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WO1997035592A1 - Antagonistes iib/iiia co-administres avec l'aspirine et/ou l'heparine - Google Patents

Antagonistes iib/iiia co-administres avec l'aspirine et/ou l'heparine Download PDF

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Publication number
WO1997035592A1
WO1997035592A1 PCT/US1997/003735 US9703735W WO9735592A1 WO 1997035592 A1 WO1997035592 A1 WO 1997035592A1 US 9703735 W US9703735 W US 9703735W WO 9735592 A1 WO9735592 A1 WO 9735592A1
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amino
sca
heparin
platelet
phenyl
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PCT/US1997/003735
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English (en)
Inventor
Robert J. Anders
Larry P. Feigen
Mark N. Milton
Peter F. Smith
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G.D. Searle & Co.
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Priority to AU22023/97A priority Critical patent/AU2202397A/en
Publication of WO1997035592A1 publication Critical patent/WO1997035592A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof

Definitions

  • This invention relates to the coadministration of a lib/Ilia receptor antagonist with aspirin for use in inhibiting platelet aggregation when administered to mammals which coadministration significantly lowers the required dosage of lib/Ilia antagonist to be administered for effectively inhibiting platelet aggregation.
  • Fibrinogen is a glycoprotein present as a normal component of blood plasma. It participates in platelet aggregation and fibrin formation in the blood clotting mechanism. Platelets are cellular elements found in whole blood which also participate in blood coagulation. Fibrinogen binding to platelets is important to normal platelet function in the blood coagulation mechanism. When a blood vessel receives an in urv, the platelets binding to fibrinogen will initiate aggregation and form a thrombus. Interaction of fibrinogen with platelets occurs through a membrane glycoprotein complex, known as GPIIb/IIIa; this is an important feature of the platelet function. Inhibitors of this interaction are useful in modulating or preventing platelet thrombus formation.
  • GPIIb/IIIa membrane glycoprotein complex
  • fibronectin is a major extracellular matrix protein, interacts with fibrinogen and fibrin, and with other structural molecules such as actin, collagen and proteoglycans.
  • Various relatively large polypeptide fragments in the cell-binding domain of fibronectin have been found to have cell-attachment activity. - 2 -
  • 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. In most of these serious cardiovascular disorders, intracoronary thrombus is present.
  • the thrombus is generally formed by activated platelets that adhere and aggregate at the site of endothelial injury. 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.
  • ASA aspirin
  • ticlopidine which predominantly interferes with the ability of adenosine diphosphate (ADP) to stimulate platelets
  • thromboxane A 2 synthetase inhibitors which act against thromboxane A 2 .
  • fgn fibrinogen binding [at the arginine-glycine- aspartate (RGD) recognition sequence] to the glycoprotein (GP) Ilb/IIIa receptor on activated platelets.
  • RGD arginine-glycine- aspartate
  • GP glycoprotein
  • Ilb/IIIa receptor glycoprotein
  • a drug therapy that inhibits platelet aggregation induced by a variety of physiological agonists would provide even greater protection than that provided by the various agents listed above.
  • Fibrinogen receptor antagonists block the fibrinogen/platelet interaction at the glycoprotein (GP) Ilb/IIIa receptors, inhibiting an essential step in thrombus formation.
  • 3S-[[ -[[4-aminoiminomethyl)- phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoic acid, a fibrinogen receptor antagonist is the active metabolite of ethyl 3S-[[4-[[4- (aminoiminomethy1)phenyl]amino]-1,4-dioxobutyl]amino]- 4-pentynoate, an orally active antithrombotic agent now in clinical trials.
  • 3S-[[4-[[4-aminoiminomethyl)phenyl]amino]-l,4- dioxobutyl]amino]-4-pentynoic acid is a GPIIb/IIIa receptor antagonist that blocks the binding of fibrinogen to the platelet and prevents platelet aggregation.
  • Intravenous 3S-[ [4-[[4- aminoiminomethyl)phenyl]amino]-l,4-dioxobutyl]amino]-4- pentynoic acid, aspirin (ASA) , heparin and combinations of these agents were evaluated in an anesthetized canine model of thrombosis and inhibition of collagen- induced ex vivo platelet aggregation was determined.
