USE OF CYCLOSPORINE ANALOGUES AS ANTITHROMBOTIC AGENTS
Disclosed herein include methods, compositions, and kits suitable for use in preventing/treating a thromboembolic disorder, preventing/reducing formation of thrombi, and reducing/inhibiting procoagulant platelet formation. The methods comprise administering to a subject in need thereof a composition comprising a cyclosporine analogue (for example, CRV431). The compositions and kits comprise a cyclosporine analogue.
1 . A method for treating a thromboembolic disorder or for primary prophylaxis or secondary prophylaxis of a thromboembolic disorder, the method comprising administering to a subject in need thereof a composition comprising a therapeutically or prophylactically effective amount of CRV431, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
2 . The method of claim 1 , wherein the thromboembolic disorder is an arterial cardiovascular thromboembolic disorder, a venous cardiovascular thromboembolic disorder, or a thromboembolic disorder in a chamber of the heart or in the peripheral circulation.
3 . The method of claim 1 , wherein the thromboembolic disorder is unstable angina, an acute coronary syndrome, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, or thrombosis resulting from a medical implant, device, or procedure in which blood is exposed to an artificial surface that promotes thrombosis.
4 . The method of claim 1 , wherein the thromboembolic disorder is stroke, myocardial infarction, unstable angina, abrupt closure following angioplasty or stent placement, thrombosis induced by a peripheral vascular surgery or a peripheral vascular disease, or a thrombotic disorder resulting from atrial fibrillation or inflammation.
5 - 8 . (canceled)
9 . The method of claim 1 , wherein platelet aggregation is not inhibited in the subject.
10 . The method of claim 1 , wherein platelet aggregation in the subject is reduced by no more than 50%, 40%, 30%, 20%, 10%, or 5% as compared to an untreated subject.
11 . The method of claim 1 , wherein CRV431 selectively inhibits formation of procoagulant platelets.
12 . A method of reducing or preventing thrombi formation, the method comprising administering to a subject in need thereof a composition comprising a therapeutically or prophylactically effective amount of CRV431, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
13 . A method of reducing or inhibiting procoagulant platelet formation, the method comprising administering to a subject in need thereof a composition comprising a therapeutically or prophylactically effective amount of CRV431, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
14 . The method of claim 13 , comprising selectively inhibiting formation of procoagulant platelets.
15 . The method of claim 13 , wherein platelet aggregation is not reduced.
16 . The method of claim 13 , wherein the subject in need thereof is a subject suffering from or at risk of developing a prothrombotic or thrombotic condition.
17 . The method of claim 16 , wherein the prothrombotic or thrombotic condition is selected from the group consisting of infection, sepsis, systemic inflammatory response syndrome, multi organ failure, thrombotic thrombocytopenia purpura, hemolytic uremia syndrome, vascularization, renal failure, ischemic repercussion injury, solid organ transplant rejection, cardiovascular disease, stroke, venous thromboembolism, autoimmune disorders, sickle cell disease, inflammatory bowel disease, acute lung injury, malignancy, myocardial infarction (primary and secondary), embolic stroke, ischemic stroke, thrombotic stroke, deep vein thrombosis (DVT), thromboembolism, portal vein thrombosis, renal vein thrombosis, jugular vein thrombosis, Budd-Chiari syndrome, Paget-Schroetter disease, cerebral venous sinus thrombosis, arterial thrombosis, and arterial embolism.
18 - 24 . (canceled)
25 . The method of claim 1 , wherein the subject in need thereof is receiving one or more additional therapeutic agents selected from an anti-coagulant agent, an antiplatelet agent, a fibrinolytic agent, or a combination thereof.
26 . The method of claim 25 , wherein the one or more additional therapeutic agents is selected from heparin, low molecular weight heparins, bivalirudin, Fondaparinux, warfarin, Acenocoumarol, Phenprocoumon, Phenindione, Abbokinase (urokinase), streptokinase, alteplase, retaplase, tenecteplase, prasugrel, aspirin, ticlopidine, clopidogrel, abciximab, eptifibatide, and tirofiba, or a combination thereof.
27 - 31 . (canceled)
32 . The method of any one of claims 1, 12, or 13 , wherein the therapeutically effective or prophylactically effective amount is administered to the subject at an effective daily dose of 10 mg to 250 mg.
33 - 71 . (canceled)