(Circulation. 1996;93:537-543.)
© 1996 American Heart Association, Inc.
Articles |
Oral Antiplatelet, Antithrombotic Efficacy of DMP 728, a Novel Platelet GPIIb/IIIa Antagonist
From The Du Pont Merck Pharmaceutical Co, Wilmington, Del.
Correspondence to Shaker A. Mousa, PhD, The Du Pont Merck Pharmaceutical Co, Exp Station, E400/3456, Wilmington, DE 19880-0400.
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Abstract |
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Background Currently used antiplatelet drugs, including aspirin and ticlopidine, are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. DMP 728 has been characterized as a potent and specific platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa) antagonist. The goals of the present study were to determine the oral antiplatelet and antithrombotic efficacies of DMP 728 in various arterial thrombosis models in dogs.
Methods and Results In conscious and anesthetized mongrel dogs, DMP 728 at 0.02 to 1.0 mg/kg PO in gelatin capsules produced dose-dependent antiplatelet effects in inhibiting ex vivo platelet aggregation induced by ADP and prolonging template bleeding time. DMP 728 effects on bleeding time prolongation could be reversed more rapidly than those on platelet aggregation inhibition. A maximal antiplatelet effect for DMP 728 was demonstrated at 1.0 mg/kg PO. DMP 728 demonstrated dose-dependent oral antiplatelet effects with an absolute oral bioavailability of 8% to 12% in dogs. Additionally, the antithrombotic efficacy of DMP 728 was examined after intravenous and oral administration at different doses in various models of arterial thrombosis. In the coronary artery Folts' model in dogs, DMP 728 demonstrated maximal antithrombotic efficacy at 0.01 mg/kg IV and <0.6 mg/kg PO. Additionally, DMP 728 at 0.1 and 1.0 mg/kg IV or PO demonstrated 60% to 100% prevention of primary thrombosis (P<.01) in an electrolytically induced carotid artery thrombosis model in dogs.
Conclusions These data suggest that DMP 728, a low-molecular-weight GPIIb/IIIa receptor antagonist, may have therapeutic potential as an oral antithrombotic agent in coronary and carotid artery thromboembolic disorders.
Key Words: platelet aggregation inhibitors • thrombosis • receptor antagonists
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Introduction |
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Recently, GPIIb/IIIa was identified as the final common pathway for all platelet agonists.1 2 The binding of adhesive proteins such as fibrinogen to GPIIb/IIIa causes platelets to aggregate.2 3 The binding of fibrinogen is mediated in part by the RGD recognition sequence, which is common to the adhesive proteins that bind to GPIIb/IIIa receptors.1 2 3 Platelet activation and the resultant aggregation have been shown to be associated with various pathological conditions, including cardiovascular and cerebrovascular thromboembolic disorders such as unstable angina, myocardial infarction, transient ischemic attack, stroke, and atherosclerosis.4 5 6 7 8 The contribution of platelets to these disease processes stems from their ability to form aggregates or platelet thrombi as a consequence of arterial wall injury. Injury of blood vessel walls could occur either acutely or chronically by various pathophysiological processes. Platelets are then activated by a number of activators or agonists that are released from within platelets or from the injured arterial walls, with subsequent adherence, aggregation to the disrupted vessel surface, and formation of an occlusive thrombus in the lumen of the vessel.9 10 11 The first GPIIb/IIIa antagonists to be developed were monoclonal antibodies such as the murine and the chimeric 7E3,12 which effectively inhibits platelet aggregation against all known platelet agonists in experimental animals and patients.12 13 The use of monoclonal antibodies as therapeutic agents, however, might present many problems such as immunogenicity and reversibility. Thus, many groups have concentrated on developing small-molecule GPIIb/IIIa antagonists.14 15 16 17 18 It was demonstrated earlier that direct intracoronary infusion of acetyl-RGDS could inhibit platelet-dependent coronary artery thrombosis, but high doses were required and the duration of action was short.19 Thus, the approach taken by different groups has been to develop analogs of RGD or modifications of the RGD sequence in an attempt to improve the pharmacodynamic (affinity and specificity to the GPIIb/IIIa integrin receptors) and pharmacokinetic properties of those analogs.14 15 16 17
In contrast to the GPIIb/IIIa antagonist approach, current antiplatelet drugs, including aspirin, ticlopidine, thromboxane A2 synthetase inhibitors or receptor antagonists, and hirudin, are effective primarily against one of the many platelet activators.20 Hence, the potential clinical benefits of an agent that inhibits platelet activation in response to all these agonists should represent a more efficacious therapeutic approach than the use of current platelet inhibitors, either alone or in combination. Additionally, a higher incidence of coronary artery reocclusion after successful thrombolytic therapy is a persistent clinical problem.21 Thus, prevention of reocclusion with an adjunctive pharmacological agent is being actively pursued with different compounds, including anticoagulants, antiplatelet agents, and maintained infusion of thrombolytics.22 23 Although intravenous GPIIb/IIIa antagonists might be useful in short-term situations, long-term repeated daily administration for the prevention and treatment of primary and secondary coronary or cerebrovascular events would require the use of an orally active agent.
