Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
10,15202530W0 98/1 1896CA 02265827 1999-03-09PCT/US97/16388-1-TITLE OF THE INVENTIONCOMBINATION THERAPY FOR REDUCING THE RISKSASSOCIATED VVITH CARDIOVASCULAR DISEASEFIELD OF THE INVENTIONThe instant invention involves a combination therapycomprising the administration of a cholesterol reducing agent such as a3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductaseinhibitor (or HMG-CoA RI) and a platelet aggregation inhibitor fortreating, preventing and reducing the risk of developing cardiovascularand cerebrovascular events and disorders in a mammal.BACKGROUND OF THE INVENTIONPlatelet activation and aggregation are involved in unstableangina and acute myocardial infarction, in reocclusion followingthrombolytic therapy and angioplasty, in transient ischemic attacks andin a variety of other vasoâocclusive disorders. When a blood vessel isdamaged either by acute intervention such as angioplasty, or morechronically by the pathophysiological processes of atherosclerosis,platelets are activated to adhere to the disrupted surface and to eachother. This activation, adherence and aggregation may lead to occlusivethrombus formation in the lumen of the blood vessel.Antiplatelet therapy has been used in a wide variety ofcardiovascular disease states and in conjunction with interventionaltherapy such as coronary artery or peripheral bypass grafting, cardiacvalve replacement, and percutaneous transluminal coronary angioplasty(PTCA). Available drugs, such as aspirin and ticlopidine (TICLID®),have shown efficacy in syndromes involving vascular occlusion,presumably due to sustained inhibition of platelet function. However,the inhibitory effects of aspirin and ticlopidine are dependent upon theagonist which activates the platelet. For example, aspirin is effective inblocking platelet aggregation induced by agonists such as collagen thatare dependent upon the cylooxygenase pathway. It is, however, lesseffective against concentrations of thrombin which can act byW0 98/1 1896l015202530CA 02265827 1999-03-09PCT/US97/16388-2-cyclooxygenase independent pathways. Likewise, the inhibitory effectsof ticlopidine, which inhibits ADP induced platelet aggregation, can beovercome by combinations of agonists. Thus, an efficacious plateletaggregation therapy that acts independently of the agonist and thepathway activating the platelet could be an important therapeuticadvance giving greater efficacy than aspirin or ticlopidine alone in abroader spectrum of thrombotic events.Integrin SuperfarnilyThe firm attachment of endothelial cells to thesubendothelial extracellular matrixris mediated via CAMS, which serveas receptors recognizing an array of adhesive proteins in theextracellular matrix. These proteins include von Willebrand factor(vWf), fibronectin, vitronectin, thrombospondin, laminins, collagenfibrils, elastin, microfibiils of elastin, and glycosaminoglycans. Most ofthe matrix adhesive molecules are the ligands for integrin receptorsexpressed in endothelial cells.lntegrins constitute an extended family ("superfamily") ofmembrane receptors interacting with adhesive proteins in plasma andextracellular matrix and with other membrane receptors (counter-receptors). The name "integrin" implies that they integrate the ligandson the outside of the cell with the cytoskeletal apparatus in the inside ofthe cell. lntegrin receptors consist of a noncovalently linked Ca2+-dependent, heterodimeric glycoprotein complex composed of on and [3subunits. The eight known integrin B subunits give rise to eight familiesin which one "founder" [3 subunit forms heterodimers with different onsubunits. There are at least 14 known Ot subunits. Receptors belongingto the [51 and [53 families are expressed in endothelial cells. The [31family, also named Very Late Antigens (VLA), is represented by thefibronectin receptor (ot5B1, or VLAâ5), the collagen receptor (oc2[31, orVLAâ2) and the laminin receptor (ot6B1). The [33 family is representedby the vitronectin receptor (OLVB3), which is structurally similar (thesame [33 subunit) to the platelet integrin receptor for fibrinogen,_g1ycoprotein (GP) Il"b/Illa complex (also referred to as oc11b[33). TheW0 98/ 118961015202530CA 02265827 1999-03-09PCT/US97I 16388-3-functional difference between these two receptors is that the plateletreceptor recognizes the 7 chain domain (HHLGGAKQAGDV) of humanfibrinogen and the endothelial vitronectin receptor does not. Bothrecognize the sequence RâG-D identified as the cell adhesion site offibronectin, vitronectin, vWf, and the on chain of human fibrinogen.Therefore, synthetic peptides containing the RâG-D sequence causedetachment of endothelial cells from the extracellular in matrix in vitro.GP IIb[1IIa Antag. onistsThe final obligatory step in platelet aggregation is thebinding of fibrinogen to an activated membraneâbound glycoproteincomplex, GP Ilb/Illa. Platelet activators such as thrombin, collagen,epinephrinevor ADP, are generated as an outgrowth of tissue damage.During activation, GP Ilb/Hla undergoes changes in conformation thatresults in exposure of occult binding sites for fibrinogen. There are sixputative recognition sites within fibrinogen for GP IIb/Illa and thusfibrinogen can potentially act as a hexavalent ligand to crossing GPIlb/Hla molecules on adjacent platelets. A deficiency in eitherfibrinogen or GP IIb/IIIa prevents normal platelet aggregationregardless of the agonist used to activate the platelets. Since the bindingof fibrinogen to its platelet receptor is an obligatory component ofnormal aggregation, GP Hb/Illa is an attractive target for anantithrombotic agent.Results from clinical trials of GP Hb/IIIa inhibitors supportthis hypothesis. The monoclonal antibody 7E3, which blocks the GPIIb/IIIa receptor, has been shown to be an effective therapy for the highrisk angioplasty population. It is used as an adjunct to percutaneoustransluminal coronary angioplasty or atherectomy for the prevention ofacute cardiac ischemic complications in patients at high risk for abruptclosure of the treated coronary vessel. Although 7E3 blocks both theIIb/IIIa receptor and the 0tv[33 receptor, its ability to inhibit plateletaggregation has been attributed to its function as a IIb/IIIa receptorbinding inhibitor.1015202530W0 98/ 1 1896CA 02265827 1999-03-09PCT/US97/163898-4-A study reported in The New England Journal of Medicinevol. 