(Circulation. 1999;100:1175-1181.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Pharmacokinetics and Pharmacodynamic Effects of a New Antibody Glycoprotein IIb/IIIa Inhibitor (YM337) in Healthy Subjects
From the Institute of Clinical Pharmacology, University Hospital, Frankfurt am Main (S.H., J.-W.B.); the Deutsche Klinik für Diagnostik, Wiesbaden (C.M.K., D.W.); and the International Institute of Thrombosis and Vascular Diseases, Frankfurt am Main (H.J.K., H.K.B.), Germany.
Correspondence to Dr med Sebastian Harder, Institute of Clinical Pharmacology, University Hospital, Theodor Stern Kai 7, D-60590 Frankfurt am Main, Germany. E-mail harder{at}em.uni-frankfurt.de
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Abstract |
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Background—This study describes the first administration of YM337, the Fab fragment of a humanized monoclonal antibody against the fibrinogen GP IIb/IIIa receptor, in healthy male humans.
Methods and Results—Platelet aggregation (20 µmol/L
ADP), platelet adhesion, fibrinogen binding, bleeding time, and
YM337 concentrations in plasma were studied in substudy 1 after single
boluses of 0.025, 0.05, 0.1, 0.2, and 0.4 mg/kg YM337 and in substudy 2
after a bolus (0.35 mg/kg) plus 6 hours of infusion at different dose
levels of YM337 (0.5, 0.75, 1.0, 1.5 µg ·
kg-1 · min-1), with abciximab as
reference drug (n=5 or 6 subjects per group). After the 0.2-mg/kg and
0.4-mg/kg boluses, fibrinogen binding was reduced by >80% and
bleeding time was prolonged to 
60 minutes. Bolus followed by
infusion of 1.0 and 1.5 µg · kg-1 ·
min-1 YM337 maintained inhibition of platelet
aggregation >80%. Aggregation and bleeding time returned to normal
within 24 hours. A bolus of 0.25 mg/kg of abciximab followed by an
infusion of 0.125 µg · kg-1 ·
min-1 showed effects similar to those observed with the
0.5- and 0.75-µg · kg-1 ·
min-1 infusion of YM337. In 53 subjects exposed to YM337,
1 case of transient thrombocytopenia and 3 minor bleeding events
occurred. No human anti-chimeric antibodies were detected 2 weeks and 2
months after administration.
Conclusions—YM337 effectively inhibits IIb/IIIa-mediated platelet aggregation and adhesion in humans. The results of this phase 1 study will give rise to further clinical evaluation of YM337.
Key Words: platelets • antibodies • glycoproteins • YM337 • abciximab
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Glycoprotein (GP) IIb/IIIa receptor antagonists prevent thrombotic occlusions in patients with acute coronary syndromes and reduce complications associated with high-risk percutaneous transluminal coronary angioplasty (PTCA).1 2 3 4 5 The first GP IIb/IIIa receptor antagonist that has been shown to be effective in larger clinical trials is the modified human-mouse chimeric monoclonal antibody (mAb) abciximab.6 YM337 is the Fab fragment of a humanized antibody against the fibrinogen receptor with only minor (compared with abciximab) affinity to the
Vß3
receptor.7 To minimize immunological responses, the murine
antibody C4G1 was humanized by grafting only the mouse
hypervariable regions onto a human IgG1 framework.7
Preclinical in vitro assessment of inhibitory effects on
platelet function parameters shows a 2- to 4-fold
stronger potency of YM337 compared with abciximab.7
Binding of fibrinogen to purified IIb/IIIa was inhibited by both agents
with similar potency.7 8 Platelet aggregation
investigated in rhesus monkeys was rapidly restored to 50% within 6
hours after a 0.5-mg/kg bolus of YM337, whereas after similar doses of
abciximab, aggregation remained inhibited over 12 to 18
hours.9 Furthermore, bleeding time was found to be less
prolonged than seen with abciximab.9 The time course of
receptor occupancy with abciximab was more sustained than with
YM337.9 From these preclinical data, a higher potency of
YM337 in regard to platelet inhibition but a faster offset of