Previous reports have described the potential clinical
implications for different intravenously active GPIIb/IIIa
antagonists such as 7E3, Integrlin, MK383, and
RO44-9883.24 More recently, oral antiplatelet
efficacy of the GPIIb/IIIa antagonist SC-54684A has been
demonstrated in dogs when given orally at 2.5 to 7.5 mg/kg
BID.25 In this report, the oral antiplatelet,
antithrombotic efficacy of DMP 728, a low-molecular-weight
novel antiplatelet agent with high affinity and specificity for
the GPIIb/IIIa receptors, is described (Fig 1
). In
particular, the present study examines the potential oral
antiplatelet efficacy of DMP 728 in coronary and
carotid artery thromboembolic disorder models at oral doses ranging
from 0.1 to 1.0 mg/kg. The results suggest that DMP 728 may have
therapeutic potential as an oral antithrombotic agent in
coronary and carotid artery thromboembolic disorders.
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Methods |
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Reagents
ADP, collagen from calf skin, epinephrine bitartrate, and other reagents used in these studies were obtained from Sigma Chemical Co. Arachidonate was purchased from Nu Chek Prep. DMP 728 (c[D-2-aminobutyryl-N2-methyl-L-arginyl-glycyl-L-aspartyl-aminomethyl-benzoic acid] methane sulfonic acid) and RGDS were synthesized at The Du Pont Merck Pharmaceutical Co.
Platelet Aggregation Assay
Venous blood was obtained from
anesthetized mongrel dogs
or healthy human donors who were free of drugs and aspirin for at least
2 weeks before blood collection. Blood was collected into citrated
Vacutainer (Becton Dickson) tubes. The blood was centrifuged
for 15 minutes at 150g (850 rpm in a Sorvall RT6000 Tabletop
Centrifuge with an H-1000 B rotor) at room temperature, and
platelet-rich plasma was removed. The remaining blood was
centrifuged for 15 minutes at 1500g (26 780 rpm) at
room temperature, and platelet-poor plasma was removed. Samples
were assayed on a PAP-4 Platelet Aggregation Profiler with
platelet-poor plasma as the blank (100% transmittance). Then
200 µL platelet-rich plasma (2 to 3x108
platelets per 1 mL) was added to each microtube, and transmittance
was set to 0%. We added 20 µL ADP (10 to 100 µmol/L) to each tube,
and the aggregation profiles were plotted (percent transmittance versus
time). For in vitro antiplatelet efficacy studies, DMP 728 (20
µL) solubilized in double-distilled water was added at different
concentrations before the addition of the platelet agonist. Results
were expressed as percent inhibition of platelet aggregation.
