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(Circulation. 1995;91:411-416.)
© 1995 American Heart Association, Inc.

Articles

Extended Inhibition of Platelet Aggregation With the Orally Active Platelet Inhibitor SC-54684A

James A. Szalony, MS; Neal F. Haas, BS; Anita K. Salyers, BS; Beatrice B. Taite, AA; Nancy S. Nicholson, MS, MBA; Devan V. Mehrotra, PhD; Larry P. Feigen, PhD

From the Department of Cardiovascular Diseases Research (J.A.S., N.F.H., A.K.S., B.B.T., N.S.N., L.P.F.) and the Department of Clinical Statistics, Searle, Skokie, Ill.

Correspondence to James A. Szalony, Searle, 4901 Searle Pkwy, Skokie, IL 60077.

	Abstract

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Background Platelet aggregation is important in thrombotic events, and platelets play a major role in the etiology of several cardiovascular diseases. Platelet aggregation requires the binding of fibrinogen (fgn) to activated platelets. Synthetic peptides modeled after the RGD binding sequence on the fgn -chain block the platelet glycoprotein (GP) IIb/IIIa receptor for fgn and effectively inhibit aggregation. SC-54684A (SCp, orally active prodrug of the active moiety SC-54701, SCa) is a mimetic of the RGD-containing peptide sequence that is recognized by the platelet GPIIb/IIIa receptor. SCa blocks the binding of fgn to the platelet and therefore prevents platelet aggregation in response to all agonists.

Methods and Results SCp was administered orally at 1.25, 2.5, 5.0, and 7.5 mg/kg in a single-dose, dose-ranging study. Blood samples were taken periodically for 24 hours, and platelet-rich plasma was prepared and tested for inhibition of ex vivo collagen-induced platelet aggregation. The plasma concentration of active moiety was determined by bioassay. The time, inhibition, and concentration data were used to predict two doses that would result in minimum daily inhibition levels of 30% and 70% when administered twice daily (0.6 and 2.4 mg/kg, respectively). SCp was administered orally to conscious dogs twice daily for 14 days (after dose adjustment). Blood samples were obtained at daily peak and trough plasma levels (predicted from dose-ranging study). Inhibition of ex vivo collagen-induced platelet aggregation and concentration of active moiety in the plasma were determined. Average inhibition of platelet aggregation and plasma concentration of active moiety amounted to approximately 21% and 14 ng/mL at 1.5 mg/kg BID and 75% and 24 ng/mL at 2.4 mg/kg BID at daily minimum plasma levels (trough) in steady state. Platelet counts in the 2.4-mg/kg group declined from 3.2x10⁵/µL to 2.5x10⁵/µL in the first 9 days of dosing, with no further decline despite continued administration of compound. No changes were observed in the animals receiving 1.5 mg/kg.

Conclusions The results of the dose-ranging study show that oral administration of SCp results in dose-dependent inhibition of platelet aggregation. As shown in the 14-day administration, this dose-dependent inhibition can be maintained for an extended period while exhibiting no adverse effects. SCp is a leading candidate for development and is currently in clinical trials.

Key Words: platelets • thrombosis • platelet aggregation inhibitors

	Introduction

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Long-term antiplatelet therapy has been found to be beneficial in patients with a history of myocardial infarction (MI), stroke, or other vascular disease.^{1 2} Commonly used antiplatelet agents such as ticlopidine and aspirin are clinically effective. Ticlopidine treatment resulted in a 30% reduction in risk of stroke, MI, or vascular death in the Canadian-American Ticlopidine Study.³ Ticlopidine was shown to reduce the risk of fatal and nonfatal stroke by 21% compared with aspirin therapy over 3 years of treatment in the Ticlopidine-Aspirin Stroke Study.⁴ In ISIS-2, oral aspirin versus placebo resulted in a 23% reduction in the risk of vascular death in the first 5 weeks after suspected acute MI. Additionally, patients treated with oral aspirin after fibrinolysis with streptokinase had a 42% reduction in the risk of vascular death when compared with patients allocated to both placebos.¹ However, there are disadvantages to current therapy. Ticlopidine inhibits aggregation only to ADP,^{5 6} and aspirin inhibits aggregation only in response to stimuli that are mediated by arachidonic acid metabolism (cyclooxygenase pathway⁷ ). Also, ticlopidine has been associated with agranulocytosis, a rare but potentially serious side effect.⁸ Aspirin not only irreversibly acetylates platelet cyclooxygenase but also inhibits endothelial cyclooxygenase and its potentially beneficial production of prostacyclin.⁹ In addition, long-term therapy with aspirin or other platelet-inhibiting, nonsteroidal anti-inflammatory drugs (NSAIDs) carries the risk of gastrotoxicity.^{9 10}

