1

Pleiotropic Properties of Pletaal and Its Benefits on Vascular Events

(Cilostazol: a Potent Selective PDE-3A Inhibitor)

2008
(04)
Askandar Tjokroprawiro
Diabetes and Nutrition Center Dr. Soetomo Teaching Hospital
Airlangga University School of Medicine, Surabaya
Summary
Cilostazol (Pletaal) is a potent selective PDE-3A inhibitor, a an oral antiplatelet
agent with a rapid onset of action that leads to a higher level of cyclic adenosine
monophosphate (cAMP), thereby suppressing platelet aggregation. In addition to its
antiplatelet effect, cilostazol inhibits neointimal formation via several mechanisms, as a
part of its pleiotropic properties in which the latter upregulates antioncogenes p53 and
p21 and hepatocyte growth factor (HGF). The increase in p53 protein blocks cell cycle
progression and induces apoptosis in smooth muscle cells (SMCs), leading to an anti
proliferative effect. The upregulation of local HGF stimulates the process of
reendothelization after vessel injury, resulting in inhibition of neointimal formation via
inhibition of abnormal SMC growth and improvement of endothelial function.
Last year (2007), from the DECLARE-Long trial, it was demonstrated that
cilostazol (in triple antiplatelet therapy) significantly reduced late loss of 6 months after
Drug-Eluting Stent (DES) implantation and the occurrence of target lesion
revascularization TLR) and major adverse cardiac events in patients with long coronary
lesion.
Most recently in 2008, randomized comparison of cilostazol vs clopidogrel after
DES in diabetic patients, Cilostazol for Diabetic Patients in Drug-Eluting Stent (CIDES)
trial demonstrated that with ASA and cilostazol for the prevention of stent restenosis is
comparable or superior to that of ASA and clopidogrel in diabetic patients who undergo
DES implantation.
Peripheral Arterial Disease (PAD) is the preferred clinical term that should be
used to denote stenotic, occlusive, and aneurysm diseases and its branch arteries,
exclusive of the coronary arteries; hence, it includes disorders of the abdominal aorta, the
renal and mesenteric arteries, and the lower extremity arteries (the latest is usually termed
PAD). However, it is important to recognize that patients with PAD are likely to have
coexistent cardiac (CHD, MI) and cerebrovascular disease (ischemic stroke events).
Classification of Recommendations of ACC/AHA 2006 consist of 3 classes (I, II,
III) and 3 levels of evidence (A, B, and C). Class-I: conditions for which there is evidence
for and/or general agreement that a given procedure on treatment is beneficial, useful, and
effective. Level of evidence-A: data derived from multiple randomized clinical trial or
meta-analysis.
Abbreviations: ABI = Ankle Brachial Index; ACC = American College of Cardiology; AHA = American Heart
Association; cAMP = Cyclic Adenosine Mono Phosphate; CIDES = Cilostazol for Diabetic Patients in Drug-Eluting
Stent; CIMT = Carotid Intima Media Thickness; DECLARE-Long = Drug-Eluting stenting followed by Cilostazol
treatment reduce LAte REstenosis in patient with Long native coronary lesions; DES = Drug-Eluting Stent; ECM =
Extra Cellular Matrix; HGF = Hepatic Growth Factor; IAS = International Arterial Stenosis; IC = Intermittent
Claudication; LPL = Lipoprotein Lipase; MI = Myocardial Infarction; PAD = Peripheral Arterial Disease; PDE =
Phosphodiesterase; PKA = Protein Kinase A; SMC = Smooth Muscle Cell; TLR = Target Lesion Revascularization;
TOSS = Trial of cilOstazol in Symptomatic intracranial arterial Stenosis; WD = Walking Distance.
PLETAAL SYMPOSIUM
Update Management of Peripheral Arterial Disease
Medan, 2 February 2008
 2

