib(Coxibs)

NSAIDS

Prostaglandin G2

Prostacyclin(endothelium)

NSAIDS

PGD

synt

hase

Thro

mbo

xane

synt

hase

PGI s

ynth

ase

PGF synthase

PGE synthase

Potent inhibitorof platelet

aggregationvasodilator

Potent activator and stimulator of

platelet aggregation vasoconstrictor

(smooth muscle)

Arachidonic acid

Phospholipase A2

Protein degradation Protein synthesis

Leukotriene

COXIBS

Atherosclerosis acute myocardial

infarction thrombosis

Platelet aggregation

Lipoxygenase pathway

Homeostasis disruption

COX-1 COX-2

COOHCH3

Cytokines IL-1IFN-120574 growth

factors

PGG2

Prostaglandin H2PGH2

PGF2

Homeostasis maintained by PGF2 and PGE2

(brain)neurophysiological

functions

PGD2TXA2

TXB2

PGI2

(platelets)

lowast

TXA2 PGI2

lowast

PGE2

Membrane phospholipid

Figure 1 Inhibition of cyclooxygenase pathway by NSAIDs Coxibs as well as nonselective NSAIDs inhibit the formation of the metabolitesof the cyclooxygenase pathway thereby disrupting the homeostasis maintained by these metabolites Coxibs cause an imbalance betweenthe levels of thromboxane and prostacyclin being more favorable towards thromboxane and decreasing prostacyclin levels leading to theaggregation of platelets and causing thrombosis

artery disease hypertension and history of stroke are at thegreatest risk of cardiovascular events after taking NSAIDs[14 15] Patients who have recently had cardiovascular bypasssurgery are advised not to take NSAIDs due to a high riskof heart attacks [16 17] The increased selectivity for COX-2 has also been reported to increase the risk of various CVD[18 19]Meta-analyses of several trials have shown that coxibs

are associated with a high risk of atherothrombotic vascularevents [20]

3 Mechanism of Action of NSAIDs

NSAIDs exert their pain relieving effect mainly by inhibit-ing the cyclooxygenase pathway (Figure 1) This pathway


is responsible for the conversion of arachidonic acid toprostaglandins and thromboxanes [21] Although COX isofficially known as prostaglandin-endoperoxide synthase(PTGS) the abbreviation ldquoCOXrdquo is commonly used forcyclooxygenase-1 and cyclooxygenase-2 in medicine Ingenetics the abbreviation PTGS is officially used for thecyclooxygenase family of genes and proteins to preventambiguity with the cytochrome c oxidase family of genes andproteins which are also abbreviated COX Arachidonic acidis the main precursor to the formation of various eicosanoidsin the cyclooxygenase pathway Of all the metabolites formedin the arachidonic acid metabolism thromboxane A2 in theplatelets is the major product which along with prostacy-clin (prostaglandin I2) maintains vascular homeostasis [22](Figure 1) Both these eicosanoids (thromboxane A2 andprostaglandin I2) have opposing effects While thromboxaneis well known for its role in vasoconstriction and aggregationof platelets prostacyclin is important for platelet aggregationinhibition and vasodilation

The COX enzyme is present as two isoforms each withdistinct functions COX-1 is constitutively expressed in thestomach kidneys intestinal mucosa and other tissues [23]It protects the mucosal lining of the stomach and playsan important role in vasoconstriction and platelet aggre-gation [23] On the other hand the inducible COX-2 isupregulated during times of inflammation where it causesvasodilation [24] COX-1 andCOX-2 are similar inmolecularweights 70 and 72 kDa respectively and show65homologywith near-identical catalytic sites (based upon informationfrom UniProtKBSwiss-Prot database) The critical differ-ence between the isoenzymes which permits the selectiveinhibition of each isoform is the substitution of isoleucine523 in COX-1 with valine in COX-2 [25] The presenceof valine which is a smaller amino acid than isoleucineallows drugs entrance to a hydrophobic side-pocket onlyaccessible in COX-2 Expression of both isoforms COX-1and COX-2 may be upregulated and downregulated undervarious pathological conditions [26] It is likely that theclassification of the COX enzymes into two isoforms wasan oversimplification [26] as COX-2 may be constitutivelyexpressed in the brain [27] kidney [28] and testes [29] In factimmunohistochemical studies have revealed the constitutiveexpression of COX-2 mRNA in the lung thyroid glandspleen and adipose tissue which was greater than COX-1 inthese tissues and in the liver both isoforms were expressedequally [29] Therefore the idea that COX-2 can only beexpressed under inducible conditions is unlikely since recentevidence suggests their occurrence in various human tissuesunder normal conditions

Coxibs disrupt the balance between the levels of throm-boxane A2 and prostaglandin I2 leading to atherosclerosisthrombosis and other cardiovascular complications Coxibsthrough their selective inhibition of COX-2 inhibit endothe-lial cell synthesis of prostacyclin [30] In the ApoEminusminusmice (model for atherosclerosis) deletion of the prostacyclinreceptor increased atherogenesis with no such effect observedin thromboxane receptor deleted mice [30] Apart from itsrole in the inhibition of cyclooxygenase pathway NSAIDshave been shown to cause cell death by the inhibition of

the Akt signaling pathway [31] downregulation of the NF-120581Bpathway [32] downregulation of the Bcl pathway [33] upreg-ulation of the nonsteroidal activated gene-1 [34] and alteringthe p53 pathway [35] all of which have been suggested tobe involved in apoptosis [36] Apoptosis (programmed celldeath) induced by NSAIDs has been suggested to be due tooxidative stress caused by increased generation of reactiveoxygen species (ROS) [37]

A series of mechanisms are involved wherein NSAIDsexert their cardiotoxic effects and cause various cardiacconditions Various non-NSAID drugs like doxorubicinazidothymidine and cisplatin have been shown to induceoxidative stress as a consequence of elevated ROS levels [38]Doxorubicin for example induced cardiotoxicity throughDNA damage and apoptosis in cardiac cells as a result ofoxidative stress which were reduced by the antioxidant effectof statin [37] It is possible that the oxidative stress induced byNSAIDs which is known to cause apoptosis and cell death issignificantly involved in causing cardiovascular dysfunction(Figure 2)

4 Incidences of CVD Induced by NSAIDs

Various clinical trials have been made during the past fewyears regarding the safety and effectiveness of NSAIDs inCVD (Table 2) Most trials focused on the CVD outcome ofNSAID use in patients with a previous history of cardiovas-cular disease Few trials were carried out on patients withno history of CVD An important finding is that not onlynonselective NSAIDs lead to the development of hyperten-sion in both normotensive and hypertensive individuals [39]but their use interferes with the antihypertensivemedicationsexcept for the calcium channel blockers [40]The risk of atrialfibrillation heart failure myocardial infarction and othercardiovascular conditions also increased in patients with ahistory of these pathological conditions (Table 2)

The CVD related outcomes in patients enrolled in theREACH (REduction of Atherothrombosis for ContinuedHealth) registry showed that in patients with establishedstable atherothrombosis use of NSAIDs increased the inci-dences of myocardial infarction and cerebrovascular con-ditions [41] Additionally this paper reported that the useof NSAIDs with other antiplatelet drugs (except aspirin)increased the rate of cardiovascular events like cardiovasculardeath myocardial infarction and stroke [41] Although a fewstudies suggest that COX selectivity does not seem to be adetermining factor for myocardial infarction [13 42] severalstudies suggest that coxibs elevate the rate of incidences ofCVD compared to nonselective NSAIDs [18ndash20] Severalclinical trials have been completed and are still ongoing butsome inconsistencies in the results exist regarding the effectof different types of NSAIDs on cardiovascular outcomes(Table 2) One meta-analysis report found that sim75 studiesinvestigating the cardiovascular risk in new NSAID usersreported an increase in the occurrence of cardiovasculardiseases within the first month of NSAID use [43] Overallthe different trials showed that several NSAIDs increasedthe risk of CVD both at low and high doses [41 43ndash45]Targeted inhibition of COX-2 even for a short term was


Table2Summaryof

results

from

clinicaltria

lson

thea

dverse

effectsof

NSA

IDso

ncardiovascular

diseases

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Cele

coxibnaproxen

sodium

and

placebo

Alzh

eimerrsquosDise

ase

Anti-Infl

ammatory

Preventio

nTrial

(ADAPT

)USA

4years

2528patie

ntsw

ithafam

ilyhisto

ryof

Alzh

eimerrsquos

Dise

ase

CVDCBV

deathMIstr

okeCH

For

TIAin

thec

elecoxib-naproxen-and

placebo-tre

ated

grou

pswe

re554

825and

568respectively

Death

ratesinthec

aseo

fpatientstaking

NSA

IDsw

ereh

igherb

utno

tstatistic

ally

significant

[44]

Cele

coxibrofecoxibvaldecoxib

diclo

fenacnaproxenibu

profen

diflu

nisaletod

olacfenop

rofen

flurbiprofen

indo

methacin

ketoprofen

ketoralacmeclofenamatemefenam

icacidm

eloxicamn

abum

eton

eoxaprozin

piroxicamsulindacandtolm

etin

Non

eUSA

5years

74838

userso

fNSA

IDsa

nd2353

5userso

fother

drugs

Thea

djustedrateratio

forR

ofecoxib

was

116forM

Iand

115forstro

kewhich

was

theh

ighestam

ongallother

NSA

IDs

inclu

ding

otherc

oxibsNaproxen

mod

estly

redu

cedther

ater

atio

(RRfor

MI0

067

andRR

forstro

ke0083)

ofcardiovascular

events

[177]

Cele

coxibibup

rofen

Non

eCh

ieti

Chieti

Italy

3mon

ths

24patie

ntsu

ndergoing

aspirin

treatmentfor

cardioprotectio

n

Ibup

rofeninterfe

redwith

theinh

ibition

ofplateletCO

X-1n

ecessary

for

cardioprotectio

nby

aspirin

[178]

Diclofenacibup

rofen

indo

methacin

ketoprofenn

aproxen

mefenam

icacid

piroxicamtenoxicam

tolfenamicacid

aceclofenactia

profenicacidm

efenam

icacidetodo

lacnabu

meton

enimesulide

andmelo

xicamrofecoxibcele

coxib

valdecoxiband

etoricoxib

Non

eFinland

3years

33309

patie

ntsw

ithfirst

MI138949controls

TheirresultssuggestthatC

OX-

selectivity

dono

tdeterminethe

adversee

ffectof

CVDby

NSA

IDsatleastcon

cerningMI

NoNSA

IDisMI-protectiv

e

[13]

Etoricoxib

anddiclo

fenac

Multin

ationalE

toric

oxib

andDiclofenacA

rthritis

Long

-term

(MED

AL)

Stud

yProgramM

ultin

ational

18mon

ths

34701

patie

nts(24913

with

osteoarthritisa

nd97

87with

rheumatoidarthritis)

Thrombo

ticcardiovascular

events

occurred

in320patie

ntsinthee

toric

oxib

grou

pand323patie

ntsinthed

iclofenac

grou

pwith

eventrates

of12

4and13

0per

100patie

nt-yearsandah

azardratio

of095

fore

toric

oxibcomparedto

diclo

fenacLo

ngterm

usageo

feith

erof

theseN

SAID

shad

similare

ffectso

nthe

rateso

fthrom

botic

cardiovascular

events

[179]

Etoricoxib

anddiclo

fenac

Etoricoxibversus

DiclofenacS

odium

Gastro

intestinal

Tolerabilityand

Effectiv

eness(ED

GE)

trialU

SA

93mon

thsfor

etoricoxib

and89

mon

thsfor

diclo

fenac

7111patie

nts

etoricoxib

(119899=3593)o

rdiclo

fenacs

odium

(119899=3518)

Ther

ateo

fthrom

botic

CVeventswas

130and12

4in

userso

fetoric

oxib

(90m

g)anddiclo

fenac(150m

g)

respectiv

elyw

ithin

28days

[180]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Ibup

rofen

naproxen

orlumira

coxib

TheTh

erapeutic

Arthritis

Research

and

Gastro

intestinalEv

entT

rial

(TARG

ET)International

Extend

edrepo

rt1832

5patie

ntsw

ithosteoarthritis

Ibup

rofenincreasedris

kof

thrombo

sisandCH

Fcomparedto

lumira

coxib

(214

versus

025)a

mon

gaspirin

usersNaproxenconferslow

erris

krelativetolumira

coxibam

ongno

naspirin

users

[181]

Diclofenacibup

rofen

andnaproxen

Non

eUSA

7years

ND

Prolon

gedexpo

sure

todiclo

fenac

increasesthe

riskof

AMI(relativer

atio

=19

ndash20)u

nlikeibu

profen

ornaproxen

[182]

Etoricoxib

anddiclo

fenac

EDGEIIU

SA193mon

thsfor

etoricoxib

and191

mon

thsfor

diclo

fenac

4086patie

ntsw

ithrheumatoidarthritis

etoricoxib119899=2032

diclo

fenac119899=2054

Ther

ateo

foccurrenceo

fAMIw

ashigh

erin

diclo

fenac(068)treated

patie

ntsthan

inetoricoxib

users(043)Also

anoverall

increase

incardiace

ventsw

asob

served

indiclo

fenactreated

grou

p(114

)versus

thee

toric

oxibgrou

p(083)

[183]

Cele

coxib(at4

00mgQD200

mgtwo

times

aday

(BID

)or

400m

gBID)

Non

eUSA

3years

7950

patie

nts(with

arthritisandother

cond

ition

s)

Theh

azardratio

forthe

CVDM

IHFor

thrombo

embo

liceventw

aslowestfor

the

400mgon

cead

ay(11)intermediatefor

the2

00mg-BIDdo

se(18)andhigh

est

forthe

400mg-BIDdo

se(31)

[184]

Ibup

rofen

naproxendiclofenac

meloxicam

ind

omethacin

piroxicam

andmefenam

icacid

Non

eUKprim

arycare

20years

7292

94NSA

IDusers

443047controls

Increase

inther

elativer

atefor

MIw

ithcumulativea

nddaily

dose

ofibup

rofen

anddiclo

fenacHigherrisk

ofMIw

ithdiclo

fenacu

se(relativer

atio

=12

1)than

ibup

rofen(relativer

atio

=10

4)or

naproxen

(relativer

atio

=10

3)

[185]

Etoricoxib

anddiclo

fenac

TheM

EDAL

Stud

yMultin

ational

194to

208mon

ths

Etoricoxib

60mgd119899=6769

90mgd119899=5012

Diclofenac119899=11717

Thethrom

botic

CVris

kHRof

etoricoxib

todiclo

fenac=

096P

rolonged

useo

feither

NSA

IDresultedin

anincreased

riskof

thrombo

ticCV

events

[186]

Naproxen

ibup

rofen

diclo

fenac

celecoxibandrofecoxib

Non

eUSA

6years

48566

patie

ntsrecently

hospita

lized

form

yocardial

infarctio

nrevascularization

orun

stableangina

pectoris

CVDris

kincreasedwith

shortterm

(lt90

days)u

seforibu

profen

with

incidence

rateratio

sof167diclo

fenac186

celecoxib13

7androfecoxib14

6bu

tnot

forn

aproxen088

[51]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Cele


ibup

rofen

naproxendiclofenacand

indo

methacin

Non

eUSA

7years

610001p

atientswith

out

CVD119899=525249w

ithhisto

ryof

CVD119899=84752

Rofecoxib(1091

events

1000

person

-years)valdecoxib

(1241

events

1000

person

-years)and

indo

methacin(1325

events

1000

person

-years)increased

CVDris

kin

patie

ntsw

ithno

histo

ryof

CVD

Rofecoxibuseincreased

riskof

cardiovascular

eventinpatie

ntsw

ithCV

D(3028

events

1000

person

-years)

[187]

Ibup

rofen

diclo

fenacrofecoxib

celecoxibandnaproxen

Non

eDanish

popu

latio

n9ndash

34days

153465healthyindividu

als

Dosed

ependent

increase

incardiovascular

eventsdu

etouseo

fdiclo

fenac(HR=16

3)rofecoxib

(HR=

213)a

ndcelecoxib(H

R=201)w

asob

served

[188]

Cele

coxibibup

rofen

andnaproxen

TheP

rospectiv

eRa

ndom

ized

Evaluatio

nof

Cele

coxibIntegrated

Safety

versus

Ibup

rofenOr

Naproxen

(PRE

CISION)

trialM

ultin

ational

2009-ongoing

20000

patie

ntsw

ithsymptom

aticosteoarthritis

orrheumatoidarthritisat

high

riskforo

rwith

establish

edCV

D

Thistrialw

illdeterm

inethe

cardiovascular

safetyof

theN

SAID

s[189]

ND

Non

eDenmark

10years

1070

92patie

ntsw

ithfirst

incidenceo

fHF

Theh

azardratio

ford

eath

duetoMIo

rHFwas

17017

513

1208122and12

8forrofecoxibcele

coxibibup

rofen

diclo

fenacnaproxenand

otherN

SAID

srespectiv

ely

[190]

Ibup

rofen

diclo

fenacnaproxen

rofecoxibcelecoxibvaldecoxiband

etoricoxib

Non

eTh

eNetherla

nds

4years

485059subjectswith

first

hospita

lisationfora

cute

myocardialinfarction

CV

andgastr

ointestin

alevents

AMIrisk

with

celecoxib(O

R253)

rofecoxib(O

R16

0)ibu

profen

(OR15

6)

anddiclo

fenac(OR15

1)was

significantly

increasedSign

ificant

increase

inCV

risk

with

currentu

seof

individu

alCO

X-2

inhibitorsandtN

SAID

s(ORfro

m117to

164)Significantd

ecreaseinAMIw

ithcurrentu

seof

naproxen

(OR048)

[191]

Ibup

rofen

naproxendiclofenac

etod

olaccelecoxibrofecoxib

Non

eNorthernDenmark

10years

32602

patie

ntsw

ithfirst

atria

lfibrillationor

flutte

rand325918po

pulatio

ncontrols

Increasedris

kof

atria

lfibrillationor

flutte

rwas

40ndash70

(lowe

stfor

non-selectiveN

SAID

sand

high

estfor

COX-

2inhibitors)

[192]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

ND

Non

eDenmark

10years

83677

patie

ntso

fwhich

423received

NSA

IDs

Deathrecurrent

MId

ueto

NSA

IDtre

atment(even

shortterm)w

assig

nificantly

high

erD

iclofenacp

osed

the

high

estrisk

ofallN

SAID

s

[193]

ND

INternationalV

Erapam

ilTrando

laprilSTud

y(INVES

T)M

ultin

ational

7years

882chronicN

SAID

users

and21694

nonchron

icNSA

IDusersPatie

ntsw

ithhypertensio

nandclinically

stablec

oron

aryartery

disease

Prim

aryou

tcom

elikea

ll-causem

ortality

nonfatalMIor

nonfatalstroke

and

second

aryindividu

alou

tcom

eslik

eall-c

ause

mortalitycardiovascular

mortalitytotalM

Iandtotalstro

keoccurred

atar

ateo

f44eventsper100

patie

nt-yearsin

thec

hron

icNSA

IDgrou

pversus

37eventsper100

patie

nt-yearsin

then

onchronicN

SAID

grou

p

[111]

Cele

coxibrofecoxibibup

rofen

diclo

fenacnaproxenand

others

Non

eDenmark

13years(with

first

MI)

128418patie

nts(77

participated

inthes

tudy)

Incidences

ofcoronary

deathor

nonfatal

recurrentM

Iwith

NSA

IDsu

seremain

unchangedwith

thetim

eelapsed

even

after

5years

[194]

ND

Non

edataob

tained

from

REdu

ctionof

Atherothrombo

sisfor

Con

tinuedHealth

(REA

CH)registry

which

inclu

desp

atientsfrom

Latin

AmericaNorth

AmericaEu

ropeA

siathe

MiddleE

astandAu

stralia

4years

4420NSA

IDusers39675

NSA

IDno

nusers

116-fold

high

erris

kof

CVDM

Iin

NSA

IDusers

[41]

MImyocardialinfarction

HFheartfailureC

VDcardiovasculard

iseasesC

BVcerebrovascular

diseasesC

HFcongestiv

eheartfailu

reH

Rhazard

ratio

OR

oddratio

NDnot

defin

edR

Rrateratio

and

TIA

transie

ntisc

hemicattackV

arious

clinicaltria

lssuggestthe

increasedincidences

ofCV

Din

NSA

IDusersTh

etablelistson

lythec

linicaltrialsrepo

rted

between2006

and2014


Thrombosis

Nonselective (inhibits COX-1 and COX-2)naproxen ibuprofen ketoprofen

COX-2 selectivevaldecoxib celecoxib rofecoxib

Apoptosis

NADPH oxidasesCell signalling pathways affectedLipoxygenases

Xanthine oxidasesNitric oxide synthases

(free radicals)

Acute myocardial infarction reperfusion injury heart failure Oxidative stress

Cardiovascular diseases

ROS

Cytochrome p450

Arachidonic acid metabolism

Platelet aggregation on the site of atherosclerotic plaque

rupture on the coronary artery wall of the heart

NSAIDs

uarr Nonsteroidal activated gene- 1uarr p53 uarr Bax darr Bcl-2uarr Mitochondrial cytochrome cuarr Apoptosis inducing factordarr Aktdarr NF-120581Bdarr Proteasome activity

O2∙minus H2O2∙OH

darr Prostacyclinuarr Thromboxane

Thromboxaneprostacyclin imbalance

Figure 2 Pathways involved in the development of cardiovascular diseases by NSAIDS The figure shows the upregulation anddownregulation of various pathways by NSAIDs leading to the development of CVD Mitochondria play a major role in the generationof ROS induced by NSAIDs followed by oxidative stress and finally CVD

found to increase the risk of atherothrombosis [46] TheCOX-2 selective NSAID rofecoxib at low doses (50mg daily)increased the occurrences of myocardial infarction by 05in approximately 8000 patients with rheumatoid arthritiscompared to 01 in those treated with naproxen (500mgtwice daily) indicating a severe thrombogenic effect of rofe-coxib compared to naproxen [47]Themain increased risk ofcardiovascular events associated with COX-2 inhibitors wasan increased risk of myocardial infarction [46]

The report of Adenomatous Polyp Prevention on Vioxx(APPROVe) trial on the adverse effect of rofecoxib on CVDultimately led to the discontinuation of this drug in severalcountries [48] Increased thromboembolic events have beenassociated with rofecoxib compared to naproxen [49] Inanother trial rofecoxib was found to be associated withcardiac arrhythmias and renal conditions [50] Howeversimilar adverse effects were not encountered in patientstreated with other COX-2 inhibitors [50] More importantlyseveral semiselective NSAIDs like diclofenac and meloxicamand nonselective NSAIDs including naproxen and ibuprofenhave also been shown to increase the incidences of CVD[46 51]Of these drugs diclofenac has been shown to increase

the occurrences of myocardial infarction and stroke evenat lower doses of lt150mgday compared to naproxen atdoses of gt1000mgday [51] This effect of diclofenac hasbeen attributed to its greater selectivity for COX-2 inhibitionIt has also been reported that ibuprofen is associated withCVD comparable to the effect of COX-2 selective inhibitorcelecoxib [20] It has been suggested that the differencebetween the effect exhibited by rofecoxib and other NSAIDsof the same class on cardiovascular incidences is due tothe distinct chemical properties and prooxidant activity ofrofecoxib [52] The toxic effect of rofecoxib was reportedlydue to its ability to reduce the low density lipoprotein (LDL)antioxidant capacity as a result of increased lipid peroxidation[52] Merck voluntarily withdrew rofecoxib (Vioxx) in 2004Pfizer was asked by the US Food and Drug Administration(FDA) to withdraw valdecoxib (Bextra) from the market in2005 because of a higher than expected number of reportsof serious and potentially life-threatening skin reactions anddeaths

Naproxen seems to show less cardiovascular events thanother commonly used NSAIDs possibly because it mimicsthe activity of acetylsalicylic acid (aspirin) by suppressing


cyclooxygenase platelet thromboxane B2 [53] However therole of naproxen in the development of CVD has been con-troversial Several studies have reported the cardioprotectiveeffect of the compound [54ndash56] and on the other handincreased cardiovascular risk has been associatedwith the useof this NSAID [57ndash59] The only NSAID which has not beenassociated with increased cardiovascular events is aspirinAspirin is the only known NSAID which has antithromboticactivity through the inhibition of platelet aggregation inthe artery of the heart thereby exhibiting cardioprotectiveeffects [60] It does so by acetylating the platelet COX-1and irreversibly suppressing thromboxane A2 productionwhich is required for platelet aggregation and thrombusformation [60] Naproxen on the other hand causes reversibleinhibition of cyclooxygenase by binding to the enzyme [61]It was found that inhibition in thromboxane A2 synthesis wasmore pronounced (75) compared to prostacyclin inhibition(50) after the oral administration of 500mg naproxen inhealthy volunteers [61]

5 NSAIDs and Reactive OxygenSpecies Generation

NSAIDs have been shown to be associated with increasedROS production (Table 3) In the heart the main producer ofROS is the mitochondria [62] Under normal physiologicalconditions mitochondria generate ROS as a consequence ofaerobic respiration [63] During aerobic respiration about 5of O2consumed via aerobic reaction is converted into ROS

[63] The mitochondria-dependent overproduction of ROShas been reported under numerous pathological conditionsincluding myocardial heart failure inflammatory diseasescancer hypertension and diabetes [64ndash67] In myocardialheart failure cardiomyocytes have been shown to be targetedby excessive ROS generation [64]

ROS levels and the redox state of a cell are consideredto be important in the dysfunction of various biologicalsignaling pathways The formation of ROS via the reductionof molecular oxygen or by the oxidation of water leads to theformation of free radicals such as superoxide anion (O

2

∙minus)hydroxyl radical (∙OH) and hydrogen peroxide (H

2O2)

Oxidative stress arises when the oxidant production (sum ofall the ROS) surpasses the antioxidant capacity in the cellsUnder normal physiological conditions low amounts of O

2

∙minus

in the cardiomyocytes are converted to the less toxic H2O2

by the enzyme superoxide dismutase (SOD) The reactionfurther proceeds by the formation of water by the action ofthe enzyme catalase or glutathione peroxidase (GPx) system[68] However when a homeostatic imbalance between thecellular antioxidant capacity and ROS levels occurs elevatedROS levels can damage cellular macromolecules includinglipids proteins and nucleic acids High levels of ROS alsoaccelerate cell death due to apoptosis as well as necrosis by theactivation of poly(adenosine diphosphate ribose) polymerase[69] and thus significantly contribute to the development ofvarious pathological conditions [70]

The generation of ATP in the mitochondria utilizes theelectrons from reduced substrates that are transferred to anacceptor molecule of the electron transport chain (ETC)

Leakage of electrons from the mitochondria ETC results inO2

∙minus formation [71] Electron leakage is potentially possibleat 9 sites in the ETC however most of the ROS seem tobe associated with complexes I and III which have beenwell studied [72] The generation of ROS increases in intactmitochondria as well as in submitochondrial particles dueto the oxidation of complex I substrates as a result ofinhibiting complex III by antimycin A [72] On the otherhand rotenone an inhibitor of complex I prevented theantimycin A induced ROS generation in mitochondria butnot in the submitochondrial particles [72]

The ROS status in the cellular system regulates manybiological processesWhile increased levels of ROS have beenshown to be involved in various pathological conditionsunder basal conditions the generation of free radicals in theheart is needed for cellular responses including regulatingmyocyte growth and maintaining vascular smooth muscletone [73] Basal levels of ROS play an important role in theincrease of cell cycle progression and intracellular signalingassociated with phosphorylation of several signaling proteinslike mitogen-activated protein kinases (MAPKs) and proteinkinase B [74] Under normal physiological conditions ROSupregulates the Akt signaling pathway and promotes cellsurvival [75] ROS also behaves as second messengers in sig-naling pathwayswherein it has been demonstrated that in thepresence of basal ROS levels tyrosine phosphatase activityis higher relative to its kinases [76] Ligand stimulation (asin the case of neutrophils through the binding of cytosolicproteins to a membrane bound oxidase) leads to increasedROS levels and deactivation of tyrosine phosphatases with aconsequent increase in the kinase activity [76]This conditionis transient and is reversed by reductions in ROS levels ROShas also been demonstrated to be involved in the modulationof transcription factors like NF-120581B Hif-1 [77] and severalcardiac transcription factors like SRF Sp1 AP-1 GATA-4 andMEF2C [78]

Current experimental data suggest that the main mecha-nism throughwhichNSAIDs exert their anticancer activity isthrough the generation of ROS leading to oxidative stress andfinally apoptosis in cancer cells [79ndash82] ROS is accompaniedby the activation and inhibition of several signaling pathwaysassociated with cell death and cell survival although contro-versies exist regarding the role of ROS in the downregulationand upregulation of these pathways [83 84]TheAkt pathwayis one of the most important pathways for promoting cellsurvival and growth and it has been shown that high ROSlevels are lethal and can inactivate the Akt signaling pathway[85] NF-120581B is an important transcription factor involved incell survival inflammation and stress responses Its down-regulation was demonstrated by exposure of HLEC (humanlymphatic endothelial cells) cells to sustained oxidative stress[86] Increased levels of H

2O2caused by addition of glucose

oxidase to HLECs prevented NF-120581B(p65) regulated geneexpression by blocking translocation of NF-120581B to the nucleus[86] NF-120581B regulated gene expression is important for abroad range of physiological processes [86]

Sulindac a nonselectiveNSAID as well as itsmetabolitesgenerates ROS in different cancer cell lines [80ndash82] Similarlydiclofenac-induced apoptosis of various kinds of cancer cells


Table3NSA

IDsind

uced

ROSgeneratio

nin

different

celltypes

(a)

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenacindo

methacin

ketoprofen

Mito

chon

drialrespiratio

nSaccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

TheseN

SAID

stargetm

itochon

driato

indu

cecelltoxicity

[95]

Ibup

rofenandnaproxen

TheseN

SAID

Sindu

cetoxicityindepend

ento

fmito

chon

drialrespiratio

n[95]

Indo

methacin

sodium

diclo

fenacflu

rbiprofen

zalto

profenand

mofezolac

ND

Hum

angastric

epith

elialcellline

AGS

AllNSA

IDse

xceptm

ofezolac

increased

apop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

AD

NAfragmentatio

nindu

ced

byindo

methacinor

flurbiprofenwas

redu

ced

byantio

xidantsIndo

methacinat1m

Mwas

apo

tent

indu

cero

fROSgeneratio

nin

thec

ells

[79]

Diclofenaca

ndnaproxen

NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

oxidasee

xpressionincreasedin

the

heartand

aortab

ydiclo

fenaca

ndnaproxen

ROSlevelsincreaseddu

etoNADPH

oxidase

[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2iso

form

ofNADPH

oxidaseisincreased

bydiclo

fenac

[114]

Aspirin

naproxenand

piroxicam

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Indo

methacin

Xanthine

oxidases

Hum

ancolonica

deno

carcinom

acells

(Caco-2cells)

Xanthine

oxidasea

ctivity

increasesb

ymore

than

100

1hou

rafte

rtreatment

[96]

Indo

methacin

Mito

chon

driasuperoxide

leakage

Ratgastricepith

elialcellline

RGM1

Indo

methacinindu

cedtheleakage

ofsuperoxide

anionin

theisolatedmito

chon

dria

from

theg

astricRG

M1cells

[93]

Indo

methacin

diclo

fenac

sodium

and

aspirin

ND

Ratgastricepith

elialcellline

RGM1and

ratsmallintestin

alepith

elialcelllineIEC

6

Indo

methacin

diclo

fenacandaspirin

ingastric

RGM1cellsandsm

allintestin

alIEC6

cells

increasedlip

idperoxidatio

n[93]

Sulin

dacsulin

dacs

ulfid

eandsulin

dacs

ulfone

ND

Pancreas

carcinom

aBXP

C3

glioblastomaA

172colon

carcinom

aDLD

-1oral

squamou

sSASandacute

myelocytic

leuk

emiaHL6

0cells

TheN

SAID

sulin

daca

ndits

metabolites

sulin

dacs

ulfid

eand

sulin

dacs

ulfone

all

increasedRO

Sgeneratio

nSulin

dacs

ulfid

eshow

edtheg

reatestR

OSgeneratio

n

[80]

Indo

methacin

piroxicam

andaspirin

Lipo

xygenases

Gastricandintestinalmucosain

mice

Results

inan

overprod

uctio

nof

leuk

otrie

nes

andprod

uctsof

5-lip

oxygenasea

ctivity

Increasesinleuk

otrie

neand5-lip

oxygenase

activ

ityhave

been

associated

with

ROS

generatio

n

[123124127]

Indo

methacin

Lipo

xygenases

Efferentgastriccirculationofpigs

Timed

ependent

form

ationof

leuk

otrie

ne-C

4[128]


