Differential effects of cilostazol and
pentoxifylline on vascular endothelial
growth factor in patients with intermittent claudication.
Reference: Clin Sci 2001;101(3):305-311.
Cilostazol is a new phosphodiesterase inhibitor with anti-platelet and
vasodilatory properties.
Cilostazol and pentoxifylline are the only two drugs that have been approved
for the treatment of
patients with intermittent claudication. However, the mechanisms by which
exercise tolerance is
improved remain unclear. Vascular endothelial growth factor (VEGF) is a
potent endothelial
mitogen that results in angiogenesis when overexpressed in human subjects.
To assess the
potential role of VEGF in the improvement in exercise tolerance, we investigated
plasma levels of
VEGF in 50 patients with intermittent claudication who were allocated randomly
to groups
receiving cilostazol (n=17), pentoxifylline (n=17) or placebo (n=16). Patients
given either
cilostazol or pentoxifylline showed a significant improvements in maximal
walking distance
compared with the placebo group (34 m and 33 m respectively, compared with
5 m; both
P<0.05). Neither cilostazol nor pentoxifylline increased the ankle-brachial
index after treatment.
Circulating VEGF levels were increased (from 116+/-29 to 169+/-45 pg/ml;
P=0.002), and the
levels of VEGF were correlated significantly with exercise tolerance in
a positive direction
(r=0.88, P=0.004), in those patients treated with cilostazol that did not
have diabetes mellitus. In
contrast, VEGF levels remained stable after the administration of pentoxifylline.
These findings
suggest that VEGF may contribute to the cilostazol-related improvement
in exercise tolerance in
non-diabetic patients. However, pentoxifylline did not affect VEGF levels,
although a similar
improvement in maximal walking distance was achieved. Thus the mechanisms
involved in the
pentoxifylline-treated group were different from those in the cilostazol-treated
group, and require
further study.
Method for the quantitative analysis of cilostazol and its metabolites
in
human plasma using LC/MS/MS.
Reference: J Pharm Biomed Anal 2001;26(4):637-650
An LC/MS/MS method for the simultaneous determination of cilostazol, a
quinolinone derivative,
and three active metabolites, OPC-13015, OPC-13213, and OPC-13217, in human
plasma
was developed and validated. Cilostazol, its metabolites, and the internal
standard, OPC-3930
were extracted from human plasma by liquid-liquid partitioning followed
by solid-phase
extraction (SPE) on a Sep-Pak silica column. The eluent from the SPE column
was then
evaporated and the residue reconstituted in a mixture of methanol/ammonium
acetate buffer (pH
6.5) (2:8 v/v). The analytes in the reconstituted solution were resolved
using reversed-phase
chromatography on a Supelcosil LC-18-DB HPLC column by an 17.5-min gradient
elution.
Cilostazol, its metabolites, and the internal standard were detected by
tandem mass spectrometry
with a Turbo Ionspray interface in the positive ion mode. The method was
validated over a linear
range of 5.0-1200.0 ng/ml for all the analytes. This method was demonstrated
to be specific for
the analytes of interest with no interference from endogenous substances
in human plasma or from
several potential concomitant medications. For cilostazol and its metabolites,
the accuracy
(relative recovery) of this method was between 92.1 and 106.4%, and the
precision (%CV) was
between 4.6 and 6.5%. During the validation, standard curve correlation
coefficients equalled or
exceeded 0.999 for cilostazol and its metabolites. These data demonstrate
the reliability and
precision of the method. The method was successfully cross-validated with
an established HPLC
method.
Antiplatelet agent cilostazol potentiates adipocyte differentiation of
3T3-L1 cells.
Atherosclerosis 2001;158(1):19-22.
Cilostazol is an antiplatelet drug, which has beneficial effects in treatment
of intermittent
claudication and decreases serum triacyiglycerol level in these patients.
In this study, we
examined adipogenic potency of cilostazol using 3T3-L1 preadipocyte cell
line because cilostazol
is one of the tissue specific phosphodiesterase (PDE) inhibitors. Addition
of cilostazol into the
differentiation medium including insulin and dexamethasone, induced the
adipocyte differentiation
without isobutyl methylxanthine (IBMX). Compared with the cells incubated
with vehicle, the
cells treated with cilostazol contain much more lipid droplets in the cells
6 days after induction of
differentiation. Adipocyte specific gene like stearoyl-CoA desaturase was
strongly induced after
addition of cilostazol. C/EBPbeta, which is induced by IBMX was also induced
by cilostazol.
These findings suggest a possibility that adipogenic effect of cilostazol
is one of the mechanisms,
by which this agent decreases blood triacylglycerol level in the intermittent
claudication patients.
Inhibition of neointimal formation after
balloon injury by cilostazol, accompanied by improvement of endothelial
dysfunction and induction of hepatocyte growth factor in rat diabetes model.
Reference: Diabetologica 2001;44(8):1034-1042.
AIMS/HYPOTHESIS: Cilostazol, a well-known phosphodiesterase type 3 (PDE3)
inhibitor for
the treatment of peripheral arterial disease, has vasodilator properties
and an anti-proliferative
action on the growth of vascular smooth muscle cells. In this study, we
tested whether cilostazol
inhibits neointimal formation and improves endothelial dysfunction after
balloon injury in
non-diabetic and diabetic rats. METHODS: Cilostazol or vehicle was administered
to
non-diabetic and streptozotocin-induced diabetic rats from 7 days before
to 14 days after
balloon injury of the carotid artery. We focused on the expression of hepatocyte
growth factor to
explore how cilostazol improved endothelial dysfunction. Also, we studied
the effects of cilostazol
on hepatocyte growth factor production in in vitro experiments. RESULTS:
At 14 days after
injury, the ratio of neointimal to medial area was decreased in rats treated
with cilostazol in
non-diabetic and diabetic animals. The impaired response to acetylcholine
in balloon injured
vessels was improved by cilostazol in non-diabetic and diabetic rats (p
< 0.05). Vascular
hepatocyte growth factor concentration was decreased in injured vessels
of non-diabetic rats
compared to uninjured vessels. Moreover, hepatocyte growth factor was further
decreased in
injured vessels of diabetic rats as compared to those of non-diabetic rats
(p < 0.05). Of note,
administration of cilostazol attenuated the decrease in hepatocyte growth
factor concentration in
injured vessels of both non-diabetic and diabetic rats (p < 0.01). Increase
in vascular hepatocyte
growth factor by cilostazol was confirmed by in vitro experiments showing
that cilostazol
increased hepatocyte growth factor concentration in cultured human vascular
smooth muscle
cells, accompanied by cAMP accumulation. CONCLUSION/INTERPRETATION: Our
study
shows that the increase in vascular hepatocyte growth factor by cilostazol
could improve
abnormal growth of vascular smooth muscle cells and endothelial dysfunction
through rapid
regeneration of endothelial cells.
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Volume
4, Number 9: September 2001
