(Circulation. 1996;93:129-134.)
© 1996 American Heart Association, Inc.
Articles |
The Protective Dose of the Potent GPIIb/IIIa Antagonist SC-54701A Is Reduced When Used in Combination With Aspirin and Heparin in a Canine Model of Coronary Artery Thrombosis
From the Department of Cardiovascular Diseases Research, Searle, Skokie, Ill.
Correspondence to Leo G. Frederick, Searle, 4901 Searle Pkwy, Skokie, IL 60077.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Background Fibrinogen receptor antagonists block the fibrinogen-platelet interaction at the GPIIb/IIIa receptors and inhibit thrombus formation. SC-54701 is the active metabolite of SC-54684A, an orally active fibrinogen receptor antagonist. We compared the efficacy of SC-54701A (SCa, hydrochloride salt) with that of aspirin (ASA) or heparin and with combination therapy in a canine model of continuous current injury.
Methods and Results Sixty-six dogs were used (6 per
treatment). SCa (15-minute loading dose followed by [//] infusion
[µg/kg per minute]: (0.87//0.39=1xSCa;
0.52//0.23=0.6xSCa; and
0.425//0.20=0.5xSCa), ASA (2.8 mg/kg), heparin (200 U/kg plus
1000
U/h), or saline (0.1 mL/kg) was administered intravenously.
Experimental time was 180 minutes of current. Time to occlusion was
increased (P<.05) by SCa (T=incidence of thrombosis)
(1xSCa, >180 minutes [T=0]; 0.6xSCa,
158±15 minutes [T=2];
0.5xSCa, 130±22 minutes [T=4]), heparin
(114±16 minutes [T=5]),
and ASA plus heparin (130±11 minutes [T=5]) relative
to saline
(58±7 minutes [T=6]). Time to occlusion for the SCa
treatments was
increased compared with ASA (64±7 minutes [T=6]). When
0.5xSCa was
administered with ASA plus heparin, time to occlusion was >180 minutes
[T=0]. SCa provided complete protection at 
90% inhibition
of ex
vivo collagen-induced platelet aggregation. Cyclic flow
variations were minimal with SCa or any treatment involving 0.5xSCa
and ASA.
Conclusions SCa has dose-dependent antithrombotic efficacy and inhibits ex vivo platelet aggregation. ASA, heparin, or saline was ineffective in this model. SCa (0.5x) plus ASA and heparin maximized the antithrombotic effect of this lower dose of SCa.
Key Words: platelets • aggregation • antithrombotic agents • thrombosis
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
The activation of platelets and the resultant aggregation have been shown to be important factors in the pathogenesis of unstable angina pectoris, transient myocardial ischemia, acute myocardial infarction, and atherosclerosis.1 2 3 4 5 6 In most of these serious cardiovascular disorders, intracoronary thrombus is present.7 8 9 The thrombus is generally formed by activated platelets that adhere and aggregate at the site of endothelial injury.10 Because of the relative contribution of activated platelets to aggregation and subsequent formation of an occlusive thrombus, antiplatelet agents have been developed that inhibit platelet aggregation, but these previous agents have limited mechanisms of action. Current antiplatelet agents include ASA, which mainly interrupts the thromboxane pathway11 ; ticlopidine, which predominantly interferes with the ability of ADP to stimulate platelets12 13 ; and thromboxane A2 synthetase inhibitors, which act against thromboxane A2.14 Attempts to inhibit platelet aggregation to all known platelet agonists have resulted in the development of new agents that block fibrinogen binding (at the arginine-glycine-aspartate [RGD] recognition sequence) to the GPIIb/IIIa receptor on activated platelets. The binding of fibrinogen to the GPIIb/IIIa receptors is considered the final common pathway of platelet aggregation that leads to thrombus formation.15 16 A drug that inhibits platelet aggregation induced by a variety of physiological agonists would provide even greater protection than that provided by the antiplatelet agents listed above.
In this report, we used a well-known canine model of electrically induced coronary artery thrombosis,17 except that the anodal current strength used to induce coronary artery thrombosis was 250 µA. We used 250-µA current because in the presence of heparin, occlusion to 150-µA current required more than 120 minutes (unpublished data), and we thought that a higher current could lead to more rapid occlusion. At the end of the study, there was no apparent difference in the time for thrombosis in the presence of heparin when 150- or 250-µA current was used.