(a)Con

tinued

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenac

CytochromeP

450enzymes

Saccharomyces

cerevisia

eyeast

cells

expressin

gthem

utantP

450

BM3M11(capableof

metabolizingdiclo

fenacs

imilar

tohu

mans)

IncreasedRO

Sprod

uctio

nbysim15

and18

times

atconcentrations

of30120583M

and50120583M

respectiv

elycom

paredto

wild

type

[140]

Diclofenacindo

methacin

ketoprofenand

naproxen

CytochromeP

450enzymes

Saccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

NSA

IDsm

etabolism

associated

with

increased

P450-related

toxicity

[95]

(b)

NSA

IDs

coxibs

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Ibup

rofen

ketoprofenand

indo

methacin

CytochromeP

450enzymes

Bacillusm

egaterium

AlltheN

SAID

scausedam

arkedincrease

inthetotalcytochromeP

450level

[142]

Aspirin

diclofenacdiflu

nisal

flurbiprofen

ibup

rofen

indo

methacin

ketoprofenm

efenam

icacidn

aproxen


etin

CytochromeP

450enzymes

Rath

epatocytes

Cytotoxicityof

diclo

fenacketoprofen

andpiroxicam

was

increasedby

cytochromeP

450causinghepatotoxicity

[138]

Diclofenaca

ndnaproxen

Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Increasedexpressio

nof

eNOSmRN

Adu

eto

theg

enerationof

H2O

2which

isrespon

sibleforu

pregulationof

eNOSat

thetranscriptio

naland

post-

transcrip

tionallevels

[114]

Rofecoxibandcelecoxib

NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

expressio

nincreasedin

theh

eart

andaortab

yrofecoxibandcelecoxib

[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2Ex

pressio

nincreasedby

rofecoxib

[114]


Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Inthea

ortathe

coxibs

didno

tsho

wany

eNOSmRN

Aexpressio

nIn

theh

eart

onlyrofecoxibshow

edas

ignificant

increase

inthee

xpressionof

eNOS

[114]

Etod

olac

ND

Hum

angastr

icepith

elialcell

lineA

GS

Increasedapop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

A[79]

Nim

esulide

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Alth

ough

otherreportsarea

vailables

uggesting

theroleo

fNSA

IDsinRO

Sform

ationthetablelistson

lythoseN

SAID

sfor

which

results

show

thattheseN

SAID

sareassociated

with

CVDor

NSA

IDsm

entio

ned

inthetext


has been reported [87] This apoptosis is mainly mediatedby an increase in the intracellular levels of the ROS [87] Inthe cardiovascular system the major sources of ROS gener-ation include the mitochondria NADPH oxidases xanthineoxidoreductases lipoxygenase cyclooxygenases nitric oxidesynthases and cytochrome P450 based enzymes (Figure 2)Continuous exposure of cardiovascular cells to oxidativestress associated with elevated ROS levels would result inaltered cellular homeostasis which could be an importantcontributing factor for various cardiovascular conditionsEndothelial cells play a critical role in maintaining vas-cular homeostasis which is important for the control ofmany cardiovascular diseases including atherosclerosis andthrombosis [88] In human umbilical vein endothelial cells(HUVEC) 160 120583M sulindac induced endothelial apoptosisas determined by a time dependent increase in annexin Vpositive cells Both sulindac and indomethacin significantlyincreased cleaved poly(ADP-ribose) polymerase (PARP) lev-els as well as increasing the level of the apoptotic activatingfactor caspase-3 [89]The apoptosis in HUVEC cells inducedby the NSAIDs was associated with reduced PPAR120575 and 14-3-3-120576 expression Under normal conditions 14-3-3-120576 bindsto phosphorylated Bad inhibiting translocation of Bad tothe mitochondria and preventing apoptosis through themitochondrial pathway However sulindac through the sup-pression of 14-3-3-120576 expression increased Bad translocationto mitochondria thereby inducing apoptosis [89]

6 Mitochondria Are the Main TargetOrganelles of the NSAIDs

It has been shown that the heart is more susceptible toROS generation induced by drugs like doxorubicin comparedto other tissues of the body although the drugs are evenlydistributed throughout the body [90] This is possibly dueto high levels of mitochondria in the heart which are themajor producers of ROS in the cardiovascular system Over90 of ATP required for the normal functioning of theheart is provided by the mitochondria which utilizes anefficient oxidative phosphorylation system ATP productionmay increase depending upon the requirements of the bodyespecially at times of excessive physical exertion or other hor-monal stimulations [91]Mitochondria are not only themajorproducers of the free radicals [72] but excessive generationof ROS in turn targets the mitochondria itself [92] NSAIDshave been shown to have adverse effects on the mitochondriaresulting in the increased production of ROS [93 94] In yeastcells different NSAIDs generated ROS which was associatedwith delayed growth in wild-type cells [95] Yeast cells lackingmitochondrial DNA were resistant to a delay in cell growth[95] More specifically the yeast deletion strains lacking thegenes encoding subunits of the mitochondrial complexes IIIand IV were significantly resistant to diclofenac as well asindomethacin and ketoprofen [95] This data suggests thatmitochondria are the main target organelles through whichthese compounds exert their toxic effect on these cells Thedata also suggest that mitochondrial complex III andor

complex IV are affected by NSAIDs resulting in increasedROS production

The nonselective NSAID indomethacin has been shownto target mitochondria by directly inhibiting mitochondrialcomplex 1 of human colonic adenocarcinoma cells Theinhibition of complex I was accompanied by a decrease in theintracellular ATP levels within 10ndash30 minutes [96] Studiesdirectly related to mitochondrial dysfunction or damage inthe presence of NSAIDs in CVD have not been carriedout but are needed (Table 2) Although the mechanismby which NSAIDs can cause mitochondrial dysfunction incardiomyocytes is not fully understood preventing increasedmitochondrial ROS levels will reduce the adverse effects ofelevated ROS levels and may reduce the incidences of CVDcaused by NSAIDs

Apart from the role of NSAIDs in causing cardiovascularincidences NSAIDs affect other cardiovascular (CV) param-eters including left ventricular function infarct size andblood pressureIn elderly patients (718 plusmn 76 years) NSAIDexposure for lt14 days showed a significantly higher left ven-tricular end-systolic dimension (+174mm) and left ventric-ular end-diastolic dimension (+369mm) with a significantlylower fractional shortening (minus603)when compared to non-NSAID users Patients with NSAID use for gt14 days werefound to have higher left end-diastolic dimension (+196mm)but no significant changes in other echocardiographic param-eters compared to non-NSAID users [97]

The impact of NSAIDs on infarct size during myocardialinfarction has only been investigated by a few laboratoriesIndomethacin (10mgkg) was found to increase myocardialinfarct size in animals while ibuprofen (625mgkgh) hadthe opposite effect [98ndash100] The authors suggested that theopposite effect on the infarct size could be attributed tovariable doses of the NSAIDs different degrees of inhibitionof prostaglandin and its by-products and others factorslike myocardial oxygen consumption [99] The same groupreported that the frequency of acute infarct expansion syn-drome in patients with symptomatic pericarditis treated withindomethacin was 22 compared to ibuprofen which wasonly 8 [101]Thedegree of infarct expansionwas also greaterin patients treated with indomethacin compared to ibuprofen[101]

Another important CV parameter is hypertension whichis one of the major contributors to the development of CVDA series of events occur in patients with prolonged highblood pressure including left ventricular hypertrophy systolicand diastolic dysfunction leading to arrhythmias and heartfailure [102] Except for aspirin all NSAIDs could potentiallyincrease blood pressure when taken at doses necessary toalleviate pain and inflammation in both hypertensive andnormotensive individuals [39]

NSAIDs through their ability to block COX enzymeslead to the inhibition of renal prostaglandin [103] Renalprostaglandins modulate several renal functions whichinclude maintaining renal homeostasis and exerting diureticand natriuretic effects [104 105] Inhibition of the natriureticeffect of COX-2 leads to an increase in sodium retentionthereby leading to excess water retention in humans [106]The inhibition of renal vasodilating prostaglandins induces


the production of vasoconstricting factors like vasopressinand endothelin-1This also results in water retention therebyleading to an increase in the total blood volume and caus-ing altered systolic and diastolic blood pressure [103 106107] NSAIDs like ibuprofen indomethacin and naproxenincrease the mean arterial pressure by 5 to 6mmHg inpatients with established hypertension [108 109] which maybe enough to raisemedical concerns under certain conditions[110] Additionally the efficiency of all antihypertensivemedications except for calcium channel blockers may be sub-stantially reduced byNSAIDs [40] SinceCVoutcomeswouldhave different pathogenesis increased ROS levels may notbe the underlying mechanism for some occurrences of CVDOther CV related parameters (such as hypertension) whichare important for the normal functioning of the heart are alsolikely to affect the CV outcome Although direct comparisonsbetween the different clinical studies shown in Table 2 are notpossible these studies suggest that CVD in NSAID users areinfluenced by the study populations used (such as with versuswithout preexisting acute myocardial infarction) Chronicuse ofNSAIDs by hypertensive individuals has been shown toincrease the incidences of myocardial infarction stroke andcardiovascular mortality compared to nonchronic NSAIDusers [111] (Table 2)

7 NSAIDs and Nicotinamide AdenineDinucleotide Phosphate-Oxidase

Apart frommitochondria being themajor source of ROS gen-eration the plasma membrane bound nicotinamide adeninedinucleotide phosphate-oxidase (NADPH oxidase) has alsobeen indicated in the production of ROS in phagocytes likeneutrophils andmacrophages where it produces an ldquooxidativeburstrdquo ofO

2

∙minus [112]NADPHoxidases are considered to be themajor source of nonmitochondrial ROS generation in manycells The formation of free radicals is due to the electrontransferred from theNADPH tomolecular oxygen during theprocess of phagocytosis The phagocytic NADPH oxidasesplay an important role in the host defensemechanism and areinvolved in killing pathogens ingested during phagocytosisApart from the phagocytic NADPH oxidase in the lastdecade NADPH oxidase-dependent ROS generation was alsoidentified in nonphagocytic cells including the endothelialcells vascular smooth muscle cells and cardiomyocytes ofthe cardiovascular system [113] Compared to the phago-cytic NADPH oxidases the nonphagocytic enzymes producelower amounts of ROS continuously and these levels mayincrease in the presence of specific extrinsic stimuli [113]More interestingly the ROS generated by NADPH oxidaseslead to an enhancement in levels of ROS produced fromother sources [112] In one such study mitochondria andNADPHoxidase 1 isoenzyme (Nox 1) were found to be closelycoordinated for sustained generation of ROS leading tooxidative stress and cell death [112]When human embryonickidney 293T cells were exposed to serum-free media elevatedROS levels occur within 5 minutes of exposure and persistedfor 8 hrs [112] Utilizing RNA interference Nox isoenzymeswere demonstrated to play a role in the induction of serum-withdrawal ROS generation Although low levels of Nox 2

and Nox 4 did not affect the generation of serum-withdrawalinduced ROS generation low levels of Nox 1 led to a decreasein the ROS formation in these cells at 8 h (late phase) Usingdifferent mitochondrial complex inhibitors such as rotenoneand potassium cyanide (KCN) mitochondria were found toplay a role in the early phase (first 30 minutes) of ROSgeneration in the cells exposed to serum-freemedia [112]Theauthors of the study suggested that mitochondrial generationof ROS occurs first followed by the action of Nox 1 in theserum deprived cell system [112]

The adverse effect of NSAIDs on the cardiovascularsystemwas evident by a study which reported that whenmalespontaneously hypertensive rats (SHR) were treated eitherwith coxibs or with nonselective NSAIDs like diclofenacand naproxen the mRNA expression of NOX enzymes 1 2and 4 was markedly increased in the heart and aorta [114]Furthermore the oxidative stress in the heart and aorta ofthe NSAID treated animals was also elevated along with anincrease in the O

2

∙minus production Of all the NSAIDs useddiclofenac was the most potent inducer of NADPH oxidases[114] The role of NADPH oxidases in the generation ofROS in the animals was ascertained by studying the effectof apocynin (an NADPH oxidase inhibitor) in the reversalof the oxidative stress induced by diclofenac [114] Activationof Nox 4 by NSAIDs like aspirin naproxen nimesulide andpiroxicam has also been reported in rat adipocytes resultingin higher production of H

2O2[115]

8 NSAIDs and Xanthine Oxidase

Xanthine oxidoreductase (XOR) is a conserved molybd-oflavoenzyme occurring in milk and some tissues includ-ing the liver heart and small intestine [116] It has twointerconvertible forms xanthine dehydrogenase (XDH) andxanthine oxidase (XO) Both enzymes catalyze the conversionof hypoxanthine to xanthine and xanthine to uric acid [116]Although both enzymes are involved in purine degradationXO is involved only in the reduction of oxygen while XDH isinvolved in the reduction of both oxygen and to a larger extentNAD+The enzymeXDHhas the ability to bind toNAD+ andfollowing the oxidation of hypoxanthine to xanthine reducesNAD+ to NADH On the other hand XO not being able tobind to NAD+ produces the free radical O

2

∙minus by the transferof electrons to molecular oxygen Apart from O

2

∙minus H2O2

was also shown to be a major free radical generated by XO[117] XDH can utilize molecular oxygen and generate ROSbut to a lesser extent than XO Compared to the other sourcesof ROS generation like mitochondria and NADPH oxidasesthe role of XOR as a producer of ROS has been previouslyoverlooked due to its relatively low activity in the heart ofanimals and human Recently the role of XOR in mediatingvarious pathological conditions has been demonstrated in thecardiovascular system due to significant increases in cellularXOR levels [118] This was evident by the inhibition of XORby compounds like allopurinol and oxypurinol which lead toa decrease in the oxidative tissue damage Apart from theirproperty of inhibiting XOR allopurinol and oxypurinol havealso been shown to act as free radical scavengers and inhibitlipid peroxidation as well as inducing heat shock proteins


during times of oxidative stress [118] Interestingly a highlevel of serum uric acid the end product of XOR has beenshown to be a marker for impaired oxidative metabolism[119]

Although the prevalence of this enzyme has beenreported in human hearts [116 120] and although increasedlevels of uric acid in myocardial heart failure have beenreported in the literature [119] the role of NSAIDs on XOin the development of various cardiovascular conditions hasnot been investigated In a study to investigate the adverseeffect of aspirin on gastric mucosal lining leading to pepticulcers and intestinal bleeding rat gastric mucosal cells wereincubated with aspirin and cytotoxicity already induced byhypoxanthineXO was determined [121] Aspirin was shownto increase the cytotoxicity induced by XO This increase incytotoxicity in the presence of hypoxanthineXO was incor-porated with an increase in uric acid levels which suggestsROS generation in these cells Aspirin had an additive effect tothese changes induced by hypoxanthineXO [121] In anotherstudy it was seen that indomethacin augmented the XOactivity in human colonic adenocarcinoma cells bymore than100 upon 60 minutes of exposure which resulted in a timedependent increase in the rate of lipid peroxidation [96]

9 NSAIDs and Lipoxygenase

Arachidonic acid that is formed by the action of diacylglyc-erol and cytosolic phospholipase A2 (cPLA

2) from the mem-

brane phospholipids is a substrate involved in the formationof either prostaglandins and thromboxanes or leukotrienes bythe cyclooxygenase and lipoxygenase pathway respectivelyThe oxidation of arachidonic acid by these enzymes leadsto the formation of ROS as the by-product [122] It wasshown that cPLA

2-arachidonic acid linked cascade could

lead to an increase in ROS generation via the lipoxygenasepathway in the rat fibroblasts [123] The same group reportedthat the generation of ROS triggered by tumor necrosisfactor- (TNF-) 120572 was mediated by the activation of cPLA

2

and the metabolism of arachidonic acid by 5-lipoxygenase[124] Lipoxygenase has been reported to be involved inthe upregulation of NADPH oxidases and increased ROSgeneration [125]

While NSAIDs are well known to inhibit the cyclooxyge-nase pathway they do not inhibit the formation of leukotri-enes by the lipoxygenase pathway NSAIDs increases arachi-donic acid levels [82 126] and arachidonic acid itself canincrease ROS generation [82] Increased levels of leukotrienesand other metabolites of the lipoxygenase pathway inducedby NSAIDs lead to gastric mucosal damage [127] Theeffect of NSAIDs like indomethacin piroxicam and aspirinon the development of gastric lesions could be reversedby 5-lipoxygenase inhibitors and leukotriene antagonists[127] This is consistent with NSAIDs increasing the lev-els of leukotrienes and products of 5-lipoxygenase activ-ity Increased occurrences of leukotriene C4 productionwere also observed in the gastric circulation induced byindomethacin [128] The gastric and intestinal lesions inthe presence of indomethacin could be reverted by 5-lipoxygenase inhibitor Increased gastricmucosal leukotriene

B4 production was observed in patients suffering fromarthritis due to prolonged NSAID treatment [129] NSAIDshave also been reported to increase the expression of 15-lipoxygenase-1 protein in colorectal cancer cells resulting inthe inhibition of cell growth and apoptosis [130] Althougha growing body of evidence supports the idea that NSAIDsupregulate the lipoxygenase pathway no direct evidence isavailable on the precise biochemical mechanism by whichNSAIDs induced lipoxygenase pathway activity increase therate of ROS generation It is possible that the upregulation ofthe lipoxygenase pathway by NSAIDs may contribute to thenet increase in free radicals leading to apoptosis and oxidativecell damage and ultimately cell death

10 NSAIDs and Cytochrome P450

Cytochrome P450 (P450) is a family of biotransformationenzymes involved in critical metabolic processes [131] Theyare a class of more than 50 enzymes that catalyze a diverseset of reactions with a wide range of chemically dissimilarsubstrates [131] In humans they are primarily membrane-associated proteins that can be found in the inner mem-brane of the mitochondria or endoplasmic reticulum of cell[132] They are predominantly expressed in the liver but arepresent in other tissues of the body as wellThis group ofproteins belongs to the heme-thiolate enzyme family andthey are involved in the oxidative metabolism of numerouscompounds of endogenous and exogenous origin [133] Therole of P450 in drug metabolism has been considered tobe a key factor in overcoming the adverse and toxicologicaleffects of drugs [134] The P450 system has been shown toplay an important role in activation of oxygen and ROSgeneration [135 136] Normally the active oxygen species areformed in situ during the P450 cycle when it reacts with asubstrate However uncoupling of the P450 system results inexcessive ROS generation and the P450 system being unableto metabolize a substrate which leads to oxidative stress andsubsequently cellular damage [133 137]

Several studies have indicated the role of P450 intoxicity induced by NSAIDs [138ndash140] One such NSAIDdiclofenac has been associated with hepatotoxicity due topoor metabolism by P450 [140] Expression of a drug metab-olizing mutant of P450 BM3M11 in yeast mimicked theoxidative metabolite profiles of diclofenac metabolized byhumanP450s [141]The treatment of the yeast cells expressingthe mutant BM3M11 with 30 120583M and 50120583M diclofenacincreased the ROS production in the cells significantly by 15and 4 times respectively compared to cells not treated withthe compound [140] In another study by the same groupit was shown that diclofenac as well as indomethacin andketoprofen showed an increase in ROS generation by 15ndash2times compared to control [95] On the other hand P450 hasbeen shown to be upregulated in bacterial cells by NSAIDslike ibuprofen ketoprofen and indomethacin by 118-fold39-fold and 30-fold respectively relative to control cells[142] Although no direct evidence is yet available on theinvolvement of P450 in the generation of ROS by NSAIDsin CVD experimental data available in other cells suggest


that NSAIDs may lead to increased ROS levels via theupregulation of P450 in cardiovascular related cells

11 NSAIDs and Nitric Oxide Synthases

Nitric oxide (NO) is among the few gaseous biological mes-sengers and can be synthesized from l-arginine by endothelialnitric oxide synthase (eNOS) NO has emerged as a keysignaling molecule for maintaining vasodilation and thedysfunction of enzymes associated with NO production hasbeen implicated in various pathological conditions includingCVD diabetes and hypertension When eNOS which isresponsible for regulating vascular homeostasis is impaireddue to a lack of the cofactor tetrahydrobiopterin (BH4) itresults in the generation of O

2

∙minus rather than NO [143] Thisstate is referred to as the uncoupled state of eNOS and ismainly attributed to the deficiency or lack of BH4 leading tothe generation of free radicals [144]The depletion of the BH4can be the result of severe oxidative stress

A 15-fold decrease in plasma nitrite levels was demon-strated in SHR treated with nonselective COX inhibitorsand coxibs [114] Although earlier reports demonstrated acardioprotective effect of naproxen a twofold decrease inplasma nitrite levels was observed after treatment of SHRwith naproxen suggesting diminished levels of bioactive NO[114] Additionally the authors reported an upregulation inthe eNOS mRNA expression levels rather than a decrease bydiclofenac and naproxen by gt2-fold This increase has beenattributed to the generation of H

2O2which increases eNOS

expression at the transcriptional and posttranscriptionallevels [145] Diclofenac treated animals showed an increasein O2

∙minus production which could be inhibited by the NOSinhibitor l-NAME NSAIDs have also been shown to impairthe NO induced vasodilation in healthy individuals possiblydue to increased oxidative stress induced by NSAIDs due tothe uncoupling of eNOS [114]

12 NSAIDs ROS and Cardiovascular Diseases

Li et al investigated the effect of several NSAIDs onfree radical generation NADPH oxidase expression eNOSexpression and nitrite levels in the rat aorta and heart usinga mouse model of hypertension as well as vasodilation inhuman subjects [114] As previously described in the sectionsNSAIDs and nicotinamide adenine dinucleotide phosphate-oxidase and NSAIDs and nitric oxide synthases this studydemonstrated that the heart and aorta of the NSAID treatedanimals showed increased O

2

∙minus production and oxidativestressTheoxidative stresswas due toROS formation bymanyenzymes including NADPH oxidases with diclofenac beingthe most potent inducer of NADPH oxidases [114]

Rat embryonic H9c2 cardiac cells exposed to celecoxibat concentrations of 10 120583M and 100 120583M demonstrated adecrease in cell viability by 45 and 92 respectively andthis was associated with a decrease in the expression levelsof the cell survival protein Bcl2 [146] However 1 120583M ofcelecoxib had no significant effect on cell viability and wasassociated with an upregulation of the Bcl

2transcript level

by sim30 This effect of such a low amount of NSAID inthe upregulation of cell survival gene expression is rathercomparable to the effect of proteasome inhibitors likeMG-132or epoxomicin which at nanomolar ranges has been reportedto actually increase the proteasome activity in the pretreatedneocortical neurons [147] Also this was the first study thatmeasured COX-2 levels directly in the cardiac cells [146]Although no significant changes in the COX-2 levels wereobserved in cells treated with 1 120583M celecoxib at 10 120583M theCOX-2 levels decreased [146]

Apart from studying the effect of NSAIDs on cardiomy-ocytes the role of NSAIDs on the COX enzyme system inplatelets is also of prime importance Platelets are impor-tant for the life-saving blood coagulation process [148] andare closely associated with CVD [149] The aggregationof platelets by agonists like ADP collagen thrombin orepinephrine leads to the formation of thrombus (microaggre-gate of platelets in fibrin mass) at the site of atheroscleroticplaque fissure on the coronary artery wall of the heart whichresults in thrombosis or CVD [150] As expected because ofthe importance of platelets in CVD the generation of ROS inplatelets has been well-studied [149] Measurement of O

2

∙minus

in platelets activated by thrombin as well as in inactivatedplatelets demonstrated that thrombin significantly increasedthe free radical (O

2

∙minus) generation by sim40 in the activatedplatelets compared to the inactivated platelets [149] Althoughthis result suggests the possibility of increased ROS formationin activated platelets no direct role of NSAIDs in theproduction of ROS in the platelets has been reported [151]However it has been demonstrated that selective COX-2inhibition led to an increase in platelet activation [152] Theincreased platelet activation by COX-2 inhibition facilitatedthrombotic vessel occlusion after the disruption of the vesselwall supporting a critical role for COX-2 inhibition inplatelet activation and aggregation leading to thrombosis[152] All these effects were accompanied by a decline in theproduction of endothelial prostacyclin Diclofenac (1mgkg)a nonselective NSAID caused significantly increased plateletvessel wall interaction with an increase in the number ofadherent platelets on the endothelium of diclofenac treatedanimals compared to the control group [153] Thromboticvessel wall occlusion was also increased in animals treatedwith diclofenac once the vessel wall had been injured [153]Thedirect contribution of ROS induced byNSAIDs to plateletactivation and aggregation is yet to be determined The roleof aspirin in cardioprotection by the inhibition of plateletaggregation due to the inhibition of platelet thromboxane A2iswell established [154 155] Similarly naproxen has also beensuggested to have significant antiplatelet effect comparable tothat of aspirin [156]

13 Possible Alternatives to NSAIDs forReduced Cardiovascular Events

With the availability of a larger selection of synthetic drugspeople are more aware of the side effects of taking drugson a regular basis Nutraceuticals or phytoceuticals are aclass of compounds that are derived from plants with feweror no side effects compared to synthetic drugs [157] but


with similar and sometimes even better beneficial biologicaleffects [158] Hyperforin obtained from the herb Hypericumperforatum has been reported to inhibit COX-1 3ndash18-foldhigher when compared to aspirin [158] Hyperforin is anatural antioxidant and has been shown to inhibit excessiveROS generation [159] as well as prostaglandin synthesis [160]Several other studies indicate the usefulness of nutraceuticalsin cardiovascular protection specifically by the inhibition ofCOX Purified anthocyanins (pigment responsible for thecolor of fruits) have been shown to have an effect on COXactivity [161] While NSAIDs like naproxen (10 120583M) andibuprofen (10 120583M) showed COX-1 inhibition of 473 and543 respectively anthocyanins from raspberries (10 120583M)and blackberries (10 120583M) showed an inhibition of 458and 385 respectively COX-2 inhibition by naproxen andibuprofen was 398 and 413 for sweet cherries it rangedfrom 36 to 48 and for berries the inhibition was between31 and 46 [161] The antioxidant activities of the antho-cyanins derived from these fruits were also high suggestingthe importance of their role in reducing ROS

In other studies the biologically active compounds ofmycelia of Grifola frondosa and Agrocybe aegerita (ediblemushrooms) were isolated and studied for their antioxidantand COX activity [162 163] The authors found that that fattyacids like ergosterol ergostra-468(14)22-tetraen-3-one and1-oleoyl-2-linoleoyl-3-palmitoylglycerol in the case of Grifolafrondosa and palmitic acid ergosterol 58-epidioxy-ergosta-622-dien-3beta-ol mannitol and trehalose in the case ofAgrocybe aegerita as determined by spectroscopic analysiswere the most potent in inhibiting both COX-1 and COX-2 [162 163] The efficiency of fish oil omega-3 fatty acidslike eicosapentaenoic acid (EPA) and docosahexaenoic acid(DCHA) [164] in preventing CVD stroke and high bloodpressure is also well established [165 166] It was suggestedthat fish oils have natural inhibitors which can inhibit COX[167] While the EPA of fish oils inhibited COX-1 more thanCOX-2 [168] DCHA was shown to be an effective inhibitorof arachidonic acid induced prostaglandin biosynthesis [169]Among the other reports available indicating the role ofnutraceuticals in the cyclooxygenase pathway calcitriol (vita-minD) [170] several types of flavonoids [171 172] andmarinederived steroids from formosan soft coral Clavularia viridis[173] all have been reported to affect prostaglandin synthesisInterestingly most of the compounds exhibit antioxidantproperties and inhibit both COX-1 and COX-2 [161 172]suggesting a role in cardioprotection

14 Conclusion

The review focuses on ROS generated by NSAIDs and its rolein CVD While the number of clinical experiments investi-gating the effects of NSAIDs on the cardiovascular eventshas significantly increased over the last two decades basicresearch related to the mechanism by which NSAIDs causecardiovascular dysfunction is limited High variability inthe clinical trials conducted (different populations dosagesexposure and types of NSAIDs) has led to results which aredifficult to interpret and compare between studies Howeverirrespective of the type of NSAID used increased occurrence

of CVD is common Clinical trials showed that the risk ofCVD is higher for coxibs than nonselective NSAIDs probablythrough the imbalance between prostacyclinthromboxanelevels

According to the Joint Meeting of the Arthritis AdvisoryCommittee and Drug Safety and Risk Management Advi-sory Committee US FDA (2014) patients with a historyof myocardial infarction heart failure hypertension andother CV risk factors are at a greater risk of developingcardiovascular diseases due to NSAIDs usage compared tonormal individuals [174] The committee concluded thatthe increased risk of fatal cardiovascular thrombotic eventsmyocardial infarction and stroke by NSAIDS should belessened by using the lowest effective dose of NSAIDs for theshortest period of time possible

Interestingly most of the studies that showed the gener-ation of ROS induced by NSAIDs in various types of cellsinvolved nonselective or semiselective NSAIDs (Table 3)However irrespective of the type of NSAIDs used eitherselective COX-2 inhibitors or the nonselective NSAIDsNSAIDs produced oxidative stress with the nonselectiveNSAIDs showing a greater degree of ROS generation [114]Therefore it may be hypothesized that it is through thegeneration of ROS as well as the upregulation and downreg-ulation of several cell survival pathways that these NSAIDsexert their thrombogenic effect Although COX-2 inhibitorshave been shown to cause CVD some COX-2 inhibitorssuch as celebrex are currently still used widely as the FDAdetermined the benefits of this drug outweigh the potentialrisks in properly selected and informed patients The use ofCOX-2 inhibitors underscores the need for compounds withNSAID like properties without the side effects

As such various aspects of NSAID induced cardiotoxi-city still need to be investigated including the significanceof NSAID induced lipoxygenase ROS generation in thecardiovascular system determining if prevention of ROSproduction reducesCVDanddetermining if ROSproductionis needed for pain relief Answers to these questionswill resultin substantial improvement on how CVD risk managementwill be conducted in the future

Abbreviations

CVD Cardiovascular diseaseCOX-1 Cyclooxygenase-1COX-2 Cyclooxygenase-2NSAIDS Nonsteroidal anti-inflammatory drugsROS Reactive oxygen species

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgment

This research was carried out using UC Davis Researchfunds


References

[1] L J Crofford ldquoUse of NSAIDs in treating patients witharthritisrdquo Arthritis Research amp Therapy vol 15 supplement 3article S2 2013

[2] Y I Cha and R N DuBois ldquoNSAIDs and cancer preventiontargets downstream of COX-2rdquoAnnual Review of Medicine vol58 pp 239ndash252 2007

[3] J Cuzick F Otto J A Baron et al ldquoAspirin and non-steroidal anti-inflammatory drugs for cancer prevention aninternational consensus statementrdquo The Lancet Oncology vol10 no 5 pp 501ndash507 2009

[4] J L Liggett X Zhang T E Eling and S J Baek ldquoAnti-tumor activity of non-steroidal anti-inflammatory drugscyclooxygenase-independent targetsrdquo Cancer Letters vol 346no 2 pp 217ndash224 2014

[5] F L Lanza F K L Chan and E M M Quigley ldquoGuidelinesfor prevention of NSAID-related ulcer complicationsrdquo TheAmerican Journal of Gastroenterology vol 104 no 3 pp 728ndash738 2009

[6] amp119886119901119900119904 119860 Lanas P Carrera-Lasfuentes Y Arguedas et al ldquoRiskof upper and lower gastrointestinal bleeding in patients takingnonsteroidal anti-inflammatory drugs antiplatelet agents oranticoagulantrdquo Clinical Gastroenterology and Hepatology 2014

[7] F Lapi L Azoulay H Yin S J Nessim and S Suissa ldquoConcur-rent use of diuretics angiotensin converting enzyme inhibitorsand angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury nestedcase-control studyrdquo British Medical Journal vol 346 no 7890Article ID e8525 2013

[8] K A Taubert ldquoCardiology patient pages can patients with car-diovascular disease take nonsteroidal antiinflammatory drugsrdquoCirculation vol 117 no 17 pp e322ndashe324 2008

[9] M Soyun J E G Hwang Z Cui and A V Gomes Non-Steroidal Anti-Inflammatory Drugs and Increased Risk of SuddenCardiac Death Nova Science Publisher Hauppauge NY USA2013

[10] F E Silverstein G Faich J L Goldstein et al ldquoGastrointestinaltoxicity with celecoxib vs nonsteroidal anti-inflammatory drugsfor osteoarthritis and rheumatoid arthritis the CLASS studya randomized controlled trialrdquo The Journal of the AmericanMedical Association vol 284 no 10 pp 1247ndash1255 2000

[11] L A G Rodramp119886119901119900119904 119894guez and L B Tolosa ldquoRisk of upper gas-trointestinal complications among users of traditional NSAIDsand COXIBs in the general populationrdquo Gastroenterology vol132 no 2 pp 498ndash506 2007

