US 20070082840A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/008284.0 A1 Porter et al. (43) Pub. Date: Apr. 12, 2007 (54) COMBINATION THERAPY FOR INHIBITION Publication Classification OF PLATELET AGGREGATION (51) Int. Cl. A6II 38/12 (2006.01) (76) Inventors: R. Stephen Porter, Franklin, TN (US); A6II 38/06 (2006.01) Kristen K. Flaharty, Fort Myers, FL A6II 38/05 (2006.01) (US); James E. Tcheng. Durham, NC A 6LX 3L/727 (2006.01) (US); John W. Ferkany, Brighton, MA A61K 3 I/5513 (2006.01) (US) A61K 31/5377 (2006.01) A6II 3/445 (2006.01) (52) U.S. Cl. ............... 514/9: 514/18: 514/317; 514/221; Correspondence Address: 514/326; 514/232.5: 514/56 CLARK & ELBNG LLP (57) ABSTRACT 101 FEDERAL STREET The invention features methods for preventing platelet acti BOSTON, MA 02110 (US) Vation and aggregation and for treating individuals Suffering from conditions or undergoing procedures that may result in (21) Appl. No.: 11/515,596 unwanted platelet aggregation. The methods are based on (22) Filed: Sep. 5, 2006 the intravenous, Subcutaneous, or transdermal administra tion of a platelet activation or aggregation inhibitor, e.g., Related U.S. Application Data Xemilofiban, followed by oral administration of the same or a different platelet activation or aggregation inhibitor. The (63) Continuation of application No. PCT/US05/07440, treatment may commence prior to a medical or Surgical filed on Mar. 7, 2005. procedure or after the outbreak of an adverse medical condition, either of which results in the activation of plate (60) Provisional application No. 60/550,792, filed on Mar. lets that may lead to thrombus formation, and may continue 5, 2004. thereafter. Patent Application Publication Apr. 12, 2007 Sheet 1 of 2 US 2007/008284.0 A1 SM-20302 SR 90.107 L-734,217 SDZ GPI 562 RWJ-50042 TP-92.01 Figure 1 Patent Application Publication Apr. 12, 2007 Sheet 2 of 2 US 2007/008284.0 A1 ME-3277 OCHCOOH OCHCOOH UR-12947 SANORG 34006 Figure 1 (continued) US 2007/008284.0 A1 Apr. 12, 2007 COMBINATION THERAPY FOR INHIBITION OF (e.g., via a patch, Sonophoresis, a microneedle array, or PLATELET AGGREGATION iontophoresis) administering a first platelet activation or aggregation inhibitor to the Subject; and orally administering CROSS-REFERENCE TO RELATED a second platelet activation or aggregation inhibitor to the APPLICATIONS subject, provided that, when the first platelet activation or aggregation inhibitor is heparin, the second platelet activa 0001) This application is a continuation of PCT/US2005/ tion or aggregation inhibitor is not aspirin, and provided that 007.440 filed Mar. 7, 2005, which, in turn, claims benefit of when the first platelet activation or aggregation inhibitor is U.S. Provisional Patent Application Ser. No. 60/550,792, RPR 109891, the second platelet activation or aggregation filed Mar. 5, 2004; the disclosures of which are each hereby inhibitor is not RPR 109891. The first and second platelet incorporated by reference in their entirety. activation or aggregation inhibitors may be the same or different. The method may further include administering a BACKGROUND OF THE INVENTION cholesterol lowering agent, an agent that modifies eicosanoid activity, a 5HT2a antagonist, nonsteroidal anti 0002 The invention relates to the field of medical treat inflammatory drugs, an adrenergic inhibitor, an angiotensin ments, in particular the inhibition of platelet aggregation. converting enzyme inhibitor, an angiotensin II receptor 0003 Fibrinogen is a glycoprotein present as a normal antagonist, a fibrilyinic agent, a beta blocker, a calcium component of blood plasma. It participates in platelet aggre channel blocker, a diuretic agent, a steroid, a steroidal gation and fibrin formation in the blood clotting mechanism. glycoside, a nicotinic acid drug, a bile acid sequestrant, a Platelets are cellular elements found in whole blood, which fibrate, ETC 588 (liposome), ETC 216 (ApoA-I Milano/ also participate in blood coagulation. Fibrinogen binding to phospholipid complex), ETC 642 (RLT Peptide), pirozadil, platelets is important for normal platelet function in the or a vasodilator or to the Subject, e.g., with the first or second blood coagulation mechanism. When a blood vessel receives platelet aggregation inhibitor or separately. an injury, the platelets binding to fibrinogen will initiate 0007 Exemplary first or second platelet activation or aggregation and form a thrombus. Injury can occur during aggregation inhibitors include a GP IIb/IIIa antagonist, a medical or Surgical procedures. In addition, certain medical heparin, tissue plasminogen activator, a Factor Xa inhibitor, conditions, such as diabetes, leads to platelet aggregation a purinergic-receptor antagonist, a thrombin inhibitor, a and thrombosis in