`Bernat et al.
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US005989578A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,989,578
`Nov. 23, 1999
`
`[54] ASSOCIATIONS OF ACTIVE PRINCIPLES
`CONTAINING CLOPIDOGRELAND AN
`ANTITHROMBOTIC AGENT
`
`[58] Field of Search ..................................... 424/489, 422,
`424/434, 427, 436, 456, 465; 514/165,
`301
`
`[75]
`
`Inventors: Andre Bernat, Cugnaux; Jean Marc
`Herbert, Tournefeuille; Pierre Savi,
`Muret, all of France
`
`[73] Assignee: Sanofi, Paris, France
`
`[21] Appl. No.:
`
`09/117,904
`
`[22] PCT Filed:
`
`Feb. 17, 1997
`
`[86] PCT No.:
`
`PCT/FR97/00296
`
`§ 371 Date:
`
`Aug. 12, 1998
`
`§ 102(e) Date: Aug. 12, 1998
`
`[87] PCT Pub. No.: W097/29753
`
`PCT Pub. Date: Aug. 21, 1997
`
`[30]
`
`Foreign Application Priority Data
`
`Feb. 19, 1996
`
`[FR]
`
`France ................................... 96 02027
`
`[51]
`
`Int. Cl.6
`
`.............................. A61F 13/00; A61F 9/02;
`A61K 9/64; A61K 9/20; A61K 9/14
`[52] U.S. Cl. .......................... 424/422; 424/427; 424/434;
`424/436; 424/456; 424/465; 424/489; 514/165;
`514/301
`
`[56]
`
`References Cited
`FOREIGN PATENT DOCUMENTS
`
`2307538 11/1976 France .
`2307538 12/1976 France .
`OTHER PUBLICATIONS
`
`Herbert, J.M. Clopidgorel and antiplatelet therapy. Expert
`Opinion Investigating Drugs. 1994. 3(5):449-455. XP
`000610730.
`Expert Opin. Invest. Drugs, 1994, 3/5 (449-455), United
`Kingdom, Herbert, J. M. Clopidogrel and antiplatelet
`therapy.
`Primary Examiner-Thurman K. Page
`Assistant Examiner--Alysia Berman
`Attorney, Agent, or Firm-Michael D. Alexander
`ABSTRACT
`[57]
`
`The invention relates to a pharmaceutical composition con(cid:173)
`taining an association of active principles, wherein the
`active principles are clopidogrel and aspirin, each constitu(cid:173)
`ent being present in a free form or in the form of a
`pharmaceutically acceptable salt.
`
`25 Claims, No Drawings
`
`IPR2015-01492
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`1
`ASSOCIATIONS OF ACTIVE PRINCIPLES
`CONTAINING CLOPIDOGRELAND AN
`ANTITHROMBOTIC AGENT
`
`The subject of the present invention is a new combina(cid:173)
`tion of active ingredients with anti-platelet aggregation
`activity consisting of clopidogrel and aspirin, and ph arm a(cid:173)
`ceutical compositions containing them.
`The active ingredients constituting the combination are
`present in the free state or in the form of one of their
`pharmacologically acceptable salts.
`During the last decade, there has been a lot of interest in
`the study of the role played by the platelets in the develop(cid:173)
`ment of diseases associated with atherosclerosis (myocardial
`infarction, angor, cerebral attack, peripheral arterial diseases
`and the like). The well-established role of the platelets in
`arterial thrombosis has allowed the development of numer(cid:173)
`ous medicaments which inhibit the functions of the platelets
`and the discovery of the essential role of ADP in the
`thrombotic process has led to the development of ticlopidin,
`a potent antithrombotic agent. This thieno[3,2-c ]pyridine
`derivative is described in Patent FR 73 03503. Ticlopidin
`selectively inhibits the platelet aggregation induced by ADP
`as well as that of other agonists, mediated by ADP [Feliste
`et al., Thromb. Res., 1987, 48, 403-415).
`In multicentre double-blind clinical studies, ticlopidin
`proved to be significantly more effective than aspirin or a
`placebo in the prevention of cerebral attack in patients
`having a high risk of vascular accidents (Gent et al., Lancet,
`1989, 8649, 1215-1220; Hass et al., N. Eng. J. Med., 1989, 30
`321, 501-507). It also proved significantly more effective
`than the placebo in patients exhibiting a high risk of central
`or peripheral vascular accidents (Janzon et al., Scand. J. Int.