effects after commencement of treatment would be expected. The aims of
the phase 1 study presented here were (1) to evaluate the
safety and tolerability of YM337 in healthy male volunteers as a single
intravenous injection (substudy 1) or when given as a
single bolus followed by a 6-hour infusion (substudy 2) and (2) to
characterize the pharmacodynamic profile and the dose-response
relationship of YM337 in humans. |
Methods |
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Study Design
In substudy 1, each of 6 subjects received a single bolus of either 0.025, 0.05, 0.1, 0.2, or 0.4 mg/kg YM337 IV; 3 volunteers received placebo. The study started with the lowest dose level. It was intended to establish the dose that inhibited 20 µmol/L ADP–induced platelet aggregation by 80%, comparable to inhibition obtained after abciximab standard doses.10
In substudy 2, a bolus of YM337 (0.35 mg/kg IV) was followed by a 6-hour infusion at 4 different dose levels. Five or 6 subjects received either 0.5, 0.75, 1.0, or 1.5 µg · kg-1 · min-1 YM337. Six other subjects received abciximab as a bolus of 0.25 µg/kg IV followed by an infusion of 0.125 µg · kg-1 · min-1, and 6 subjects received placebo.
Subject Selection and Study Protocol
Both substudies were approved by the local Institutional Review
Board, and study subjects gave their written informed consent. Subjects
in both substudies (n=68) had a mean age of 28 years, a mean weight of
76 kg, and a mean height of 175 cm. All volunteers had normal findings
in the physical and laboratory examinations and normal platelet
counts (150x103 to
400x103/µL).
Investigations
Ex Vivo Platelet Aggregation
Samples were collected for platelet aggregation in substudy
1 at 0, 0.25, 1, 6, and 24 hours and in substudy 2 at 0, 0.25, 1, 2, 6,
8, 10, 24, and 48 hours. Platelet aggregation induced by 20
µmol/L ADP was studied in platelet-rich plasma (PRP) with a
turbidimetric light-transmittance device (APACT, Labor).
Fibrinogen Binding
Samples were collected for fibrinogen binding in substudy 1 at
0, 0.25, 1, 6, and 24 hours and in substudy 2 at 0, 0.25, 1, 2, 6, 8,
10, 24, and 48 hours. Samples were drawn into a tube containing 3.8%
sodium citrate, and PRP was prepared. Platelets were counted by a
cell counter, and PRP was diluted with platelet-poor plasma (PPP)
to 250 000 platelets/µL. ADP was added at a final concentration
of 100 µmol/L, and the samples were incubated for 10 minutes.
Platelets were fixed with formaldehyde at a final concentration of
0.5%. After washing and resuspension, samples were incubated with
fluorescein (FITC)–conjugated anti-human fibrinogen
chicken antibodies (Biopool AB) for 30 minutes. Labeled platelets
in PRP were analyzed by FACScan cytometer (Becton Dickinson).
Aquisition and processing of data from 10 000 platelets were
carried out with Lysis-II software. The mean fluorescence
intensity values of the predose probes were set to
100%.11
Platelet Adhesion
Inhibition of platelet adhesion in PRP was assessed in
substudy 1 at 0, 0.25, 1, 6, and 24 hours and in substudy 2 at 0, 0.25,
1, 2, 6, 8, 10, 24, and 48 hours. A Buerker counting chamber
(siliconized glass) was filled with PRP. After 10 minutes of
incubation, the coverslip was removed and the counting chamber was
rinsed, and adhering platelets were fixed with
glutaraldehyde and counted microscopically. Results are
given as adhesion index, ie, count in 1
mm2x100/platelet count in PRP/µL (normal
values 0.7 to 2.0).12
Platelet-Induced Thrombin Generation Time
Platelet-induced thrombin generation time (PITT) registers
aggregation and coagulation of PRP in the presence of low
concentrations (0.5 µg/mL) of hirudin. Samples were collected in
substudy 1 at 0, 0.25, 1, 6, and 24 hours and in substudy 2 at 0, 0.25,
1, 2, 6, 8, 10, 24, and 48 hours. The test was performed with a
turbidimetric light-transmittance device (Universal Aggregometer, B.
