Carbon monoxide-based therapies and implantable devices for the treatment of vascular disease

Abstract

Disclosed herein are methods of treating venous thrombosis and vascular inflammation through administration of carbon monoxide and/or a carbon monoxide releasing molecule. Also disclosed herein are devices capable of releasing carbon monoxide for the purpose of treating microvascular, arterial and venous thromboembolism and/or inflammation.

We claim: 
     
         1 . A method of treating physiological venous thrombosis in a patient in need thereof comprising administering to the patient a therapeutically effective amount of: (i) carbon monoxide (“CO”), (ii) a carbon monoxide releasing molecule (“CORM”) or a pharmaceutically acceptable salt thereof, or (iii) both CO and a CORM or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein the CORM is selected from the group consisting of tricarbonyldichlororuthenium (II) dimer (“CORM-2”), tricarbonylchloro(glycinato)ruthenium (II) (“CORM-3”), [Me 4 N][Mn(CO) 4 (thioacetate) 2 ] (“CORM-371”), dimanganese decacarbonyl, iron pentacarbonyl, and a combination thereof. 
     
     
         3 . The method of  claim 2 , wherein the CORM is CORM-3. 
     
     
         4 . The method of  claim 1 , wherein the CORM is selected from the group consisting of dicholormethane, sodium boranocarbonate (“CORM-A1), and a combination thereof. 
     
     
         5 . The method of  claim 1 , wherein the CORM is coupled to a targeted delivery vector. 
     
     
         6 . The method of  claim 1 , further comprising administering to the patient one or more therapeutic agents. 
     
     
         7 . The method of  claim 6 , wherein the one or more therapeutic agents comprises nitric oxide or a compound that releases nitric oxide, oxygen, an anticoagulant, an anti-inflammatory agent, a protease activated receptor (“PAR”) inhibitor, a thienopyridine, a lipoxygenase-derived platelet inhibitor, a cell adhesion molecule inhibitor, or combinations thereof;
 optionally wherein the compound that releases nitric oxide selected from the group consisting of SIN-1, NCX-4016, NCX-701, nitroglycerin, sodium nitroprusside, and a combination thereof; 
 optionally wherein the anticoagulant is selected from the group consisting of a coumarin, an indandione, a factor Xa inhibitor, factor XI inhibitor, factor XII inhibitor, factor XIII inhibitor, a heparin, a thrombin inhibitor, and a combination thereof; 
 optionally wherein the factor Xa inhibitor is fondaparinux, rivaroxaban, apixaban, edoxaban, otamixaban, letaxaban, eribaxaban, darexaban, or a combination thereof; 
 optionally wherein the heparin is dalteparin, tinzaparin, enoxaparin, heparin, danaparoid, or a combination thereof; and 
 optionally wherein the thrombin inhibitor is bivalirudin, dabigatran, argatroban, desirudin, lepirudin, or combinations thereof. 
 
     
     
         8 . The method  claim 1 , wherein the CO and/or CORM or pharmaceutically acceptable salt thereof is administered by inhalation, by infusion, by injection, enterically, intraperitoneally, or topically; optionally wherein the CORM is encased in a nanoparticle or nanodisk; and optionally wherein the nanoparticle or nanodisk comprises biodegradable polylactic acid (“PLA”), biodegradable polyglycolic acid (“PGA”), biodegradable poly(lactic-co-glycolic acid) (“PGLA”), or a combination thereof, or the nanoparticle is a liposome. 
     
     
         9 . An implantable device comprising a surface coupled to: (i) carbon monoxide (“CO”), (ii) a carbon monoxide releasing molecule (“CORM”) or a pharmaceutically acceptable salt thereof, or (iii) both CO and a CORM or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The implantable device of  claim 9 , wherein the surface is:
 (a) coated with the CO and/or CORM or a pharmaceutically acceptable salt thereof;   (b) impregnated with the CO and/or CORM or a pharmaceutically acceptable salt thereof;   (c) layered with the CO and/or CORM or a pharmaceutically acceptable salt thereof;   (d) engrafted with the CO and/or CORM or a pharmaceutically acceptable salt thereof;   (e) covalently bound to the CO and/or CORM or a pharmaceutically acceptable salt thereof; or   (f) a combination of any of (a)-(e);   optionally wherein the CORM is encased in a nanoparticle or nanodisk; and   optionally wherein the nanoparticle or nanodisk comprises biodegradable polylactic acid (“PLA”), biodegradable polyglycolic acid (“PGA”), biodegradable poly(lactic-co-glycolic acid) (“PGLA”), or the nanoparticle is a liposome.   
     