Oral Antiplatelet Effects of DMP 728
Conscious Dogs
Experimental procedures. Mongrel dogs of either sex
weighing between 8 and 12 kg were used. For basal ex vivo platelet
aggregatory response, two venous blood samples were drawn by
venipuncture from a catheterized cephalic vein of each dog.
Percent platelet aggregation in response to 100 µmol/L ADP was
assessed as previously described. DMP 728 was administered orally
(single dose) in soft gelatin capsules at 0.02 to 1.0 mg/kg PO. Blood
samples were placed on a platform rocker until assayed for percent
platelet aggregation as previously described.26 The
oral antiplatelet efficacy of orally administered DMP 728 was
calculated by comparing percent aggregation response of samples after
DMP 728 administration to that of basal samples from within the same
dog. Percent inhibition of platelet aggregation was then calculated
for samples obtained from the different dogs.
Anesthetized
Dogs
Experimental procedures. Mongrel dogs of either
sex weighing between 8 and 12 kg were anesthetized by
administration of 30 mg/kg IV Nembutal sodium solution (Abbott
Laboratories, 50-mg/mL vial). Dogs were placed on a respiratory pump
(model 665, Harvard Apparatus) in which the stroke volume
of the respirator pump was adjusted to the dogs' weights. Both femoral
arteries were cannulated: one was attached to a transducer that
monitored heart rate and blood pressure on a chart recorder (Gould
recorder 2800S) throughout the study; the other was used for
repeated blood sampling. The femoral vein was also cannulated to
administer DMP 728 solubilized in physiological
saline and for maintenance of anesthesia as
needed.
Experimental protocol. Dogs were dosed either intravenously (0.005 to 1.0 mg/kg into the cannulated femoral vein over 2 minutes after a basal blood sample) or orally (0.1 to 1.0 mg/kg PO in soft gelatin capsules) with DMP 728. Bleeding time was determined before and at different intervals after DMP 728 administration. Blood samples were collected into Vacutainer tubes (4.5-mL draw, each containing 0.5 mL of 0.05 mol/L sodium citrate) before and at different intervals after administration of DMP 728. Blood samples were placed on a platform rocker until assayed for platelet aggregation, platelet counts, and DMP 728 plasma levels. Plasma levels of DMP 728 were measured by HPLC with the fluorescence detection method.27
Bleeding time. The effect of DMP 728 on bleeding time (minutes) was assessed on the back of the tongue. A Simplate device (Organon Teknika Corp) was applied to the surface of the tongue to make a uniform incision, and blood was blotted with filter paper at 30-second intervals until bleeding completely stopped; the cutoff time was 15 minutes. Bleeding time was assessed before and at different intervals after administration of DMP 728.
Platelet counts. From each blood sample, 100 µL citrated whole blood was used for platelet counting (Coulter Corp counter T-540).
Arterial Thrombosis Models in Dogs
Coronary Artery
Thrombosis in Dogs (Folts'
Model)
Experimental procedures. The in vivo coronary
artery platelet-rich thrombus model was described previously in
detail.28 29 Twenty-nine purposely bred mongrel dogs
of either sex weighing between 8 and 15 kg were anesthetized
and handled as previously described. Additionally, a left thoracotomy
was performed at the fifth intercostal space, and the heart was then
placed in a pericardial cradle. The LCx was dissected and freed from
facia and branches for a distance of 15 to 20 mm. A Doppler flow
probe was placed around the distal portion of the vessel segment, and
coronary flow was monitored throughout the study. Dogs were
allowed to stabilize for 20 minutes, and the hyperemic response
of the dissected LCx was determined by two repeated brief
(20-second) total occlusions 3 to 5 minutes apart. After restoration of
basal flow for 20 minutes, a 2.5-mm-long plastic cylinder was
placed on the proximal portion of the LCx, creating a critical
stenosis that reduced the lumen area of the vessel up to 80%,
thereby preventing the hyperemic response while minimally
affecting basal flow. The clip was then moved to one side, and a
portion of the LCx was mechanically damaged by gentle clamping of the
vessel. The stenotic clip was then moved back onto the damaged
vessel segment. This resulted in repeated CFR followed by restoration
of flow on dislodging or gentle shaking around the clip. Basal
measurements of the frequency of CFR, heart rate, and mean
arterial blood pressure were recorded, and then either
saline (control group) or DMP 728 (treated groups) was administered
(0.005 or 0.01 mg/kg IV or 0.6 or 1.0 mg/kg PO). The previously
described parameters were monitored for up to 3 hours after
treatment.