`Med., 1990, 227, 301-308).
`Although it is known, to date, that aspirin and ticlopidin 35
`act via two different mechanisms of action, numerous stud-
`ies have compared the efficacy of these two medicaments
`and it is only very recently that a few studies have suggested
`that ticlopidin, administered in combination with aspirin,
`could be of great interest in relation to acute thrombosis, as 40
`a replacement of current poorly effective treatments, in
`patients in whom a metallic endovascular prostheses had
`been implanted (Van Belle et al., Cor. Art. Dis., 1995, 6,
`341-345).
`The combination of ticlopidin and aspirin is claimed in 45
`patent FR 75 12084 for its use as anti-platelet aggregation
`agent endowed with a haemodynamic effect which is con(cid:173)
`siderably qualitatively and quantitatively superior to that of
`ticlopidin alone. These results were demonstrated with the
`aid of pharmacological studies which related to the platelet 50
`aggregation inhibiting properties by making measurements
`of the platelet aggregation induced by ADP or collagen. The
`results which were obtained are predictive of a therapeutic
`importance of the ticlopidin-aspirin combination in some
`types of acute thrombosis following in particular some 55
`surgical operations but are not sufficient to deduce therefrom
`an indication in the secondary prevention of vascular acci(cid:173)
`dents in atherometous disease or alternatively in endarter(cid:173)
`ectomy or fitting of metallic endovascular prostheses.
`It is moreover known that other combinations of anti- 60
`platelet aggregation agents, such as for example the com(cid:173)
`bination aspirin-dipyridamole, have been the subject of
`clinical studies against dipyridamole alone or aspirin alone
`in the study of the prevention of cerebral vascular accident
`or of occlusion of the vascular shunt in patients. The 65
`conclusion of these studies was that the aspirin(cid:173)
`dipyridamole combination does not possess any significant
`
`2
`beneficial effect greater than that observed with dipy(cid:173)
`ridamole alone or aspirin alone in the secondary prevention
`of cerebral atherothrombotic ischaemia or towards throm(cid:173)
`bosis (Acta. Neural. Scand., 1987, 76(6), 413-421;
`5 Thrombosis, 1994, Alert No. 12; Thrombosis, 1994, Alert
`No. 9. Thrombosis, 1993, Alert No. 9; Thrombosis, 1993,
`Alert No. 2).
`The fitting of metallic endovascular prostheses at the
`coronary and carotid level can be considered today as an
`10 important therapeutic advance in the prevention and treat(cid:173)
`ment of central and peripheral vascular accidents. However,
`these prostheses exhibit a potent prothrombotic effect due to
`their metallic nature which it is essential today to prevent
`with the aid of antithrombotic agents and mainly anti-
`15 platelet aggregation agents.
`Another thienopyridin derivative, clopidogrel described
`in EP 099 802 has also proved to be a potent anti thrombotic,
`acting through a mechanism of action identical to that of
`ticlopidin (Savi et al., J. Pharmacal. Exp. Ther., 1994, 269,
`20 772-777; Herbert et al., Cardiovasc. Drug Rev., 1993, 11,
`180-198).
`Its use could be beneficial in relation to pathological
`states such as disorders of the cardiovascular and cere(cid:173)
`brovascular system such as the thromboembolic disorders
`25 associated with atherosclerosis or with diabetes such as
`unstable angina, cerebral attack, restenosis following
`angioplasty, endarterectomy or fitting of metallic endovas(cid:173)
`cular prostheses, with rethrombosis following thrombolysis,
`with infarction, with dementia of ischaemic origin, with
`peripheral arterial diseases, with haemodialyses, with
`auricular fibrillations or during the use of vascular prosthe(cid:173)
`ses or aortocoronary bypasses or in relation to stable or
`unstable angor.
`Clopidogrel is, depending on the aggregation agents
`used, in animals and in man about 10 to 50 times more
`effective than ticlopidin. Furthermore, unlike the latter,
`clopidogrel exhibits a practically immediate anti(cid:173)
`aggregation activity which appears within 15 minutes after
`the administration whereas ticlopidin requires, in order to be
`effective, a prolonged administration of at least 3 days at
`much higher doses. Furthermore, unlike ticlopidin, clopi(cid:173)
`dogrel can be administered by the intravenous route and
`exhibits, by this route, anti-aggregation effects which are
`completely equivalent to those obtained by the oral route
`(Herbert et al., Cardiovasc. Drug Rev., 1993, 11, 180--198).