[12] J L Goldstein F E Silverstein N M Agrawal et al ldquoReducedrisk of upper gastrointestinal ulcer complications with cele-coxib a novel COX-2 inhibitorrdquo The American Journal ofGastroenterology vol 95 no 7 pp 1681ndash1690 2000

[13] A Helin-Salmivaara A Virtanen R Vesalainen et al ldquoNSAIDuse and the risk of hospitalization for firstmyocardial infarctionin the general population a nationwide case-control study fromFinlandrdquo European Heart Journal vol 27 no 14 pp 1657ndash16632006

[14] M Amer V R Bead J Bathon R S Blumenthal and DN Edwards ldquoUse of nonsteroidal anti-inflammatory drugsin patients with cardiovascular disease a cautionary talerdquoCardiology in Review vol 18 no 4 pp 204ndash212 2010

[15] A Rostom P Moayyedi and R Hunt ldquoCanadian consensusguidelines on long-term nonsteroidal anti-inflammatory drugtherapy and the need for gastroprotection benefits versus risksrdquo

Alimentary PharmacologyampTherapeutics vol 29 no 5 pp 481ndash496 2009

[16] N A Nussmeier A A Whelton M T Brown et al ldquoCompli-cations of the COX-2 inhibitors parecoxib and valdecoxib aftercardiac surgeryrdquoTheNew England Journal of Medicine vol 352no 11 pp 1081ndash1091 2005

[17] E M Antman J S Bennett A Daugherty C Furberg HRoberts and K A Taubert ldquoUse of nonsteroidal antiinflamma-tory drugs an update for clinicians a scientific statement fromthe American Heart Associationrdquo Circulation vol 115 no 12pp 1634ndash1642 2007

[18] M E Farkouh and B P Greenberg ldquoAn evidence-based reviewof the cardiovascular risks of nonsteroidal anti-inflammatorydrugsrdquo The American Journal of Cardiology vol 103 no 9 pp1227ndash1237 2009

[19] D Mukherjee S E Nissen and E J Topol ldquoRisk of cardio-vascular events associated with selective COX-2 inhibitorsrdquoTheJournal of the American Medical Association vol 286 no 8 pp954ndash959 2001

[20] N Bhala J Emberson A Merhi et al ldquoVascular and upper gas-trointestinal effects of non-steroidal anti-inflammatory drugsmeta-analyses of individual participant data from randomisedtrialsrdquoThe Lancet vol 382 no 9894 pp 769ndash779 2013

[21] T G Brock R W McNish and M Peters-Golden ldquoArachi-donic acid is preferentially metabolized by cyclooxygenase-2to prostacyclin and prostaglandin E2rdquoThe Journal of BiologicalChemistry vol 274 no 17 pp 11660ndash11666 1999

[22] S U Monrad F Kojima M Kapoor et al ldquoGenetic deletion ofmPGES-1 abolishes PGE2 production in murine dendritic cellsand alters the cytokine profile but does not affect maturationor migrationrdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 84 no 3-4 pp 113ndash121 2011

[23] R N DuBois S B Abramson L Crofford et al ldquoCyclooxyge-nase in biology and diseaserdquoThe FASEB Journal vol 12 no 12pp 1063ndash1073 1998

[24] J Clairia ldquoCyclooxygenase-2 biologyrdquo Current PharmaceuticalDesign vol 9 no 27 pp 2177ndash2190 2003

[25] A Zarghi and S Arfaei ldquoSelective COX-2 inhibitors a reviewof their structure-activity relationshipsrdquo Iranian Journal ofPharmaceutical Research vol 10 no 4 pp 655ndash683 2011

[26] W L Smith R M Garavito and D L DeWitt ldquoProstaglandinendoperoxide H synthases (cyclooxygenases)-1 and -2rdquo TheJournal of Biological Chemistry vol 271 no 52 pp 33157ndash331601996

[27] D Maamp119886119901119900119904 119904liamp119886119901119900119904 119899ska R Woamp119886119901119900119904 119911niak A Kaliszekand I Modelska ldquoExpression of cyclooxygenase-2 in astrocytesof human bRAin after global ischemiardquo Folia Neuropathologicavol 37 no 2 pp 75ndash79 1999

[28] F Nantel E Meadows D Denis B Connolly K M Mettersand A Giaid ldquoImmunolocalization of cyclooxygenase-2 in themacula densa of human elderlyrdquo FEBS Letters vol 457 no 3 pp475ndash477 1999

[29] N Zidar K Odar D Glavac M Jerse T Zupanc and D StajerldquoCyclooxygenase in normal human tissuesmdashis COX-1 really aconstitutive isoform andCOX-2 an inducible isoformrdquo Journalof Cellular andMolecular Medicine vol 13 no 9 pp 3753ndash37632009

[30] E Fosslien ldquoCardiovascular complications of non-steroidalanti-inflammatory drugsrdquo Annals of Clinical amp LaboratoryScience vol 35 no 4 pp 347ndash385 2005


[31] J Song Q Chen and D Xing ldquoEnhanced apoptotic effects bydownregulating Mcl-1 evidence for the improvement of photo-dynamic therapy with Celecoxibrdquo Experimental Cell Researchvol 319 no 10 pp 1491ndash1504 2013

[32] Y Lin L Bai W Chen and S Xu ldquoThe NF-120581B activationpathways emerging molecular targets for cancer preventionand therapyrdquo Expert Opinion onTherapeutic Targets vol 14 no1 pp 45ndash55 2010

[33] A Bank J Yu and L Zhang ldquoNSAIDs downregulate Bcl-XLand dissociate BAX and Bcl-X L to induce apoptosis in coloncancer cellsrdquo Nutrition and Cancer vol 60 supplement 1 pp98ndash103 2008

[34] I-Y Kim S-Y Park Y Kang D Thapa H G Choi and J-AKim ldquoRole of nonsteroidal anti-inflammatory drug-activatedgene-1 in docetaxel-induced cell death of human colorectalcancer cells with different p53 statusrdquo Archives of PharmacalResearch vol 34 no 2 pp 323ndash330 2011

[35] Y-J Zhang Q Dai S-MWu et al ldquoSusceptibility for NSAIDs-induced apoptosis correlates to p53 gene status in gastric cancercellsrdquo Cancer Investigation vol 26 no 9 pp 868ndash877 2008

[36] B B Aggarwal and S Shishodia ldquoMolecular targets of dietaryagents for prevention and therapy of cancerrdquo BiochemicalPharmacology vol 71 no 10 pp 1397ndash1421 2006

[37] MYoshida I ShiojimaH Ikeda and I Komuro ldquoChronic dox-orubicin cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway and attenuated by pitavastatinthrough the inhibition of Rac1 activityrdquo Journal ofMolecular andCellular Cardiology vol 47 no 5 pp 698ndash705 2009

[38] DGDeavall EAMartin JMHorner andRRoberts ldquoDrug-induced oxidative stress and toxicityrdquo Journal of Toxicology vol2012 Article ID 645460 13 pages 2012

[39] T D Warner and J A Mitchell ldquoCOX-2 selectivity alonedoes not define the cardiovascular risks associated with non-steroidal anti-inflammatory drugsrdquo The Lancet vol 371 no9608 pp 270ndash273 2008

[40] W B White ldquoCardiovascular effects of the cyclooxygenaseinhibitorsrdquo Hypertension vol 49 no 3 pp 408ndash418 2007

[41] P Kohli P G Steg C P Cannon et al ldquoNSAID use andassociation with cardiovascular outcomes in outpatients withstable atherothrombotic diseaserdquo The American Journal ofMedicine vol 127 no 1 pp 53e1ndash60e1 2014

[42] M Mamdani D N Juurlink D S Lee et al ldquoCyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes inelderly patients a population-based cohort studyrdquo The Lancetvol 363 no 9423 pp 1751ndash1756 2004

[43] P McGettigan and D Henry ldquoCardiovascular risk withnon-steroidal anti-inflammatory drugs systematic reviewof population-based controlled observational studiesrdquo PLoSMedicine vol 8 no 9 Article ID e1001098 2011

[44] ADAPT Research Group ldquoCardiovascular and cerebrovascularevents in the randomized controlled Alzheimerrsquos disease anti-inflammatory prevention trial (ADAPT)rdquo PLoS Clinical Trialsvol 1 no 7 article e33 2006

[45] S D Solomon J J V McMurray M A Pfeffer et al ldquoCar-diovascular risk associated with celecoxib in a clinical trial forcolorectal adenoma preventionrdquo The New England Journal ofMedicine vol 352 no 11 pp 1071ndash1080 2005

[46] P M Kearney C Baigent J Godwin H Halls J R Embersonand C Patrono ldquoDo selective cyclo-oxygenase-2 inhibitors andtraditional non-steroidal anti-inflammatory drugs increase the

risk of atherothrombosis Meta-analysis of randomised trialsrdquoThe British Medical Journal vol 332 no 7553 pp 1302ndash13052006

[47] C Bombardier L Laine A Reicin et al ldquoComparison ofupper gastrointestinal toxicity of rofecoxib and naproxen inpatients with rheumatoid arthritisrdquo The New England Journalof Medicine vol 343 no 21 pp 1520ndash1528 2000

[48] R S Bresalier R S Sandler H Quan et al ldquoCardiovascularevents associated with rofecoxib in a colorectal adenomachemoprevention trialrdquo The New England Journal of Medicinevol 352 no 11 pp 1092ndash1102 2005

[49] M A Konstam M R Weir A Reicin et al ldquoCardiovascularthrombotic events in controlled clinical trials of rofecoxibrdquoCirculation vol 104 no 19 pp 2280ndash2288 2001

[50] J Zhang E LDing andY Song ldquoAdverse effects of cyclooxyge-nase 2 inhibitors on renal and arrhythmia events meta-analysisof randomized trialsrdquo The Journal of the American MedicalAssociation vol 296 no 13 pp 1619ndash1632 2006

[51] W A Ray C Varas-Lorenzo C P Chung et al ldquoCardiovascularrisks of nonsteroidal antiinflammatory drugs in patients afterhospitalization for serious coronary heart diseaserdquo CirculationCardiovascular Quality and Outcomes vol 2 no 3 pp 155ndash1632009

[52] R P Mason M F Walter H P McNulty et al ldquoRofecoxibincreases susceptibility of human LDL and membrane lipidsto oxidative damage a mechanism of cardiotoxicityrdquo Journal ofCardiovascular Pharmacology vol 47 supplement 1 pp S7ndashS142006

[53] M L Capone M G Sciulli S Tacconelli et al ldquoPharmacody-namic interaction of naproxen with low-dose aspirin in healthysubjectsrdquo Journal of the American College of Cardiology vol 45no 8 pp 1295ndash1301 2005

[54] E Rahme L Pilote and J LeLorier ldquoAssociation betweennaproxen use and protection against acute myocardial infarc-tionrdquoArchives of Internal Medicine vol 162 no 10 pp 1111ndash11152002

[55] D H Solomon R J Glynn R Levin and J Avorn ldquoNon-steroidal anti-inflammatory drug use and acute myocardialinfarctionrdquo Archives of Internal Medicine vol 162 no 10 pp1099ndash1104 2002

[56] D J Watson T Rhodes B Cai and H A Guess ldquoLowerrisk of thromboembolic cardiovascular events with naproxenamong patients with rheumatoid arthritisrdquo Archives of InternalMedicine vol 162 no 10 pp 1105ndash1110 2002

[57] W A Ray C M Stein K Hall J R Daugherty and M RGriffin ldquoNon-steroidal anti-inflammatory drugs and risk ofserious coronary heart disease an observational cohort studyrdquoThe Lancet vol 359 no 9301 pp 118ndash123 2002

[58] D J Graham D Campen R Hui et al ldquoRisk of acutemyocardial infarction and sudden cardiac death in patientstreated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs nested case-control studyrdquoThe Lancet vol 365 no 9458 pp 475ndash481 2005

[59] MMamdani P Rochon D N Juurlink et al ldquoEffect of selectivecyclooxygenase 2 inhibitors and naproxen on short-term risk ofacute myocardial infarction in the elderlyrdquo Archives of InternalMedicine vol 163 no 4 pp 481ndash486 2003

[60] A Undas K E Brummel-Ziedins and K G MannldquoAntithrombotic properties of aspirin and resistance toaspirin beyond strictly antiplatelet actionsrdquo Blood vol 109 no6 pp 2285ndash2292 2007


[61] O Vesterqvist and K Green ldquoEffects of naproxen on the in vivosynthesis of thromboxane and prostacyclin in manrdquo EuropeanJournal of Clinical Pharmacology vol 37 no 6 pp 563ndash5651989

[62] J F Turrens andA Boveris ldquoGeneration of superoxide anion bythe NADH dehydrogenase of bovine heart mitochondriardquo TheBiochemical Journal vol 191 no 2 pp 421ndash427 1980

[63] J E Klaunig and L M Kamendulis ldquoThe role of oxidativestress in carcinogenesisrdquo Annual Review of Pharmacology andToxicology vol 44 pp 239ndash267 2004

[64] T Ide H Tsutsui S Kinugawa et al ldquoMitochondrial electrontransport complex I is a potential source of oxygen free radicalsin the failing myocardiumrdquo Circulation Research vol 85 no 4pp 357ndash363 1999

[65] X Li P Fang J Mai E T Choi H Wang and X F YangldquoTargeting mitochondrial reactive oxygen species as noveltherapy for inflammatory diseases and cancersrdquo Journal ofHematology amp Oncology vol 6 article 19 2013

[66] S I Dikalov and Z Ungvari ldquoRole of mitochondrial oxidativestress in hypertensionrdquo The American Journal of PhysiologymdashHeart and Circulatory Physiology vol 305 no 10 pp H1417ndashH1427 2013

[67] M T Coughlan D R Thorburn S A Penfold et al ldquoRage-induced cytosolic ROS promote mitochondrial superoxidegeneration in diabetesrdquo Journal of the American Society ofNephrology vol 20 no 4 pp 742ndash752 2009

[68] K Raedschelders DM Ansley andDD Y Chen ldquoThe cellularand molecular origin of reactive oxygen species generationduring myocardial ischemia and reperfusionrdquo Pharmacology ampTherapeutics vol 133 no 2 pp 230ndash255 2012

[69] A J M Watson J N Askew and R S P BensonldquoPoly(adenosine diphosphate ribose) polymerase inhibitionprevents necrosis induced by H

2O2

but not apoptosisrdquoGastroenterology vol 109 no 2 pp 472ndash482 1995

[70] F J Giordano ldquoOxygen oxidative stress hypoxia and heartfailurerdquo The Journal of Clinical Investigation vol 115 no 3 pp500ndash508 2005

[71] M Jastroch A S Divakaruni S Mookerjee J R Treberg andM D Brand ldquoMitochondrial proton and electron leaksrdquo Essaysin Biochemistry vol 47 pp 53ndash67 2010

[72] Q Chen E J Vazquez S Moghaddas C L Hoppel andE J Lesnefsky ldquoProduction of reactive oxygen species bymitochondria central role of complex IIIrdquo The Journal ofBiological Chemistry vol 278 no 38 pp 36027ndash36031 2003

[73] H Y Lim W Wang J Chen K Ocorr and R Bodmer ldquoROSregulate cardiac function via a distinct paracrine mechanismrdquoCell Reports vol 7 no 1 pp 35ndash44 2014

[74] J Boonstra and J A Post ldquoMolecular events associated withreactive oxygen species and cell cycle progression in mam-malian cellsrdquo Gene vol 337 pp 1ndash13 2004

[75] H Pelicano R-H Xu M Du et al ldquoMitochondrial respirationdefects in cancer cells cause activation of Akt survival pathwaythrough a redox-mediated mechanismrdquo Journal of Cell Biologyvol 175 no 6 pp 913ndash923 2006

[76] T Finkel ldquoOxygen radicals and signalingrdquo Current Opinion inCell Biology vol 10 no 2 pp 248ndash253 1998

[77] G L Wang B-H Jiang E A Rue and G L SemenzaldquoHypoxia-inducible factor 1 is a basic-helix-loop-helix-PASheterodimer regulated by cellular O

2tensionrdquo Proceedings of the

National Academy of Sciences of theUnited States of America vol92 no 12 pp 5510ndash5514 1995

[78] S K Law C S-L Leung K L Yau et al ldquoRegulation ofmultipletranscription factors by reactive oxygen species and effectsof pro-inflammatory cytokines released during myocardialinfarction on cardiac differentiation of embryonic stem cellsrdquoInternational Journal of Cardiology vol 168 no 4 pp 3458ndash3472 2013

[79] H Kusuhara H Komatsu H Sumichika and K SugaharaldquoReactive oxygen species are involved in the apoptosis inducedby nonsteroidal anti-inflammatory drugs in cultured gastriccellsrdquoEuropean Journal of Pharmacology vol 383 no 3 pp 331ndash337 1999

[80] M Adachi H Sakamoto R Kawamura W Wang K Imaiand Y Shinomura ldquoNonsteroidal anti-inflammatory drugs andoxidative stress in cancer cellsrdquo Histology and Histopathologyvol 22 no 4ndash6 pp 437ndash442 2007

[81] T Minami M Adachi R Kawamura Y Zhang Y Shinomuraand K Imai ldquoSulindac enhances the proteasome inhibitorbortezomib-mediated oxidative stress and anticancer activityrdquoClinical Cancer Research vol 11 no 14 pp 5248ndash5256 2005

[82] C Giardina and M S Inan ldquoNonsteroidal anti-inflammatorydrugs short-chain fatty acids and reactive oxygen metabolismin human colorectal cancer cellsrdquo Biochimica et BiophysicaActamdashMolecular Cell Research vol 1401 no 3 pp 277ndash2881998

[83] E Barbieri and P Sestili ldquoReactive oxygen species in skeletalmuscle signalingrdquo Journal of Signal Transduction vol 2012Article ID 982794 17 pages 2012

[84] I Dolado and A R Nebreda ldquoAKT and oxidative stress teamup to kill cancer cellsrdquo Cancer Cell vol 14 no 6 pp 427ndash4292008

[85] S-Y Kim S Bae K-H Choi and S An ldquoHydrogen peroxidecontrols Akt activity via ubiquitinationdegradation pathwaysrdquoOncology Reports vol 26 no 6 pp 1561ndash1566 2011

[86] MWu Q Bian Y Liu et al ldquoSustained oxidative stress inhibitsNF-120581B activation partially via inactivating the proteasomerdquoFreeRadical Biology and Medicine vol 46 no 1 pp 62ndash69 2009

[87] A Inoue S Muranaka H Fujita T Kanno H Tamai and KUtsumi ldquoMolecular mechanism of diclofenac-induced apopto-sis of promyelocytic leukemia dependency on reactive oxygenspecies Akt Bid cytochrome c and caspase pathwayrdquo FreeRadical Biology amp Medicine vol 37 no 8 pp 1290ndash1299 2004

[88] C Michiels ldquoEndothelial cell functionsrdquo Journal of CellularPhysiology vol 196 no 3 pp 430ndash443 2003

[89] J-Y Liou C-CWu B-R Chen L B Yen andKKWu ldquoNons-teroidal anti-inflammatory drugs induced endothelial apoptosisby perturbing peroxisome proliferator-activated receptor-deltatranscriptional pathwayrdquo Molecular Pharmacology vol 74 no5 pp 1399ndash1406 2008

[90] M Hacker ldquoAdverse drug reactionsrdquo in Pharmacology Prin-ciples and Practice M Hacker W S Messer II and K ABachmann Eds pp 327ndash352 Elsevier New York NY USA2009

[91] D A Harris and A M Das ldquoControl of mitochondrial ATPsynthesis in the heartrdquo The Biochemical Journal vol 280 part3 pp 561ndash573 1991

[92] S W Ballinger ldquoMitochondrial dysfunction in cardiovasculardiseaserdquo Free Radical Biology amp Medicine vol 38 no 10 pp1278ndash1295 2005

[93] Y Nagano H Matsui O Shimokawa et al ldquoRebamipide atten-uates nonsteroidal anti-inflammatory drugs (NSAID) inducedlipid peroxidation by the manganese superoxide dismutase


(MnSOD) overexpression in gastrointestinal epithelial cellsrdquoJournal of Physiology and Pharmacology vol 63 no 2 pp 137ndash142 2012

[94] R Moreno-Samp119886119901119900119904 119886nchez C Bravo C Vamp119886119901119900119904 119886squez GAyala L H Silveira and M Martamp119886119901119900119904 119894nez-Lavamp119886119901119900119904 119894nldquoInhibition and uncoupling of oxidative phosphorylation bynonsteroidal anti-inflammatory drugs Study in mitochondriasubmitochondrial particles cells and whole heartrdquo BiochemicalPharmacology vol 57 no 7 pp 743ndash752 1999

[95] J S van Leeuwen B Unlu N P E Vermeulen and J CVos ldquoDifferential involvement of mitochondrial dysfunctioncytochrome P450 activity and active transport in the toxicityof structurally related NSAIDsrdquo Toxicology in Vitro vol 26 no2 pp 197ndash205 2012

[96] C Carrasco-Pozo M Gotteland and H Speisky ldquoApplepeel polyphenol extract protects against indomethacin-induceddamage in Caco-2 cells by preventing mitochondrial complex Iinhibitionrdquo Journal of Agricultural and Food Chemistry vol 59no 21 pp 11501ndash11508 2011

[97] K E van den Hondel M Eijgelsheim R Ruiter J C MWitteman A Hofman and B H C Stricker ldquoEffect of short-term NSAID use on echocardiographic parameters in elderlypeople a population-based cohort studyrdquo Heart vol 97 no 7pp 540ndash543 2011

[98] B I Jugdutt G M Hutchins B H Bulkley B Pitt and L CBecker ldquoEffect of indomethacin on collateral blood flow andinfarct size in the conscious dogrdquo Circulation vol 59 no 4 pp734ndash743 1979

[99] B I Jugdutt and L C Becker ldquoProstaglandin inhibition andmyocardial infarct sizerdquo Clinical Cardiology vol 4 no 3 pp117ndash124 1981

[100] B I Jugdutt G M Hutchins B H Bulkley and L C BeckerldquoSalvage of ischemic myocardium by ibuprofen during infarc-tion in the conscious dogrdquoThe American Journal of Cardiologyvol 46 no 1 pp 74ndash82 1980

[101] B I Jugdutt and C A Basualdo ldquoMyocardial infarct expansionduring indomethacin or ibuprofen therapy for symptomaticpost infarction pericarditis Influence of other pharmacologicagents during early remodellingrdquo The Canadian Journal ofCardiology vol 5 no 4 pp 211ndash221 1989

[102] M H Drazner ldquoThe progression of hypertensive heart diseaserdquoCirculation vol 123 no 3 pp 327ndash334 2011

[103] A Whelton ldquoRenal and related cardiovascular effects of con-ventional and COX-2-specific NSAIDs and non-NSAID anal-gesicsrdquoAmerican Journal ofTherapeutics vol 7 no 2 pp 63ndash742000

[104] T J Schnitzer ldquoCyclooxygenase-2mdashspecific inhibitors are theysaferdquoTheAmerican Journal of Medicine vol 110 no 1 pp 46Sndash49S 2001

[105] A N DeMaria and M R Weir ldquoCoxibsmdashbeyond the GI tractrenal and cardiovascular issuesrdquo Journal of Pain and SymptomManagement vol 25 no 2 pp S41ndashS49 2003

[106] C Stollberger and J Finsterer ldquoSide effects of conventionalnonsteroidal anti-inflammatory drugs and celecoxib moresimilarities than differencesrdquo Southern Medical Journal vol 97no 2 p 209 2004

[107] W M Bennett W L Henrich and J S Stoff ldquoThe renaleffects of nonsteroidal anti-inflammatory drugs summary andrecommendationsrdquo The American Journal of Kidney Diseasesvol 28 no 1 pp S56ndashS62 1996

[108] J E Pope J J Anderson and D T Felson ldquoA meta-analysis ofthe effects of nonsteroidal anti-inflammatory drugs on blood

pressurerdquo Archives of Internal Medicine vol 153 no 4 pp 477ndash484 1993

[109] A G Johnson T V Nguyen and R O Day ldquoDo non-steroidal anti-inflammatory drugs affect blood pressure Ameta-analysisrdquo Annals of Internal Medicine vol 121 no 4 pp289ndash300 1994

[110] S A Grover L Coupal and H Zowall ldquoTreating osteoarthritiswith cyclooxygenase-2-specific inhibitors what are the benefitsof avoiding blood pressure destabilizationrdquo Hypertension vol45 no 1 pp 92ndash97 2005

[111] A A Bavry A Khaliq Y Gong EMHandberg RM Cooper-Dehoff and C J Pepine ldquoHarmful effects of NSAIDs amongpatients with hypertension and coronary artery diseaserdquo TheAmerican Journal of Medicine vol 124 no 7 pp 614ndash620 2011

[112] S B Lee I H Bae Y S Bae and H D Um ldquoLink betweenmitochondria and NADPH oxidase 1 isozyme for the sustainedproduction of reactive oxygen species and cell deathrdquo TheJournal of Biological Chemistry vol 281 no 47 pp 36228ndash362352006

[113] A C Cave A C Brewer A Narayanapanicker et al ldquoNADPHoxidases in cardiovascular health and diseaserdquo Antioxidants ampRedox Signaling vol 8 no 5-6 pp 691ndash728 2006

[114] H Li M Hortmann A Daiber et al ldquoCyclooxygenase 2-selective and nonselective nonsteroidal anti-inflammatorydrugs induce oxidative stress by up-regulating vascularNADPH oxidasesrdquo Journal of Pharmacology and ExperimentalTherapeutics vol 326 no 3 pp 745ndash753 2008

[115] H Vamp119886119901119900119904 119886zquez-MezaM Z de Pina J P Pardo H Riveros-Rosas R Villalobos-Molina and E Pina ldquoNon-steroidal anti-inflammatory drugs activateNADPHoxidase in adipocytes andraise theH

2O2pool to prevent cAMP-stimulated protein kinase

a activation and inhibit lipolysisrdquo BMCBiochemistry vol 14 no1 article 13 2013

[116] C E Berry and J M Hare ldquoXanthine oxidoreductase andcardiovascular disease molecular mechanisms and pathophys-iological implicationsrdquoThe Journal of Physiology vol 555 no 3pp 589ndash606 2004

[117] E E Kelley N K H Khoo N J Hundley U Z Malik B AFreeman and M M Tarpey ldquoHydrogen peroxide is the majoroxidant product of xanthine oxidaserdquo Free Radical Biology ampMedicine vol 48 no 4 pp 493ndash498 2010

[118] P Pacher A Nivorozhkin and C Szabamp119886119901119900119904 119900 ldquoTherapeuticeffects of xanthine oxidase inhibitors renaissance half a centuryafter the discovery of allopurinolrdquoPharmacological Reviews vol58 no 1 pp 87ndash114 2006

[119] F Leyva S Anker JW Swan et al ldquoSerum uric acid as an indexof impaired oxidative metabolism in chronic heart failurerdquoEuropean Heart Journal vol 18 no 5 pp 858ndash865 1997

[120] J D Gladden B R Zelickson J L Guichard et al ldquoXanthineoxidase inhibition preserves left ventricular systolic but notdiastolic function in cardiac volume overloadrdquo The AmericanJournal of PhysiologymdashHeart and Circulatory Physiology vol305 no 10 pp H1440ndashH1450 2013

[121] YMitobe H Hiraishi T Sasai T Shimada andA Terano ldquoTheeffects of aspirin on antioxidant defences of cultured rat gastricmucosal cellsrdquo Alimentary Pharmacology and TherapeuticsSupplement vol 14 supplement 1 pp 10ndash17 2000

[122] M R Yun H M Park K W Seo S J Lee D S Imand C D Kim ldquo5-Lipoxygenase plays an essential role in 4-HNE-enhanced ROS production in murine macrophages viaactivation of NADPH oxidaserdquo Free Radical Research vol 44no 7 pp 742ndash750 2010


[123] C-H Woo Z-W Lee B-C Kim K-S Ha and J-H KimldquoInvolvement of cytosolic phospholipase A2 and the subse-quent release of arachidonic acid in signalling by Rac for thegeneration of intracellular reactive oxygen species in Rat-2fibroblastsrdquo Biochemical Journal vol 348 no 3 pp 525ndash5302000

[124] C H Woo Y W Eom M H Yoo et al ldquoTumor necrosisfactor-alpha generates reactive oxygen species via a cytosolicphospholipase A

2-linked cascaderdquo The Journal of Biological

Chemistry vol 275 no 41 pp 32357ndash32362 2000[125] K-J Cho J-M Seo and J-H Kim ldquoBioactive lipoxygenase

metabolites stimulation of NADPH oxidases and reactive oxy-gen speciesrdquoMolecules and Cells vol 32 no 1 pp 1ndash5 2011

[126] S A Sagi S Weggen J Eriksen T E Golde and E HKoo ldquoThe non-cyclooxygenase targets of non-steroidal anti-inflammatory drugs lipoxygenases peroxisome proliferator-activated receptor inhibitor of 120581B kinase and NF120581B do notreduce amyloid 12057342 productionrdquo The Journal of BiologicalChemistry vol 278 no 34 pp 31825ndash31830 2003

[127] K D Rainsford ldquoThe effects of 5-lipoxygenase inhibitors andleukotriene antagonists on the development of gastric lesionsinduced by nonsteroidal antiinflammatory drugs in micerdquoAgents and Actions vol 21 no 3-4 pp 316ndash319 1987

[128] K D Rainsford ldquoLeukotrienes in the pathogenesis of NSAID-induced gastric and intestinal mucosal damagerdquo Agents andActions vol 39 pp C24ndashC26 1993

[129] N Hudson M Balsitis S Everitt and C J Hawkey ldquoEnhancedgastricmucosal leukotriene B4 synthesis in patients taking non-steroidal anti-inflammatory drugsrdquo Gut vol 34 no 6 pp 742ndash747 1993

[130] I Shureiqi D Chen J J Lee et al ldquo15-LOX-1 a novel moleculartarget of nonsteroidal anti-inflammatory drug-induced apop-tosis in colorectal cancer cellsrdquo Journal of the National CancerInstitute vol 92 no 14 pp 1136ndash1142 2000

[131] T Lynch and A Price ldquoThe effect of cytochrome P450metabolismon drug response interactions and adverse effectsrdquoTheAmerican Family Physician vol 76 no 3 pp 391ndash396 2007

[132] K Berka T Hendrychovamp119886119901119900119904 119886 P Anzenbacher and MOtyepka ldquoMembrane position of ibuprofen agrees with sug-gested access path entrance to cytochromeP450 2C9 active siterdquoJournal of Physical Chemistry A vol 115 no 41 pp 11248ndash112552011

[133] R C Zangar D R Davydov and S Verma ldquoMechanisms thatregulate production of reactive oxygen species by cytochromeP450rdquo Toxicology and Applied Pharmacology vol 199 no 3 pp316ndash331 2004

[134] C C Ogu and J LMaxa ldquoDrug interactions due to cytochromeP450rdquo Proceedings (Baylor University Medical Center) vol 13no 4 pp 421ndash423 2000

[135] S Puntarulo and A I Cederbaum ldquoProduction of reactiveoxygen species by microsomes enriched in specific humancytochrome P450 enzymesrdquo Free Radical Biology amp Medicinevol 24 no 7-8 pp 1324ndash1330 1998

[136] C Ioannides and D F V Lewis ldquoCytochromes P450 in thebioactivation of chemicalsrdquo Current Topics in Medicinal Chem-istry vol 4 no 16 pp 1767ndash1788 2004

[137] D F V Lewis ldquoOxidative stress the role of cytochromesP450 in oxygen activationrdquo Journal of Chemical Technology andBiotechnology vol 77 no 10 pp 1095ndash1100 2002

[138] M Jurima-Romet K Crawford and H S Huang ldquoCompar-ative cytotoxicity of non-steroidal anti-inflammatory drugs in

primary cultures of rat hepatocytesrdquo Toxicology in Vitro vol 8no 1 pp 55ndash66 1994

[139] J A G Agamp119886119901119900119904 119906ndez E Garcamp119886119901119900119904 119894a-Martamp119886119901119900119904 119894nand C Martamp119886119901119900119904 119894nez ldquoGenetically based impairment inCYP2C8- and CYP2C9-dependent NSAID metabolism as arisk factor for gastrointestinal bleeding is a combination ofpharmacogenomics and metabolomics required to improvepersonalized medicinerdquo Expert Opinion on Drug Metabolismamp Toxicology vol 5 no 6 pp 607ndash620 2009

[140] J S van Leeuwen G Vredenburg S Dragovic T F J TjongJ C Vos and N P E Vermeulen ldquoMetabolism related toxicityof diclofenac in yeast as model systemrdquo Toxicology Letters vol200 no 3 pp 162ndash168 2011

[141] G Di Nardo and G Gilardi ldquoOptimization of the bacterialcytochrome P450 BM3 system for the production of humandrug metabolitesrdquo International Journal of Molecular Sciencesvol 13 no 12 pp 15901ndash15924 2012