  • 3S-[[4-[[4-aminoiminomethyl)phenyl]-amino]-l,4- dioxobutyl]amino]-4-pentynoic acid prevents thrombotic occlusion and inhibits platelet aggregation in a dose- dependent manner.
  • the present invention is directed to coadministration of the fibrinogen receptor antagonists 3S-[[4-[ [4-aminoiminomethyl)phenyl]amino]-l,4- dioxobutyl]amino]-4-pentynoic acid or ethyl 3S-[[4-[[4- ( minoiminomethy1)phenyl]amino]-l,4-dioxobutyl]amino]- 4-pentynoate together with an anti-platelet agent such as aspirin and/or an anti-coagulant such as heparin.
  • an anti-platelet agent such as aspirin and/or an anti-coagulant such as heparin.
  • Such coadministration comprises administering a therapeutically effective amount of aspirin or heparin to a mammal in need of a platelet aggregation inhibitor which therapeutically effective amount significantly lowers the amount of 3S-[[4-[[4- aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4- pentynoic acid or ethyl 3S-[[4-[[4-[[4-
  • These compounds are useful in inhibiting the binding of fibrinogen to blood platelets, inhibiting aggregation of blood platelets, treatment of thrombus formation or embolus formation, and in the prevention of thrombus formation or embolus formation. These compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds can be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex Ilb/IIIa receptor is desired. These compounds can also be used to prevent or modulate the progress of myocardial infarction, unstable angina and thrombotic stroke, when longer-term treatment may be desirable.
  • peripheral arteries arterial grafts, carotid endarterectomy
  • cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption.
  • the aggregated platelets may form thrombi and thromboemboli.
  • These compounds may be administered to surgical patients to prevent the formation of thrombi and thromboemboli.
  • the title compound was prepared by treating the final product of the previous example with porcine liver esterase.
  • Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 100 mg/kg body weight daily and more usually 0.01 to 10 mg/kg.
  • Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
  • the compounds useful in the present invention may be administered orally, parenterally, by inhalation spray, rectally, transdermally or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
  • Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • 3S-[[4-[[4- (aminoiminomethyl)phenyl]amino]-l,4-dioxobutyl]amino]- 4-pentynoate or pharmaceutically acceptable salts thereof can be co-administered with suitable anti ⁇ coagulants such as heparin or warfarin and/or anti- platelet agents, such as indomethacin, ibuprofen, naproxen, diclofenac, ticlopidine or aspirin while significantly reducing the dosage amount of 3S-[[4-[[4- aminoiminomethyl)phenyl]amino]-1,4-dioxobuty1]amino]-4- pentynoic acid or ethynoic acid or eth
  • anti-coagulant agents denotes agents that inhibit blood coagulation.
  • agents include warfarin or heparin, including low molecular weight heparin (LMWH) , and pharmaceutically acceptable salts or prodrugs thereof.
  • LMWH low molecular weight heparin
  • the heparin employed herein may be, for example, the sodium or sulfate salts thereof.
  • anti-platelet agents denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets.
  • agents include the various known non-steroidal anti-inflammatory drugs such as indomethacin, ibuprofen, naproxen, diclofenac, aspirin and piroxicam.
  • Another suitable anti-platelet agent is ticlopidine.
  • Aspirin acetylsalicyclic acid or ASA
  • ASA acetylsalicyclic acid
  • Thromboembolic disorders are known to have a diverse pathophysiological makeup. Therefore, there is a need for a therapeutic approach to the treatment of these disorders which takes into account the diverse pathophysiological makeup of such diseases, and which includes components ameliorating each of the various pathophysiological aspects.
  • a combination therapy containing an anti-coagulant agent such as heparin, or an antiplatelet agent such as aspirin, in combination with a Ilb/IIIa antagonist such as 3S-[[4-[[4- aminoiminomethy1)phenyl]amino]-1,4-dioxobutyl]amino]-4- pentynoic acid or ethyl 3S-[[4-[[4- (aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]- 4-pentynoate, or pharmaceutically acceptable salts thereof can provide such a therapy.