Braun), and the clotting times after stimulation of the platelets
by the rotating surface of the cuvette are given (normal values 7 to 12
minutes).13
Bleeding Time
Bleeding time was determined in substudy 1 at 0, 0.25, 1, 6, and
24 hours and in substudy 2 at 0, 0.25, 1, 2, 6, 8, 10, 24, and 48
hours. A cuff was placed around the arm and inflated to maintain a
pressure of 40 mm Hg. Incision was made by a Simplate R device
(Organon Inc). Blood was removed by a swab every 15 seconds, and
the time until bleeding stopped was recorded up to 90 minutes.
Drug-Specific Antibodies
Plasma samples obtained before and 2 weeks and 2 months after
exposure to the study drugs were tested on human anti-chimeric
antibodies (HACAs). Determination of HACAs based on an enzyme
immunoassay in which sera from YM337-, abciximab-, and placebo-treated
subjects were incubated against YM337, abciximab, and normal human Fab
molecules bound to microtiter plates. Blood samples were initially
tested at dilutions of 1:10 down to 1:270. Depending on the optical
density, samples were diluted further. Postdose samples were
potentially scored seropositive for YM337 or abciximab when the optical
density exceeded 0.4 and revealed an optical density twice that of the
corresponding predose sample.
Pharmacokinetics
Concentrations of YM337 were determined in PRP and in PPP by an
ELISA method.14 Platelets in PRP were lysed, and the
samples were kept frozen at -70°C until analysis. The
lower limit of quantification was 100 ng/mL in PRP and 50 ng/mL in PPP.
Linearity of the method was proven up to 8000 ng/mL after appropriate
dilution. Pharmacokinetic data were obtained in substudy 1 before
treatment and 5, 10, 15, and 30 minutes after the injection and after
1, 2, 3, 5, 8, and 24 hours. In substudy 2, blood was sampled before
treatment and 0.25, 1, 2, 4, 6, 8, 10, 24, and 48 hours after start of
the infusion.
Statistical Evaluation
Results are presented as mean±SD. In substudy 1, the
0.25- and 24-hour target parameters were compared with
their baseline value by use of Wilcoxon's matched-pairs
signed-rank test. In substudy 2, the 6- and 24-hour values were
compared with the results of the placebo group and the group receiving
abciximab by the Mann-Whitney U test.
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Results |
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Tolerability
A total of 53 subjects were exposed to YM337. Three minor bleeding events occurred (renewed bleeding from incision of a previous bleeding time assessment). In 1 subject receiving infusion of 0.75 µg · kg-1 · min-1 YM337, platelet count in whole blood dropped from 209x103/µL before treatment to 143x103/µL after 15 minutes, 98x103/µL after 6 hours, and a nadir of 60x103/µL after 48 hours; full recovery was attained after 96 hours. Prestudy and poststudy examinations did not reveal signs of inherent platelet dysfunction. In all other subjects, no changes in platelet count during and after administration exceeding ±15% of the pretreatment values were observed.
Human Anti-chimeric Antibodies
Of the predose samples, 35% responded to human Fab fragments as
well as to YM337 and abciximab, indicating the presence of nonspecific
antibodies against Fab fragments. This anti-Fab response was stable
over time and did not vary on administration of placebo, YM337, or
abciximab, as was demonstrated by the optical density values obtained
with the postdose samples 2 weeks and 2 months after the drug
administration. None of the treated subjects revealed a specific HACA
response against either YM337 or abciximab.