[142] N English V Hughes and C R Wolf ldquoInduction ofcytochrome P-450 BM-3 (CYP 102) by non-steroidal anti-inflammatory drugs in Bacillus megateriumrdquo Biochemical Jour-nal vol 316 part 1 pp 279ndash283 1996

[143] S Kawashima and M Yokoyama ldquoDysfunction of endothe-lial nitric oxide synthase and atherosclerosisrdquo ArteriosclerosisThrombosis and Vascular Biology vol 24 no 6 pp 998ndash10052004

[144] N J Alp and K M Channon ldquoRegulation of endothelial nitricoxide synthase by tetrahydrobiopterin in vascular diseaserdquoArteriosclerosis Thrombosis and Vascular Biology vol 24 no3 pp 413ndash420 2004

[145] G R Drummond H Cai M E Davis S Ramasamy and D GHarrison ldquoTranscriptional and posttranscriptional regulationof endothelial nitric oxide synthase expression by hydrogenperoxiderdquoCirculation Research vol 86 no 3 pp 347ndash354 2000

[146] K K Sakane C J Monteiro W Silva et al ldquoCellular and-molecular studies of the effects of a selective COX-2 inhibitorcelecoxib in the cardiac cell line H9c2 and their correlation withdeath mechanismsrdquo Brazilian Journal of Medical and BiologicalResearch vol 47 no 1 pp 50ndash59 2014

[147] C-S Lee L Y Tee T Warmke et al ldquoA proteasomal stressresponse pre-treatment with proteasome inhibitors increasesproteasome activity and reduces neuronal vulnerability tooxidative injuryrdquo Journal of Neurochemistry vol 91 no 4 pp996ndash1006 2004

[148] M I Furman S E Benoit M R Barnard et al ldquoIncreasedplatelet reactivity and circulating monocyte-platelet aggregatesin patients with stable coronary artery diseaserdquo Journal of theAmerican College of Cardiology vol 31 no 2 pp 352ndash358 1998

[149] B Wachowicz B Olas H M Zbikowska and A BuczynskildquoGeneration of reactive oxygen species in blood plateletsrdquoPlatelets vol 13 no 3 pp 175ndash182 2002

[150] V Fuster J Badimon J H Chesebro and J T Fallon ldquoPlaquerupture thrombosis and therapeutic implicationsrdquo Haemosta-sis vol 26 supplement 4 pp 269ndash284 1996

[151] E R Bates andW C Lau ldquoControversies in antiplatelet therapyfor patientswith cardiovascular diseaserdquoCirculation vol 111 no17 pp e267ndashe271 2005

[152] M A Buerkle S Lehrer H-Y Sohn P Conzen U Pohl andF Krotz ldquoSelective inhibition of cyclooxygenase-2 enhancesplatelet adhesion in hamster arterioles in vivordquo Circulation vol110 no 14 pp 2053ndash2059 2004


[153] L Struthmann N Hellwig J Pircher et al ldquoProthromboticeffects of diclofenac on arteriolar platelet activation and throm-bosis in vivordquo Journal of Thrombosis and Haemostasis vol 7 no10 pp 1727ndash1735 2009

[154] N L Capurro L C Lipson R O Bonow R E GoldsteinN R Shulman and S E Epstein ldquoRelative effects of aspirinon platelet aggregation and prostaglandin-mediated coronaryvasodilation in the dogrdquoCirculation vol 62 no 6 pp 1221ndash12271980

[155] K Schror ldquoAspirin and platelets the antiplatelet action ofaspirin and its role in thrombosis treatment and prophylaxisrdquoSeminars in Thrombosis and Hemostasis vol 23 no 4 pp 349ndash356 1997

[156] G A FitzGerald and C Patrono ldquoThe coxibs selectiveinhibitors of cyclooxygenase-2rdquo The New England Journal ofMedicine vol 345 no 6 pp 433ndash442 2001

[157] V Brower ldquoA nutraceutical a day may keep the doctor awayrdquoEMBO Reports vol 6 no 8 pp 708ndash711 2005

[158] D Albert I Zundorf T Dingermann W E Muller DSteinhilber and O Werz ldquoHyperforin is a dual inhibitor ofcyclooxygenase-1 and 5-lipoxygenaserdquo Biochemical Pharmacol-ogy vol 64 no 12 pp 1767ndash1775 2002

[159] J Lee N Koo and D B Min ldquoReactive oxygen species agingand antioxidative nutraceuticalsrdquo Comprehensive Reviews inFood Science and Food Safety vol 3 no 1 pp 21ndash33 2004

[160] B Seaver and J R Smith ldquoInhibition of COX isoforms bynutraceuticalsrdquo Journal of Herbal Pharmacotherapy vol 4 no2 pp 11ndash18 2004

[161] N P Seeram R A Momin M G Nair and L D BourquinldquoCyclooxygenase inhibitory and antioxidant cyanidin glyco-sides in cherries and berriesrdquo Phytomedicine vol 8 no 5 pp362ndash369 2001

[162] Y Zhang G L Mills and M G Nair ldquoCyclooxygenaseinhibitory and antioxidant compounds from the mycelia of theedible mushroom Grifola frondosardquo Journal of Agricultural andFood Chemistry vol 50 no 26 pp 7581ndash7585 2002

[163] Y Zhang G L Mills and M G Nair ldquoCyclooxygenaseinhibitory and antioxidant compounds from the fruiting bodyof an edible mushroom Agrocybe aegeritardquo Phytomedicine vol10 no 5 pp 386ndash390 2003

[164] P C Norris and E A Dennis ldquoOmega-3 fatty acids causedramatic changes inTLR4 andpurinergic eicosanoid signalingrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 22 pp 8517ndash8522 2012

[165] P M Kris-Etherton W S Harris and L J Appel ldquoFishconsumption fish oil omega-3 fatty acids and cardiovasculardiseaserdquo Circulation vol 106 no 21 pp 2747ndash2757 2002

[166] P M Kris-Etherton W S Harris and L J Appel ldquoFishconsumption fish oil omega-3 fatty acids and cardiovasculardiseaserdquo Arteriosclerosis thrombosis and vascular biology vol23 no 2 pp e20ndashe30 2003

[167] L G Cleland M J James and S M Proudman ldquoFish oil whatthe prescriber needs to knowrdquoArthritis ResearchampTherapy vol8 article 202 2006

[168] M Wada C J DeLong Y H Hong et al ldquoEnzymes andreceptors of prostaglandin pathways with arachidonic acid-derived versus eicosapentaenoic acid-derived substrates andproductsrdquo The Journal of Biological Chemistry vol 282 no 31pp 22254ndash22266 2007

[169] E J Corey C Shih and J R Cashman ldquoDocosahexaenoicacid is a strong inhibitor of prostaglandin but not leukotriene

biosynthesisrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 80 no 12part 1 pp 3581ndash3584 1983

[170] J Moreno A V Krishnan D M Peehl and D FeldmanldquoMechanisms of vitamin D-mediated growth inhibition inprostate cancer cells inhibition of the prostaglandin pathwayrdquoAnticancer Research vol 26 no 4 pp 2525ndash2530 2006

[171] K A OrsquoLeary S de Pascual-Teresa P W Needs Y P Bao NM OrsquoBrien and G Williamson ldquoEffect of flavonoids and vita-min E on cyclooxygenase-2 (COX-2) transcriptionrdquo MutationResearch vol 551 pp 245ndash254 2004

[172] A Bitto F Squadrito N Irrera et al ldquoFlavocoxid a nutraceu-tical approach to blunt inflammatory conditionsrdquo Mediators ofInflammation vol 2014 Article ID 790851 8 pages 2014

[173] C-H Chang Z-H Wen S-K Wang and C-Y Duh ldquoNewanti-inflammatory steroids from the Formosan soft coralClavu-laria viridisrdquo Steroids vol 73 no 5 pp 562ndash567 2008

[174] U S Food and Drug Administration ldquoThrombotic cardiovascu-lar events associated with NSAID use regulatory history andresults of literature search (RCTs)rdquo in Proceedings of the JointMeeting of theArthritis AdvisoryCommittee andDrug Safety andRisk Management Advisory Committee February 2014

[175] A Bernareggi ldquoThe pharmacokinetic profile of nimesulide inhealthy volunteersrdquo Drugs vol 46 no 1 supplement pp 64ndash72 1993

[176] E Kumpulainen P Valitalo M Kokki et al ldquoPlasma and cere-brospinal fluid pharmacokinetics of flurbiprofen in childrenrdquoBritish Journal of Clinical Pharmacology vol 70 no 4 pp 557ndash566 2010

[177] D H Solomon J Avorn T Sturmer R J Glynn H Mogunand S Schneeweiss ldquoCardiovascular outcomes in new usersof coxibs and nonsteroidal antiinflammatory drugs high-risksubgroups and time course of riskrdquo Arthritis and Rheumatismvol 54 no 5 pp 1378ndash1389 2006

[178] G Renda S Tacconelli M L Capone et al ldquoCelecoxibibuprofen and the antiplatelet effect of aspirin in patients withosteoarthritis and ischemic heart diseaserdquo Clinical Pharmacol-ogy andTherapeutics vol 80 no 3 pp 264ndash274 2006

[179] C P Cannon S P Curtis G A FitzGerald et al ldquoCardiovas-cular outcomes with etoricoxib and diclofenac in patients withosteoarthritis and rheumatoid arthritis in the MultinationalEtoricoxib and Diclofenac Arthritis Long-term (MEDAL) pro-gramme a randomised comparisonrdquo The Lancet vol 368 no9549 pp 1771ndash1781 2006

[180] H S B Baraf C Fuentealba M Greenwald et al ldquoGastroin-testinal side effects of etoricoxib in patients with osteoarthritisresults of the etoricoxib versus diclofenac sodium gastrointesti-nal tolerability and effectiveness (EDGE) trialrdquo The Journal ofRheumatology vol 34 no 2 pp 408ndash420 2007

[181] M E Farkouh J D Greenberg R V Jeger et al ldquoCardio-vascular outcomes in high risk patients with osteoarthritistreated with ibuprofen naproxen or lumiracoxibrdquo Annals of theRheumatic Diseases vol 66 no 6 pp 764ndash770 2007

[182] S S Jick J A Kaye and H Jick ldquoDiclofenac and acutemyocardial infarction in patients with no major risk factorsrdquoBritish Journal of Clinical Pharmacology vol 64 no 5 pp 662ndash667 2007

[183] K Krueger L Lino R Dore et al ldquoGastrointestinal tolerabilityof etoricoxib in rheumatoid arthritis patients results of theetoricoxib vs diclofenac sodium gastrointestinal tolerability andeffectiveness trial (EDGE-II)rdquoAnnals of the Rheumatic Diseasesvol 67 no 3 pp 315ndash322 2008


[184] S D Solomon J Wittes P V Finn et al ldquoCardiovascular risk ofcelecoxib in 6 randomized placebo-controlled trials the crosstrial safety analysisrdquo Circulation vol 117 no 16 pp 2104ndash21132008

[185] T-P van Staa S Rietbrock E Setakis and H G M LeufkensldquoDoes the varied use of NSAIDs explain the differences in therisk of myocardial infarctionrdquo Journal of Internal Medicine vol264 no 5 pp 481ndash492 2008

[186] B Combe G Swergold J McLay et al ldquoCardiovascular safetyand gastrointestinal tolerability of etoricoxib vs diclofenac ina randomized controlled clinical trial (The MEDAL study)rdquoRheumatology vol 48 no 4 pp 425ndash432 2009

[187] C L Roumie N N Choma L Kaltenbach E F MitchelJr P G Arbogast and M R Griffin ldquoNon-aspirin NSAIDscyclooxygenase-2 inhibitors and risk for cardiovascular events-stroke acute myocardial infarction and death from coronaryheart diseaserdquo Pharmacoepidemiology and Drug Safety vol 18no 11 pp 1053ndash1063 2009

[188] E L Fosboslashl G H Gislason S Jacobsen et al ldquoRisk ofmyocardial infarction and death associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) among healthyindividuals a nationwide cohort studyrdquo Clinical PharmacologyandTherapeutics vol 85 no 2 pp 190ndash197 2009

[189] M C Becker T H Wang L Wisniewski et al ldquoRationaledesign and governance of Prospective Randomized Evaluationof Celecoxib Integrated Safety versus Ibuprofen Or Naproxen(PRECISION) a cardiovascular end point trial of nonsteroidalantiinflammatory agents in patients with arthritisrdquoThe Ameri-can Heart Journal vol 157 no 4 pp 606ndash612 2009

[190] G H Gislason J N Rasmussen S Z Abildstrom et alldquoIncreased mortality and cardiovascular morbidity associatedwith use of nonsteroidal anti-inflammatory drugs in chronicheart failurerdquo Archives of Internal Medicine vol 169 no 2 pp141ndash149 2009

[191] M W van der Linden S van der Bij P Welsing E J KuipersandRMCHerings ldquoThebalance between severe cardiovascu-lar and gastrointestinal events amongusers of selective andnon-selective non-steroidal anti-inflammatory drugsrdquo Annals of theRheumatic Diseases vol 68 no 5 pp 668ndash673 2009

[192] M Schmidt C F Christiansen F Mehnert K J Rothman andH T Soslashrensen ldquoNon-steroidal anti-inflammatory drug use andrisk of atrial fibrillation or flutter population based case-controlstudyrdquoThe British Medical Journal vol 343 no 7814 Article IDd3450 2011

[193] A-M Schjerning Olsen E L Fosboslashl J Lindhardsen et alldquoDuration of treatment with nonsteroidal anti-inflammatorydrugs and impact on risk of death and recurrent myocardialinfarction in patientswith priormyocardial infarction a nation-wide cohort studyrdquo Circulation vol 123 no 20 pp 2226ndash22352011

[194] A M S Olsen E L Fosboslashl J Lindhardsen et al ldquoLong-termcardiovascular risk of nonsteroidal anti-inflammatory drug useaccording to time passed after first-time myocardial infarctiona nationwide cohort studyrdquo Circulation vol 126 no 16 pp1955ndash1963 2012


Table1Listof

NSA

IDsw

iththeirrecom

mendeddo

sesa

ndlevelsin

thec

irculation

Genericname

Chem

icalname

Recommendeddo

sages

(may

vary

depend

ingon

thea

geandcond

ition

)

Levelsin

thec

irculation(120583M

and120583gmL)

(dosed

ependent)

Traden

ame

Diclofenac

2-[(26-D

ichlorop

henyl)a

mino]ph

enyl

acetic

acid

25mgndash150m

gday

5120583M

(15120583gmL)

and7120583

M(20120583gmL)

[for5

0mgand75

mgdo

sesrespectiv

ely]

ZorvolexC

ataflam

Cam

biaVo

ltaren

VoltarengelArthrotec

(com

binedwith

miso

prostol)

FlectorZipsor

Penn

said

Indo

methacin

[1-(4-C

hlorob

enzoyl)-5-metho

xy-2-

methyl-1H-in

dol-3

-yl]a

cetic

acid

25mgndash200m

gday

3120583Mndash6120583M

(1to

2120583gmL)

TivorbexInd

ocinInd

ocin

SR

Indo

-Lem

mon

Ind

omethagan

Ketoprofen

2-(3-Benzoylph

enyl)p

ropano

icacid

25mgndash300m

gday

2120583

Mto

22120583M

(043to

562120583gmL)

[50m

gdo

se]

OruvailNexcede

Ibup

rofen

2-(4-Isobu

tylphenyl)prop

anoica

cid

100m

gndash800m

gday

97120583

Mndash291120583M

(20ndash

60120583gmL)

[400

mg

dose]

AdvilMotrin

andNurofenV

icop

rofen

(com

binedwith

hydrocod

one)D

uexis

(com

binedwith

famotidine)

Naproxen

(2S)-2-(6-Metho

xy-2-naphthyl)prop

anoic

acid

250m

gndash1000

mgday

(bothoralandIV

)

377120583M

(95120583

gmL)

[500

mgdo

seon

ceevery12hor

1000

mg

dose

for5

days]

Naprosyn

EC-N

aprosyn

Naprapac

(cop

ackagedwith

lansop

razole)Aleve

AccordA

naprox

DSAn

aproxAntalgin

ApranaxTrexim

et(com

binedwith

sumatrip

tansuccinate)andVimovo

(com

binedwith

esom

eprazolemagnesiu

m)

Sulin

dac

(1Z)-5-Fluo

ro-2-m

ethyl-1-[4-

(methylsu

lfinyl)b

enzylid

ene]-1H-in

den-3-

ylacetic

acid

200m

gndash40

0mgday

14120583Mndash6120583M

(05ndash20120583gmL)[con

stant

fora

lldo

ses]

Clinoril

Ketorolac

5-Be

nzoyl-2

3-dihydro-1H-pyrrolizine-1-

carboxylic

acid

10mgndash40

mgday

39120583M

(10120583

gmL)

Torado

lSprix

Piroxicam

4-Hydroxy-2-m

ethyl-N

-(2-pyrid

inyl)-2H

-12

-benzothiazine-3-carbo

xamide11-

dioxide

02m

gndash20

mgday

5120583M

to6120583

M(15to

2120583gmL)

[single

20mgdo

se]9120583M

to24120583M

(3ndash8120583gmL)

[for2

0mgrepeated

doses]

Feldene


Table1Con

tinued

Genericname

Chem

icalname

Recommendeddo

sages

(may

vary

depend

ingon

thea

geandcond

ition

)

Levelsin

thec

irculation(120583M

and120583gmL)

(dosed

ependent)

Traden

ame

Nim

esulide

N-(4-Nitro-2-

phenoxyphenyl)m

ethanesulfo

namide

100m

gtwiced

aily

10120583M

to20120583M

(286to

458)m

gL

[100

mg]

[175]

Sulid

eNim

aloxM

esulidX

iloxNise

Nexen

Nidolon

Diflun

isal

2101584041015840-D

ifluo

ro-4-hydroxy-3-

biph

enylcarboxylic

acid

250m

gndash1000

mg

164120583

M(41120583

gmL)

[250

mgdo

ses]

348120583

M(87120583

gmL)

[500

mgdo

ses]and

496120583

M(124120583gmL)

[single100

0mgd

ose]

Dolob

id

Flurbiprofen

2-(2-Fluoro-4-biph

enylyl)propano

icacid

50mgndash300m

gday

60120583M

(14mgL)

[065m

gkg

offlu

rbiprofenIV

][176]

Ansaid

Mefenam

icacid

2-[(23-

Dim

ethylphenyl)a

mino]benzoicacid

250m

gfollo

wed

by500m

gevery6ho

urs

83120583

M(20120583

gmL)

[250

mgsin

gled

oses]

Ponstel

Tolm

etin

[1-Methyl-5


-pyrrol-

2-yl]acetic

acid

5mgndash1800

mgday

156120583

M(40120583

gmL)

[400

mgoraldo

se]

TolectinTolectin

DSTo

lectin

600

Thetablelistson

lythoseNSA

IDsthath

avebeen

mentio

nedin

Table3alon

gwith

theirrecom

mendeddo

sesa

ndrespectiv

econcentrations

inthecirculation

Mosto

fthe

inform

ationregardingthedo

sagesa

ndlevelsin

serum

orplasmaof

theNSA

IDsh

asbeen

takenfro

mtheFD

Aapproved

sitehttpwwwdrugsc

omN

imesulideistheon

lyNSA

IDin

thelistthatisn

otavailablein

theUSA

Referencesfor

theplasma

concentrations

offlu


regivenin

thetable

Serum

concentrations

Plasm

acon

centratio

ns






COX-1(constitutive)

COX-2(inducible)


NSAIDS

Prostaglandin G2


NSAIDS

PGD

synt

hase

Thro

mbo

xane

synt

hase

PGI s

ynth

ase

PGF synthase

PGE synthase





(smooth muscle)

Arachidonic acid

Phospholipase A2


Leukotriene

COXIBS






COX-1 COX-2

COOHCH3


factors

PGG2


PGF2



functions

PGD2TXA2

TXB2

PGI2

(platelets)

lowast

TXA2 PGI2

lowast

PGE2

















Table2Summaryof

results

from

clinicaltria

lson

thea

dverse

effectsof

NSA

IDso

ncardiovascular

diseases

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Cele

coxibnaproxen

sodium

and

placebo

Alzh

eimerrsquosDise

ase

Anti-Infl

ammatory

Preventio

nTrial

(ADAPT

)USA

4years

2528patie

ntsw

ithafam

ilyhisto

ryof

Alzh

eimerrsquos

Dise

ase

CVDCBV

deathMIstr

okeCH

For

TIAin

thec


placebo-tre

ated

grou

pswe

re554

825and

568respectively

Death

ratesinthec

aseo

fpatientstaking

NSA

IDsw

ereh

igherb

utno

tstatistic

ally

significant

[44]

Cele


diclo

fenacnaproxenibu

profen

diflu

nisaletod

olacfenop

rofen

flurbiprofen

indo

methacin

ketoprofen


icacidm

eloxicamn

abum

eton

eoxaprozin


etin

Non

eUSA

5years

74838

userso

fNSA

IDsa

nd2353

5userso

fother

drugs

Thea

djustedrateratio

forR

ofecoxib

was

116forM

Iand

115forstro

kewhich

was

theh

ighestam

ongallother

NSA

IDs

inclu

ding

otherc

oxibsNaproxen

mod

estly

redu

cedther

ater

atio

(RRfor

MI0

067

andRR

forstro

ke0083)

ofcardiovascular

events

[177]

Cele

coxibibup

rofen

Non

eCh

ieti

Chieti

Italy

3mon

ths

24patie

ntsu

ndergoing

aspirin

treatmentfor

cardioprotectio

n

Ibup

rofeninterfe

redwith

theinh

ibition

ofplateletCO

X-1n

ecessary

for

cardioprotectio

nby

aspirin

[178]

Diclofenacibup

rofen

indo

methacin

ketoprofenn

aproxen

mefenam

icacid

piroxicamtenoxicam

tolfenamicacid

aceclofenactia

profenicacidm

efenam

icacidetodo

lacnabu

meton

enimesulide

andmelo

xicamrofecoxibcele

coxib

valdecoxiband

etoricoxib

Non

eFinland

3years

33309

patie

ntsw

ithfirst

MI138949controls


OX-

selectivity

dono

tdeterminethe

adversee

ffectof

CVDby

NSA

IDsatleastcon

cerningMI

NoNSA

IDisMI-protectiv

e

[13]

Etoricoxib

anddiclo

fenac

Multin

ationalE

toric

oxib

andDiclofenacA

rthritis

Long

-term

(MED

AL)

Stud

yProgramM

ultin

ational

18mon

ths

34701

patie

nts(24913

with

osteoarthritisa

nd97

87with


Thrombo

ticcardiovascular

events

occurred

in320patie

ntsinthee

toric

oxib

grou

pand323patie

ntsinthed

iclofenac

grou

pwith

eventrates

of12

4and13

0per

100patie

nt-yearsandah

azardratio

of095

fore

toric

oxibcomparedto

diclo

fenacLo

ngterm

usageo

feith

erof

theseN

SAID

shad

similare

ffectso

nthe

rateso

fthrom

botic

cardiovascular

events

[179]

Etoricoxib

anddiclo

fenac

Etoricoxibversus

DiclofenacS

odium

Gastro

intestinal

Tolerabilityand

Effectiv

eness(ED

GE)

trialU

SA

93mon

thsfor

etoricoxib

and89

mon

thsfor

diclo

fenac

7111patie

nts

etoricoxib

(119899=3593)o

rdiclo

fenacs

odium

(119899=3518)

Ther

ateo

fthrom

botic

CVeventswas

130and12

4in

userso

fetoric

oxib

(90m

g)anddiclo

fenac(150m

g)

respectiv

elyw

ithin

28days

[180]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Ibup

rofen

naproxen

orlumira

coxib

TheTh

erapeutic

Arthritis

Research

and

Gastro

intestinalEv

entT

rial

(TARG

ET)International

Extend

edrepo

rt1832

5patie

ntsw

ithosteoarthritis

Ibup

rofenincreasedris

kof

thrombo

sisandCH

Fcomparedto

lumira

coxib

(214

versus

025)a

mon

gaspirin


erris

krelativetolumira

coxibam

ongno

naspirin

users

[181]

Diclofenacibup

rofen

andnaproxen

Non

eUSA

7years

ND

Prolon

gedexpo

sure

todiclo

fenac

increasesthe

riskof

AMI(relativer

atio

=19

ndash20)u

nlikeibu

profen

ornaproxen

[182]

Etoricoxib

anddiclo

fenac

EDGEIIU

SA193mon

thsfor

etoricoxib

and191

mon

thsfor

diclo

fenac

4086patie

ntsw



diclo

fenac119899=2054

Ther

ateo

foccurrenceo

fAMIw

ashigh

erin

diclo

fenac(068)treated

patie

ntsthan

inetoricoxib

users(043)Also

anoverall

increase

incardiace

ventsw

asob

served

indiclo

fenactreated

grou

p(114

)versus

thee

toric

oxibgrou

p(083)

[183]

Cele

coxib(at4

00mgQD200

mgtwo

times

aday

(BID

)or

400m

gBID)

Non

eUSA

3years

7950

patie

nts(with

arthritisandother

cond

ition

s)

Theh

azardratio

forthe

CVDM

IHFor

thrombo

embo

liceventw

aslowestfor

the

400mgon

cead


the2

00mg-BIDdo

se(18)andhigh

est

forthe

400mg-BIDdo

se(31)

[184]

Ibup

rofen

naproxendiclofenac

meloxicam

ind

omethacin

piroxicam

andmefenam

icacid

Non

eUKprim

arycare

20years

7292

94NSA

IDusers

443047controls

Increase

inther

elativer

atefor

MIw

ithcumulativea

nddaily

dose

ofibup

rofen

anddiclo

fenacHigherrisk

ofMIw

ithdiclo

fenacu

se(relativer

atio

=12

1)than

ibup

rofen(relativer

atio

=10

4)or

naproxen

(relativer

atio

=10

3)

[185]

Etoricoxib

anddiclo

fenac

TheM

EDAL

Stud

yMultin

ational

194to

208mon

ths

Etoricoxib

60mgd119899=6769

90mgd119899=5012


Thethrom

botic

CVris

kHRof

etoricoxib

todiclo

fenac=

096P

rolonged

useo

feither

NSA

IDresultedin

anincreased

riskof

thrombo

ticCV

events

[186]

Naproxen

ibup

rofen

diclo

fenac


Non

eUSA

6years

48566

patie

ntsrecently

hospita

lized

form

yocardial

infarctio

nrevascularization

orun

stableangina

pectoris

CVDris

kincreasedwith

shortterm

(lt90

days)u

seforibu

profen

with

incidence

rateratio

sof167diclo

fenac186

celecoxib13

7androfecoxib14

6bu

tnot

forn

aproxen088

[51]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Cele


ibup

rofen


indo

methacin

Non

eUSA

7years

610001p

atientswith

out

CVD119899=525249w

ithhisto

ryof

CVD119899=84752

Rofecoxib(1091

events

1000

person

-years)valdecoxib

(1241

events

1000

person

-years)and

indo

methacin(1325

events

1000

person

-years)increased

CVDris

kin

patie

ntsw

ithno

histo

ryof

CVD


riskof

cardiovascular

eventinpatie

ntsw

ithCV

D(3028

events

1000

person

-years)

[187]

Ibup

rofen

diclo

fenacrofecoxib


Non

eDanish

popu

latio

n9ndash

34days


als

Dosed

ependent

increase

incardiovascular

eventsdu

etouseo

fdiclo

fenac(HR=16

3)rofecoxib

(HR=

213)a

ndcelecoxib(H

R=201)w

asob

served

[188]

Cele

coxibibup

rofen

andnaproxen

TheP

rospectiv

eRa

ndom

ized

Evaluatio

nof

Cele

coxibIntegrated

Safety

versus

Ibup

rofenOr

Naproxen

(PRE

CISION)

trialM

ultin

ational

2009-ongoing

20000

patie

ntsw

ithsymptom

aticosteoarthritis


high

riskforo

rwith

establish

edCV

D

Thistrialw

illdeterm

inethe

cardiovascular

safetyof

theN

SAID

s[189]

ND

Non

eDenmark

10years

1070

92patie

ntsw

ithfirst

incidenceo

fHF

Theh

azardratio

ford

eath

duetoMIo

rHFwas

17017

513

1208122and12

8forrofecoxibcele

coxibibup

rofen

diclo

fenacnaproxenand

otherN

SAID

srespectiv

ely

[190]

Ibup

rofen

diclo

fenacnaproxen


etoricoxib

Non

eTh

eNetherla

nds

4years

485059subjectswith

first

hospita

lisationfora

cute


CV

andgastr

ointestin

alevents

AMIrisk

with

celecoxib(O

R253)

rofecoxib(O

R16

0)ibu

profen

(OR15

6)

anddiclo

fenac(OR15

1)was

significantly

increasedSign

ificant

increase

inCV

risk

with

currentu

seof

individu

alCO

X-2

inhibitorsandtN

SAID

s(ORfro

m117to

164)Significantd

ecreaseinAMIw

ithcurrentu

seof

naproxen

(OR048)

[191]

Ibup

rofen

naproxendiclofenac

etod


Non

eNorthernDenmark

10years

32602

patie

ntsw

ithfirst

atria

lfibrillationor

flutte

rand325918po

pulatio

ncontrols

Increasedris

kof

atria

lfibrillationor

flutte

rwas

40ndash70

(lowe

stfor

non-selectiveN

SAID

sand

high

estfor

COX-

2inhibitors)

[192]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

ND

Non

eDenmark

10years

83677

patie

ntso

fwhich

423received

NSA

IDs

Deathrecurrent

MId

ueto

NSA

IDtre

atment(even

shortterm)w

assig

nificantly

high

erD

iclofenacp

osed

the

high

estrisk

ofallN

SAID

s

[193]

ND

INternationalV

Erapam

ilTrando

laprilSTud

y(INVES

T)M

ultin

ational

7years

882chronicN

SAID

users

and21694

nonchron

icNSA

IDusersPatie

ntsw

ithhypertensio

nandclinically

stablec

oron

aryartery

disease

Prim

aryou

tcom

elikea

ll-causem

ortality

nonfatalMIor

nonfatalstroke

and

second

aryindividu

alou

tcom

eslik

eall-c

ause


mortalitytotalM

Iandtotalstro

keoccurred

atar

ateo

f44eventsper100

patie

nt-yearsin

thec

hron

icNSA

IDgrou

pversus

37eventsper100

patie

nt-yearsin

then

onchronicN

SAID

grou

p

[111]

Cele

coxibrofecoxibibup

rofen

diclo

fenacnaproxenand

others

Non

eDenmark

13years(with

first

MI)

128418patie

nts(77

participated

inthes

tudy)

Incidences

ofcoronary

deathor

nonfatal

recurrentM

Iwith

NSA

IDsu

seremain

unchangedwith

thetim

eelapsed

even

after

5years

[194]

ND

Non

edataob

tained

from

REdu

ctionof

Atherothrombo

sisfor

Con

tinuedHealth

(REA

CH)registry

which

inclu

desp

atientsfrom

Latin

AmericaNorth

AmericaEu

ropeA

siathe

MiddleE

astandAu

stralia

4years

4420NSA

IDusers39675

NSA

IDno

nusers

116-fold

high

erris

kof

CVDM

Iin

NSA

IDusers

[41]


HFheartfailureC

VDcardiovasculard

iseasesC

BVcerebrovascular

diseasesC

HFcongestiv

eheartfailu

reH

Rhazard

ratio

OR

oddratio

NDnot

defin

edR

Rrateratio

and

TIA

transie

ntisc

hemicattackV

arious

clinicaltria

lssuggestthe

increasedincidences

ofCV

Din

NSA

IDusersTh

etablelistson

lythec

linicaltrialsrepo

rted

between2006

and2014


Thrombosis



Apoptosis



(free radicals)



ROS

Cytochrome p450




NSAIDs
















2


2O2)


2

∙minus












Table3NSA

IDsind

uced

ROSgeneratio

nin

different

celltypes

(a)

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenacindo

methacin

ketoprofen

Mito

chon

drialrespiratio

nSaccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

TheseN

SAID

stargetm

itochon

driato

indu

cecelltoxicity

[95]

Ibup

rofenandnaproxen

TheseN

SAID

Sindu

cetoxicityindepend

ento

fmito

chon

drialrespiratio

n[95]

Indo

methacin

sodium

diclo

fenacflu

rbiprofen

zalto

profenand

mofezolac

ND

Hum

angastric

epith

elialcellline

AGS

AllNSA

IDse

xceptm

ofezolac

increased

apop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

AD

NAfragmentatio

nindu

ced

byindo

methacinor

flurbiprofenwas

redu

ced

byantio

xidantsIndo

methacinat1m

Mwas

apo

tent

indu

cero

fROSgeneratio

nin

thec

ells

[79]