     
         11 . The implantable device of  claim 9 , wherein the device is a vascular stent, a vascular filter, a vascular catheter or lead, a cardiopulmonary bypass circuit, an intracardiac occlusion device, an intracardiac valve, an implantable ventricular assist device, a extracorporeal membrane oxygenation circuit, or an implantable graft at the blood interface. 
     
     
         12 . The implantable device of  claim 9 , wherein the surface comprises polylactic acid (“PLA”), polyglycolic acid (“PGA”), poly(lactic-co-glycolic acid) (“PGLA”), or a combination thereof. 
     
     
         13 . The implantable device of  claim 9 , wherein the CORM is selected from the group consisting of tricarbonyldichlororuthenium (II) dimer (“CORM-2”), tricarbonylchloro(glycinato)ruthenium (II) (“CORM-3”), [Me 4 N][Mn(CO) 4 (thioacetate) 2 ] (“CORM-371”), dimanganese decacarbonyl, iron pentacarbonyl, and a combination thereof. 
     
     
         14 . The device of  claim 13 , wherein the CORM is CORM-3. 
     
     
         15 . The device of  claim 9 , wherein the CORM is a selected from the group consisting of dicholormethane, sodium boranocarbonate (“CORM-A1”), and a combination thereof. 
     
     
         16 . The device of  claim 9 , wherein the CORM is coupled to a targeted delivery vector. 
     
     
         17 . A method of treating a disease or condition associated with low or no blood flow, sickle cell disease, or a combination thereof, in a patient in need thereof comprising:
 (a) administering to the patient a therapeutically effective amount of: (i) CO, (ii) a CORM or pharmaceutically acceptable salt thereof, or (iii) both CO and a CORM or a pharmaceutically acceptable salt thereof; wherein the disease or condition is selected from primary or recurrent venous thrombophlebitis, arteriovenous shunt failure, stroke, myocardial infarction, transient ischemic attack, aortic thrombosis, limb vascular thrombus, limb ischemia, mesenteric vessel thrombus, cerebral venous thrombus, cancer-associated thrombus, venous stent thrombosis, arterial stent thrombosis, vascular inflammation, atrial fibrillation, atrial flutter-related thrombus, endovascular heat-induced thrombus, valve thrombosis, catheter thrombosis, thrombosis associated with tissue ablation procedures, implantable lead-associated thrombosis, and a combination thereof; or   (b) implanting the device of  claim 9  in the patient.   
     
     
         18 . The method of  claim 17 , wherein the device of  claim 9  is implanted in the patient and the patient suffers from a disease or condition selected from venous thromboembolism (“VTE”), native or artificial thrombosis, primary or recurrent thrombophlebitis, arteriovenous shunt failure, stroke, myocardial infarction, transient ischemic attack, aortic thrombosis, limb vascular thrombus, limb ischemia, mesenteric vessel thrombus, cerebral venous thrombus, cancer-associated thrombus, venous stent thrombosis, arterial stent thrombosis, vascular inflammation, atrial fibrillation, atrial flutter-related thrombus, endovascular heat-induced thrombus, valve thrombosis, catheter thrombosis, thrombosis associated with tissue ablation procedures, implantable lead-associated thrombosis, and a combination thereof. 
     
     
         19 . The method of  claim 17 , further comprising administering to the patient one or more therapeutic agents. 
     
     
         20 . The method of  claim 19 , wherein the one or more therapeutic agents comprises carbon monoxide, nitric oxide or a compound that releases nitric oxide, oxygen, an anticoagulant, an anti-inflammatory agent, a protease activated receptor (“PAR”) inhibitor, a thienopyridine, a lipoxygenase-derived platelet inhibitor, a cell adhesion molecule inhibitor, or combinations thereof;
 optionally wherein the compound that releases nitric oxide selected from the group consisting of SIN-1, NCX-4016, NCX-701, nitroglycerin, sodium nitroprusside, and a combination thereof; 
 optionally wherein the anticoagulant is selected from the group consisting of a coumarin, an indandione, a factor Xa inhibitor, factor XI inhibitor, factor XII inhibitor, factor XIII inhibitor, a heparin, a thrombin inhibitor, and a combination thereof; 
 optionally wherein the factor Xa inhibitor is fondaparinux, rivaroxaban, apixaban, edoxaban, otamixaban, letaxaban, eribaxaban, darexaban, or a combination thereof; 
 optionally wherein the heparin is dalteparin, tinzaparin, enoxaparin, heparin, danaparoid, or a combination thereof; and 
 optionally wherein the thrombin inhibitor is bivalirudin, dabigatran, argatroban, desirudin, lepirudin, or combinations thereof.