Management of peripheral arterial disease and intermittent claudication.
Reference: J Am Board Fam Pract 2001;14(6):4430-50
BACKGROUND: Peripheral arterial disease (PAD) is the chronic obstruction
of the arteries
supplying the lower extremities. The most common symptom is intermittent
claudication resulting
in aching pain, numbness, weakness, or fatigue in the muscle groups of
the lower extremities.
METHODS: Using the key words "peripheral arterial disease," "intermittent
claudication,"
"atherosclerosis," and "cardiovascular disease," MEDLINE databases were
searched from 1970
to the present. The most recent articles pertinent to current treatment
recommendations for PAD
and intermittent claudication were selected to document this review. RESULTS
AND
CONCLUSIONS: Symptoms of intermittent claudication are induced by walking
or exercise and
usually resolve with rest. Disease severity varies from patients who are
asymptomatic to those
who have unremitting symptoms. A high overlap exists between PAD and coronary
artery and
cerebrovascular disease. Risks for long-term morbidity and mortality are
identical for PAD,
intermittent claudication, and coronary artery disease. Treatment of PAD
is aimed at maintaining
or improving functional status, reducing or eliminating ischemic symptoms,
and preventing disease
progression. Exercise and aggressive risk factor modification represent
the cornerstones of
treatment. Risk factors include smoking, diabetes, lipid abnormalities,
hypertension, C-reactive
protein, lipoprotein(a), and hyperhomocystinemia. Antiplatelet and lipid-altering
therapies
decrease risk of atherosclerotic vascular complications and are being studied
to improve
intermittent claudication. Cilostazol, a new antiplatelet, antithrombotic
agent, reduces claudication
symptoms. Angiogenic growth factors have shown preliminary success in patients
with rest pain
and ischemic ulcers and are being investigated for use in patients with
intermittent claudication.
Invasive revascularization procedures can be considered for patients with
critical limb ischemia or
when medical therapy fails.
Effect of cilostazol on endothelial cell denudation and proliferation in
canine vein grafts.
Reference: Surg Today 2001;31(10):891-4.
The purpose of the present study was to examine the effects of cilostazol
on endothelial cell
denudation and proliferation in vein grafts used as arterial substitutes.
Unilateral aortoiliac bypass
was performed using the lateral jugular vein in 20 mongrel dogs. The animals
were divided into
two groups according to whether or not cilostazol was given. The grafts
were removed at
intervals of 1 day and 50 days, and the luminal surface was assessed for
endothelial cell coverage
(%). The denudation of endothelial cells was less extensive in the cilostazol
group than in the
control group on postoperative day 1. There was significantly more proliferation
of endothelial
cells in the control group over the course of time than in the cilostazol
group. In conclusion,
cilostazol significantly prevented early endothelial cell denudation, although
it did not appear to
stimulate successive endothelial cell proliferation. Therefore, cilostazol
may help preserve an
intact intima, which would potentially result in the inhibition of intimal
hyperplasia.
Effects of cilostazol on resting ankle pressures and exercise-induced
ischemia in patients with intermittent claudication.
Reference: Vasc Med 2001;6(3):151-6
During exercise, patients with intermittent claudication (IC) have decreased
limb arterial blood
pressure that recovers during rest. A novel method for assessing dynamic
recovery of function is
measurement of the hemodynamic response after exercise. Cilostazol (Pletal),
a new agent for the
treatment of IC, increases walking distance and may decrease ischemic burden.
The objective of
this study was to assess the effect of cilostazol versus placebo on hemodynamic
measurements
after exercise-induced ischemia in patients with IC. Two double-blind,
placebo-controlled studies
with similar inclusion/exclusion criteria and duration (24 weeks) were
pooled. Patients walked on
a treadmill at 2.0 miles/h (3.2 km/h) on a 12.5% grade until the claudication-limited
maximal
walking distance (MWD) was reached. Anterior and posterior tibial pressures
were measured
with Doppler ultrasound at baseline and at 1, 5, and 9 min during recovery.
Area under the curve
(AUC), a measure of the time course of recovery of systolic pressure after
exercise-induced
ischemia, and ankle-brachial index (ABI) were calculated and compared using
analysis of
variance (ANOVA). All three treatment groups (308 patients randomized to
cilostazol 100 mg
bid, 303 to cilostazol 50 mg bid, and 299 to placebo) had similar baseline
characteristics. Mean
post-exercise AUC for cilostazol 100 mg and 50 mg bid versus placebo increased
by 0.31 (p =
0.001) and 0.26 (p = 0.004), respectively. Mean resting ABI increased by
0.03 (p = 0.0039)
and 0.04 (p = 0.0001) in the cilostazol 100 mg and 50 mg bid groups, respectively.
In
conclusion, following 24 weeks of treatment, cilostazol increased the ABI
at rest and improved
the recovery time of ankle pressures post-exercise.
Inhibition of Lipopolysaccharide-Induced Apoptosis by Cilostazol in
Human Umbilical Vein Endothelial Cells.
Reference: J Pharmacol Exp Ther 2002;300(2):709-715.
This work describes the pharmacological inhibition by cilostazol and its
metabolites, OPC-13015
and OPC-13213, of the apoptosis in the human umbilical vein endothelial
cells (HUVECs)
damaged by lipopolysaccharide (LPS) in comparison with its analog, cilostamide.
Cilostazol and
OPC-31213 caused a significant suppression of cell death induced by LPS
(1 &mgr;g/ml) in a
concentration-dependent manner but a modest suppression by cilostamide
and OPC-13015.
These compounds potently inhibited the 5,5-dimethyl-1-pyrroline-1-oxide
(DMPO)/(.)OH
adduct formation and significantly reduced the increased intracellular
reactive oxygen species
(ROS) and tumor necrosis factor-alpha (TNF-alpha) production induced by
LPS (1 &mgr;g/ml).
An apoptotic death of HUVECs by 1 &mgr;g/ml LPS (DNA ladders on electrophoresis)
was
strongly suppressed by all these compounds. Incubation with LPS caused
a marked decrease in
Bcl-2 protein, which was significantly reversed by cilostazol and its analogs.
The greatly
increased Bax protein expression and cytochrome c release by LPS were,
in contrast,
suppressed by cilostazol and, to a lesser degree, by others. In conclusion,
cilostazol and its
analogs exert a strong protection against apoptotic cell death by scavenging
hydroxyl radicals and
intracellular ROS with reduction in TNF-alpha formation and by increasing
Bcl-2 protein
expression and decreasing Bax protein and cytochrome c release.
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Volume
5, Number 2: February 2002