SCa is an orally active compound that is currently in clinical trials
as an antithrombotic agent for chronic use. The active metabolite of
this compound is SC-54701. We evaluated the antithrombotic efficacy of
intravenous SCa (Fig 1
), the hydrochloride
salt of the metabolite that potently inhibits the binding of fibrinogen
to GPIIb/IIIa receptors.18 We also compared ASA and
heparin with SCa in this model and tested the hypothesis that
combinations of SCa, with ASA or with heparin, or a combination of the
three agents would show enhanced antithrombotic effect.
|
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Reagents
Lysine-ASA was obtained from Synthélabo. Collagen from equine tendon was purchased from Chrono-log Corp. Sodium heparin from beef lung was obtained from Upjohn Co. Saline was purchased from Baxter Healthcare Corp. SCa (SC-54701A) was synthesized at Searle (Skokie, Ill).
Surgical Preparation and Instrumentation
Sixty-six mongrel
dogs of either sex weighing between 14 and
26 kg were anesthetized by intravenous
administration of pentobarbital sodium solution (30 mg/kg). A
supplemental dose of the anesthetic (65 to 130 mg) was administered as
required. The dogs were endotracheally intubated and placed on a
respirator (Biological Research Apparatus) with the stroke
volume adjusted to 20 mL/kg and a frequency of 12 breaths per minute.
Peripheral arterial blood pressure was
monitored with a pressure transducer (Micron Instruments) connected to
a catheter placed in the right femoral artery. A catheter was inserted
into the right femoral vein for withdrawing blood samples and another
was inserted into the left jugular vein for administering
intravenous fluids. A left thoracotomy was performed in the
fifth intercostal space, and the heart was suspended in a pericardial
cradle. A 2- to 3-cm segment of the LCCA was isolated distal to the
first diagonal branch. The small intervening coronary branches
over the isolated segment were ligated. The artery was instrumented
from proximal to distal with an ultrasonic flow probe, a stimulation
electrode, and a Goldblatt clamp. The flow probe was connected to a
Doppler flowmeter (Crystal Biotech) to monitor the mean and the
phasic LCCA blood flow velocities. The stimulation electrode and its
placement in the LCCA and the methodology to induce an occlusive
coronary thrombus have been described in detail
previously.19 20 21 Briefly, the needle
tip of the electrode
was inserted into the LCCA, ensuring its contact with the intraluminal
surface of the vessel just under the Goldblatt clamp. The clamp was
adjusted to reduce the peak reactive hyperemia after a
10-second period of total occlusion, without affecting the baseline
mean LCCA blood flow velocity. Continuous recordings of blood
pressure and LCCA blood flow velocity (mean and phasic) were obtained
on a multichannel recorder (Gould Inc).
Experimental Protocol
Approximately 30 minutes after the
preparation of the dogs, the
study was continued by the administration of one of the treatments
presented in Table 1. The 0.6xSCa, 0.5xSCa,
and 0.4xSCa doses in Table 1 represent the reduced doses
of
the highest dose of SCa tested. Each dog was used only once. At 30
minutes, the stimulation electrode was connected in series with a 12-
to 112-K
variable resistor to the positive terminal of a 9-V
battery. The electrical circuit was completed by securing a needle
electrode into a subcutaneous site and to the negative terminal of the
battery. The anodal current delivered to the tip of the stimulation
electrode was monitored and maintained at 250 µA. The number and the
frequency of CFV that preceded the formation of an occlusive thrombus
were recorded. CFV were observed as spontaneous shifts in mean and
phasic LCCA blood flow velocities, with the sudden return of these
variables to baseline. Folts et al22 showed that these
cyclic phenomena were caused by platelet thrombi that formed in the
narrowed lumen. Subsequent studies by Bush et al23
confirmed that CFV were due to platelet aggregation. Other
investigators have demonstrated that when platelets aggregate they
release substances including serotonin and
thromboxane A2, which cause increased
coronary vasoconstriction at sites of coronary
stenosis and endothelial injury.24
These vasoactive substances also have been shown to be important
mediators of CFV.23 25 Proper positioning of the
electrode
in the LCCA was confirmed by visual inspection at the end of the
experiment. Each experiment lasted for 180 minutes of anodal current
unless the dog died after an occlusive thrombus was formed.
