Methods and compositions for treating platelet-related disorders

Abstract

Provided are prophylactic and therapeutic methods of treatment of subjects for the purpose of inhibiting vaso-occlusive events, including embolism, by administering agents, including anagrelide and anagrelide derivatives, which reduce the number of circulating platelets to low normal to below normal levels. Methods and pharmaceutical preparations comprising such agents are provided.

1 . A method for treating a subject to inhibit a vaso-occlusive event, comprising administering anagrelide or a derivative or analog thereof to a subject in need of such treatment, wherein the anagrelide or derivative or analog thereof is administered in an amount effective to reduce platelet count in the subject to at least a low normal level.  
     
     
         2 . The method of  claim 1 , wherein: 
 the anagrelide or a derivative or analog thereof is provided in a controlled release delivery system; and    the delivery system is formulated to administer an amount of the anagrelide or the anagrelide derivative or analog at a rate and in an amount effective to reduce platelet count in the subject to at least a low normal level but without significantly affecting platelet function.    
     
     
         3 . The method of  claim 1 , wherein the subject does not have a hematological proliferative disorder.  
     
     
         4 . The method of  claim 2 , wherein the subject does not have a hematological proliferative disorder  
     
     
         5 . The method of  claim 1 , wherein the subject has a normal platelet count prior to treatment.  
     
     
         6 . The method of  claim 1 , wherein the subject has an above normal platelet count prior to treatment.  
     
     
         7 . The method of  claim 1 , wherein the subject is a human.  
     
     
         8 . The method of  claim 1 , wherein the subject has vascular disease.  
     
     
         9 . The method of  claim 8 , wherein the vascular disease is selected from the group consisting of arteriosclerosis, cardiovascular disease, cerebrovascular disease, renovascular disease, mesenteric vascular disease, pulmonary vascular disease, ocular vascular disease and peripheral vascular disease.  
     
     
         10 . The method of  claim 1 , wherein the subject has had a primary vaso-occlusive event.  
     
     
         11 . The method of  claim 1 , wherein the subject has a condition selected from the group consisting of hypercholesterolemia, hypertension and atherosclerosis.  
     
     
         12 . The method of  claim 1 , wherein the anagrelide or derivative or analog thereof is administered to the subject prior to a surgical procedure.  
     
     
         13 . The method of  claim 12 , wherein the surgical procedure is selected from the group consisting of coronary angiography, coronary stent placement, coronary by-pass surgery, carotid artery procedure, peripheral stent placement, vascular grafting, thrombectomy, peripheral vascular surgery, vascular surgery, organ transplant, artificial heart transplant, vascular angioplasty, vascular laser therapy, vascular replacement and vascular stenting.  
     
     
         14 . The method of  claim 1 , wherein the anagrelide or derivative or analog thereof is administered to the subject after a surgical procedure.  
     
     
         15 . The method of  claim 14 , wherein the surgical procedure is selected from the group consisting of coronary angiography, coronary stent placement, coronary by-pass surgery, carotid artery procedure, peripheral stent placement, vascular grafting, thrombectomy, peripheral vascular surgery, vascular surgery, organ transplant, artificial heart transplant, vascular angioplasty, vascular laser therapy, vascular replacement and vascular stenting.  
     
     
         16 . The method of  claim 2 , wherein the controlled release delivery system further comprises another therapeutic compound selected from among an inhibitor of platelet function, an anti-coagulant agent and a fibrinolytic agent.  
     