330, No. 14, pp. 956-961 (1994) showed a decrease from 12.8% to8.3% in the combined endpoints of death, non-fatal myocardialinfarction (MI) and need for urgent revascularization with fibrinogenreceptor blockade. This benefit was at the expense of some additionalrisk of bleeding, with the need for transfusion increasing from 3% to6%, and the incidence of patients with decreased hematocrit increasingfrom 7% to 15%, 7E3 was added to the standard regime of heparin andaspirin thus leaving few hemostatic control mechanisms intact. Theclinical benefits of this drugcould be seen at 6 months.- Many other studies have shown that blocking the GPlIb/[Ilareceptor will stop platelet aggregation induced by all of the agonists andthus prevent thrombus formation but leave platelet adhesion relativelyintact. The 7E3 monoclonal antibody is described in Coller et al., Ann.NY/lead. Sci. 1991; 6I4:193-213; and Coller er al., J. Clin Invest.1985; 76:101-108. Others have used agents based on the RGD sequence,including snake venom proteins, small peptides, and peptidomimetics(Cook et al., Drugs 0fFuture, 1994; I9:135-159; and Cox et al.,Medicinal Research Reviews, 1994; I4:l95-228). VThe snake venom proteins, termed disintegrins, haveprovided important structural information, but their antigenicity haslimited their development as therapeutic agents (Cook et al., ibid.; andCox et al., ibid.). Integrelin (also known as INTEGRILINTM) is a cyclicpeptide that is based on the KGD sequence in the snake venom proteinbarbourin (Cook et al., ibia'.; and Cox et a1., ibid.). It inhibits ligandbinding to GP IIb/Illa but has very little effect on ligand binding toOLVI33. Among the non-peptide compounds are Ro 44-9883 and MK-383, which are administered intravenously, and are also selective forGPIIb/IIIa (Cook et al., ibid.; and Cox et al., ibia'.). Orally activeagents include SC54684, which is a prodrug (i.e., it requiresbiotransformation in vivo to its active form) with high oralbioavailability and Ro 43-8857, GRl44053, and DMP728, which arethemselves the active inhibitors (Cook et al., ibid.; and Cox et al., ibid.).Literally thousands of other compounds have been synthesized in an1015202530W0 98/11896CA 02265827 1999-03-09PCT/US97/ 16388-5-attempt to obtain optimal potency, metabolic stability, receptorspecificity, and favorable intravascular survival. Despite variations inthese compounds, virtually of all of them when they are in their activeform retain the basic charge relations of the RGD sequence with apositive charge separated from a negative charge by approximately 10-20 A (Cook er al., ibid.; and Cox et al., ibid.).Platelet aggregation is profoundly inhibited whenincreasing concentrations of murine 7E3 or c7E3 Fab are added toplatelet-rich plasma in vitro or administered in incremental doses toanimals or humans in vivo (Coller er al., Ann. NY Acad., ibid.; Tchenget al., ibid.; and Sirnoons et al., Circulation 1994; 89596-603). There isan excellent correlation between the percentage of receptors blocked andthe inhibition of aggregation, with nearly complete inhibition ofaggregation when 80% or more of the receptors are blocked (Coller etal., Ann. NY Acad., ibid.).The results of the 7E3 study support the hypothesis thatblockade of GPIIb/IIIa receptors is more effective than aspirin inpreventing platelet thrombi, even in the presence of heparin. They alsosupport the hypothesis that platelet-dependent thrombi frequentlycontribute significantly to the development of ischemic complicationsafter PTCA, even when minor mechanical dissections are present.It has been clear for several decades that elevated bloodcholesterol is a major risk factor for coronary heart disease, and manystudies have shown that the risk of CHD events can be reduced by lipid-lowering therapy. Prior to 1987, the lipidâlowering armamentariumwas limited essentially to a low saturated fat and cholesterol diet, thebile acid sequestrants (cholestyramine and colestipol), nicotinic acid(niacin), the fibrates and probucol. Unfortunately, all of thesetreatments have limited efficacy or tolerability, or both. With theintroduction of lovastatin, the first inhibitor of HMG-CoA reductase tobecome available for prescription in 1987, for the first time physicianswere able to obtain large reductions in plasma cholesterol with very fewadverse effects.l015202530W0 98/11896CA 02265827 1999-03-09PCT/US97/ 16388-5-Recent studies have unequivocally demonstrated thatlovastatin, sirnvastatin and pravastatin, all members of the HMG-CoAreductase inhibitor class, slow the progression of atherosclerotic lesionsin the coronary and carotid arteries. Simvastatin and pravastatin havealso been shown to reduce the risk of coronary heart disease events, andin the case of sirnvastatin a highly significant reduction in the risk ofcoronary death and total mortality has been shown by the Scandinavian- Sirnvastatin Survival Study. This study also provided some evidence fora reduction in cerebrovascular events. Additional studies have shownthat HMG CoA RI's may have an effect on platelet aggregation.Improved treatments for inhibiting platelet aggregation arecurrently being sought for the large number of individuals who are atrisk for reocclusion following thrombolytic therapy and angioplasty,transient ischemic attacks and a variety of other vaso-occlusivedisorders. The instant invention addresses this problem by providing acombination therapy comprised of a platelet aggregation inhibitor withan HMG-CoA RI, and more particularly, a GP Ha/IIIb receptorantagonist with an HMG-CoA RI. When administered as part of acombination therapy, the platelet aggregation inhibitor together with theHMG-CoA RI provide enhanced inhibition of platelet aggregation ascompared to administration of either the HMG-CoA R1 or the plateletaggregation inhibitor alone. Due to the greater benefit of the drugcombination, lesser dosage amounts of the platelet aggregation inhibitor,and more particularly the GP Ila/IIIb receptor antagonist, may beneeded to achieve the desired clinical result, thereby resulting inimproved safety.SUMMARY OF THE INVENTIONOne object of the instant invention is to provide a novelcombination therapy