Resuscitation was not attempted. Lack of antithrombotic efficacy was
established if zero flow in the LCCA was observed for a minimum of 30
minutes.
|
Ex Vivo Platelet Aggregation and Platelet
Counts
Peripheral venous blood was collected into citrated
Vacutainer tubes (containing 0.3 mL of 3.8% sodium citrate solution),
and platelet-rich plasma was obtained by
centrifugation (model Technospin R, Sorvall
Instruments, DuPont) of the blood at 266g for 6 minutes at
24°C. Platelet-poor plasma was obtained by further
centrifugation at 2000g for 10 minutes at
24°C. Samples were assayed on an aggregometer (model PAP-4, Bio/Data
Corp) with platelet-poor plasma as the blank. The aggregations
were performed by adding 50 µL of collagen (33.3 µg/mL final
concentration) to 450 µL of platelet-rich plasma and
measuring aggregation for 3 minutes. Throughout this article,
platelet aggregation refers to collagen-induced platelet
aggregation. Blood samples used in platelet aggregation were
collected at the following time periods: before treatment
administration (baseline), immediately before anodal stimulation (at 30
minutes), at 60 minutes, then at 1-hour intervals to the end of
experimentation. The blood samples at 60, 120, and 180 minutes were
averaged (since the three blood samples yielded similar data) to obtain
the steady state platelet inhibition value for all comparisons
except for saline and heparin (since no 120-minute sample was taken,
samples from 60 and 180 minutes were used). Results are expressed as
percent inhibition and represent steady state conditions.
Venous blood for whole blood platelet counts was collected into Vacutainer tubes (containing 0.04 mL of 7.5% EDTA solution) at baseline. Platelet counts were determined with a Coulter counter (model S-Plus IV).
Bioassay for SCa Plasma Levels
SCa plasma levels were
determined from the blood samples used
for platelet aggregation. Plasma levels of SCa were measured with
the use of a modification of a bioassay method previously
described.26 The bioassay used plasma from treated dogs as
the source of inhibitor to be tested in vitro against
normal (naive) platelets from donor dogs. Briefly,
platelet-rich plasma from nontreated dogs was added to wells
containing plasma samples from treated dogs in a 96-well microtiter
plate. ADP (20 µmol/L) was added to the platelet suspension in
each well to induce aggregation. Optical density at 405 nm was measured
on all wells simultaneously in a platereader (Thermomax
microplate reader, Molecular Devices). The results were quantified by
comparison to a standard inhibition curve prepared in plasma with the
use of known amounts of SCa.
Data Analysis
Data are expressed as mean±SEM. All
tests for statistical
significance were nonparametric. When dose dependency was
expected, that is, higher doses resulting in longer times to zero flow
and greater percent inhibitions than lower doses, the data were
analyzed by one-tailed 
2 bar-square
trend tests. Other comparisons were made using either one- or
two-tailed Dunnett tests. Differences were considered significant
at P<.05.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Group Characteristics
The platelet aggregations and the platelet counts did not differ (P>.05) among the 11 groups of dogs before treatment. Ventricular fibrillation (arrhythmia) occurred in 6 dogs after each developed an occlusive thrombus in the LCCA. Each of the following treatment groups had 1 dog that incurred ventricular fibrillation: ASA, heparin, ASA combined with heparin, and 0.4xSCa combined with ASA and heparin. The remaining 2 dogs were from the saline control. No dog was excluded from data analysis because of ventricular fibrillation.
Effects of SCa, ASA, Heparin, Saline, and ASA/Heparin
The
comparative antithrombotic effects and percent inhibition of
ex vivo platelet aggregation of SCa, ASA, heparin, saline, and ASA
combined with heparin are shown in Fig 2. The three
doses of SCa were more efficacious in preventing an occlusive thrombus
than ASA, heparin, ASA combined with heparin, or the saline control.
Thrombosis did not occur in any of the dogs treated with 1xSCa; it did
occur before the completion of the 180 minutes of current in all of the
dogs treated with saline or ASA. The time to zero flow was
significantly prolonged by the three doses of SCa (1xSCa, >180
minutes; 0.6xSCa, 158±15 minutes; and 0.5xSCa,
130±22 minutes)
relative to the treatment with ASA (64±7 minutes) and saline
(58±7
minutes). The time to zero flow for 1xSCa was >180 minutes; this time
merely established the end of the experimental protocol with no
occlusion. The time to zero flow was increased by heparin (114±16
minutes), and the combination of ASA with heparin (130±11 minutes)
compared with the saline treatment, but 1xSCa provided a significantly
longer time to zero flow than either of these treatments.
|
P<.05 vs ASA/heparin.
A
dose-dependent increase in the steady state inhibition of
platelet aggregation was obtained after the administration of the
three dose regimens of SCa (1xSCa, 92±5%; 0.6xSCa,
83±3%; and
0.5xSCa, 70±4%, respectively). The dose regimens of SCa leading
to
>90% inhibition of platelet aggregation either increased the time
to zero flow or prevented thrombotic occlusion (Fig 3).
