Methods and compositions for treating platelet-related disorders

Abstract

Pharmaceutical preparations comprising one or more agents that reduce the number of circulating platelets to low normal or below normal levels formulated in a delivery system are provided. The pharmaceutical preparations are useful in the prophylactic and therapeutic treatment of subjects for the purpose of inhibiting vaso-occlusive events, including embolism, by reducing the number of circulating platelets to low normal to below normal levels.

1 . A pharmaceutical composition, comprising a platelet reducing agent that reduces platelet number, wherein the composition is formulated in a controlled release delivery system.  
   
   
       2 . The pharmaceutical composition of  claim 1 , wherein the delivery system is a time-release system, a delayed release system or a sustained release system.  
   
   
       3 . The pharmaceutical composition of  claim 2 , wherein the delivery system comprises an erosional system or a diffusional system.  
   
   
       4 . The pharmaceutical composition of  claim 3 , wherein the platelet reducing agent is a cAMP phosphodiesterase inhibitor.  
   
   
       5 . The pharmaceutical composition of  claim 1 , wherein the platelet reducing agent is anagrelide (6,7-dichloro-1,5-dihydroimidazo-[2,1-b]quinazolin-2(3H)-one) or a derivative of anagrelide.  
   
   
       6 . The pharmaceutical composition of  claim 5 , wherein the platelet reducing agent is anagrelide.  
   
   
       7 . The pharmaceutical composition of  claim 5 , wherein the delivery system is a sustained release system.  
   
   
       8 . The pharmaceutical composition of  claim 5 , wherein the derivative of anagrelide has an increased specificity towards a megakaryocyte lineage-restricted cell than anagrelide.  
   
   
       9 . The pharmaceutical composition of  claim 5 , wherein the derivative of anagrelide is more effective at reducing levels of platelets than anagrelide.  
   
   
       10 . The pharmaceutical composition of  claim 5 , wherein the derivative of anagrelide is N-cyclohexyl-N-methyl-4-(7-oxy-1,2,3,5-tetrahydroimadazo-[2,1-b]quinazolin-2-one) or 6,7-dichloro-1,2,3,5-tetrahydroimidazo-[2,1-b]-quinazolin-2-one.  
   
   
       11 . The pharmaceutical composition of  claim 5 , wherein the derivative of anagrelide is selected from among 1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one, 7-bromo-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one, 7-nitro-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one, 7-amino-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one, 6-hydroxy-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one, 7-hydroxy-1,2,3,5-tetrahydroimidazo-[2,1-b]-quinazolin-2-one, 8-bromo-6-[H]-1,2,3,4-tetrahydroimidazo-[2,1-b]-quinazolin-2-one, 6-methyl-7-nitro-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one, 7-bromo-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one, 7-chloro-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one, 6-chloro-7-bromo-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one, 6,7-dichloro-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one, 7-amino-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one, 7-amino-6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one, 6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one, 3-(carboxymethyl)-3,4-dihydro-5-methyl-4-methylene-1H-quinazolin-2-one, 3-(carboxymethyl)-4,5-dimethyl-1,2,3,4-tetrahydro-quinazoline-2-one, 2-chloro-3-carethoxymethyl-4,5-dimethyl-3,4-dihydroquinazoline, 5,6-dimethyl-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one, 3-(carbethoxymethyl)-3,4-dihydro-6-methylene-1H-quinazolin-2-one, 3-(carbethoxymethyl)-4,6-dimethyl-1,2,3,4-tetrahydroqionazolin-2-one, 2-chloro-3-carbethoxymethyl-4,6-dimethyl-3,4-dihydro-quinazoline, 5,7-dimethyl-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-2-one, 5-methyl-3-(carbethoxymethyl)-1,2,3,4-tetrahydroquinazolin-2-one, 2-chloro-3-carbethoxymethyl-5-methyl-3,4-dihyrdoquinazoline hydrochloride and 6-methyl-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-2-one.  
   
   
       12 . The pharmaceutical composition of  claim 5 , wherein the dose of the agent is from about 0.01 mg/kg per day to 1000 mg/kg per day.  
   
   
       13 . The pharmaceutical composition of  claim 5 , wherein the effective amount is in the range of 30 μg/kg/day to 150 μg/kg/day.  
   
   
       14 . The pharmaceutical composition of  claim 5 , wherein the effective amount is in the range of 1 μg/kg/day to 10 μg/kg/day.  
   
   
       15 . The pharmaceutical composition of  claim 5 , wherein the effective amount is in the range of 1 μg/kg/day to 0.150 μg/kg/day.  
   
   
       16 . The pharmaceutical composition of  claim 5 , wherein the delivery system administers an amount of the agent effective to reduce platelet numbers to low normal levels in a subject.  
   
   
       17 . The pharmaceutical composition of  claim 5 , wherein the delivery system administers an amount of the agent effective to reduce platelet numbers to below normal levels in a subject.  
   