Carotid Artery Thrombosis in Dogs (Electrolytic
Injury
Model)
Experimental procedures. The model used in this study
is a modification of that described by Romson et al.30 The
experimental procedure results in the formation of a
platelet-rich intravascular thrombus at the site of the
electrolytically induced lesion. The femoral artery response to the
electrolytic injury is similar to that observed in the canine
coronary artery in which intimal wall injury secondary to
application of a direct anodal current leads to platelet adherence
with the resultant occlusive thrombus formation.29 30
Dogs
were instrumented as described earlier. A 20- to 30-mm segment of the
carotid artery was exposed and freed from facia, and branches were
tied. Anodal current was applied through an intravascular electrode
composed of a Teflon-insulated, silver-coated copper wire (28
gauge). Penetration of the vessel wall by the electrode was facilitated
by attachment of the tip of a 23-gauge hypodermic needle to the
uninsulated part of the electrode. Each intra-arterial
electrode was connected to the positive pole (anodal) of a
dual-channel stimulator (nickel-cadmium battery, 9 V connected
to 250 000-
potentiometer in series). The cathode was connected to
a distant subcutaneous site. The current delivered to the
arterial wall was monitored continuously and maintained at
150 µA. Proper positioning of the electrode in the carotid artery was
confirmed by visual inspection at the end of each experiment. In all
experiments, the anodal current was applied for a maximum of 3 hours.
Flow was monitored throughout the experiment by placement of a
Doppler flow probe (model 100, Triton Technology). The experimental
protocol is described in Fig 2.
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Pharmacokinetics of DMP 728 in Dogs
Dogs obtained
from Marshall Farms (North Rose, NY), 
8 to 10
months old and weighing 9 to 13 kg at the time of dosing, were used in
the pharmacokinetic studies. All dogs fasted overnight and received
standard certified commercial dog food (400 g Wayne Certified Dog Chow
No. 8727) 6 hours after dosing over a 2-hour feeding period and were
allowed water ad libitum. Three conscious dogs received 1.0 mg/kg DMP
728 in 5% dextrose in water for injection as a single
intravenous dose through the jugular vein, and three
conscious dogs received 2 mg/kg DMP 728 in distilled water as a single
oral dose by gavage through intubation. Blood samples (1.2 mL) were
collected from the jugular vein by venipuncture at
predetermined time points into heparinized Vacutainers. Plasma was
harvested after centrifugation of whole blood at
150g for 15 minutes. Plasma samples were kept frozen at
-20°C until analysis by HPLC.27 A
relatively high dose was selected in the assessment of the
pharmacokinetics of DMP 728 primarily to attain accurate determinations
of plasma levels, especially at the later times because of the limited
detection limits for the HPLC method used.
Statistical Analysis
Data are expressed as mean±SEM.
The design of the experimental
protocol in certain sections of the study allowed each dog to serve as
its own control with regard to the basal values (percent aggregation
and basal bleeding time). When there were repeated measurements over
time, data were analyzed with repeated-measures ANOVA. For
single measurements, data were analyzed by either paired or
group analysis with Student's t test or ANOVA when
applicable; differences were considered significant at
P<.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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In Vitro Antiplatelet Efficacy
DMP 728 resulted in concentration-dependent antiplatelet effects in inhibiting agonist-induced (100 µmol/L ADP) platelet aggregation with an IC50 of 0.015 and 0.046 µmol/L in platelets obtained from mongrel dogs and humans, respectively (Fig 3
).