Each regimen of SCa produced a level of inhibition that was
significantly greater than that obtained from the heparin (13±2%),
ASA combined with heparin (24±10%), or saline (9±2%) treatments.
Only 1xSCa and 0.6xSCa significantly inhibited platelet
aggregation relative to ASA (25±15%).
|
Effects of Decreased Doses of SCa Given in Combination With ASA,
Heparin, or ASA Combined With Heparin
Fig 4 compares
the antithrombotic efficacy and the
percent inhibition of platelet aggregation produced by 1xSCa with
that obtained by treatment with 0.5xSCa combined with ASA or heparin
or combined with ASA and heparin. The combination of 0.5xSCa with ASA
resulted in an occlusive thrombus in only 1 of the 6 dogs. When
0.5xSCa was administered with heparin, there was a significant
reduction in the percent of steady state inhibition of platelet
aggregation relative to 1xSCa (67±4% versus 92±5%), but
the
antithrombotic efficacy (100%) was similar to that of 1xSCa. The
0.5xSCa treatment combined with ASA and heparin was as effective as
1xSCa in preventing LCCA thrombosis. A further decrease from
0.5xSCa
to 0.4xSCa with the ASA and heparin combination was less efficacious,
as there was LCCA occlusion in 2 of the 6 dogs. The maximum steady
state inhibition of platelet aggregation (96±3%) was observed in
the group of dogs treated with 0.5xSCa combined with ASA and
heparin.
|
P<.05 vs
0.5xSCa/ASA/heparin.
CFV During Stimulation of the LCCA
Table 2
summarizes the CFV observed during anodal
stimulation of the LCCA, and a representative
illustration of CFV is included in Fig 5. As indicated
in Table 2, CFV were observed in only 1 of 6 dogs from the
groups
treated with 1xSCa, 0.5xSCa combined with ASA, or 0.5xSCa in
combination with ASA and heparin. The number of CFV was also
significantly smaller in these groups compared with that observed in
the groups treated with either ASA, heparin, or ASA combined with
heparin.
|
|
Plasma Levels of SCa
Table 3 shows the results
of plasma levels of SCa
with the corresponding inhibition of platelet aggregation at steady
state conditions. As expected, the dose-dependent increase in mean
percent inhibition of platelet aggregation was associated with a
dose-dependent elevation of plasma SCa levels.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Antithrombotic therapy with ASA, heparin, or the combination is only partially effective in the prevention of coronary thrombus formation.27 28 Therefore, research toward the development of more effective antithrombotic and anticoagulant agents or combinations of both agents is intensifying. Platelet binding of fibrinogen, by means of the RGD recognition sequence of the GPIIb/IIIa-receptor complex, represents the final pathway of platelet aggregation and subsequent thrombus formation. This final pathway is common to all known platelet agonists.16 29 30 Therefore, the binding of fibrinogen to GPIIb/IIIa receptors provides an excellent target for therapeutic intervention in thrombosis-related disorders such as the acute ischemic coronary syndromes.1 2 3 4 5 6 Several molecules have been shown to block fibrinogen binding to platelet GPIIb/IIIa receptors and therefore prevent the formation of platelet thrombi.21 31 32 33
In this study, we used a well-characterized canine model of coronary artery thrombosis to evaluate the efficacy of intravenous SCa, a new agent that inhibits the binding of fibrinogen to the GPIIb/IIIa receptor.18 SCa is the hydrochloride salt of the active metabolite of SC-54684A (an orally active inhibitor of platelet aggregation34 presently in clinical trials). We also evaluated intravenous ASA, heparin, and the effects of a decreased dose of the drug with ASA, heparin, or with all three agents in the same animal model.
The various regimens of SCa (loading dose [µg/kg per minute] for 15 minutes followed by [//] a maintenance infusion [µg/kg per minute]: 0.87//0.39, 0.52//0.23, and 0.425//0.20) were selected to obtain a range of ex vivo inhibition of platelet aggregation. Previous studies (unpublished data) have demonstrated that steady state ex vivo inhibition of platelet aggregation can be achieved with a constant infusion of SCa. In this study, the bolus/maintenance infusion SCa dosing regimens achieved steady state inhibition of platelet aggregation in a shorter time period than that of the constant infusion. Although collagen was the only agonist used for platelet aggregation in the present study, other studies have shown that SCa was effective at inhibiting platelet aggregation resulting from other stimuli, including ADP18 and thrombin (in washed platelets, unpublished data).