Optimal treatment of PAD, and intermittent claudication (IC) require current

strategies that include exercise therapy, risk-factor modification, stop smoking, and
pharmacotherapy.
Treatment options for IC can be divided into 3 groups:
1. FDA-approved Drugs: Cilostazol, Pentoxifylline
2. Established drugs with some or potential benefits: Naftidrofuryl, Buflomedil
3. Incompletely studied drugs
Cilostazol (CS) has been approved in the US for the treatment of IC since 1999.
Pleiotropic properties of CS can be summarized as follows.
1. Antiplatelet and antithrombotic effects: PDE-3 inhibitor with subsequent
elevation of intracellular cAMP levels.
2A.Adenosine uptake-inhibitor in A1-receptor in cardiomyocyte. Stimulated A1-
receptor in cardiomyocyte causes increased cardiac contractility, and possible
arrhythmia, SMC relaxation, inhibition of SMC proliferation and platelet
aggregation, and lowering plasma lipids; whereas inhibition of A1-receptors
in cardiomyocyte by cilostazol may reduce cardiac contractility (within
normal limit), but minimizes possible arrhythmias
2B.Adenosine uptake-stimulator in A2-receptor in the membranes of SMC and
platelet may cause SMC relaxation and inhibition of platelet aggregation,.
3. Antimitogenic effects (blocks secretion of P-selectin; P-selectin is assumed to
be involved in platelet dependent mitogenesis)
4. LPL-activator with the following decreased TG and increased HDL-Chol.
5. Study in 2004 reported that CS as a selective PDE3-inhibitor, reduces
microalbuminuria at the insulin-resistant stage by inhibition of TGF-, and
ECM protein expansion; hence, CS may be beneficial to lessen early
glomerular nephropathy in state of insulin resistance.
6. The pivotal pleiotropic properties of cilostazol on cardiovascular system are
upregulates p53 & p21 and HGF which result in inhibition of neointimal
formation and in renovation (reendothelization) of vessel injury to improve
endothelial function, respectively.

Several studies supported such pleiotropic properties of CS revealed in several

clinical benefits such as, cilostazol:
1. decreased CIMT
2. inhibited proliferation of SMC (increased p53 and p21: both are important for
apoptosis of SMC)
3. decreased ischemic brain infarction (decreased apoptotic and oxidative cell
death, increased Bcl-2 protein expression and decreased Bax-protein and
cytochrome c release)
4. prevented the progression of symptomatic International Arterial Stenosis
(IAS)
5. is effective regimen for prevention of stent thrombosis and restenosis after
DES implantation in patients with diabetes or with long coronary lesions as
reported in DECLARE (2007) and CIDES (2008) trials.

ACC/AHA-2006 Guidelines and Recommendations on CS for the Management of

patients with lower extremity PAD can be partly presented below.
Class-I: 1. CS (100mg orally 2 times per day) is indicated as an effective therapy
to improve symptoms and increased WD in patients with PAD and IC (in the absence of
heart failure) with Level of Evidence-A
 3

2. A therapeutic trial of CS should be considered in all patients with

lifestyle-limiting claudication (in the absence of heart failure) with Level of Evidence-A
Cilostazol has been generally well tolerated, with the most common adverse
events e.g.: headache, dizziness, and diarrhea; however, such side effects can be
minimized if CS taken b.i.d half an hour before or two hours after breakfast and dinner.
Cilostazol improves maximal WD by 40% to 60% after 12 to 24 weeks of
treatment. Cilostazol increases ABI modestly, but hemodynamic effect cannot account for
the improvement in claudication. A meta-analysis indicates that CS also improves
walking ability and health related quality of life. Cilostazol administered at 100 mg twice
daily is more effective than 50 mg twice daily.
Conclusions Cilostazol (CS) is a selective PDE-3A inhibitor, which has
pleiotropic effects: 1. antiplatelet / Anti thrombotic activity; 2. vasodilation effects; 3.
antimitogenic effects; 4. lipid-modulating effects. In addition, microalbuminuria reducing
effect of is CS due to inhibition of TGF-1, and ECM expansion. ACC/AHA-2006
Guidelines for the management of lower extremity (PAD) recommended that CS is
indicated as an effective therapy to improve symptoms of WD, and IC (Class-I Level of
Evidence-A). This FDA-approved drug (1999) should be prescribed for all intermittent
claudication-patients with limited quality of life. A meta-analysis indicated the superiority
of CS to improve WD and health-related quality of life. The progression of symptomatic
IAS in cilostazol treatment was significantly lower than in placebo treatment. Either in
dual antiplatelet therapy (DES in diabetic patients) or in triple one (DES in long coronary
lesions), cilostazol significantly reduced late loss at 6 months after DES implantation.
Note: dual antiplatelet therapy = ASA plus clopidogrel; triple antiplatelet therapy = ASA
plus clopidogrel and cilostazol.

Introduction
Peripheral arterial disease (PAD) is the preferred clinical term that should be used
to denote stenotic, occlusive, and aneurysmal disease of the aorta and its branches arteries
(lower extremity, renal, mesenteric, and abdominal aortic), exclusive of the coronary
arteries.
Classification of PAD according to Fontaines Stages, and Rutherfords Categories
(can be seen in TABLE-1) are generally to be accepted for daily clinical staging
(Dormandy et al 2000).