Pharmacokinetics
After the dose of 0.1 mg/kg, YM337 was detectable only in small
amounts in PPP over 20 minutes after the bolus was given (Figure 1
, top). If one considers the difference
PRP-PPP as the drug concentration at the platelets, Figure 1
might be read as follows: After the 0.1-mg/kg bolus, YM337 is
rapidly bound to platelets, and no drug appears as free drug in
PPP. After the 0.2-mg/kg and the 0.4-mg/kg boluses, "excess"
amounts of YM337 not bound at the platelets appear in PPP but are
rapidly cleared after 4 hours (Table 2). The bottom of Figure 1
shows the PRP and PPP concentrations after the different
infusion regimens. The initial drug concentrations were determined by
the bolus dose, but PPP concentrations rose dose-dependently and fell
immediately when the infusion was stopped. The PRP concentrations
showed a less dose-dependent behavior, and at the end of the infusion,
PRP concentrations varied between 2188 ng/mL (0.5 µg ·
kg-1 · min-1) and
3148 ng/mL (1.5 µg · kg-1 ·
min-1). After 24 hours, no drug was detectable
in PPP, and PRP concentrations after the different infusion regimens
were of a similar magnitude of 1300 ng/mL (Table 2).
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0.1 mg/kg, • 0.2 mg/kg, 
0.4 mg/kg).
Bottom, Bolus 0.35 mg/kg, followed by an infusion (
1.5 µg
· kg-1 · min-1).
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Pharmacodynamics
Substudy 1
In general, no effect was seen after 0.025-µg/kg and
0.05-µg/kg IV bolus doses of YM337 (data not shown). Maximal
inhibition of 20 µmol/L ADP–induced platelet aggregation
averaged 94% after the 0.4-µg/kg bolus dose (Table 1, Figure 2). Pretreatment values for the
platelet adhesion index varied between 1.1 and 1.48; after 0.25
hours, the adhesion index was reduced to 0.001 after the 0.4-µg/kg
bolus. Fibrinogen binding was maximally reduced to 53% after the
0.1-µg/kg bolus, 33% after the 0.2-µg/kg bolus, and 25% after the
0.4-µg/kg bolus. Bleeding time was prolonged to 62 minutes after the
0.4-µg/kg bolus. After 24 hours, fibrinogen binding returned to 65%
to 100% (Table 1, Figure 2).
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). Top, Inhibition of ADP (20 µmol)–induced platelet
aggregation; middle, bleeding time; bottom, fibrinogen binding.
Substudy 2
Maximal inhibition of ADP-induced platelet aggregation was
obtained at 0.25 hours and averaged between 90% and 95% after the
various infusion regimens (Figure 3). At
the end of the 6-hour infusion period, inhibition was between 54% (0.5
µg · kg-1 ·
min-1) and 93% (1.5 µg ·
kg-1 · min-1).
Maximal inhibition immediately after the bolus abciximab was 77% and
37% after 6 hours of infusion. ADP-induced aggregation returned
to normal 24 hours after start of the infusion (Table 2
, Figure 4).
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bolus
dose of 0.25 µg/kg abciximab, infusion rate 0.125 µg ·
kg-1 · min-1) or placebo (
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After the initial bolus, bleeding time was maximally prolonged to >60
minutes with YM337 as well as after abciximab. At 6 hours,
YM337-induced prolongation of bleeding time increased dose-dependently
and averaged 18 minutes with 0.5 µg ·
kg-1 · min-1 up to
65 minutes with 1.5 µg · kg-1 ·
min-1. Eighteen hours after the end of the
infusion, bleeding times were normal or remained only slightly
prolonged (Table 2, Figure 4).
PITT values determined 6 hours after start of the infusion were
significantly prolonged with YM337 and abciximab, averages ranging
between 13 minutes (1.0 µg · kg-1
· min-1 YM337) and 21 minutes (0.75 µg
· kg-1 · min-1
YM337) (Table 2).