Treatment of anesthetized dogs with the three different regimens of SCa achieved a dose-dependent, steady state inhibition of ex vivo platelet aggregation that resulted in a dose-related sustained antithrombotic effect. The dose of SCa leading to approximately 90% inhibition of platelet aggregation appears to be completely protective. A salient finding is that 0.5xSCa given together with low-dose ASA, or with heparin, or with ASA plus heparin prevented arterial occlusion in 17 of 18 dogs. The presence or absence of mural thrombus at the site of injury was not determined in animals that had no thrombotic occlusion at the end of the experiment. Since ASA, heparin, or ASA combined with heparin was not effective in this model, and 4 of 6 dogs incurred LCCA thrombosis after 0.5xSCa, the data suggest an enhanced antithrombotic effect between SCa, ASA, and heparin.
Although both treatments of 0.5xSCa combined with heparin and 0.5xSCa administered with ASA plus heparin maintained coronary artery patency, the latter regimen showed a reduction in dogs having CFV (3 of 6 versus 1 of 6 dogs, respectively). The reduction of 1xSCa to 0.4xSCa combined with ASA and heparin provides less efficacy and increased CFV relative to the 0.5xSCa combinations. These data suggest an enhanced antithrombotic effect for SCa, ASA, and heparin used in combination. Because of differences in the mechanisms of these agents to inhibit platelet aggregation, one might expect that their concomitant use would result in an enhanced inhibition of platelet aggregation compared with the response of each agent alone. These results are consistent with findings of other groups who have reported that the antiaggregatory platelet effects by a GPIIb/IIIa receptor antagonist may be enhanced by ASA.35 This augmented effect may permit decreased doses of each treatment to obtain the added antithrombotic effect.
Although the chief mechanism of action for ASA is inhibition of thromboxane A2 production by inhibiting cyclooxygenase, a previous study36 using this model found that antithrombotic activity was not totally dependent on inhibition of thromboxane A2 production. In that study, high-dose intravenous ASA (20 mg/kg) but not low-dose oral or intravenous ASA (4.6 mg/kg) reduced the inhibition of thrombotic artery occlusion even though both doses of ASA effectively prevented ex vivo platelet aggregation in response to arachidonic acid. In a separate study, we showed that a 30 mg/kg intravenous dose of ASA was not completely effective, preventing occlusion in 4 of 6 dogs (data not presented). The implication is that even at its maximum activity, ASA cannot ensure complete protection against LCCA thrombosis in the model. This is not an unexpected finding, since ASA only prevents thromboxane A2–mediated aggregation while minimally affecting collagen, ADP, and thrombin-induced aggregation.
The CFV and the number of dogs with CFV appear to be less frequent in the groups that received 1xSCa, 0.5xSCa in combination with ASA, or 0.5xSCa with ASA and heparin. SCa alone or in combination with ASA may afford some protection against the development of CFV. These CFV varied considerably in magnitude and frequency, probably for several reasons. The amount of damaged intima with the 250-µA direct current could differ considerably between experiments. The variability of the levels of circulating catecholamines in anesthetized animals, depending in part on the depth of anesthesia and the amount of surgical stress, may also contribute to CFV.37 Nevertheless, maximum protection against CFV was seen at 1xSCa and 0.5xSCa with ASA, again suggesting that in the presence of ASA the protective dose of SCa can be about half of that needed without ASA. However, 0.5xSCa with ASA had acute occlusion in 1 of 6 dogs, whereas 0.5xSCa plus heparin alone or with 0.5xSCa plus ASA and heparin prevented occlusion, documenting the need for heparin.
In summary, the present study shows that SCa, a GPIIb/IIIa receptor antagonist, yields sustained levels of inhibition of ex vivo platelet aggregation that result in antithrombotic efficacy in a canine model of coronary artery occlusion. Furthermore, because of the very different mechanisms of action of SCa, ASA, and heparin, the 0.5xSCa dose combined with ASA and heparin provided an enhanced antithrombotic effect, suggesting that decreased doses of SCa may be used in conjunction with ASA and heparin in the clinic for acute thrombotic-related events. Neither heparin nor ASA alone was efficacious in this model.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
The authors would like to acknowledge the assistance of Dr Richard M. Bittman and Matthew M. Hutmacher of the Department of Preclinical Statistics, Searle, Skokie, Ill, for statistical analysis of the data.