  • a combination therapy containing an anti-coagulant agent such as heparin, or an antiplatelet agent such as aspirin, in combination with a Ilb/IIIa antagonist such as 3S-[[4-[[4- aminoiminomethy1)phenyl]amino]-1,4-dioxobutyl]amino
  • the glycoprotein Ilb/IIIa compounds used in this invention and the anti ⁇ coagulant agent and/or anti-platelet agent can be administered at the same time (that is, together) , or in any order, for example the Ilb/IIIa antagonists used in this invention are administered first, followed by administration of the anti-coagulant agent and/or anti ⁇ platelet agent.
  • the administration of the Ilb/IIIa antagonists used in this invention and any anti ⁇ coagulant agent and/or anti-platelet agent occurs less than about one hour apart, more preferably less than about 30 minutes apart, even more preferably less than about 15 minutes apart, and most preferably less than about 5 minutes apart.
  • administering is oral.
  • oral agent, oral inhibitor, oral compound, or the like, as used herein denote compounds which may be orally administered.
  • the Ilb/IIIa antagonist compounds of this invention and the anti-coagulant agent and/or anti-platelet agent are both administered in the same fashion (that is, for example, both orally) , if desired, they may each be administered in different fashions (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously) .
  • the dosage of the combination products of the invention may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age.
  • a daily dosage may be about 5 milligrams to 60 milligrams of the Ilb/IIIa antagonist compounds useful in this invention and about 160 to 1500 milligrams of the anticoagulant, preferably about 5 to 40 milligrams of the Ilb/IIIa antagonist compound useful in this invention and about 160 to 1000 milligrams of the anti-coagulants per day.
  • typically a daily dosage may be about 5 to 60 milligrams of the Ilb/IIIa antagonist compounds useful in the present invention and about 75 to 325 milligrams of the anti ⁇ platelet agent, preferably about 5 to 40 milligrams of the Ilb/IIIa antagonist compounds useful in the present invention and about 160 to 325 milligrams of antiplatelet agents, per day.
  • Ilb/IIIa antagonists While the normal dosage of Ilb/IIIa antagonists would be in the range of about 20 mg to about 25 mg twice a day or higher, which may overlap the current combination therapy dose, it has now been found that the therapeutically effective amount of Ilb/IIIa antagonist administered in the combination therapy, is less than the amount administered when the Ilb/IIIa antagonist is administered alone, to achieve the same therapeutic effect.
  • the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect which would be obtained as a result of addition of further agents in accordance with the present invention.
  • the Ilb/IIIa antagonist compounds useful in the present invention are administered to humans in dosages of 5 mg, 10 mg, 15 mg and 20 mg twice a day and aspirin is given in dosages ranging from 160- 325 mg once a day.
  • PRP Platelet-rich plasma
  • PPP Platelet poor plasma
  • IC J0 median inhibitory concentration
  • Lysine-ASA was obtained from Synthelabo (Brussels, Belgium) .
  • Collagen from equine tendon was purchased from Chrono-log Corporation (Havertown, PA) .
  • Sodium heparin from beef lung was obtained from Upjohn Company (Kalamazoo, MI) .
  • Saline was purchased from Baxter Health Corporation (Deerfield, IL) .
  • 3S-[[4-[[4- aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4- pentynoic acid was synthesized at G.D. Searle & Co. (Skokie, IL) .
  • LCCA left circumflex coronary artery
  • 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 flow meter (Crystal Biotech, Hopkinton, MA) in order 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 are described in detail in Mickelson et al. Circulation, 1990; 81:617-627; Shebuski et al..
  • the 0.6 x SCa, 0.5 x SCa and 0.4 x SCa doses in Table 2 represent the reduced doses of the highest dose of SCa tested. Each dog was utilized only once. At 30 minutes, the stimulation electrode was then connected in series with a 12 K Ohms-112 K Ohms 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 ⁇ A. The number and the frequency of cyclic flow variations (CFV) that preceded the formation of an occlusive thrombus were recorded.
