Methods, compositions and articles of manufacture for enhancing survivability of cells, tissues, organs, and organisms

Abstract

The present invention concerns the use of oxygen antagonists and other active compounds for inducing stasis or pre-stasis in cells, tissues, and/or organs in vivo or in an organism overall, in addition to enhancing their survivability. It includes compositions, methods, articles of manufacture and apparatuses for enhancing survivability and for achieving stasis or pre-stasis in any of these biological materials, so as to preserve and/or protect them. In specific embodiments, there are also therapeutic methods and apparatuses for organ transplantation, hyperthermia, wound healing, hemorrhagic shock, cardioplegia for bypass surgery, neurodegeneration, hypothermia, and cancer using the active compounds described.

1 . A pharmaceutical composition comprising Formula I or IV, or salt thereof and a pharmaceutically acceptable excipient, wherein Formula I and IV comprise:
 wherein X is Se;   wherein Y is N or O;   
       
         
           
           
               
               
           
         
         wherein R1 is H, C, lower alkyl, a lower alcohol, or CN; 
         wherein R2 is H, C, lower alkyl, or a lower alcohol, or CN; 
         wherein n is 0 or 1; 
         wherein m is 0 or 1; 
         wherein k is 0, 1, 2, 3, or 4; and, 
         wherein p is 1 or 2; 
       
       
         
           
           
               
               
           
         
         wherein: 
         X is Se or Se—Se; 
         n and m are independently 0 or 1; and 
         wherein R 21  and R 22  are independently hydrogen, halo, cyano, phosphate, thio, alkyl, alkenyl, alkynyl, alkoxy, aminoalkyl, cyanoalkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, alkylsulfonic acid, thiosulfonic acid, alkylthiosulfonic acid, thioalkyl, alkylthio, alkylthioalkyl, alkylaryl, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkylthiocarbonyl, aminocarbonyl, amino thiocarbonyl, alkylaminothiocarbonyl, haloalkylcarbonyl, alkoxycarbonyl, aminoalkylthio, hydroxyalkylthio, cycloalkyl, cycloalkenyl, aryl, aryloxy, heteroaryloxy, heterocyclyl, heterocyclyloxy, sulfonic acid, sulfonic alkyl ester, thiosulfate, or sulfonamido; and Y is cyano, isocyano, amino, alkyl amino, aminocarbonyl, aminocarbonyl alkyl, alkylcarbonylamino, amidino, guanidine, hydrazino, hydrazide, hydroxyl, alkoxy, aryloxy, hetroaryloxy, cyloalkyloxy, carbonyloxy, alkylcarbonyloxy, haloakylcarbonyloxy, arylcarbonyloxy, carbonylperoxy, alkylcarbonylperoxy, arylcarbonylperoxy, phosphate, alkylphosphate esters, sulfonic acid, sulfonic alkyl ester, thiosulfate, thiosulfenyl, sulfonamide; —R 23 R 24 , wherein R 23  is Se or Se—Se, and R 24  is defined as for R 21  herein, or Y is 
       
       
         
           
           
               
               
           
         
         wherein X, R 21  and R 22 , are as defined herein. 
       
     
     
         2 .- 3 . (canceled) 
     
     
         4 . A method of reducing cellular damage due to a disease, an adverse medical condition, or a surgery, comprising providing to a subject in need thereof an effective amount of the pharmaceutical composition according to  claim 1 . 
     
     
         5 . The method of  claim 4 , wherein said pharmaceutical composition is a liquid. 
     
     
         6 . The method of  claim 4 , wherein said pharmaceutical composition is a gas. 
     
     
         7 . The method of  claim 4 , wherein the disease or adverse medical condition is selected from the group consisting of hemorrhagic shock, myocardial infarction, cardiac arrest, ischemia/reperfusion injury, unstable angina, post-angioplasty, aneurysm, trauma, stroke, coronary artery bypass graft (CABG) surgery, and blood loss. 
     
     
         8 . A method of protecting biological matter from an injury, the onset or progression of a disease, or death comprising providing to the matter, before the injury, the onset or progression of a disease, or death, an effective amount of thereof an effective amount of the pharmaceutical composition according to  claim 1 , wherein the effective amount is less than an amount that can induce stasis in the biological matter. 
     
     
         9 .- 14 . (canceled) 
     
     
         15 . The method of  claim 8 , wherein the injury comprises hypoxic or ischemic conditions, and wherein the method enhances survivability of the matter. 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 15 , wherein the ischemic or hypoxic condition is due to myocardial infarction, stroke, blood loss, coronary artery bypass graft (CABG) surgery, or angioplasty. 
     
     
         18 .- 22 . (canceled) 
     
     
         23 . A method of protecting biological matter from an injury, the onset or progression of a disease, or death comprising providing to the matter, before the injury, the onset or progression of a disease, or death, an effective amount the pharmaceutical composition of  claim 1 , wherein the effective amount is less than an amount that can induce stasis in the biological matter and wherein the biological matter is hemorrhaging. 
     
     
         24 .- 32 . (canceled) 
     
     
         33 . The method of claim  29 , wherein the surgery is cardiopulmonary surgery.