`This is not the case for ticlopidin which can only be
`administered by the oral route.
`Quite surprisingly and unexpectedly, the clopidogrel(cid:173)
`aspirin combination of the invention proved to be endowed
`with a synergistic activity of the two active ingredients. This
`effect is characterized in relation to the aggregation of rabbit
`platelets with collagen, sole aggregation agent which can be
`used because of its joint dependency, by ADP and by the
`metabolism of arachidonic acid.
`Furthermore, a similar synergistic effect was observed in
`relation to the formation of a thrombus of arterial origin
`induced by the implantation of a thrombogenic surface (silk
`thread) implanted in a catheter joining the carotid artery and
`the jugular vein of the rabbit.
`The combinations according to the invention do not
`increase the haemorrhagic risk assessed by the extension of
`the bleeding time and are, moreover, not very toxic. Their
`toxicity is compatible with their use as medicament for the
`treatment of the disorders and of the diseases of thrombotic
`origin mentioned above.
`The combinations according to the invention can be
`formulated in pharmaceutical compositions for administra-
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`3
`tion to mammals, including man, for the treatment of the
`abovementioned diseases.
`According to the invention, clopidogrel and aspirin can
`be administered in the form of a pharmaceutically accept(cid:173)
`able salt.
`These salts are those commonly used in pharmacy, such
`as acetate, benzoate, fumarate, maleate, citrate, tartrate,
`gentisate, methane sulphonate, ethane sulphonate, benzene
`sulphonate, lauryl sulphonate, dobesilate and paratoluene
`sulphonate.
`In the text which follows, the quantities of clopidogrel
`and of aspirin are expressed as clopidogrel and aspirin
`equivalents in non-salified, free form.
`Advantageously, the compositions of the invention com(cid:173)
`prise clopidogrel and aspirin in a molar ratio (aspirin/ 15
`clopidogrel) of between 2.5 and 11.5, preferably between 5
`and 9, better still between 7 and 8.
`The combinations according to the invention can be used
`at daily doses of clopidogrel or of aspirin of 0.1 to 100 mg
`per kilo of body weight of the mammal to be treated.
`In human beings, the dose may vary for each of the
`components from 1 to 500 mg per day, depending on the age
`of the subject to be treated and the type of treatment:
`prophylactic or curative.
`In the pharmaceutical compositions of the present 25
`invention, the active ingredients are generally formulated in
`dosage units containing from 0.1 to 500 mg of the said active
`ingredient per unit dosage.
`The subject of the present invention is therefore the
`pharmaceutical compositions which contain, as active 30
`ingredient, a combination of clopidogrel and aspirin. These
`compositions are preferably made so as to be administerable
`by the oral or parenteral route.
`In the pharmaceutical compositions of the present inven(cid:173)
`tion for oral, sublingual, subcutaneous, intramuscular, 35
`intravenous, intradermal, local or rectal administration, the
`active ingredient may be administered in unit forms for
`administration, mixed with conventional pharmaceutical
`carriers, to animals and to human beings. The appropriate
`unit forms for administration comprise the forms for oral 40
`administration such as tablets, gelatin capsules, powders,
`granules and oral solutions or suspensions, the forms for
`sublingual or buccal administration, the forms for
`subcutaneous, intramuscular, intravenous, intranasal or
`intraocular administration and the forms for rectal adminis- 45
`tration.
`When a solid composition in the form of tablets is
`prepared, the main active ingredient is mixed with a phar(cid:173)
`maceutical vehicle such as gelatin, starch, lactose, magne(cid:173)
`sium stearate, talc, gum arabic and the like. The tablets can 50
`be coated with sucrose or other appropriate materials or
`alternatively they can be treated such that they have a
`prolonged or delayed activity and that they continuously
`liberate a predetermined quantity of active ingredient.
`A preparation in the form of gelatin capsules is obtained 55
`by mixing the active ingredient with a diluent and by
`pouring the mixture obtained into soft or hard gelatin
`capsules.
`A preparation in syrup or elixir form may contain the
`active ingredient together with a sweetener, preferably calo- 60
`rie free, methylparaben or propylparaben as antiseptic, as
`well as a taste enhancer and an appropriate colouring.