Another approach to inhibiting platelet aggregation is to block fibrinogen (fgn) binding to glycoprotein (GP) IIb/IIIa on the membranes of activated platelets using anti-GPIIb/IIIa antibodies or small, nonpeptide mimetics of the RGDX sequence on the fgn -chain. Because fgn binding to GPIIb/IIIa on activated platelets is an obligatory step in platelet aggregation,¹¹ these molecules block aggregation regardless of the activating stimulus. This mechanism should afford these compounds greater benefit in the circulation, where multiple stimuli are present (eg, exposed subendothelial collagen in injured vessels or shear forces near atherosclerotic plaques).

SC-54684A (SCp) is a prodrug of a nonpeptide mimetic of the tetrapeptide RGDF. SCp is relatively inactive when tested in vitro but leads to inhibition of ex vivo platelet aggregation after oral administration. The active metabolite of SCp, SC-54701A (SCa), is a potent inhibitor of GPIIb/IIIa and exhibits specificity for this receptor with respect to other integrins.¹² SCp has a greater oral bioavailability and longer duration of action than any agent of this class described in the literature to date.^{13 14 15 16} This report describes the use of SCp to maintain platelet inhibition in dogs over a 2-week period. We demonstrate the effects of repeated dosing and show that SCp leads to predictable and reversible antiplatelet effects. There were no serious adverse effects associated with administration of SCp.

The specificity, oral bioavailability, duration characteristics, and the apparent safety of SCp indicate that it has potential for clinical use as an oral agent for the prevention of platelet aggregation resulting in thrombosis. Based on these characteristics, SCp has been chosen as a leading candidate for development and is currently in clinical trials.

	Materials

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Dogs (beagles; weight, 7 to 10 kg) were purchased from White Eagle, Doylestown, Pa. Platelet-rich plasma (PRP) for the bioassay was prepared from blood obtained from untreated dogs. Collagen (equine tendon, Chrono-Log) was diluted 1:2 (vol/vol) with isotonic glucose solution to yield a concentration of 333 µg/mL. Both SCa, 3S-[[4-[[4(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate, monohydrochloride, used as a standard in the bioassay, and SCp, ethyl 3S-[[4-[[4(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate, monohydrochloride were synthesized at Searle. SCp was administered as the hydrochloride salt (MW, 428.2). Oral doses were calculated on the basis of the free base (MW, 358.4). A 1-mg/kg dose of the ester is 2.79 µmol/kg, which is equivalent to 1.19 mg/kg of hydrochloride salt.

	Methods

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Ex Vivo Aggregation
Ex vivo platelet aggregation was measured in the dose-ranging study and several times during the extended dosing study. Two-milliliter blood samples were withdrawn from the cephalic veins of conscious dogs into tubes containing 0.2 mL 3.8% Na citrate. Blood was centrifuged at 266g for 6 minutes to prepare PRP. Platelet-poor plasma (PPP) from untreated dogs, which had been collected, pooled, and frozen previously, was used to set the baseline in the aggregometer (Bio/Data aggregation profiler, model PAP-4). A common pool of PPP was used in all aspects of this study so that the baseline would be the same for aggregations that were performed. Percent aggregation was established by adding 50 µL of collagen (33.3 µg/mL, final concentration) to 450 µL of PRP and measuring aggregation for 4 minutes.

Bioassay
The concentration of the active agent (SCa) in plasma was estimated using plasma from treated dogs to inhibit aggregation in PRP from donor dogs by the method of Salyers et al.¹⁷ Briefly, blood was collected in citrate (9:1 vol/vol) from nontreated dogs and centrifuged (500g, 3 minutes, x2) to yield PRP (platelet count 4.0x10⁸ platelets/mL). The remaining blood sample was centrifuged at 1800g for 10 minutes to obtain PPP used to set baseline in the aggregometer and for dilution of samples. Plasma (225 µL) from treated dogs was mixed with 225 µL of PRP from donor dogs and incubated for 2 minutes at 37°C in the aggregometer. Collagen (50 µL, 333 µg/mL) was added, and aggregation was monitored for an additional 4 minutes. Final percent aggregation was recorded. Percent inhibition was calculated, and the concentration of active compound in plasma from treated dogs was calculated by comparison with the inhibition observed in a standard curve of plasma to which had been added known amounts of SCa. If the sample plasma from the treated animals produced 80% inhibition, the sample was diluted with PPP to produce inhibition that was within the 20% to 80% range of the standard curve.