Diclofenaca

ndnaproxen

NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

oxidasee


the

heartand

aortab

ydiclo

fenaca

ndnaproxen


etoNADPH

oxidase

[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2iso

form

ofNADPH

oxidaseisincreased

bydiclo

fenac

[114]

Aspirin

naproxenand

piroxicam

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Indo

methacin

Xanthine

oxidases

Hum

ancolonica

deno

carcinom

acells

(Caco-2cells)

Xanthine

oxidasea

ctivity

increasesb

ymore

than

100

1hou

rafte

rtreatment

[96]

Indo

methacin

Mito

chon

driasuperoxide

leakage

Ratgastricepith

elialcellline

RGM1

Indo

methacinindu

cedtheleakage

ofsuperoxide

anionin

theisolatedmito

chon

dria

from

theg

astricRG

M1cells

[93]

Indo

methacin

diclo

fenac

sodium

and

aspirin

ND

Ratgastricepith

elialcellline

RGM1and

ratsmallintestin

alepith

elialcelllineIEC

6

Indo

methacin

diclo

fenacandaspirin

ingastric

RGM1cellsandsm

allintestin

alIEC6

cells

increasedlip

idperoxidatio

n[93]

Sulin

dacsulin

dacs

ulfid

eandsulin

dacs

ulfone

ND

Pancreas

carcinom

aBXP

C3

glioblastomaA

172colon

carcinom

aDLD

-1oral

squamou

sSASandacute

myelocytic

leuk

emiaHL6

0cells

TheN

SAID

sulin

daca

ndits

metabolites

sulin

dacs

ulfid

eand

sulin

dacs

ulfone

all

increasedRO

Sgeneratio

nSulin

dacs

ulfid

eshow

edtheg

reatestR

OSgeneratio

n

[80]

Indo

methacin

piroxicam

andaspirin

Lipo

xygenases


mice

Results

inan

overprod

uctio

nof

leuk

otrie

nes

andprod

uctsof

5-lip

oxygenasea

ctivity

Increasesinleuk

otrie

neand5-lip

oxygenase

activ

ityhave

been

associated

with

ROS

generatio

n

[123124127]

Indo

methacin

Lipo

xygenases


Timed

ependent

form

ationof

leuk

otrie

ne-C

4[128]


(a)Con

tinued

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenac

CytochromeP

450enzymes

Saccharomyces

cerevisia

eyeast

cells

expressin

gthem

utantP

450

BM3M11(capableof

metabolizingdiclo

fenacs

imilar

tohu

mans)

IncreasedRO

Sprod

uctio

nbysim15

and18

times

atconcentrations

of30120583M

and50120583M

respectiv

elycom

paredto

wild

type

[140]

Diclofenacindo

methacin

ketoprofenand

naproxen

CytochromeP

450enzymes

Saccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

NSA

IDsm

etabolism

associated

with

increased

P450-related

toxicity

[95]

(b)

NSA

IDs

coxibs

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Ibup

rofen

ketoprofenand

indo

methacin

CytochromeP

450enzymes

Bacillusm

egaterium

AlltheN

SAID

scausedam

arkedincrease


450level

[142]

Aspirin

diclofenacdiflu

nisal

flurbiprofen

ibup

rofen

indo

methacin

ketoprofenm

efenam

icacidn

aproxen


etin

CytochromeP

450enzymes

Rath

epatocytes

Cytotoxicityof

diclo

fenacketoprofen

andpiroxicam

was

increasedby

cytochromeP


[138]

Diclofenaca

ndnaproxen

Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Increasedexpressio

nof

eNOSmRN

Adu

eto

theg

enerationof

H2O

2which

isrespon

sibleforu

pregulationof

eNOSat

thetranscriptio

naland

post-

transcrip

tionallevels

[114]


NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

expressio

nincreasedin

theh

eart

andaortab


[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2Ex

pressio

nincreasedby

rofecoxib

[114]


Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Inthea

ortathe

coxibs

didno

tsho

wany

eNOSmRN

Aexpressio

nIn

theh

eart

onlyrofecoxibshow

edas

ignificant

increase

inthee

xpressionof

eNOS

[114]

Etod

olac

ND

Hum

angastr

icepith

elialcell

lineA

GS

Increasedapop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

A[79]

Nim

esulide

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Alth

ough

otherreportsarea

vailables

uggesting

theroleo

fNSA

IDsinRO

Sform


lythoseN

SAID

sfor

which

results

show

thattheseN

SAID

sareassociated

with

CVDor

NSA

IDsm

entio

ned

inthetext















2




2


2O2[115]



2


2

∙minus H2O2







2) from the mem-




2











2








2



2transcript level



2

∙minus


2







14 Conclusion






Abbreviations




Acknowledgment



References










































































2O2














































































































































Table1Con

tinued

Genericname

Chem

icalname

Recommendeddo

sages

(may

vary

depend

ingon

thea

geandcond

ition

)

Levelsin

thec

irculation(120583M

and120583gmL)

(dosed

ependent)

Traden

ame

Nim

esulide

N-(4-Nitro-2-

phenoxyphenyl)m

ethanesulfo

namide

100m

gtwiced

aily

10120583M

to20120583M

(286to

458)m

gL

[100

mg]

[175]

Sulid

eNim

aloxM

esulidX

iloxNise

Nexen

Nidolon

Diflun

isal

2101584041015840-D

ifluo

ro-4-hydroxy-3-

biph

enylcarboxylic

acid

250m

gndash1000

mg

164120583

M(41120583

gmL)

[250

mgdo

ses]

348120583

M(87120583

gmL)

[500

mgdo

ses]and

496120583

M(124120583gmL)

[single100

0mgd

ose]

Dolob

id

Flurbiprofen

2-(2-Fluoro-4-biph

enylyl)propano

icacid

50mgndash300m

gday

60120583M

(14mgL)

[065m

gkg

offlu

rbiprofenIV

][176]

Ansaid

Mefenam

icacid

2-[(23-

Dim

ethylphenyl)a

mino]benzoicacid

250m

gfollo

wed

by500m

gevery6ho

urs

83120583

M(20120583

gmL)

[250

mgsin

gled

oses]

Ponstel

Tolm

etin

[1-Methyl-5


-pyrrol-

2-yl]acetic

acid

5mgndash1800

mgday

156120583

M(40120583

gmL)

[400

mgoraldo

se]

TolectinTolectin

DSTo

lectin

600

Thetablelistson

lythoseNSA

IDsthath

avebeen

mentio

nedin

Table3alon

gwith

theirrecom

mendeddo

sesa

ndrespectiv

econcentrations

inthecirculation

Mosto

fthe

inform

ationregardingthedo

sagesa

ndlevelsin

serum

orplasmaof

theNSA

IDsh

asbeen

takenfro

mtheFD

Aapproved

sitehttpwwwdrugsc

omN

imesulideistheon

lyNSA

IDin

thelistthatisn

otavailablein

theUSA

Referencesfor

theplasma

concentrations

offlu


regivenin

thetable

Serum

concentrations

Plasm

acon

centratio

ns






COX-1(constitutive)

COX-2(inducible)


NSAIDS

Prostaglandin G2


NSAIDS

PGD

synt

hase

Thro

mbo

xane

synt

hase

PGI s

ynth

ase

PGF synthase

PGE synthase





(smooth muscle)

Arachidonic acid

Phospholipase A2


Leukotriene

COXIBS






COX-1 COX-2

COOHCH3


factors

PGG2


PGF2



functions

PGD2TXA2

TXB2

PGI2

(platelets)

lowast

TXA2 PGI2

lowast

PGE2

















Table2Summaryof

results

from

clinicaltria

lson

thea

dverse

effectsof

NSA

IDso

ncardiovascular

diseases

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Cele

coxibnaproxen

sodium

and

placebo

Alzh

eimerrsquosDise

ase

Anti-Infl

ammatory

Preventio

nTrial

(ADAPT

)USA

4years

2528patie

ntsw

ithafam

ilyhisto

ryof

Alzh

eimerrsquos

Dise

ase

CVDCBV

deathMIstr

okeCH

For

TIAin

thec


placebo-tre

ated

grou

pswe

re554

825and

568respectively

Death

ratesinthec

aseo

fpatientstaking

NSA

IDsw

ereh

igherb

utno

tstatistic

ally

significant

[44]

Cele


diclo

fenacnaproxenibu

profen

diflu

nisaletod

olacfenop

rofen

flurbiprofen

indo

methacin

ketoprofen


icacidm

eloxicamn

abum

eton

eoxaprozin


etin

Non

eUSA

5years

74838

userso

fNSA

IDsa

nd2353

5userso

fother

drugs

Thea

djustedrateratio

forR

ofecoxib

was

116forM

Iand

115forstro

kewhich

was

theh

ighestam

ongallother

NSA

IDs

inclu

ding

otherc

oxibsNaproxen

mod

estly

redu

cedther

ater

atio

(RRfor

MI0

067

andRR

forstro

ke0083)

ofcardiovascular

events

[177]

Cele

coxibibup

rofen

Non

eCh

ieti

Chieti

Italy

3mon

ths

24patie

ntsu

ndergoing

aspirin

treatmentfor

cardioprotectio

n

Ibup

rofeninterfe

redwith

theinh

ibition

ofplateletCO

X-1n

ecessary

for

cardioprotectio

nby

aspirin

[178]

Diclofenacibup

rofen

indo

methacin

ketoprofenn

aproxen

mefenam

icacid

piroxicamtenoxicam

tolfenamicacid

aceclofenactia

profenicacidm

efenam

icacidetodo

lacnabu

meton

enimesulide

andmelo

xicamrofecoxibcele

coxib

valdecoxiband

etoricoxib

Non

eFinland

3years

33309

patie

ntsw

ithfirst

MI138949controls


OX-

selectivity

dono

tdeterminethe

adversee

ffectof

CVDby

NSA

IDsatleastcon

cerningMI

NoNSA

IDisMI-protectiv

e

[13]

Etoricoxib

anddiclo

fenac

Multin

ationalE

toric

oxib

andDiclofenacA

rthritis

Long

-term

(MED

AL)

Stud

yProgramM

ultin

ational

18mon

ths

34701

patie

nts(24913

with

osteoarthritisa

nd97

87with


Thrombo

ticcardiovascular

events

occurred

in320patie

ntsinthee

toric

oxib

grou

pand323patie

ntsinthed

iclofenac

grou

pwith

eventrates

of12

4and13

0per

100patie

nt-yearsandah

azardratio

of095

fore

toric

oxibcomparedto

diclo

fenacLo

ngterm

usageo

feith

erof

theseN

SAID

shad

similare

ffectso

nthe

rateso

fthrom

botic

cardiovascular

events

[179]

Etoricoxib

anddiclo

fenac

Etoricoxibversus

DiclofenacS

odium

Gastro

intestinal

Tolerabilityand

Effectiv

eness(ED

GE)

trialU

SA

93mon

thsfor

etoricoxib

and89

mon

thsfor

diclo

fenac

7111patie

nts

etoricoxib

(119899=3593)o

rdiclo

fenacs

odium

(119899=3518)

Ther

ateo

fthrom

botic

CVeventswas

130and12

4in

userso

fetoric

oxib

(90m

g)anddiclo

fenac(150m

g)

respectiv

elyw

ithin

28days

[180]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Ibup

rofen

naproxen

orlumira

coxib

TheTh

erapeutic

Arthritis

Research

and

Gastro

intestinalEv

entT

rial

(TARG

ET)International

Extend

edrepo

rt1832

5patie

ntsw

ithosteoarthritis

Ibup

rofenincreasedris

kof

thrombo

sisandCH

Fcomparedto

lumira

coxib

(214

versus

025)a

mon

gaspirin


erris

krelativetolumira

coxibam

ongno

naspirin

users

[181]

Diclofenacibup

rofen

andnaproxen

Non

eUSA

7years

ND

Prolon

gedexpo

sure

todiclo

fenac

increasesthe

riskof

AMI(relativer

atio

=19

ndash20)u

nlikeibu

profen

ornaproxen

[182]

Etoricoxib

anddiclo

fenac

EDGEIIU

SA193mon

thsfor

etoricoxib

and191

mon

thsfor

diclo

fenac

4086patie

ntsw



diclo

fenac119899=2054

Ther

ateo

foccurrenceo

fAMIw

ashigh

erin

diclo

fenac(068)treated

patie

ntsthan

inetoricoxib

users(043)Also

anoverall

increase

incardiace

ventsw

asob

served

indiclo

fenactreated

grou

p(114

)versus

thee

toric

oxibgrou

p(083)

[183]

Cele

coxib(at4

00mgQD200

mgtwo

times

aday

(BID

)or

400m

gBID)

Non

eUSA

3years

7950

patie

nts(with

arthritisandother

cond

ition

s)

Theh

azardratio

forthe

CVDM

IHFor

thrombo

embo

liceventw

aslowestfor

the

400mgon

cead


the2

00mg-BIDdo

se(18)andhigh

est

forthe

400mg-BIDdo

se(31)

[184]

Ibup

rofen

naproxendiclofenac

meloxicam

ind

omethacin

piroxicam

andmefenam

icacid

Non

eUKprim

arycare

20years

7292

94NSA

IDusers

443047controls

Increase

inther

elativer

atefor

MIw

ithcumulativea

nddaily

dose

ofibup

rofen

anddiclo

fenacHigherrisk

ofMIw

ithdiclo

fenacu

se(relativer

atio

=12

1)than

ibup

rofen(relativer

atio

=10

4)or

naproxen

(relativer

atio

=10

3)

[185]

Etoricoxib

anddiclo

fenac

TheM

EDAL

Stud

yMultin

ational

194to

208mon

ths

Etoricoxib

60mgd119899=6769

90mgd119899=5012


Thethrom

botic

CVris

kHRof

etoricoxib

todiclo

fenac=

096P

rolonged

useo

feither

NSA

IDresultedin

anincreased

riskof

thrombo

ticCV

events

[186]

Naproxen

ibup

rofen

diclo

fenac


Non

eUSA

6years

48566

patie

ntsrecently

hospita

lized

form

yocardial

infarctio

nrevascularization

orun

stableangina

pectoris

CVDris

kincreasedwith

shortterm

(lt90

days)u

seforibu

profen

with

incidence

rateratio

sof167diclo

fenac186

celecoxib13

7androfecoxib14

6bu

tnot

forn

aproxen088

[51]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Cele


ibup

rofen


indo

methacin

Non

eUSA

7years

610001p

atientswith

out

CVD119899=525249w

ithhisto

ryof

CVD119899=84752

Rofecoxib(1091

events

1000

person

-years)valdecoxib

(1241

events

1000

person

-years)and

indo

methacin(1325

events

1000

person

-years)increased

CVDris

kin

patie

ntsw

ithno

histo

ryof

CVD


riskof

cardiovascular

eventinpatie

ntsw

ithCV

D(3028

events

1000

person

-years)

[187]

Ibup

rofen

diclo

fenacrofecoxib


Non

eDanish

popu

latio

n9ndash

34days


als

Dosed

ependent

increase

incardiovascular

eventsdu

etouseo

fdiclo

fenac(HR=16

3)rofecoxib

(HR=

213)a

ndcelecoxib(H

R=201)w

asob

served

[188]

Cele

coxibibup

rofen

andnaproxen

TheP

rospectiv

eRa

ndom

ized

Evaluatio

nof

Cele

coxibIntegrated

Safety

versus

Ibup

rofenOr

Naproxen

(PRE

CISION)

trialM

ultin

ational

2009-ongoing

20000

patie

ntsw

ithsymptom

aticosteoarthritis


high

riskforo

rwith

establish

edCV

D

Thistrialw

illdeterm

inethe

cardiovascular

safetyof

theN

SAID

s[189]

ND

Non

eDenmark

10years

1070

92patie

ntsw

ithfirst

incidenceo

fHF

Theh

azardratio

ford

eath

duetoMIo

rHFwas

17017

513

1208122and12

8forrofecoxibcele

coxibibup

rofen

diclo

fenacnaproxenand

otherN

SAID

srespectiv

ely

[190]

Ibup

rofen

diclo

fenacnaproxen


etoricoxib

Non

eTh

eNetherla

nds

4years

485059subjectswith

first

hospita

lisationfora

cute


CV

andgastr

ointestin

alevents

AMIrisk

with

celecoxib(O

R253)

rofecoxib(O

R16

0)ibu

profen

(OR15

6)

anddiclo

fenac(OR15

1)was

significantly

increasedSign

ificant

increase

inCV

risk

with

currentu

seof

individu

alCO

X-2

inhibitorsandtN

SAID

s(ORfro

m117to

164)Significantd

ecreaseinAMIw

ithcurrentu

seof

naproxen

(OR048)

[191]

Ibup

rofen

naproxendiclofenac

etod


Non

eNorthernDenmark

10years

32602

patie

ntsw

ithfirst

atria

lfibrillationor

flutte

rand325918po

pulatio

ncontrols

Increasedris

kof

atria

lfibrillationor

flutte

rwas

40ndash70

(lowe

stfor

non-selectiveN

SAID

sand

high

estfor

COX-

2inhibitors)

[192]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

ND

Non

eDenmark

10years

83677

patie

ntso

fwhich

423received

NSA

IDs

Deathrecurrent

MId

ueto

NSA

IDtre

atment(even

shortterm)w

assig

nificantly

high

erD

iclofenacp

osed

the

high

estrisk

ofallN

SAID

s

[193]

ND

INternationalV

Erapam

ilTrando

laprilSTud

y(INVES

T)M

ultin

ational

7years

882chronicN

SAID

users

and21694

nonchron

icNSA

IDusersPatie

ntsw

ithhypertensio

nandclinically

stablec

oron

aryartery

disease

Prim

aryou

tcom

elikea

ll-causem

ortality

nonfatalMIor

nonfatalstroke

and

second

aryindividu

alou

tcom

eslik

eall-c

ause


mortalitytotalM

Iandtotalstro

keoccurred

atar

ateo

f44eventsper100

patie

nt-yearsin

thec

hron

icNSA

IDgrou

pversus

37eventsper100

patie

nt-yearsin

then

onchronicN

SAID

grou

p

[111]

Cele

coxibrofecoxibibup

rofen

diclo

fenacnaproxenand

others

Non

eDenmark

13years(with

first

MI)

128418patie

nts(77

participated

inthes

tudy)

Incidences

ofcoronary

deathor

nonfatal

recurrentM

Iwith

NSA

IDsu

seremain

unchangedwith

thetim

eelapsed

even

after

5years

[194]

ND

Non

edataob

tained

from

REdu

ctionof

Atherothrombo

sisfor

Con

tinuedHealth

(REA

CH)registry

which

inclu

desp

atientsfrom

Latin

AmericaNorth

AmericaEu

ropeA

siathe

MiddleE

astandAu

stralia

4years

4420NSA

IDusers39675

NSA

IDno

nusers

116-fold

high

erris

kof

CVDM

Iin

NSA

IDusers

[41]


HFheartfailureC

VDcardiovasculard

iseasesC

BVcerebrovascular

diseasesC

HFcongestiv

eheartfailu

reH

Rhazard

ratio

OR

oddratio

NDnot

defin

edR

Rrateratio

and

TIA

transie

ntisc

hemicattackV

arious

clinicaltria

lssuggestthe

increasedincidences

ofCV

Din

NSA

IDusersTh

etablelistson

lythec

linicaltrialsrepo

rted

between2006

and2014


Thrombosis



Apoptosis



(free radicals)



ROS

Cytochrome p450




NSAIDs
















2


2O2)


2

∙minus












Table3NSA

IDsind

uced

ROSgeneratio

nin

different

celltypes

(a)

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenacindo

methacin

ketoprofen

Mito

chon

drialrespiratio

nSaccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

TheseN

SAID

stargetm

itochon

driato

indu

cecelltoxicity

[95]

Ibup

rofenandnaproxen

TheseN

SAID

Sindu

cetoxicityindepend

ento

fmito

chon

drialrespiratio

n[95]

Indo

methacin

sodium

diclo

fenacflu

rbiprofen

zalto

profenand

mofezolac

ND

Hum

angastric

epith

elialcellline

AGS

AllNSA

IDse

xceptm

ofezolac

increased

apop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

AD

NAfragmentatio

nindu

ced

byindo

methacinor

flurbiprofenwas

redu

ced

byantio

xidantsIndo

methacinat1m

Mwas

apo

tent

indu

cero

fROSgeneratio

nin

thec

ells

[79]

Diclofenaca

ndnaproxen

NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

oxidasee


the

heartand

aortab

ydiclo

fenaca

ndnaproxen


etoNADPH

oxidase

[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2iso

form

ofNADPH

oxidaseisincreased

bydiclo

fenac

[114]

Aspirin

naproxenand

piroxicam

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Indo

methacin

Xanthine

oxidases

Hum

ancolonica

deno

carcinom

acells

(Caco-2cells)

Xanthine

oxidasea

ctivity

increasesb

ymore

than

100

1hou

rafte

rtreatment

[96]

Indo

methacin

Mito

chon

driasuperoxide

leakage

Ratgastricepith

elialcellline

RGM1

Indo

methacinindu

cedtheleakage

ofsuperoxide

anionin

theisolatedmito

chon

dria

from

theg

astricRG

M1cells

[93]

Indo

methacin

diclo

fenac

sodium

and

aspirin

ND

Ratgastricepith

elialcellline

RGM1and

ratsmallintestin

alepith

elialcelllineIEC

6

Indo

methacin

diclo

fenacandaspirin

ingastric

RGM1cellsandsm

allintestin

alIEC6

cells

increasedlip

idperoxidatio

n[93]

Sulin

dacsulin

dacs

ulfid

eandsulin

dacs

ulfone

ND

Pancreas

carcinom

aBXP

C3

glioblastomaA

172colon

carcinom

aDLD

-1oral

squamou

sSASandacute

myelocytic

leuk

emiaHL6

0cells

TheN

SAID

sulin

daca

ndits

metabolites

sulin

dacs

ulfid

eand

sulin

dacs

ulfone

all

increasedRO

Sgeneratio

nSulin

dacs

ulfid

eshow

edtheg

reatestR

OSgeneratio

n

[80]

Indo

methacin

piroxicam

andaspirin

Lipo

xygenases


mice

Results

inan

overprod

uctio

nof

leuk

otrie

nes

andprod

uctsof

5-lip

oxygenasea

ctivity

Increasesinleuk

otrie

neand5-lip

oxygenase

activ

ityhave

been

associated

with

ROS

generatio

n

[123124127]

Indo

methacin

Lipo

xygenases


Timed

ependent

form

ationof

leuk

otrie

ne-C

4[128]


(a)Con

tinued

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenac

CytochromeP

450enzymes

Saccharomyces

cerevisia

eyeast

cells

expressin

gthem

utantP

450

BM3M11(capableof

metabolizingdiclo

fenacs

imilar

tohu

mans)

IncreasedRO

Sprod

uctio

nbysim15

and18

times

atconcentrations

of30120583M

and50120583M

respectiv

elycom

paredto

wild

type

[140]

Diclofenacindo

methacin

ketoprofenand

naproxen

CytochromeP

450enzymes

Saccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

NSA

IDsm

etabolism

associated

with

increased

P450-related

toxicity

[95]

(b)

NSA

IDs

coxibs

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Ibup

rofen

ketoprofenand

indo

methacin

CytochromeP

450enzymes

Bacillusm

egaterium

AlltheN

SAID

scausedam

arkedincrease


450level

[142]

Aspirin

diclofenacdiflu

nisal

flurbiprofen

ibup

rofen

indo

methacin

ketoprofenm

efenam

icacidn

aproxen


etin

CytochromeP

450enzymes

Rath

epatocytes

Cytotoxicityof

diclo

fenacketoprofen

andpiroxicam

was

increasedby

cytochromeP


[138]

Diclofenaca

ndnaproxen

Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Increasedexpressio

nof

eNOSmRN

Adu

eto

theg

enerationof

H2O

2which

isrespon

sibleforu

pregulationof

eNOSat

thetranscriptio

naland

post-

transcrip

tionallevels

[114]


NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

expressio

nincreasedin

theh

eart

andaortab


[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2Ex

pressio

nincreasedby

rofecoxib

[114]


Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Inthea

ortathe

coxibs

didno

tsho

wany

eNOSmRN

Aexpressio

nIn

theh

eart

onlyrofecoxibshow

edas

ignificant

increase

inthee

xpressionof

eNOS

[114]

Etod

olac

ND

Hum

angastr

icepith

elialcell

lineA

GS

Increasedapop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

A[79]

Nim

esulide

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Alth

ough

otherreportsarea

vailables

uggesting

theroleo

fNSA

IDsinRO

Sform


lythoseN

SAID

sfor

which

results

show

thattheseN

SAID

sareassociated

with

CVDor

NSA

IDsm

entio

ned

inthetext















2




2


2O2[115]



2


2

∙minus H2O2







2) from the mem-




2











2








2



2transcript level



2

∙minus


2







14 Conclusion






Abbreviations




Acknowledgment



References










































































2O2


















































































































































COX-1(constitutive)

COX-2(inducible)


NSAIDS

Prostaglandin G2


NSAIDS

PGD

synt

hase

Thro

mbo

xane

synt

hase

PGI s

ynth

ase

PGF synthase

PGE synthase





(smooth muscle)

Arachidonic acid

Phospholipase A2


Leukotriene

COXIBS






COX-1 COX-2

COOHCH3


factors

PGG2


PGF2



functions

PGD2TXA2

TXB2

PGI2

(platelets)

lowast

TXA2 PGI2

lowast

PGE2

















Table2Summaryof

results

from

clinicaltria

lson

thea

dverse

effectsof

NSA

IDso

ncardiovascular

diseases

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Cele

coxibnaproxen

sodium

and

placebo

Alzh

eimerrsquosDise

ase

Anti-Infl

ammatory

Preventio

nTrial

(ADAPT

)USA

4years

2528patie

ntsw

ithafam

ilyhisto

ryof

Alzh

eimerrsquos

Dise

ase

CVDCBV

deathMIstr

okeCH

For

TIAin

thec


placebo-tre

ated

grou

pswe

re554

825and

568respectively

Death

ratesinthec

aseo

fpatientstaking

NSA

IDsw

ereh

igherb

utno

tstatistic

ally

significant

[44]

Cele


diclo

fenacnaproxenibu

profen

diflu

nisaletod

olacfenop

rofen

flurbiprofen

indo

methacin

ketoprofen


icacidm

eloxicamn

abum

eton

eoxaprozin


etin

Non

eUSA

5years

74838

userso

fNSA

IDsa

nd2353

5userso

fother

drugs

Thea

djustedrateratio

forR

ofecoxib

was

116forM

Iand

115forstro

kewhich

was

theh

ighestam

ongallother

NSA

IDs

inclu

ding

otherc

oxibsNaproxen

mod

estly

redu

cedther

ater

atio

(RRfor

MI0

067

andRR

forstro

ke0083)

ofcardiovascular

events

[177]

Cele

coxibibup

rofen

Non

eCh

ieti

Chieti

Italy

3mon

ths

24patie

ntsu

ndergoing

aspirin

treatmentfor

cardioprotectio

n

Ibup

rofeninterfe

redwith

theinh

ibition

ofplateletCO

X-1n

ecessary

for

cardioprotectio

nby

aspirin

[178]

Diclofenacibup

rofen

indo

methacin

ketoprofenn

aproxen

mefenam

icacid

piroxicamtenoxicam

tolfenamicacid

aceclofenactia

profenicacidm

efenam

icacidetodo

lacnabu

meton

enimesulide

andmelo

xicamrofecoxibcele

coxib

valdecoxiband

etoricoxib

Non

eFinland

3years

33309

patie

ntsw

ithfirst

MI138949controls


OX-

selectivity

dono

tdeterminethe

adversee

ffectof

CVDby

NSA

IDsatleastcon

cerningMI

NoNSA

IDisMI-protectiv

e

[13]

Etoricoxib

anddiclo

fenac

Multin

ationalE

toric

oxib

andDiclofenacA

rthritis

Long

-term

(MED

AL)

Stud

yProgramM

ultin

ational

18mon

ths

34701

patie

nts(24913

with

osteoarthritisa

nd97

87with


Thrombo

ticcardiovascular

events

occurred

in320patie

ntsinthee

toric

oxib

grou

pand323patie

ntsinthed

iclofenac

grou

pwith

eventrates

of12

4and13

0per

100patie

nt-yearsandah

azardratio

of095

fore

toric

oxibcomparedto

diclo

fenacLo

ngterm

usageo

feith

erof

theseN

SAID

shad

similare

ffectso

nthe

rateso

fthrom

botic

cardiovascular

events

[179]

Etoricoxib

anddiclo

fenac

Etoricoxibversus

DiclofenacS

odium

Gastro

intestinal

Tolerabilityand

Effectiv

eness(ED

GE)

trialU

SA

93mon

thsfor

etoricoxib

and89

mon

thsfor

diclo

fenac

7111patie

nts

etoricoxib

(119899=3593)o

rdiclo

fenacs

odium

(119899=3518)

Ther

ateo

fthrom

botic

CVeventswas

130and12

4in

userso

fetoric

oxib

(90m

g)anddiclo

fenac(150m

g)

respectiv

elyw

ithin

28days

[180]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Ibup

rofen

naproxen

orlumira

coxib

TheTh

erapeutic

Arthritis

Research

and

Gastro

intestinalEv

entT

rial

(TARG

ET)International

Extend

edrepo

rt1832

5patie

ntsw

ithosteoarthritis

Ibup

rofenincreasedris

kof

thrombo

sisandCH

Fcomparedto

lumira

coxib

(214

versus

025)a

mon

gaspirin


erris

krelativetolumira

coxibam

ongno

naspirin

users

[181]

Diclofenacibup

rofen

andnaproxen

Non

eUSA

7years

ND

Prolon

gedexpo

sure

todiclo

fenac

increasesthe

riskof

AMI(relativer

atio

=19

ndash20)u

nlikeibu

profen

ornaproxen

[182]

Etoricoxib

anddiclo

fenac

EDGEIIU

SA193mon

thsfor

etoricoxib

and191

mon

thsfor

diclo

fenac

4086patie

ntsw



diclo

fenac119899=2054

Ther

ateo

foccurrenceo

fAMIw

ashigh

erin

diclo

fenac(068)treated

patie

ntsthan

inetoricoxib

users(043)Also

anoverall

increase

incardiace

ventsw

asob

served

indiclo

fenactreated

grou

p(114

)versus

thee

toric

oxibgrou

p(083)

[183]

Cele

coxib(at4

00mgQD200

mgtwo

times

aday

(BID

)or

400m

gBID)

Non

eUSA

3years

7950

patie

nts(with

arthritisandother

cond

ition

s)

Theh

azardratio

forthe

CVDM

IHFor

thrombo

embo

liceventw

aslowestfor

the

400mgon

cead


the2

00mg-BIDdo

se(18)andhigh

est

forthe

400mg-BIDdo

se(31)

[184]

Ibup

rofen

naproxendiclofenac

meloxicam

ind

omethacin

piroxicam

andmefenam

icacid

Non

eUKprim

arycare

20years

7292

94NSA

IDusers

443047controls

Increase

inther

elativer

atefor

MIw

ithcumulativea

nddaily

dose

ofibup

rofen

anddiclo

fenacHigherrisk

ofMIw

ithdiclo

fenacu

se(relativer

atio

=12

1)than

ibup

rofen(relativer

atio

=10

4)or

naproxen

(relativer

atio

=10

3)

[185]

Etoricoxib

anddiclo

fenac

TheM

EDAL

Stud

yMultin

ational

194to

208mon

ths

Etoricoxib

60mgd119899=6769

90mgd119899=5012


Thethrom

botic

CVris

kHRof

etoricoxib

todiclo

fenac=

096P

rolonged

useo

feither

NSA

IDresultedin

anincreased

riskof

thrombo

ticCV

events

[186]

Naproxen

ibup

rofen

diclo

fenac


Non

eUSA

6years

48566

patie

ntsrecently

hospita

lized

form

yocardial

infarctio

nrevascularization

orun

stableangina

pectoris

CVDris

kincreasedwith

shortterm

(lt90

days)u

seforibu

profen

with

incidence

rateratio

sof167diclo

fenac186

celecoxib13

7androfecoxib14

6bu

tnot

forn

aproxen088

[51]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Cele


ibup

rofen


indo

methacin

Non

eUSA

7years

610001p

atientswith

out

CVD119899=525249w

ithhisto

ryof

CVD119899=84752

Rofecoxib(1091

events

1000

person

-years)valdecoxib

(1241

events

1000

person

-years)and

indo

methacin(1325

events

1000

person

-years)increased

CVDris

kin

patie

ntsw

ithno

histo

ryof

CVD


riskof

cardiovascular

eventinpatie

ntsw

ithCV

D(3028

events

1000

person

-years)