`The water-dispersible granules or powders may contain
`the active ingredient mixed with dispersing agents or wet(cid:173)
`ting agents, or suspending agents, such as 65
`polyvinylpyrrolidone, as well as sweeteners or flavour cor-
`rectors.
`
`4
`For rectal administration, suppositories are used which
`are prepared with binders which melt at the rectal
`temperature, for example cocoa butter or polyethylene gly(cid:173)
`cols.
`For parenteral, intranasal or intraocular administration,
`aqueous suspensions, isotonic saline solutions, sterile and
`injectable solutions are used which contain dispersing agents
`and/or wetting agents which are pharmacoligically
`compatible, for example propylene glycol or butylene gly-
`10 col.
`The active ingredient can also be formulated in the form
`of microcapsules, optionally with one or more carriers or
`additives.
`The active ingredients of the combinations can also be
`provided in the form of a complex with cyclodextrin, for
`example a-, ~- or y-cyclodextrin, 2-hydroxypropyl-~
`cyclodextrin or methyl-~-cyclodextrin.
`When the compositions of the invention are administered
`in man by the parenteral or oral route, it is preferable that the
`20 daily dose of clopidogrel is between 50 and 100 mg, the
`daily dose of aspirin being between 100 and 500 mg.
`It will be noted that according to the invention, clopi-
`dogrel and aspirin can both be administered by the oral
`route, or both by the parenteral route or one can be admin(cid:173)
`istered by the oral route (preferably aspirin) and the other by
`the parenteral route (preferably clopidogrel).
`According to a preferred embodiment, the daily dose of
`clopidogrel administered in man by the parenteral and/or
`oral route is between 65 and 100 mg, better still between 65
`and 85 mg, the daily dose of aspirin administered by the
`parenteral route being between 200 and 400 mg, better still
`between 315 and 335 mg.
`Preferably, the dose of clopidogrel is in this case 75 mg
`per day and the dose of aspirin is 325 mg per day.
`The combinations of active ingredients according to the
`invention have been the subject of pharmacological studies.
`Tests were carried out in relation to the test of aggregation
`of rabbit platelets with collagen as described above (Born et
`al., J. Physiol., 1963, 168, 178-95). Briefly, 2.5 to 3 kg New
`Zealand rabbits were treated by the oral route with ticlopidin
`(100 mg/kg/d) for 3 days or by the intravenous route with
`clopidogrel (10 mg/kg). One hour after the last
`administration, the animals were treated by the intravenous
`route with aspirin (1 mg/kg).
`Five minutes after the administration of aspirin, the
`animals were anaesthetized with ether and 2 ml of blood
`were collected from the median artery of the ear and mixed
`with 0.2 ml of a 3.8% solution of sodium citrate in water.
`The platelet-rich plasma was obtained by centrifugation of
`the blood at 500 g for 10 minutes at 15° C. The number of
`platelets was then adjusted to 106 cells per ,ul with the aid of
`plasma low in platelets, obtained by centrifugation (3000 g,
`15 min.) of anticoagulated blood.
`The aggregation of the platelets was measured according
`to the method of Born (Born et al., J. Physiol., 1963, 168,
`178-95) with the aid of a double canal aggregometer
`(Chrono Log) with stirring (900 rpm) at 37° C. The aggre-
`gation of the platelets was induced by collagen (12.5 ,ug!ml).
`The antithrombotic effect of the clopidogrel or ticlopidin
`combination with aspirin was determined in relation to the
`formation of a thrombus on a silk thread present in an
`arteriovenous shunt implanted between the carotid artery
`and the jugular vein of the rabbit as described by Umetsu et
`al. (Thromb. Haemostas., 1978, 39, 74--83) . Briefly, 2.5 to
`3 kg New Zealand rabbits were treated by the oral route with
`ticlopidin (100 mg!kg/d) for 3 days or by the intravenous
`route with clopidogrel (10 mg!kg).
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`The animals were anaesthetized by subcutaneous admin(cid:173)
`istration of sodium pentobarbital (30 mg/kg). Two polyeth(cid:173)
`ylene tubes 12 em long (internal diameter: 0.6 mm; external
`diameter: 0.9 mm) attached by a central part 6 em long
`(internal diameter: 0.9 mm) containing a silk thread 5 em 5
`long were placed between the right carotid artery and the left
`jugular vein. One hour after the last administration of
`ticlopidin or of clopidogrel, the animals were treated by the
`intravenous route with aspirin (1 mg/kg). The central part of
`the shunt was then placed and then removed after 20 minutes
`of circulation of blood in the shunt. The weight of the 10
`thrombus present on the silk thread was then determined.