TABLE -1 Classification of Peripheral Arterial Disease

Fontaines Stages and Rutherfords Categories
(Dormandy et al 2000)
Fontaine Rutherford
Stage Clinical Grade Category Clinical
I Asymptomatic 0 0 Asymptomatic
IIa Mild Claudication I 1 Mild Claudication
IIb Moderate-severe Claudication I 2 Moderate Claudication
I 3 Severe Claudication
III Ischemic Rest Pain II 4 Ischemic Rest Pain
IV Ulceration or Gangrene III 5 Minor Tissue Loss
IV 6 Ulceration or Gangrene

The clinical manifestations of PAD are a major cause of acute and chronic illness, and are
associated with decrements in functional capacity and quality of life, and then they may
cause limb amputation, and increased the risk of death. Hence, it is important to
 4

recognize that patients with PAD are likely to have coexistent cardiac and
cerebrovascular disease such that there is an elevated risk of myocardial infarction and
stroke ischemic events and an associated increased mortality from CHD and stroke.
The US-FDA in 1999 has approved drugs for the management of intermittent
claudication (PAD of Stage-IIa and IIb Fontaines Stages, and Grade-I or Categories 1, 2,
3 Rutherfords Categories): cilostazol and pentoxifylline.
Cilostazol is a potent, reversible, PDE-3 inhibitor. The inhibition of PDE follows
for the increased availability of cAMP; the latter mediates many agonist-induced platelet
inhibitory, vasodilatory, vascular antiproliferative responses (antimitogenic effects), and
shows lipid-modulating effects (Schrr 2002, Jacoby et al 2004).
ACC/AHA Guidelines-2006 for the management of patients with PAD (lower
extremity, renal, mesenteric, and abdominal aortic) recommended cilostazol (100 mg bid)
in Class-I with Level of Evidence-A for medical and pharmacological treatment for
intermittent claudication
The aim of this presentation/paper is to transfer the recent knowledge of
antiplatelet agents (focus on cilostazol) which has platelet inhibitory, vasodilatory, and
vascular antiproliferative responses (antimitogenic), and has lipid-modulating effects, to
GPs, residents, internists, and other associated specialist. In addition, the beneficial
effects of cilostazol for the prevention of stent restenosis either in patients with diabetes
(CIDES-trial) or in patients with long coronary lesions (DECLARE-Long Trial).

Classification of Recommendations of ACC/AHA 2006

A classification of recommendations and level of evidence have been assigned to
each recommendation. Classifications of Recommendations and Levels of Evidence are
expressed in the American College of Cardiology (ACC) / American Heart Association
(AHA) format as follows (TABLE-2)

TABLE-2 Classification of Recommendations and Level of Evidence

(ACC / AHA 2006)
Class I Condition for which there is evidence for and /or general agreement that a
given procedure or treatment is beneficial, useful, and effective
Class II Condition for which there is conflicting evidence and/or a divergence of
opinion about the usefulness/efficacy of a procedure or treatment
Class IIa: weight of evidence/opinion is in favour of usefulness/efficacy
Class IIb: Usefulness/efficacy is less well established by evidence/opinion
Class III Conditions for which there is evidence and/or general agreement that a
procedure/treatment is not useful/effective and in some cases may be
harmful
Level of Level of Evidence A: Data derived from multiple randomized clinical
Evidence trials of meta-analyses
Level of Evidence B: Data derived from a single randomized trial or non-
randomized studies
Level of Evidence C: Only consensus opinion of experts, case studies, or
standard-of-care

Cilostazol: Pleiotropic Properties with Several Clinical Benefits

Presently, the degrading enzyme of cGMP, ie PDE (Phosphodiesterase), comes
from a family of 7 types such as: PDE-1, 2, 3, 4, 5, 6, and 7. PDE-3 catalyses both cAMP
and cGMP, and its affinity is known to be the highest among the PDE isozymes. Further,
 5