[187]

Ibup

rofen

diclo

fenacrofecoxib


Non

eDanish

popu

latio

n9ndash

34days


als

Dosed

ependent

increase

incardiovascular

eventsdu

etouseo

fdiclo

fenac(HR=16

3)rofecoxib

(HR=

213)a

ndcelecoxib(H

R=201)w

asob

served

[188]

Cele

coxibibup

rofen

andnaproxen

TheP

rospectiv

eRa

ndom

ized

Evaluatio

nof

Cele

coxibIntegrated

Safety

versus

Ibup

rofenOr

Naproxen

(PRE

CISION)

trialM

ultin

ational

2009-ongoing

20000

patie

ntsw

ithsymptom

aticosteoarthritis


high

riskforo

rwith

establish

edCV

D

Thistrialw

illdeterm

inethe

cardiovascular

safetyof

theN

SAID

s[189]

ND

Non

eDenmark

10years

1070

92patie

ntsw

ithfirst

incidenceo

fHF

Theh

azardratio

ford

eath

duetoMIo

rHFwas

17017

513

1208122and12

8forrofecoxibcele

coxibibup

rofen

diclo

fenacnaproxenand

otherN

SAID

srespectiv

ely

[190]

Ibup

rofen

diclo

fenacnaproxen


etoricoxib

Non

eTh

eNetherla

nds

4years

485059subjectswith

first

hospita

lisationfora

cute


CV

andgastr

ointestin

alevents

AMIrisk

with

celecoxib(O

R253)

rofecoxib(O

R16

0)ibu

profen

(OR15

6)

anddiclo

fenac(OR15

1)was

significantly

increasedSign

ificant

increase

inCV

risk

with

currentu

seof

individu

alCO

X-2

inhibitorsandtN

SAID

s(ORfro

m117to

164)Significantd

ecreaseinAMIw

ithcurrentu

seof

naproxen

(OR048)

[191]

Ibup

rofen

naproxendiclofenac

etod


Non

eNorthernDenmark

10years

32602

patie

ntsw

ithfirst

atria

lfibrillationor

flutte

rand325918po

pulatio

ncontrols

Increasedris

kof

atria

lfibrillationor

flutte

rwas

40ndash70

(lowe

stfor

non-selectiveN

SAID

sand

high

estfor

COX-

2inhibitors)

[192]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

ND

Non

eDenmark

10years

83677

patie

ntso

fwhich

423received

NSA

IDs

Deathrecurrent

MId

ueto

NSA

IDtre

atment(even

shortterm)w

assig

nificantly

high

erD

iclofenacp

osed

the

high

estrisk

ofallN

SAID

s

[193]

ND

INternationalV

Erapam

ilTrando

laprilSTud

y(INVES

T)M

ultin

ational

7years

882chronicN

SAID

users

and21694

nonchron

icNSA

IDusersPatie

ntsw

ithhypertensio

nandclinically

stablec

oron

aryartery

disease

Prim

aryou

tcom

elikea

ll-causem

ortality

nonfatalMIor

nonfatalstroke

and

second

aryindividu

alou

tcom

eslik

eall-c

ause


mortalitytotalM

Iandtotalstro

keoccurred

atar

ateo

f44eventsper100

patie

nt-yearsin

thec

hron

icNSA

IDgrou

pversus

37eventsper100

patie

nt-yearsin

then

onchronicN

SAID

grou

p

[111]

Cele

coxibrofecoxibibup

rofen

diclo

fenacnaproxenand

others

Non

eDenmark

13years(with

first

MI)

128418patie

nts(77

participated

inthes

tudy)

Incidences

ofcoronary

deathor

nonfatal

recurrentM

Iwith

NSA

IDsu

seremain

unchangedwith

thetim

eelapsed

even

after

5years

[194]

ND

Non

edataob

tained

from

REdu

ctionof

Atherothrombo

sisfor

Con

tinuedHealth

(REA

CH)registry

which

inclu

desp

atientsfrom

Latin

AmericaNorth

AmericaEu

ropeA

siathe

MiddleE

astandAu

stralia

4years

4420NSA

IDusers39675

NSA

IDno

nusers

116-fold

high

erris

kof

CVDM

Iin

NSA

IDusers

[41]


HFheartfailureC

VDcardiovasculard

iseasesC

BVcerebrovascular

diseasesC

HFcongestiv

eheartfailu

reH

Rhazard

ratio

OR

oddratio

NDnot

defin

edR

Rrateratio

and

TIA

transie

ntisc

hemicattackV

arious

clinicaltria

lssuggestthe

increasedincidences

ofCV

Din

NSA

IDusersTh

etablelistson

lythec

linicaltrialsrepo

rted

between2006

and2014


Thrombosis



Apoptosis



(free radicals)



ROS

Cytochrome p450




NSAIDs
















2


2O2)


2

∙minus












Table3NSA

IDsind

uced

ROSgeneratio

nin

different

celltypes

(a)

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenacindo

methacin

ketoprofen

Mito

chon

drialrespiratio

nSaccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

TheseN

SAID

stargetm

itochon

driato

indu

cecelltoxicity

[95]

Ibup

rofenandnaproxen

TheseN

SAID

Sindu

cetoxicityindepend

ento

fmito

chon

drialrespiratio

n[95]

Indo

methacin

sodium

diclo

fenacflu

rbiprofen

zalto

profenand

mofezolac

ND

Hum

angastric

epith

elialcellline

AGS

AllNSA

IDse

xceptm

ofezolac

increased

apop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

AD

NAfragmentatio

nindu

ced

byindo

methacinor

flurbiprofenwas

redu

ced

byantio

xidantsIndo

methacinat1m

Mwas

apo

tent

indu

cero

fROSgeneratio

nin

thec

ells

[79]

Diclofenaca

ndnaproxen

NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

oxidasee


the

heartand

aortab

ydiclo

fenaca

ndnaproxen


etoNADPH

oxidase

[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2iso

form

ofNADPH

oxidaseisincreased

bydiclo

fenac

[114]

Aspirin

naproxenand

piroxicam

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Indo

methacin

Xanthine

oxidases

Hum

ancolonica

deno

carcinom

acells

(Caco-2cells)

Xanthine

oxidasea

ctivity

increasesb

ymore

than

100

1hou

rafte

rtreatment

[96]

Indo

methacin

Mito

chon

driasuperoxide

leakage

Ratgastricepith

elialcellline

RGM1

Indo

methacinindu

cedtheleakage

ofsuperoxide

anionin

theisolatedmito

chon

dria

from

theg

astricRG

M1cells

[93]

Indo

methacin

diclo

fenac

sodium

and

aspirin

ND

Ratgastricepith

elialcellline

RGM1and

ratsmallintestin

alepith

elialcelllineIEC

6

Indo

methacin

diclo

fenacandaspirin

ingastric

RGM1cellsandsm

allintestin

alIEC6

cells

increasedlip

idperoxidatio

n[93]

Sulin

dacsulin

dacs

ulfid

eandsulin

dacs

ulfone

ND

Pancreas

carcinom

aBXP

C3

glioblastomaA

172colon

carcinom

aDLD

-1oral

squamou

sSASandacute

myelocytic

leuk

emiaHL6

0cells

TheN

SAID

sulin

daca

ndits

metabolites

sulin

dacs

ulfid

eand

sulin

dacs

ulfone

all

increasedRO

Sgeneratio

nSulin

dacs

ulfid

eshow

edtheg

reatestR

OSgeneratio

n

[80]

Indo

methacin

piroxicam

andaspirin

Lipo

xygenases


mice

Results

inan

overprod

uctio

nof

leuk

otrie

nes

andprod

uctsof

5-lip

oxygenasea

ctivity

Increasesinleuk

otrie

neand5-lip

oxygenase

activ

ityhave

been

associated

with

ROS

generatio

n

[123124127]

Indo

methacin

Lipo

xygenases


Timed

ependent

form

ationof

leuk

otrie

ne-C

4[128]


(a)Con

tinued

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenac

CytochromeP

450enzymes

Saccharomyces

cerevisia

eyeast

cells

expressin

gthem

utantP

450

BM3M11(capableof

metabolizingdiclo

fenacs

imilar

tohu

mans)

IncreasedRO

Sprod

uctio

nbysim15

and18

times

atconcentrations

of30120583M

and50120583M

respectiv

elycom

paredto

wild

type

[140]

Diclofenacindo

methacin

ketoprofenand

naproxen

CytochromeP

450enzymes

Saccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

NSA

IDsm

etabolism

associated

with

increased

P450-related

toxicity

[95]

(b)

NSA

IDs

coxibs

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Ibup

rofen

ketoprofenand

indo

methacin

CytochromeP

450enzymes

Bacillusm

egaterium

AlltheN

SAID

scausedam

arkedincrease


450level

[142]

Aspirin

diclofenacdiflu

nisal

flurbiprofen

ibup

rofen

indo

methacin

ketoprofenm

efenam

icacidn

aproxen


etin

CytochromeP

450enzymes

Rath

epatocytes

Cytotoxicityof

diclo

fenacketoprofen

andpiroxicam

was

increasedby

cytochromeP


[138]

Diclofenaca

ndnaproxen

Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Increasedexpressio

nof

eNOSmRN

Adu

eto

theg

enerationof

H2O

2which

isrespon

sibleforu

pregulationof

eNOSat

thetranscriptio

naland

post-

transcrip

tionallevels

[114]


NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

expressio

nincreasedin

theh

eart

andaortab


[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2Ex

pressio

nincreasedby

rofecoxib

[114]


Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Inthea

ortathe

coxibs

didno

tsho

wany

eNOSmRN

Aexpressio

nIn

theh

eart

onlyrofecoxibshow

edas

ignificant

increase

inthee

xpressionof

eNOS

[114]

Etod

olac

ND

Hum

angastr

icepith

elialcell

lineA

GS

Increasedapop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

A[79]

Nim

esulide

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Alth

ough

otherreportsarea

vailables

uggesting

theroleo

fNSA

IDsinRO

Sform


lythoseN

SAID

sfor

which

results

show

thattheseN

SAID

sareassociated

with

CVDor

NSA

IDsm

entio

ned

inthetext















2




2


2O2[115]



2


2

∙minus H2O2







2) from the mem-




2











2








2



2transcript level



2

∙minus


2







14 Conclusion






Abbreviations




Acknowledgment



References










































































2O2























































































































































Table2Summaryof

results

from

clinicaltria

lson

thea

dverse

effectsof

NSA

IDso

ncardiovascular

diseases

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Cele

coxibnaproxen

sodium

and

placebo

Alzh

eimerrsquosDise

ase

Anti-Infl

ammatory

Preventio

nTrial

(ADAPT

)USA

4years

2528patie

ntsw

ithafam

ilyhisto

ryof

Alzh

eimerrsquos

Dise

ase

CVDCBV

deathMIstr

okeCH

For

TIAin

thec


placebo-tre

ated

grou

pswe

re554

825and

568respectively

Death

ratesinthec

aseo

fpatientstaking

NSA

IDsw

ereh

igherb

utno

tstatistic

ally

significant

[44]

Cele


diclo

fenacnaproxenibu

profen

diflu

nisaletod

olacfenop

rofen

flurbiprofen

indo

methacin

ketoprofen


icacidm

eloxicamn

abum

eton

eoxaprozin


etin

Non

eUSA

5years

74838

userso

fNSA

IDsa

nd2353

5userso

fother

drugs

Thea

djustedrateratio

forR

ofecoxib

was

116forM

Iand

115forstro

kewhich

was

theh

ighestam

ongallother

NSA

IDs

inclu

ding

otherc

oxibsNaproxen

mod

estly

redu

cedther

ater

atio

(RRfor

MI0

067

andRR

forstro

ke0083)

ofcardiovascular

events

[177]

Cele

coxibibup

rofen

Non

eCh

ieti

Chieti

Italy

3mon

ths

24patie

ntsu

ndergoing

aspirin

treatmentfor

cardioprotectio

n

Ibup

rofeninterfe

redwith

theinh

ibition

ofplateletCO

X-1n

ecessary

for

cardioprotectio

nby

aspirin

[178]

Diclofenacibup

rofen

indo

methacin

ketoprofenn

aproxen

mefenam

icacid

piroxicamtenoxicam

tolfenamicacid

aceclofenactia

profenicacidm

efenam

icacidetodo

lacnabu

meton

enimesulide

andmelo

xicamrofecoxibcele

coxib

valdecoxiband

etoricoxib

Non

eFinland

3years

33309

patie

ntsw

ithfirst

MI138949controls


OX-

selectivity

dono

tdeterminethe

adversee

ffectof

CVDby

NSA

IDsatleastcon

cerningMI

NoNSA

IDisMI-protectiv

e

[13]

Etoricoxib

anddiclo

fenac

Multin

ationalE

toric

oxib

andDiclofenacA

rthritis

Long

-term

(MED

AL)

Stud

yProgramM

ultin

ational

18mon

ths

34701

patie

nts(24913

with

osteoarthritisa

nd97

87with


Thrombo

ticcardiovascular

events

occurred

in320patie

ntsinthee

toric

oxib

grou

pand323patie

ntsinthed

iclofenac

grou

pwith

eventrates

of12

4and13

0per

100patie

nt-yearsandah

azardratio

of095

fore

toric

oxibcomparedto

diclo

fenacLo

ngterm

usageo

feith

erof

theseN

SAID

shad

similare

ffectso

nthe

rateso

fthrom

botic

cardiovascular

events

[179]

Etoricoxib

anddiclo

fenac

Etoricoxibversus

DiclofenacS

odium

Gastro

intestinal

Tolerabilityand

Effectiv

eness(ED

GE)

trialU

SA

93mon

thsfor

etoricoxib

and89

mon

thsfor

diclo

fenac

7111patie

nts

etoricoxib

(119899=3593)o

rdiclo

fenacs

odium

(119899=3518)

Ther

ateo

fthrom

botic

CVeventswas

130and12

4in

userso

fetoric

oxib

(90m

g)anddiclo

fenac(150m

g)

respectiv

elyw

ithin

28days

[180]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Ibup

rofen

naproxen

orlumira

coxib

TheTh

erapeutic

Arthritis

Research

and

Gastro

intestinalEv

entT

rial

(TARG

ET)International

Extend

edrepo

rt1832

5patie

ntsw

ithosteoarthritis

Ibup

rofenincreasedris

kof

thrombo

sisandCH

Fcomparedto

lumira

coxib

(214

versus

025)a

mon

gaspirin


erris

krelativetolumira

coxibam

ongno

naspirin

users

[181]

Diclofenacibup

rofen

andnaproxen

Non

eUSA

7years

ND

Prolon

gedexpo

sure

todiclo

fenac

increasesthe

riskof

AMI(relativer

atio

=19

ndash20)u

nlikeibu

profen

ornaproxen

[182]

Etoricoxib

anddiclo

fenac

EDGEIIU

SA193mon

thsfor

etoricoxib

and191

mon

thsfor

diclo

fenac

4086patie

ntsw



diclo

fenac119899=2054

Ther

ateo

foccurrenceo

fAMIw

ashigh

erin

diclo

fenac(068)treated

patie

ntsthan

inetoricoxib

users(043)Also

anoverall

increase

incardiace

ventsw

asob

served

indiclo

fenactreated

grou

p(114

)versus

thee

toric

oxibgrou

p(083)

[183]

Cele

coxib(at4

00mgQD200

mgtwo

times

aday

(BID

)or

400m

gBID)

Non

eUSA

3years

7950

patie

nts(with

arthritisandother

cond

ition

s)

Theh

azardratio

forthe

CVDM

IHFor

thrombo

embo

liceventw

aslowestfor

the

400mgon

cead


the2

00mg-BIDdo

se(18)andhigh

est

forthe

400mg-BIDdo

se(31)

[184]

Ibup

rofen

naproxendiclofenac

meloxicam

ind

omethacin

piroxicam

andmefenam

icacid

Non

eUKprim

arycare

20years

7292

94NSA

IDusers

443047controls

Increase

inther

elativer

atefor

MIw

ithcumulativea

nddaily

dose

ofibup

rofen

anddiclo

fenacHigherrisk

ofMIw

ithdiclo

fenacu

se(relativer

atio

=12

1)than

ibup

rofen(relativer

atio

=10

4)or

naproxen

(relativer

atio

=10

3)

[185]

Etoricoxib

anddiclo

fenac

TheM

EDAL

Stud

yMultin

ational

194to

208mon

ths

Etoricoxib

60mgd119899=6769

90mgd119899=5012


Thethrom

botic

CVris

kHRof

etoricoxib

todiclo

fenac=

096P

rolonged

useo

feither

NSA

IDresultedin

anincreased

riskof

thrombo

ticCV

events

[186]

Naproxen

ibup

rofen

diclo

fenac


Non

eUSA

6years

48566

patie

ntsrecently

hospita

lized

form

yocardial

infarctio

nrevascularization

orun

stableangina

pectoris

CVDris

kincreasedwith

shortterm

(lt90

days)u

seforibu

profen

with

incidence

rateratio

sof167diclo

fenac186

celecoxib13

7androfecoxib14

6bu

tnot

forn

aproxen088

[51]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Cele


ibup

rofen


indo

methacin

Non

eUSA

7years

610001p

atientswith

out

CVD119899=525249w

ithhisto

ryof

CVD119899=84752

Rofecoxib(1091

events

1000

person

-years)valdecoxib

(1241

events

1000

person

-years)and

indo

methacin(1325

events

1000

person

-years)increased

CVDris

kin

patie

ntsw

ithno

histo

ryof

CVD


riskof

cardiovascular

eventinpatie

ntsw

ithCV

D(3028

events

1000

person

-years)

[187]

Ibup

rofen

diclo

fenacrofecoxib


Non

eDanish

popu

latio

n9ndash

34days


als

Dosed

ependent

increase

incardiovascular

eventsdu

etouseo

fdiclo

fenac(HR=16

3)rofecoxib

(HR=

213)a

ndcelecoxib(H

R=201)w

asob

served

[188]

Cele

coxibibup

rofen

andnaproxen

TheP

rospectiv

eRa

ndom

ized

Evaluatio

nof

Cele

coxibIntegrated

Safety

versus

Ibup

rofenOr

Naproxen

(PRE

CISION)

trialM

ultin

ational

2009-ongoing

20000

patie

ntsw

ithsymptom

aticosteoarthritis


high

riskforo

rwith

establish

edCV

D

Thistrialw

illdeterm

inethe

cardiovascular

safetyof

theN

SAID

s[189]

ND

Non

eDenmark

10years

1070

92patie

ntsw

ithfirst

incidenceo

fHF

Theh

azardratio

ford

eath

duetoMIo

rHFwas

17017

513

1208122and12

8forrofecoxibcele

coxibibup

rofen

diclo

fenacnaproxenand

otherN

SAID

srespectiv

ely

[190]

Ibup

rofen

diclo

fenacnaproxen


etoricoxib

Non

eTh

eNetherla

nds

4years

485059subjectswith

first

hospita

lisationfora

cute


CV

andgastr

ointestin

alevents

AMIrisk

with

celecoxib(O

R253)

rofecoxib(O

R16

0)ibu

profen

(OR15

6)

anddiclo

fenac(OR15

1)was

significantly

increasedSign

ificant

increase

inCV

risk

with

currentu

seof

individu

alCO

X-2

inhibitorsandtN

SAID

s(ORfro

m117to

164)Significantd

ecreaseinAMIw

ithcurrentu

seof

naproxen

(OR048)

[191]

Ibup

rofen

naproxendiclofenac

etod


Non

eNorthernDenmark

10years

32602

patie

ntsw

ithfirst

atria

lfibrillationor

flutte

rand325918po

pulatio

ncontrols

Increasedris

kof

atria

lfibrillationor

flutte

rwas

40ndash70

(lowe

stfor

non-selectiveN

SAID

sand

high

estfor

COX-

2inhibitors)

[192]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

ND

Non

eDenmark

10years

83677

patie

ntso

fwhich

423received

NSA

IDs

Deathrecurrent

MId

ueto

NSA

IDtre

atment(even

shortterm)w

assig

nificantly

high

erD

iclofenacp

osed

the

high

estrisk

ofallN

SAID

s

[193]

ND

INternationalV

Erapam

ilTrando

laprilSTud

y(INVES

T)M

ultin

ational

7years

882chronicN

SAID

users

and21694

nonchron

icNSA

IDusersPatie

ntsw

ithhypertensio

nandclinically

stablec

oron

aryartery

disease

Prim

aryou

tcom

elikea

ll-causem

ortality

nonfatalMIor

nonfatalstroke

and

second

aryindividu

alou

tcom

eslik

eall-c

ause


mortalitytotalM

Iandtotalstro

keoccurred

atar

ateo

f44eventsper100

patie

nt-yearsin

thec

hron

icNSA

IDgrou

pversus

37eventsper100

patie

nt-yearsin

then

onchronicN

SAID

grou

p

[111]

Cele

coxibrofecoxibibup

rofen

diclo

fenacnaproxenand

others

Non

eDenmark

13years(with

first

MI)

128418patie

nts(77

participated

inthes

tudy)

Incidences

ofcoronary

deathor

nonfatal

recurrentM

Iwith

NSA

IDsu

seremain

unchangedwith

thetim

eelapsed

even

after

5years

[194]

ND

Non

edataob

tained

from

REdu

ctionof

Atherothrombo

sisfor

Con

tinuedHealth

(REA

CH)registry

which

inclu

desp

atientsfrom

Latin

AmericaNorth

AmericaEu

ropeA

siathe

MiddleE

astandAu

stralia

4years

4420NSA

IDusers39675

NSA

IDno

nusers

116-fold

high

erris

kof

CVDM

Iin

NSA

IDusers

[41]


HFheartfailureC

VDcardiovasculard

iseasesC

BVcerebrovascular

diseasesC

HFcongestiv

eheartfailu

reH

Rhazard

ratio

OR

oddratio

NDnot

defin

edR

Rrateratio

and

TIA

transie

ntisc

hemicattackV

arious

clinicaltria

lssuggestthe

increasedincidences

ofCV

Din

NSA

IDusersTh

etablelistson

lythec

linicaltrialsrepo

rted

between2006

and2014


Thrombosis



Apoptosis



(free radicals)



ROS

Cytochrome p450




NSAIDs
















2


2O2)


2

∙minus












Table3NSA

IDsind

uced

ROSgeneratio

nin

different

celltypes

(a)

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenacindo

methacin

ketoprofen

Mito

chon

drialrespiratio

nSaccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

TheseN

SAID

stargetm

itochon

driato

indu

cecelltoxicity

[95]

Ibup

rofenandnaproxen

TheseN

SAID

Sindu

cetoxicityindepend

ento

fmito

chon

drialrespiratio

n[95]

Indo

methacin

sodium

diclo

fenacflu

rbiprofen

zalto

profenand

mofezolac

ND

Hum

angastric

epith

elialcellline

AGS

AllNSA

IDse

xceptm

ofezolac

increased

apop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

AD

NAfragmentatio

nindu

ced

byindo

methacinor

flurbiprofenwas

redu

ced

byantio

xidantsIndo

methacinat1m

Mwas

apo

tent

indu

cero

fROSgeneratio

nin

thec

ells

[79]

Diclofenaca

ndnaproxen

NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

oxidasee


the

heartand

aortab

ydiclo

fenaca

ndnaproxen


etoNADPH

oxidase

[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2iso

form

ofNADPH

oxidaseisincreased

bydiclo

fenac

[114]

Aspirin

naproxenand

piroxicam

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Indo

methacin

Xanthine

oxidases

Hum

ancolonica

deno

carcinom

acells

(Caco-2cells)

Xanthine

oxidasea

ctivity

increasesb

ymore

than

100

1hou

rafte

rtreatment

[96]

Indo

methacin

Mito

chon

driasuperoxide

leakage

Ratgastricepith

elialcellline

RGM1

Indo

methacinindu

cedtheleakage

ofsuperoxide

anionin

theisolatedmito

chon

dria

from

theg

astricRG

M1cells

[93]

Indo

methacin

diclo

fenac

sodium

and

aspirin

ND

Ratgastricepith

elialcellline

RGM1and

ratsmallintestin

alepith

elialcelllineIEC

6

Indo

methacin

diclo

fenacandaspirin

ingastric

RGM1cellsandsm

allintestin

alIEC6

cells

increasedlip

idperoxidatio

n[93]

Sulin

dacsulin

dacs

ulfid

eandsulin

dacs

ulfone

ND

Pancreas

carcinom

aBXP

C3

glioblastomaA

172colon

carcinom

aDLD

-1oral

squamou

sSASandacute

myelocytic

leuk

emiaHL6

0cells

TheN

SAID

sulin

daca

ndits

metabolites

sulin

dacs

ulfid

eand

sulin

dacs

ulfone

all

increasedRO

Sgeneratio

nSulin

dacs

ulfid

eshow

edtheg

reatestR

OSgeneratio

n

[80]

Indo

methacin

piroxicam

andaspirin

Lipo

xygenases


mice

Results

inan

overprod

uctio

nof

leuk

otrie

nes

andprod

uctsof

5-lip

oxygenasea

ctivity

Increasesinleuk

otrie

neand5-lip

oxygenase

activ

ityhave

been

associated

with

ROS

generatio

n

[123124127]

Indo

methacin

Lipo

xygenases


Timed

ependent

form

ationof

leuk

otrie

ne-C

4[128]


(a)Con

tinued

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenac

CytochromeP

450enzymes

Saccharomyces

cerevisia

eyeast

cells

expressin

gthem

utantP

450

BM3M11(capableof

metabolizingdiclo

fenacs

imilar

tohu

mans)

IncreasedRO

Sprod

uctio

nbysim15

and18

times

atconcentrations

of30120583M

and50120583M

respectiv

elycom

paredto

wild

type

[140]

Diclofenacindo

methacin

ketoprofenand

naproxen

CytochromeP

450enzymes

Saccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

NSA

IDsm

etabolism

associated

with

increased

P450-related

toxicity

[95]

(b)

NSA

IDs

coxibs

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Ibup

rofen

ketoprofenand

indo

methacin

CytochromeP

450enzymes

Bacillusm

egaterium

AlltheN

SAID

scausedam

arkedincrease


450level

[142]

Aspirin

diclofenacdiflu

nisal

flurbiprofen

ibup

rofen

indo

methacin

ketoprofenm

efenam

icacidn

aproxen


etin

CytochromeP

450enzymes

Rath

epatocytes

Cytotoxicityof

diclo

fenacketoprofen

andpiroxicam

was

increasedby

cytochromeP


[138]

Diclofenaca

ndnaproxen

Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Increasedexpressio

nof

eNOSmRN

Adu

eto

theg

enerationof

H2O

2which

isrespon

sibleforu

pregulationof

eNOSat

thetranscriptio

naland

post-

transcrip

tionallevels

[114]


NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

expressio

nincreasedin

theh

eart

andaortab


[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2Ex

pressio

nincreasedby

rofecoxib

[114]


Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Inthea

ortathe

coxibs

didno

tsho

wany

eNOSmRN

Aexpressio

nIn

theh

eart

onlyrofecoxibshow

edas

ignificant

increase

inthee

xpressionof

eNOS

[114]

Etod

olac

ND

Hum

angastr

icepith

elialcell

lineA

GS

Increasedapop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

A[79]

Nim

esulide

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Alth

ough

otherreportsarea

vailables

uggesting

theroleo

fNSA

IDsinRO

Sform


lythoseN

SAID

sfor

which

results

show

thattheseN

SAID

sareassociated

with

CVDor

NSA

IDsm

entio

ned

inthetext















2




2


2O2[115]



2


2

∙minus H2O2







2) from the mem-




2











2








2



2transcript level



2

∙minus


2







14 Conclusion






Abbreviations




Acknowledgment



References










































































2O2














































































































































Table2Summaryof

results

from

clinicaltria

lson

thea

dverse

effectsof

NSA

IDso

ncardiovascular

diseases

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Cele

coxibnaproxen

sodium

and

placebo

Alzh

eimerrsquosDise

ase

Anti-Infl

ammatory

Preventio

nTrial

(ADAPT

)USA

4years

2528patie

ntsw

ithafam

ilyhisto

ryof

Alzh

eimerrsquos

Dise

ase

CVDCBV

deathMIstr

okeCH

For

TIAin

thec


placebo-tre

ated

grou

pswe

re554

825and

568respectively

Death

ratesinthec

aseo

fpatientstaking

NSA

IDsw

ereh

igherb

utno

tstatistic

ally

significant

[44]

Cele


diclo

fenacnaproxenibu

profen

diflu

nisaletod

olacfenop

rofen

flurbiprofen

indo

methacin

ketoprofen


icacidm

eloxicamn

abum

eton

eoxaprozin


etin

Non

eUSA

5years

74838

userso

fNSA

IDsa

nd2353

5userso

fother

drugs

Thea

djustedrateratio

forR

ofecoxib

was

116forM

Iand

115forstro

kewhich

was

theh

ighestam

ongallother

NSA

IDs

inclu

ding

otherc

oxibsNaproxen

mod

estly

redu

cedther

ater

atio

(RRfor

MI0

067

andRR

forstro

ke0083)

ofcardiovascular

events

[177]

Cele

coxibibup

rofen

Non

eCh

ieti

Chieti

Italy

3mon

ths

24patie

ntsu

ndergoing

aspirin

treatmentfor

cardioprotectio

n

Ibup

rofeninterfe

redwith

theinh

ibition

ofplateletCO

X-1n

ecessary

for

cardioprotectio

nby

aspirin

[178]

Diclofenacibup

rofen

indo

methacin

ketoprofenn

aproxen

mefenam

icacid

piroxicamtenoxicam

tolfenamicacid

aceclofenactia

profenicacidm

efenam

icacidetodo

lacnabu

meton

enimesulide

andmelo

xicamrofecoxibcele

coxib

valdecoxiband

etoricoxib

Non

eFinland

3years

33309

patie

ntsw

ithfirst

MI138949controls


OX-

selectivity

dono

tdeterminethe

adversee

ffectof

CVDby

NSA

IDsatleastcon

cerningMI

NoNSA

IDisMI-protectiv

e

[13]

Etoricoxib

anddiclo

fenac

Multin

ationalE

toric

oxib

andDiclofenacA

rthritis

Long

-term

(MED

AL)

Stud

yProgramM

ultin

ational

18mon

ths

34701

patie

nts(24913

with

osteoarthritisa

nd97

87with


Thrombo

ticcardiovascular

events

occurred

in320patie

ntsinthee

toric

oxib

grou

pand323patie

ntsinthed

iclofenac

grou

pwith

eventrates

of12

4and13

0per

100patie

nt-yearsandah

azardratio

of095

fore

toric

oxibcomparedto

diclo

fenacLo

ngterm

usageo

feith

erof

theseN

SAID

shad

similare

ffectso

nthe

rateso

fthrom

botic

cardiovascular

events

[179]

Etoricoxib

anddiclo

fenac

Etoricoxibversus

DiclofenacS

odium

Gastro

intestinal

Tolerabilityand

Effectiv

eness(ED

GE)

trialU

SA

93mon

thsfor

etoricoxib

and89

mon

thsfor

diclo

fenac

7111patie

nts

etoricoxib

(119899=3593)o

rdiclo

fenacs

odium

(119899=3518)

Ther

ateo

fthrom

botic

CVeventswas

130and12

4in

userso

fetoric

oxib

(90m

g)anddiclo

fenac(150m

g)

respectiv

elyw

ithin

28days

[180]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Ibup

rofen

naproxen

orlumira

coxib

TheTh

erapeutic

Arthritis

Research

and

Gastro

intestinalEv

entT

rial

(TARG

ET)International

Extend

edrepo

rt1832

5patie

ntsw

ithosteoarthritis

Ibup

rofenincreasedris

kof

thrombo

sisandCH

Fcomparedto

lumira

coxib

(214

versus

025)a

mon

gaspirin


erris

krelativetolumira

coxibam

ongno

naspirin

users

[181]

Diclofenacibup

rofen

andnaproxen

Non

eUSA

7years

ND

Prolon

gedexpo

sure

todiclo

fenac

increasesthe

riskof

AMI(relativer

atio

=19

ndash20)u

nlikeibu

profen

ornaproxen

[182]

Etoricoxib

anddiclo

fenac

EDGEIIU

SA193mon

thsfor

etoricoxib

and191

mon

thsfor

diclo

fenac

4086patie

ntsw



diclo

fenac119899=2054

Ther

ateo

foccurrenceo

fAMIw

ashigh

erin

diclo

fenac(068)treated

patie

ntsthan

inetoricoxib

users(043)Also

anoverall

increase

incardiace

ventsw

asob

served

indiclo

fenactreated

grou

p(114

)versus

thee

toric

oxibgrou

p(083)

[183]

Cele

coxib(at4

00mgQD200

mgtwo

times

aday

(BID

)or

400m

gBID)

Non

eUSA

3years

7950

patie

nts(with

arthritisandother

cond

ition

s)