Oral Administration
Dose Range Study
Eight dogs were weighed and randomly divided into four groups of two. Before administration of SCp, two blood samples (2x2 mL each) were drawn by venipuncture from the cephalic vein of each animal. Platelet aggregation was measured as described above. Aggregation in these samples was used as the baseline (0% inhibition). SCp was administered orally (single dose) by gelatin capsule. Four doses (n=2/dose) were administered: 1.25, 2.5, 5.0, and 7.5 mg/kg. Blood samples (2x2 mL) were collected at selected times for 14 hours and again at 24 hours after dosing. Blood was centrifuged, and PRP was prepared as described above. The remaining blood was centrifuged for 2 minutes at 12 000g to prepare PPP for determination of concentration of active moiety in the plasma samples by bioassay (see above). Inhibition of collagen-induced platelet aggregation was determined by comparing aggregation responses in the samples after compound administration with the responses of samples before compound administration (baseline). Inhibition and plasma concentration data were analyzed and, using the principle of superposition, two doses were predicted that would lead to minimum daily inhibition of 30% or 70% at the time of minimum plasma concentration (just before the morning dose) when the compound was administered twice daily.

Extended Administration
Dogs were assigned to two treatment groups (n=4/group). Control aggregation was determined as stated previously. Treatment was by oral administration of SCp in gelatin capsules and continued for 16 days. A third group of four dogs received placebo and served as controls. Dogs were dosed (initially one group received 0.6 mg/kg and the other received 2.4 mg/kg BID) twice daily, at 7:30 AM and 3:30 PM. The study was designed to achieve plasma levels that resulted in 30% and 70% inhibition in steady state at the time of minimum plasma concentration, as predicted from the dose range study. Blood samples were collected by venipuncture for determination of ex vivo platelet aggregation, plasma concentration of active compound as measured by bioassay, platelet count and platelet volume (as part of a complete blood count, [CBC]), cell differentials, activated partial thromboplastin time, prothrombin time, fibrinogen concentration, and liver/kidney function (Table). CBC was performed using a Coulter S+IV using the manufacturer's reagents and recommended procedures. Coagulation parameters were measured using a Biodata MCA 110 using the manufacturer's reagents and recommended procedures. Liver function parameters were measured using a Cobas Fara I & II using the manufacturer's reagents and recommended procedures (Roche Diagnostic Systems Inc). Kidney function parameters were measured using a Synchron AS/Astra 8 using the manufacturer's reagents and recommended procedures (Beckman Instruments Inc). A repeated-measures ANOVA was used to detect statistically significant differences in the square roots of platelet counts between treated and control groups. Blood samples were collected before initial dosing and during the course of treatment at specified intervals. Samples to determine minimum plasma concentration and inhibition were collected immediately before morning dosing, 16 hours after previous dosing. Samples to determine maximum plasma concentration and inhibition were collected 5 hours after administration of the morning dose (time of peak concentration observed in the dose-ranging study). Aggregation measurements were made each day for the first 3 days to ensure that the targeted platelet inhibition levels were achieved. Dose adjustments were made based on these aggregation measurements. After 2 days, the 0.6-mg/kg dose was adjusted upward to 1.2 mg/kg and then to 1.5 mg/kg on day 3 because the inhibition of aggregation was less than predicted by the dose-ranging study. Subsequent samples were obtained every third day for a total of 17 days. Plasma samples collected for bioassay throughout the study were frozen for subsequent analysis.