comprised of a therapeutically effective amount ofa cholesterol reducing agent such as an HMG-CoA reductase inhibitor incombination with a platelet aggregation inhibitor which is useful forinhibiting platelet aggregation and for inhibiting the formation ofthrombotic occlusions in mammals. The instant invention further1015202530W0 98/ l 1896CA 02265827 1999-03-09PCT/US97/ 16388-7-provides novel methods for treating, preventing and reducing the risk ofoccurrence of cardiovascular and cerebrovascular events and relatedvaso-occlusive disorders. Another object of this invention is to providepharmaceutical compositions which can be used with the above-described methods. A further object is to provide a kit comprised of anHMG-CoA reductase inhibitor composition and a platelet aggregationinhibitor composition. Additional objects will be evident from thefollowing detailed description.DETAILED DESCRIPTION OF THE INVENTIONThe instant invention involves a novel combination therapycomprising the administration of a therapeutically effective amount ofan HMG-CoA R1 in combination with a therapeutically effective amountof a platelet aggregation inhibitor to a mammal, and more particularly,to a human. The combination therapy is used to inhibit plateletaggregation in mammals who are in need of such inhibition, and toprevent or treat disorders related to platelet aggregation.The instant invention also provides pharmaceuticalcompositions comprised of a therapeutically effective amount of anHMG-CoA R1 in combination with a therapeutically effective amount ofa platelet aggregation inhibitor and a pharmaceutically acceptablecarrier. One embodiment of the instant compositions is a singlecomposition adapted for oral administration comprised of atherapeutically effective amount of an HMG-CoA R1 in combinationwith a therapeutically effective amount of a platelet aggregationinhibitor and a pharmaceutically acceptable carrier.A compound which inhibits HMG-CoA reductase is used incombination with a platelet aggregation inhibitor to practice the instantinvention. Examples of HMG~CoA reductase inhibitors that may beused include but are not limited to lovastatin (MEVACOR®; see USPatent No. 4,231,938), simvastatin (ZOCOR®; see US Patent No.4,444,784), pravastatin (PRAVACHOL®; see US Patent No.4,346,227), ï¬uvastatin (LESCOL®; see US Patent No. 5,354,772),atorvastatin (LIPITOR®; see US Patent No. 5,273,995) and cerivastatinW01015202530CA 02265827 1999-03-0998/11896 PCT/US97/16388-3-(also known as rivastatin; see US Patent No. 5,177,080). The structuralformulas of these and additional HMG-CoA reductase inhibitors thatmay be used in the instant methods are described at page 87 of M.Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (5 February 1996). Preferably, the HMG-CoA RI is selected fromlovastatin and simvastatin.The term HMG-CoA reductase inhibitor is intended toinclude all pharmaceutically acceptable salt, ester and lactone forms ofcompounds which have HMG-CoA reductase inhibitory activity, andtherefore the use of such salts, esters and lactone forms is includedwithin the scope of this invention. 9Compounds which have inhibitory activity for HMG-CoAreductase can be readily identified by using assays wellâknown in theart. For example, see the assays described or cited in U.S. Patent4,231,938 at col. 6, and WO 84/02131 at pp. 30-33.A compound which inhibits platelet aggregation is used incombination with an HMG-CoA reductase inhibitor to practice theinstant invention. In one embodiment of the instant invention, thecompound which inhibits platelet aggregation is an antagonist for theglycoprotein Ilb/Hla fibrinogen receptor. Examples of glycoproteinIIb/Hla receptor antagonists are described in United States Patent No.âs5,470,849, 5,463,011, 5,455,243, 5,451,578, 5,446,056, 5,441,952,5,422,249, 5,416,099, 5,405,854, 5,397,791, 5,393,760, 5,389,631,5,380,713, 5,374,622, 5,358,956, 5,344,783, 5,340,798, 5,338,723,5,334,596, 5,321,034, 5,318,899 (e.g. cyclic heptapeptides such as Mpr(AcetimidylâLys)-G1yâAsp-Trp-Phe-Cys-NH2, Mpr-(Acetimidy1-Lys)-Gly-AspâTrpâPheâPenâNH2, Mpr-(PhenylimidylâLys)-Gly-Asp-Trp-Phe-Pen-NH2, and Mpr-(Phenylimidyl-Lys)âGly-Asp-Trp-PheâCys-NH2, wherein Mpr is mercapto propionyl), 5,312,923, 5,294,616,5,292,756, 5,281,585, 5,272,158, 5,264,420, 5,260,307, 5,239,113 (e.g.ethyl 3-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4âpentynoate), 5,227,490, 5,206,373, 4,703,036 (e.g.N-MethylâD-phenylalanyl-N-[(1S)â1-formyl-4-guanidinobutyl]-L-prolinamide); European Patent publication No.âs EP 505 868 (e.g., ((1-CA 02265827 1999-03-09W0 98/1 1896 PCT /US97/ 16388-9-(2-((4â(aminoirninomethyl)benzoyl)amino)-3-(4âhydroxyphenyl)-1 -oxopropyl)-4-piperidinyl)oxy)â(S)-acetic acid), EP 333 356, and EP 656348; and International Publication No.'s W0 93/ 1 1 152 (e.g., Nâ(2-(2-(((3-((aminoiminomethy1)amino)propyl)amino)-carbonyl)-1-5 piperidnyl)-1-(cyclohexylmethyl)-2âoxoethyl)-(R,S)âglycine),W094/18981, WO 94/22820, WO 95/14683, and WO 97/15568,all of which are herein incorporated by reference, and wherein thescope of this invention includes, but is not limited to, the use of each ofthe specifically disclosed compounds therein. They are described as10 useful for inhibiting ï¬brinogen binding and inhibiting clot formation.In particular, the GP IIb/IIIa receptor antagonist is selectedfrom the following compounds and the pharmaceutically acceptablesalts, esters, and solvates (including hydrates) thereof: [3(R)-[2âpiperidin-4-y1)ethyl]-2-piperidoneâ 1 ]acetyl-3(R)âmethyl-[3-alanine15 described in United States Patent No. 5,281,585, (see compound 57 incolumn 67) and referred to herein as Compound A:Q 3: O HH N/'\/COOHCompound A;205â[(4âPiperidinyl)methoxy]-2-indolecarbony1â2(S)âphenylsulfonyl-amino-B-alanine described in W0 97/ 15568 at page 20 as compound 2-6, and referred to herein as Compound B:CA 02265827 1999-03-09W0 98/11896 PCT/US97ll6388- 10 -I CO2H 9NH \: N: âfr /HÂ¥<NHSO2PhHO .Compound B;2(S)-[(pâToluenesulfonyl)amino]-3-[[[5,6,7,8-tetrahydro-4-oxo~5-[2-5 (piperidin-4-yl)ethyl]-4H-pyrazoloâ[ 1 ,5âa] [1 ,4]diazepin-2-yi]carbonyl]-amino]propiom'c acid described in/âW0 94/18981, and referred to hereinas Compound C:co HH©\ (CH2)2âN)l\/>/[NH/?