 Neuroprotective
effect of cilostazol against focal cerebral ischemia via antiapoptotic
action in rats.
Reference: Pharmacol Exp Ther 2002;300(3):787-93.
This study examined the protective effects of cilostazol on cerebral infarcts
produced by
subjecting rats to 2-h occlusion of the left middle cerebral artery followed
by 24-h reperfusion.
The ischemic cerebral infarct consistently involved the cortex and striatum.
The infarct size was
significantly reduced, when rats received 10 mg/kg cilostazol intravenously
5 min or 1 h after the
completion of 2-h ischemia. Cyclic AMP level was significantly elevated
in the cortex of 4- and
12-h reperfusion (P < 0.01) following treatment with cilostazol (10
mg/kg, 5 min after 2-h
ischemia) accompanied by decreased tumor necrosis factor-alpha level. Samples
from the
regions corresponding to the penumbra showed markedly reduced Bcl-2 protein
level and, in
contrast, high levels of Bax protein and cytochrome c release. Cilostazol
decreased Bax protein
and cytochrome c release and increased the levels of Bcl-2 protein. Cilostazol
(10(-7)-10(-5)
M) potently and concentration dependently scavenged hydroxyl and peroxyl
radicals. In
conclusion, cilostazol treatment decreases ischemic brain infarction in
association with inhibition of
apoptotic and oxidative cell death.
Successful
pharmacologic treatment of lower extremity ulcerations in 5 patients with
chronic critical limb ischemia.
Reference: J Am Board Fam Pract 2002;15(1):55-62.
BACKGROUND: Ischemic ulcerations of the distal lower extremities are a
manifestation of
chronic critical limb ischemia. Without restoration of arterial flow, subsequent
gangrene and limb
loss can ensue. Unfortunately, revascularization is not always possible.
METHODS: A literature
search of MEDLINE was performed and a case series of 5 patients with lower
extremity
ischemic ulcerations is described. RESULTS AND CONCLUSION: Five patients
with severe
peripheral artery disease had nonhealing lower extremity ischemic ulcerations.
Because 3 patients
were not ideal candidates for percutaneous or surgical intervention, and
2 refused invasive
therapy, they were treated with cilostazol. Between 7 and 24 weeks after
beginning cilostazol
therapy, the ulcerations healed in all 5 patients. Three of the patients
experienced resolution of
concurrent ischemic rest pain. One patient underwent a posttreatment noninvasive
arterial study
that documented improved large- and small-vessel perfusion. The antiplatelet,
antithrombotic, and
vasodilatory effects, in addition to possible unrecognized actions of cilostazol,
appeared to
promote wound healing in this small group of patients with chronic critical
limb ischemia. When
revascularization is not ideal therapy for ischemic ulcers, a pharmacologic
approach with
cilostazol might induce healing and obviate limb amputation.
Cilostazol (Pletal[reg]): A Dual Inhibitor of Cyclic Nucleotide
Phosphodiesterase Type 3 and Adenosine Uptake.
Reference: Cardiovasc Drug Rev 2001;19(4):369-386.
Cilostazol (Pletal[reg]), a quinolinone derivative, has been approved in
the U.S. for the treatment
of symptoms of intermittent claudication (IC) since 1999 and for related
indications since 1988 in
Japan and other Asian countries. The vasodilatory and antiplatelet actions
of cilostazol are due
mainly to the inhibition of phosphodiesterase 3 (PDE3) and subsequent elevation
of intracellular
cAMP levels. Recent preclinical studies have demonstrated that cilostazol
also possesses the
ability to inhibit adenosine uptake, a property that may distinguish it
from other PDE3 inhibitors,
such as milrinone. Elevation of interstitial and circulating adenosine
levels by cilostazol has been
found to potentiate the cAMP-elevating effect of PDE3 inhibition in platelets
and smooth muscle,
thereby augmenting antiplatelet and vasodilatory effects of the drug. In
contrast, elevation of
interstitial adenosine by cilostazol in the heart has been shown to reduce
increases in cAMP
caused by the PDE3-inhibitory action of cilostazol, thus attenuating the
cardiotonic effects.
Cilostazol has also been reported to inhibit smooth muscle cell proliferation
in vitro and has been
demonstrated in a clinical study to favorably alter plasma lipids: to decrease
triglyceride and to
increase HDL-cholesterol levels. One, or a combination of several of these
effects may contribute
to the clinical benefits and safety of this drug in IC and other disease
conditions secondary to
atherosclerosis. In eight double-blind randomized placebo-controlled trials,
cilostazol significantly
increased maximal walking distance, or absolute claudication distance on
a treadmill. In addition,
cilostazol improved quality of life indices as assessed by patient questionnaire.
One large
randomized, double-blinded, placebo-controlled, multicenter competitor
trial demonstrated the
superiority of cilostazol over pentoxifylline, the only other drug approved
for IC. Cilostazol has
been generally well-tolerated, with the most common adverse events being
headache, diarrhea,
abnormal stools and dizziness. Studies involving off-label use of cilostazol
for prevention of
coronary thrombosis/restenosis and stroke recurrence have also recently
been reported.
Pharmacotherapy
of intermittent claudication.
Reference: Expert Opin Pharmacother 2001;2(11):1725-36.
Intermittent claudication (IC) is leg muscle pain, cramping and fatigue
brought on by exercise and
is the primary symptom of peripheral arterial disease. The goals of pharmacotherapy
for IC are to
increase the walking capacity/quality of life and to decrease rates of
amputation. In 1988,
pentoxifylline was the only drug that had reasonable supportive clinical
trial evidence for being
beneficial in IC. Since then a number of drugs have shown benefit or potential
in IC. Cilostazol, a
specific inhibitor of phosphodiesterase 3 and activator of lipoprotein
lipase, clearly increases
pain-free and absolute walking distances in claudicants. However, cilostazol
does cause minor
side effects including headache, diarrhoea, loose stools and flatulence.
Naftidrofuryl, a serotonin
(5-HT(2)) receptor antagonist and antiplatelet drug, is beneficial in claudicants.
Inhibitors of
platelet aggregation (including nitric oxide from L -arginine or glyceryl
trinitrate) and
anticoagulants (low molecular weight heparin, defibrotide) probably have
both short and
long-term benefits in IC. In addition, intravenous infusions of prostaglandins
(PGs) PGE(1) and
PGI(2) have an established role in severe peripheral arterial disease and
the recent introduction of
longer lasting and/or oral forms of the PGs makes them more likely to be
useful in the IC
associated with less severe forms of the disease. There are some exciting
new approaches to the
treatment of IC, including propionyl-L-carnitine and basic fibroblast growth
factor (bFGF).
|
Volume
5, Number 3: March 2002