PDE-3 is characterized by its strong inhibition to cGMP, whereas cGMP is the most
important molecule for SMC relaxation. PDE-3 is present both in the vascular SMC and
in the platelet and has become the target in the treatment of atherosclerotic lesions.
Furthermore, inhibition of PDE-3 (PDE-3 inhibitor) can also prevent the
progression of arteriosclerosis based from the fact that platelets produce PDGF which is
responsible for the proliferation of vascular SMCs.
The pleiotropic properties of cilostazol (CS) have been summarized from Schrr (2002),
and Jacoby et al (2004) by Tjokroprawiro (2006) as follows.
1. Potent inhibitor of platelet aggregation and vasodilator of vascular smooth muscle
2. Inhibitor of SMC proliferation (inhibits PDGF secretion, increases p53 and p21)
3. Lipid-modulator due to activated LPL(decrease in triglyceride and increase in
HDL-cholesterol)
4. Adenosine Uptake-Inhibitor (its selectivity at A1 Receptors in Cardiomyocyte)
It can be concluded that several properties of CS (PDE-3 inhibitor, LPL-activator,
Adenosine uptake-inhibitor in cardiomyocyte (FIGURE-3), and antimitogenic) may result
in pleiotropic clinical benefits for the prevention and treatment of PAD and its associated
diseases as briefly described in this paper.

FIGURE-1. The Roles of Three in One on Platelet Function

Drug Information 2000, (Provided: Tjokroprawiro 2000-2008)
Three in One: cAMP, Cytosolic Ca++, AA in One Platelet
SATE TC: Serotonin, ADP, Thrombin, Epinephrine TXA2 , Collagen

Cilostazol may be regarded as the first representative of a new family of anti thrombotic
agents by selective inhibition on one of 7 Phosphodiesterase families, called PDE 3.
Cilostazol may cause increased intracellular level of cAMP, decreased in intracellular Ca +
+
-ion concentration (decreased cytosolic Ca++), and subsequently, primary and secondary
platelet aggregations may be inhibited (FIGURE 1).
 6

Cytosolic Ca++ (intracellular Ca++-ion) in platelet may cause:

1. increased releasing reaction (serotonin, ADP, thrombine, epinephrine TX2,
collagen: SATE TC)
2. activated GP IIb/IIIa receptors (which may bind with fibrinogen)
3. activated GPIb/V/IX receptors (which may bind with von Willebrand Factor)
4. high shearing stress.
All these effects result in platelet aggregation. Cyclic-AMP may lower cytosolic Ca ++ in
platelet and in SMC, and such a decreased cytosolic Ca ++ subsequently results in anti-
platelet aggregation, and SMC-relaxation and inhibition of SMC-proliferation (as seen in
FIGURE-1). Hence, cAMP may counteract the effect of SATE-TC (Serotonin, ADP,
Thrombin, Epinephrine TXA2, Collagen), the 6 stimuli for degradation of Ca-stored
granule in platelet, in which these components will increase cytosolic-Ca++ concentration.

FIGURE-2. The Roles of Three in One on Platelet Function

Drug Information 2000 (Provided: Tjokroprawiro 2000-2008)
SATE-TC : Serotonin, ADP, Thrombin, Epinephrine TXA2, Collagen
Three in One : cAMP, Cytosolic Ca++, AA in One Platelet
 7

As seen in FIGURE-2, these 3 (three) important components (cAMP, cytosolic

++
Ca , AA) in One Platelet will be termed Three in One Platelet (TOP). Hence, it can
be concluded that the quality of platelet is dependent on the quality of TOP. The
description of FIGURE1, FIGURE2, and FIGURE3 will be more easily understood
during presentation of this paper.
Adenosine may bind with A2 receptors in SMC and in platelet, and A1 receptor
in myocyte of the heart (FIGURE-3). Via G S protein in SMC and platelet, activated A2
receptors may activate adenyl cyclase which subsequently increases cAMP and then
activated PKA, and results in relaxation of SMC and also results in inhibition of platelet
aggregation. However, CS potently increases cAMP in SMC and platelet by inhibiting
cAMP degradation.
G1 protein in A1 receptor of cardiomyocyte will be activated by Adenosine, but
this activation will be inhibited by CS and may result in inhibition of adenyl cyclase;
consequently, it results in decreased cAMP and inactivated PKA, and hence, small
decreased cardiac contractility may purse (unwanted side effect), however, it will be
followed with less possibility of arrhythmias (FIGURE-3). Fatal arrhythmias have been
described with the use of milrinone, another inhibitor of PDE-3. Compared with
milrinone, CS is more selective in its inhibition of cardiac PDE-3 activity, and this
property will be greatly beneficial for cardiac contractility and arrhytmias.
Taken together, FIGURE-3 can explain how adenosine works differently if this
substance taken by A1-receptor in cardiomyocyte and by A2-receptors in SMCs and
platelet.

