Volume
3, Number 1: January 2000
Usefulness of cilostazol versus ticlopidine in coronary artery
stenting
Effect of beta-agonists on production of cytokines by activated T cells obtained from asthmatic patients and normal subjects.
Effects of a branched-chain amino acid-enriched diet on chronic hepatic
encephalopathy in dogs.
Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus
neuropathy.
Usefulness of cilostazol versus ticlopidine in coronary artery stenting.
Reference: Am J Cardiol. 1999 Dec 15;84(12):1375-80.
A combination of ticlopidine and aspirin has been accepted as the standard antithrombotic regimen after coronary stenting. However, ticlopidine poses serious side effects such as neutropenia or thrombocytopenia. Cilostazol, a cyclic adenosine monophosphate phosphodiesterase inhibitor, is a novel antiplatelet agent with vasodilatory properties. We compared the efficacy and safety of cilostazol plus aspirin (C+A) with ticlopidine plus aspirin (T+A) in elective coronary stenting. Three hundred patients were randomly assigned to receive C+A or T+A 2 days before stenting. The primary end point was a composite of angiographic stent thrombosis, or major cardiac events (death, myocardial infarction, bypass surgery, repeat intervention) at 30 days. The secondary end points were bleeding vascular complications, neutropenia, thrombocytopenia, or side effects requiring discontinuation of the drugs at 30 days. The primary end point was reached in 1.4% in the C+A group and 2.0% in the T+A group (p = 1.0). The rate of bleeding vascular complications was 1.4% in the C+A group and 2.0% in the T+A group (p = 1.0). The rate of drug-related side effects was not statistically different between the 2 groups but slightly higher in the T+A group than in the C+A group (2.7% vs 0.7%, p = 0.37). However, neutropenia was seen in 2 patients only in the T+A group. As a poststenting antithrombotic, C+A is as effective as T+A in preventing major cardiac events including stent thrombosis, and safer in that it does not cause neutropenia despite the fact that there is no statistical difference in the incidence of adverse effects and complications.
Compared with ticlopidine,
cilostazol has comparable effects in preventing major cardiac events including
angiographic stent thrombosis during the 30 days after elective coronary
stenting. Although there was no significant difference in the composite
frequency of adverse effects, neutropenia can be effectively avoided with use of
cilostazol. This trial is also significant in that the study population
represented nonselected patients with complex coronary lesions and the stents
included a variety of currently used stents, either tube or coil stents.
Aspirin acts by inactivating prostaglandin G/H synthase, resulting in a
permanent loss of the enzyme's cyclooxygenase activity, the first step in the
conversion of arachidonic acid to thromboxane A2. Ticlopidine is the
prototypic adenosine diphosphate (ADP) receptor antagonist that selectively
inhibits ADP-induced platelet aggregation with no direct effects on arachidonic
acid metabolism. Its mechanism of action is tied to inhibiting the platelet
2-methylthio-ADP-binding receptor. Inhibition of ADP-induced exposure of the
fibrinogen-binding site of the platelet glycoprotein IIb/IIIa receptor may be a
secondary mechanism of action.
Cilostazol is a cilostamide (2-oxoquinolone) derivative with a plasma half-life
of 10.5 ± 4.4 hours after oral administration. Cilostazol is a platelet
aggregation inhibitor and arterial vasodilator that has been used mainly for the
treatment of atherosclerotic peripheral artery obstructive disease. Cilostazol
inhibits type III phosphodiesterase activity in platelets and vascular smooth
muscle cells, thereby increasing intracellular levels of cyclic adenosine
monophosphate by blocking its hydrolysis. Increased cyclic adenosine
monophosphate concentration in platelets inhibits thromboxane A2
production and platelet aggregation by inhibiting phospholipase and
cyclooxygenase. Cilostazol inhibits both primary and secondary platelet
aggregation in response to ADP, collagen, epinephrine, and arachidonic acid. In
a small, double-blind crossover study, cilostazol was a better inhibitor of
thromboxane-stimulated platelet aggregation than either aspirin or ticlopidine.