`The results shown in TABLE 1 indicate that clopidogrel
`(10 mg/kg) or aspirin (1 mg/kg) administered by the intra(cid:173)
`venous route in a single dose in rabbit inhibit the aggregation
`of the platelets which is induced by collagen. Ticlopidin,
`administered by the oral route (100 mg/kg/d) for 3 days also 15
`exhibits a significant inhibitory effect in relation to the
`aggregation of the platelets with collagen.
`In all cases, the joint administration of clopidogrel and
`aspirin resulted in a significant synergistic effect in relation
`to the aggregation of the platelets with collagen. That is to 20
`say that when the products were administered in
`combination, the anti-aggregation effect obtained was
`always greater than the mere sum of the effects of the two
`test products taken separately.
`Compared with the mere additive effect observed
`between the anti-aggregation effect of ticlopidin and aspirin 25
`obtained and claimed in patent FR 73 03503, this activity is
`completely new and unexpected.
`In the same manner, the antithrombotic activity of clo(cid:173)
`pidogrel was potentiated by combination with aspirin. Under
`these conditions, and as in relation to the aggregation of the 30
`platelets with collagen, a significant synergistic effect was
`observed (TABLE 2).
`
`60
`
`The values indicated in the table are the mean values on
`five experiments ± standard errors (n=5)
`We claim:
`1. A pharmaceutical composition comprising a combina(cid:173)
`tion of clopidogrel aspirin, both constituents being present in 65
`the free state or in the form of a pharmaceutically acceptable
`salt.
`
`6
`2. A pharmaceutical composition according to claim 1,
`comprising clopidogrel and aspirin in combination with at
`least one pharmaceutical excipient.
`3. A pharmaceutical composition according to claim 2 in
`a form administerable by the parenteral route or by the oral
`route.
`4. A pharmaceutical composition according to claim 3
`wherein clopidogrel and aspirin are present in an aspirin/
`clopidogrel molar ratio of between 2.5 and 11.5.
`5. A pharmaceutical composition according to claim 1 for
`the treatment of a pathology induced by platelet aggregation.
`6. A method for the treatment of a pathology induced by
`platelet aggregation, which comprises administering to a
`human in need of such treatment, a dose of 1 to 500 mg per
`day of clopidogrel and a dose of 1 to 500 mg per day of
`aspirin, the doses being expressed in equivalent quantity of
`clopidogrel and of aspirin in free form.
`7. A method according to claim 6, in which the treatment
`involves the administration by the parenteral and/or oral
`route of 50 to 100 mg of clopidogrel per day and of 100 to
`500 mg of aspirin per day.
`8. A method according to claim 6, in which the treatment
`involves the administration by the parenteral and/or oral
`route of 65 to 100 mg of clopidogrel per day and of 200 to
`400 mg of aspirin per day.
`9. A method for the treatment of a pathology induced by
`platelet aggregation comprising the administration of an
`effective quantity of clopidogrel and, concomitantly, the
`administration of an effective quantity of aspirin, the clopi(cid:173)
`dogrel and the aspirin being administered in the free state or
`in the form of a pharmaceutically acceptable salt.
`10. A method according to claim 9, wherein the pathology
`induced by platelet aggregation is chosen from stable angor,
`unstable angor, disorders of the cardiovascular and cere-
`35 brovascular system, disorders associated with the use of
`vascular prostheses and disorders associated with aortocoro(cid:173)
`nary bypasses.
`11. A method according to claim 10, wherein the disorders
`of the cardiovascular and cerebrovascular system are chosen
`from thromboembolic disorders associated with
`atherosclerosis, with diabetes, with rethrombosis following
`thrombolysis, with infarction, with dementia of ischaemic
`origin, with peripheral arterial diseases, with haemodialysis
`and with auricular fibrillations.
`12. A method according to claim 11, wherein the throm(cid:173)
`boembolic disorders associated with atherosclerosis and
`with diabetes are chosen from unstable angina, cerebral
`attack, restenosis following angioplasty, endarterectomy and
`the fitting of metallic endovascular prostheses.