Evidence Based Information About Cilostazol

(Pleiotropic Properties with Several Clinical Benefits)
Several selected reports favour the effects of cilostazol (CS) are listed below

I CILOSTAZOL (1996, 1998)

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Cilostazol increases walking distance (WD) in patients with intermittent

claudication = IC (Elam et al 1998) : improvement of microhemorrheological
factors and or skeletal muscle oxygen metabolism (Tsuchiya et al 1996)
II CILOSTAZOL (1996, 1998)
Cilostazol improves symptoms of IC, plasma lipoproteins, etc :
1 HDL-Chol 12.2%, TG 23%, apo A1 / apo B Ratio, LDL-Chol (No
change), 35% treadmill walking time, 9.03% ABI (Elam et al, 1998)
2 HDL-Chol, TG, T-Chol (No change), improvement of subjective symptoms
(Noma et al, 1992)
3 improves platelet function, T-Chol , HDL-Chol , TxB2, TG (Suehero et

S
S
al, 1993) : No Change
S

III CILOSTAZOL (1998)

1 increases absolute claudication distance (ACD) (Money et al 1998)
2 increases initial claudication distance (ICD) on treadmill & increases ACD
(Dawson et al, 1998)
3 improves WD in patients with IC (Beebe et al, 1998)
4 withdrawal of CS worsens walking of IC, pentoxifylline does not (Dawson et al, 1998)
IV CILOSTAZOL (1998, 2000)
1 reduces restenosis following balloon angioplasty and target lesion revascula-
rization (Tsuchigane, 1998)
2 inhibits proliferation of SMC, accompanied by p 53 - p 21 mediated apoptosis,
thus CS may be assumed as "antiproliferative" drug against SMC growth
(Hayashi et al, 2000)
3 has beneficial positive chronotropic effect in patients with bradyarrhythmias,
esp. bradycardic atrial fibrillation & sick sinus syndrome (Atarashi et al, 1998)
V CILOSTAZOL (1996, 1998)
1 Pharmacologic characteristic of CS are not affected by age or gender (Suri, 1998)
2 CS in an effective inhibitor of SIPA : Shear Stress - Induced Platelet
Aggregation thus, CS may be important for prevention and treatment of PAD
(Minami et al, 1997)
3 CS inhibitory actions on platelet functions are potently enhanced in the presence
of PGI2 (Kimura, 1998)
4 CS increases nitric oxide synthesis in IL-1-stimulated SMC, at least partially
through a cAMP-dependent pathway (Ikeda, 1996)
VI CILOSTAZOL (1995,1999, 2000)
1 improve nerve Na+-K+-ATPase activity & cAMP content. Hence, CS may be a
potent drug for clinical treatment of diabetic neuropathy (Naka et al, 1995)
2 CS (Gotoh et al, 2000) :
Preventive effect on the recurrence of cerebral infarction, even in patients
with lacunar infarction
Rate of RR-reduction of CS is higher than ASA and other APAs
No increase risk of cerebral haemorrhage
3 CS and ASA co-administration : 23-35% increase in inhibition of ADP-induced
ex-vivo platelet aggregation (Mallikoarjun et al, 1999)
VII. CILOSTAZOL (2000)
 9

Cyclic-AMP has a direct inhibitory action against abnormal vascular SMC

growth, accompanied by the induction of anti-oncogenes, p53, and p21, and apoptosis
(Hayashi et al 2000). It is suggested that p53/p21, may mediate the inhibitory effect of
cAMP on SMC proliferation induced by PDGF. Hence, agents (CS, etc) that cause
accumulation of cAMP may be considered as anti - proliferative drugs against vascular
SMC proliferation.

VIII. CILOSTAZOL (2000)

Hepatic Growth Factor (HGF) is important in the restoration of endothelial cells
as an important treatment regimen to inhibit the proliferation of the vascular SMC. But,
it does not posses any proliferating action like VEGF (an endothelium specific growth
factor). The reduction of local HGF production is related to the decrease in endothealial
function as seen in poorly controlled diabetes. Studies confirmed that HGF genes are
present in the CRE (cAMP-Responsible Element). Thus, there is a possibility that drugs
(CS, etc) with cAMP increasing effect may also increase HGF production (Shinichiro et
al 2000). Hence, the vascular SMC growth inhibition of the anti - platelet agent CS and
the possibility of endothelium regeneration by HGF are most likely of great benefits in
the treatment of atherosclerosis (esp. in diabetes mellitus).