View this table: [in this window] [in a new window]   Table 1. Clinical Chemistry Tests of Liver and Kidney Function

	Results

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Dose Range Study
Doses of 1.25 mg/kg to 7.5 mg/kg led to dose- and time-dependent inhibition of collagen-induced platelet aggregation (Fig 1a). Plasma concentrations of the active compound after oral administration of SCp were determined by bioassay (Fig 1b). Maximum concentrations of the active metabolite measured in the plasma were 60, 128, 245, and 393 ng/mL after doses of 1.25, 2.5, 5.0, and 7.5 mg/kg, respectively, suggesting that plasma levels were proportional to oral dose. This evidence of dose proportionality allowed for prediction of doses required in a long-term study based on pharmacokinetic parameters. One dog receiving 1.25 mg/kg exhibited no response and was not included in the analysis or figures. Doses that were predicted to yield the steady-state target trough levels were 0.6 mg/kg BID to yield a 10-ng/mL plasma concentration, expected to produce 30% inhibition, and 2.4 mg/kg BID to yield a 23 ng/mL plasma concentration, expected to produce 70% inhibition. Anticipated time to achieve steady-state target trough levels was about 48 hours.

View larger version (18K): [in this window] [in a new window]   Figure 1. Line plots. a, Percent inhibition of ex vivo platelet aggregation vs time after administration of a single oral dose of SCp. SCp was administered in a gelatin capsule and blood samples drawn periodically after dosing. Platelet-rich plasma (PRP) was prepared, and and inhibition of ex vivo platelet aggregation to collagen was measured in an aggregometer. Aggregation in PRP collected before dosing was used as a control for each animal. Platelet-poor plasma (PPP) for bioassay was prepared from the remaining blood. For each point, n=2 except 1.25 mg/kg, for which one dog showed no activity and was not included. b, Plasma concentration of active compound as measured by bioassay vs time after administration of a single oral dose of SCp. SCp was administered in a gelatin capsule, blood samples were drawn periodically after dosing, and PPP was prepared. Sample PPP was mixed 1:1 with PRP collected from naive donor dogs, and collagen-stimulated aggregation was measured in an aggregometer. Aggregation with PPP collected before dosing was used as a control for each animal. Inhibition with PPP collected after dosing was compared with a standard curve of SCa to determine plasma concentration. For each point, n=2 except 1.25 mg/kg for which one dog showed no activity and was not included.

Extended Administration
Platelet Inhibition
SCp was administered to animals twice daily for 16 days. Aggregation measurements performed on samples taken on day 17 indicated that recovery of platelet function was in progress. Platelet function was fully restored (no inhibition of aggregation) in all animals by day 20. Fig 2 illustrates the trough levels of platelet inhibition for both the high-dose and low-dose groups at steady state. During the steady-state period, average inhibition of platelet aggregation at the high dose of 2.4 mg/kg BID amounted to 76±3%, and average inhibition at the low dose of 1.5 mg/kg BID was 27±1%.

View larger version (15K): [in this window] [in a new window]   Figure 2. Plot of minimum daily level of inhibition of ex vivo platelet aggregation over the period of extended dosing. Blood samples to determine minimum inhibition were collected immediately before morning dosing (16 hours after previous dosing). Platelet-rich plasma (PRP) was prepared, and an inhibition of ex vivo platelet aggregation to collagen was measured in an aggregometer. Aggregation in PRP collected before initiation of dosing was used as a control for each animal. Platelet-poor plasma for bioassay was prepared from the remaining blood. Low dose was 0.6 mg/kg at a, 1.2 mg/kg at b, and 1.5 mg/kg at c. Data are presented as mean±SE (n=4).

No bleeding episodes, either spontaneous or after blood sampling, were observed in any of the animals. The time required to stop bleeding after venipuncture was not observed to be any longer in treated animals than in control dogs, even when platelet inhibition was 100%. Template bleeding times were not measured in the animals from the present study. A correlation of bleeding time and ex vivo platelet aggregation after treatment with SCa is presented by Nicholson et al.¹²

Plasma Concentrations
Steady-state trough plasma concentrations were 24±3 ng/mL and 14±1 ng/mL for the 2.4-mg/kg BID and the 1.5-mg/kg BID doses, respectively (Fig 3a). Fig 3b illustrates peak and trough plasma levels of active compound after administration of 2.4 mg/kg BID. Peak plasma concentrations in these animals averaged 99±23 ng/mL over the 2-week, steady-state period.