`13. A method according to claim 9, involving the admin(cid:173)
`istration in man of 1 to 500 mg per day of clopidogrel and
`of 1 to 500 mg per day of aspirin, the doses being expressed
`in equivalent quantity of clopidogrel and of aspirin in free
`form.
`14. A method according to claim 9, involving the admin(cid:173)
`istration in man by the parenteral and/or oral route of 50 to
`100 mg per day of clopidogrel and of 100 to 500 mg per day
`of aspirin, the doses being expressed in equivalent quantity
`of clopidogrel and of aspirin in free form.
`15. A method according to claim 9, involving the admin(cid:173)
`istration in man by the parenteral and/or oral route of 65 to
`100 mg per day of clopidogrel and of 200 to 400 mg per day
`of aspirin, the doses being expressed in equivalent quantity
`of clopidogrel and of aspirin in free form.
`16. A method according to claim 15 involving the admin(cid:173)
`istration in man by the parenteral and/or oral route of 65 to
`85 mg per day of clopidogrel and of 315 to 335 mg per day
`
`TABLE 1
`
`Effect of the products alone or in combination in
`relation to the aggregation of rabbit platelets with
`colla en.
`
`Active ingredients
`
`Doses
`
`% inhibition
`
`Ticlopidin
`Clopidogrel
`Aspirin
`Ticlopidin + Aspirin
`Clopidogrel +Aspirin
`
`100 mg/kg/0- 3 0
`10 mg/kg
`1 mg/kg
`100 + 1 mg/kg
`10 + 1 mg/kg
`
`35 ± 3%
`42 ± 6%
`21 ± 2%
`52± 6%
`98 ± 1%
`
`The values indicated in the table are the mean values on
`five experiments ± standard errors (n=5)
`
`TABLE 2
`
`Effect of the products alone or in combination in
`relation to the formation of an arterial thrombus on a
`silk thread implanted in an arteriovenous shunt in
`rabbit.
`
`Active ingredients
`
`Doses
`
`% inhibition
`
`Ticlopidin
`Clopidogrel
`Aspirin
`Ticlopidin + Aspirin
`Clopidogrel +Aspirin
`
`100 mg/kg/0- 3 0
`10 mg/kg
`1 mg/kg
`100 + 1 mg/kg
`10 + 1 mg/kg
`
`25 ± 9%
`34 ± 4%
`19 ± 5%
`45 ± 3%
`82 ± 1%
`
`40
`
`45
`
`50
`
`55
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`of aspirin, the doses being expressed in equivalent quantity
`of clopidogrel and of aspirin in free form.
`17. A pharmaceutical composition according to claim 4
`wherein clopidogrel and aspirin are present in an aspirin/
`clopidogrel molar ratio of between 5 and 9.
`18. A pharmaceutical composition according to claim 2
`for the treatment of a pathology induced by platelet aggre(cid:173)
`gation.
`19. A pharmaceutical composition according to claim 3
`for the treatment of a pathology induced by platelet aggre(cid:173)
`gation.
`20. A pharmaceutical composition according to claim 4
`for the treatment of a pathology induced by platelet aggre(cid:173)
`gation.
`21. A pharmaceutical composition according to claim 17 15
`for the treatment of a pathology induced by platelet aggre(cid:173)
`gation.
`22. A method according to claim 8, in which the treatment
`involves the administration by the parenteral and/or oral
`route of 65 to 85 mg of clopidogrel per day and of 315 to 335 20
`mg of aspirin per day.
`
`8
`23. A method according to claim 6 wherein the pathology
`induced by platelet aggregation is chosen from stable angor,
`unstable angor, disorders of the cardiovascular and cere(cid:173)
`brovascular system, disorders associated with aortocoronary
`5 bypasses and disorders associated with the use of vascular
`prostheses.
`24. A method according to claim 23, wherein the disorders
`of the cardiovascular and cerebrovascular system are chosen
`10 from thromboembolic disorders associated with atheroscle-
`rosis or diabetes, rethrombosis following thrombolysis,
`infarction, dementia of ischaemic origin, peripheral arterial
`diseases, haemodialyses and auricular fibrillations.
`25. A method according to claim 24, wherein the throm(cid:173)
`boembolic disorders associated with atherosclerosis or dia(cid:173)
`betes are chosen from unstable angina, cerebral attack,
`restenosis following angioplasty, endarterectomy, and the
`fitting of metallic endovascular prostheses.
`
`* * * * *
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