< 2( NâN H NHSO2 CH310 Compound C;MK-383 (2âS-(nâButy1suIfonylamino)-3[4âpiperidin-4-yI)butyloxyphenyl]propionic acid hydrochloride, and also known astirofiban) described in United States Patent 5,292,756; DMP 728; DMP15 754 ((R)âmethy1-3-[[[3-[4-(aminoiminomethyDphenyl]-4,5-dihydro-5-isoxazo1yl]acety1]amino]âNâ(butoxycarbony1)-L-alanine monoacetate)from DuPontâMerck, described in W0 95/ 14683 and in TetrahedronLetters, 1996, 37 :4455-4458:'Y""â1"Y"ââ"â"â'*â ââ âT "" ââVââââ"âFââ " â â '1CA 02265827 1999-03-09W0 98/ 11896 PCT /U S97! 16388-11-HN H HN O/\/\| . ?H2â N\O~â N\/âcoco:-13ODMP 754;5 R044-9883,ARo43-8857 and R048-3657 (acetic acid, [[1-[2-[[4-[amino(hydroxyimino)methyl]benzoyl] amino] -1 -oxopropyl] ~4-piperidinyl]oxy]-, ethyl ester, and also known as sibrafiban) fromHoffman-LaRoche; sibrafiban and related compounds are described inEP 656 348:10 -o NOHJk/OCH3CH2O 0 CH3 NH2"âwK*~H . ;xemlofiban (ethyl 3-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-15 dioxobutyl]amino]â4~pentynoate, also known as xemilofiban and SC-54684), particularly the HC1 salt thereof, described in U.S. Patent No.'s5,344,957 and 5,239,113:HCECii O HNCH3CH2O o NH220 xemlofiban;CA 02265827 1999-03-09W0 98/1 1896 PCT/US97/ 16388-12-fradafiban ((3S,5S)-5-[[(4'-Amidino-4âbiphenyl)oxy]methyl]-2-oxo-3-pyrrolidineacetic acid, also known as BIBU-104) as described in U.S.Patent No. 5,541,343 assigned to Thomae:Fradafiban ;orbofiban (N-[[(3S)-1-(p-Amidinophenyl)-2-oxo-3-pyrrolidinyl-carbarnoyl]âBâalanine, ethyl ester), particularly the monoacetate and10 monoacetate hydrate forms thereof, as described in U.S. Patent No.5,484,946 assigned to Searle:: NHCH2CH3O M Q 0 NH2Orbofiban ;15SB 2l4857 ((â)-(S)-2-[7-(4,4'-Bipiperidin-lâylcarbonyl)-4âmethylâ3-oxo-2,3,4,5-tetrahydro-1H-l ,4âbenzodiazepinâ2-yl]acetic acid) fromSmithKline Beecham, as described in W0 95/ 18619; ZDâ2486 ((R)-3-Methyl-4-[4-[4â(4-pyridyl)piperazin-1-yl]phenoxy]butyric acid) from20 Zeneca, as described in U.S. Patent No.'s 5,556,977 and 5,563,141;TAKâO29 from Takeda; RPR 109891 from Rhone Polenc Rorer;GRl44053 from Glaxo; GR233548 from Glaxo; and SDZ 562 fromSandoz.The compounds MK-383, DMP 728, Ro44â9883, R043-25 8857, SC-54684 and GRl44053 are described in Cook et al., Drugs of ?"*âV*1~---«vP~~-~~~~--- "âP"â"' r Y " âR -r1015202530W0 98/1 1896CA 02265827 1999-03-09PCT/U S97/ 16388-13-the Future, i994, 19(2) :l35-159, and Cox et al., Medicinal ResearchReviews, 1994, 14 :l95-228. DMP 728 is also described in Circulation,1996, 93 :537-543; and GRl44053 is also described in Thrombosis andHematosis, 1993, 69 :lO71. TAK 029 is described in J. Pharmacologyand Experimental Therapeutics, 1996, 277 :502â5l0. Xemlofiban isdescribed in Circulation, 1995, 92 :233l.More particularly, the GP IIb/IIIa receptor antagonist isselected from Compound A, Compound B, and DMP 754, which are allorally available compounds. Most particularly, the GP IIb/IIIa receptorantagonist is DMP 754.One test which is used to evaluate fibrinogen IIb/IIIareceptor antagonist activity is based on evaluation of inhibition of ADP-stimulated platelets. Aggregation requires that fibrinogen bind to andoccupy the platelet fibrinogen receptor site. Inhibitors of fibrinogenbinding inhibit aggregation. In the ADPâstimulated platelet aggregationassay, human platelets are isolated from fresh blood, collected into acidcitrate/dextrose by differential centrifugation followed by gel filtrationon Sepharose 2B in divalent ionâfree Tyrode's buffer (pH 7.4)containing 2% bovine serum albumin. 'Platelet aggregation is measured at 37°C in a Chronologaggregometer. The reaction mixture contains gel-filtered humanplatelets (2 x 108 per ml), fibrinogen (100 micrograms per ml (ug/ml)),Ca2+ (1 mM), and the compound to be tested. The aggregation isinitiated by adding 10 mM ADP 1 minute after the other componentsare added. The reaction is then allowed to proceed for at least 2minutes. The extent of inhibition of aggregation is expressed as thepercentage of the rate of aggregation observed in the absence ofinhibitor. The IC50 is the dose of a particular compound inhibitingaggregation by 50% relative to a control lacking the compound.Compounds which are selective GP IIb/IIIa receptorantagonists may be employed in the instant invention, as well ascompounds which block both the GP IIb/IIIa receptor and the otV[33vitronectin receptor, such as the monoclonal antibody 7E3. Compoundswhich are selective for the glycoprotein Ilb/IHa receptor are those1015202530W0 98/1 1896CA 02265827 1999-03-09PCT/US97/16388-14-having a preference (e.g. 10-fold) for binding to IIb/IIIa as compared toother receptors of the integrin family (e.g. on/[33, oL5B1,oLvB5).Selectivity of these compounds can be readily determined by personsskilled in the art.In another embodiment of this invention, the compoundwhich inhibits platelet aggregation is one that blocks ADP inducedplatelet aggregation. Examples of such compounds include ticlopidine(TICLlD®), and_ clopidogrel (PLAVIX®).In a further embodiment of this invention, the compoundwhich inhibits platelet aggregation is selected from aspirin anddipyridamole.Herein, the term platelet aggregation inhibitor (or inhibitorof platelet aggregation) is intended to include all pharmaceuticallyacceptable salt, ester and solvate forms, including hydrates, ofcompounds which have platelet aggregation inhibitory activity as well asproâdrug forms. Such pro-drugs are compounds which do not haveplatelet aggregation inhibitoryiactivity outside the body but becomeactive as inhibitors after they are administered to the patient. Thereforethe use of such salts, esters solvate forms and pro-drugs of plateletaggregation inhibitors is included within the scope of this invention.Likewise, the term GP IIb/IIIa receptor antagonist isintended to include all pharmaceutically acceptable salt, ester and solvateforms, including hydrates, of compounds which have GP IIb/IIIareceptor antagonist activity as well as pro-drug forms. Such pro-drugsare compounds which do not have GP IIb/IIIa receptor antagonistactivity outside the body but become active as antagonists after they areadministered to the patient. Therefore the use of such salts, esters,solvate forms and pro-drugs of GP IIb/IIIa receptor antagonists is alsoincluded within the scope of this invention. Proâdrug forms of IIb/IIIareceptor antagonists generally are not active