  • CMV cyclic flow variations
  • Peripheral venous blood was collected into citrated Vacutainer tubes (containing 0.3 ml of 3.8% sodium citrate solution) and platelet-rich plasma (PRP) was obtained by centrifugation (model Technospin R, Sorvall Instruments, DuPont, Wilmington, DE) the blood at 266 x g for 6 minutes at 24°C Platelet-poor plasma (PPP) was obtained by further centrifugation at 2000 x g for 10 minutes at 24°C. Samples were assayed on an aggregometer (model PAP-4, Bio/Data Corporation, Hatboro, PA) with PPP as the blank.
  • the aggregations were performed by adding 50 ⁇ l of collagen (33.3 ⁇ l/ml final concentration) to 450 ⁇ l of PRP and measuring aggregation for 3 minutes.
  • 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, 60 and 180 minute samples 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, Hialeah, FL) .
  • Bioassav for SCa Plasma Levels were determined from the blood samples used for platelet aggregation. Plasma levels of SCa were measured using a modification of a bioassay method previously described in Salyers et al. , Throm. Res., 1994, 75:409-417.
  • 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, PRP from non-treated dogs was added to wells containing plasma samples from treated dogs in a 96 well microtiter plate. ADP (20 ⁇ M) was added to the platelet suspension in each well to induce aggregation.
  • Optical density at 405 nanometers was measured on all wells simultaneously in a platereader (Thermomax microplate reader. Molecular Devices, Menlo Park, CA) . The results were quantified by comparison to a standard inhibition curve prepared in plasma using known amounts of SCa.
  • the time to zero flow was increased by heparin (114 ⁇ 16 minutes) and the combination of ASA with heparin (130 ⁇ 11 minutes) compared to the saline treatment but 1 x SCa provided a significantly longer time to zero flow than either of these treatments.
  • a dose-dependent increase in the steady-state inhibition of platelet aggregation was obtained after the administration of the three dose regiments of SCa (1 X SCa, 92 ⁇ 5; 0.6 X SCa, 83 ⁇ 3; 0.5 X SCa, 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.
  • Figure 1 compares the antithrombotic efficacy and the percent inhibition of platelet aggregation produced by SCa to that obtained by treatment with a decreased dose of SCa (0.5 x SCa) combined with ASA, or heparin; or combined with ASA and heparin.
  • SCa 0.5 x SCa
  • ASA heparin
  • the combination of 0.5 x SCa with ASA resulted in an occlusive thrombus in only 1 of the 6 dogs.
  • 0.5 x SCa was administered with heparin, there was a significant reduction in the percent of steady-state inhibition of platelet aggregation relative l x SCa (67 ⁇ 4% vs 92 ⁇ 5%) but the antithrombotic efficacy (100%) was similar to that of 1 x SCa.
  • the 0.5 x SCa treatment combined with ASA and heparin was as effective as 1 x SCa in preventing LCCA thrombosis.
  • a further decrease from 0.5 x SCa to 0.4 x SCa 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 0.5 x SCa combined with ASA and heparin.
  • Table 3 summarizes the CFV observed during anodal stimulation of the LCCA. As indicated in Table 3, CFV were observed in only 1 of 6 dogs from the groups treated with 1 x SCa, 0.5 x SCa combined with ASA, or 0.5 x SCa in combination with ASA and heparin. The number of CFV was also significantly smaller in these groups compared to that observed in the groups treated with either ASA, heparin or ASA combined with heparin. Table 3
  • Plasma Levels of SCa shows the results of plasma levels of SCa with the corresponding inhibition of platelet aggregation at steady-state conditions. The dose-dependent increase in mean percent inhibition of platelet aggregation was associated with a dose-dependent elevation of plasma SCa levels. Table 4
  • Antithrombotic therapy with ASA, heparin, or the combination is only partially effective in the prevention of coronary thrombus formation. Development of more effective antithrombotic and anticoagulant agents or combinations of both agents is desired.
  • Platelet binding of fgn, 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. Therefore, the binding of fgn to GPIIb/IIIa receptors provides an excellent target for therapeutic intervention in thrombosis-related disorders such as the acute ischemic coronary syndromes.