Cilostazol is 10 to 30 times more potent than aspirin in inhibiting platelet
aggregation. Unlike aspirin, cilostazol does not inhibit synthesis of
prostaglandin I2, which has antithrombotic, antiplatelet, and
vasodilatory properties. Cilostazol also acts as an arterial vasodilator through
its relaxant effect on vascular smooth muscle cells. Arterial vasodilation
conceptually has a beneficial effect on elastic recoil after implantation of
stents. In addition, cilostazol inhibits replication and growth of rat vascular
smooth muscle cells in vitro, and favorably modifies plasma lipoproteins by
increasing high-density lipoprotein cholesterol, apolipoprotein A1, and reducing
triglycerides.
In the present study, randomization was performed before stenting. Patients
remained in the trial even if stenting results were suboptimal (2.0%). The only
exclusion criteria were the medical conditions that rendered patients unsuitable
for antiplatelet regimen. The stented lesions were complex as evidenced by the
fact that type B2 and C comprised 70%, and small vessel disease (<3.0 mm in
reference vessel diameter) comprised 42%. Although the definitions vary slightly
throughout each trial, the rate of major cardiac events in both the C+A (1.4%)
and T+A (2.0%) groups were low and similar to those of previously reported large
randomized trials using ticlopidine and aspirin after coronary stenting:
Intracoronary Stenting and Antithrombotic Regimen trial,1.6%, the Stent
Anticoagulation Restenosis Study (STARS), 0.6%, and the Full Anticoagulation
versus Aspirin and Ticlopidine (FANTASTIC) trial, 2.4%. The rate of stent
vessel thrombosis in ISAR (0.8%) and STARS (0.6%) was also similar to our data
in both the C+A (0.7%) and T+A (0.7%) groups. In the FANTASTIC trial, which is
the only large randomized trial including patients with suboptimal results, the
incidence of acute occlusion and subacute thrombosis was 2.4% and 0.4%,
respectively, which differs from our data: no acute occlusion and 0.7% subacute
thrombosis in each group. This difference can be explained by the starting time
of ticlopidine. In the FANTASTIC trial, ticlopidine was started after stenting,
but we started T+A or C+A 2 days before stenting. Ticlopidine needs at least 2
days to reach effective therapeutic concentrations in vivo. Cilostazol, however,
takes its maximum antiplatelet effect within 1 day. Previous studies using
cilostazol after coronary stenting revealed that major cardiac events and stent
thrombosis occurred in <1% of patients. In our trial, all subacute
stent thromboses occurred within the first week of the procedure irrespective of
the antithrombotic regimen. This implies that 2 weeks' treatment of either
antiplatelet combination may suffice to prevent stent thrombosis. Through
analysis of primary end points, we found 2 important observations. First,
combination of C+A is as effective as the current standard of T+A in preventing
stent thrombosis and major cardiac events after coronary stenting. Second, even
in patients with suboptimal results after stenting, although the number was
small, either C+A or T+A administered at least 2 days before stenting can
prevent acute occlusion effectively. Another finding is that Q-wave myocardial
infarction occurred in 40% of those who reached the primary end point, which is
evidence that the possible clinical outcomes of stent thrombosis remain severe.
Additionally our data demonstrated that benefit from combined antiplatelet
therapy of either C+A or T+A is not linked to a certain stent design or
material.