Fibrinogen binding was maximally reduced with YM337 to (average)
values between 20% and 30% 0.25 hour after the bolus was given
(Figure 3). At 6 hours, fibrinogen binding ranged between 20%
and 34% (Figure 4, Table 2). With abciximab, fibrinogen
binding was maximally reduced to 43% after 0.25 hour and averaged 50%
after 6 hours of infusion. Eighteen hours after the end of the 6-hour
infusion, binding remained significantly reduced to 50% with all
doses of YM337 as well as abciximab (Figure 3).
Relationships between the fibrinogen binding and corresponding values
of the 20 µmol/L ADP–induced platelet aggregation and
between the fibrinogen binding and bleeding times could be
characterized by curvilinear or asymptotic
monoexponential functions, in which fibrinogen binding
must be reduced to 30% to 40% to reach a 50% reduction in
platelet aggregation as well as a 2-fold increase in bleeding time
(Figure 5).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The principal findings from these phase 1 studies were that (1) both IIb/IIIa antagonists lead to a complete reduction of platelet aggregation and adhesion, markedly prolonged bleeding times, and inhibition of platelet-induced thrombin generation; (2) all these parameters returned to baseline 18 hours after termination of the infusion; and (3) thrombocytopenia is also possible with the new, humanized mAb YM337. It must be emphasized that these results are limited to the typical phase 1 setting: altogether, 53 healthy male subjects were exposed, and possible interactions with drugs administered in clinical situations (aspirin and heparin) could not be taken into consideration.
The IIb/IIIa receptor antagonist abciximab and the peptide or peptidomimetic IIb/IIIa receptor antagonists eptifibatide and tirofiban are used in PTCA and in acute coronary syndromes.1 2 3 4 5 Other drugs, eg, humanized antibodies and orally available RGD peptidomimetics, are in different stages of clinical development.7 15 16 The preclinical pharmacology of the humanized mAb YM337 shows similar IIb/IIIa receptor binding but a faster decline of effects compared with abciximab in animal experiments.9 In these first human studies, however, the pharmacodynamic profile of YM337 resembles that of abciximab with regard to magnitude and rate of recovery of platelet inhibition, and in contrast to animal data,9 bleeding time was prolonged to a similar magnitude. Thrombocytopenia, possibly related to immunogenic response mediated by anti-chimeric antibodies,17 is reported to occur in 2% to 4% of all patients treated with abciximab and other GP IIb/IIIa inhibitors.17 18 In our study, 1 of 53 subjects exposed to YM337 showed transient thrombocytopenia that started 15 minutes after start of the infusion. Data obtained in another phase 1 study with YM337 revealed 1 more case of thrombocytopenia in a subset of 34 exposed subjects (Yamanouchi Europe BV, Leiderdorp, Netherlands, data on file). A rough estimate therefore gives a 2% incidence of thrombocytopenia with YM337, comparable to that with abciximab.18 None of the subjects exhibited development of drug-specific anti-chimeric antibodies. From these first human data, however, differences in antigenicity between YM337 and abciximab could not be claimed.
