New Mechanism of Action for
Cilostazol: Interplay Between Adenosine
and Cilostazol in Inhibiting Platelet Activation.
Reference: J Cardiovasc Pharmacol 2002;40(4):577-585.
Cilostazol, a potent phosphodiesterase 3 inhibitor and anti-thrombotic
agent, was recently shown
to inhibit adenosine uptake into cardiac myocytes and vascular cells. In
the present studies,
cilostazol inhibited [ H]-adenosine uptake in both platelets and erythrocytes
with a median
inhibitory concentration (IC ) of 7 &mgr; Next collagen-induced platelet
aggregation was studied
and it was found that adenosine (1 &mgr; ), having no effect by itself,
shifted the IC of cilostazol
from 2.66 &mgr; to 0.38 &mgr; (p < 0.01). This shifting was
due to an enhanced accumulation
of cAMP in platelets and was significantly larger than that by the combination
of adenosine and
milrinone, which has no effect on adenosine uptake. Similarly, cilostazol,
by blocking adenosine
uptake, enhanced the adenosine-mediated cAMP increase in Chinese hamster
ovary cells that
overexpress human A receptor. Furthermore, the inhibitory effect of cilostazol
on platelet
aggregation in whole blood was significantly reversed by ZM241385 (100
n ), an A adenosine
receptor antagonist, and by adenosine deaminase (2 U/ml). These data suggest
that the inhibitory
effects of cilostazol on adenosine uptake and phosphodiesterase 3 together
elevate intracellular
cAMP, resulting in greater inhibition of agonist-induced platelet activation
Debulking and stenting versus debulking
only of coronary artery disease in
patients treated with cilostazol (final results of ESPRIT).
Reference: Am J Cardiol 2002;90(6):573.
Stenting inhibits vascular constrictive remodeling after directional coronary
atherectomy (DCA).
Cilostazol has been reported to control neointimal proliferation after
stenting. This study's aim
was to examine the effect of debulking and stenting with antirestenotic
medication on restenosis.
After optimal DCA, 117 lesions were randomly assigned to either the DCA
with stent
(DCA-stent) (58 lesions) group or the DCA only (59 lesions) group. Multilink
stents were
implanted in the DCA-stent group. Cilostazol (200 mg/day) without aspirin
was administered to
both groups for 6 months. Ticlopidine (200 mg/day) was given to the DCA-stent
group for 1
month. Serial quantitative angiography and intravascular ultrasound (IVUS)
were performed at
the time of the procedure and at 6-month follow-up. The primary end point
was 6-month
angiographic restenosis. Clinical event rates at 1 year were also assessed.
Baseline characteristics
were similar. All procedures were successful. No adverse effects to cilostazol
were observed.
Postprocedural lumen diameter was significantly larger (3.27 vs 2.92 mm;
p <0.0001) in the
DCA-stent group. However, the follow-up lumen diameter was not significantly
different (2.53 vs
2.41 mm, DCA-stent vs DCA). IVUS revealed that intimal proliferation was
significantly larger in
the DCA-stent group (4.2 vs 1.5 mm(2); p <0.0001), which accounted for
the similar follow-up
lumen area (6.5 vs 7.1 mm(2)). The restenosis rate was low in both groups
(5.4% vs 8.9%), and
the difference was not significant. Clinical event rates at 1 year were
also not significantly
different. These results suggest that optimal lesion debulking by DCA does
not always need
adjunctive stenting if cilostazol is administered.
Amino
acid dysbalance in liver failure is favourably influenced by
recirculating albumin dialysis (MARS).
Reference: Liver 2002;22(S2):35-39.
INTRODUCTION: Dysbalance between branched chain (BCAA) and aromatic amino
acids
(AAA), which can be quantified by a low Fischer's Index (SigmaBCAA/SigmaAAA),
as well as
elevated levels of free tryptophan in plasma are common in hepatic failure
and may contribute to
the development of hepatic encephalopathy. AIM: To evaluate the influence
of a new
extracorporeal detoxification system for liver failure (Molecular Adsorbents
Recirculating System,
MARS(R), i.e. dialysis against a recirculating albumin solution cleaned
online by charcoal and an
anion exchange resin) on plasma tryptophan and Fischer's Index. METHODS:
Plasma samples
were taken before, during and after MARS treatments (n = 11, mean blood
flow 135 ml/min,
mean dialysate flow 120 ml/min, high flux polysulfone membrane). Simultaneous
to blood
sampling, aliquots of the albumin dialysate were taken between the elements
of the dialysate
circuit. RESULTS: Fischer's Index in systemic blood increased during MARS
by 24% (from
1.44 to 1.79, P < 0.001; mean treatment duration, 5.5 h). Systemic tryptophan
level was
significantly reduced at the same time (-25%, n = 8). Amino acid removal
rates from plasma
during a single dialyser passage ranged from 10 to 53%. In particular,
AAA were preferentially
removed (42-44% throughout treatment), while BCAA removal was 28-46% initially
and later
declined to 24-28%. A maximum concentration gradient between plasma and
dialysate was
maintained for the AAA throughout treatment through their apparently complete
removal by the
charcoal adsorber. Conversely, BCAA removal at both adsorbers was only
minor. As a result,
Fischer's Index showed a significant increase in the processed plasma,
which became even more
pronounced with increasing treatment duration. CONCLUSIONS: MARS enables
an elevation
of a pathologically decreased Fischer's Index as well as a reduction of
systemic tryptophan levels
in patients with liver failure. The effects of MARS on plasma amino acid
dysbalance may
contribute to an improvement of hepatic encephalopathy.
Evidence-based symptom relief of intermittent claudication: efficacy
and safety of cilostazol
Reference: Diabetes Obes Metab 2002;4(S2):S20-5.
Intermittent claudication (IC) is a common, debilitating symptom of atherosclerotic
peripheral
arterial disease. There are two therapeutic objectives in patients with
IC: relief of symptoms and
secondary prevention of acute thrombotic complications. Among patients
with Fontaine stage II
disease, surgical revascularization for symptom relief is reserved for
those in whom
exercise/lifestyle modification and medical therapy has failed. To improve
exercise tolerance in IC
requires favourable alteration in the oxygen supply/demand relationship
in the lower limb.
Following the largest ever clinical trials programme in patients with IC,
cilostazol, a
phosophodiesterase III inhibitor, has been licensed for symptom relief
in the UK. In double-blind,
randomized, placebo-controlled trials involving over 2000 patients, cilostazol
100 mg b.d.
produced significant and sustained improvements in pain-free and maximal
walking distances as
well as improved subjective assessments of quality of life. In particular,
comparative studies with
pentoxifylline (oxpentifylline) showed that cilostazol had significantly
greater effects on functional
outcome and exhibited good patient tolerance.
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Volume
5, Number 10: October 2002