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Oral Antiplatelet Efficacy in Dogs
Conscious Dogs
DMP 728 given orally in soft gelatin capsules to conscious mongrel
dogs at different doses ranging from 0.02 to 1.0 mg/kg PO resulted in a
dose-dependent antiplatelet effect (Fig 4).
DMP 728 at these doses did not have any significant effects on
platelet counts (data not shown). Maximal antiplatelet
effects and 24-hour duration (40% to 60% inhibition at 24 hours after
administration) were achieved after single dose of DMP 728 (0.5 to 1.0
mg/kg PO). After analysis of the data with
repeated-measures ANOVA, the antiplatelet effect of DMP 728
at this dose in inhibiting ex vivo platelet aggregation was shown
to be statistically significant (P<.01) at all time points
except at the 0.25-hour point (P<.05) compared with
control. With the same analysis, the antiplatelet
effect of DMP 728 at 0.02 mg/kg PO was not statistically significant.
At 0.1 mg/kg PO, the antiplatelet efficacy was shown to be
statistically significant (P<.05) only at the 6-to-24-hour
time point.
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Anesthetized Dogs
The antiplatelet
efficacy of DMP 728 was determined
previously in anesthetized mongrel dogs at doses ranging from
0.001 to 1.0 mg/kg IV bolus by monitoring ex vivo ADP-induced
platelet aggregation (percent inhibition), bleeding time (minutes),
platelet count, and DMP 728 plasma levels.26 The
duration of the antiplatelet effect of DMP 728 was shown to be
dose-dependent. DMP 728 given to dogs at 0.01 mg/kg IV bolus
exhibited maximal efficacy in inhibiting platelet aggregation. In
the present investigation, 0.1 to 1.0 mg/kg IV or PO demonstrated
maximal and sustained antiplatelet effects (100% inhibition of
platelet aggregation, 20- to 25-minute prolongation of bleeding
time for up to 6 hours at 0.1 mg/kg IV and 1.0 mg/kg PO (Table
1). DMP 728 did not affect platelet count, red or
white blood cell count, or hematocrit when administered at 0.1 to 1.0
mg/kg IV or PO in anesthetized dogs (data not shown).
Additionally, DMP 728 did not have any effects on the different
coagulation parameters such as prothrombin, thrombin, or
activated partial thrombin time (data not shown). A close
correlation between the in vitro and ex vivo antiplatelet
inhibitory efficacy of DMP 728 in dogs was noted on the
basis of plasma levels as previously reported.26 At plasma
concentrations of 10 to 15 ng/mL, DMP 728 resulted in 50% to 60%
inhibition of ex vivo platelet aggregation.
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Antithrombotic Efficacy in Dogs
Coronary Artery
Thrombosis in Dogs (Folts'
Model)
In this model, a platelet-dependent thrombus is produced
in a mechanically injured coronary artery (LCx) in the presence
of a high degree of arterial
constriction.28 29 Under these conditions,
coronary blood flow is occluded as a platelet-rich
thrombus forms, which is followed by spontaneous dislodging of the
thrombus in a cyclic manner (CFR). This study examined the
antithrombotic efficacy of DMP 728 at 0.005 and 0.01 mg/kg IV bolus in
this platelet-mediated thrombosis model. In 20
anesthetized dogs, arterial injury, along with a
high degree of stenosis of the LCx, resulted in cyclic
platelet-rich thrombus formation, leading to repeated patterns
of CFR. In saline-treated dogs (n=11), seven to eight CFR continued
consistently throughout the experiment. DMP 728 at 0.005 and
0.01 mg/kg IV bolus (n=4 and n=5, respectively) or 0.6 and 1.0
mg/kg PO
(n=4 and n=6) prevented CFR in 2 of 4, 5 of 5, 3 of 3, and 6 of
6 dogs,
respectively (Fig 5). Maximal antiplatelet and
antithrombotic efficacies were demonstrated at 0.01 mg/kg IV bolus and
0.6 mg/kg PO in anesthetized dogs (Table 1
and Fig
5). The
onset for the antithrombotic effects of DMP 728 was immediate, with a
dose-dependent duration of action. The antithrombotic efficacy of
DMP 728 also was maintained on rechallenge with epinephrine
(data not shown). When administered orally, DMP 728 resulted in maximal
antithrombotic efficacy at 0.6 to 1.0 mg/kg (Fig 5). At these
doses,
DMP 728 prevented the incidences of CFR in 100% of the dogs for the
total period (3 hours) of the study (Fig 5).