  • Several molecules have been shown to block fgn binding to platelet GPIIb/IIIa receptors and therefore prevent the formation of platelet thrombi.
  • the present data shows that 3S-[[4-[[4- aminoiminomethy1)phenyl]amino]-l,4-dioxobutyl]amino]-4- pentynoic acid, 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 or heparin, the 0.5 x SCa dose combined with these agents provide a protective antithrombotic effect, suggesting that decreased doses of the drug may be used in conjunction with ASA and heparin in the clinic for acute thrombotic-related events. Neither heparin nor ASA alone is efficacious in this model.

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Abstract

La présente invention concerne la co-administration d'antagonistes de récepteurs de fibrinogènes, en l'occurrence l'acide 3S-[[4-[[4-(aminoiminométhyl)phényl]amino]-1,4-dioxobutyl]amino]-4-pentynoïque ou l'éthyle 3S-[[4-[[4-(aminoiminométhyl)phényl]amino]-1,4-dioxobutyl]amino]-4-pentynoate, en association avec un agent anti-thrombocytaire tel que l'aspirine et/ou un anticoagulant tel que l'héparine.
PCT/US1997/003735 1996-03-28 1997-03-19 Antagonistes iib/iiia co-administres avec l'aspirine et/ou l'heparine WO1997035592A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999045913A1 (fr) * 1998-03-13 1999-09-16 Merck & Co., Inc. Therapie associee destinee au syndrome ischemique coronarien aigu ainsi qu'a des troubles connexes
US6103705A (en) * 1996-11-27 2000-08-15 Aventis Pharmaceuticals Products Inc. Pharmaceutical composition comprising a compound having anti-Xa activity and a platelet aggregation antagonist compound
US6136794A (en) * 1998-02-02 2000-10-24 Merck & Co., Inc. Platelet aggregation inhibition using low molecular weight heparin in combination with a GP IIb/IIIa antagonist
US6511968B1 (en) 1998-03-13 2003-01-28 Merck & Co., Inc. Combination therapy for treating, preventing, or reducing the risks associated with acute coronary ischemic syndrome and related conditions
US6518244B2 (en) 2000-03-09 2003-02-11 Intimax Corporation Combinations of heparin cofactor II agonist and platelet IIb/IIIa antagonist, and uses thereof
US6770660B2 (en) 2002-05-06 2004-08-03 Artery Llc Method for inhibiting platelet aggregation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FREDERICK LG ET AL: "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.", CIRCULATION, JAN 1 1996, 93 (1) P129-34, UNITED STATES, XP000677534 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6103705A (en) * 1996-11-27 2000-08-15 Aventis Pharmaceuticals Products Inc. Pharmaceutical composition comprising a compound having anti-Xa activity and a platelet aggregation antagonist compound
EP0946185A4 (fr) * 1996-11-27 2001-06-27 Aventis Pharm Prod Inc COMPOSITION PHARMACEUTIQUE COMPRENANT UN COMPOSE A ACTIVITE ANTI-Xa ET UN COMPOSE ANTAGONISTE DE L'AGREGATION PLAQUETTAIRE
US6136794A (en) * 1998-02-02 2000-10-24 Merck & Co., Inc. Platelet aggregation inhibition using low molecular weight heparin in combination with a GP IIb/IIIa antagonist
WO1999045913A1 (fr) * 1998-03-13 1999-09-16 Merck & Co., Inc. Therapie associee destinee au syndrome ischemique coronarien aigu ainsi qu'a des troubles connexes
US6511968B1 (en) 1998-03-13 2003-01-28 Merck & Co., Inc. Combination therapy for treating, preventing, or reducing the risks associated with acute coronary ischemic syndrome and related conditions
US6518244B2 (en) 2000-03-09 2003-02-11 Intimax Corporation Combinations of heparin cofactor II agonist and platelet IIb/IIIa antagonist, and uses thereof
US6770660B2 (en) 2002-05-06 2004-08-03 Artery Llc Method for inhibiting platelet aggregation

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