antagonists until after theyare metabolised in the body to the active drug form; such prodrugs maybe, but are not limited to, ester derivatives. Ester derivatives of thedescribed compounds may act as prodrugs which, when absorbed intothe bloodstream of a warm-blooded animal, may cleave in such a1015202530CA 02265827 1999-03-09W0 98/1 1896 PCT/U S97/ 16388-15-manner as to release the drug form and permit the drug to affordimproved therapeutic efficacy. An example of such a pro-drug is Ro48-3657.Herein, the term "pharmaceutically acceptable salts" shallmean non-toxic salts of the compounds employed in this invention whichare generally prepared by reacting the free acid with a suitable organicor inorganic base. Examples of such salts include, but are not limitedto, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate,fumarate, gluceptate, gluconate, gliitamate, glycollylarsanilate,hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate,malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote,palmitate, panthothenate, phosphate/diphosphate, polygalacturonate,salicylate, sodium, stearate, subacetate, succinate, tarmate, tartrate,teoclate, tosylate, triethiodide, valerate.The terms "active agent(s)" and "active drug(s)"' are usedherein as a way to refer to both the HMG-CoA reductase inhibitors andthe platelet aggregation inhibitors which are employed in the instantmethods and compositions. Both terms are intended to encompass allsalt, ester and pro-drug forms of HMG-CoA reductase inhibitors andplatelet aggregation inhibitors, even where the pro-drug form is notactive itself but is converted to the active drug form afteradministration.As used herein, the term "composition" is intended toencompass a product comprising the specified ingredients, in specifiedamounts where amounts are specified, as well as any product whichresults directly or indirectly from combination of the specifiedingredients, in the specified amounts where amounts are specified.As used herein, the term "myocardial infarction" isintended to include both Qâwave and non-Q-wave myocardial infarction,unless otherwise noted.10I5202530W0 98/1 1896CA 02265827 1999-03-09PCT/US97/163898-16..The instant method involves the administration of an HMG-CoA reductase inhibitor in combination with a platelet aggregationinhibitor. This combination therapy includes administration of a singlepharmaceutical dosage formulation which contains both the HMG-CoAreductase inhibitor and the platelet aggregation inhibitor, as well asadministration of each active agent in its own separate pharmaceuticaldosage formulation. While the HMG-CoA reductase inhibitor can beadministered orally or parenterally, oral dosing is preferred. The GPIIb/IIIa receptor antagonist can be administered orally, intravenously,transderrnally (for example using an iontophoretic patch), intraocularly,intranasally or by other routes known to those skilled in the medicalarts, taking into account that certain GP IIb/IIIa receptor antagonists aredeveloped for oral administration while others may be developed fornonâoral routes such as intravenous administration. Ticlopidine,clopidogrel, aspirin and dipyridamole are administered orally.Preferably, both active agents of the instant combination therapy areadministered orally, and most preferably the active agents are combinedin a single oral dosage formulation.For example, a GP IIb/IIIa receptor antagonist and anHMG-CoA reductase inhibitor can be administered to the patienttogether in one oral composition such as a tablet or capsule. Anotherexample would be a single oral composition comprised of aspirin and anHMG-CoA reductase inhibitor. Alternatively, the combination therapymay comprise administration of an oral HMG-CoA reductase inhibitorcomposition with a separate oral aspirin composition, or with a separateGP IIb/IIIa receptor antagonist composition formulated for oral,intravenous, transdermal, intraocular, or intranasal administration.Where separate dosage formulations are used, the HMG-CoA reductase inhibitor and the platelet aggregation inhibitor can beadministered at essentially the same time, i.e., concurrently, or atseparately staggered times, i.e, sequentially. Similarly, a GP IIb/IIIareceptor antagonist may be administered on an intravenous regimen,while the patient is orally dosed once a day with a conventional orcontrolled-release formulation of an HMG-CoA reductase inhibitor.W0 98/1 18961015202530CA 02265827 1999-03-09PCT/U S97/ 16388-17-Combination therapy is understood to include all these regimens.Administration in these various ways are suitable for the presentinvention as long as the beneficial pharmaceutical effect of the plateletaggregation inhibitor and HMGâCoA reductase inhibitor are realized bythe patient at substantially the same time. Such beneficial effect isachieved when the target blood level concentrations of each active drugare maintained at substantially the same time. Concurrent oraladministration is preferred.It is expected that a combination therapy of intravenouslyadministered GP IIb/IIIa receptor antagonist with orally administeredHMG-CoA reductase inhibitor could be used in response to an acutemedical event where inhibition of platelet aggregation is needed, andmay generally be administered for a period of time of one or two weeksor up to a month or longer if deemed necessary. Where thecombination therapy involves for example oral administration of boththe GP IIb/IIIa receptor antagonist and the HMG-CoA reductaseinhibitor, the therapy may be administered on a longer-term chronicbasis, such as a period of several months or years, for as long as deemedmedically appropriate for the patient. 