Vital organs. Interaction offibrinogen with phosphodiesterase inhibitor (e.g., dipyridamole), a platelets occurs through a membrane glycoprotein complex, cyclooxygenase inhibitor (e.g., aspirin), a CD40 antagonist, known as glycoprotein IIb/IIIa (GPIb/IIIa). Inhibitors of and a leukotriene inhibitor. Examples of GPIb/IIIa antago this interaction are useful in modulating or preventing nists include tirofiban, abciximab, eptifibatide, TRM-147, platelet thrombus formation. SM-20302, L-378167, rClf A, ME-3230, SR-121787, 0004 The activation of platelets and the resultant aggre UR-12947, L-734217, DMP-757, EMD-96717, SDZ-GPI gation have been shown to be important factors in the 562, RG-13965, SB-207448, SC-56929, RWJ-50042, UR pathogenesis of acute coronary syndrome, unstable angina 4005, L-703014, SKF-106760, CRL-42796, HMR-1794, pectoris, transient myocardial ischemia, acute myocardial CGH-400, Ro-43-5054, Barbourin, Bitistatin, SC-49992, infarction, peripheral arterial occlusion, and atherosclerosis. TP-9201, MA-16N7C2, roxifiban (DMP-754), lamifiban, In most of these serious cardiovascular disorders, intracoro Xemilofiban, lotrafiban, sibrafiban, DU-728, DMP-728, nary or intra-arterial thrombus is present. The thrombus is MK-852, SC-52012A, echistatin, TAK-029, ME-3277, generally formed by activated platelets that adhere and T-250, MS-180, TA-993, elarofiban (RWJ-53308), croma aggregate at the site of endothelial injury or plaque rupture. fiban (CT-50352), YM-337, lefradafiban (BIBU-104), Because of the relative contribution of activated platelets to fradafiban (BIBU-52), ZD-2486, RPR-109891, gantofiban, aggregation and Subsequent formation of an occlusive GR-144053F, and pharmaceutically acceptable salts thereof. thrombus, antiplatelet agents have been developed that Exemplary heparins include low molecular weight heparins, inhibit platelet activation or aggregation. Such as ardeparin, certoparin, dalteparin, enoxaparin, nadro parin, reviparin, SNAD-UFH, SNAC-UFH, or tinazaparin. SUMMARY OF THE INVENTION Factor Xa inhibitors include coumadin, danaparoid, fonda parinux, CL-1031, DPC 906, Sanorg-34006, MCM 16, 0005 The present invention provides methods for pre MCM 17, BAY 59-7939, KFA-1982, GH9001, DPC423, venting platelet activation and aggregation and for treating ZD4927, DX-9065a, YM 60828, SR 90107, FXV673, and individuals Suffering from conditions or undergoing proce tifacogin. The purinergic-receptor antagonist is for example dures that may result in unwanted platelet aggregation. The a P2Y or P2Y antagonist or both. P2Y antagonists methods are based on the intravenous, Subcutaneous, or include clopidogrel, cangrelor, and ticlopidine, and P2Y transdermal administration of a platelet activation or aggre antagonists include ATP and MRS 2179 (2'-deoxy-N6-me gation inhibitor, e.g., xemilofiban, followed by oral admin thyladenosine 3',5'-bisphosphate). Exemplary thrombin istration of the same or a different platelet activation or inhibitors re bivalirudin, lepirudin, argatroban, melagatran, aggregation inhibitor. The treatment may commence prior to Ximelagatran, antithrombin IIII, dermatan, mesoglycan, a medical or Surgical procedure or after the outbreak of an MB-015, H-376/95, BIBR 1048, efegatran, TRI-50B, adverse medical condition, either of which results in the inogatran, V19, and PEG-r-hirudin. CD40 antagonists activation of platelets that may lead to thrombus formation, include soluble CD40 ligand and a CD40 antibody, and and may continue thereafter. leukotriene inhibitors include monelukast, Zafirlukast, and 0006. In one aspect, the invention features a method of Zileuton. inhibiting platelet aggregation in a Subject including the 0008. When the subject has a body mass index of greater steps of intravenously, Subcutaneously, or transdermally than 30, 4 to 10 mg of the first platelet activation or US 2007/008284.0 A1 Apr. 12, 2007 aggregation inhibitor is typically administered, and when the Vation or aggregation inhibitor, e.g., xemilofiban, may be subject has a body mass index of less than 30, 1 to 3 mg of administered for at least 1 day, e.g., at least 2, 7, 14, or 30 the first platelet activation or aggregation inhibitor is typi days. cally administered. 0011. The invention further features a method of inhib 0009. The intravenous, transdermal, or subcutaneous iting platelet aggregation in a Subject including Subcutane administration may also occur prior to or during a medical ously administering a platelet aggregation, a Factor Xa or Surgical procedure, e.g., a cardiovascular interventional inhibitor, a heparin, and a thrombin inhibitor to the subject. procedure. Exemplary cardiovascular interventional proce The platelet aggregation inhibitor is, for example, a GP dures include percutaneous