IX. CILOSTAZOL (2001)

After one year treatment with CS in patients with type-2 DM, carotid intima
media thickness (CIMT) can be significantly decreased (Ahn et al 2001)

X. CILOSTAZOL as Dual Inhibitor of PDE 3, and Adenosine Uptake (2001)

Adenosine receptors are found in the vascular SMC and platelet in one side (A 2
-receptors), and in the cardiomyocyte (A1 receptor) in the other side (FIGURE 1,
FIGURE 2, FIGURE 3).
The binding of adenosine with A2 - receptors in SMC and in platelet may result in
relaxation and anti-aggregation, respectively.
The binding of adenosine with A1 receptor may cause small decreased cardiac
contractility but less incidence of arrhythmia. Cilostazol has been claimed as PDE 3-
inhibitor (cAMP enhancer) and adenosine uptake-inhibitor (FIGURE 3). Inhibition of
PDE3 increases intracellular cAMP, causes vasodilation and inhibition of platelet
aggregation, and both effects are thought to be beneficial for patients with intermittent
claudication. PDE 3-inhibition also has positive cardiac inotropic and chronotropic
effects. Inhibition of adenosine uptake by cilostazol elevates intertitial and circulatory
adenosine concentrations. These elevations have the favorable consequences of
enhancing the antiplatelet and vasodilatory effects, while diminishing the unwanted side
effects due to the inhibition of binding of adenosine with A1 receptor in the
cardiomyocyte (FIGURE 3).
Adenosine binds A2 - receptors, and activates Gs-protein to stimulate adenyl
cyclase (AC), and augments the effects from PDE3 inhibition: increase of blood flow
and inhibition of platelet aggregation (FIGURE 3). On the other hand, the binding of
adenosine with A1- receptor, will activate G1-protein to inhibit AC, and has been shown
to attenuate PKA-mediated modulation in cardiac function (Liu et al 2001). However,
cilostazol has selectively in its inhibition of cardiac PDE 3 activity, and may minimize
such unwanted side effects.

XI. CILOSTAZOL (2002)

Kamishirado et al (2002) demonstrated that aspirin plus CS therapy might be an
effective regimen for the prevention of, not only stent thrombosis, but also restenosis.
 10

XII. CILOSTAZOL (2002)

Cilostazol treatment decreases ischemic brain infarction in association with
inhibition of apoptotic and oxidative cell death (Choi et al 2002). Following treatment
with CS was accompanied by decreased TNF level. In the regions of penumbra are
found markedly reduced Bcl-2 protein levels and, in contrast, high levels of Bax-protein
and Cytochrom c release. Cilostazol decreased Bax-protein and cytochrom c release,
and increased the levels of Bcl-2 protein (beneficial antiapoptotic effect). Cilostazol
potently and concentration dependently scavenged hydroxyl and peroxylradicals. Thus,
cilostazol and its analogues exert a strong protection against apoptotic cell death by
scavenging hydroxyl radicals and intracellular ROS (antioxidant effect) with reduction
in TNF formation and by increasing Bcl 2-protein expression and decreasing Bax-
protein and cytochrom c release. Thus, cilostazol shows both antiapoptotic and
antioxidative effects.

XIII. CILOSTAZOL (2002)

Cilostazol and OPC-13213 (active cilostazol metabolite, but not OPC 13015)
caused a significant suppression of cell death induced by LPS. These drugs potently
inhibited hydroxyl adduct formation and significantly reduced the increased
intracellular ROS and TNF. An apoptotic death by lipopolysaccharide (LPS) was
strongly suppressed by these compound. LPS caused a marked decrease in Bcl2-protein,
which was reversed by cilostazol and its analogues. The greatly increased Bax-protein
expression and cytochrom c release by LPS were, in contrast, suppressed by cilostazol
and, to a lesser degree, by others (Kim et al 2002)

XIV. CILOSTAZOL (2002)

A total of 89 diabetic patients were allocated at random to the cilostazol group (n
= 43) or the control (n = 46). After the study period 3.2 0.5 years no subjects showed
silent brain infarction or stroke during the study period. In contrast, 2 out of 46 subjects
in the control group showed symptomatic brain infarctions and 10 out of 34 subjects
with infarct-like region. CIMT had increased (p < 0.01) by 0.18 0.19 mm in the
control group. These data demonstrated that CS could prevent the onset of silent brain
infarction in Japanese subjects with Type 2 DM. In addition, an increase in carotid
intima media thickness (CIMT) could be able to predict the onset of silent brain
infarction (Tagawa et al 2002)