'Therapeutically effective amounts of the plateletaggregation inhibitors and the HMGâCoA reductase inhibitors aresuitable for use in the compositions and methods of the presentinvention. The term "therapeutically effective amount" is intended tomean that amount of a drug or pharmaceutical agent that will elicit thebiological or medical response of a tissue, a system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician. The dosage regimen utilizing an HMGâCoA RI incombination with a platelet aggregation inhibitor is selected inaccordance with a variety of factors including type, species, age, weight,sex and medical condition of the patient; the severity of the condition tobe treated; the route of administration; the renal and hepatic function ofthe patient; and the particular compound or salt or ester thereofemployed. Since two different active agents are being used together in acombination therapy, the potency of each of the agents and the enhancedW0 98/ 1 18961015202530- 1-«-1--qr-ââ-1--~~ - â~CA 02265827 1999-03-09PCT/US97/16388-18-effects achieved by combining them together must also be taken intoaccount. A consideration of these factors is well within the purview ofthe ordinarily skilled clinician for the purpose of determining thetherapeutically effective amounts of the drug combination needed toprevent, counter, or arrest the progress of the condition.Dosage information for HMG-CoA RI's is well known inthe art, since several HMG-CoA RI's are marketed in the U.S. Inparticular, the daily dosage amounts of the HMG-CoA reductaseinhibitor may be the same or similar to those amounts which areemployed for antiâhypercholesterolemic treatment and which aredescribed in the Physiciansâ Desk Reference (PDR). For example, seethe 50th Ed. of the PDR, 1996 (Medical Economics Co); in particular,see at page 216 the heading "Hypolipidemics," sub-heading "HMG-CoAReductase Inhibitors," and the reference pages cited therein.Preferably, the oral dosage amount of HMG-CoA R1 is from about 1 to200 mg/day, and more preferably from about 5 to 160 mg/day.However, dosage amounts will vary depending on the potency of thespecific HMG-CoA reductase inhibitor used as well as other factors asnoted above. Also, the dosage amount of HMG-CoA reductase inhibitorneeded to achieve the desired effect will be affected by the dosageamount and potency of the IIb/IIIa receptor antagonist or other plateletaggregation inhibitor which is employed in the combined therapy. AnHMG-CoA RI which has sufficiently greater potency may be given insubâmilligram daily dosages.As examples, the daily dosage amount for sirnvastatin maybe selected from 5 mg, 10 mg, 20 mg, 40 mg, 80 mg and 160 mg; forlovastatin, 10 mg, 20 mg, 40 mg and 80 mg; for ï¬uvastatin sodium, 20mg, 40 mg and 80 mg; and for pravastatin sodium, 10 mg, 20 mg, and40 mg. The daily dosage amount for atorvastatin calcium may be in therange of from l mg to 160 mg, and more particularly from 5 mg to 80mg, including dosage amounts of 10 mg, 20 mg and 40 mg. Oraladministration may be in single or divided doses of two, three, or fourtimes daily, although a single daily dose of the HMG-CoA R1 ispreferred.â+--0-HIIIIM-1-»â~ »-â«v~«-~ W0 98/1 18961015202530CA 02265827 1999-03-09PCT/US97/ 16388-19-â Oral dosages of GP Hb/IIIa receptor antagonists when usedfor the indicated effects, will range between about 0.001 mg per kg ofbody weight per day (mg/kg/day) to about 50 mg/kg/day and preferably0.005-20 mg/kg/day and most preferably 0.005-10 mg/kg/day., Suitableoral tablets and capsules containâ between 0.1 mg and 5 g, preferablybetween 0.5 mg and 2 g, most preferably between 0.5 mg and lg, forexample, 0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 150 mg, 250 mg, or 500mg of GP Ilb/Hla receptor antagonist. Oral administration may be inone or divided doses of two, three, or four times daily. A single dailydose is preferred.Intravenously, the most preferred doses for GP IIb/IIIareceptor antagonists will range from about 0.5 ug to about 5 -mg/kg/minute during a constant rate infusion, to achieve a plasma levelconcentration during the period of time of administration of between0.1 ng/ml and 1 ug/ml.Dosage amounts for ticlopidine are described in thePhysiciansâ Desk Re erence . Dosage amounts of aspirin for theindicated effects are known to those skilled in medical arts, andgenerally range from about 75 mg to about 325 mg per day.â Forexample, a formulation may contain 75 mg, 80 mg, 160 mg, 250 mg, or325 mg of aspirin.Suitable oral formulations of clopidogrel may contain from25 mg to 500 mg, preferably from 75 mg to 375 mg, and mostpreferably from 75 mg to 150 mg of clopidogrel. For example, theformulation may contain 25 mg, 50 mg, 75 mg, 150 mg, 250 mg, or500 mg of clopidogrel. Oral administration may be in one or divideddoses of two, three, or four times daily. A single daily dose ispreferred.The active agents employed in the instant combinationtherapy can be administered in such oral forms as tablets, capsules (eachof which includes sustained release or timed release formulations), pills,powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.The instant invention includes the use of both oral rapidârelease andtime-controlled release pharmaceutical formulations (see, e.g., U.S.1015202530W0 98/11896CA 02265827 1999-03-09PCT/US97/16388-20-Patent No. 5,366,738 which describes controlled release formulations).Suitable intravenous compositions for the GP IIb/IIIa receptorantagonists include bolus or extended infusion. Such oral andintravenous compositions are known to those of ordinary skill in thepharmaceutical arts. For example, see Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, PA.The active drugs can be administered in admixture withpharmaceutical diluents, excipients or carriers (collectively referred toherein as "carrier" materials) suitably selected with respect to theintended form of administration, that is, oral tablets, capsules, elixirs,syrups and the like, and consistent 'with conventional pharmaceuticalpractices.For instance, for oral administration in the form of a tabletor capsule, the active drug component can be combined with a non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch,sucrose, glucose, modified sugars, modified starches, methyl celluloseand its derivatives, dicalcium phosphate, calcium sulfate, mannitol,sorbitol and other reducing and non-reducing sugars, magnesiumstearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calciumstearate and the like. For oral administration in liquid form, the drugcomponents can be combined with non-toxic, pharrnaceuticallyacceptable inert carrier such as ethanol, glycerol, water and the like.Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring and ï¬avoring agents can also beincorporated into the mixture. Stabilizing agents such as antioxidants(BHA, BHT, propyl gallate, sodium ascorbate, citric acid) can also beadded to stabilize the dosage forms. Other suitable components includegelatin, sweeteners, natural and synthetic gums such as acacia,tragacanth or alginates, carboxymethylcellulose, polyethylene glycol,waxes and the like.The active drugs can also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be1015202530W0 98/1 1896CA 02265827 1999-03-09PCT/US97/ 16388-21-formed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.Active drug may also be delivered by the use of monoclonalantibodies as individual carriers to which the compound molecules arecoupled. Active drug may also be coupled with soluble polymers astargetable drug carriers. Such polymers can include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyâethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, activedrug may be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyglycolic acid, copolymers of polylactic and polyglycolic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross linked oramphipathic block copolymers of hydrogels.The compositions and methods of the present invention maybe used as treatment for acute cardiovascular and cerebrovascularevents, as well as for chronic therapy for prevention or reduction ofrisk of occurrence of cardiovascular and cerebrovascular events. Forexample, the compositions of this invention, and methods foradministering the combination therapy of a platelet aggregationinhibitor with an HMG-CoA reductase inhibitor, are useful for treating,preventing or reducing the risk of occurrence of acute coronaryischemic syndrome in mammals, and more particularly in humans, whoare at risk of developing acute coronary ischemic syndrome. Acutecoronary ischemic syndrome includes the conditions of unstable anginaand nonâQ-wave myocardial infarction.Compositions and methods of the invention may be used toprevent or reduce the risk of formation of thrombi and thromboemboliand therefore to prevent or reduce the risk of thrombotic occlusions andreocclusions. They are useful in surgery on peripheral arteries (arterialgrafts, carotid endaterectomy) and in cardiovascular surgery wheremanipulation of arteries and organs, and/or the interaction of plateletswith artificial surfaces, leads to platelet aggregation and potentialW0 98/ 1 18961015202530CA 02265827 1999-03-09PCTIUS97/16388-22-formation of thrombi and thromboemboli. For example, thecombination therapy can be used for preventing or reducing the risk ofoccurrence of platelet thrombosis, thromboembolism and reocclusionafter acute intervention such as atherectomy, angioplasty (PTCA),coronary artery bypass procedures or cardiac valve replacement. Thecombination therapy can also be used for preventing or reducing therisk of occurrence of platelet thrombosis, thromboembolism andreocclusion during and after thrombolytic therapy. Since blood vesselscan also sustain chronic damage by the pathophysiological processes ofatherosclerosis, patients with atherosclerosis can also be treated with theinstant combination therapy to prevent or reduce the risk of occlusivethrombus formation. The instant combination therapy can be used totreat, prevent or reduce the risk of intermittent claudication, which is aclinical manifestation of peripheral vessel disease. Combination therapyof an HMGâC0A reductase inhibitor with a GP IIb/IIIa receptorantagonist may reduce the risk of thrombocytopenia.The instant combination therapy can also be used to treat,prevent or reduce the risk of a first or subsequent Qâwave myocardialinfarction in persons at risk for such events as well as to prevent orreduce the risk of restenosis in persons at risk for restenosis. âAdditionally, the instant combination therapy can be used for treating,preventing or reducing the risk of occurrence of acute cerebrovascularischemic events such as a first or subsequent thrombotic stroke ortransient ischemic attack. In general, the instant combination therapycan be used whenever antiplatelet therapy, or inhibition of plateletaggregation, is needed.The compositions and methods of the present inventionare also useful in combination with procedures for treating patientswith other anticoagulants (e.g. thrombin inhibitors such as heparinand Factor Xa inhibitors such as warfarin), and thrombolytic agents(e.g. streptokinase and tissue plasminogen activator). The instantcombination therapy can also be co-adminstered with a [3-adrenergicreceptor blocker. In particular, a combination of an HMG-COA RIwith aspirin can be co-administered with a [3âadrenergic receptor1015202530CA 02265827 1999-03-09W0 98/1 1896 PCT/US97/ 16388-23-blocker to reduce the risk of coronary heart disease andcerebrovascular clinical events such as myocardial infarction, strokeand cardiovascular death, particularly in post-MI patients. Examplesof [3-adrenergic receptor blockers include but are not limited toacebutolol, atenolol, betaxolol, bioprolol, carteolol, labetalol,metoprolol, nadolol, penbutolol, pindolol, propanolol, and timolol.Dosage amounts of [3-adrenergic receptor blockers are described inthe PDR. 'In accordance with this invention, a therapeuticallyeffective amount of an HMGâCoA RI and a therapeutically effectiveamount of a platelet aggregation inhibitor can be used for thepreparation of a medicament useful for inhibiting platelet aggregation,and for treating, preventing or reducing the risk of developing acutecoronary ischemic syndrome in mammals, particularly in humans.Additionally, a therapeutically effective amount of an HMGâCoA RI anda therapeutically effective amount of a platelet aggregation inhibitor canbe used for the preparation of a medicament useful for preventing orreducing the risk of formation of thrombi and thromboemboli, forpreventing or reducing the risk of thrombotic occlusions andreocclusions, for treating, preventing or reducing the risk of a first orsubsequent myocardial infarction, for preventing or reducing the risk ofrestenosis, for treating, preventing or reducing the risk of acutecerebrovascular ischemic events such as a first or subsequent thromboticstroke or transient ischemic attack, and for halting or slowing theprogression of atherosclerotic disease. More particularly, atherapeutically effective amount of an HMGâCoA RI and atherapeutically effective amount of a platelet aggregation inhibitor canbe used together for the preparation of a medicament suitable for oraladministration which is useful for the above-described treatments.Similarly, a therapeutically effective amount of an HMGâCoA RI can beused for the preparation of a medicament for use in combination with atherapeutically effective amount of a platelet aggregation inhibitor,which is useful for the above-described treatments. Also, atherapeutically effective amount of a platelet aggregation inhibitor can1015202530',.....?