The inhibitory effects of GP IIb/IIIa
inhibitors on ADP-induced aggregation and on fibrinogen
binding have been used as a surrogate for the clinical efficacy of
these drugs.19 20 Effects on platelet adhesion and
thrombin generation have been only inconsistently reported, and
the inhibitory effect on these parameters is
seen with both abciximab and YM337. The effects of IIb/IIIa
inhibitors on thrombin generation have been described
earlier.21 Although the inhibitory effect on
thrombin generation after specific IIb/IIIa blockade can be augmented
in vitro by a specific
Vß3
antagonist,21 our in vivo results did not show
differences in the PITT assay between abciximab (with similar affinity
to IIb/IIIa and Vß3
receptors) and YM337 (exhibiting a higher affinity to IIb/IIIa
receptors). The contribution of this anticoagulant effect to the
clinical efficacy remains unclear, but this finding may be important
when interactions with anticoagulants must be
considered.22 23
Because in substudy 1 no direct comparison with abciximab was planned,
the target was to obtain values that have been published for the
"standard" abciximab dosing scheme (meaning an inhibition of
20 µmol/L ADP–induced platelet aggregation >80%) with 
1
of the doses of YM337 tested.10 19 By extrapolation of the
data obtained from substudy 1, this criterion led to the selection of a
bolus dose of 0.35 mg/kg in substudy 2. In this study, it was intended
to maintain the level of 80% reduction in ADP-induced aggregation and
fibrinogen binding over the infusion period. Although both YM337 and
abciximab decreased 20 µmol/L ADP–induced aggregation shortly
after the bolus by 80%, the standard bolus of abciximab decreased
fibrinogen binding by only 55% (in contrast to 80% with YM337),
whereas published data on abciximab show that this dose should block
IIb/IIIa receptors by 80%.10 19 The discrepancy between
our results on fibrinogen binding and reports on receptor occupancy of
abciximab could not yet be explained. It might be noteworthy that the
receptor binding assay used in the above-cited studies determines the
amount of free abciximab binding sites by competition of receptor-bound
abciximab with 125I-labeled
abciximab,10 20 whereas the fibrinogen binding assay
determines the amount of free IIb/IIIa binding sites by competition of
mAb bound at IIb/IIIa receptors with the natural ligand
fibrinogen,11 24 pointing to differences in the tightness
of IIb/IIIa binding of the 2 mAbs in the presence of fibrinogen.
Despite the observation that fibrinogen binding 6 hours after start of
the infusion was not different in the 4 dosing groups, a dose-dependent
increase in the inhibition of ADP-induced aggregation and in bleeding
time was seen (Figures 3 and 4). If the PPP and PRP
concentrations are taken into consideration, this finding might be
explained by the following model: PPP concentrations showed a
dose-dependent increase, but the amount bound to platelets (the
difference between PRP and PPP from Table 2) was quite similar
with all infusion regimens, suggesting a saturation of IIb/IIIa binding
sites in the unactivated state. Aggregation is induced in PRP,
where free YM337 (the PPP level) is also present and therefore
perhaps capable of interfering with platelets during the activation
process. This also applies to the bleeding time, in which the in vivo
activation of platelets by the dermal incision is countered by free
YM337. One further interesting observation in both studies was that
antiplatelet effects and bleeding time were rapidly declining
despite relatively high concentrations of YM337 in PRP after 24 hours.
One explanation is that after short-term exposure with a IIb/IIIa
antagonist (eg, after a bolus), receptors show up at the
platelet surface (perhaps as a consequence of outside-in
signaling), but in the absence of free drug levels, these new receptors
are not inhibited. Supposing an "early" rearrangement of IIb/IIIa
receptors after the bolus,25 a subsequent infusion might
therefore be necessary to interfere with the new receptors, leading to
the preservation of 50% reduction in fibrinogen binding even 18
hours after termination of the infusion, as seen in our study and by
others.20 21 However, a steep and curvilinear relationship
between fibrinogen binding and aggregation exists, as well as between
fibrinogen binding and bleeding time, and fibrinogen binding must be
decreased by 50% to obtain a significant effect on these
parameters (Figure 5). Nevertheless, because the
curve describing the relationship between receptor binding and
inhibition of functional parameters is very steep, even a
small increase in unblocked receptors (also augmented by generation of
new platelets within 24 hours) in the range >50% fibrinogen
binding is followed by a marked restoration of aggregation properties
and bleeding time, which is the final cause for the rapid decline of
inhibitory effects on platelet function after cessation
of the infusion.
In conclusion, the new humanized mAb YM337 effectively inhibits IIb/IIIa-mediated platelet aggregation in humans. A bolus of 0.25 mg/kg abciximab IV followed by an infusion of 0.125 µg · kg-1 · min-1 showed effects similar to those observed with the 0.5- and 0.75-µg · kg-1 · min-1 infusions of YM337. In a total of 53 subjects exposed to YM337, 1 case of transient thrombocytopenia occurred, and no HACAs were detected 2 weeks and 2 months after administration. The results of this phase 1 study will give rise to further evaluation of YM337 in which the comparative clinical profile of abciximab has to be established.