Theh

azardratio

forthe

CVDM

IHFor

thrombo

embo

liceventw

aslowestfor

the

400mgon

cead


the2

00mg-BIDdo

se(18)andhigh

est

forthe

400mg-BIDdo

se(31)

[184]

Ibup

rofen

naproxendiclofenac

meloxicam

ind

omethacin

piroxicam

andmefenam

icacid

Non

eUKprim

arycare

20years

7292

94NSA

IDusers

443047controls

Increase

inther

elativer

atefor

MIw

ithcumulativea

nddaily

dose

ofibup

rofen

anddiclo

fenacHigherrisk

ofMIw

ithdiclo

fenacu

se(relativer

atio

=12

1)than

ibup

rofen(relativer

atio

=10

4)or

naproxen

(relativer

atio

=10

3)

[185]

Etoricoxib

anddiclo

fenac

TheM

EDAL

Stud

yMultin

ational

194to

208mon

ths

Etoricoxib

60mgd119899=6769

90mgd119899=5012


Thethrom

botic

CVris

kHRof

etoricoxib

todiclo

fenac=

096P

rolonged

useo

feither

NSA

IDresultedin

anincreased

riskof

thrombo

ticCV

events

[186]

Naproxen

ibup

rofen

diclo

fenac


Non

eUSA

6years

48566

patie

ntsrecently

hospita

lized

form

yocardial

infarctio

nrevascularization

orun

stableangina

pectoris

CVDris

kincreasedwith

shortterm

(lt90

days)u

seforibu

profen

with

incidence

rateratio

sof167diclo

fenac186

celecoxib13

7androfecoxib14

6bu

tnot

forn

aproxen088

[51]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Cele


ibup

rofen


indo

methacin

Non

eUSA

7years

610001p

atientswith

out

CVD119899=525249w

ithhisto

ryof

CVD119899=84752

Rofecoxib(1091

events

1000

person

-years)valdecoxib

(1241

events

1000

person

-years)and

indo

methacin(1325

events

1000

person

-years)increased

CVDris

kin

patie

ntsw

ithno

histo

ryof

CVD


riskof

cardiovascular

eventinpatie

ntsw

ithCV

D(3028

events

1000

person

-years)

[187]

Ibup

rofen

diclo

fenacrofecoxib


Non

eDanish

popu

latio

n9ndash

34days


als

Dosed

ependent

increase

incardiovascular

eventsdu

etouseo

fdiclo

fenac(HR=16

3)rofecoxib

(HR=

213)a

ndcelecoxib(H

R=201)w

asob

served

[188]

Cele

coxibibup

rofen

andnaproxen

TheP

rospectiv

eRa

ndom

ized

Evaluatio

nof

Cele

coxibIntegrated

Safety

versus

Ibup

rofenOr

Naproxen

(PRE

CISION)

trialM

ultin

ational

2009-ongoing

20000

patie

ntsw

ithsymptom

aticosteoarthritis


high

riskforo

rwith

establish

edCV

D

Thistrialw

illdeterm

inethe

cardiovascular

safetyof

theN

SAID

s[189]

ND

Non

eDenmark

10years

1070

92patie

ntsw

ithfirst

incidenceo

fHF

Theh

azardratio

ford

eath

duetoMIo

rHFwas

17017

513

1208122and12

8forrofecoxibcele

coxibibup

rofen

diclo

fenacnaproxenand

otherN

SAID

srespectiv

ely

[190]

Ibup

rofen

diclo

fenacnaproxen


etoricoxib

Non

eTh

eNetherla

nds

4years

485059subjectswith

first

hospita

lisationfora

cute


CV

andgastr

ointestin

alevents

AMIrisk

with

celecoxib(O

R253)

rofecoxib(O

R16

0)ibu

profen

(OR15

6)

anddiclo

fenac(OR15

1)was

significantly

increasedSign

ificant

increase

inCV

risk

with

currentu

seof

individu

alCO

X-2

inhibitorsandtN

SAID

s(ORfro

m117to

164)Significantd

ecreaseinAMIw

ithcurrentu

seof

naproxen

(OR048)

[191]

Ibup

rofen

naproxendiclofenac

etod


Non

eNorthernDenmark

10years

32602

patie

ntsw

ithfirst

atria

lfibrillationor

flutte

rand325918po

pulatio

ncontrols

Increasedris

kof

atria

lfibrillationor

flutte

rwas

40ndash70

(lowe

stfor

non-selectiveN

SAID

sand

high

estfor

COX-

2inhibitors)

[192]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

ND

Non

eDenmark

10years

83677

patie

ntso

fwhich

423received

NSA

IDs

Deathrecurrent

MId

ueto

NSA

IDtre

atment(even

shortterm)w

assig

nificantly

high

erD

iclofenacp

osed

the

high

estrisk

ofallN

SAID

s

[193]

ND

INternationalV

Erapam

ilTrando

laprilSTud

y(INVES

T)M

ultin

ational

7years

882chronicN

SAID

users

and21694

nonchron

icNSA

IDusersPatie

ntsw

ithhypertensio

nandclinically

stablec

oron

aryartery

disease

Prim

aryou

tcom

elikea

ll-causem

ortality

nonfatalMIor

nonfatalstroke

and

second

aryindividu

alou

tcom

eslik

eall-c

ause


mortalitytotalM

Iandtotalstro

keoccurred

atar

ateo

f44eventsper100

patie

nt-yearsin

thec

hron

icNSA

IDgrou

pversus

37eventsper100

patie

nt-yearsin

then

onchronicN

SAID

grou

p

[111]

Cele

coxibrofecoxibibup

rofen

diclo

fenacnaproxenand

others

Non

eDenmark

13years(with

first

MI)

128418patie

nts(77

participated

inthes

tudy)

Incidences

ofcoronary

deathor

nonfatal

recurrentM

Iwith

NSA

IDsu

seremain

unchangedwith

thetim

eelapsed

even

after

5years

[194]

ND

Non

edataob

tained

from

REdu

ctionof

Atherothrombo

sisfor

Con

tinuedHealth

(REA

CH)registry

which

inclu

desp

atientsfrom

Latin

AmericaNorth

AmericaEu

ropeA

siathe

MiddleE

astandAu

stralia

4years

4420NSA

IDusers39675

NSA

IDno

nusers

116-fold

high

erris

kof

CVDM

Iin

NSA

IDusers

[41]


HFheartfailureC

VDcardiovasculard

iseasesC

BVcerebrovascular

diseasesC

HFcongestiv

eheartfailu

reH

Rhazard

ratio

OR

oddratio

NDnot

defin

edR

Rrateratio

and

TIA

transie

ntisc

hemicattackV

arious

clinicaltria

lssuggestthe

increasedincidences

ofCV

Din

NSA

IDusersTh

etablelistson

lythec

linicaltrialsrepo

rted

between2006

and2014


Thrombosis



Apoptosis



(free radicals)



ROS

Cytochrome p450




NSAIDs
















2


2O2)


2

∙minus












Table3NSA

IDsind

uced

ROSgeneratio

nin

different

celltypes

(a)

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenacindo

methacin

ketoprofen

Mito

chon

drialrespiratio

nSaccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

TheseN

SAID

stargetm

itochon

driato

indu

cecelltoxicity

[95]

Ibup

rofenandnaproxen

TheseN

SAID

Sindu

cetoxicityindepend

ento

fmito

chon

drialrespiratio

n[95]

Indo

methacin

sodium

diclo

fenacflu

rbiprofen

zalto

profenand

mofezolac

ND

Hum

angastric

epith

elialcellline

AGS

AllNSA

IDse

xceptm

ofezolac

increased

apop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

AD

NAfragmentatio

nindu

ced

byindo

methacinor

flurbiprofenwas

redu

ced

byantio

xidantsIndo

methacinat1m

Mwas

apo

tent

indu

cero

fROSgeneratio

nin

thec

ells

[79]

Diclofenaca

ndnaproxen

NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

oxidasee


the

heartand

aortab

ydiclo

fenaca

ndnaproxen


etoNADPH

oxidase

[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2iso

form

ofNADPH

oxidaseisincreased

bydiclo

fenac

[114]

Aspirin

naproxenand

piroxicam

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Indo

methacin

Xanthine

oxidases

Hum

ancolonica

deno

carcinom

acells

(Caco-2cells)

Xanthine

oxidasea

ctivity

increasesb

ymore

than

100

1hou

rafte

rtreatment

[96]

Indo

methacin

Mito

chon

driasuperoxide

leakage

Ratgastricepith

elialcellline

RGM1

Indo

methacinindu

cedtheleakage

ofsuperoxide

anionin

theisolatedmito

chon

dria

from

theg

astricRG

M1cells

[93]

Indo

methacin

diclo

fenac

sodium

and

aspirin

ND

Ratgastricepith

elialcellline

RGM1and

ratsmallintestin

alepith

elialcelllineIEC

6

Indo

methacin

diclo

fenacandaspirin

ingastric

RGM1cellsandsm

allintestin

alIEC6

cells

increasedlip

idperoxidatio

n[93]

Sulin

dacsulin

dacs

ulfid

eandsulin

dacs

ulfone

ND

Pancreas

carcinom

aBXP

C3

glioblastomaA

172colon

carcinom

aDLD

-1oral

squamou

sSASandacute

myelocytic

leuk

emiaHL6

0cells

TheN

SAID

sulin

daca

ndits

metabolites

sulin

dacs

ulfid

eand

sulin

dacs

ulfone

all

increasedRO

Sgeneratio

nSulin

dacs

ulfid

eshow

edtheg

reatestR

OSgeneratio

n

[80]

Indo

methacin

piroxicam

andaspirin

Lipo

xygenases


mice

Results

inan

overprod

uctio

nof

leuk

otrie

nes

andprod

uctsof

5-lip

oxygenasea

ctivity

Increasesinleuk

otrie

neand5-lip

oxygenase

activ

ityhave

been

associated

with

ROS

generatio

n

[123124127]

Indo

methacin

Lipo

xygenases


Timed

ependent

form

ationof

leuk

otrie

ne-C

4[128]


(a)Con

tinued

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenac

CytochromeP

450enzymes

Saccharomyces

cerevisia

eyeast

cells

expressin

gthem

utantP

450

BM3M11(capableof

metabolizingdiclo

fenacs

imilar

tohu

mans)

IncreasedRO

Sprod

uctio

nbysim15

and18

times

atconcentrations

of30120583M

and50120583M

respectiv

elycom

paredto

wild

type

[140]

Diclofenacindo

methacin

ketoprofenand

naproxen

CytochromeP

450enzymes

Saccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

NSA

IDsm

etabolism

associated

with

increased

P450-related

toxicity

[95]

(b)

NSA

IDs

coxibs

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Ibup

rofen

ketoprofenand

indo

methacin

CytochromeP

450enzymes

Bacillusm

egaterium

AlltheN

SAID

scausedam

arkedincrease


450level

[142]

Aspirin

diclofenacdiflu

nisal

flurbiprofen

ibup

rofen

indo

methacin

ketoprofenm

efenam

icacidn

aproxen


etin

CytochromeP

450enzymes

Rath

epatocytes

Cytotoxicityof

diclo

fenacketoprofen

andpiroxicam

was

increasedby

cytochromeP


[138]

Diclofenaca

ndnaproxen

Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Increasedexpressio

nof

eNOSmRN

Adu

eto

theg

enerationof

H2O

2which

isrespon

sibleforu

pregulationof

eNOSat

thetranscriptio

naland

post-

transcrip

tionallevels

[114]


NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

expressio

nincreasedin

theh

eart

andaortab


[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2Ex

pressio

nincreasedby

rofecoxib

[114]


Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Inthea

ortathe

coxibs

didno

tsho

wany

eNOSmRN

Aexpressio

nIn

theh

eart

onlyrofecoxibshow

edas

ignificant

increase

inthee

xpressionof

eNOS

[114]

Etod

olac

ND

Hum

angastr

icepith

elialcell

lineA

GS

Increasedapop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

A[79]

Nim

esulide

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Alth

ough

otherreportsarea

vailables

uggesting

theroleo

fNSA

IDsinRO

Sform


lythoseN

SAID

sfor

which

results

show

thattheseN

SAID

sareassociated

with

CVDor

NSA

IDsm

entio

ned

inthetext















2




2


2O2[115]



2


2

∙minus H2O2







2) from the mem-




2











2








2



2transcript level



2

∙minus


2







14 Conclusion






Abbreviations




Acknowledgment



References










































































2O2














































































































































Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Ibup

rofen

naproxen

orlumira

coxib

TheTh

erapeutic

Arthritis

Research

and

Gastro

intestinalEv

entT

rial

(TARG

ET)International

Extend

edrepo

rt1832

5patie

ntsw

ithosteoarthritis

Ibup

rofenincreasedris

kof

thrombo

sisandCH

Fcomparedto

lumira

coxib

(214

versus

025)a

mon

gaspirin


erris

krelativetolumira

coxibam

ongno

naspirin

users

[181]

Diclofenacibup

rofen

andnaproxen

Non

eUSA

7years

ND

Prolon

gedexpo

sure

todiclo

fenac

increasesthe

riskof

AMI(relativer

atio

=19

ndash20)u

nlikeibu

profen

ornaproxen

[182]

Etoricoxib

anddiclo

fenac

EDGEIIU

SA193mon

thsfor

etoricoxib

and191

mon

thsfor

diclo

fenac

4086patie

ntsw



diclo

fenac119899=2054

Ther

ateo

foccurrenceo

fAMIw

ashigh

erin

diclo

fenac(068)treated

patie

ntsthan

inetoricoxib

users(043)Also

anoverall

increase

incardiace

ventsw

asob

served

indiclo

fenactreated

grou

p(114

)versus

thee

toric

oxibgrou

p(083)

[183]

Cele

coxib(at4

00mgQD200

mgtwo

times

aday

(BID

)or

400m

gBID)

Non

eUSA

3years

7950

patie

nts(with

arthritisandother

cond

ition

s)

Theh

azardratio

forthe

CVDM

IHFor

thrombo

embo

liceventw

aslowestfor

the

400mgon

cead


the2

00mg-BIDdo

se(18)andhigh

est

forthe

400mg-BIDdo

se(31)

[184]

Ibup

rofen

naproxendiclofenac

meloxicam

ind

omethacin

piroxicam

andmefenam

icacid

Non

eUKprim

arycare

20years

7292

94NSA

IDusers

443047controls

Increase

inther

elativer

atefor

MIw

ithcumulativea

nddaily

dose

ofibup

rofen

anddiclo

fenacHigherrisk

ofMIw

ithdiclo

fenacu

se(relativer

atio

=12

1)than

ibup

rofen(relativer

atio

=10

4)or

naproxen

(relativer

atio

=10

3)

[185]

Etoricoxib

anddiclo

fenac

TheM

EDAL

Stud

yMultin

ational

194to

208mon

ths

Etoricoxib

60mgd119899=6769

90mgd119899=5012


Thethrom

botic

CVris

kHRof

etoricoxib

todiclo

fenac=

096P

rolonged

useo

feither

NSA

IDresultedin

anincreased

riskof

thrombo

ticCV

events

[186]

Naproxen

ibup

rofen

diclo

fenac


Non

eUSA

6years

48566

patie

ntsrecently

hospita

lized

form

yocardial

infarctio

nrevascularization

orun

stableangina

pectoris

CVDris

kincreasedwith

shortterm

(lt90

days)u

seforibu

profen

with

incidence

rateratio

sof167diclo

fenac186

celecoxib13

7androfecoxib14

6bu

tnot

forn

aproxen088

[51]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Cele


ibup

rofen


indo

methacin

Non

eUSA

7years

610001p

atientswith

out

CVD119899=525249w

ithhisto

ryof

CVD119899=84752

Rofecoxib(1091

events

1000

person

-years)valdecoxib

(1241

events

1000

person

-years)and

indo

methacin(1325

events

1000

person

-years)increased

CVDris

kin

patie

ntsw

ithno

histo

ryof

CVD


riskof

cardiovascular

eventinpatie

ntsw

ithCV

D(3028

events

1000

person

-years)

[187]

Ibup

rofen

diclo

fenacrofecoxib


Non

eDanish

popu

latio

n9ndash

34days


als

Dosed

ependent

increase

incardiovascular

eventsdu

etouseo

fdiclo

fenac(HR=16

3)rofecoxib

(HR=

213)a

ndcelecoxib(H

R=201)w

asob

served

[188]

Cele

coxibibup

rofen

andnaproxen

TheP

rospectiv

eRa

ndom

ized

Evaluatio

nof

Cele

coxibIntegrated

Safety

versus

Ibup

rofenOr

Naproxen

(PRE

CISION)

trialM

ultin

ational

2009-ongoing

20000

patie

ntsw

ithsymptom

aticosteoarthritis


high

riskforo

rwith

establish

edCV

D

Thistrialw

illdeterm

inethe

cardiovascular

safetyof

theN

SAID

s[189]

ND

Non

eDenmark

10years

1070

92patie

ntsw

ithfirst

incidenceo

fHF

Theh

azardratio

ford

eath

duetoMIo

rHFwas

17017

513

1208122and12

8forrofecoxibcele

coxibibup

rofen

diclo

fenacnaproxenand

otherN

SAID

srespectiv

ely

[190]

Ibup

rofen

diclo

fenacnaproxen


etoricoxib

Non

eTh

eNetherla

nds

4years

485059subjectswith

first

hospita

lisationfora

cute


CV

andgastr

ointestin

alevents

AMIrisk

with

celecoxib(O

R253)

rofecoxib(O

R16

0)ibu

profen

(OR15

6)

anddiclo

fenac(OR15

1)was

significantly

increasedSign

ificant

increase

inCV

risk

with

currentu

seof

individu

alCO

X-2

inhibitorsandtN

SAID

s(ORfro

m117to

164)Significantd

ecreaseinAMIw

ithcurrentu

seof

naproxen

(OR048)

[191]

Ibup

rofen

naproxendiclofenac

etod


Non

eNorthernDenmark

10years

32602

patie

ntsw

ithfirst

atria

lfibrillationor

flutte

rand325918po

pulatio

ncontrols

Increasedris

kof

atria

lfibrillationor

flutte

rwas

40ndash70

(lowe

stfor

non-selectiveN

SAID

sand

high

estfor

COX-

2inhibitors)

[192]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

ND

Non

eDenmark

10years

83677

patie

ntso

fwhich

423received

NSA

IDs

Deathrecurrent

MId

ueto

NSA

IDtre

atment(even

shortterm)w

assig

nificantly

high

erD

iclofenacp

osed

the

high

estrisk

ofallN

SAID

s

[193]

ND

INternationalV

Erapam

ilTrando

laprilSTud

y(INVES

T)M

ultin

ational

7years

882chronicN

SAID

users

and21694

nonchron

icNSA

IDusersPatie

ntsw

ithhypertensio

nandclinically

stablec

oron

aryartery

disease

Prim

aryou

tcom

elikea

ll-causem

ortality

nonfatalMIor

nonfatalstroke

and

second

aryindividu

alou

tcom

eslik

eall-c

ause


mortalitytotalM

Iandtotalstro

keoccurred

atar

ateo

f44eventsper100

patie

nt-yearsin

thec

hron

icNSA

IDgrou

pversus

37eventsper100

patie

nt-yearsin

then

onchronicN

SAID

grou

p

[111]

Cele

coxibrofecoxibibup

rofen

diclo

fenacnaproxenand

others

Non

eDenmark

13years(with

first

MI)

128418patie

nts(77

participated

inthes

tudy)

Incidences

ofcoronary

deathor

nonfatal

recurrentM

Iwith

NSA

IDsu

seremain

unchangedwith

thetim

eelapsed

even

after

5years

[194]

ND

Non

edataob

tained

from

REdu

ctionof

Atherothrombo

sisfor

Con

tinuedHealth

(REA

CH)registry

which

inclu

desp

atientsfrom

Latin

AmericaNorth

AmericaEu

ropeA

siathe

MiddleE

astandAu

stralia

4years

4420NSA

IDusers39675

NSA

IDno

nusers

116-fold

high

erris

kof

CVDM

Iin

NSA

IDusers

[41]


HFheartfailureC

VDcardiovasculard

iseasesC

BVcerebrovascular

diseasesC

HFcongestiv

eheartfailu

reH

Rhazard

ratio

OR

oddratio

NDnot

defin

edR

Rrateratio

and

TIA

transie

ntisc

hemicattackV

arious

clinicaltria

lssuggestthe

increasedincidences

ofCV

Din

NSA

IDusersTh

etablelistson

lythec

linicaltrialsrepo

rted

between2006

and2014


Thrombosis



Apoptosis



(free radicals)



ROS

Cytochrome p450




NSAIDs
















2


2O2)


2

∙minus












Table3NSA

IDsind

uced

ROSgeneratio

nin

different

celltypes

(a)

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenacindo

methacin

ketoprofen

Mito

chon

drialrespiratio

nSaccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

TheseN

SAID

stargetm

itochon

driato

indu

cecelltoxicity

[95]

Ibup

rofenandnaproxen

TheseN

SAID

Sindu

cetoxicityindepend

ento

fmito

chon

drialrespiratio

n[95]

Indo

methacin

sodium

diclo

fenacflu

rbiprofen

zalto

profenand

mofezolac

ND

Hum

angastric

epith

elialcellline

AGS

AllNSA

IDse

xceptm

ofezolac

increased

apop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

AD

NAfragmentatio

nindu

ced

byindo

methacinor

flurbiprofenwas

redu

ced

byantio

xidantsIndo

methacinat1m

Mwas

apo

tent

indu

cero

fROSgeneratio

nin

thec

ells

[79]

Diclofenaca

ndnaproxen

NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

oxidasee


the

heartand

aortab

ydiclo

fenaca

ndnaproxen


etoNADPH

oxidase

[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2iso

form

ofNADPH

oxidaseisincreased

bydiclo

fenac

[114]

Aspirin

naproxenand

piroxicam

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Indo

methacin

Xanthine

oxidases

Hum

ancolonica

deno

carcinom

acells

(Caco-2cells)

Xanthine

oxidasea

ctivity

increasesb

ymore

than

100

1hou

rafte

rtreatment

[96]

Indo

methacin

Mito

chon

driasuperoxide

leakage

Ratgastricepith

elialcellline

RGM1

Indo

methacinindu

cedtheleakage

ofsuperoxide

anionin

theisolatedmito

chon

dria

from

theg

astricRG

M1cells

[93]

Indo

methacin

diclo

fenac

sodium

and

aspirin

ND

Ratgastricepith

elialcellline

RGM1and

ratsmallintestin

alepith

elialcelllineIEC

6

Indo

methacin

diclo

fenacandaspirin

ingastric

RGM1cellsandsm

allintestin

alIEC6

cells

increasedlip

idperoxidatio

n[93]

Sulin

dacsulin

dacs

ulfid

eandsulin

dacs

ulfone

ND

Pancreas

carcinom

aBXP

C3

glioblastomaA

172colon

carcinom

aDLD

-1oral

squamou

sSASandacute

myelocytic

leuk

emiaHL6

0cells

TheN

SAID

sulin

daca

ndits

metabolites

sulin

dacs

ulfid

eand

sulin

dacs

ulfone

all

increasedRO

Sgeneratio

nSulin

dacs

ulfid

eshow

edtheg

reatestR

OSgeneratio

n

[80]

Indo

methacin

piroxicam

andaspirin

Lipo

xygenases


mice

Results

inan

overprod

uctio

nof

leuk

otrie

nes

andprod

uctsof

5-lip

oxygenasea

ctivity

Increasesinleuk

otrie

neand5-lip

oxygenase

activ

ityhave

been

associated

with

ROS

generatio

n

[123124127]

Indo

methacin

Lipo

xygenases


Timed

ependent

form

ationof

leuk

otrie

ne-C

4[128]


(a)Con

tinued

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenac

CytochromeP

450enzymes

Saccharomyces

cerevisia

eyeast

cells

expressin

gthem

utantP

450

BM3M11(capableof

metabolizingdiclo

fenacs

imilar

tohu

mans)

IncreasedRO

Sprod

uctio

nbysim15

and18

times

atconcentrations

of30120583M

and50120583M

respectiv

elycom

paredto

wild

type

[140]

Diclofenacindo

methacin

ketoprofenand

naproxen

CytochromeP

450enzymes

Saccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

NSA

IDsm

etabolism

associated

with

increased

P450-related

toxicity

[95]

(b)

NSA

IDs

coxibs

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Ibup

rofen

ketoprofenand

indo

methacin

CytochromeP

450enzymes

Bacillusm

egaterium

AlltheN

SAID

scausedam

arkedincrease


450level

[142]

Aspirin

diclofenacdiflu

nisal

flurbiprofen

ibup

rofen

indo

methacin

ketoprofenm

efenam

icacidn

aproxen


etin

CytochromeP

450enzymes

Rath

epatocytes

Cytotoxicityof

diclo

fenacketoprofen

andpiroxicam

was

increasedby

cytochromeP


[138]

Diclofenaca

ndnaproxen

Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Increasedexpressio

nof

eNOSmRN

Adu

eto

theg

enerationof

H2O

2which

isrespon

sibleforu

pregulationof

eNOSat

thetranscriptio

naland

post-

transcrip

tionallevels

[114]


NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

expressio

nincreasedin

theh

eart

andaortab


[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2Ex

pressio

nincreasedby

rofecoxib

[114]


Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Inthea

ortathe

coxibs

didno

tsho

wany

eNOSmRN

Aexpressio

nIn

theh

eart

onlyrofecoxibshow

edas

ignificant

increase

inthee

xpressionof

eNOS

[114]

Etod

olac

ND

Hum

angastr

icepith

elialcell

lineA

GS

Increasedapop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

A[79]

Nim

esulide

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Alth

ough

otherreportsarea

vailables

uggesting

theroleo

fNSA

IDsinRO

Sform


lythoseN

SAID

sfor

which

results

show

thattheseN

SAID

sareassociated

with

CVDor

NSA

IDsm

entio

ned

inthetext















2




2


2O2[115]



2


2

∙minus H2O2







2) from the mem-




2











2








2



2transcript level



2

∙minus


2







14 Conclusion






Abbreviations




Acknowledgment



References










































































2O2














































































































































Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

Cele


ibup

rofen


indo

methacin

Non

eUSA

7years

610001p

atientswith

out

CVD119899=525249w

ithhisto

ryof

CVD119899=84752

Rofecoxib(1091

events

1000

person

-years)valdecoxib

(1241

events

1000

person

-years)and

indo

methacin(1325

events

1000

person

-years)increased

CVDris

kin

patie

ntsw

ithno

histo

ryof

CVD


riskof

cardiovascular

eventinpatie

ntsw

ithCV

D(3028

events

1000

person

-years)

[187]

Ibup

rofen

diclo

fenacrofecoxib


Non

eDanish

popu

latio

n9ndash

34days


als

Dosed

ependent

increase

incardiovascular

eventsdu

etouseo

fdiclo

fenac(HR=16

3)rofecoxib

(HR=

213)a

ndcelecoxib(H

R=201)w

asob

served

[188]

Cele

coxibibup

rofen

andnaproxen

TheP

rospectiv

eRa

ndom

ized

Evaluatio

nof

Cele

coxibIntegrated

Safety

versus

Ibup

rofenOr

Naproxen

(PRE

CISION)

trialM

ultin

ational

2009-ongoing

20000

patie

ntsw

ithsymptom

aticosteoarthritis


high

riskforo

rwith

establish

edCV

D

Thistrialw

illdeterm

inethe

cardiovascular

safetyof

theN

SAID

s[189]

ND

Non

eDenmark

10years

1070

92patie

ntsw

ithfirst

incidenceo

fHF

Theh

azardratio

ford

eath

duetoMIo

rHFwas

17017

513

1208122and12

8forrofecoxibcele

coxibibup

rofen

diclo

fenacnaproxenand

otherN

SAID

srespectiv

ely

[190]

Ibup

rofen

diclo

fenacnaproxen


etoricoxib

Non

eTh

eNetherla

nds

4years

485059subjectswith

first

hospita

lisationfora

cute


CV

andgastr

ointestin

alevents

AMIrisk

with

celecoxib(O

R253)

rofecoxib(O

R16

0)ibu

profen

(OR15

6)

anddiclo

fenac(OR15

1)was

significantly

increasedSign

ificant

increase

inCV

risk

with

currentu

seof

individu

alCO

X-2

inhibitorsandtN

SAID

s(ORfro

m117to

164)Significantd

ecreaseinAMIw

ithcurrentu

seof

naproxen

(OR048)

[191]

Ibup

rofen

naproxendiclofenac

etod


Non

eNorthernDenmark

10years

32602

patie

ntsw

ithfirst

atria

lfibrillationor

flutte

rand325918po

pulatio

ncontrols

Increasedris

kof

atria

lfibrillationor

flutte

rwas

40ndash70

(lowe

stfor

non-selectiveN

SAID

sand

high

estfor

COX-

2inhibitors)

[192]


Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

ND

Non

eDenmark

10years

83677

patie

ntso

fwhich

423received

NSA

IDs

Deathrecurrent

MId

ueto

NSA

IDtre

atment(even

shortterm)w

assig

nificantly

high

erD

iclofenacp

osed

the

high

estrisk

ofallN

SAID

s

[193]

ND

INternationalV

Erapam

ilTrando

laprilSTud

y(INVES

T)M

ultin

ational

7years

882chronicN

SAID

users

and21694

nonchron

icNSA

IDusersPatie

ntsw

ithhypertensio

nandclinically

stablec

oron

aryartery

disease

Prim

aryou

tcom

elikea

ll-causem

ortality

nonfatalMIor

nonfatalstroke

and

second

aryindividu

alou

tcom

eslik

eall-c

ause


mortalitytotalM

Iandtotalstro

keoccurred

atar

ateo

f44eventsper100

patie

nt-yearsin

thec

hron

icNSA

IDgrou

pversus

37eventsper100

patie

nt-yearsin

then

onchronicN

SAID

grou

p

[111]

Cele

coxibrofecoxibibup

rofen

diclo

fenacnaproxenand

others

Non

eDenmark

13years(with

first

MI)

128418patie

nts(77

participated

inthes

tudy)

Incidences

ofcoronary

deathor

nonfatal

recurrentM

Iwith

NSA

IDsu

seremain

unchangedwith

thetim

eelapsed

even

after

5years

[194]

ND

Non

edataob

tained

from

REdu

ctionof

Atherothrombo

sisfor

Con

tinuedHealth

(REA

CH)registry

which

inclu

desp

atientsfrom

Latin

AmericaNorth

AmericaEu

ropeA

siathe

MiddleE

astandAu

stralia

4years

4420NSA

IDusers39675

NSA

IDno

nusers

116-fold

high

erris

kof

CVDM

Iin

NSA

IDusers

[41]


HFheartfailureC

VDcardiovasculard

iseasesC

BVcerebrovascular

diseasesC

HFcongestiv

eheartfailu

reH

Rhazard

ratio

OR

oddratio

NDnot

defin

edR

Rrateratio

and

TIA

transie

ntisc

hemicattackV

arious

clinicaltria

lssuggestthe

increasedincidences

ofCV

Din

NSA

IDusersTh

etablelistson

lythec

linicaltrialsrepo

rted

between2006

and2014


Thrombosis



Apoptosis



(free radicals)



ROS

Cytochrome p450




NSAIDs
















2


2O2)


2

∙minus












Table3NSA

IDsind

uced

ROSgeneratio

nin

different

celltypes

(a)

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenacindo

methacin

ketoprofen

Mito

chon

drialrespiratio

nSaccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

TheseN

SAID

stargetm

itochon

driato

indu

cecelltoxicity

[95]

Ibup

rofenandnaproxen

TheseN

SAID

Sindu

cetoxicityindepend

ento

fmito

chon

drialrespiratio

n[95]

Indo

methacin

sodium

diclo

fenacflu

rbiprofen

zalto

profenand

mofezolac

ND

Hum

angastric

epith

elialcellline

AGS

AllNSA

IDse

xceptm

ofezolac

increased

apop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

AD

NAfragmentatio

nindu

ced

byindo

methacinor

flurbiprofenwas

redu

ced

byantio

xidantsIndo

methacinat1m

Mwas

apo

tent

indu

cero

fROSgeneratio

nin

thec

ells

[79]

Diclofenaca

ndnaproxen

NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

oxidasee


the

heartand

aortab

ydiclo

fenaca

ndnaproxen


etoNADPH

oxidase

[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2iso

form

ofNADPH

oxidaseisincreased

bydiclo

fenac

[114]

Aspirin

naproxenand

piroxicam

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Indo

methacin

Xanthine

oxidases

Hum

ancolonica

deno

carcinom

acells

(Caco-2cells)

Xanthine

oxidasea

ctivity

increasesb

ymore

than

100

1hou

rafte

rtreatment

[96]