   
       18 . The pharmaceutical composition of  claim 1 , wherein the agent is provided in an amount to reduce platelet levels to below 2×10 5  platelets per μl in a human subject.  
   
   
       19 . The pharmaceutical composition of  claim 1 , wherein the agent is provided in an amount to reduce platelet levels to below 1×10 5  platelets per μl in a human subject.  
   
   
       20 . The pharmaceutical composition of  claim 5 , wherein the platelet reducing agent is dispersed in a matrix.  
   
   
       21 . The pharmaceutical composition of  claim 20 , wherein the matrix is formulated to achieve a reduction in peak level of agent in the subject.  
   
   
       22 . The pharmaceutical composition of  claim 20 , wherein the matrix is formulated to administer a dose of agent that maintains a desired platelet count in a subject.  
   
   
       23 . The pharmaceutical composition of  claim 20 , wherein the matrix comprises a polymer or cholesterol.  
   
   
       24 . The pharmaceutical composition of  claim 20 , wherein the matrix comprises a binding agent.  
   
   
       25 . The pharmaceutical composition of  claim 24 , wherein the binding agent is selected from among polyethylene glycol, polyvinylpyrollidone, hydroxymethylcellulose and hydroxypropylmethylcellulose.  
   
   
       26 . The pharmaceutical composition of  claim 20 , wherein the matrix comprises a lubricating agent.  
   
   
       27 . The pharmaceutical composition of  claim 26 , wherein the lubricating agent is selected from among stearic acid, magnesium stearate, calcium stearate.  
   
   
       28 . The pharmaceutical composition of  claim 20 , wherein the matrix comprises: 
 (a) 20-80% cholesterol powder;    (b) 20-80% cholesterol prills, 100-1200 microns in diameter;    (c) 0.1-5.0% biocompatible binding agent;    (d) 0.1-5.0% biocompatible lubricating agent.    
   
   
       29 . The pharmaceutical composition of  claim 5 , 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.  
   
   
       30 . The pharmaceutical composition of  claim 5 , wherein the delivery system comprises a lipid, a sterol, a fatty acid, a neutral fat, a wax or a combination thereof.  
   
   
       31 . The pharmaceutical composition of  claim 5 , wherein the delivery system comprises a hydrogel delivery system.  
   
   
       32 . The pharmaceutical composition of  claim 5 , wherein the delivery system comprises microcapsules.  
   
   
       33 . The pharmaceutical composition of  claim 32 , 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.  
   
   
       34 . The pharmaceutical composition of  claim 5 , wherein the composition is formulated for administration by a route selected from among oral, rectal, topical, nasal, intradermal, intramuscular and parenteral routes.  
   
   
       35 . The pharmaceutical composition of  claim 5 , wherein the composition is formulated for daily administration.  
   
   
       36 . The pharmaceutical composition of  claim 5 , wherein the composition is formulated to be administered in multiple doses per day.  
   
   
       37 . The pharmaceutical composition of  claim 5 , further comprising aspirin.  
   
   
       38 . The pharmaceutical composition of  claim 5 , further comprising heparin or coumarin.  
   
   
       39 . The pharmaceutical composition of  claim 5 , further comprising another therapeutic compound selected from among an inhibitor of platelet function, an anti-coagulant agent and a fibrinolytic agent.  
   
   
       40 . The pharmaceutical composition of  claim 39 , 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.  
   
   
       41 . The pharmaceutical composition of  claim 40 , wherein the inhibitor of platelet function is selected from the group consisting of aspirin, abciximab, clopidogrel and dipyridamole.  
   
   
       42 . The pharmaceutical composition of  claim 40 , wherein the inhibitor of platelet function is clopidogrel.  
   
   
       43 . The pharmaceutical composition of  claim 39 , wherein the anti-coagulant agent is selected from among ardeparin sodium, bivalirudin, bromindione, coumarin, dalteparin sodium, desirudin, dicumarol, heparin, lyapolate sodium, nafamostat mesylate, phenprocoumon, sulfatide, tinzaparin sodium and warfarin sodium.  
   
   
       44 . The pharmaceutical composition of  claim 39 , wherein the fibrinolytic agent is selected from among ancrod, anistreplase, bisobrin lactate, brinolase, a Hageman factor fragment, prostacyclin, molsidomine, streptokinase, a tissue plasminogen activator (TPA) and urokinase.  
   
   
       45 . The pharmaceutical composition of  claim 39 , wherein the therapeutic compound is an angiotensin converting enzyme (ACE) inhibitor.  
   
   
       46 . The pharmaceutical composition of  claim 45 , wherein the ACE inhibitor is selected from among an acylmercapto proline, a mercaptoalkanoyl proline, a carboxyalkyl dipeptide, a carboxyalkyl dipeptide mimic and a phosphinylalkanoyl proline.  
   