Received April 20, 1995; revision received August 1, 1995; accepted August 6, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
-
Hirsh PD, Hillis LD, Campbell WB, Firth BG,
Willerson JT. Release of prostaglandins and
thromboxane into the coronary circulation in
patients with ischemic heart disease. N
Engl J Med. 1981;304:685-691. [Abstract]
-
Fitzgerald DJ, Roy L, Catella F, FitzGerald GA.
Platelet activation in unstable coronary disease.
N Engl J Med. 1986;315:983-989. [Abstract]
-
Willerson JT, Hillis LD, Winniford M, Buja LM.
Speculation regarding mechanisms responsible for acute ischemic
heart disease syndromes. J Am Coll
Cardiol. 1986;8:245-250. [Medline]
[Order article via Infotrieve]
-
Rubenstein MD, Wall RT, Baim DS, Harrison DC.
Platelet activation in clinical coronary artery disease and
spasm. Am Heart J. 1981;102:363-367. [Medline]
[Order article via Infotrieve]
-
Smitherman TC, Milam M, Woo J, Willerson JT, Frenkel
EP. Elevated beta thromboglobulin in
peripheral venous blood of patients with acute myocardial
ischemia: direct evidence for enhanced platelet reactivity
in vivo. Am J Cardiol. 1981;48:395-402. [Medline]
[Order article via Infotrieve]
-
Fuster V, Steele PM, Chesebro JH. Role of
platelet and thrombosis in coronary atherosclerotic disease
and sudden death. J Am Coll Cardiol. 1985;5:175B-184B.
-
Ridolfi RL, Hutchins GM. The relationship
between coronary artery lesions and myocardial infarcts:
ulceration of atherosclerotic plaques precipitating coronary
thrombosis. Am Heart J. 1977;93:468-486.[Medline]
[Order article via Infotrieve]
-
Vetrovec GW, Crowley MJ, Overton H, Richardson
DW. Intracoronary thrombus in syndromes of unstable
myocardial ischemia: autopsy evidence of recurrent mural
thrombosis with peripheral embolization culminating in
total vascular occlusion. Am Heart J. 1981;102:1202-1208. [Medline]
[Order article via Infotrieve]
-
Falk E. Unstable angina with fatal outcome:
dynamic coronary thrombosis leading to infarction and/or sudden
death. Circulation. 1985;71:699-708.
[Abstract/Free Full Text]
-
Willerson JT, Golino P, Eidt J, Campbell WB, Buja
LM. Specific platelet mediators and unstable
coronary artery lesions: experimental evidence and potential
clinical implications. Circulation. 1989;80:198-205.
[Abstract/Free Full Text]
-
Smith JB, Willis AL. Aspirin selectively
inhibits prostaglandin production in human
platelets. Nature. 1971;231:235-237.
-
Thebault JJ, Blatri CE, Blanchard JF, Panak EA.
Effects of ticlopidine, a new platelet aggregation
inhibitor, in man. Clin Pharmacol Ther. 1975;18:485-491. [Medline]
[Order article via Infotrieve]
-
Pengo V, Boschello M, Marzari A, Baca M, Schivazappa L,
Dalla-Volta S. Adenosine diphosphate (ADP)-induced
alpha-granule release from platelets of native whole blood is
reduced by ticlopidine but not by aspirin or
dipyridamole. Thromb Haemost. 1986;56:147-150. [Medline]
[Order article via Infotrieve]
-
Golino P, Ashton JH, Glas-Greenwalt P, McNatt J, Buja
LM, Willerson JT. Mediation of reocclusion by
thromboxane A2 and serotonin after
thrombolysis with tPA in a canine preparation of
coronary thrombosis. Circulation. 1988;77:678-684.
[Abstract/Free Full Text]
-
Bennett JS, Vilaire G. Exposure of platelet
fibrinogen receptors by ADP and epinephrine.
J Clin Invest. 1979;64:1393-1401.
-
Peerschke EI, Zucker MB, Grant RA, Egan JJ, Johnson
MM. Correlation between fibrinogen binding to human
platelets and platelet aggregability. Blood. 1980;55:841-847.
[Abstract/Free Full Text]
-
Schumacher WA, Lee EC, Lucchesi BR. Augmentation
of streptokinase-induced thrombolysis by heparin
and prostacyclin. J Cardiovasc Pharmacol. 1985;7:739-746. [Medline]
[Order article via Infotrieve]
-
Nicholson NS, Panzer-Knodle SG, Salyers AK, Taite BB,
Szalony JA, Haas NF, King LW, Zablocki JA, Keller BT, Broschat K,
Engleman VW, Herin M, Jacqmin P, Feigen LP. SC-54684A: an orally
active inhibitor of platelet aggregation.
