Method for the quantitative analysis of
cilostazol and its metabolites in
human plasma using LC/MS/MS.
Reference: J Phar Biomed Anal 2001;26(4):637-50.
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.
Differential effects of cilostazol and pentoxifylline on vascular endothelial
growth factor in patients with intermittent claudication.
Reference: Clin Sci 2001;101(3):305-11.
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.
Cilostazol for prevention of thrombosis and restenosis after intracoronary
stenting
Reference: Ann Pharmacother 2001;35(9):1108-13.
OBJECTIVE: To evaluate the potential use of cilostazol in intracoronary
stenting. DATA
SOURCES: Clinical literature was accessed through MEDLINE (1966-March 2001).
Key
search terms included cilostazol, intracoronary stenting, and coronary
angioplasty. Abstracts of
clinical trials presented at major cardiology professional association
meetings were also reviewed.
DATA SYNTHESIS: Intracoronary stent placement represents the fastest growing
medical
device implant. Complications of stent implantation include acute and subacute
vessel closure, as
well as late restenosis. Currently, antiplatelet agents are used for preventive
therapy. Cilostazol is
a vasodilating antiplatelet agent that reversibly inhibits platelet aggregation
induced by many
factors. In seven randomized trials comparing cilostazol with either aspirin
or ticlopidine,
cilostazol was found to be superior to aspirin and equivalent to ticlopidine
in decreasing both
cardiac events and rates of restenosis. In addition, cilostazol was found
to be well tolerated, with
no reports of adverse hematologic events. CONCLUSIONS: Although further
comparative trials
are required, cilostazol appears to be a safe and effective alternative
to clopidogrel and
glycoprotein IIb/IIIa receptor antagonists following intracoronary stent
implantation.
Peripheral arterial disease detection, awareness, and treatment in primary
care
Reference: JAMA 2001;286(11):1317-24.
CONTEXT: Peripheral arterial disease (PAD) is a manifestation of systemic
atherosclerosis that
is common and is associated with an increased risk of death and ischemic
events, yet may be
underdiagnosed in primary care practice. OBJECTIVE: To assess the feasibility
of detecting
PAD in primary care clinics, patient and physician awareness of PAD, and
intensity of risk factor
treatment and use of antiplatelet therapies in primary care clinics. DESIGN
AND SETTING: The
PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS)
program, a
multicenter, cross-sectional study conducted at 27 sites in 25 cities and
350 primary care
practices throughout the United States in June-October 1999. PATIENTS:
A total of 6979
patients aged 70 years or older or aged 50 through 69 years with history
of cigarette smoking or
diabetes were evaluated by history and by measurement of the ankle-brachial
index (ABI). PAD
was considered present if the ABI was 0.90 or less, if it was documented
in the medical record,
or if there was a history of limb revascularization. Cardiovascular disease
(CVD) was defined as
a history of atherosclerotic coronary, cerebral, or abdominal aortic aneurysmal
disease. MAIN
OUTCOME MEASURES: Frequency of detection of PAD; physician and patient
awareness of
PAD diagnosis; treatment intensity in PAD patients compared with treatment
of other forms of
CVD and with patients without clinical evidence of atherosclerosis. RESULTS:
PAD was
detected in 1865 patients (29%); 825 of these (44%) had PAD only, without
evidence of CVD.
Overall, 13% had PAD only, 16% had PAD and CVD, 24% had CVD only, and 47%
had
neither PAD nor CVD (the reference group). There were 457 patients (55%)
with newly
diagnosed PAD only and 366 (35%) with PAD and CVD who were newly diagnosed
during the
survey. Eighty-three percent of patients with prior PAD were aware of their
diagnosis, but only
49% of physicians were aware of this diagnosis. Among patients with PAD,
classic claudication
was distinctly uncommon (11%). Patients with PAD had similar atherosclerosis
risk factor
profiles compared with those who had CVD. Smoking behavior was more frequently
treated in
patients with new (53%) and prior PAD (51%) only than in those with CVD
only (35%; P
<.001). Hypertension was treated less frequently in new (84%) and prior
PAD (88%) only vs
CVD only (95%; P <.001) and hyperlipidemia was treated less frequently
in new (44%) and
prior PAD (56%) only vs CVD only (73%, P<.001). Antiplatelet medications
were prescribed
less often in patients with new (33%) and prior PAD (54%) only vs CVD only
(71%, P<.001).
Treatment intensity for diabetes and use of hormone replacement therapy
in women were similar
across all groups. CONCLUSIONS: Prevalence of PAD in primary care practices
is high, yet
physician awareness of the PAD diagnosis is relatively low. A simple ABI
measurement identified
a large number of patients with previously unrecognized PAD. Atherosclerosis
risk factors were
very prevalent in PAD patients, but these patients received less intensive
treatment for lipid
disorders and hypertension and were prescribed antiplatelet therapy less
frequently than were
patients with CVD. These results demonstrate that underdiagnosis of PAD
in primary care
practice may be a barrier to effective secondary prevention of the high
ischemic cardiovascular
risk associated with PAD.
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Volume
4, Number 10, October 2001