Bleeding and/or vascular complications were major concerns in the
anticoagulation era. In the present study they were infrequent and not different
between the C+A group (1.4%) and the T+A group (2.0%). This figure not only
confirms the low incidence of bleeding or vascular complications with the use of
antithrombotic agents, but also showed that the rate of complications does not
differ from that of the large randomized trials using ticlopidine and aspirin:
ISAR trial, 1.2%, STARS trial, 2.2%, FANTASTIC trial, 3.6%. Our data also
support previous studies using cilostazol, which reported no vascular
complications or major hemorrhages. Drug-related side effects, previously
defined, were not different between the C+A and T+A groups (0.7% vs 2.7%, p =
0.37). However, adverse effects occurred more frequently in the T+A group, and
an especially serious side effect, neutropenia, was observed in 2 patients
(1.3%) in only the T+A group. It resolved spontaneously without causing any
significant clinical events. Among the adverse effects of ticlopidine, skin
rashes, gastrointestinal discomfort, liver dysfunction, and neutropenia are the
most relevant. Although severe side effects are rare with a treatment duration
of 4 weeks, neutropenia is a matter of serious concern. In 2 large
population-based studies using ticlopidine, neutropenia occurred at a rate of
2.4%.Although 1-month use of ticlopidine incurred no serious adverse event due
to neutropenia in large stent trials, and the incidence of ticlopidine-induced
neutropenia peaked at 2 to 3 months in stroke prevention trials, it can occur as
early as 15 days after treatment, may not always be reversible, and in rare
cases may be fatal. One patient in the T+A group had a platelet count of
92,000/mm3 at day 30. Although it did not match our criteria of
thrombocytopenia, it attracted our attention because there are continuing
reports on thrombotic thrombocytopenic purpura after stenting and the use of
ticlopidine. However low the incidence of such adverse effects may be, these
severe conditions clearly underly the need for complete blood count monitoring
in routine clinical practice at least once within a month when using ticlopidine.
In contrast, there was no leukopenia, no neutropenia, and no thrombocytopenia in
the C+A group, suggesting no need for monitoring complete blood count during 30
days' follow-up. Large population-based studies using cilostazol uniformly
demonstrated that it was safe with no serious side effects such as neutropenia
or thrombocytopenia. Side effects requiring discontinuation of drugs were rare
in both the C+A and the T+A groups (0.7% vs 1.4%, p = 1.0) in this trial. Other
studies using cilostazol after stenting showed that there were few adverse
effects that forced patients to discontinue cilostazol. Among the adverse
effects of the C+A group were palpitation, headache, gastrointestinal
disturbances, or skin rashes, which are usually transient or tolerable.
Ticlopidine can lead to liver dysfunction because its activity is dependent on
hepatic biotransformation. Severe liver injury, albeit rarely, can occur. The
Canadian American Ticlopidine Study reported a 4.4% incidence of abnormal liver
function tests, causing 2.3% of the patients to discontinue therapy. We
performed 30-day follow-up liver function tests (not included in the original
protocol) in the latter 80 consecutive patients of each group. Two patients
(2.5%) in only the T+A group developed asymptomatic liver dysfunction, which
later normalized without treatment. This suggested that use of cilostazol can
avoid potential liver dysfunction associated with ticlopidine.
Effect of beta-agonists on production of cytokines by activated T cells obtained from asthmatic patients and normal subjects.
Reference: J Asthma. 1999 Oct;36(7):619-26.
Intracellular levels of cAMP were found to regulate T cell activity. We examined whether beta2-agonists altered cytokine production and
cyclic adenosine monophosphate (cAMP) accumulation in concanavalin A (ConA)-activated peripheral T cells from asthmatic patients.
Procaterol and isoproterenol weakly decreased the ConA-elicited interleukin (IL)-4 and IL-5 secretion; however, the inhibitory effect of
procaterol on the ConA-induced IL-2 secretion was inferior to that of isoproterenol in normal controls and was little in asthmatics. The
intracellular accumulation of cAMP by procaterol was not altered compared with that by isoproterenol. Results suggest that there is a
qualitative difference between procaterol- and isoproterenol-induced cAMP accumulation in T cells.
Effects of a branched-chain amino acid-enriched diet on chronic hepatic
encephalopathy in dogs.
Reference: Metab Brain Dis
1999;14(2):103-15.
A decreased ratio of branched-chain amino acids (BCAA) to aromatic amino acids (AAA) is considered an important pathogenetic factor in
hepatic encephalopathy (HE). A relationship between the deranged BCAA/AAA ratio and dopaminergic dysfunction through the formation
of "false" neurotransmitters has been postulated. The intermediate lobe of the pituitary is more pronounced in dogs than in humans and
because it is primarily under dopaminergic inhibitory influence, it may serve as an indicator of alterations in dopaminergic neurotransmission.