Circulation. 1995;91:403-410.
[Abstract/Free Full Text]
-
Mickelson JK, Simpson PJ, Cronin M, Homeister JW,
Laywell E, Kitzen J, Lucchesi BR. Antiplatelet antibody
[7E3 F(ab')2] prevents rethrombosis after
recombinant
tissue-type plasminogen
activator-induced coronary artery
thrombolysis in a canine model.
Circulation. 1990;81:617-627.
[Abstract/Free Full Text]
-
Shebuski RJ, Stabilito IJ, Sitko GR, Polokoff
MH. Acceleration of recombinant tissue-type plasminogen
activator-induced thrombolysis and prevention of reocclusion by
the combination of heparin and the Arg-Gly-Asp-containing peptide
bitistatin in a canine model of coronary thrombosis.
Circulation. 1990;82:169-177.
[Abstract/Free Full Text]
-
Tschopp JF, Driscoll EM, Mu D-X, Black SC,
Pierschbacher MD, Lucchesi BR. Inhibition of coronary
artery reocclusion after thrombolysis with an
RGD-containing peptide with no significant effect on bleeding
time. Coron Artery Dis. 1993;4:809-817. [Medline]
[Order article via Infotrieve]
-
Folts JD, Crowell EB Jr, Rowe GG. Platelet
aggregation in partially obstructed vessels and its elimination with
aspirin. Circulation. 1976;54:365-370.
[Abstract/Free Full Text]
-
Bush LR, Campbell WB, Buja LM, Tilton GD, Willerson
JT. Effects of the selective thromboxane synthetase
inhibitor dazoxiben on variations in cyclic blood flow in
stenosed canine coronary arteries.
Circulation. 1984;69:1161-1170.
[Abstract/Free Full Text]
-
Golino P, Ashton JH, Buja LM, Rosolowsky M, Taylor AL,
McNatt J, Campbell WB, Willerson JT. Local platelet
activation causes vasoconstriction of large epicardial canine
coronary arteries in vivo: thromboxane
A2 and serotonin are possible
mediators. Circulation. 1989;79:154-166.
[Abstract/Free Full Text]
-
Bush LR, Campbell WB, Kern K, Tilton GD, Apprill P,
Ashton J, Schmitz J, Buja LM, Willerson JT. The effects of
2-adrenergic and serotonergic receptor
antagonists on cyclic blood flow alterations in stenosed
canine coronary arteries. Circ
Res. 1984;55:642-652. [Abstract/Free Full Text]
-
Salyers AK, Szalony JA, Taite BB, Haas NF, Mehrotra DV,
Feigen LP, Nicholson NS. A new method for measurement of plasma
concentration of orally active glycoprotein IIb/IIIa
antagonists. Thromb Res. 1994;75:409-417. [Medline]
[Order article via Infotrieve]
-
Johns JA, Gold HK, Leinbach RC, Yasuda T, Gimple LW,
Werner W, Finkelstein D, Newell J, Ziskind AA, Collen D.
Prevention of coronary artery reocclusion and reduction in late
coronary artery stenosis after
thrombolytic therapy in patients with acute myocardial
infarction: a randomized study of maintenance infusion of
recombinant human tissue-type plasminogen
activator. Circulation. 1988;78:546-556.
[Abstract/Free Full Text]
-
Theroux P, Quimet H, McCans J, Latour JG, Joly P, Levy
G, Pelletier E, Juneau M, Stasiak J, de Guise P, Pelletier GB, Rinzler
D, Waters DD. Aspirin, heparin, or both to treat acute unstable
angina. N Engl J Med. 1988;319:1105-1111. [Abstract]
-
Marguerie GA, Plow EF, Edgington TS. Human
platelets possess an inducible and saturable receptor specific for
fibrinogen. J Biol Chem. 1979;254:5357-5363.
[Free Full Text]
-
Travis J. Biotech gets a grip on cell adhesion:
frontier in biotechnology. Science. 1993;260:906-908.
[Free Full Text]
-
Feigen LP, Nicholson NS, King LW, Campion JG, Tjoeng
FS, Panzer-Knodle SG. SC-49992, a mimetic of the peptide
arginine-glycine-aspartic acid-phenylalanine that blocks
platelet aggregation, enhances recombinant tissue
plasminogen activator-induced
thrombolysis and prevents reocclusion in a canine model
of coronary artery thrombosis. J
Pharmacol Exp Ther. 1993;267:1191-1197.
