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 composition, comprising anagrelide or an analog of anagrelide, wherein the composition is formulated for transdermal delivery. 
   
   
       2 . The composition of  claim 1 , wherein:
 the composition provides a dosage of the anagrelide or an analog of anagrelide ranging from 1 μg/kg/day to 10 mg/kg/day to an adult human subject; and   the average adult human subject weighs about 70 kg.   
   
   
       3 . The composition of  claim 2 , wherein the composition provides a dosage of the anagrelide or an analog of anagrelide ranging from 30 μg/kg/day to 150 μg/kg/day. 
   
   
       4 . The composition of  claim 1  that is provided as a skin patch. 
   
   
       5 . The composition of  claim 1 , wherein the anagrelide or analog of anagrelide is dispersed in a matrix. 
   
   
       6 . The composition of  claim 1 , further comprising a solvent or carrier. 
   
   
       7 . The composition of  claim 6 , wherein the solvent is selected from among propylene glycol, polyethylene glycol, a vegetable oil and ethyl oleate. 
   
   
       8 . The composition of  claim 6 , wherein the carrier is water or an alcoholic/aqueous solution. 
   
   
       9 . The composition of  claim 1 , further comprising an inhibitor of platelet function and/or an anti-coagulant agent. 
   
   
       10 . The composition of  claim 9 , 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, defibrotide, 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, theophylline, pentoxifylline, 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, clofibrate, and caffeine. 
   
   
       11 . The composition of  claim 9 , wherein the inhibitor of platelet function is selected from the group consisting of aspirin, abciximab, clopidogrel and dipyridamole. 
   
   
       12 . The composition of  1 , further comprising another therapeutic compound selected from among anti-coagulant agents, anti-inflammatory agents, anti-thrombotic agents, anti-platelet agents, fibrinolytic agents, lipid reducing agents, direct thrombin inhibitors, glycoprotein IIb/IIIa receptor inhibitors, agents that bind to cellular adhesion molecules and inhibit the ability of white blood cells to attach to such molecules, calcium channel blockers, beta-adrenergic receptor blockers, cyclooxygenase-2 inhibitors, and angiotensin system inhibitors.