âr. ...__.,.,. ..W0 98/ 1 1896CA 02265827 1999-03-09PC T/U S97/ 1 6388-24-be used for the preparation of a medicament for use in combination witha therapeutically effective amount of an HMG-CoA RI, which is usefulfor the aboveâdescribed treatments.An additional embodiment of the instant inventioninvolves a kit comprised of an HMG-CoA R1 in an oral dosageformulation and a platelet aggregation inhibitor in a separate oraldosage formulation. More particularly, the kit is comprised of anHMG-CoA RI selected from the group consisting of lovastatin,simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin; andthe platelet aggregation inhibitor is selected from the groupconsisting of a GP Hb/Illa receptoiâ antagonist, ticlopidine,clopidogrel, aspirin and dipyridamole. In one class of thisembodiment the HMG-CoA RI is selected from lovastatin andsimvastatin, and more particularly the HMG-CoA R1 is simvastatin.In a second class of this embodiment, the platelet aggregationinhibitor is a GP IIb/IIIa receptor antagonist selected from the groupconsisting of Compound âA, Compound B, and DMP 754. In a thirdclass of this embodiment, the platelet aggregation inhibitor is aspirin.One example of this embodiment is a kit comprised ofan oral dosage formulation of simvastatin and an oral dosageformulation of aspirin. The packaging for the kit could be designedand manufactured in a variety of ways. A preferred example is ablister package containing rows of a simvastatin tablet and an aspirintablet placed side by side on the same blister card, each of the twotablets in its own blister bubble, with calendar or similar typemarkings on the card that convey to the user that one "pair" oftablets (i.e., one simvastatin tablet and one aspirin tablet) is to beingested per day. A kit containing simvastatin and a GP IIb/IIIareceptor antagonist such as Compound A, Compound B, or DMP 754could be designed in a similar fashion.A further class of this embodiment involves the kitdescribed above further comprising an oral dosage formulation of aa pharmaceutically active agent selected from a Bâadrenergic receptorblocker and an angiotensin II receptor antagonist, in addition to the--1--u-nrrfâ 7 1r10W0 98/1 1896CA 02265827 1999-03-09PCTlUS97/ 16388-25-HMG-CoA RI and the platelet aggregation inhibitor. Moreparticularly, Bâadrenergic receptor blockers without intrinsicsympathomimetic activity (ISA) and without alpha blockingproperties have a cardioprotective effect for patients who have had amyocardial infarction and can be employed in the kit. Atenolol,metoprolol, betaxolol and acebutolol are beta blockers without ISA.Losartan potassium is currently marketed in the U.S. under thetrademark COZAAR®, and is one example of an angiotensin IIreceptor antagonist that could be employed in the kit. Dosages forbeta blockers and for losartan potassium are commonly known tothose skilled in the phannaceuticafarts and can be found, forexample in the Physiciarfs Desk Reference.Examples of dosage formulations are as follows.W0 98/ I 1896CA 02265827 1999-03-09PCT/US97/16388_ 25 _EXAMPLE 1Tablet PreparationTablets containing simvastatin and a glycoprotein5 IIb/IIIa receptor antagonist can be prepared as illustrated below:Ingredient Amountsimvastatin ' 1 mg - 200 mg.glycoprotein IIb/IIIa receptor antagonist 0.1 mg â 5 g10diluentbinderdisintegl-am excipients qs. 200 - 400 mg.lubricantEXAMPLE 2Tablet Preparation15Tablets containing 25.0, 50.0, and 100.0 mg, respectively,of a GP IIb/IIIa receptor antagonist are prepared as illustrated below:TABLE FOR DOSES CONTAINING20 FROM 25-l00MG OF GP HB/IIIA RECEPTOR ANTAGONISTAmount-maGP IIb/IIIa receptor 25.0 50.0 100.0antagonistMicrocrystalline cellulose 37.25 100.0 200.0Modified food corn starch 37.25 4.25 8.5Magnesium stearate 0.50 0.75 1.5W0 98/1 189610152025CA 02265827 1999-03-09PCTlUS97l16388-27-All of the active compound, cellulose, and a portion of thecorn starch are mixed and granulated to 10% corn starch paste. Theresulting granulation is sieved, dried and blended with the remainder ofthe corn starch and the magnesium stearate. The resulting granulation isthen compressed into tablets containing 25.0, 50.0, and 100.0 mg,respectively, of active ingredient per tablet.EXAMPLE 3Intravenous formulations An intravenous dosage form of the GP IIb/IIIa receptorantagonist is prepared as follows:AmountGP IIb/IIIa receptor antagonist 0.5âl0.0mgSodium Citrate 5-50mgCitric Acid 1âl5mgSodium Chloride lâ8mgWater for Injection (USP) q.s. to 1 LUtilizing the above quantities, the active compound isdissolved at room temperature in a previously prepared solution ofsodium chloride, citric acid, and sodium citrate in Water for Injection(USP, see page 1636 of United States Pharrnacopeia/National Forrnularyfor 1995, published by United States Pharmacopeial Convention, Inc.,Rockville, Maryland, copyright 1994.While the invention has been described and illustratedwith reference to certain particular embodiments thereof, thoseskilled in the art will appreciate that various changes, modificationsand substitutions can be made therein without departing from thespirit and scope of the invention. For example, effective dosagesother than the particular dosages as set forth herein above may beapplicable as a consequence of variations in the responsiveness of themammal being treated for any of the indications for the active agents10CA 02265827 1999-03-09W0 98/ 1 1896 PCT/US97/16388-23-used in the instant invention as indicated above. Likewise, thespecific pharmacological responses observed may vary according toand depending upon the particular active compound selected orwhether there are present pharmaceutical carriers, as well as the typeof formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims whichâ follow and that such claims be interpreted asbroadly as is reasonable.TT 'T"ââlâ|" T T â