XV. ANTIMITOGENIC EFFECTS OF CILOSTAZOL (2002)

In addition to inhibitory platelet aggregation, cilostazol also blocks the surface
expression of the platelet fibrinogen receptor (GPIIb/IIIa), as well as alpha-granule
secretion of P-selectin (Inoue et al 1999). P-selectin is assumed to be involved in
platelet-dependent mitogenesis. This effect might contribute to inhibition of restenosis
(Schrr 2002); however, other activaties of cilostazol might also be involved. For
example, Kayanoki et al (1997) demonstrated the inhibition of heparin-binding
epidermal growth factor (HB-EGF) by cilostazol in macrophages and smooth muscle
cell (SMCs). HB-EGF is one of the most potent mitogens for SMCs and inhibition of its
expression is clearly of relevance for inhibition of mitogenesis. Thus, cilostazol acts as
an antimitogenic agent by several mechanisms.

XVI. CILOSTAZOL (2003)

Rational and design of the randomized, multicenter, Cilostazol for RESTenosis Trial
(CREST) concluded that cilostazol possesses antiplatelet, antiproliferative and other
 11

properties that may minimize or prevent in-stent coronary restenosis. The CREST trial
is larger, more rigorously conducted trial that may confirm an important role of
cilostazol in the long-term management of patients with coronary arterial disease after
uncomplicated coronary stent implantation.

XVII. CILOSTAZOL REDUCES MICROALBUMINURIA (2004)

In insulin resistance or hyperinsulinemia, increased glomerular hyperfiltration and
microalbuminuria may occur due to the expression of TGF-1, and ECM protein such
as fibronectin and type IV collagen. Tohma et al (2004) demonstrated cilostazol
reduced glomerular hyperfiltration and microalbuminuria at the insulin-resistant
prediabetic stage by inhibition of TGF-, and ECM protein expression. Thus, cilostazol
may be beneficial to lessen the development of early glomerular nephropathy in a state
of insulin resistance.

XVIII. CILOSTAZOL (2005)

Kwon et al (2005) in TOSS (Trial of cilOstazol in Symptomatic intracranial arterial
Stenosis) demonstrated that:
CS + ASA significantly prevents the progression of symptomatic IAS (Intracranial
Arterial Stenosis) than ASA monotheraphy.
CS + ASA no increase risk bleeding tendency.

XIX. ACC/AHA (2006) GUIDELINES AND RECOMMENDATIONS FOR THE

MANAGEMENT OF PATIENTS WITH PERIPHERAL ARTERIAL DISEASE

These guidelines address the diagnosis and management of atherosclerotic,

aneurysmal, and thrombotic peripheral arterial diseases (PADs). The clinical
manifestations of PAD are major causes of acute and chronic illness, and are associated
with decrement in functional capacity adequality of life, and then cause limb
amputation, and increase the risk of death. Whereas the term peripheral arterial
disease encompasses a large series of disorders that affects arterial beds exclusive the
coronary arteries, but includes the disorders of the abdominal aorta, renal, mesenteric
arteries, and lower extremity arteries.
The ACC/AHA Guidelines and Recommendations (2006) are shortly described in
this paper are focused on the Management of PAD. Fontaines Stage and Rutherfords
Categories can be seen in TABLE-1 (Dormandy et al 2000). Classifications of
Recommendations and levels of Evidence are expressed in the ACC/AHA format as
listed in TABLE-2
Recommendations:
- Cilostazol: Class-I with Level of Evidence A
- Pentoxififylline (as second-line alternative therapy to cilostazol): Class IIb with
Level Evidence B
Both drugs are used for medical and pharmacological treatment for claudication
Recommendations: Class I (Cilostazol)
1. Cilostazol (100mg orally bid) is indicated as an effective therapy to improve
symptoms and increase WD in patients with lower extremity PAD, and IC (in the
absence of heart failure) with Level of Evidence-A
2. A therapeutic trial of cilostazol should be considered in all patients with lifestyle
limiting claudication (in the absence of heart failure) with Level of Evidence-A
 12

Cilostazol improves maximal WD by 40% to 60% after 12 to 24 weeks of therapy.

Cilostazol increases ABI modestly, but the hemodynamic effect cannot account for the
improvement in claudication. A meta-analysis indicates that cilostazol also improves
walking ability and heath-related quality of life.