View larger version (17K): [in this window] [in a new window]   Figure 3. a, Plot of minimum daily plasma concentration of active compound, as measured by bioassay, over the period of extended dosing. Blood samples to determine minimum plasma concentration were collected immediately before morning dosing (16 hours after previous dosing). Platelet-poor plasma (PPP) was prepared. Sample PPP was mixed 1:1 with platelet-rich plasma collected from naive donor dogs, and collagen-stimulated aggregation was measured in an aggregometer. Aggregation with PPP collected before initiation of dosing was used as a control for each animal. Inhibition with PPP collected after dosing was compared with a standard curve of SCa to determine plasma concentration. Low dose was 0.6 mg/kg at a, 1.2 mg/kg at b, and 1.5 mg/kg at c. Data are presented as mean±SE (n=4). b, Plot of maximum and minimum daily plasma concentrations of active compound, as measured by bioassay, over the period of extended dosing for animals receiving 2.4 mg/kg BID SC-54684. Blood sample to determine minimum plasma concentration was collected immediately before morning dosing and 16 hours after previous dosing. Blood sample to determine maximum plasma concentration was collected 5 hours after morning dosing (time of peak concentration observed in the dose range study.) PPP was prepared. Sample PPP was mixed 1:1 with platelet-rich plasma collected from naive donor dogs, and collagen-stimulated aggregation was measured in an aggregometer. Aggregation using PPP collected before initiation of dosing was used as a control for each animal. Inhibition using PPP collected after dosing was compared with a standard curve of SCa to determine plasma concentration. Data are presented as mean±SE (n=4).

Hematologic Profile
Fig 4 illustrates the results of platelet count determinations during the study. Platelet count was reduced from about 320 000/µL before treatment to about 250 000/µL by day 9 in the high-dose group. No further decrease was noted despite continued dosing. Using a repeated-measures ANOVA, on average, square roots of platelet counts in the 2.4-mg/kg BID group were found to be significantly lower (P<.05) than those in the control group on days 6 through 20. (The square root transformation was used to make the data better suited for a formal statistical analysis.) Despite the relative decrease, platelet counts in all dogs remained within the normal range. No changes were seen in the low-dose group. Platelet volumes were increased slightly (9.9 fL initial, 12.9 fL final) in the high-dose group. No changes were seen in the low-dose group. Data summarized in Fig 5 suggest an inverse relation between platelet count and platelet volume. No changes were observed in any other test in the CBC (data not shown). No changes were observed in the blood coagulation parameters of prothrombin time, activated partial thromboplastin time, or plasma fibrinogen concentrations (data not shown).

View larger version (16K): [in this window] [in a new window]   Figure 4. Plot of whole blood platelet counts over the period of extended dosing. Low dose was 0.6 mg/kg at a, 1.2 mg/kg at b, and 1.5 mg/kg at c. Data are presented as mean±SE (n=4). *Significantly lower than control mean (P<.05).

View larger version (18K): [in this window] [in a new window]   Figure 5. Plot of whole blood platelet counts and platelet volumes over the period of extended dosing for the animals receiving 2.4 mg/kg BID. Data are presented as mean±SE (n=4).

Clinical Chemistry
Liver and kidney function data from blood samples taken before and after the study during the long-term study were analyzed. Since it was expected that any effects would be dose related, the observed differences between the prestudy and poststudy values were analyzed by a sequential trend testing strategy. Using this approach (for each variable separately), the means in the placebo and 1.5-mg/kg group were formally compared only if the difference between means in the placebo and 2.4-mg/kg group was deemed statistically significant. Since the direction of the drug effect (if any) was unknown, a two-sided trend test was used (a trend analog of the Brown-Forsythe test¹⁸ ). The only evidence of statistical significance in terms of prestudy and poststudy differences was found in the comparison placebo versus 2.4 mg/kg for albumin (31±1 and 31±1 versus 31±1 and 32±2; prestudy and poststudy, placebo versus 2.4 mg/kg, respectively.) Data from other clinical chemistry tests did not exhibit any differences and are not shown.

	Discussion

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In several large clinical trials, long-term antiplatelet therapy has been shown to reduce MI, stroke, and vascular mortality in patients at high risk for occlusive vascular disease.^{1 19 20} It is expected that orally active inhibitors of platelet GPIIb/IIIa will be of great clinical value as highly potent and specific antiplatelet agents. Recently, there have been reports of cyclic peptide and RGD peptidomimetic GPIIb/IIIa antagonists that exhibited some degree of oral bioavailability.^{13 14 15 16 21} In this report, we describe a compound with the highest level of oral bioavailability thus far reported. We also demonstrate for the first time that long-term therapy with an orally active GPIIb/IIIa antagonist leads to a stable, reversible antiplatelet effect without severe adverse effects.