   
       47 . The pharmaceutical composition of  claim 45 , wherein the ACE inhibitor is selected from among captopril, zofenopril, enalapril, lisinopril, quinapril, ramipril, perindopril, cilazapril, benazapril, fosinopril and trandolopril.  
   
   
       48 . The pharmaceutical composition of  claim 39 , wherein the therapeutic compound is a diadenosine 5′,5′″-P1,P4-tetraphosphate (Ap4A) analog or a cyclooxygenase inhibitor.  
   
   
       49 . The pharmaceutical composition of  claim 39 , wherein the anti-coagulant is a glycosoaminoglycan.  
   
   
       50 . The pharmaceutical composition of  claim 5 , wherein the delivery system is formulated to administer an amount of the agent effective to reduce platelet numbers in a subject by at least 10%.  
   
   
       51 . The pharmaceutical composition of  claim 5 , wherein the delivery system is formulated to administer an amount of the agent effective to reduce platelet numbers in a subject by at least 20%.  
   
   
       52 . The pharmaceutical composition of  claim 5 , wherein the delivery system is formulated to administer an amount of the agent effective to reduce platelet numbers in a subject by at least 50%.  
   
   
       53 . A method of treating a subject to inhibit a vaso-occlusive event, comprising administering to a subject in need of such treatment a controlled release delivery system comprising anagrelide or an anagrelide derivative, wherein the delivery system is formulated to administer an amount of the anagrelide or the anagrelide derivative effective to reduce platelet count in the subject by at least 10% of pre-treatment levels.  
   
   
       54 . The method of  claim 53 , wherein the platelet count is reduced to at least a low normal level.  
   
   
       55 . The method of  claim 53 , wherein the subject has a normal platelet count prior to treatment.  
   
   
       56 . The method of  claim 53 , wherein the subject has an above normal platelet count prior to treatment.  
   
   
       57 . The method of  claim 53 , wherein the subject is a human.  
   
   
       58 . The method of  claim 53 , wherein the subject has vascular disease.  
   
   
       59 . The method of  claim 58 , 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.  
   
   
       60 . The method of  claim 53 , wherein the subject has had a primary vaso-occlusive event.  
   
   
       61 . The method of  claim 53 , wherein the subject has a condition selected from the group consisting of hypercholesterolemia, hypertension and atherosclerosis.  
   
   
       62 . The method of  claim 53 , wherein the subject will undergo an elective surgical procedure.  
   
   
       63 . The method of  claim 62 , 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.  
   
   
       64 . The method of  claim 53 , wherein the subject has undergone a surgical procedure.  
   
   
       65 . The method of  claim 64 , 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.  
   
   
       66 . The method of  claim 53 , wherein the effective amount is in the range of 1 μg/kg/day to 10 μg/kg/day.  
   
   
       67 . The method of  claim 53 , wherein the effective amount is in the range of 1 μg/kg/day to 0.150 μg/kg/day.  
   
   
       68 . The method of  claim 53 , 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.  
   
   
       69 . The method of  claim 68 , 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.  
   
   
       70 . The method of  claim 69 , wherein the inhibitor of platelet function is selected from the group consisting of aspirin, abciximab, clopidogrel and dipyridamole.  
   
   
       71 . The method of  claim 53 , wherein the controlled release delivery system comprises a matrix in which the anagrelide or the anagrelide derivative is dispersed.  
   
   
       72 . The method of  claim 71 , wherein the matrix is formulated to achieve a reduction in peak level of agent in the subject.  
   
   
       73 . The method of  claim 53 , 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.  
   
   
       74 . The method of  claim 53 , wherein the delivery system comprises a lipid, a sterol, a fatty acid, a neutral fat, a wax or a combination thereof.  
   
   
       75 . The method of  claim 53 , wherein the delivery system comprises a hydrogel delivery system.  
   
   
       76 . The method of  claim 53 , wherein the delivery system comprises microcapsules.  
   
   
       77 . The method of  claim 76 , 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.  
   
   
       78 . The method of  claim 53 , wherein the delivery system is formulated for administration by a route selected from among oral, rectal, topical, nasal, intradermal, intramuscular and parenteral routes.  
   
   
       79 . The method of  claim 53 , wherein platelet count is reduced by at least 20%.  
   
   
       80 . The method of  claim 53 , wherein platelet count is reduced by at least 50%.  
   
   
       81 . The method of  claim 53 , wherein platelet count is reduced to below 200×10 3  platelets per μl.  
   
   
       82 . The method of  claim 53 , wherein platelet count is reduced to below 150×10 3  platelets per μl.  
   
   
       83 . The method of  claim 53 , wherein platelet count is reduced to below 100×10 3  platelets per μl.  
   
   
       84 . The method of  claim 53 , wherein platelet count is reduced by at least 10% and to an amount above 200×10 3  platelets per μl.  
   
   
       85 . The method of  claim 53 , wherein platelet count is reduced by at least 10% and to an amount below 200×10 3  platelets per μl.