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Acknowledgments |
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This work was sponsored by Yamanouchi Europe BV. The valuable contributions of Dr T. Tan (Yamanouchi Europe BV) are appreciated.
Received March 26, 1999; revision received June 7, 1999; accepted June 14, 1999.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Califf RM. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med. 1994;330:956–961.
2. Simoons ML. Randomized placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet. 1997;349:1429–1435.[Medline] [Order article via Infotrieve]
3. Tcheng JE, for the IMPACT II investigators. Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Lancet. 1997;349:1422–1428.[Medline] [Order article via Infotrieve]
4. The EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet. 1998;352:87–92.[Medline] [Order article via Infotrieve]
5.
Platelet Receptor Inhibition in Ischemic
Syndrome Management in Patients Limited by Unstable Signs and Symptoms
(PRISM-PLUS) Study Investigators. Inhibition of the platelet
glycoprotein IIb/IIIa receptor with tirofiban in unstable
angina and non-Q-wave myocardial infarction. N Engl J
Med. 1998;338:1488–1497.
6. Coller BS. Platelet GPIIb/IIIa antagonists: the first anti-integrin receptor therapeutics. J Clin Invest. 1997;100(suppl 11):S57–S60.
7. Kaku S, Yano S, Kawasaki T, Sakai Y, Suzuki K, Kawamura K, Masuho Y, Satoh N, Takenaka T, Landolfi NF, Co MS. Comparison of the antiplatelet agent potential of the whole molecule, F(ab)2 and Fab fragments of humanized anti-GPIIb/IIIa monoclonal antibody in monkeys. Gen Pharmacol. 1996;27:435–439.[Medline] [Order article via Infotrieve]
8. Kaku S, Kawasaki T, Hisamichi N, Sakai Y, Taniuchi Y, Inagaki O, Yano S, Suzuki K, Terazaki C, Masuho Y, Satoh N, Takenaka T, Yanagi K, Ohshima N. Antiplatelet and antithrombotic effects of YM337, the Fab fragment of a humanized anti-GPIIb/IIIa monoclonal antibody in monkeys. Thromb Haemost. 1996;75:679–684.[Medline] [Order article via Infotrieve]
9. Suzuki K, Sakai Y, Hisamichi N, Taniuchi Y, Sato K, Terazaki C, Kaku S, Kawasaki T, Jano S, Inagaki O, Masuho Y. Comparison of the antiplatelet effect of YM337 and abciximab in rhesus monkeys. Eur J Pharmacol. 1997;336:169–176.[Medline] [Order article via Infotrieve]
10.
Tcheng JE, Ellis SG, George BS, Kereiakes DJ, Kleiman
NS, Talley JD, Wang AL, Weisman HF, Califf RM, Topol EJ.
Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin
antiplatelet antibody FAB 7E3 in high-risk coronary
angioplasty. Circulation. 1994;90:1757–1764.
11. Faraday N, Goldschmidt-Clermont P, Dise K, Bray PF. Quantitation of soluble fibrinogen binding to platelets by fluorescence-activated flow cytometry. J Lab Clin Med. 1994;123:728–740.[Medline] [Order article via Infotrieve]
12. Bizzaro N. EDTA-dependent pseudothrombocytopenia: a clinical and epidemiological study of 112 cases, with 10-year follow-up. Am J Hematol. 1995;50:103–109.[Medline] [Order article via Infotrieve]
13. Basic-Micic M, Roman C, Herpel U, Kling E, Scholz B, Breddin HK. Platelet-induced thrombin generation time: a new sensitive global assay for platelet function and coagulation. Haemostasis. 1992;22:309–321.[Medline] [Order article via Infotrieve]
14. Kaku S, Kawasaki T, Sakai Y, Taniuchi Y, Yano S, Suzuki K, Terazaki C, Kawamura K, Masuho Y, Satoh N, Takenaka T, Yanagi K, Oshima N. Antithrombotic effect of a humanized anti-GPIIb/IIIa monoclonal antibody, YM207, in a photochemically induced thrombosis model in monkeys. Eur J Pharmacol. 1995;279:115–121.[Medline] [Order article via Infotrieve]
15.