We investigated the effects of a diet with a high BCAA/AAA ratio (HR) and an isonitrogenous diet with a low BCAA/AAA ratio
(LR) on several physical and biochemical parameters including pituitary function in dogs with portocaval shunts and 40% hepatectomy and in
sham-operated pair-fed controls, in a double-blind, randomized cross-over study. Portocaval-shunted dogs had hyperammonemia (33+/-3
microM (mean +/- SEM) before and 214+/-21 after surgery)) and signs of HE. Their BCAA/AAA ratio in plasma and CSF
decreased from 4.3+/-0.3 and 2.3+/-0.3 before surgery to 1.3+/-0.1 and 0.5+/-0.1 after surgery, respectively. These parameters remained unaltered in the
control dogs. The consumption of the LR diet was significantly higher than consumption of the HR diet. In the
portocaval-shunted dogs, plasma ammonia concentration was higher on the HR diet than on the LR diet (344+/-52 v 246+/-45) and the HE grade was worse. The
BCAA/AAA ratio remained abnormal in HE dogs during the feeding of both diets. The basal and haloperidol-stimulated release of
alpha-melanotropin and cortisol in plasma were not significantly different between or within groups during any period. In contrast, urinary
cortisol excretion was increased in the HE dogs after surgery (urinary cortisol:creatinine ratio (x10(-6)) 8.5+/-1.4 before and 30.4+/-8.9
after surgery). The basal plasma concentration of adrenocorticotropin in HE dogs was decreased after surgery (68.3+/-10.2 ng/L before and
40.8+/-4.4 after surgery). This indicates a non-pituitary-dependent hyperresponsiveness of the adrenals. We conclude from these results that
chronic HE in dogs is not associated with an abnormal dopaminergic neurotransmission at least at the level of the pituitary, and that it is not
the content of the dietary neutral amino acids but rather the total protein intake that may have a beneficial effect on HE.
Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus
neuropathy.
Reference: Neurology
1999;53(9):2113-21.
OBJECTIVE: To determine whether microscopic vasculitis explains the clinical and pathologic features of diabetic lumbosacral
radiculoplexus neuropathy (DLSRPN).
BACKGROUND: DLSRPN is usually attributed to metabolic derangement or ischemic injury, but microscopic vasculitis as the sole cause needs consideration.
METHODS: We prospectively studied the clinical, laboratory, and EMG features as well as the pathology of distal cutaneous nerve biopsy specimens of patients with DLSRPN.
RESULTS: Study of DLSRPN nerve biopsy specimens (n = 33) compared with those from healthy controls (n = 14) and those with diabetic polyneuropathy (n = 21) provided strong evidence for ischemic injury (axonal degeneration, multifocal fiber loss, focal perineurial necrosis and thickening, injury neuroma, neovascularization, and swollen fibers with accumulated organelles), which we attribute to microscopic vasculitis (epineurial vascular and perivascular inflammation, vessel wall necrosis, and evidence of previous bleeding). Segmental demyelination was significantly associated with multifocal fiber loss.
CONCLUSIONS:
1) This severe, debilitating neuropathy begins with symptoms unilaterally and focally in the leg, thigh, or buttock and spreads to involve the other regions of the same and then opposite side and is due to multifocal involvement of lumbosacral roots, plexus, and peripheral nerve (i.e., diabetic lumbosacral radiculoplexus neuropathy).
2) Motor, sensory, and autonomic fibers are all involved.
3) Ischemic injury explains the clinical features and pathologic abnormalities of nerve.
4) The proximate cause of the ischemic injury appears to be microscopic vasculitis.
5) The segmental demyelination is probably secondary to ischemic axonal dystrophy, thus providing a unifying hypothesis for both axonal degeneration and segmental demyelination.