We demonstrated in our preliminary dose-ranging study that plasma levels of SCa (measured by bioassay) were proportional to dose in the range from 1.25 to 7.5 mg/kg. Pharmacokinetic predictions were used to define a regimen that would result in target plasma concentrations of SCa leading to the desired levels of platelet inhibition. Although the lower dose had to be adjusted twice, steady-state platelet inhibition for both doses was achieved after 4 days. These results demonstrate that a desired antiplatelet effect may be achieved quickly despite the steep dose-response curve exhibited by these compounds.¹²

The dosing regimen was designed to maintain specific levels of platelet inhibition at trough plasma concentrations of SCa (ie, the lowest concentrations during a 24-hour period). SCp was administered twice daily in an effort to minimize the difference between peak and trough plasma concentrations. After dosing, SCa concentrations, and subsequently, platelet inhibition, increased to a peak approximately 5 hours after dosing. However, at no time did SCa levels or inhibition fall below the desired targets. To maintain the target trough levels, peak levels of SCa were about four times those measured at the trough. For example, at the 2.4-mg/kg BID dose, plasma concentrations at peak were 99 ng/mL compared with 24 ng/mL at trough. The peak to trough ratio may be of interest because the potential for adverse effects is likely to increase with increasing plasma levels of active compound. Inhibition was 100% for only a portion of the day for both the 1.5- and 2.4-mg/kg doses. These doses gave the target levels of inhibition (27% and 76%) of collagen-induced platelet aggregation at trough levels.

In the present study, collagen was the only agonist used for platelet aggregation because it is the agonist routinely used in our ex vivo procedures. However, previous studies have shown that SCa is effective at inhibiting platelet aggregation resulting from several stimuli, including ADP,¹² thrombin (in washed platelets), and electrical injury of the endothelium (data not shown).

Several parameters were monitored over the course of the study, in addition to the animals being observed for general condition. Platelet counts decreased in the group receiving the high dose for the first 9 days of the study, with subsequent counts being relatively constant. In addition, there was an increase in platelet volume that followed the same course as the decrease in platelet count. The causes and implications for this apparent relation are unknown. Kleiman et al²² reported thrombocytopenia in 6 of 54 patients receiving the antiplatelet antibody 7E3 Fab. Severe thrombocytopenia occurred in 2 of 54 patients but in none after a change in the procedure for handling the antibody. In the 4 less severe cases, the authors do not exclude the 7E3 Fab as a cause of the thrombocytopenia but do show that there is no common time course between the incidents. The effect of chronic inhibition of the GPIIb/IIIa receptor on platelet counts in humans remains to be determined. However, at no time in the present study did platelet counts fall below the normal range for the dog.

The only evidence of statistical significance in the clinical chemistry profile was an increase in the serum albumin levels of the 2.4-mg/kg animals. Because no change was observed in the 1.5-mg/kg group and the albumin levels in the high-dose group remained within the normal range for the dog, this increase was not considered biologically significant.

This report shows that an orally available compound based on the RGD sequence of fibrinogen can give persistent inhibition of ex vivo platelet aggregation. This inhibition is dose related and predictable from concentrations of active compound in the plasma. At doses and plasma concentrations resulting in 76% and 27% minimum daily inhibition of aggregation, only minor physiological effects (slight increase in platelet volume and decrease in platelet count and a statistically although not biologically significant increase in serum albumin concentration) were observed. No parameters fell outside of normal ranges for the dog. From this study, it is estimated that a dose of 2.0 mg/kg BID would provide a minimum of 50% inhibition of ex vivo platelet aggregation over a 24-hour period. However, it is not yet known what degree of inhibition will be required chronically to prevent thrombotic events.

Recent studies with the anti–GPIIb/IIIa antibody 7E3 suggest that >90% inhibition of platelet aggregation is required to prevent acute thrombotic events in percutaneous transluminal coronary angioplasty,²² while studies with integrilin in unstable angina showed a significant reduction in ischemic events with 40% inhibition of aggregation.²³ Further studies will be required to determine what level of inhibition will be required in both chronic and acute situations with this new class of platelet inhibitors. SCp is under development as an oral RGD mimetic antiplatelet agent and is currently in clinical trials.

Received May 27, 1994; accepted August 19, 1994.

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