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Carotid Artery Thrombosis in Dogs (Electrolytic Injury
Model)
A total of 30 mongrel dogs divided into five groups were
entered
in this arm of the study. The effect of DMP 728 on the incidence of
occlusion, time to occlusion, and thrombus weight (Table 2) of
an electrolytically induced thrombosis in a canine
carotid artery model was examined. DMP 728 administered at 0.1 to 1.0
mg/kg IV or PO resulted in 60% to 100% prevention of the incidence of
occlusion (Table 2). DMP 728 administration resulted in a
significant
prolongation of the time to occlusion, along with a significant
reduction (P<.01) in the weight of the thrombus formed
(Table 2). A significant prolongation of the time to occlusion
to >240
minutes (ie, 100% prevention of the incidence of occlusion for up to
the maximum period of the study) was demonstrated.
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Pharmacokinetics of DMP 728
The oral absorption of DMP 728 is
shown to be rapid, with peak
plasma concentrations attained within 1.4 hours (1.4±0.06 hours) after
oral administration at 2.0 mg/kg PO (Fig 6). The rate of
gastrointestinal absorption after 2.0 mg/kg PO of DMP 728 in aqueous
solution is similar to that after 2.0 mg/kg PO in gelatin capsule. Fig
6 shows the mean plasma concentration–time curves of DMP
728;
Table 3 shows the pharmacokinetic
parameters. DMP 728 has been shown not to be metabolized
and to be excreted mainly through the kidney in unchanged form (data
not shown). The mean values for half-life, systemic clearance, and
volume of distribution are 4.7 hours, 4.3
mL·min-1·kg-1,
and 0.8 L/kg, respectively. The absolute oral bioavailability of DMP
728 in dogs was 9.3% (Table 3).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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It is well recognized that GPIIb/IIIa, through its binding to circulating fibrinogen, is the final common pathway for all agonist-induced platelet aggregate formation.1 2 3 The binding of fibrinogen is mediated in part by the RGD recognition sequence, which is common to other adhesive proteins that bind to GPIIb/IIIa receptors or other integrins.3 Several RGD-containing peptides and the 7E3 monoclonal antibody against GPIIb/IIIa have been shown to block fibrinogen binding and prevent the formation of platelet thrombi.14 15 16 18 31 However, problems are associated with the use of peptides as antithrombotic agents, including their short survival time or metabolic instability in the circulation, which might be advantageous in permitting rapid reversal of the antihemostatic effect in bleeding but clearly poses a burden in terms of quantity needed and the lack of oral activity. This certainly is not the case with DMP 728, which is metabolically stable and very effective at extremely low doses when given orally in solution or soft gelatin capsules. In contrast to other antiplatelet agents such as aspirin, ticlopidine, and hirudin, which are effective primarily against some but not all platelet agonists in inhibiting platelet aggregation in human platelet-rich plasma, DMP 728 demonstrated high affinity and similar potency in inhibiting platelet aggregation, regardless of the agonist used.32 33 Additionally, DMP 728 demonstrated a high degree of selectivity toward GPIIb/IIIa receptors compared with the closely related vitronectin receptors on endothelial cells or other adhesion receptors on platelets or leukocytes.31 DMP 728 is shown to be metabolically stable under various conditions. In vivo studies in rats and dogs demonstrated a lack of metabolism. Additionally, a minimal and perhaps insignificant level (15% to 25%) of plasma protein binding was demonstrated with DMP 728. Oral or intravenous administration of DMP 728 in anesthetized dogs produced a dose-dependent inhibition of ex vivo platelet aggregation. The oral antiplatelet effects of DMP 728 were shown at relatively low single dose levels (0.1 to 1.0 mg/kg PO) compared with the higher dose levels required from the