Indo

methacin

Mito

chon

driasuperoxide

leakage

Ratgastricepith

elialcellline

RGM1

Indo

methacinindu

cedtheleakage

ofsuperoxide

anionin

theisolatedmito

chon

dria

from

theg

astricRG

M1cells

[93]

Indo

methacin

diclo

fenac

sodium

and

aspirin

ND

Ratgastricepith

elialcellline

RGM1and

ratsmallintestin

alepith

elialcelllineIEC

6

Indo

methacin

diclo

fenacandaspirin

ingastric

RGM1cellsandsm

allintestin

alIEC6

cells

increasedlip

idperoxidatio

n[93]

Sulin

dacsulin

dacs

ulfid

eandsulin

dacs

ulfone

ND

Pancreas

carcinom

aBXP

C3

glioblastomaA

172colon

carcinom

aDLD

-1oral

squamou

sSASandacute

myelocytic

leuk

emiaHL6

0cells

TheN

SAID

sulin

daca

ndits

metabolites

sulin

dacs

ulfid

eand

sulin

dacs

ulfone

all

increasedRO

Sgeneratio

nSulin

dacs

ulfid

eshow

edtheg

reatestR

OSgeneratio

n

[80]

Indo

methacin

piroxicam

andaspirin

Lipo

xygenases


mice

Results

inan

overprod

uctio

nof

leuk

otrie

nes

andprod

uctsof

5-lip

oxygenasea

ctivity

Increasesinleuk

otrie

neand5-lip

oxygenase

activ

ityhave

been

associated

with

ROS

generatio

n

[123124127]

Indo

methacin

Lipo

xygenases


Timed

ependent

form

ationof

leuk

otrie

ne-C

4[128]


(a)Con

tinued

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenac

CytochromeP

450enzymes

Saccharomyces

cerevisia

eyeast

cells

expressin

gthem

utantP

450

BM3M11(capableof

metabolizingdiclo

fenacs

imilar

tohu

mans)

IncreasedRO

Sprod

uctio

nbysim15

and18

times

atconcentrations

of30120583M

and50120583M

respectiv

elycom

paredto

wild

type

[140]

Diclofenacindo

methacin

ketoprofenand

naproxen

CytochromeP

450enzymes

Saccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

NSA

IDsm

etabolism

associated

with

increased

P450-related

toxicity

[95]

(b)

NSA

IDs

coxibs

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Ibup

rofen

ketoprofenand

indo

methacin

CytochromeP

450enzymes

Bacillusm

egaterium

AlltheN

SAID

scausedam

arkedincrease


450level

[142]

Aspirin

diclofenacdiflu

nisal

flurbiprofen

ibup

rofen

indo

methacin

ketoprofenm

efenam

icacidn

aproxen


etin

CytochromeP

450enzymes

Rath

epatocytes

Cytotoxicityof

diclo

fenacketoprofen

andpiroxicam

was

increasedby

cytochromeP


[138]

Diclofenaca

ndnaproxen

Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Increasedexpressio

nof

eNOSmRN

Adu

eto

theg

enerationof

H2O

2which

isrespon

sibleforu

pregulationof

eNOSat

thetranscriptio

naland

post-

transcrip

tionallevels

[114]


NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

expressio

nincreasedin

theh

eart

andaortab


[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2Ex

pressio

nincreasedby

rofecoxib

[114]


Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Inthea

ortathe

coxibs

didno

tsho

wany

eNOSmRN

Aexpressio

nIn

theh

eart

onlyrofecoxibshow

edas

ignificant

increase

inthee

xpressionof

eNOS

[114]

Etod

olac

ND

Hum

angastr

icepith

elialcell

lineA

GS

Increasedapop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

A[79]

Nim

esulide

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Alth

ough

otherreportsarea

vailables

uggesting

theroleo

fNSA

IDsinRO

Sform


lythoseN

SAID

sfor

which

results

show

thattheseN

SAID

sareassociated

with

CVDor

NSA

IDsm

entio

ned

inthetext















2




2


2O2[115]



2


2

∙minus H2O2







2) from the mem-




2











2








2



2transcript level



2

∙minus


2







14 Conclusion






Abbreviations




Acknowledgment



References










































































2O2














































































































































Table2Con

tinued

NSA

IDClinicaltrialn

amelocatio

nDurationof

study

Num

bero

fpatientsselected

Effect

References

ND

Non

eDenmark

10years

83677

patie

ntso

fwhich

423received

NSA

IDs

Deathrecurrent

MId

ueto

NSA

IDtre

atment(even

shortterm)w

assig

nificantly

high

erD

iclofenacp

osed

the

high

estrisk

ofallN

SAID

s

[193]

ND

INternationalV

Erapam

ilTrando

laprilSTud

y(INVES

T)M

ultin

ational

7years

882chronicN

SAID

users

and21694

nonchron

icNSA

IDusersPatie

ntsw

ithhypertensio

nandclinically

stablec

oron

aryartery

disease

Prim

aryou

tcom

elikea

ll-causem

ortality

nonfatalMIor

nonfatalstroke

and

second

aryindividu

alou

tcom

eslik

eall-c

ause


mortalitytotalM

Iandtotalstro

keoccurred

atar

ateo

f44eventsper100

patie

nt-yearsin

thec

hron

icNSA

IDgrou

pversus

37eventsper100

patie

nt-yearsin

then

onchronicN

SAID

grou

p

[111]

Cele

coxibrofecoxibibup

rofen

diclo

fenacnaproxenand

others

Non

eDenmark

13years(with

first

MI)

128418patie

nts(77

participated

inthes

tudy)

Incidences

ofcoronary

deathor

nonfatal

recurrentM

Iwith

NSA

IDsu

seremain

unchangedwith

thetim

eelapsed

even

after

5years

[194]

ND

Non

edataob

tained

from

REdu

ctionof

Atherothrombo

sisfor

Con

tinuedHealth

(REA

CH)registry

which

inclu

desp

atientsfrom

Latin

AmericaNorth

AmericaEu

ropeA

siathe

MiddleE

astandAu

stralia

4years

4420NSA

IDusers39675

NSA

IDno

nusers

116-fold

high

erris

kof

CVDM

Iin

NSA

IDusers

[41]


HFheartfailureC

VDcardiovasculard

iseasesC

BVcerebrovascular

diseasesC

HFcongestiv

eheartfailu

reH

Rhazard

ratio

OR

oddratio

NDnot

defin

edR

Rrateratio

and

TIA

transie

ntisc

hemicattackV

arious

clinicaltria

lssuggestthe

increasedincidences

ofCV

Din

NSA

IDusersTh

etablelistson

lythec

linicaltrialsrepo

rted

between2006

and2014


Thrombosis



Apoptosis



(free radicals)



ROS

Cytochrome p450




NSAIDs
















2


2O2)


2

∙minus












Table3NSA

IDsind

uced

ROSgeneratio

nin

different

celltypes

(a)

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenacindo

methacin

ketoprofen

Mito

chon

drialrespiratio

nSaccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

TheseN

SAID

stargetm

itochon

driato

indu

cecelltoxicity

[95]

Ibup

rofenandnaproxen

TheseN

SAID

Sindu

cetoxicityindepend

ento

fmito

chon

drialrespiratio

n[95]

Indo

methacin

sodium

diclo

fenacflu

rbiprofen

zalto

profenand

mofezolac

ND

Hum

angastric

epith

elialcellline

AGS

AllNSA

IDse

xceptm

ofezolac

increased

apop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

AD

NAfragmentatio

nindu

ced

byindo

methacinor

flurbiprofenwas

redu

ced

byantio

xidantsIndo

methacinat1m

Mwas

apo

tent

indu

cero

fROSgeneratio

nin

thec

ells

[79]

Diclofenaca

ndnaproxen

NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

oxidasee


the

heartand

aortab

ydiclo

fenaca

ndnaproxen


etoNADPH

oxidase

[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2iso

form

ofNADPH

oxidaseisincreased

bydiclo

fenac

[114]

Aspirin

naproxenand

piroxicam

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Indo

methacin

Xanthine

oxidases

Hum

ancolonica

deno

carcinom

acells

(Caco-2cells)

Xanthine

oxidasea

ctivity

increasesb

ymore

than

100

1hou

rafte

rtreatment

[96]

Indo

methacin

Mito

chon

driasuperoxide

leakage

Ratgastricepith

elialcellline

RGM1

Indo

methacinindu

cedtheleakage

ofsuperoxide

anionin

theisolatedmito

chon

dria

from

theg

astricRG

M1cells

[93]

Indo

methacin

diclo

fenac

sodium

and

aspirin

ND

Ratgastricepith

elialcellline

RGM1and

ratsmallintestin

alepith

elialcelllineIEC

6

Indo

methacin

diclo

fenacandaspirin

ingastric

RGM1cellsandsm

allintestin

alIEC6

cells

increasedlip

idperoxidatio

n[93]

Sulin

dacsulin

dacs

ulfid

eandsulin

dacs

ulfone

ND

Pancreas

carcinom

aBXP

C3

glioblastomaA

172colon

carcinom

aDLD

-1oral

squamou

sSASandacute

myelocytic

leuk

emiaHL6

0cells

TheN

SAID

sulin

daca

ndits

metabolites

sulin

dacs

ulfid

eand

sulin

dacs

ulfone

all

increasedRO

Sgeneratio

nSulin

dacs

ulfid

eshow

edtheg

reatestR

OSgeneratio

n

[80]

Indo

methacin

piroxicam

andaspirin

Lipo

xygenases


mice

Results

inan

overprod

uctio

nof

leuk

otrie

nes

andprod

uctsof

5-lip

oxygenasea

ctivity

Increasesinleuk

otrie

neand5-lip

oxygenase

activ

ityhave

been

associated

with

ROS

generatio

n

[123124127]

Indo

methacin

Lipo

xygenases


Timed

ependent

form

ationof

leuk

otrie

ne-C

4[128]


(a)Con

tinued

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenac

CytochromeP

450enzymes

Saccharomyces

cerevisia

eyeast

cells

expressin

gthem

utantP

450

BM3M11(capableof

metabolizingdiclo

fenacs

imilar

tohu

mans)

IncreasedRO

Sprod

uctio

nbysim15

and18

times

atconcentrations

of30120583M

and50120583M

respectiv

elycom

paredto

wild

type

[140]

Diclofenacindo

methacin

ketoprofenand

naproxen

CytochromeP

450enzymes

Saccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

NSA

IDsm

etabolism

associated

with

increased

P450-related

toxicity

[95]

(b)

NSA

IDs

coxibs

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Ibup

rofen

ketoprofenand

indo

methacin

CytochromeP

450enzymes

Bacillusm

egaterium

AlltheN

SAID

scausedam

arkedincrease


450level

[142]

Aspirin

diclofenacdiflu

nisal

flurbiprofen

ibup

rofen

indo

methacin

ketoprofenm

efenam

icacidn

aproxen


etin

CytochromeP

450enzymes

Rath

epatocytes

Cytotoxicityof

diclo

fenacketoprofen

andpiroxicam

was

increasedby

cytochromeP


[138]

Diclofenaca

ndnaproxen

Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Increasedexpressio

nof

eNOSmRN

Adu

eto

theg

enerationof

H2O

2which

isrespon

sibleforu

pregulationof

eNOSat

thetranscriptio

naland

post-

transcrip

tionallevels

[114]


NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

expressio

nincreasedin

theh

eart

andaortab


[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2Ex

pressio

nincreasedby

rofecoxib

[114]


Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Inthea

ortathe

coxibs

didno

tsho

wany

eNOSmRN

Aexpressio

nIn

theh

eart

onlyrofecoxibshow

edas

ignificant

increase

inthee

xpressionof

eNOS

[114]

Etod

olac

ND

Hum

angastr

icepith

elialcell

lineA

GS

Increasedapop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

A[79]

Nim

esulide

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Alth

ough

otherreportsarea

vailables

uggesting

theroleo

fNSA

IDsinRO

Sform


lythoseN

SAID

sfor

which

results

show

thattheseN

SAID

sareassociated

with

CVDor

NSA

IDsm

entio

ned

inthetext















2




2


2O2[115]



2


2

∙minus H2O2







2) from the mem-




2











2








2



2transcript level



2

∙minus


2







14 Conclusion






Abbreviations




Acknowledgment



References










































































2O2














































































































































Thrombosis



Apoptosis



(free radicals)



ROS

Cytochrome p450




NSAIDs
















2


2O2)


2

∙minus












Table3NSA

IDsind

uced

ROSgeneratio

nin

different

celltypes

(a)

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenacindo

methacin

ketoprofen

Mito

chon

drialrespiratio

nSaccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

TheseN

SAID

stargetm

itochon

driato

indu

cecelltoxicity

[95]

Ibup

rofenandnaproxen

TheseN

SAID

Sindu

cetoxicityindepend

ento

fmito

chon

drialrespiratio

n[95]

Indo

methacin

sodium

diclo

fenacflu

rbiprofen

zalto

profenand

mofezolac

ND

Hum

angastric

epith

elialcellline

AGS

AllNSA

IDse

xceptm

ofezolac

increased

apop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

AD

NAfragmentatio

nindu

ced

byindo

methacinor

flurbiprofenwas

redu

ced

byantio

xidantsIndo

methacinat1m

Mwas

apo

tent

indu

cero

fROSgeneratio

nin

thec

ells

[79]

Diclofenaca

ndnaproxen

NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

oxidasee


the

heartand

aortab

ydiclo

fenaca

ndnaproxen


etoNADPH

oxidase

[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2iso

form

ofNADPH

oxidaseisincreased

bydiclo

fenac

[114]

Aspirin

naproxenand

piroxicam

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Indo

methacin

Xanthine

oxidases

Hum

ancolonica

deno

carcinom

acells

(Caco-2cells)

Xanthine

oxidasea

ctivity

increasesb

ymore

than

100

1hou

rafte

rtreatment

[96]

Indo

methacin

Mito

chon

driasuperoxide

leakage

Ratgastricepith

elialcellline

RGM1

Indo

methacinindu

cedtheleakage

ofsuperoxide

anionin

theisolatedmito

chon

dria

from

theg

astricRG

M1cells

[93]

Indo

methacin

diclo

fenac

sodium

and

aspirin

ND

Ratgastricepith

elialcellline

RGM1and

ratsmallintestin

alepith

elialcelllineIEC

6

Indo

methacin

diclo

fenacandaspirin

ingastric

RGM1cellsandsm

allintestin

alIEC6

cells

increasedlip

idperoxidatio

n[93]

Sulin

dacsulin

dacs

ulfid

eandsulin

dacs

ulfone

ND

Pancreas

carcinom

aBXP

C3

glioblastomaA

172colon

carcinom

aDLD

-1oral

squamou

sSASandacute

myelocytic

leuk

emiaHL6

0cells

TheN

SAID

sulin

daca

ndits

metabolites

sulin

dacs

ulfid

eand

sulin

dacs

ulfone

all

increasedRO

Sgeneratio

nSulin

dacs

ulfid

eshow

edtheg

reatestR

OSgeneratio

n

[80]

Indo

methacin

piroxicam

andaspirin

Lipo

xygenases


mice

Results

inan

overprod

uctio

nof

leuk

otrie

nes

andprod

uctsof

5-lip

oxygenasea

ctivity

Increasesinleuk

otrie

neand5-lip

oxygenase

activ

ityhave

been

associated

with

ROS

generatio

n

[123124127]

Indo

methacin

Lipo

xygenases


Timed

ependent

form

ationof

leuk

otrie

ne-C

4[128]


(a)Con

tinued

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenac

CytochromeP

450enzymes

Saccharomyces

cerevisia

eyeast

cells

expressin

gthem

utantP

450

BM3M11(capableof

metabolizingdiclo

fenacs

imilar

tohu

mans)

IncreasedRO

Sprod

uctio

nbysim15

and18

times

atconcentrations

of30120583M

and50120583M

respectiv

elycom

paredto

wild

type

[140]

Diclofenacindo

methacin

ketoprofenand

naproxen

CytochromeP

450enzymes

Saccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

NSA

IDsm

etabolism

associated

with

increased

P450-related

toxicity

[95]

(b)

NSA

IDs

coxibs

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Ibup

rofen

ketoprofenand

indo

methacin

CytochromeP

450enzymes

Bacillusm

egaterium

AlltheN

SAID

scausedam

arkedincrease


450level

[142]

Aspirin

diclofenacdiflu

nisal

flurbiprofen

ibup

rofen

indo

methacin

ketoprofenm

efenam

icacidn

aproxen


etin

CytochromeP

450enzymes

Rath

epatocytes

Cytotoxicityof

diclo

fenacketoprofen

andpiroxicam

was

increasedby

cytochromeP


[138]

Diclofenaca

ndnaproxen

Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Increasedexpressio

nof

eNOSmRN

Adu

eto

theg

enerationof

H2O

2which

isrespon

sibleforu

pregulationof

eNOSat

thetranscriptio

naland

post-

transcrip

tionallevels

[114]


NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

expressio

nincreasedin

theh

eart

andaortab


[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2Ex

pressio

nincreasedby

rofecoxib

[114]


Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Inthea

ortathe

coxibs

didno

tsho

wany

eNOSmRN

Aexpressio

nIn

theh

eart

onlyrofecoxibshow

edas

ignificant

increase

inthee

xpressionof

eNOS

[114]

Etod

olac

ND

Hum

angastr

icepith

elialcell

lineA

GS

Increasedapop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

A[79]

Nim

esulide

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Alth

ough

otherreportsarea

vailables

uggesting

theroleo

fNSA

IDsinRO

Sform


lythoseN

SAID

sfor

which

results

show

thattheseN

SAID

sareassociated

with

CVDor

NSA

IDsm

entio

ned

inthetext















2




2


2O2[115]



2


2

∙minus H2O2







2) from the mem-




2











2








2



2transcript level



2

∙minus


2







14 Conclusion






Abbreviations




Acknowledgment



References










































































2O2



















































































































































2


2O2)


2

∙minus












Table3NSA

IDsind

uced

ROSgeneratio

nin

different

celltypes

(a)

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenacindo

methacin

ketoprofen

Mito

chon

drialrespiratio

nSaccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

TheseN

SAID

stargetm

itochon

driato

indu

cecelltoxicity

[95]

Ibup

rofenandnaproxen

TheseN

SAID

Sindu

cetoxicityindepend

ento

fmito

chon

drialrespiratio

n[95]

Indo

methacin

sodium

diclo

fenacflu

rbiprofen

zalto

profenand

mofezolac

ND

Hum

angastric

epith

elialcellline

AGS

AllNSA

IDse

xceptm

ofezolac

increased

apop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

AD

NAfragmentatio

nindu

ced

byindo

methacinor

flurbiprofenwas

redu

ced

byantio

xidantsIndo

methacinat1m

Mwas

apo

tent

indu

cero

fROSgeneratio

nin

thec

ells

[79]

Diclofenaca

ndnaproxen

NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

oxidasee


the

heartand

aortab

ydiclo

fenaca

ndnaproxen


etoNADPH

oxidase

[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2iso

form

ofNADPH

oxidaseisincreased

bydiclo

fenac

[114]

Aspirin

naproxenand

piroxicam

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Indo

methacin

Xanthine

oxidases

Hum

ancolonica

deno

carcinom

acells

(Caco-2cells)

Xanthine

oxidasea

ctivity

increasesb

ymore

than

100

1hou

rafte

rtreatment

[96]

Indo

methacin

Mito

chon

driasuperoxide

leakage

Ratgastricepith

elialcellline

RGM1

Indo

methacinindu

cedtheleakage

ofsuperoxide

anionin

theisolatedmito

chon

dria

from

theg

astricRG

M1cells

[93]

Indo

methacin

diclo

fenac

sodium

and

aspirin

ND

Ratgastricepith

elialcellline

RGM1and

ratsmallintestin

alepith

elialcelllineIEC

6

Indo

methacin

diclo

fenacandaspirin

ingastric

RGM1cellsandsm

allintestin

alIEC6

cells

increasedlip

idperoxidatio

n[93]

Sulin

dacsulin

dacs

ulfid

eandsulin

dacs

ulfone

ND

Pancreas

carcinom

aBXP

C3

glioblastomaA

172colon

carcinom

aDLD

-1oral

squamou

sSASandacute

myelocytic

leuk

emiaHL6

0cells

TheN

SAID

sulin

daca

ndits

metabolites

sulin

dacs

ulfid

eand

sulin

dacs

ulfone

all

increasedRO

Sgeneratio

nSulin

dacs

ulfid

eshow

edtheg

reatestR

OSgeneratio

n

[80]

Indo

methacin

piroxicam

andaspirin

Lipo

xygenases


mice

Results

inan

overprod

uctio

nof

leuk

otrie

nes

andprod

uctsof

5-lip

oxygenasea

ctivity

Increasesinleuk

otrie

neand5-lip

oxygenase

activ

ityhave

been

associated

with

ROS

generatio

n

[123124127]

Indo

methacin

Lipo

xygenases


Timed

ependent

form

ationof

leuk

otrie

ne-C

4[128]


(a)Con

tinued

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenac

CytochromeP

450enzymes

Saccharomyces

cerevisia

eyeast

cells

expressin

gthem

utantP

450

BM3M11(capableof

metabolizingdiclo

fenacs

imilar

tohu

mans)

IncreasedRO

Sprod

uctio

nbysim15

and18

times

atconcentrations

of30120583M

and50120583M

respectiv

elycom

paredto

wild

type

[140]

Diclofenacindo

methacin

ketoprofenand

naproxen

CytochromeP

450enzymes

Saccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

NSA

IDsm

etabolism

associated

with

increased

P450-related

toxicity

[95]

(b)

NSA

IDs

coxibs

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Ibup

rofen

ketoprofenand

indo

methacin

CytochromeP

450enzymes

Bacillusm

egaterium

AlltheN

SAID

scausedam

arkedincrease


450level

[142]

Aspirin

diclofenacdiflu

nisal

flurbiprofen

ibup

rofen

indo

methacin

ketoprofenm

efenam

icacidn

aproxen


etin

CytochromeP

450enzymes

Rath

epatocytes

Cytotoxicityof

diclo

fenacketoprofen

andpiroxicam

was

increasedby

cytochromeP


[138]

Diclofenaca

ndnaproxen

Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Increasedexpressio

nof

eNOSmRN

Adu

eto

theg

enerationof

H2O

2which

isrespon

sibleforu

pregulationof

eNOSat

thetranscriptio

naland

post-

transcrip

tionallevels

[114]


NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

expressio

nincreasedin

theh

eart

andaortab


[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2Ex

pressio

nincreasedby

rofecoxib

[114]


Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Inthea

ortathe

coxibs

didno

tsho

wany

eNOSmRN

Aexpressio

nIn

theh

eart

onlyrofecoxibshow

edas

ignificant

increase

inthee

xpressionof

eNOS

[114]

Etod

olac

ND

Hum

angastr

icepith

elialcell

lineA

GS

Increasedapop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

A[79]

Nim

esulide

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Alth

ough

otherreportsarea

vailables

uggesting

theroleo

fNSA

IDsinRO

Sform


lythoseN

SAID

sfor

which

results

show

thattheseN

SAID

sareassociated

with

CVDor

NSA

IDsm

entio

ned

inthetext















2




2


2O2[115]



2


2

∙minus H2O2







2) from the mem-




2











2








2



2transcript level



2

∙minus


2







14 Conclusion






Abbreviations




Acknowledgment



References










































































2O2














































































































































Table3NSA

IDsind

uced

ROSgeneratio

nin

different

celltypes

(a)

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenacindo

methacin

ketoprofen

Mito

chon

drialrespiratio

nSaccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

TheseN

SAID

stargetm

itochon

driato

indu

cecelltoxicity

[95]

Ibup

rofenandnaproxen

TheseN

SAID

Sindu

cetoxicityindepend

ento

fmito

chon

drialrespiratio

n[95]

Indo

methacin

sodium

diclo

fenacflu

rbiprofen

zalto

profenand

mofezolac

ND

Hum

angastric

epith

elialcellline

AGS

AllNSA

IDse

xceptm

ofezolac

increased

apop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

AD

NAfragmentatio

nindu

ced

byindo

methacinor

flurbiprofenwas

redu

ced

byantio

xidantsIndo

methacinat1m

Mwas

apo

tent

indu

cero

fROSgeneratio

nin

thec

ells

[79]

Diclofenaca

ndnaproxen

NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

oxidasee


the

heartand

aortab

ydiclo

fenaca

ndnaproxen


etoNADPH

oxidase

[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2iso

form

ofNADPH

oxidaseisincreased

bydiclo

fenac

[114]

Aspirin

naproxenand

piroxicam

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Indo

methacin

Xanthine

oxidases

Hum

ancolonica

deno

carcinom

acells

(Caco-2cells)

Xanthine

oxidasea

ctivity

increasesb

ymore

than

100

1hou

rafte

rtreatment

[96]

Indo

methacin

Mito

chon

driasuperoxide

leakage

Ratgastricepith

elialcellline

RGM1

Indo

methacinindu

cedtheleakage

ofsuperoxide

anionin

theisolatedmito

chon

dria

from

theg

astricRG

M1cells

[93]

Indo

methacin

diclo

fenac

sodium

and

aspirin

ND

Ratgastricepith

elialcellline

RGM1and

ratsmallintestin

alepith

elialcelllineIEC

6

Indo

methacin

diclo

fenacandaspirin

ingastric

RGM1cellsandsm

allintestin

alIEC6

cells

increasedlip

idperoxidatio

n[93]

Sulin

dacsulin

dacs

ulfid

eandsulin

dacs

ulfone

ND

Pancreas

carcinom

aBXP

C3

glioblastomaA

172colon

carcinom

aDLD

-1oral

squamou

sSASandacute

myelocytic

leuk

emiaHL6

0cells

TheN

SAID

sulin

daca

ndits

metabolites

sulin

dacs

ulfid

eand

sulin

dacs

ulfone

all

increasedRO

Sgeneratio

nSulin

dacs

ulfid

eshow

edtheg

reatestR

OSgeneratio

n

[80]

Indo

methacin

piroxicam

andaspirin

Lipo

xygenases


mice

Results

inan

overprod

uctio

nof

leuk

otrie

nes

andprod

uctsof

5-lip

oxygenasea

ctivity

Increasesinleuk

otrie

neand5-lip

oxygenase

activ

ityhave

been

associated

with

ROS

generatio

n

[123124127]

Indo

methacin

Lipo

xygenases


Timed

ependent

form

ationof

leuk

otrie

ne-C

4[128]


(a)Con

tinued

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenac

CytochromeP

450enzymes

Saccharomyces

cerevisia

eyeast

cells

expressin

gthem

utantP

450

BM3M11(capableof

metabolizingdiclo

fenacs

imilar

tohu

mans)

IncreasedRO

Sprod

uctio

nbysim15

and18

times

atconcentrations

of30120583M

and50120583M

respectiv

elycom

paredto

wild

type

[140]

Diclofenacindo

methacin

ketoprofenand

naproxen

CytochromeP

450enzymes

Saccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

NSA

IDsm

etabolism

associated

with

increased

P450-related

toxicity

[95]

(b)

NSA

IDs

coxibs

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Ibup

rofen

ketoprofenand

indo

methacin

CytochromeP

450enzymes

Bacillusm

egaterium

AlltheN

SAID

scausedam

arkedincrease


450level

[142]

Aspirin

diclofenacdiflu

nisal

flurbiprofen

ibup

rofen

indo

methacin

ketoprofenm

efenam

icacidn

aproxen


etin

CytochromeP

450enzymes

Rath

epatocytes

Cytotoxicityof

diclo

fenacketoprofen

andpiroxicam

was

increasedby

cytochromeP


[138]

Diclofenaca

ndnaproxen

Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Increasedexpressio

nof

eNOSmRN

Adu

eto

theg

enerationof

H2O

2which

isrespon

sibleforu

pregulationof

eNOSat

thetranscriptio

naland

post-

transcrip

tionallevels

[114]


NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

expressio

nincreasedin

theh

eart

andaortab


[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2Ex

pressio

nincreasedby

rofecoxib

[114]


Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Inthea

ortathe

coxibs

didno

tsho

wany

eNOSmRN

Aexpressio

nIn

theh

eart

onlyrofecoxibshow

edas

ignificant

increase

inthee

xpressionof

eNOS

[114]

Etod

olac

ND

Hum

angastr

icepith

elialcell

lineA

GS

Increasedapop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

A[79]

Nim

esulide

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Alth

ough

otherreportsarea

vailables

uggesting

theroleo

fNSA

IDsinRO

Sform


lythoseN

SAID

sfor

which

results

show

thattheseN

SAID

sareassociated

with

CVDor

NSA

IDsm

entio

ned

inthetext















2




2


2O2[115]



2


2

∙minus H2O2







2) from the mem-




2











2








2



2transcript level



2

∙minus


2







14 Conclusion






Abbreviations




Acknowledgment



References










































































2O2














































































































































(a)Con

tinued

NSA

IDs

Non

selectivesemise

lective

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Diclofenac

CytochromeP

450enzymes

Saccharomyces

cerevisia

eyeast

cells

expressin

gthem

utantP

450

BM3M11(capableof

metabolizingdiclo

fenacs

imilar

tohu

mans)

IncreasedRO

Sprod

uctio

nbysim15

and18

times

atconcentrations

of30120583M

and50120583M

respectiv

elycom

paredto

wild

type

[140]

Diclofenacindo

methacin

ketoprofenand

naproxen

CytochromeP

450enzymes

Saccharomyces

cerevisia

eYeast

cells

BY4741

andmito

chon

drial

DNAdeletio

n(rho

0 )str

ains

NSA

IDsm

etabolism

associated

with

increased

P450-related

toxicity

[95]

(b)

NSA

IDs

coxibs

Sourceso

fROSgeneratio

nCellsmod

elsanim

alsstudied

Outcomes

References

Ibup

rofen

ketoprofenand

indo

methacin

CytochromeP

450enzymes

Bacillusm

egaterium

AlltheN

SAID

scausedam

arkedincrease


450level

[142]

Aspirin

diclofenacdiflu

nisal

flurbiprofen

ibup

rofen

indo

methacin

ketoprofenm

efenam

icacidn

aproxen


etin

CytochromeP

450enzymes

Rath

epatocytes

Cytotoxicityof

diclo

fenacketoprofen

andpiroxicam

was

increasedby

cytochromeP


[138]

Diclofenaca

ndnaproxen

Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Increasedexpressio

nof

eNOSmRN

Adu

eto

theg

enerationof

H2O

2which

isrespon

sibleforu

pregulationof

eNOSat

thetranscriptio

naland

post-

transcrip

tionallevels

[114]


NADPH

oxidases

Spon

taneou

shypertensiver

ats

NADPH

expressio

nincreasedin

theh

eart

andaortab


[114]

Hum

anEA

hy926

Endo

thelialcells

Nox2Ex

pressio

nincreasedby

rofecoxib

[114]


Endo

thelialn

itricoxide

synthase

Spon

taneou

shypertensiver

ats

Inthea

ortathe

coxibs

didno

tsho

wany

eNOSmRN

Aexpressio

nIn

theh

eart

onlyrofecoxibshow

edas

ignificant

increase

inthee

xpressionof

eNOS

[114]

Etod

olac

ND

Hum

angastr

icepith

elialcell

lineA

GS

Increasedapop

totic

DNAfragmentatio

nandexpressio

nof

COX-

2mRN

A[79]

Nim

esulide

NADPH

oxidases

Ratadipo

cytes

Activ

ationof

NOX4iso

form

ofNADPH

oxidaser

esultsin

theg

enerationof

H2O

2[115]

Alth

ough

otherreportsarea

vailables

uggesting

theroleo

fNSA

IDsinRO

Sform


lythoseN

SAID

sfor

which

results

show

thattheseN

SAID

sareassociated

with

CVDor

NSA

IDsm

entio

ned

inthetext















2




2


2O2[115]



2


2

∙minus H2O2







2) from the mem-




2











2








2



2transcript level



2

∙minus


2







14 Conclusion






Abbreviations




Acknowledgment



References










































































2O2



























































































































































2




2


2O2[115]



2


2

∙minus H2O2







2) from the mem-




2











2








2



2transcript level



2

∙minus


2







14 Conclusion






Abbreviations




Acknowledgment



References










































































2O2

















































































































































2




2


2O2[115]



2


2

∙minus H2O2







2) from the mem-




2











2








2



2transcript level



2

∙minus


2







14 Conclusion






Abbreviations




Acknowledgment



References










































































2O2


















































































































































2) from the mem-




2











2








2



2transcript level



2

∙minus


2







14 Conclusion






Abbreviations




Acknowledgment



References










































































2O2

















































































































































2








2



2transcript level



2

∙minus


2







14 Conclusion






Abbreviations




Acknowledgment



References










































































2O2
















































































































































14 Conclusion






Abbreviations




Acknowledgment



References










































































2O2














































































































































References










































































2O2























































































































































































2O2























































































































































2O2






































































































































































































































































































































































































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