[Abstract/Free Full Text]
-
Collen D, Lu RH, Stassen J-M, Vreys I, Yasuda T,
Bunting S, Gold HK. Antithrombotic effects and bleeding time
prolongation with synthetic platelet GPIIb/IIa
inhibitors in animal models of platelet-mediated
thrombosis. Thromb Haemost. 1994;71:95-102. [Medline]
[Order article via Infotrieve]
-
Mousa SA, Bozarth JM, Forsythe MS, Jackson SM,
Leamy A, Diemer MM, Kapil RP, Knabb RM, Mayo MC, Pierce SK, De Grado
WF, Thoolen MJ, Reilly TM. Antiplatelet and
antithrombotic efficacy of DMP 728, a novel platelet GPIIb/IIIa
receptor antagonist.
Circulation. 1994;89:3-12.
[Abstract/Free Full Text]
-
Szalony JA, Haas NF, Salyers AK, Taite BB, Mehrotra DV,
Feigen LP, Nicholson NS. Extended inhibition of platelet
aggregation with the orally active platelet inhibitor
SC-54684A. Circulation. 1995;91:403-410.
-
Freed MI, Boike S, Zariffa N, Jorkasky DK.
Effects of acetylsalicylic acid on inhibition of ex
vivo platelet aggregation and secretion by SKF 107260, a novel
GPIIb/IIIa receptor antagonist. Thromb
Haemost. 1994;72:622-626. [Medline]
[Order article via Infotrieve]
-
Mickelson JK, Hoff PT, Homeister JW, Fantone JC,
Lucchesi BR. High dose intravenous aspirin, not low
dose intravenous or oral aspirin, inhibits thrombus
formation and stabilizes blood flow in experimental coronary
vascular injury. J Am Coll Cardiol. 1993;21:502-510. [Abstract]
-
Folts JD, Gallagher K, Rowe GG. Blood flow
reduction in stenosed canine coronary arteries: vasospasm or
platelet aggregation? Circulation. 1982;65:248-255.
[Abstract/Free Full Text]
This article has been cited by other articles:
 |
|
 |
|
  J. K. Hennan, J. Huang, T. D. Barrett, E. M. Driscoll, D. E. Willens, A. M. Park, L. J. Crofford, and B. R. Lucchesi Effects of Selective Cyclooxygenase-2 Inhibition on Vascular Responses and Thrombosis in Canine Coronary Arteries Circulation, August 14, 2001; 104(7): 820 - 825. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Harder, C. M. Kirchmaier, H. J. Krzywanek, D. Westrup, J.-W. Bae, and H. K. Breddin Pharmacokinetics and Pharmacodynamic Effects of a New Antibody Glycoprotein IIb/IIIa Inhibitor (YM337) in Healthy Subjects Circulation, September 14, 1999; 100(11): 1175 - 1181. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Honda, Y. Tomiyama, T. Aoki, M. Shiraga, Y. Kurata, J. Seki, and Y. Matsuzawa Association Between Ligand-Induced Conformational Changes of Integrin alpha IIbbeta 3 and alpha IIbbeta 3-Mediated Intracellular Ca2+ Signaling Blood, November 15, 1998; 92(10): 3675 - 3683. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. G. Frederick, O. D. Suleymanov, J. A. Szalony, B. B. Taite, A. K. Salyers, L. W. King, L. P. Feigen, and N. S. Nicholson Protective Effect of Oral Xemilofiban in Arterial Thrombosis in Dogs : Increased Activity in Combination With Aspirin Circulation, August 25, 1998; 98(8): 813 - 820. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Hoffmann, A. Bernat, P. Savi, and J. M. Herbert Prevention of Thrombosis and Enhancement of Thrombolysis in Rabbits by SR 121787, a Glycoprotein II/III Antagonist J. Pharmacol. Exp. Ther., August 1, 1998; 286(2): 670 - 675. [Abstract] [Full Text]
|
|
|
|
|
|
C. Simpfendorfer, K. Kottke-Marchant, M. Lowrie, R. J. Anders, D. M. Burns, D. P. Miller, C. S. Cove, A. C. DeFranco, S. G. Ellis, D. J. Moliterno, et al. First Chronic Platelet Glycoprotein IIb/IIIa Integrin Blockade : A Randomized, Placebo-Controlled Pilot Study of Xemilofiban in Unstable Angina With Percutaneous Coronary Interventions Circulation, July 1, 1997; 96(1): 76 - 81. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||