Mousa SA, DeGrado WF, Mu D, Kapil RP, Lucchesi BR,
Reilly TM. Oral antiplatelet, antithrombotic efficacy of DMP 728, a
novel platelet GP IIb/IIIa antagonist.
Circulation. 1996;93:537–543.
16.
Szalony JA, Haas NF, Salyers AK, Taite BB, Nicholson
NS, Mehrotra DV, Feigen LP. Extended inhibition of platelet
aggregation with the orally active platelet inhibitor
SC-54684A. Circulation. 1995;91:411–416.
17.
Berkowitz SD, Harrington RA, Rund MM, Tcheng JE. Acute
profound thrombocytopenia after c7E3Fab (abciximab) therapy.
Circulation. 1997;95:809–813.
18. Giugliano RP, Hyatt RR. Thrombocytopenia with GP IIb/IIIa-inhibitors: a meta-analysis. J Am Coll Cardiol. 1998;31(suppl):185A. Abstract.
19.
Mascelli MA, Worley S, Veriabo NJ, Lance ET, Mack S,
Schaible T, Weisman HF, Jordan RE. Rapid assessment of platelet
function with a modified whole-blood aggregometer in
percutaneous transluminal coronary angioplasty
patients receiving anti–GP IIb/IIIa therapy. Circulation. 1997;96:3860–3866.
20. Harrington RA, Kleiman NS, Kottke-Marchant K, Lincoff AM, Tcheng JE, Sigmon KN, Joseph D, Rios G, Trainor K, Rose D. Immediate and reversible platelet inhibition after intravenous administration of a peptide glycoprotein IIb/IIIa inhibitor during percutaneous coronary intervention. Am J Cardiol. 1995;76:1222–1227.[Medline] [Order article via Infotrieve]
21. Reverter JC, Beguin S, Kessels H, Kumar R, Hemker HC, Coller BS. Inhibition of platelet-mediated, tissue factor induced thrombin generation by the mouse/human chimeric 7E3 antibody: potential implications for the effect of c7E3Fab treatment on acute thrombosis and "clinical restenosis." J Clin Invest. 1996;98:863–874.[Medline] [Order article via Infotrieve]
22.
Ammar T, Scudder LE, Coller BS. In vitro effects of the
platelet glycoprotein IIb/IIIa receptor
antagonist c7E3 Fab on the activated clotting time.
Circulation. 1997;95:614–617.
23.
Frederick LG, Suleymanov OD, King LW, Salyers AK,
Nicholson NS, Feigen LP. The protective dose of the potent GP IIb/IIIa
antagonist SC-54701A is reduced when used in combination
with aspirin and heparin in a canine model of coronary artery
thrombosis. Circulation. 1996;93:129–134.
24. Liu CZ, Wang YW, Shen MC, Huang TF. Analysis of human platelet glycoprotein IIb-IIIa by fluorescein isothiocyanate-conjugated disintegrins with flow cytometry. Thromb Haemost. 1994;72:919–925.[Medline] [Order article via Infotrieve]
25. Kleiman NS, Raizner AE, Jordan R, Wang AL, Norton D, Mace KF, Joshi A, Coller BS, Weisman HF. Differential inhibition of platelet aggregation induced by adenosine diphosphate or a thrombin receptor-activating peptide in patients treated with bolus chimeric 7E3 Fab: implications for inhibition of the internal pool of GPIIb/IIIa receptors. J Am Coll Cardiol. 1995;26:1665–1671.[Abstract]
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