     
         17 . The method of  claim 16 , wherein the inhibitor of platelet function is selected from among acadesine, anipamil, argatroban, aspirin, clopidogrel, a cyclooxygenase inhibitor, a nonsteroidal anti-inflammatory drug, the synthetic compound FR-122047, danaparoid sodium, dazoxiben hydrochloride, a diadenosine 5′,5′″-P1,P4-tetraphosphate (Ap4A) analog, difibrotide, dilazep dihydrochloride, 1,2-glyceryl dinitrate, 1,3-glyceryl dinitrate, dipyridamole, dopamine, 3-methoxytyramine, efegatran sulfate, enoxaparin sodium, glucagon, a glycoprotein IIb/IIIa antagonist, Ro-43-8857, L-700,462, ifetroban, ifetroban sodium, iloprost, isocarbacyclin methyl ester, isosorbide-5-mononitrate, itazigrel, ketanserin, BM-13.177, lamifiban, lifarizine, molsidomine, nifedipine, oxagrelate, prostaglandin E (PGE), a platelet activating factor antagonist, lexipafant, prostacyclin (PGI2), a pyrazine, pyridinol carbamate, abciximab, sulfinpyrazone, BN-50727, BN-52021, CV-4151, E-5510, FK-409, GU-7, KB-2796, KBT-3022, KC-404, KF-4939, OP-41483, TRK-100, TA-3090, TFC-612, ZK-36374, 2,4,5,7-tetrathiaoctane, 2,4,5,7-tetrathiaoctane 2,2-dioxide, 2,4,5-trithiahexane, theophyllin, pentoxifyllin, a thromboxane inhibitor, a thromboxane synthetase inhibitor, picotamide, sulotroban, ticlopidine, tirofiban, trapidil, triclopidine, trifenagrel, trilinolein, a 3-substituted 5,6-bis(4-methoxyphenyl)-1,2,4-triazine, an antibody to glycoprotein IIb/IIIa, an anti-serotonin drug, dipyridamole, clofibrate, caffeine and ticlopidine.  
     
     
         18 . The method of  claim 17 , wherein the inhibitor of platelet function is selected from the group consisting of aspirin, abciximab, clopidogrel and dipyridamole.  
     
     
         19 . The method of  claim 2 , wherein the controlled release delivery system comprises a matrix in which the anagrelide or the anagrelide derivative or analog is dispersed.  
     
     
         20 . The method of  claim 19 , wherein the matrix is formulated to achieve a reduction in peak level of agent in the subject.  
     
     
         21 . The method of  claim 2 , wherein the delivery system comprises one or more than one polymer selected from among a poly(lactide-glycolide), a copolyoxalate, a polycaprolactone, a polyesteramide, a polyorthoester, a polyhydroxybutyric acid or a polyanhydride.  
     
     
         22 . The method of  claim 2 , wherein the delivery system comprises a lipid, a sterol, a fatty acid, a neutral fat, a wax or a combination thereof.  
     
     
         23 . The method of  claim 2 , wherein the delivery system comprises a hydrogel delivery system.  
     
     
         24 . The method of  claim 2 , wherein the delivery system comprises microcapsules.  
     
     
         25 . The method of  claim 24 , wherein the microcapsules comprise one or more than one polymer selected from among a poly(lactide-glycolide), a copolyoxalate, a polycaprolactone, a polyesteramide, a polyorthoester, a polyhydroxybutyric acid or a polyanhydride.  
     
     
         26 . The method of  claim 2 , wherein the delivery system is formulated for administration by a route selected from among oral, rectal, topical, nasal, intradermal, intramuscular and parenteral routes.  
     
     
         27 . The method of  claim 1 , wherein platelet count is reduced by at least 20%.  
     
     
         28 . The method of  claim 1 , wherein platelet count is reduced by at least 50%.  
     
     
         29 . The method of  claim 1 , wherein platelet count is reduced to below 200×10 3  platelets per μl.  
     
     
         30 . The method of  claim 1 , wherein platelet count is reduced to below 150×10 3  platelets per μl.  
     
     
         31 . The method of  claim 1 , wherein platelet count is reduced to below 100×10 3  platelets per μl.  
     
     
         32 . The method of  claim 1 , wherein platelet count is reduced by at least 10% and to an amount above 200×10 3  platelets per μl.  
     
     
         33 . The method of  claim 1 , wherein platelet count is reduced by at least 10% and to an amount below 200×10 3  platelets per μl.