recently reported orally active GPIIb/IIIa antagonist SC-54684A (2.5 to 5.0 mg/kg PO twice a day in dogs).25 It also was shown that the antagonism of GPIIb/IIIa receptors in anesthetized dogs by DMP 728 had no effects on any of the different hemodynamic parameters (data not shown) or platelet counts over the wide range of doses administered. There was no observed spontaneous bleeding at any sites other than the confined sites of bleeding time measurements. These data suggest that DMP 728 is a potent and orally active antiplatelet and antithrombotic agent with high affinity for GPIIb/IIIa. Additionally, the high affinity and specificity of DMP 728 for GPIIb/IIIa might explain the observed optimal efficacy-to-safety ratios. Antithrombotic efficacy was demonstrated in various models of arterial thrombosis. In an in vitro isolated rabbit aorta perfused with epinephrine-primed human blood and injured either by external clamping or with balloon-induced intimal wall injury, DMP 728 maximally inhibited both platelet deposition and arterial flow reduction at 0.1 µmol/L.33 Neither aspirin nor ticlopidine at concentrations up to 1 mmol/L was effective in this model. In the Folts' model, DMP 728 inhibited CFR with an ED50 of 0.005 mg/kg IV and ED100 of 0.01 mg/kg IV and <0.6 mg/kg PO. In the Folts' model, DMP 728 (0.01 mg/kg IV or 0.6 mg/kg PO) demonstrated maximal efficacy in inhibiting ex vivo platelet aggregation, totally preventing CFR, and maintaining coronary flow and coronary arterial patency. These studies suggest the potential of DMP 728 in unstable angina. In contrast, aspirin (0.5 to 5.0 mg/kg IV) was shown to be marginally effective in this model and ineffective against epinephrine-reinduced CFR.16 Hence, it is anticipated that DMP 728 might be more effective than aspirin in platelet-mediated thrombosis because platelet activation could be reinduced following elevation of catecholamines, rupture of atherosclerotic plaques, or progression of atherosclerotic lesions. Furthermore, maximal efficacy against epinephrine-reinduced CFR was demonstrated with other GPIIb/IIIa antagonists such as SK&F 106760.16 These results suggest greater efficacy for GPIIb/IIIa antagonists compared with aspirin or ticlopidine.
In the carotid artery thrombosis model in dogs, DMP 728 (0.1 to 1.0 mg/kg IV or PO) demonstrated antithrombotic efficacy in electrically induced carotid artery thrombosis. Despite the increased thrombogenic stimulus as demonstrated in the electrolytically induced arterial thrombosis in the carotid artery, DMP 728 also could limit further platelet deposition at the site of the damage. However, it remains to be determined in a clinical setting how long after thrombolysis platelet inhibition must be sustained to render injured vessel and residual thrombus mass nonthrombogenic. These studies indicate that DMP 728 is a potent antithrombotic agent in preventing thrombus formation at different levels of injury or at different proportions of platelet or fibrin involvement. These data suggest that DMP 728, a low-molecular-weight GPIIb/IIIa receptor antagonist, may have therapeutic potential as an effective oral antithrombotic agent in coronary and carotid artery thromboembolic disorders. It is clear that the antithrombotic efficacious doses vary according to the type of model used. In the Folts' model in which the thrombus is mainly platelet dependent, relatively low doses of DMP 728 resulted in maximal antithrombotic efficacy. In contrast, in the electrolytic injury model in which the thrombus is associated with mixed platelet, fibrin, monocyte, and red blood cells, relatively high doses of DMP 728 are required for maximal antithrombotic efficacy.
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Selected Abbreviations and Acronyms |
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Received May 24, 1995; revision received August 10, 1995; accepted September 11, 1995.
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References |
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