XX. CILOSTAZOL after DES Implantation from DECLARE-Long Trial (2007)

Lee at al 2007 (from the DECLARE-Long trial) investigated whether cilostazol
reduces or does not neointimal hyperplasia after DES implantation in complex (long)
coronary lesions. They performed a randomized a multicenter prospective study
comparing triple antiplatelet therapy (ASA, clopidogrel, and cilostazol) versus dual
antiplatelet therapy (ASA and clopidogrel) for 6 months in patients with long coronary
lesions treated with DES. The study revealed that ciolostazol significantly reduced late
loss at 6 months after DES implantation and the evidence of target lesion
revascularization (TLR) and major adverse cardiac events of those patients.
XXI. CILOSTAZOL (2008)
Ahn et al (2008) studied the effects of cilostazol on restenosis after successful
deployment of DES in patients with diabetes mellitus. They concluded that combination
therapy (ASA and cilostazol) for the prevention of stent restenosis is comparable or
superior to that of ASA and clopidogrel in patients who undergo DES implantation.

Based on the reports of several studies, the author summarized minimally 16

properties and clinical benefits of cilostazol as seen in FIGURE 4.

Conclusions
I. The summarized roles of CS can be seen in the TABLE-3 and FIGURE-4.
Cilostazol as a PDE 3inhibitor, LPL-activator, and an Adenosine uptakeinhibitor in
cardiomyocyte have been assumed as the main triple properties of cilostazol which are
able to result in several clinical benefits.
 13

II. Adenosine is a Ligand for A1 receptor in cardiacmyocyte (which results in

small reduced cardiac contractility, but less possible arrhythmia), and for A2 receptors in
platelet and SMC (which result in anti-platelet aggregation, and relaxation, respectively).
Cilostazol is adenosine uptake inhibitor in cardiomyocyte and PDE 3-inhibitor and
SMC and platelet, thus: intracellular cAMP levels are increased in platelet and SMC
(anti-platelet aggregation and SMC relaxation), otherwise unwanted side effects of
adenosine in cardiocmyocyte (small reduced contractility, but less possibility of
arrhythmias) are minimized. Cilostazol also has antimitogenic effects, cilostazol may
reduce microalbuminuria in the insulin-resistant prediabetic stage. The pleiotropic
properties and clinical uses, esp. for diabetic patients (TABLE-3 and FIGURE-4) of
cilostazol are most likely of great therapeutic benefits in the prevention and treatment of
either PAD, IC, or other related atherosclerotic diseases (CAD and restenosis in DSE,
Stroke, Neuropathy, Early Nephropathy, Gangrene, etc)
III. Selected summary of ACC/AHA 2006 Guidelines and Recommendations for
the Management of PAD are listed below
1. Medical and Pharmacological Treatment for Claudication are Cilostazol
and Pentoxifylline
2. Classification of Recommendations and Levels of Evidence
Cilostazol (first-line therapy): Class-I with Level of Evidence-A and A
Pentoxifylline (second-line therapy): Class-IIb with Level of Evidence A and C
a. Cilostazol for WD and IC (in the absence of heart failure): Class-I with
Level of Evidence-A
b. Cilostazol for all patients with lifestyle-limiting claudication: Class-I with
Level of Evidence-A
3. Cilostazol improves WD by 40-60% after 12-24 week therapy.
IV. The most important properties of cilostazol on cardiovascular system are to
upregulate antioncogenes p53 and p21 and HGF.
The increase in p53 protein may stop cell cycle progression and induces apoptosis
in vascular SMC, leading to antiproliferative effects, and inhibition of neointimal
formation may pursue (important for the prevention of DES restenosis).
Whereas the upregulation of local HGF stimulates the process of
reendothelization for vessel injuries, resulting renovation of endothelial cells and
endothelial function.
The properties and clinical benefits of cilostazol can be also found in TABLE 3.
 14

ACC/AHA 2006 : Guidelines and Recommendations

Cilostazol is Recommended as Class-I with Level of Evidence-A in the Medical treatment for
Claudication
Cilostazol should be considered in all patients with Lifestyle-limiting Claudication
Cilostazol improves Walking Distance by 40-60% after 12 24 weeks of therapy
Cilostazol should be given at least 0.5 hour before or 2 hours after breakfast and dinner
Dose 100mg twice daily is more effective than 50mg twice daily.
DECLARE-2007 and CIDES-2008:
Reduce restenosis of DES (Drug-Eluting Stent) Implantation
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 15

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